Arginine residue at position 573 in Enterococcus hirae vacuolar-type ATPase NtpI subunit plays a crucial role in Na+ translocation.
The 76-kDa NtpI subunit constitutes the membrane-embedded V(0) moiety of Enterococcus hirae vacuolar type Na+-ATPase with a 16-kDa NtpK hexamer containing Na+ binding sites. In this study, we investigated the role of an arginine residue, which is highly conserved among the corresponding subunits of bacterial vacuolar-type ATPases, at position 573 of NtpI. Substitution of Glu, Leu, or Gln for Arg-573 abolished sodium transport and sodium-stimulated ATP hydrolysis of the enzyme. The conservative replacement of Arg by Lys lowered both activities about one-fifth of those of the wild type enzyme. We have reported previously on ATP-dependent negative cooperativity for Na+ coupling of this enzyme (Murata, T., Kakinuma, Y., and Yamato, I. (2001) J. Biol. Chem. 276, 48337-48340). The negative cooperativity for the Na+ dependence of ATPase activity was weakened by the mutation R573K; the Hill coefficients for the wild type and mutant enzymes at a saturated ATP concentration were 0.22 +/- 0.03 and 0.40 +/- 0.05, respectively. The Hill coefficients of both enzymes at limited ATP concentrations approached 1. These results indicate that NtpI Arg-573 is indispensable for sodium translocation and for the cooperative features of E. hirae vacuolar-type ATPase.


Comprehensive machine-learning survival framework develops a consensus model in large-scale multicenter cohorts for pancreatic cancer.
As the most aggressive tumor, the outcome of pancreatic cancer (PACA) has not improved observably over the last decade. Anatomy-based TNM staging does not exactly identify treatment-sensitive patients, and an ideal biomarker is urgently needed for precision medicine. Based on expression files of 1280 patients from 10 multicenter cohorts, we screened 32 consensus prognostic genes. Ten machine-learning algorithms were transformed into 76 combinations, of which we selected the optimal algorithm to construct an artificial intelligence-derived prognostic signature (AIDPS) according to the average C-index in the nine testing cohorts. The results of the training cohort, nine testing cohorts, Meta-Cohort, and three external validation cohorts (290 patients) consistently indicated that AIDPS could accurately predict the prognosis of PACA. After incorporating several vital clinicopathological features and 86 published signatures, AIDPS exhibited robust and dramatically superior predictive capability. Moreover, in other prevalent digestive system tumors, the nine-gene AIDPS could still accurately stratify the prognosis. Of note, our AIDPS had important clinical implications for PACA, and patients with low AIDPS owned a dismal prognosis, higher genomic alterations, and denser immune cell infiltrates as well as were more sensitive to immunotherapy. Meanwhile, the high AIDPS group possessed observably prolonged survival, and panobinostat may be a potential agent for patients with high AIDPS. Overall, our study provides an attractive tool to further guide the clinical management and individualized treatment of PACA.


Expression, purification and transduction of PEP-1-botulinum neurotoxin type A (PEP-1-BoNT/A) into skin.
Botulinum neurotoxin A (BoNT/A) has been used therapeutically to treat muscular hypercontractions and sudomotor hyperactivity and it has been reported that BoNT/A might have analgesic properties in headache. PEP-1 peptide is a known carrier peptide that delivers full-length native proteins in vitro and in vivo. In this study, a BoNT/A gene were fused with PEP-1 peptide in a bacterial expression vector to produce a genetic in-frame PEP-1-BoNT/A fusion protein. The expressed and purified PEP-1-BoNT/A fusion proteins were efficiently transduced into cells in a time- and dose-dependent manner when added exogenously in a culture medium. In addition, immunohistochemical analysis revealed that PEP-1-BoNT/A fusion protein efficiently penetrated into the epidermis as well as the dermis of the subcutaneous layer, when sprayed on mice skin. These results suggest that PEP-1-BoNT/A fusion protein provide an efficient strategy for therapeutic delivery in various human diseases related to this protein.


Quantitative Kinetoplast DNA Assessment During Treatment of Mucosal Leishmaniasis as a Potential Biomarker of Outcome: A Pilot Study.
Mucosal leishmaniasis (ML) is a disfiguring manifestation of Leishmania (Viannia) infection. We evaluated parasite load (PL) over time as a potential biomarker of treatment outcome in ML. PL was assessed with kinetoplast DNA quantitative real-time polymerase chain reaction (kDNA-qPCR) at enrollment, days 14 and 21-28 of therapy and 3, 6, 12-18, and 18-24 months after treatment of ML and correlated to demographic, clinical, and parasitologic factors. Forty-four patients were enrolled: 30 men and 14 women. Enrollment PL differed significantly by causative species (P < 0.001), and was higher in patients with severe ML (nasal and laryngeal involvement) compared with those with only isolated nasal involvement (median = 1,285 versus 51.5 parasites/μg tissue DNA; P = 0.005). Two patterns of PL emerged: pattern 1 (N = 23) was characterized by a sequential decline in PL during and after therapy until kDNA was undetectable. Pattern 2 (N = 18) was characterized by clearance of detectable kDNA during treatment, followed by an increased PL thereafter. All patients who failed treatment (N = 4) demonstrated pattern 1. Leishmania (Viannia) braziliensis was overrepresented among those with pattern 2 (P = 0.019). PL can be quantified by cytology brush qPCR during and after treatment in ML. We demonstrate that treatment failure was associated with undetectable PL, and L. (V.) braziliensis infection was overrepresented in those with rebounding PL.


BMI levels with MS Bone mineral density levels in adults with multiple sclerosis: a meta-analysis.
Multiple sclerosis (MS) and osteoporosis (OP) affect a substantial proportion of the population. Accumulating evidence suggests that MS patients are at high risk for OP. We performed a meta-analysis to identify risk factors for lowered bone mineral density (BMD) in MS patients. We searched for articles within the Medline, Embase and Cochrane Library databases, published up to March 2014, pertaining to associations between MS and BMD. A total of 11 studies was included in the meta-analysis. The analysis indicated that MS patients have reduced lumbar spine, femur neck, and hip BMD compared with healthy controls (lumbar spine, standardized mean difference (SMD) = -0.76, 95% CI: -1.07, -0.45; femur neck, SMD = -0.56, 95% CI: -0.84, -0.29; and hip, SMD = -0.62, 95% CI: -0.96, -0.29). Further subgroup analysis revealed that a disease duration of >7 years, total steroid dose during the disease of >15 g, and an Expanded Disability Status Scale (EDSS) score of > 3, increased the risk of reduced BMD in the lumbar spine and femoral neck, but not in the hip. Meta-regression analysis did not explain the heterogeneity in the clinical characteristics or outcome definitions. Our meta-analysis suggests that MS patients have reduced overall BMD compared with healthy controls. Furthermore, disease duration (>7 years), total steroid dose (>15 g), and EDSS score (>3) are risk factors for reduced BMD in MS patients.


Serum ferritin concentration in early pregnancy and risk of subsequent development of gestational diabetes: A prospective study.
Elevated serum ferritin concentration is associated with insulin resistance and diabetes. Recently it has also been described in gestational diabetes mellitus (GDM). A prospective study was done to determine whether there was a relationship between serum ferritin concentration in early pregnancy and the risk of GDM. A study was performed on 1,384 pregnant women with gestational age of 12-16 weeks. A blood sample was obtained for measurement of ferritin in the first trimester. Diagnosis of GDM was done by 75 gr oral glucose tolerance test between 24-28 wk. Women who developed GDM had a higher concentration of serum ferritin than women who did not develop GDM (p=0.01). A ferritin concentration of 45 ng/ml was calculated to be the 75th percentile for healthy pregnant women. Considering this level 32% in the GDM group and 25.2%of normal subjects exhibited high ferritin levels (p=0.01). The risk of GDM with these high levels of ferritin was 1.4-fold higher than that for subjects with lower concentrations. The Odds Ratio was 1.4 (95% CI= 1-1.87) (p=0.01). After adjusted for age Odds Ratio was 1.38 (95% CI=1.02-1.86) (p=0.03) and after adjustment for pre-pregnancy Body Mass index, the adjusted odds ratio was 1.31 (CI= 0.96-1.79) (p=0.08). After multivariable adjustment (age and body mass index), the adjusted odds ratio was 1.3 (0.95-1.8) (p=0.09). High serum ferritin can be regarded as a significant risk factor for the development of gestational diabetes.


H2O2-induced mild stress in relation with in vitro ovine oocyte developmental competence: implications for blastocyst apoptosis and related genes expression.
In this study, in vitro maturation was performed in presence of various concentrations (0, 10, 100, or 1000 µM) of H2O2. The intracellular glutathione (GSH) level, fertilization, cleavage, and blastocyst rates, total cell number, and apoptotic cell number and expression of Bax, Bcl-2, and p53 genes in blastocyst-stage embryos were studied. At 10 μM H2O2 concentration, a higher GSH level was detected in comparison to the other groups while oocytes exposed to 1000 μM H2O2 had the lowest GSH level. Treatment of oocytes with 1000 μM H2O2 decreased the rate of two pronuclei formation as compared with other groups. A higher rate of blastocyst formation was seen in 100 μM H2O2 group as compared with the control group. However, exogenous H2O2 in maturation medium did not affect total cell numbers and apoptotic cell ratio at the blastocyst stage. Moreover, mRNA transcript abundance of Bax, Bcl-2, and p53 genes was similar between blastocysts derived from H2O2-induced oocytes and control blastocysts. Treatment of oocytes with H2O2 at mild level during in vitro maturation had a positive effect on GSH level and this, in turn, may lead to improvement in preimplantation embryonic development.


Structural instabilities in lamellar diblock copolymer thin films during solvent vapor uptake.
We have studied the structural rearrangements in a lamellae-forming poly(styrene-b-butadiene) film during exposure to toluene vapor. Real-time, in situ grazing-incidence small-angle X-ray scattering allowed us to identify distinct kinetic regimes: First, the lamellae swell linearly, and the blocks stretch uniaxially. Then, the blocks relax to a more globular molecular conformation, and the lamellar thickness abruptly shrinks again. The increased interfacial area culminates in a dramatic instability causing a major rearrangement of the lamellar stack and the formation of new lamellae. Finally, the lamellar thickness levels off, and the interfaces flatten again.


Potentially functional polymorphism in the promoter region of prodynorphin gene may be associated with protection against cocaine dependence or abuse.
It has been demonstrated that the opioid peptide dynorphin plays a role in modulating responses to several psychoactive substances including cocaine. Our laboratory and others have found that mRNA levels of dynorphin in the caudate and putamen are elevated after acute or chronic cocaine exposure in rats. Recently, a 68-base pair (bp) repeat polymorphism within the core promoter region of the human prodynorphin gene has been reported to occur in alleles containing one, two, three, or four copies. This repeat contains a putative AP-1 transcription factor binding site; reporter gene constructs with three or four, but not one or two, copies of the tandem repeats were shown to be associated with increases in transcriptional activation in in vitro cellular assays. We hypothesize that this polymorphism may be associated with individual differences in vulnerability to cocaine dependence or abuse. From an ongoing study of the genetics of addiction, 174 subjects were studied, including individuals with a primary diagnosis (DSM-IV criteria) of cocaine dependence (N = 61) or abuse (N = 22), and controls with no history of any substance dependence or abuse (N = 91). We designed primers for polymerase chain reaction (PCR) to amplify sequences of the promoter region of the prodynorphin gene containing the repeat element. The association of alleles containing three or four repeats with cocaine dependence/abuse was examined. With data stratified by ethnic group, pooled relative risk (RR) with Mantel-Haenszel Chi square was calculated: RR = 0.59 (95% confidence interval 0.37-0.95), chi2 (1) = 4.14, P = 0.042. Our results suggest that this allelic variation at the promoter region of the prodynorphin gene (alleles with three or four repeats), which may result in enhanced transcription of the gene, may contribute to relative protection and decrease individual vulnerability to develop cocaine dependence or abuse.


Clinical studies of granulocyte colony stimulating factor (G-CSF).
Granulocyte colony stimulating factor (G-CSF) can safely stimulate the production of neutrophils in normal and neutropenic patients. Phase II studies have shown potential benefit when G-CSF is given after chemotherapy and bone marrow transplantation and in dose intensification studies. Studies in myelodysplasia, chronic neutropenia and AIDS all show great promise. Phase III studies are now in progress, which will help identify precisely the role of this exciting molecule.


Cost-effectiveness of Response-Adapted De-escalation of Immunotherapy in Advanced Melanoma.
Combination immunotherapy with nivolumab and ipilimumab has markedly improved outcomes for patients with advanced melanoma. However, these therapies pose a considerable financial burden to both patients and the health care system. The ADAPT-IT trial demonstrated comparable progression-free and overall survival for patients with response-adapted ipilimumab discontinuation compared with standard of care (SOC). To determine the cost-effectiveness of ipilimumab discontinuation for patients with interim imaging-confirmed tumor response in the treatment of advanced melanoma. This cost-effectiveness analysis was performed using data from the ADAPT-IT (follow-up of 33 months) and CheckMate 067 (follow-up of 6.5 years) trials, as well as published literature over the ADAPT-IT trial duration of 33 months. The analysis was performed in a US setting from a US-payer perspective, and the willingness-to-pay (WTP) threshold was set at $100 000/quality-adjusted life-year (QALY). A total of 355 patients with previously untreated melanoma (unresectable stage III or IV metastatic melanoma) were included. Response-adapted ipilimumab discontinuation compared with SOC therapy. The primary outcomes of the CheckMate trial were overall survival and progression-free survival, while that of ADAPT-IT was objective response. This informed a decision model to estimate lifetime costs and QALYs associated with both strategies. Incremental cost, effectiveness, and cost-effectiveness ratio were assessed. Sensitivity and scenario analyses were performed to account for variability in trials and input parameters. Of the 355 patients included in the analysis, 41 patients were from the ADAPT-IT trial (median age, 65 years; 28 [68%] male) and 314 patients from the CheckMate 067 trial (median age, 61 years; 206 [66%] male). Response-adapted treatment was the cost-effective option in 94.0% of scenarios based on Monte Carlo simulations, with a dominant incremental cost-effectiveness ratio and an incremental net monetary benefit of $28 849 compared with SOC therapy. Cost savings were estimated at $19 891 per patient compared with SOC. In scenario analyses, current SOC was only considered as a cost-effective option under best survival assumptions and if the willingness-to-pay threshold exceeded $630 000/QALY. This economic evaluation demonstrated that response-adapted treatment de-escalation in patients with advanced melanoma may lead to considerable savings in health care costs and could represent the most cost-effective strategy across various resource settings. Future trials should aim to provide further evidence on noninferiority.


Second-order Level-crossing Sampling Analog to Digital Converter for Electrocardiogram Delineation and Premature Ventricular Contraction Detection.
This paper presents an electrocardiogram (ECG) delineation and arrhythmia heartbeat detection system using a novel second-order level-crossing sampling analog to digital converter (ADC) for real-time data compression and feature extraction. The proposed system consists of the front-end integrated circuit of the data converter, the delineation algorithm, and the arrhythmia detection algorithm. Compared with conventional level-sampling ADCs, the proposed circuit updates tracking thresholds using linear extrapolation, which forms a second-order level-crossing sampling ADC that has sloped sampling levels. The computing is done digitally and is implemented by modifying the digital control logic of a conventional Successive-approximation-register (SAR) ADC. The system separates the sampling and quantization processes and only selects the turning points in the input waveform for quantization. The output of the proposed data converter consists of both the digital value of the selected sampling points and the timestamp between the selected sampling points. The main advantages are data savings for the data converter and the following digital signal processing or communication circuits, which are ideal for low-power sensors. The test chip was fabricated using a 180nm CMOS process. When sensing sparse signals such as ECG signals the proposed ADC achieves a compression factor of 8.33. The delineation algorithm uses a triangle filter method to locate the fiducial points and measures the intervals, slopes, and morphology of the QRS complex and the P/T waves. Those extracted features are then used in the arrhythmia heartbeat detection algorithm to identify Premature Ventricular Contraction (PVC). The overall performance of the system is evaluated using the MIT-BIH database and the QT database, which is also compared with the recently reported systems. The accuracy, sensitivity, specificity, PPV, and F1 score are 97.3%, 89.6%, 97.8%, 73.3%, and 0.81 for detecting PVC.


Design, synthesis, characterization, and OFET properties of amphiphilic heteroleptic tris(phthalocyaninato) europium(III) complexes. The effect of crown ether hydrophilic substituents.
Two amphiphilic heteroleptic tris(phthalocyaninato) europium complexes with hydrophilic crown ether heads and hydrophobic octyloxy tails [Pc(mCn)(4)]Eu[Pc(mCn)(4)]Eu[Pc(OC(8)H(17))(8)] [m = 12, n = 4, H(2)Pc(12C4)(4) = 2,3,9,10,16,17,23,24-tetrakis(12-crown-4)phthalocyanine; m = 18, n = 6, H(2)Pc(18C6)(4) = 2,3,9,10,16,17,23,24-tetrakis(18-crown-6)phthalocyanine; H(2)Pc(OC(8)H(17))(8) = 2,3,9,10,16,17,23,24-octakis(octyloxy)phthalocyanine] (1, 2) were designed and prepared from the reaction between homoleptic bis(phthalocyaninato) europium compound [Pc(mCn)(4)]Eu[Pc(mCn)(4)] (m = 12, n = 4; m = 18, n = 6) and metal-free H(2)Pc(OC(8)H(17))(8) in the presence of Eu(acac)(3).H(2)O (Hacac = acetylacetone) in boiling 1,2,4-trichlorobenzene. These novel sandwich triple-decker complexes were characterized by a wide range of spectroscopic methods and electrochemically studied. With the help of the Langmuir-Blodgett technique, these typical amphiphilic triple-decker complexes were fabricated into organic field effect transistors (OFET) with top contact configuration on bare SiO(2)/Si substrate, hexamethyldisilazane-treated SiO(2)/Si substrate, and octadecyltrichlorosilane (OTS)-treated SiO(2)/Si substrate, respectively. The device performance is revealed to be dependent on the species of crown ether substituents and substrate surface treatment. OFETs fabricated from the triple decker with 12-crown-4 hydrophilic substituents, 1, allow the hole transfer in the direction parallel to the aromatic phthalocyanine rings. In contrast, the devices of a triple-decker compound containing 18-crown-6 as hydrophilic heads, 2, transfer holes in a direction along the long axis of the assembly composed of face-to-face aggregated triple-decker molecules, revealing the effect of molecular structure, specifically the crown ether substituents on the film structure and OFET functional properties. The carrier mobility for hole as high as 0.33 cm(2) V(-1) s(-1) and current modulation of 7.91 x 10(5) were reached for the devices of triple-decker compound 1 deposited on the OTS-treated SiO(2)/Si substrates, indicating the effect of substrate surface treatment on the OFET performance due to the improvement on the film quality as demonstrated by the atomic force microscope investigation results.


Corrected ASD: case closed?
Ellis-van Creveld syndrome (EvC) is a rare autosomal recessive chondroectodermal dysplasia, associated with mutations in the EVC1 and EVC2 genes (4p16). The management of EvC is multidisciplinary, and early diagnosis is of the utmost importance for efficient and timely treatment. The main prognostic determinant is presence of a heart defect. The authors describe the case of a 42-year-old man referred to our outpatient cardiology clinic, following surgical repair of an atrial septal defect. He had presented to different medical specialties on numerous occasions since childhood, but remained without a clear diagnosis for more than 40 years. This case reinforces the need for a holistic view when assessing a patient with congenital heart disease. Moreover, this illustrates the importance of communication and discussion between different medical specialties.


FBXO34 promotes latent HIV-1 activation by post-transcriptional modulation.
ABSTRACTAcquired immunodeficiency syndrome (AIDS) cannot be completely cured, mainly due to the existence of a latent HIV-1 reservoir. However, our current understanding of the molecular mechanisms underlying the establishment and maintenance of HIV-1 latent reservoir is not comprehensive. Here, using a genome-wide CRISPR-Cas9 activation library screening, we identified E3 ubiquitin ligase F-box protein 34 (FBXO34) and the substrate of FBXO34, heterogeneous nuclear ribonucleoprotein U (hnRNP U) was identified by affinity purification mass spectrometry, as new host factors related to HIV-1 latent maintenance. Overexpression of FBXO34 or knockout of hnRNP U can activate latent HIV-1 in multiple latent cell lines. FBXO34 mainly promotes hnRNP U ubiquitination, which leads to hnRNP U degradation and abolishment of the interaction between hnRNP U and HIV-1 mRNA. In a latently infected cell line, hnRNP U interacts with the ReV region of HIV-1 mRNA through amino acids 1-339 to hinder HIV-1 translation, thereby, promoting HIV-1 latency. Importantly, we confirmed the role of the FBXO34/hnRNP U axis in the primary CD4+ T lymphocyte model, and detected differences in hnRNP U expression levels in samples from patients treated with antiretroviral therapy (ART) and healthy people, which further suggests that the FBXO34/hnRNP U axis is a new pathway involved in HIV-1 latency. These results provide mechanistic insights into the critical role of ubiquitination and hnRNP U in HIV-1 latency. This novel FBXO34/hnRNP U axis in HIV transcription may be directly targeted to control HIV reservoirs in patients in the future.


Exploring the role of ghrelin as novel regulator of gonadal function.
In mammals, proper gonadal function critically relies on a complex regulatory network of systemic (endocrine) and locally-produced (paracrine and autocrine) signals. Among others, a number of factors primarily involved in the control of energy balance and metabolism have been proven as putative modulators of the gonadal axis, thus providing the basis for the well-known link between energy homeostasis and fertility. Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R), has been recently demonstrated as a pleiotropic regulator involved in a large array of endocrine and non-endocrine functions, including food intake and energy balance. However, the potential reproductive role of this newly discovered molecule has remained largely neglected. Yet, we review herein several lines of evidence which strongly suggest the involvement of ghrelin in the control of some aspects of gonadal function. Thus, expression of ghrelin has been demonstrated in mature Leydig cells of rat and human testis, as well as in steroidogenically active luteal and interstitial hilus cells of the ovary. In addition, expression of the functional ghrelin receptor, the GHS-R type 1a, has been shown in Sertoli and Leydig cells of the testis, and in follicular, luteal, surface epithelial and interstitial hilus cells of the ovary. In terms of function, ghrelin has been proven to dose-dependently inhibit testicular testosterone secretion in vitro, and to modulate Leydig cell proliferation in vivo, as well as the expression of relevant testicular genes, such as that encoding stem cell factor. Moreover, extragonadal actions of ghrelin upon the reproductive axis have been also reported, as ghrelin was able to suppress LH secretion in vivo and to decrease LH responsiveness to GnRH in vitro. In summary, the data so far available strongly suggest that, through local and/or systemic actions, ghrelin operates as a novel regulator of gonadal function that may contribute to the integrated control of energy balance and reproduction.


Subtotal vesical necrosis as a result of infected traumatic bladder hematoma: A rare case with a literature review of bladder necrosis due to hematoma.
Subtotal bladder necrosis following bladder hematoma is rare. We report such a case following blunt abdominal injury. The urologic presentation was delayed hematuria which settled with conservative management but was followed by the development of urosepsis. Computed tomography scan showed full bladder due to long-standing liquified bladder hematoma. Suprapubic exploration revealed a bladder wall abscess which was drained (secondarily infected hematoma). Excision of the subtotal necrotic bladder and ileal conduit with left ureteroileal anastomosis was done later. The patient also had a simultaneous right renal and ureteric injury as an independent simultaneous event which required initial nephrostomy placement. It later healed with complete obliteration of the right renal pelvis which was managed by right nephrectomy later. A literature review of cases of vesical necrosis caused by hematomas (of different locations and etiology) is discussed.


Triple metachronous colon cancer.
A 72-year-old male with an early stage "node-negative" sigmoid colon cancer developed 2 separate "node-negative" early stage colon cancers during a subsequent colonoscopy surveillance regimen, the first in the descending colon 7 years later, and the second in the cecum almost 14 years after the first cancer was resected. After the initial symptomatic cancer, all subsequent neoplastic disease, including malignant cancers were completely asymptomatic. This entity, multiple primary cancers, likely reflected the use of a colonoscopic surveillance regimen.


Energy barriers in the conversion of bicyclobutane to gauche-1,3-butadiene from the anti-hermitian contracted Schrödinger equation.
In 1959 Charles Coulson popularized the idea of computing a molecule's ground-state energy as a functional of the two-electron reduced density matrix (2-RDM) without the many-electron wave function. For 50 years, however, a practical, direct calculation of the 2-RDM was not achieved because the 2-RDM must be constrained by N-representability conditions to represent an N-electron system. Recently, two general approaches to the direct calculation of the 2-RDM have emerged including the solution of the anti-Hermitian contracted Schrodinger equation (ACSE) [Mazziotti, Phys. Rev. Lett., 2006, 97, 143002]. In this article, after further extending the theoretical development of the ACSE method for multireference correlation, we apply the ACSE to studying an unresolved question regarding the opening of bicyclobutane to gauche-1,3-butadiene by conrotatory and disrotatory pathways. Previous theoretical values for the disrotatory energy barrier reveal a disagreement between correlation methods on the order of 10 kcal/mol. By capturing significantly more correlation energy than traditional multireference methods, the ACSE provides new insight into this discrepancy. The ACSE energy for the conrotatory energy barrier agrees with the 40.6 +/- 2.5 kcal/mol experimental value.


The impact of maternal RSV vaccine to protect infants in Gavi-supported countries: Estimates from two models.
Interventions to protect young infants against respiratory syncytial virus (RSV) are in advanced phases of development and are expected to be available in the foreseeable future. Gavi, the Vaccine Alliance, included maternal vaccines and infant monoclonal antibodies for RSV as part of the 2018 vaccine investment strategy (VIS) and decided to support these products subject to licensure, World Health Organization prequalification, Strategic Advisory Group of Experts recommendation, and meeting the financial assumptions used as the basis of the investment case. Impact estimates reported in this manuscript were used to inform the Gavi VIS. We compared two independent vaccine impact models to evaluate a potential maternal RSV vaccine's impact on infant health in 73 Gavi-supported countries. Key inputs were harmonized across both models. We analyzed various scenarios to evaluate the effect of uncertain model parameters such as vaccine efficacy, duration of infant protection, and infant disease burden. Estimates of averted cases, severe cases, hospitalizations, deaths, and disability-adjusted life years (DALYs) were calculated over the 2023-2035 horizon. A maternal RSV vaccine with 60% efficacy offering 5 months of infant protection implemented across 73 low- and middle-income countries could avert 10.1-12.5 million cases, 2.8-4.0 million hospitalizations, 123.7-177.7 thousand deaths, and 8.5-11.9 million DALYs among infants under 6 months of age for the duration of analysis (2023-2035). Maternal RSV vaccination was projected to avert up to 42% of estimated RSV deaths among infants under 6 months in year 2035. Alternative scenario analyses with higher disease burden assumptions showed that a maternal vaccine could avert as many as 325-355 thousand deaths among infants under 6 months. RSV maternal immunization is projected to substantially reduce mortality and morbidity among young infants if introduced across Gavi-supported countries. This work was supported by Bill & Melinda Gates Foundation, Seattle, WA, and Respiratory Syncytial Virus Consortium in Europe. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation or of the Respiratory Syncytial Virus Consortium. LW is supported by Research Foundation-Flanders (1234620 N).


Effects of sesamin on chondroitin sulfate proteoglycan synthesis induced by interleukin-1beta in human chondrocytes.
Numerous studies have reported on the health benefits of sesamin, a major lignin found in sesame (S. indicum) seeds. Recently, sesamin was shown to have the ability to promote chondroitin sulfate proteoglycan synthesis in normal human chondrocytes. This study assesses the anti-inflammatory effect of sesamin on proteoglycans production in 3D chondrocyte cultures. To evaluate the effects of sesamin on IL-1β-treated human articular chondrocytes (HAC) pellets, the pellets were pre-treated with IL-1β then cultured in the presence of various concentrations of sesamin for 21 days. During that period, the expression of IL-1β, glycosaminoglycans (GAGs) content and Chondroitin sulfate proteoglycans (CSPGs) synthesis genes (ACAN, XT-1, XT-2, CHSY1 and ChPF) was measured. The GAGs accumulation in the extracellular matrix was determined on day 21 by histological analysis. There was clear evidence that sesamin upregulated expression of all the CSPGs synthesis genes, in contrast to the down-regulation of IL-1β expression both in genes and in protein levels. The level of release and matrix accumulation of GAGs in IL-1β pre-treated HAC pellets in the presence of sesamin was recovered. These results correlate with the histological examination which showed that sesamin enhanced matrix CSPGs accumulation. Sesamin enhances CSPGs synthesis, suppresses IL-1β expression and ameliorates IL-1β induced inflammation in human chondrocytes. Sesamin could have therapeutic benefits for treating inflammation in osteoarthritis.


Efficacy of Copper and New Bactericides for Managing Olive Knot in California.
Baseline sensitivities were established for kasugamycin and oxytetracycline for 147 strains of Pseudomonas savastanoi pv. savastanoi collected from olive knots throughout California. Minimum inhibitory concentrations for ≥95% growth inhibition ranged from 1.86 to 11.52 and 0.13 to 0.40 µg/ml for kasugamycin and oxytetracycline, respectively. In copper sensitivity evaluations, 95.3% of the strains collected grew at concentrations of metallic copper equivalent (MCE) of <20 µg/ml, 2.7% grew at MCE between 20 and 30 µg/ml (moderately sensitive), and 2% grew at MCE of 150 µg/ml (resistant). Copper resistance was never reported previously in the olive knot pathogen, and pathogenicity studies confirmed a high virulence of the copper-resistant strains. In comparative field studies, kasugamycin at 200 µg/ml performed equally to the standard copper hydroxide treatment (MCE of 1,260 µg/ml) for reducing knot development on lateral wounds of Arbequina and Manzanillo olive inoculated with a copper-sensitive strain and was better than copper using a highly copper-resistant strain. Oxytetracycline at 200 µg/ml was not as effective as copper or kasugamycin but significantly reduced the disease as compared with the untreated control. Field studies on application timings of copper, kasugamycin, and copper-kasugamycin mixtures to inoculated wounds indicated that treatments within 24 h of inoculation resulted in higher disease control than applications at later times. In greenhouse trials, copper or copper-kasugamycin applied to wounds 7 days before inoculation persisted and reduced knot incidence by >50%. Our findings indicate that kasugamycin is an effective bactericide for controlling olive knot and that the time of any bactericide application after inoculation is critical in managing the disease.


Effect of lanthanum on voltage-dependent gating of a cloned mammalian neuronal potassium channel.
The effect of the trivalent cation lanthanum (La3+) on voltage-dependent gating of a cloned mammalian neuronal Kv1.1 potassium channel was studied under whole-cell voltage-clamp conditions in oocytes of Xenopus laevis. La3+ (100 microM) was found to decrease the potassium currents at all test potentials and to shift the midpoint of the fraction open channels/membrane voltage curve by approximately +20 mV. The opening and closing time constants of Kv1.1 channels were empirically fitted with a 4th power Hodgkin-Huxley formalism, or with mono- and multi-exponentials. It was found that La3+ slowed down the kinetics of activation, speeded up those of deactivation, and shifted the opening kinetics by approximately + 60 mV. Interestingly, all these parameters of channel gating were not affected equally by La3+. Furthermore, amplitudes of the inward tail currents evoked at potentials more negative than the potassium equilibrium potential (E(K+)) were more strongly inhibited by La3+ than those of the outward tail currents evoked at potentials more positive than E(K+). This suggests voltage-dependent block and binding of La3+ to the Kv1.1 channel protein. We conclude that these actions cannot be explained in terms of surface charge considerations alone. Our results provide evidence for a direct interaction with the potassium channel protein, shedding new light on the mechanism of action of this lanthanide.


The Importance of Mutational Drivers in GBM.
Glioblastoma (GBM) is the most aggressive primary brain tumor, providing few effective therapeutic options, given the tumor heterogeneity and the accumulation of different genetic abnormalities that cause treatment failure. The many different genetic and epigenetic alterations present in GBM lead to modification of several major signaling pathways resulting in brain tumor growth, progression, and therapeutic resistance. Many functionally important mutations have been discovered, known as neutral passengers. IDH1/2, EZH2, and DNMT3A are the best known epigenetic modifiers in cancer. These mutations are important in determining disease prognosis such that the status of the MGMT gene is a direct target of chemotherapy. For these reasons, newly developed technologies are necessary to determine new candidate targets for targeted-therapy development in GBM. The determination of mutations will aid in this and in the discovery of combinations of targeted and conventional therapies to improve GBM treatment.


The Development and Validation of Elder Self-Neglect Scale (ESNS) in Iranian Community-dwelling Older Population.
The aim of this study was to develop a valid and reliable elder self-neglect scale (ESNS) for field research on Iranian community-dwelling older adults. This mixed-method exploratory study was conducted in three stages: (1) item generation using literature review, (2) item reduction by expert panels, and (3) assessing the psychometric properties. In the third stage, the face, content, and construct validity (exploratory factor analysis) were performed on the first sample (n = 450), and the final 26-item scale was developed. After that, confirmatory factor analysis and reliability were assessed on the second sample (n = 250). Data were analyzed using IBM-SPSS v.23 and AMOS v.24. Exploratory factor analysis identified six factors with a total variance of 77.53%. The goodness of fit was indicated by Structural Equation Modeling. The Cronbach's alpha was estimated at 0.85. The optimal cutoff point was 73. This scale with 26 items seems to be an effective tool in screening elder self-neglect.


The incidence of lower-extremity amputation and bone resection in diabetic foot ulcer patients treated with a human fibroblast-derived dermal substitute.
Diabetic foot ulcers (DFUs) are frequently recalcitrant and at risk for infection, which may lead to lower-extremity amputation or bone resection. Reporting the incidence of amputations/bone resections may shed light on the relationship of ulcer healing to serious complications. This study aimed to evaluate the incidence of amputations/bone resections in a randomized controlled trial comparing human fibroblast-derived dermal substitute plus conventional care with conventional care alone for the treatment of DFUs. Ulcer-related amputation/bone resection data were extracted from data on all adverse events reported for the intent-to-treat population (N = 314), and amputations were categorized by type: below the knee, Syme, Chopart, transmetatarsal, ray, toe, or partial toe. Data were analyzed retrospectively for the incidence of amputation/bone resection by treatment. Randomized controlled trial. Patients with full-thickness DFUs greater than 6 weeks' duration. Standard wound care plus human fibroblast-derived dermal substitute versus standard wound care alone. The incidence of amputation/bone resection in the study was 8.9% (28/314) overall, 5.5% (9/163) for patients receiving human fibroblast-derived dermal substitute, and 12.6% (19/151) for patients receiving conventional care (P = .031). Of the 28 cases of amputation/bone resection, 27 were preceded by ulcer-related infection. There were significantly fewer amputations/bone resections in patients who received human fibroblast-derived dermal substitute versus conventional care, likely related to the lower incidence of infection adverse events observed in the human fibroblast-derived dermal substitute treatment group.


Comparative efficacy of different insecticides in the treatment of cattle hypodermosis in north-eastern Algeria.
The efficacy of different drugs (microdose of ivermectin, doramectin and moxidectin at the recommended doses and topically applied rotenone) against the first, second and third instar larvae of Hypoderma bovis and H. lineatum was studied in cattle in the El Tarf area (northeastern Algeria). Before performing the efficacy trials, the life cycle of the warble fly was studied at the slaughterhouse between July 1993 and June 1994. This survey revealed that both species of warble fly were present in this area: L1 larvae of H. lineatum were found around the oesophagus between August and January, whereas L1 larvae of H. bovis were observed around the spine from November until March. Warbles were present under the skin from the end of October until May. The nymphal phase took place between February and May. As a result of this study the authors recommend applying chemoprophylaxis (treatment against L1) in September. This work also confirmed the excellent efficacy of avermectins and milbemycins against the three instar larvae of Hypoderma sp. under the field conditions prevailing in Algeria. Rotenone has a lower efficacy (95%) which is limited to the second and third instar larvae. However, this drug appears useful in dairy cattle.


Azithromycin and lower respiratory tract infections.
Azithromycin is a macrolide antibiotic that has been structurally modified from erythromycin with an expanded spectrum of activity and improved tissue pharmacokinetic characteristics relative to erythromycin. This allows once-daily administration for 3-5 days of treatment compared with traditional multi dosing 7-10-day treatment regimens. It has been successfully employed in lower respiratory tract infections. Recent data indicate that azithromycin may exert anti-inflammatory/immunomodulatory effects that may be of use in the treatment of both acute and chronic airway diseases. This review examines the role of azithromycin in lower respiratory tract infections analysing published data on exacerbations of chronic bronchitis, community-acquired pneumonia and cystic fibrosis both in adults and children. In addition, pharmacokinetic and pharmacodynamic properties of the drug are also considered.


Luminescent behavior of cadmium sulfide quantum dots for gallic acid estimation.
Thioglycolic acid capped cadmium sulfide (CdS/T) quantum dots have been synthesized using wet chemistry and their optical behavior has been investigated using UV-visible absorption and fluorescence spectroscopy. The role of the capping agent, sulfide source concentration, pH and temperature has been studied and discussed. Studies showed that alkaline pH leads to a decrease in the size of quantum dots and reflux temperature above 70 °C resulted in red-shift of emission spectra which is due to narrowing of the bandgap. Further, to reduce the toxicity and photochemical instability of quantum dots, the quantum dots have been functionalized with polyethylene glycol (PEG), which resulted in a 20% enhancement of the fluorescence intensity. The application potential of CdS/T-PEG quantum dots was further studied using gallic acid as a model compound. The sensing is based on fluorescence quenching of quantum dots in the presence of gallic acid, and this study showed linearity in the range from 1.3 × 10(-8) to 46.5 × 10(-8) mM, with a detection limit of 3.6 × 10(-8) mM.


Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods.
The present article focuses on psychoneuroendocrine effects of cannabinoids in developing animals, with special emphasis on the perinatal, periweanling and periadolescent periods. We describe and discuss published data dealing with acute and long-term effects of exposure to cannabinoid agonists in such critical periods. Human studies have demonstrated that the consumption of marijuana by women during pregnancy affects the neurobehavioural development of their children. Investigations using animal models provide useful information for a better understanding of the long-lasting deleterious consequences of cannabis exposure during pregnancy and lactation. The increasing use of cannabis among adolescents and its associated public health problems have led to a parallel increase in basic research on appropriate animal models. Chronic administration of cannabinoid agonists during the periadolescent period causes persistent behavioural alterations in adult animals. Some of these alterations may be related to a possible increased risk of psychosis and other neuropsychiatric disorders in early onset cannabis users.


[Interferon-stimulating properties of immunomodulators].
The interferon-stimulating effect of immunomodulators is manifested after their combined inoculation with double-stranded NRAs (dsRNA) of natural and synthetic origin, and depends upon the time of administration of an inducer with respect to an immunomodulator and upon the dose of dsRNA. It is manifested as prolongation of interferon circulation in the bloodstream of animals up to 3 days when inosiplex is used as an immunomodulator. A still greater effect is observed when its derivative ASK is used instead of inosiplex. The interferon-stimulating effect of immunomodulators is due to cells of the immune system.


Physical Activity Surveillance in Adolescents with Type 1 Diabetes: A Pilot Mixed-Methods Investigation.
Type 1 diabetes (T1D) affects over 2,500 children in Ireland. Insulin replacement is the mainstay of treatment for T1D, and physical activity (PA) is an important, modifiable lifestyle factor for sustaining health. Surveillance of PA for both research and clinical purposes in paediatric T1D has been limited. This study deployed both quantitative (accelerometry) and qualitative (self-report) measures to assess habitual PA patterns in children with T1D. Twenty-one participants (9 females, 12 males) between 10 and 17 years (mean 13.7 ± 1.94 years) were recruited from an Outpatients Paediatric Diabetes Clinic. Total steps, standing time (minutes (mins)) and sitting time (mins) were recorded using the activPAL 3 microactivity monitor. Clinical parameters (HbA1c, insulin regimen, and weight centiles) were measured. A self-report diary was used to measure perceived activity levels. The findings of this study show that participant children with T1D are not achieving the required steps per day to sustain physical health (recommended minimum 11,500). Females (mean = 7,306 steps ± 5,468) achieved significantly less (p = 0.001) steps per day compared to males (10,806 steps ± 5,904). No significant differences were found between genders for sitting time or standing time. Overweight or obesity was identified in 44% of female participants and 15% of male participants. Mean HbA1c for both females 8.25% (67 mmol/mol) and males 7.97% (64 mmol/mol) was above the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommended <7.0% (53 mmol/mol) for children. Further research is warranted to investigate PA promotion strategies in populations of children with paediatric T1D.


Absorption of soluble and isophane semi-synthetic human and porcine insulin in insulin-dependent diabetic subjects.
A double-blind cross-over study of the sc absorption of radiolabelled semi-synthetic human (SHI) and purified porcine (PPI) insulin was made. Absorption of both isophane (n = 10) and soluble insulin (n = 8) was studied. There was no significant difference between the disappearance from the injection site, the plasma free insulin concentrations, or blood glucose levels after sc injection of the isophane preparations. A faster disappearance of the soluble SHI (as judged from T/50 and AUC) was found (both P-values less than 0.01). However, no difference was observed between the plasma insulin concentrations at any time point (P less than 0.05). Blood glucose levels showed no statistical differences between the two soluble preparations. The data indicate minor differences between the pharmacokinetics of SHI and PPI, but these seem of no clinical importance.


The influence of natural head position on the assessment of facial morphology.
Skeletal relationships play a major part in determining occlusal relationships, and that is why they also affect orthodontic treatment. Facial morphology can be assessed by clinical or radiological methods. Soft tissue analysis of the face is accepted as an integral part of orthodontic diagnosis and treatment planning. The aim of the study was to determine the impact of the inclination between the Frankfort horizontal(FH) and the extracranial horizontal (HOR) lines with the head in the natural position (NHP) on the assessment of facial morphology. Lateral facial photographs of 200 young adult males and females were taken with the head in the natural head position and then analyzed. Each image was rotated in order to position the Frankfort line parallel to the extracranial horizontal line. Twelve landmarks on each of the 400 profile photographs (200 originals,200 processed) were identified, and nine linear measurements and three angular measurements were assessed. The inclination angle between the extracranial horizontal line and the Frankfort horizontal line in the NHP varied from -7.1° to 5.6° (mean -1.20°). Significant correlations were found between the inclination angle FH/HOR and both sagittal and vertical morphology predictors such as the sections N-Sn (r = 0.3737, p = 0.0001), Sn-Gn(r = 0.3231, p = 0.0000), and both facial angles (r = 0.9774, p = 0.0000) and proflle angles (r = 0.9654, p = 0.0000). A comparison of soft tissue measurements determined with reference to the Frankfort horizontal and extracranial horizontal lines with the head in the natural position reveals significant differences


Dynamics of arginase gene evolution in metazoans.
In the present study, a comprehensive analysis of the arginase gene family in metazoans was performed. A total of 126 arginase genes have been identified in 44 species. Phylogenetic analyses indicate that arginase genes consist of four groups. Conservative and divergent gene structures are found among the groups. The syntenies also exist in distantly related genomes among multiple species. Adaptive evolution shows that, while purifying selection may have been the main force driving the evolution of the arginases, some of critical sites responsible for the functional divergence may have been under positive selection. Overall, the data obtained from our investigation contribute to a better understanding of the complexity of the arginase gene family and of the function and evolution of this family in metazoans.


Brain natriuretic peptide (BNP) may play a major role in risk stratification based on cerebral oxygen saturation by near-infrared spectroscopy in patients undergoing major cardiovascular surgery.
A previous study reported that low baseline cerebral oxygen saturation (ScO2) (≤50%) measured with near-infrared spectroscopy was predictive of poor clinical outcomes after cardiac surgery. However, such findings have not been reconfirmed by others. We conducted the current study to evaluate whether the previous findings would be reproducible, and to explore mechanisms underlying the ScO2-based outcome prediction. We retrospectively investigated 573 consecutive patients, aged 20 to 91 (mean ± standard deviation, 67.1 ± 12.8) years, who underwent major cardiovascular surgery. Preanesthetic baseline ScO2, lowest intraoperative ScO2, various clinical variables, and hospital mortality were examined. Bivariate regression analyses revealed that baseline ScO2 correlated significantly with plasma brain natriuretic peptide concentration (BNP), hemoglobin concentration (Hgb), estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF) (p < 0.0001 for each). Baseline ScO2 correlated with BNP in an exponential manner, and BNP was the most significant factor influencing ScO2. Logistic regression analyses revealed that baseline and lowest intraoperative ScO2 values, but not relative ScO2 decrements, were significantly associated with hospital mortality (p < 0.05), independent of the EuroSCORE (p < 0.01). Receiver operating curve analysis of ScO2 values and hospital mortality revealed an area under the curve (AUC) of 0.715 (p < 0.01) and a cutoff value of ≤50.5% for the baseline and ScO2, and an AUC of 0.718 (p < 0.05) and a cutoff value of ≤35% for the lowest intraoperative ScO2. Low baseline ScO2 (≤50%) was associated with increases in intubation time, intensive care unit stay, hospital stay, and hospital mortality. Baseline ScO2 was reflective of severity of systemic comorbidities and was predictive of clinical outcomes after major cardiovascular surgery. ScO2 correlated most significantly with BNP in an exponential manner, suggesting that BNP plays a major role in the ScO2-based outcome prediction.


Bioinspired Development of P(St-MAA)-Avermectin Nanoparticles with High Affinity for Foliage To Enhance Folia Retention.
Pesticides are chemical or biological substances to control pests and protect the crop yield. Most pesticides suffering from large amounts of losses in the environment lead to damage of ecological systems and food pollution. To reduce their losses and increase the utilization rate, we have developed bioinspired mussel avermectin nanoparticles [P(St-MAA)-Av-Cat] with strong adhesion to crop foliage by the emulsion-solvent evaporation method and chemical modification. They were near spheres with a diameter of around 120 nm. They displayed remarkable high avermectin content of more than 50% (w/w) and presented excellent storage stability as well as continuous sustained release. The photosensitive avermectins loaded were highly improved against ultraviolet light. Meanwhile, the retention rate of P(St-MAA)-Av-Cat on the crop foliage surfaces was significantly increased. As a result, the indoor toxicity of P(St-MAA)-Av-Cat was highly enhanced. The adhesive property strongly depended upon the functional groups on the nanoparticle surface. The multimodal binding mode of P(St-MAA)-Av-Cat to the crop foliage surface resulted in stronger adhesion and a longer retention time.


An occupational tale of two cities: minorities in London and New York.
In this paper, queuing theory is tested through an examination of the occupational attainment of six groups of non-whites in London and New York. Workers in the dominant economy are distinguished from those in the niche economy and emphasis is placed on the former. Black male immigrants in New York and black female immigrants in London hold more favorable occupational status. These results reflect differences in (1) the presence of indigenous minorities--African Americans and Puerto Ricans--in New York but not London, and (2) the relatively low position of indigenous minority males compared to the relatively middling position of indigenous minority females in New York's labor queue.


The pathogenic mechanism of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis.
The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex, basal ganglia, brainstem, and spinal cord, and commonly involves the muscles of the upper and/or lower extremities, and the muscles of the bulbar and/or respiratory regions. However, as the disease progresses, it affects the adjacent body regions, leading to generalized muscle weakness, occasionally along with memory, cognitive, behavioral, and language impairments; respiratory dysfunction occurs at the final stage of the disease. The disease has a complicated pathophysiology and currently, only riluzole, edaravone, and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries. The TAR DNA-binding protein 43 inclusions are observed in 97% of those diagnosed with amyotrophic lateral sclerosis. This review provides a preliminary overview of the potential effects of TAR DNA-binding protein 43 in the pathogenesis of amyotrophic lateral sclerosis, including the abnormalities in nucleoplasmic transport, RNA function, post-translational modification, liquid-liquid phase separation, stress granules, mitochondrial dysfunction, oxidative stress, axonal transport, protein quality control system, and non-cellular autonomous functions (e.g., glial cell functions and prion-like propagation).


Cross-sectional association between behavioral symptoms and potential elder abuse among subjects in home care in Italy: results from the Silvernet Study.
The objectives of this study were to evaluate the prevalence of potential elder abuse among older adults receiving home care and to assess the association between behavioral symptoms and potential abuse. Data on 4,630 subjects aged 65 or older receiving home care in Italy were collected using the Minimum Data Set for Home Care assessment. Potential abuse included signs of physical or emotional abuse and neglect. Behavioral symptoms were present if the participant exhibited one or more of the following symptoms in the 3 days before the assessment: wandering, verbally abusive, physically abusive, socially inappropriate behavior, and active resistance to care. Mean age of participants was 80.5 years (standard deviation: 7.7) and 2,761 (60%) were female. Signs of potential abuse were identified in 336 of 3,869 (9%) participants without behavioral symptoms and 126 of 761 (17%) with behavioral symptoms. After adjustment for potential confounders, presence of behavioral symptoms was significantly associated with potential abuse (odds ratio [OR]: 1.56; 95% confidence interval [CI]: 1.21-2.00). Examining behavioral symptoms separately, wandering was negatively associated with potential abuse (OR: 0.58; 95% CI: 0.36-0.97), whereas other symptoms were positively associated with this outcome (verbally abusive behavior OR: 1.69, 95% CI: 1.24-2.31; physically abusive behavior OR: 1.42, 95% CI: 1.00-2.03; socially inappropriate behavior OR: 1.78, 95% CI: 1.26-2.53; active resistance of care OR: 1.69, 95% CI: 1.20-2.38). Signs of potential abuse are common among older adults in home care in Italy and they are associated with the presence of behavioral symptoms.


A surrogate-based metaheuristic global search method for beam angle selection in radiation treatment planning.
An important element of radiation treatment planning for cancer therapy is the selection of beam angles (out of all possible coplanar and non-coplanar angles in relation to the patient) in order to maximize the delivery of radiation to the tumor site and minimize radiation damage to nearby organs-at-risk. This category of combinatorial optimization problem is particularly difficult because direct evaluation of the quality of treatment corresponding to any proposed selection of beams requires the solution of a large-scale dose optimization problem involving many thousands of variables that represent doses delivered to volume elements (voxels) in the patient. However, if the quality of angle sets can be accurately estimated without expensive computation, a large number of angle sets can be considered, increasing the likelihood of identifying a very high quality set. Using a computationally efficient surrogate beam set evaluation procedure based on single-beam data extracted from plans employing equallyspaced beams (eplans), we have developed a global search metaheuristic process based on the nested partitions framework for this combinatorial optimization problem. The surrogate scoring mechanism allows us to assess thousands of beam set samples within a clinically acceptable time frame. Tests on difficult clinical cases demonstrate that the beam sets obtained via our method are of superior quality.


Relative sedimentation of hematopoietic progenitors in human cord blood, peripheral blood, and bone marrow as determined by counterflow centrifugal elutriation.
The current use of cord blood (CB) and peripheral blood (PB) stem cells as alternatives or adjunctives to bone marrow (BM) for hematopoietic reconstitution in the treatment of various diseases prompted an examination of the progenitors of these tissues by counterflow centrifugal elutriation (CCE). The cells, obtained from normal donors not primed with colony-stimulating factors, were centrifuged at 3000 rpm in a Beckman Sanderson Chamber. Fractions (Frs.) were collected at (1) 18 ml/min, (2) 25 ml/min, (3) 32 ml/min, (4) 40 ml/min, and (5) the rotor-off fraction. Clonogenic assays revealed differences in the fraction localizations for CB and PB when compared to BM, i.e., recovery of the colony-forming units for CB and PB was greater in the small-medium cell size CCE fractions, and those from BM were found primarily among the medium-large cell size fractions. Thus, although colony-forming unit granulocyte/macrophage colonies were distributed throughout Frs. 2-5 of BM, CB and PB showed 80% of the total to be in Frs. 2 and 3. Further, although burst-forming unit erythroid colonies of BM were distributed equally in Frs. 2 and 3, greater than 70% of the total burst-forming unit erythroid colonies in CB and PB were found in Fr. 2. Distribution of the CD34 cells in the fractions correlated with the colony-forming units in that these were found primarily in Frs. 2 and 3 of CB and PB, whereas they were present in significant numbers throughout Frs. 1-5 of BM. We interpret these findings to indicate CB and PB to be qualitatively similar in their hematopoietic lineage development and to contain a greater proportion of early versus late progenitors relative to those found in BM.


Synthesis of Nickel Nanowires with Tunable Characteristics.
A one-step synthesis of magnetic nickel nanowires (NiNWs) with tunable characteristics is reported. The method is simple and easy to be conducted, leading to high compatibility with scaling-up. It is discovered that the size and morphology of NiNWs can be adjusted by tuning the reaction temperature, time length, as well as surfactant concentration. It is found that the products have shown high purity which remained after being stored for several months. A remarkable enhanced saturation magnetization of the product was also observed, compared to that of bulk nickel. By providing both practical experimental details and in-depth mechanism, the work introduced in this paper may advance the mass production and further applications of NiNWs.


Knowledge and understanding of health insurance: challenges and remedies.
As coverage is expanded in health systems that rely on consumers to choose health insurance plans that best meet their needs, interest in whether consumers possess sufficient understanding of health insurance to make good coverage decisions is growing. The recent IJHPR article by Green and colleagues-examining understanding of supplementary health insurance (SHI) among Israeli consumers-provides an important and timely answer to the above question. Indeed, their study addresses similar problems to the ones identified in the US health care market, with two notable findings. First, they show that overall-regardless of demographic variables-there are low levels of knowledge about SHI, which the literature has come to refer to more broadly as "health insurance literacy." Second, they find a significant disparity in health insurance literacy between different SES groups, where Jews were significantly more knowledgeable about SHI compared to their Arab counterparts.The authors' findings are consistent with a growing body of literature from the U.S. and elsewhere, including our own, presenting evidence that consumers struggle with understanding and using health insurance. Studies in the U.S. have also found that difficulties are generally more acute for populations considered the most vulnerable and consequently most in need of adequate and affordable health insurance coverage.The authors' findings call attention to the need to tailor communication strategies aimed at mitigating health insurance literacy and, ultimately, access and outcomes disparities among vulnerable populations in Israel and elsewhere. It also raises the importance of creating insurance choice environments in health systems relying on consumers to make coverage decisions that facilitate the decision process by using "choice architecture" to, among other things, simplify plan information and highlight meaningful differences between coverage options.


Spontaneous retrospective clinical evaluation of a new phytoestrogen-based cosmetic gel cream on postmenopausal women's skin.
The purpose of this study is to evaluate the efficacy of daily application of a new phytoestrogen-based cosmetic gel cream on postmenopausal women's skin. Sixty postmenopausal women were evaluated. Each subject was initially (T0) submitted to a hydration and sebometry test. A quantity of 50 ml of phytoestrogen-containing gel cream was given for one month to each patient. At the end of the month (T1), the tests were repeated. At the end of the study, 85% of the women showed an improvement of facial skin hydration. All the women who took part in the study had facial skin sebum normalization. The present study confirms that cosmetic preparations containing phytoestrogen are able to reduce skin aging, according to several published clinical trials. Nevertheless, the absence of a control group and the short observation time limited this study.


Role of drug therapies in the treatment of alcoholism: alcohol and anxiety--alcohol and depression.
Drug therapies are often used in therapeutic programs for alcoholics. This paper focuses on the use of psychotropic agents which can be used at different stages in the alcoholic disease process. It does not cover specific drug therapies for alcoholism (aversion, chemical restraint, dissuasion), nor nonspecific drug therapies (vitamins, magnesium) the interest and limits of which are well known. All types of psychotropic drugs, antianxiety drugs, antidepressants, thymoregulators, neuroleptics, and beta-blockers are used, with two main indications: (a) to prevent or to treat the withdrawal syndrome and (b) to diminish the psychopathological factors related to alcoholism (anxiety or depression, for example), in order to avoid pathological recourse to alcohol. Recently, attempts have been made to decrease the craving for alcohol in humans after detoxification. Although psychotropic drugs are often used in the management of alcoholics, such management is not limited to them, but also includes psychotherapy and social measures.


[Impact of rapid influenza test during influenza epidemic in all febrile children less than 6 years old in a pediatric emergency department].
To determine the impact of rapid influenza test (RIT) on the prescription of additional tests, antibiotics and oseltamivir, and the influence of oseltamivir on clinical signs and parents' day work stoppage. Prospective study in the pediatric emergency department of Nice University Hospital from 29th January 2007 to 3rd March 2007 including children from 1 month to 6 years old with fever greater or equal to 38.5 degrees C for less than 48 h. Virologic research on nasopharyngeal aspiration was: immunofluorescence, cell culture and RIT Quickvue. Clinical informations, additional tests and treatments were registered for each child. An antiviral treatment (oseltamivir) was proposed to children older than 1 year with positive RIT. Evolution at 7 days was evaluated by phone contact. One hundred and seventy-seven children were included (mean age 24 months, sex-ratio 1.88). The RIT was positive in 42.3% (n=75). Compared with cell culture, the sensibility, specificity, positive predictive value and negative predictive value of the RIT were, respectively, 95.6, 91.6, 88 and 97%. Clinical signs significantly correlated to influenza were: impairment, rhinitis and acute otitis media. In the RIT positive group, there were significantly less additional tests (13 versus 36) and particularly urinalysis (5 versus 19), and more spreading in the family (p=0.0002). There was not any significant difference concerning hospitalizations, antibiotic prescriptions, or parents' day work stoppage. During influenza epidemic, in a pediatric emergency department, RIT allows a reduction of additional tests in febrile young children, particularly urinalysis.


Satellite potentials as a measure of neuromuscular disorders.
The study was carried out to investigate the characteristics of satellite potentials and their validity in clinical electromyography. Conventional needle electromyography was applied to the right biceps brachii and tibialis anterior muscles of 41 controls, 22 neuropathies, and 17 myopathies. Satellites were defined as small extrapotentials, preceding/following the main motor unit action potential (MUAP) component and separated from it by an isoelectrical interval of > 1 ms. The normal mean satellite rate was 1.6% (biceps brachii) and 1.2% (tibialis anterior). In the biceps brachii (tibialis anterior) muscle it was 5 (5) times higher for neuropathies (P = 0.005, P = 0.006) and 5 (6) times higher for myopathies (P = 0.006, P = 0.003). MUAP parameters were not significantly different, whether satellites were considered or ignored. Evaluation of the satellite rate increased detection rates of neuromuscular disorders by up to 13%. The satellite rate proved a valuable and easily available, supplemental electromyographic parameter for the discrimination and detection of neuromuscular disorders.


MicroRNA-93 alleviates neuropathic pain through targeting signal transducer and activator of transcription 3.
Emerging evidence suggests that microRNAs (miRNAs) play a critical role in the pathogenesis of neuropathic pain. However, the exact role of miRNAs in regulating neuropathic pain remains largely unknown. In this study, we aimed to investigate the potential role of miR-93 in a rat model of neuropathic pain induced by chronic constriction sciatic nerve injury (CCI). We found a significant decrease of miR-93 in the spinal cord of CCI rats compared with sham rats. Overexpression of miR-93 significantly alleviated neuropathic pain development and reduced inflammatory cytokine expression, including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 in CCI rats. By bioinformatic analysis and dual-luciferase reporter assay, we found that miR-93 directly targeted the 3'-untranslated region (UTR) of signal transducer and activator of transcription 3 (STAT3), an important regulator of inflammation. Overexpression of miR-93 markedly suppressed the expression of STAT3 in vitro and in vivo. Furthermore, overexpression of STAT3 significantly reversed the miR-93 overexpression-induced suppressive effects on neuropathic pain development and neuroinflammation. Taken together, our study suggests that miR-93 inhibits neuropathic pain development of CCI rats possibly through inhibiting STAT3-mediated neuroinflammation. Our findings indicate that miR-93 may serve as a novel therapeutic target for neuropathic pain intervention.


Improving cardiovascular care for indigenous populations.
The challenges and opportunities for provision of, and access to, reliable chronic cardiovascular health care for Indigenous people were addressed by expert speakers from New Zealand and Australia. It is well recognised that cardiovascular disease is a life-long concern, requiring reliable follow-up, early transition of clinical research into practice and ongoing support of patients. The clinical outcomes and long-term prognosis of individuals with cardiovascular disease are critically dependent upon the quality and availability of follow-up and chronic care facilities. This paper summarises the principal issues identified by the expert speakers for the provision of chronic cardiovascular health care to Indigenous peoples in Australia and New Zealand; identifies common challenges and describes important initiatives which the Cardiac Society of Australia and New Zealand (CSANZ), in partnership with health care professionals, communities and governments, can undertake in order to achieve the goals of uniform and equitable health care for chronic cardiovascular disease in all the Indigenous peoples, relevant to the needs of these peoples, in New Zealand and Australia. The issues addressed by the meeting include: 1) Determination of appropriate models for effective delivery of cardiovascular health care. (2) Who should deliver cardiovascular health care and what are the workforce requirements. (3) What support systems and infrastructure are required. (4) How can primary care and secondary specialist services be effectively integrated.


Time-resolved methods in biophysics. 3. Fluorescence lifetime correlation spectroscopy.
We present a thorough introduction into the recently developed fluorescence lifetime correlation spectroscopy (FLCS). The theoretical basis of FLCS is explained, and the method is applied to the study of a dynamic transition between two fluorescence lifetime states in a dye-protein complex.


Emergency endoscopic nasobiliary drainage without the aid of fluoroscopy.
Endoscopic nasobiliary drainage without the aid of fluoroscopy, as an emergency procedure, was performed successfully in four patients with severe calculous cholangitis. There were no complications. All the patients improved and three were taken for definitive surgery later.


Disease Modeling in Stem Cell-Derived 3D Organoid Systems.
Organoids are 3D in vitro culture systems derived from self-organizing stem cells. They can recapitulate the in vivo architecture, functionality, and genetic signature of original tissues. Thus, organoid technology has been rapidly applied to understanding stem cell biology, organogenesis, and various human pathologies. The recent development of human patient-derived organoids has enabled disease modeling with precision, highlighting their great potential in biomedical applications, translational medicine, and personalized therapy. In light of recent breakthroughs using organoids, it is only apt that we appreciate the advantages and shortcomings of this technology to exploit its full potential. We discuss recent advances in the application of organoids in studying cancer and hereditary diseases, as well as in the examination of host cell-microorganism interactions.


Induction of renin-angiotensin system in human testis in vivo.
To better understand the local renin-angiotensin system in Leydig cells of the human testis, the plasma renin activity (PRA) and plasma concentration of angiotensin II (PAII) in the left internal spermatic vein (ISV) and cubital vein (CV) were measured at the time of surgical repair of varicocele in 27 patients. Fourteen of the patients were given a single i.m. injection of hCG (10,000 IU/m2) 4 days before the operation, whereas the remaining 13 were not treated. Although the mean PRA or PAII levels in the CV in the treated and nontreated groups were similar, both levels in the ISV in the treated group were significantly higher than in the nontreated group (p less than 0.05). For PAII levels in the treated group, nine of 11 patients with an increased PRA level showed significantly higher levels than the normal peripheral PAII value. The serum testosterone levels in the same ISV were also much higher in the treated group than in the nontreated group (p less than 0.001). These results suggested the possibility that sex steroids might influence the renin-angiotensin system in Leydig cells.


Fibronectin in corneal wound healing.
Fibronectin is an extracellular structural protein with the unique ability to bind to both cells and collagen. It plays a major role in the development of the cornea. The universal appearance of fibronectin within 8 hours of corneal wounding has promoted major interest in its wound healing properties. The early clinical evidence for fibronectin treatment of recurrent corneal erosion and certain forms of keratitis sicca is strong. The current major problem preventing commercial use is the antigenic nature of fibronectin derived from separate species. Human pooled fibronectin has been suggested as a commercial source of this ubiquitously occurring protein.


Predictive value of quantitative contrast-enhanced ultrasound in hepatocellular carcinoma recurrence after ablation.
To investigate the relationship between contrast-enhanced ultrasound (CEUS), basic fibroblast growth factor (bFGF), endothelin-1 (ET-1), and hepatocellular carcinoma (HCC) recurrence after ablation. A total of 51 HCC patients (38 males and 13 females) who received radiofrequency ablation in our hospital from June 2012 to July 2014 were enrolled in this study. The patients were divided into two groups: recurrence group and non-recurrence group. Routine abdominal examination was first performed in the horizontal position. Then the patients underwent CEUS and immunohistochemical staining before receiving radiofrequency ablation. All patients were followed-up every three months for one year. The results of CEUS and serum tumor marker levels were evaluated and combined together to estimate HCC recurrence and metastasis. Patients were divided into two groups: recurrence group and non-recurrence group. Quantitative parameters of CEUS and tumor expression levels of bFGF and ET-1 were compared between the two groups, respectively. Binary logistic regression analysis was used to analyze the relationship between CEUS quantitative parameters, expression levels of ET-1 and bFGF, and HCC recurrence after ablation. Based on the quantitative parameters of CEUS before patients received radiofrequency ablation, the levels of tumor rise time (tRT), tumor time to peak (tTTP), tumor peak intensity (tPI) and tumor-parenchymal peak intensity (t-pPI) in the recurrence group were significantly lower than those in the non-recurrence group (16.6 ± 6.1 vs 23.2 ± 7.0, P = 0.000; 41.2 ± 10.2 vs 59.6 ± 14.2, P = 0.000; 23.8 ± 6.7 vs 31.4 ± 6.4, P = 0.000; 7.1 ± 3.4 vs 14.6 ± 7.4, P = 0.000; respectively). The expression levels of bFGF in the recurrence group were significantly higher than those in the non-recurrence group (P < 0.05). Levels of tTTP showed a significant inverse correlation with the level of bFGF in tumors (r = -0.312, P = 0.037). The Binary logistic regression analysis results revealed that the levels of tRT, tTTP, tPI and the level of bFGF were associated with HCC recurrence after radiofrequency ablation (P < 0.05). CEUS is a noninvasive and effective method for evaluating the angiogenesis of HCC, and predicting its recurrence and prognosis.


Attached and planktonic Listeria monocytogenes global proteomic responses and associated influence of strain genetics and temperature.
Contamination of industrial and domestic food usage environments by the attachement of bacterial food-borne pathogen Listeria monocytogenes has public health and economic implications. Comprehensive proteomics experiments using label-free liquid chromatography/tandem mass spectrometry were used to compare the proteomes of two different L. monocytogenes strains (Siliken_1/2c and F2365_4b), which show very different capacities to attach to surfaces. Growth temperature and strain type were highly influential on the proteomes in both attached and planktonic cells. On the basis of the proteomic data, it is highly unlikely that specific surface proteins play a direct role in adherence to inanimate surfaces. Instead, strain-dependent responses related to cell envelope polymer biosynthesis and stress response regulation likely contribute to a different ability to attach and also to survive external stressors. Collectively, the divergent proteome-level responses observed define strain- and growth-temperature-dependent differences relevant to attachment efficacy, highlight relevant proteins involved in stress protection in attached cells, and suggest that strain differences and growth conditions are important in relation to environmental persistence.


Effects of experimental bleaching agents on the mineral content of sound and demineralized enamels.
High concentrations of hydrogen peroxide can cause adverse effects on composition and structure of teeth. However, the addition of calcium and fluoride in bleaching agents may reduce enamel demineralization. To evaluate chemical changes of sound and demineralized enamels submitted to high concentrations of hydrogen peroxide containing fluoride (F) or calcium (Ca). Enamel blocks of bovine incisors with standard dimensions were obtained and half of them were submitted to pH-cycling to promote initial enamel caries lesions. Sound and demineralized enamel samples were divided into (n=10): (C) Control (no whitening treatment); (HP) 35% hydrogen peroxide; and two experimental groups: (HPF) 35% HP+0.2% F and (HPC) 35% HP+0.2% Ca. Experimental groups were submitted to two in-office bleaching sessions and agents were applied 3 times for 15 min to each session. The control group was kept in remineralizing solution at 37°C during the bleaching treatment. The surface mineral content of sound and demineralized enamels was determined through Fourier Transform Raman spectroscopy (FT-Raman), Energy dispersive Micro X-ray fluorescence spectroscopy (μ-EDXRF); and the subsurface, through cross-sectional microhardness (CSMH). In addition, polarized light microscopy (PLM) images of enamel subsurface were observed. According to three-way (FT-Raman and μ-EDXRF analyses) or two-way analysis of variance (ANOVA) (CSMH) and Tukey test (α=5%), the calcium or fluoride added to high-concentrated bleaching agents increased phosphate and carbonate concentrations on sound and demineralized enamels (p<0.05). However, HPC and HPF were unable to completely reverse the subsurface mineral loss promoted by bleaching on sound and demineralized enamels. The calcium/ phosphate (Ca/P) ratio of sound enamel decreased after HP treatment (p<0.001). Even though experimental bleaching agents with Ca or F reduced mineral loss for both sound and demineralized enamel surfaces, these agents were unable to reverse the enamel subsurface demineralization.


Mitral valve replacement for an annular submitral aneurysm of the left ventricle.
Successful surgical repair of an annular submitral aneurysm of the left ventricle in two patients is described. In both cases the diagnosis was made at surgery and they were treated successfully by transatrial closure of the aneurysm with Teflon felted sutures and mitral valve replacement. This is the first report of the use of mitral valve replacement for this condition.


Contribution of hepatic adenosine A1 receptors to renal dysfunction associated with acute liver injury in rats.
Acute liver injury is associated with renal insufficiency, whose mechanism may be related to activation of the hepatorenal reflex. We previously showed that intrahepatic adenosine is involved in activation of the hepatorenal reflex to restrict urine production in both healthy rats and in rats with cirrhosis. The aim of the present study was to test the hypothesis that activation of intrahepatic adenosine receptors is involved in the pathogenesis of the renal insufficiency seen in acute liver injury. Acute liver injury was induced by intraperitoneal injection of thioacetamide (TAA, 500 mg/kg) in rats. The animals were instrumented 24 hours later to monitor systemic, hepatic, and renal circulation and urine production. Severe liver injury developed following TAA insult, which was associated with renal insufficiency, as demonstrated by decreased (approximately 25%) renal arterial blood flow, a lower (approximately 30%) glomerular filtration rate, and decreased urine production. Further, the increase in urine production following volume expansion challenge was inhibited. Intraportal, but not intravenous, administration of a nonselective adenosine receptor antagonist, 8-phenyltheophylline, improved urine production. To specify receptor subtype, the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an adenosine A(1) receptor antagonist) and 3,7-dimethyl-1-propargylxanthine (DMPX, an adenosine A(2) receptor antagonist) were compared. Intraportal but not intravenous administration of DPCPX greatly improved impaired renal function induced by acute liver injury, and this beneficial effect was blunted in rats with liver denervation. In contrast, neither intraportal nor intravenous administration of DMPX showed significant improvement in renal function. In conclusion, an activated hepatorenal reflex, triggered by intrahepatic adenosine A(1) receptors, contributed to the pathogenesis of the water and sodium retention associated with acute liver injury.


Impact of arbuscular mycorrhizal fungal inoculants on subsequent arbuscular mycorrhizal fungi colonization in pot-cultured field pea (Pisum sativum L.).
The use of commercial inoculants containing non-resident arbuscular mycorrhizal fungi (AMF) is an emerging technology in field crop production in Canada. The objective of this study was to assess the impact of AMF inoculants containing either a single species (Glomus irregulare) or mixed species (G. irregulare, Glomus mosseae, and Glomus clarum) on AMF root colonization and consequent plant growth parameters of field pea grown using pot cultures. Field pea was grown in both sterilized and non-sterile (i.e., natural) field-collected soil containing resident AMF and received three inoculation treatments: uninoculated control, G. irregulare only, and a mixture of AMF species of G. irregulare, G. mosseae, and G. clarum. After 42 days, the AMF community assembled in field pea roots was assessed by cloning and sequencing analysis on the LSU-ITS-SSU rDNA gene, together with a microscopic assessment of colonization, biomass production, nutrient uptake, and N(2) fixation. The identity of AMF inoculants had a significant effect on field pea performance. The mixed species AMF inoculant performed better than the single species G. irregulare alone by promoting mycorrhizal colonization, field pea biomass, N and P uptake, and N(2) fixation and did not result in a significant compositional change of the AMF community that subsequently assembled in field pea roots. In contrast, the single species G. irregulare inoculant did not significantly enhance field pea biomass, N and P uptake, and N(2) fixation, although a significant compositional change of the subsequent AMF community was observed. No significant interactions affecting these measurements were detected between the resident AMF and the introduced AMF inoculants. The observation that the mixed species AMF inoculant promoted plant growth parameters without necessarily affecting the subsequent AMF community may have important implications regarding the use of non-resident AMF inoculants in agricultural production.


Antihelminthic and antiangiogenic effects of zinc oxide nanoparticles on intestinal and muscular phases of trichinellosis.
Trichinellosis is a worldwide zoonotic disease affecting a wide range of mammals, including humans. It has intestinal and muscular phases. The current work was done to experimentally evaluate the efficacy of zinc oxide nanoparticles (ZnO NPs) and their combination with albendazole on intestinal and muscular stages of Trichinella spiralis (T. spiralis) infection. We had five main groups of mice: Group 1, non-infected control; Group 2, infected control; Group 3, infected and treated with albendazole; Group 4, infected and treated with ZnO NPs; and Group 5, infected and treated with albendazole and ZnO NPs. Each group was divided into two subgroups (A for the intestinal phase and B for the muscular phase). Drug effects were evaluated by parasitological, histopathological, and biochemical studies, including oxidant/antioxidant analysis and vascular endothelial growth factor (VEGF) gene expression in muscle tissue by quantitative real-time PCR. ZnO NPs resulted in a significant reduction of both intestinal and muscular phases of T. spiralis. Their combination with albendazole resulted in the complete eradication of adult worms and the maximum reduction of larval deposition in muscle tissue. Additionally, the treatment showed improvement in T. spiralis-induced pathological changes and oxidative stress status. Moreover, a significant decrease in VEGF gene expression was detected in the treated groups when compared with the infected control. In conclusion, ZnO NPs presented an antihelminthic effect against both adult and larval stages of T. spiralis. In addition, it enhanced antioxidant status and suppressed angiogenesis in muscle.


Early life benefits and later life costs of a two amino acid deletion in Drosophila simulans.
Linking naturally occurring genotypic variation to the organismal phenotype is critical to our understanding of, and ability to, model biological processes such as adaptation to novel environments, disease, and aging. Rarely, however, does a simple mutation cause a single simple observable trait. Rather it is more common for a mutation to elicit an entangled web of responses. Here, we employ biochemistry as the thread to link a naturally occurring two amino acid deletion in a nuclear encoded mitochondrial protein with physiological benefits and costs in the fly Drosophila simulans. This nuclear encoded gene produces a protein that is imported into the mitochondrion and forms a subunit of complex IV (cytochrome c oxidase, or cox) of the electron transport chain. We observe that flies homozygous for the deletion have an advantage when young but pay a cost later in life. These data show that the organism responds to the deletion in a complex manner that gives insight into the mechanisms that influence mitochondrial bioenergetics and aspects of organismal physiology.


NF2: the wizardry of merlin.
Neurofibromatosis type II (NF2) is an autosomal dominant cancer syndrome characterized by the formation of tumors of the nervous system, particularly schwannomas and meningiomas. The NF2 gene is also implicated in the development of sporadic schwannomas and meningiomas, as well as tumor types seemingly unrelated to the NF2 disorder, such as malignant mesotheliomas. Inactivation of NF2 occurs by a "two-hit" mechanism, as proposed by Al Knudson, and the NF2 gene behaves as a classical tumor suppressor gene. The NF2 gene product, merlin, exhibits homology with the ezrin-radixin-moesin family of membrane-cytoskeleton-linking proteins. During the past several years, there has been intensive investigation aimed at elucidating the mechanisms underlying merlin's functions. In this review, we summarize the involvement of NF2 inactivation in tumorigenesis. We also discuss observations implicating merlin in cell motility and cell proliferation, with a focus on recent findings linking merlin to Rac signaling.


Antiplasmid activity of tricyclic compounds.
Three representative groups of tricyclic psychopharmacons were shown to have antiplasmid activity. The first group, e.g., comprises promazine, chlorpromazine, promethazine, levo- and dextromepromazine, thioridazine, diethazine, thiethylperazine. There are two heteroatoms (S and N) in the ring system of these compounds. In the second group, which includes desipramine, imipramine, however, there is only one heteroatom N, or S in chlorprothixene, chlorpenthixols and in the third group amitriptyline, maprotiline contain no heteroatoms. The medical significance of plasmid elimination by tricyclic psychopharmacons and related compounds in vitro is that this opens up a new perspective in the struggle against bacterial resistance to antibiotics. This approach utilizes the beneficial side-effect of the plasmid curing ability of these psychopharmacons, and may serve as a guideline for drug design in the future, to develop related substances which are potent in eliminating the drug resistance-carrying plasmids of bacteria, but which have no other pharmacological effects. Here we propose a new mechanism for plasmid curing by tricyclic drugs.


Comprehensive two-dimensional high-performance liquid chromatography for the isolation of overexpressed proteins and proteome mapping.
A two-dimensional liquid chromatographic system is described here which uses size-exclusion liquid chromatography (SEC) followed by reversed-phase liquid chromatography (RPLC) to separate the mixture of proteins resulting from the lysis of Escherichia coli cells and to isolate the proteins that they produce. The size-exclusion chromatography can be conducted under either denaturing or nondenaturing conditions. Peaks eluting from the first dimension are automatically subjected to reversed-phase chromatography to separate similarly sized proteins on the basis of their various hydrophobicities. The RPLC also serves to desalt the analytes so that they can be detected in the deep ultraviolet region at 215 nm regardless of the SEC mobile phase used. The two-dimensional (2D) chromatograms produced in this manner then strongly resemble the format of stained 2D gels, in that spots are displayed on a X-Y axis and intensity represents quantity of analyte. Following chromatographic separation, the analytes are deposited into six 96-well (576 total) polypropylene microtiter plates via a fraction collector. Interesting fractions are analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/MS) or electrospray mass spectrometry (ESI/MS) depending on sample concentration, which both yield accurate (2 to 0.02%) molecular weight information on intact proteins without any additional sample preparation, electroblotting, destaining, etc. The remaining 97% of a fraction can then be used for other analyses, such Edman sequencing, amino acid analysis, or proteolytic digestion and sequencing by tandem mass spectrometry. This 2D HPLC protein purification and identification system was used to isolate the src homology (SH2) domain of the nonreceptor tyrosine kinase pp60c-src and beta-lactamase, both inserted into E. coli, as well as a number of native proteins comprising a small portion of the E. coli proteome.


Peculiar polarization response in chiral liquid crystal stacks for multispectral camouflage.
Chiral liquid crystals are self-organized Bragg reflectors which respond to circularly polarized light. Manipulation of the chiral structure has aroused great research interest. The x-y plane two-dimensional patterning of chiral liquid crystals leads to reflective planar optics, and the z-axis modulation results in a variety of photonic bandgap controls. Here, the optical properties of even-number left- and right-handed chiral liquid crystal stacks are investigated, with emphasis on the linear polarization response. Under certain conditions, a linearly polarized incidence can result in a linearly polarized reflected light. More intriguingly, the linear polarization has different forms of response to thick and thin chiral liquid crystal sublayers and responds to the rotation of liquid crystal alignment. Based on the peculiar polarization response, a new type of wavelength-response camouflage and anti-counterfeiting is conceptually proposed, which can hide two different images simultaneously within a small spectral range. Our work paves the way for three-dimensional manipulation of chiral liquid crystals and enlightens novel applications.


Choroidal thickness measurements in different ethnicities using swept source optical coherence tomography: repeatability and assessment.
Swept-source optical coherence tomography may not provide reliable measurements of choroidal thickness for pigmented subjects. The repeatability of choroidal thickness measurements in young healthy adults was investigated using swept source optical coherence tomography. Choroidal thickness was measured using swept source optical coherence tomography in 98 healthy subjects (49 South Asian and 49 Caucasian) aged between 19 and 28 years old. Repeated radial scan images centred on the fovea were obtained from the right eye with 5 min between measurements. Choroidal thickness values were obtained from the built-in automated segmentation algorithm for the 9 subfields defined by the Early Treatment Diabetic Retinopathy Study. Interclass correlation coefficients and Bland-Altman methods were used to assess test-retest repeatability. The mean ± standard deviation sub-foveal choroidal thickness was 316.53 ± 63.36 µm for the Caucasian group and 292.70 ± 60.13 µm for the South Asian group. Bland-Altman analysis showed smaller test-retest variability for choroidal thickness measurements in the Caucasian group (mean difference ± SD = -0.01 ± 6.59 µm) compared to the South Asian group (mean difference ± SD = -2.38 ± 12.20 µm). No relationship was found between the mean choroidal thickness and mean spherical equivalent of refractive error for both subject groups. Swept source optical coherence tomography is capable of obtaining choroidal thickness measurements with good repeatability. However, test-retest limits of agreement are substantially greater in South Asian subjects, suggesting that successful identification of the choroidal scleral interface may be affected by the amount of pigmentation present in the retinal and choroidal tissues.


The relationship between challenging behaviour and anxiety in adults with intellectual disabilities: a literature review.
Anxiety and challenging behaviour (CB) often occur simultaneously in people with intellectual disabilities (ID). Understanding the associations between anxiety and CB may contribute to more accurate diagnoses and management of both anxiety and CB in this population. To examine the relationship between anxiety and CB. A literature review covering the period from January 2000 to January 2012. Seven studies about the relationship between psychiatric disorders, including anxiety, and CB were identified. These studies confirm the relationship between anxiety and CB in people with ID, although the precise nature of this relationship remains unclear. The study points toward the existence of a moderate association between anxiety and CB. Further research is needed to clarify the complex nature of the association between anxiety and CB.


Early non-immunological post transplant complications: a single center experience.
To assess non-immunological complications affecting renal transplant patients in the first six months after transplantation in Al-Karama hospital, Baghdad, Iraq, we studied 68 patients (49 males, 19 females) attending the clinic during the year 2006. Forty six (67%) patients received kidneys from related and 22 (33%) from unrelated donors. The patients revealed the following complications: post transplant hypertension in 28 (41%) patient, infection (mostly bacterial) in 27 (37%), new onset diabetes in 11 (16%), calcineurin inhibitor toxicity in 10 (14%), anemia in 8 (12%), surgical complications in 7 (10%), slow graft recovery in 4 (6%), cardiovascular complications in 3 (4%), and Kaposi sarcoma in 2 (2.9%). Transient hyperglycemia, hypertension, infection and diabetes mellitus were the commonest early complications of renal transplantation. The incidence of complications is comparable to the average reported in the literature, especially in this region of the world.