Free-Standing Organic Transistors and Circuits with Sub-Micron Thicknesses.
The realization of wearable electronic devices with extremely thin and flexible form factors has been a major technological challenge. While substrates typically limit the thickness of thin-film electronic devices, they are usually necessary for their fabrication and functionality. Here we report on ultra-thin organic transistors and integrated circuits using device components whose substrates that have been removed. The fabricated organic circuits with total device thicknesses down to 350 nm have electrical performance levels close to those fabricated on conventional flexible substrates. Moreover, they exhibit excellent mechanical robustness, whereby their static and dynamic electrical characteristics do not change even under 50% compressive strain. Tests using systematically applied compressive strains reveal that these free-standing organic transistors possess anisotropic mechanical stability, and a strain model for a multilayer stack can be used to describe the strain in this sort of ultra-thin device. These results show the feasibility of ultimate-thin organic electronic devices using free-standing constructions.


Temporal changes in functional outcomes of stapled and hand-sewn ileal pouch-anal anastomosis for ulcerative colitis and familial adenomatous polyposis.
Little is known about how ileal pouch-anal anastomosis (IPAA) influences anorectal manometric data. This study aimed to clarify temporal changes in anorectal manometric data and faecal incontinence in IPAA. We examined 32 patients with ulcerative colitis (UC) or familial adenomatous polyposis (FAP) undergoing restorative proctocolectomy with stapled or hand-sewn IPAA. Maximum resting pressure (MRP) and maximum squeezing pressure (MSP) were analysed before and 1-3, 6-9, and 12-24 months after IPAA. Cleveland Clinic Florida-Faecal Incontinence Score (CCF-FIS) was measured 6-9 and 12-24 months after IPAA. Fourteen patients underwent stapled IPAA and 18 patients underwent hand-sewn IPAA. MRP decreased 1-3 months after stapled IPAA (median: 42.3 mmHg vs. 60.0 mmHg at preoperative value, p = 0.039), but recovered afterwards. In hand-sewn IPAA, the median MRP decreased to 29.5 mmHg at 1-3 months after IPAA (baseline: 64.8 mmHg, p < 0.0001), and remained unchanged thereafter. Stapled IPAA did not affect MSP; however, hand-sewn IPAA caused a reduction in the median MSP from 191.3 mmHg to 141.3 mmHg at 1-3 months (p = 0.035), which gradually increased afterwards. The median CCFFIS was 5.5 points at 6-9 months and 2 points at 12-24 months after stapled IPAA. The score was high (11 points) at 6-9 months but decreased to 5 points at 12-24 months after hand-sewn IPAA (p = 0.022). We present time trends in functional outcomes of IPAA. MRP showed a transient decrease after stapled IPAA, whereas it remained low after hand-sewn IPAA. CCFFIS was high only at 6-9 months after hand-sewn IPAA.


Imaging of Hepatobiliary Cancer.
The liver and biliary tree are common sites of primary and secondary malignancies. MRI followed by CT is the mainstay for the imaging characterization of these malignancies with the dynamically acquired contrast enhanced phases being the most important for diagnosis. The liver imaging reporting and data system classification provides a useful framework for reporting lesions in patents with underlying cirrhosis or who are at high risk for developing hepatocellular carcinoma. Detection of metastases is improved with the use of liver specific MRI contrast agents and diffusion weighted sequences. Aside from hepatocellular carcinoma, which is often diagnosed noninvasively, other primary hepatobiliary tumors may require biopsy for definite diagnosis, especially when presenting with nonclassic imaging findings. In this review, we examine the imaging findings of common and less common hepatobiliary tumors.


Myocardial infarction induces sympathetic hyperinnervation via a nuclear factor-κB-dependent pathway in rabbit hearts.
Cardiac sympathetic hyperinnervation after myocardial infarction (MI) is associated with a high incidence of lethal arrhythmia. However, the mechanisms of nerve sprouting induced by MI are unclear. In this study, we showed a nuclear factor-κB (NF-κB) signaling pathway involved in cardiac sympathetic hyperinnervation after MI in rabbit hearts. An MI model was induced by ligation of the coronary artery in rabbits, which were then euthanized after 7 days. Rabbits with MI showed sympathetic hyperinnervation, as revealed by immunohistochemical analysis of the density of nerve fibers positive for growth-associated protein 43 (GAP43) and tyrosine hydroxylase (TH). Using western blot and real-time RT-PCR techniques, we found that MI was associated with activation of NF-κB signaling and consequent upregulation of nerve growth factor. Intravenous administration with the NF-κB inhibitor pyrrolidine dithiocarbamate (100mg/kg/day) inhibited NF-κB activation and ameliorated sympathetic hyperinnervation after MI. These results suggest that cardiac nerve sprouting after MI is associated in part with NF-κB activation and may be one of the mechanisms responsible for sympathetic hyperinnervation induced by MI.


Writing the introduction.
The introduction section of a scientific paper aims to introduce a specific topic and to stimulate the reader's interest. It provides background information about what has already been done by others, supported by a limited number of relevant references. The reader should be informed about the purpose of the paper, what it will address, and how it relates to previous work.


Prescribing of inappropriate medication in nursing home residents in Germany according to a French consensus list: a cross-sectional cohort study.
The current use of inappropriate medication in elderly nursing home residents (NHRs) in Germany is unclear. We therefore set out to analyse the frequency and patterns of potentially inappropriate drug prescriptions in elderly NHRs in Germany. We utilised prescription data for NHRs 65 years or older from a large German health insurance company during a period of 3 months. Inappropriate drugs were identified from a recently reported French consensus list. Data for 7271 (83.7%) females and 1414 (16.3%) males were available for analysis. The average age was 83.6 ± 7.3 years. Overall 48 inappropriate drugs were prescribed resulting in a total of 3825 inappropriate drug prescriptions which accounted for 4.3% of all documented prescriptions (n = 88,695). One thousand nine hundred and three (21.9%) residents received at least one inappropriate drug prescription. Using logistic regression we detected no significant influence of gender or level of care on frequency of inappropriate prescriptions. However, age had a significant influence; with increasing age the frequency of residents receiving inappropriate medications decreased steadily (r = -0.92, p = 0.003) and ranged from a maximum of 32.8% in the group between 65 and 69 years to a minimum of 15.2% in residents older than 94 years. This observation was paralleled by a significant and continuous decrease of drug prescription rates with increasing age (r = -0.88, p = 0.009). The present analysis demonstrates that about one out of five elderly NHRs received at least one inappropriate drug prescription. Additional studies may aim to establish a list of frequently prescribed inappropriate drugs for Germany.


A biosynthetic classification of fungal and streptomycete fused-ring aromatic polyketides.
Polyketides are one of the largest and most structurally diverse classes of naturally occurring compounds, ranging from simple aromatic metabolites to complex macrocyclic lactones. Fungi and filamentous bacteria, particularly the actinomycetes, are major sources of polycyclic aromatic structures, which include many clinically important antibiotics and other useful metabolites. These fused-ring polyketides are formed by the action of polyketide synthases (PKSs), which catalyse the assembly, folding and cross-linking of poly-beta-ketoacyl intermediates. In view of the taxonomic gulf between the eukaryotic fungi and prokaryotic bacteria, it is not surprising that they are rarely found to produce structurally identical fused-ring metabolites. A review of [(13)C(2)]acetate incorporation data has revealed consistent differences in the reported cyclisation patterns, which require regiospecifically distinct cross-linking of otherwise identical linear polyketide precursors. This observation provides the basis for a structural and biosynthetic classification of microbial fused-ring polyketides, which has a number of useful ramifications.


Surface engineered gold nanoparticles through highly stable metal-surfactant complexes.
Monodispersed Au nanoparticles were synthesized by the reduction of Au-decyltrimethylammonium bromide (Au-DTAB), which was easily prepared via the reaction of HAuCl4 and DTAB. This Au-DTAB complex is highly stable in air and moisture, and suitable for large-scale synthesis of uniform-sized Au nanoparticles. The nanoparticles were characterized by transmission electron microscopy, optical absorption spectrometry, X-ray diffraction, and Fourier Transform infrared spectroscopy. The size of Au nanoparticles was controlled in the range of 5-10nm by changing the concentrations of reducing agent and Au precursor. The resulting Au nanoparticles were transferred to the aqueous phase after surface engineering using multidentate polymeric ligands with multiple imidazole functional groups. Polymeric imidazole ligands (PILs) demonstrated enhanced binding stability with the Au surface, and overcame the disadvantage of multidentate thiol ligand systems which have oxidative cross-linking and the formation of disulfide bonding. The colloidal stability of surface engineered Au nanoparticles with PILs was investigated by dynamic light scattering (DLS) characterization.


A preliminary report on hepatic pigmentation in Falkland Islands sheep.
Pigmentation of hepatocytes and Kupffer's cells with lipofuscin and melanin-like pigment is described. The occurrence of pigmented reticulo-endothelial cells in the lungs and lymphoid tissue was also noted. No discernible impairment of function accompanied the pigmentation.


Assessment of contractile response to dobutamine stress by means of ECG-gated myocardial SPECT: comparison with myocardial perfusion and fatty acid metabolism.
The present study assessed left ventricular performance during dobutamine stress measured using gated SPECT, and compared the results to myocardial perfusion and fatty acid metabolism. Thirty-six patients with myocardial infarction given (99m)Tc-sestamibi or (99m)Tc-tetrofosmin were examined by gated SPECT at rest and during dobutamine stress (4-20 microg x kg(-1) x min(-1)). After acquiring data at the highest dose, 201TlCl was injected and dual-isotope SPECT was performed to assess myocardial ischemia. Thirty of 36 patients also underwent myocardial SPECT with 123I-BMIPP. Regional wall motion changes during dobutamine infusion were determined from the gated SPECT data and classified as: (1) Improvement, (2) Worsening, (3) No change, and (4) Biphasic response. For myocardial segments of each infarct area, stress 201Tl, rest (99m)Tc and (123)I-BMIPP uptakes were graded on a five-point scoring system of defects from 0 (normal) to 4 (grossly defective). Rest 99mTc defect score index (DSI) in No change area was significantly higher than that in Biphasic area. The ADSI (stress 201Tl - rest (99m)Tc) in Biphasic area was significantly higher than those in Improvement and No change areas. The deltaDSI (BMIPP - (99m)Tc) in Worsening area tended to be higher than that in No Change area. Regional contractile response to dobutamine stress analyzed by gated SPECT showed that the response in-myocardial infarct areas could be classified by rest and stress myocardial perfusion and BMIPP accumulation.


Surgical management of endocervical and decidual polyps during pregnancy: systematic review and meta-analysis.
To evaluate the impact of endocervical and decidual polypectomy on obstetrical outcomes of pregnant women. MEDLINE, Scopus, ClinicalTrials.gov, Scielo, EMBASE, Cochrane Library at the CENTRAL Register of Controlled Trials, and LILACS were searched from inception to April 2021. No language or geographical restrictions were applied. Inclusion criteria regarded observational studies concerning pregnant women with a cervical lesion who underwent cervical polypectomy. Co-primary outcomes were incidence of late pregnancy loss and preterm birth in women with endocervical or decidual polypectomy as well as polypectomy versus expectant management. Random effect meta-analyses to calculate risk ratio (RR) with 95% confidence interval (CI) were performed. Quality assessment of included papers was performed using Newcastle-Ottawa Scale criteria. Three studies, with data provided for 3097 women, were included in quantitative analysis, with comparisons between endocervical and decidual polyps extracted from two studies and 156 patients. After a first trimester endocervical or decidual polypectomy, no significant differences were found for late pregnancy losses (RR 0.29 [95% CI 0.05, 1.80], I2 = 11%). Risk for preterm birth was significantly higher for decidual polyps' removal (RR 6.13 [95% CI 2.57, 14.59], I2 = 0%). One paper compared cervical polypectomy vs expectant management, with increased incidence of late pregnancy loss (4/142 vs 5/2799; p < 0.001) and preterm birth (19/142 vs 115/2799; p < 0.001) in women subjected to polypectomy. Evidence regarding the removal of cervical polyps in pregnancy is extremely limited. However, the removal of either decidual or endocervical polyps seems associated with increased risk of pregnancy loss and preterm birth, with increased preterm birth risk following endocervical rather than decidual polypectomy.


Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer's disease mouse model.
Klotho, an aging-suppressor gene, encodes a protein that potentially acts as a neuroprotective factor by modulating insulin-like growth factor 1 signaling and oxidative stress. In the present study, we investigated the potential role of Klotho in the therapeutic effect of ligustilide against Alzheimer's disease (AD)-like neuropathologies and memory impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. Ligustilide treatment (10 and 40 mg/kg for 8 weeks, intragastrically) in 10-month-old SAMP8 mice reduced memory deficits, amyloid-β(1)-42 accumulation, tau phosphorylation, and neuron loss, increased mitochondrial manganese-superoxide dismutase and catalase expression and activity, and decreased malondialdehyde, protein carbonyl, and 8-hydroxydesoxyguanosine levels in the brain. Ligustilide upregulated Klotho expression in the cerebral choroid plexus and serum, decreased Akt and Forkhead box class O1 phosphorylation. Moreover, ligustilide inhibited the insulin-like growth factor 1 pathway and induced Forkhead box class O1 activation in 293T cells along with Klotho upregulation. An inverse correlation was found between Klotho expression and the AD phenotype, suggesting that Klotho might be a novel therapeutic target for age-related AD, and Klotho upregulation might contribute to the neuroprotective effect of ligustilide against AD.


Comparative Efficacy and Safety of 11 Drugs as Therapies for Adults With Neuropathic Pain After Spinal Cord Injury: A Bayesian Network Analysis Based on 20 Randomized Controlled Trials.
To provide an updated analysis of the efficacy and safety of drugs for the management of neuropathic pain (NP) after spinal cord injury (SCI) based on Bayesian network analysis. A Bayesian network meta-analysis of literature searches within PubMed, Cochrane Library, Embase, and Web of Science databases from their inception to February 21 2021 was conducted without language restrictions. Paired and network meta-analyses of random effects were used to estimate the total standardized mean deviations (SMDs) and odds ratios (ORs). A total of 1,133 citations were identified and 20 RCTs (including 1,198 patients) involving 11 drugs and placebos for post-SCI NP selected. The 5 outcomes from all 11 drugs and placebos had no inconsistencies after Bayesian network analysis. BTX-A gave the most effective pain relief for the 4 weeks, following a primary outcome. No significant differences were found among drugs with regard to adverse events of the primary outcome. Gabapentin, BTX-A, and pregabalin were found to be the most helpful in relieving secondary outcomes of mental or sleep-related symptoms with differences in SMDs, ranging from -0.63 to -0.86. Tramadol triggered more serious adverse events than any of the other drugs with differences in ORs ranging from 0.09 to 0.11. BTX-A, gabapentin, pregabalin, amitriptyline, ketamine, lamotrigine, and duloxetine were all effective for NP management following SCI. Lamotrigine and gabapentin caused fewer side effects and had better efficacy in relieving mental or sleep-related symptoms caused by SCI-related NP. Tramadol, levetiracetam, carbamazepine, and cannabinoids could not be recommended due to inferior safety or efficacy. [https://inplasy.com/inplasy-2020-7-0061/], identifier [INPLASY202070061].


Power dissipated measurement of an ultrasonic generator in a viscous medium by flowmetric method.
A new flowmetric method of the power dissipated by an ultrasound generator in an aqueous medium has been developed in previous works and described in a preceding paper [V. Mancier, D. Leclercq, Ultrasonics Sonochemistry 14 (2007) 99-106]. The works presented here are an enlargement of this method to a high viscosity liquid (glycerol) for which the classical calorimetric measurements are rather difficult. As expected, it is shown that the dissipated power increases with the medium viscosity. It was also found that this flowmetric method gives good results for various quantities of liquid and positioning of the sonotrode in the tank. Moreover, the important variation of viscosity due to the heating of the liquid during experiments does not disturb flow measurements.


Clinical and radiological findings in Schinzel-Giedion syndrome.
The absence of a definitive genetic test for the autosomal recessive condition Schinzel-Giedion syndrome is a significant handicap to the recognition of this disorder. Radiological features have been an important aspect of many of the published cases. In a series of six cases, we now establish a consistency among many of the radiological features in affected cases which will be an important diagnostic aid in identifying future cases. This is confirmed by reference to an extensive review of previously published instances of the syndrome. Moreover, the clinical data, including previously unpublished photographs, which we detail from our patients will assist in enhanced diagnosis in the future.


Lactic acid modified rare earth-based nanomaterials for enhanced radiation therapy by disturbing the glycolysis.
Deficient deposition of X-rays and strong capacity of repairing damage DNA of cancer cells limit the effect of radiation therapy (RT). Herein, we synthesize CsLu2F7 nanoparticles with lactic acid (LA) ligands (CsLu2F7-LA) to overcome these limitations. The high-Z atoms of Lu and Cs can deposit more X-rays for generating enhanced hydroxyl radicals (·OH). Meanwhile, the LA ligand will guide CsLu2F7-LA to target monocarboxylic acid transporter (MCT) and impede the transportation of free LA, leading to decreased glycolysis and DNA damage repair. Consequently, the curative effect of RT will be enhanced and the strategy of LA accumulation induced radiosensitization is proved by in vivo and in vitro experiments, which will bring prospects for enhanced RT with nanomedicine.


Increased levels of c-fos and c-myc mRNA in ATP-stimulated endothelial cells.
In bovine aortic endothelial cells, ATP induced a transient and sequential accumulation of c-fos and c-myc mRNA, which was detected after 1 hour and 3 hours, respectively. The effect of ATP on c-fos mRNA was stronger than that of TNF and bFGF. Both ATP and bFGF increased c-myc mRNA after a 3 hour treatment, whereas TNF did not. If none of the 3 agonists tested induced a selective expression of c-fos or c-myc, each of them was associated with a different quantitative combination of the 2 signals, which might be related to the distinct responses that they trigger in endothelial cells.


[Sleep disorders related to HIV treatment.]
HIV Clinical Guidelines have positioned integrase inhibitors recently as first-line treatment. However, two of these drugs have also been associated with adverse side effects on the central nervous system, especially with sleep disturbances. The objective was to analyse the influence of bictegravir and dolutegravir on the sleep quality in HIV patients. An observational, cross-sectional study was carried out between December 2020 and January 2021 in HIV patients attended in a pharmacy care clinic. Demographic and adherence variables were collected. Sleep quality was measured using the Pittsburgh questionnaire or PSQI. We classified patients into two groups: patients with bictegravir or dolutegravir in their treatment (study group) and the rest (control group). The influence of the variables collected on the PSQI result was analysed using the Chi-Square test for categorical variables and the student t-test or Mann-Whitney U test for continuous variables. One hundred and nineteen patients were included. 64% in the study group and 67% in the control group suffered from sleep disorders according to the PSQI questionnaire (p=0.788). Neither were statistical differences found when the different components of sleep were analysed between the two groups. A high percentage of patients, regardless of whether their treatment includes bictegravir or dolutegravir, have problems with their sleep quality. We didn't find a correlation between sleep quality and treatment with bictegravir or dolutegravir compared to the other treatments.


Serine Protease-Mediated Cutaneous Inflammation: Characterization of an Ex Vivo Skin Model for the Assessment of Dexamethasone-Loaded Core Multishell-Nanocarriers.
Standard experimental set-ups for the assessment of skin penetration are typically performed on skin explants with an intact skin barrier or after a partial mechanical or chemical perturbation of the stratum corneum, but they do not take into account biochemical changes. Among the various pathological alterations in inflamed skin, aberrant serine protease (SP) activity directly affects the biochemical environment in the superficial compartments, which interact with topically applied formulations. It further impacts the skin barrier structure and is a key regulator of inflammatory mediators. Herein, we used short-term cultures of ex vivo human skin treated with trypsin and plasmin as inflammatory stimuli to assess the penetration and biological effects of the anti-inflammatory drug dexamethasone (DXM), encapsulated in core multishell-nanocarriers (CMS-NC), when compared to a standard cream formulation. Despite a high interindividual variability, the combined pretreatment of the skin resulted in an average 2.5-fold increase of the transepidermal water loss and swelling of the epidermis, as assessed by optical coherence tomography, as well as in a moderate increase of a broad spectrum of proinflammatory mediators of clinical relevance. The topical application of DXM-loaded CMS-NC or DXM standard cream revealed an increased penetration into SP-treated skin when compared to untreated control skin with an intact barrier. Both formulations, however, delivered sufficient amounts of DXM to effectively suppress the production of interleukin-6 (IL-6), interleukin-8 (IL-8) and Thymic Stromal Lymphopoietin (TSLP). In conclusion, we suggest that the herein presented ex vivo inflammatory skin model is functional and could improve the selection of promising drug delivery strategies for anti-inflammatory compounds at early stages of development.


Dyslexia.
Developmental dyslexia (DD) is a specific and persistent disability affecting the acquisition of written language. Prevalence is estimated to be between 5% and 17% of school-aged children; it therefore represents a major public health issue. Neurological in origin, its causes are unknown, although there is a clear genetic component. Diagnosis rests upon the use of standardized tests and tools to assess reading and spelling, as well as phonological skills. The importance of early diagnosis cannot be overemphasized and much current research is focusing on screening and prediction, particularly through use of objective imaging techniques (e.g., EEG/MEG), which have implicated cortical abnormalities in central auditory processing (Giraud et al., 2005, 2008). Remediation should be intensive, begin as early as possible, and be tailored to the individual. Phonics based treatments are most effective and several variants, incorporating temporal auditory, articulatory, or multisensory training exercises, have been developed or proposed. Clinical improvements in phonological skills and reading with such treatments have been shown to correlate with changes in the brains of dyslexic children in several functional imaging studies.


The promise and potential challenges of intermittent preventive treatment for malaria in infants (IPTi).
Intermittent preventive treatment (IPT) administers a full therapeutic course of an anti-malarial drug at predetermined intervals, regardless of infection or disease status. It is recommended by the World Health Organization (WHO) for protecting pregnant women from the adverse effects of malaria (IPTp) and shows great potential as a strategy for reducing illness from malaria during infancy (IPTi). Administered concurrently with standard immunizations, IPTi is expected to reduce the frequency of clinical disease, but to allow blood-stage infections to occur between treatments, thus allowing parasite-specific immunity to develop. While wide deployment of IPTi is being considered, it is important to assess other potential effects. Transmission conditions, drug choice and administration schedule will likely affect the possibility of post-treatment rebound in child morbidity and mortality and the increased spread of parasite drug resistance and should be considered when implementing IPTi.


Pearl Index study with levonorgestrel-releasing intravaginal rings: using pharmacokinetic results to investigate treatment compliance as a potential contributor for contraceptive failure.
What is the reason for insufficient contraceptive efficacy of levonorgestrel (LNG) delivered by intravaginal ring (IVR) releasing comparable amounts of LNG as approved progestogen-only pills (POPs)? The pharmacokinetic (PK) evaluation in a subpopulation indicated that the steady-state concentration of plasma LNG was markedly lower in the participants in the USA compared to those in Japan suggesting non-compliance in the US participants which may explain a clearly higher Pearl Index (PI) in USA (8.2, unadjusted PI) compared to Japan (1.4, unadjusted PI). Contraceptive efficacy of LNG in POPs has been demonstrated following different routes of administration (e.g. orally, implants, intrauterine systems), and the PK is well-characterized including a target exposure needed for contraception. Exposure above this target concentration was reached in Phase 1 studies using IVR delivering 40 µg LNG per day. The primary objective of this multicenter, open-label, single-arm study conducted in the USA and in Japan was to assess the contraceptive efficacy of an LNG-containing IVR during a planned treatment period of 1 year in healthy women 18-35 years of age. The study was planned to be conducted in 1600 participants (1300 in the USA, 300 in Japan). The study was prematurely terminated after approximately one-third of the planned exposure was reached due to a high number of pregnancies (28) in the US study population. In total, 1471 participants were treated (1166 participants in the USA and 305 participants in Japan). The PI as a measure of contraceptive efficacy was calculated from the frequency of unintended pregnancies during treatment. LNG exposure in the systemic circulation was assessed during treatment in 136 participants (PK subgroups: 106 in the USA and 30 in Japan). The PK evaluation in the PK subgroups indicated that the steady-state concentration of plasma LNG after 6 months was markedly lower in the participants in the USA (geometric mean 91.2 ng/l) compared to those in Japan (263.8 ng/l). This PK finding cannot be explained by the regional differences in body weight observed between the PK subgroups, thus suggesting non-compliance in the US participants. In 15.7% of the samples collected in the USA and 3.5% samples in Japan, the LNG concentration at steady state was below the lower limit of quantification (10 ng/l), which is not expected with the required continuous use of the IVR documented in most of the eDiaries. The planned duration of treatment was 12 months, but due to the premature termination of the study none of the participants completed the 12-month treatment. All data collected until the study termination were considered, but it is to be noted that the amount of missing data limits the conclusions that can be drawn from the data. The results of this study triggered the termination of the project, because the objective to show sufficient contraceptive efficacy of the LNG IVR was not met. The choice of a user-dependent contraceptive method with an LNG dose that is not inhibiting ovulation is not advisable for women who may have compliance issues. The study was funded by Bayer AG and all authors are employees of Bayer AG. NCT02403401.


Evidence for the presence of a phosphatidylinositol anchor on the lipoarabinomannan and lipomannan of Mycobacterium tuberculosis.
The recent availability (Hunter, S.W., Gaylord, H., and Brennan, P.J. (1986) J. Biol. Chem. 261, 12345-12351) of the well known arabinomannan of Mycobacterium leprae and Mycobacterium tuberculosis as the pure native lipoarabinomannan has resulted in its implication in key aspects of the immunopathogenesis of leprosy and tuberculosis. We had indicated that the lipid moiety of lipoarabinomannan is probably based on a diacylglycerol unit in that glycerol and the two fatty acids, hexadecanoate and 10-methyloctadecanoate, were identified. In addition, lipoarabinomannan was also shown to contain myo-inositol 1-phosphate. Evidence is now presented, based on selective radiolabeling and analysis of various cleavage fragments, that the inositol phosphate exists as both an alkalilable phosphodiester and as part of a phosphatidylinositol "membrane anchor." The mannan of M. tuberculosis was also isolated as the native lipomannan. It also apparently contains a phosphatidylinositol unit but is devoid of the alkali-labile inositol phosphate residues. These lipopolysaccharides are apparently multiglycosylated versions of the well known myocobacterial mannosyl phosphatidylinositols and are prokaryotic versions of the growing list of phosphatidylinositol-anchored macromolecules. Immunogold labeling demonstrates that lipoarabinomannan is a true antigenic capsular or extracellular product of M. tuberculosis. The presence of a phosphatidylinositol residue on lipoarabinomannan may explain its interaction with macrophage membranes and role in mycobacterial pathogenesis.


Insulin effect on serum potassium and auto-inhibition of insulin secretion is intact in a patient with leprechaunism despite severe impairment of substrates metabolism.
The effect of insulin on glucose, protein metabolism, circulating fatty acids (FFA), potassium (K(+)) and C-peptide concentrations were investigated in a 12-year-old girl with leprechaunism. The mutations do not affect the insulin-receptor binding affinity and insulin-stimulated auto-phosphorylation of the receptor. The subject was studied with a primed-continuous infusion of [6,6 - (2)H(2)] glucose and [1-(13)C] leucine during a basal period followed by two steps of insulin infusion (1 and 10 mU/kg/min) of 2 h each, during which plasma glucose level decreased from 131 to 115 and then to 95 mg/dL. Whole body glucose disposal was virtually unaffected by insulin, slightly decreasing from 21 micromol/kg/min in the basal period to 20 and to 19 micromol/kg/min during the two steps of insulin infusion, respectively. The endogenous leucine flux, an index of proteolysis, was completely insensitive to insulin, being 182, 189 and 180 micromol/kg/min, in the three periods, respectively. The FFA concentration (an indirect index of lipolysis) decreased from 1135 to 799 during step 1. During step 2 the FFA concentration rebounded to 917 micromol/L. The concentration of K(+) decreased from 4.2 to 3.2 mmol/L and an infusion of 20 mEq/h of KCl was necessary to prevent further hypokalemia (final value 3.3 mmol/l). The C-peptide concentration declined from 1.85 to 0.97 and then to 0.29 pmol/mL. The dissociation of control exerted by insulin on K+ uptake and on beta-cell secretion may rely on a differential expression and folding of the mutated receptors in the different insulin target tissues.


Structural study of novel vaccinia virus E3L and dsRNA-dependent protein kinase complex.
E3L (RNA-binding protein E3) is one of the key IFN resistance genes encoded by VV and consists of 190 amino acids with a highly conserved carboxy-terminal double-stranded RNA-binding domain (dsRBD). PKR (dsRNA-dependent protein kinase) is an IFN-induced protein involved in anti-cell and antiviral activity. PKR inhibits the initiation of translation through alpha subunit of the initiation factor eIF2 (eIF2α) and mediates several transcription factors such as NF-κB, p53 or STATs. Activated PKR also induces apoptosis in vaccinia virus infection. E3L is required for viral IFN resistance and directly binds to PKR to block activation of PKR. In this work, we determined the three-dimensional complex structure of E3L and PKR using cryo-EM and determined the important residues involved in the interaction. In addition, PKR peptide binds to E3L and can increase protein levels of phosphorus-PKR and phosphorus-eIF2α-induced cell apoptosis through upregulation of phosphorus-PKR in HEK293 cells. Taken together, structural insights into E3L and PKR will provide a new optimization and development of vaccinia virus drugs.


Immunoaffinity purification, partial sequence, and subcellular localization of rat liver phospholipase A2.
Monoclonal antibodies against rat liver mitochondrial phospholipase A2 were used to develop a rapid immunoaffinity chromatography for enzyme purification. The purified enzyme showed a single band upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The sequence of the N-terminal 24 amino acids was determined. This part of the sequence showed only 25% homology with that of rat pancreatic phospholipase A2 but was 96% identical to that of rat platelet and rat spleen membrane-associated phospholipase A2. These enzymes are distinguished from pancreatic phospholipases A2 by the absence of Cys-11. In rat liver phospholipase A2 activity has been reported in various subcellular fractions. All of these require Ca2+ and have a pH optimum in the alkaline region, but little is known about the structural relationship and quantitative distribution of these enzymes. We have investigated these points after solubilization of the phospholipase A2 activity from total homogenates and crude subcellular fractions by extraction with 1 M potassium chloride. Essentially all of the homogenate activity could be solubilized by this procedure indicating that the enzymes occurred in soluble or peripherally membrane-associated form. Gel filtration and immunological cross-reactivity studies indicated that phospholipases A2 solubilized from membrane fractions shared a common epitope with the mitochondrial enzyme. The quantitative distribution of the immunopurified enzyme activity among subcellular fractions followed closely that of the mitochondrial marker cytochrome c oxidase. Rat liver cytosol contained additional Ca2+-dependent and -independent phospholipase activities.


Adenosine A1 receptor-mediated excitation of nociceptive afferents innervating the normal and arthritic rat knee joint.
We tested the hypothesis that adenosine excites nociceptive primary afferents innervating the knee joint. Neuronal recordings were made from fine nerve filaments innervating the knee joint in rats anaesthetized with pentobarbitone. Drugs were injected close-arterially (i.a.) or into the articular space (i.art.). We studied normal and chronically inflamed arthritic joints, the latter 14-21 days after a single intra-articular injection of Freund's Complete Adjuvant, performed under halothane anaesthesia. Adenosine injected i.a. caused delayed (approximately 10 s) excitation of the majority of polymodal C-fibre afferents, and had similar effects when injected directly into the joint. Adenosine triphosphate (ATP) had biphasic effects on discharge, a fast (<1 s) excitation was followed by a delayed increase similar to that seen with adenosine. The adenosine A1 receptor agonists N6-cyclopentyladenosine (CPA) and N-[(1S,trans)-2-hydroxypentyl] adenosine (GR79236) also excited the C-fibre afferents. The A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) antagonized the responses evoked by adenosine, CPA, and the delayed increase seen after ATP, indicating that excitation of the nociceptive afferents was mediated via adenosine A1 receptors. Adenosine and ATP evoked delayed excitatory effects of similar magnitude, regardless of whether or not the knee joint was chronically inflamed. The increased basal discharge observed in arthritic joints was unaffected by DPCPX, which implies that the increase in spontaneous activity associated with arthritis is unlikely to involve tonically released adenosine. The results support the hypothesis that adenosine excites primary afferent nociceptive nerve terminals in the rat knee joint, an effect mediated by adenosine A1 receptors. ATP, adenosine, and A1 receptors may play a role in generating the peripheral nociceptive (pain) signal.


Physical activity and sedentary lifestyle in children as time-limited functions: usefulness of the principal component analysis method.
This study was designed to examine the hourly variation in and the interplay between physical activity and sedentary behavior (SB) in order to highlight key time periods for physical activity interventions for children. Data for physical activity and SB obtained with ActiGraph in 56 boys and 47 girls aged from 8 to 11 years. These data were divided into sixty minute-time samples for moderate-to-vigorous physical activity (MVPA) and SB, and analyzed using a principal component analysis (PCA) and correlation statistics. The PCA provides 10 factors which account for 80.4% of the inertia. Only two of these factors did not display competition between MVPA and SB. Contrary to some reports, a coefficient of correlation of -.68 (p < 10(-4)) was found between daily time spent at MVPA and SB. Some salient traits of children's behaviors were shown through PCA. The results suggested that efficacy of interventions targeting the morning hours (07:00 AM-11:59 AM) and the afternoon period (02:00 PM-05:59 PM) warrants attention.


[Effects of a beta-adrenergic blocking drug, atenolol, on efferent renal nerve activity in rabbits (author's transl)].
Postganglionic sympathetic nerve activity (renal nerve) decreased significantly during i.v. infusion of a beta-adrenergic blocking drug, atenolol, in anesthetized rabbits. This phenomenon, at least in part reflex in nature, may contribute to the hypotensive effect of atenolol.


Deprescription of aspirin for primary prevention is uncommon at discharge in hospitalised patients with gastrointestinal bleeding.
Guidelines recommend against aspirin for primary prevention of cardiovascular events in individuals with a history of gastrointestinal bleeding (GIB). It is unknown how often patients on primary prevention aspirin hospitalised with GIB have aspirin discontinued at discharge. To determine the rate of aspirin deprescription and explore long-term outcomes in patients taking aspirin for primary prevention of cardiovascular events. We evaluated all patients hospitalised at Yale-New Haven Hospital between January 2014 and October 2021 with GIB who were on aspirin for primary prevention. Our primary endpoint was the frequency of aspirin deprescription at discharge. Our secondary endpoints were post-discharge hospitalisations for major adverse cardiovascular events (MACE) or GIB. Time-to-event analysis was performed using Kaplan-Meier curves and the log-rank test. We identified 320 patients with GIB on aspirin for primary prevention: median age was 72 (interquartile range [IQR] 61-81) years and 297 (92.8%) were on aspirin 81 mg daily. Only 25 (9.0%) patients surviving their hospitalisation were deprescribed aspirin at discharge. Among 260 patients with follow-up (median 1103 days; IQR 367-1670), MACE developed post-discharge in 2/25 (8.0%) with aspirin deprescription versus 37/235 (15.7%) with aspirin continuation (log-rank p = 0.28). 0/25 patients with aspirin deprescription had subsequent hospitalisation for GIB versus 17/235 (7.2%) who continued aspirin (log-rank p = 0.13). Aspirin for primary cardiovascular prevention was rarely deprescribed at discharge in patients hospitalised with GIB. Processes designed to ensure appropriate deprescription of aspirin are crucial to improve adherence to guidelines, thereby improving the risk-benefit ratio in patients at high risk of subsequent GIB hospitalisations with minimal increased risk of MACE.


Placental mesenchymal dysplasia with beckwith-wiedemann syndrome fetus in the context of biparental and androgenic cell lines.
Placental mesenchymal dysplasia (PMD) is a distinct placental disorder that may coexist with a normal fetus. In one-third of cases, the fetus exhibits Beckwith-Wiedemann Syndrome (BWS). In the present study, we report a case of PMD changes associated with an unusual genetic constitution. Pathological examination showed an enlarged placenta with a mixture of normal but also numerous clusters of grape-like fluid-filled vesicles confined to the stem villi without trophoblast proliferation. Some stem villi contained many large vessels filled by partially organized thrombi consistent with PMD. The fetus presented an enlarged liver and cytomegaly in the adrenal glands, hyperplastic islets of Langerhans in the pancreas, and some microcysts with cuboidal epithelium in the kidneys. These findings suggest the Beckwith-Wiedemann syndrome phenotype. DNA genetic markers showed three alleles for three independent markers and two alleles for the 12 others. Fluorescent in situ hybridization (FISH) demonstrated that villous trophoblast and fetal tissues are diploid. The haploid paternal complement found in the androgenetic cells was different from that found in biparental cells, suggesting a double fertilization event. Preferential distribution of the androgenetic cells into the placenta explains the predominance of molar villi with an apparently normal fetus. This represents a well-documented case of androgenic and biparental mixture of cell types in both fetal and placental tissues.


DNA sequence profile of TP53 gene mutations in childhood B-cell non-Hodgkin's lymphomas: prognostic implications.
The TP53 gene encodes a nuclear protein implicated in the regulation of the cell cycle, DNA repair, and apoptosis. TP53 mutations and other alterations have been described in numerous types of tumors, and some of these have been associated with poor prognosis. The aim of this study was to characterize TP53 mutations in childhood B non-Hodgkin's lymphoma, their correlation with clinical prognostic factors and response to therapy. Samples from 49 children with B non-Hodgkin's lymphoma were examined for TP53 alterations by single-strand conformation polymorphism analysis (SSCP) of exons 5-9, direct sequencing and by p53 immunohistochemistry. Mutations of TP53 were detected in 11 of 49 (22.5%) patients and more specifically in 20% of Burkitt's lymphoma. The sequence analysis showed missense mutations in 10 cases and an insertion mutation in one case. Mutations of the transition type occurred more frequently than transversions (seven of 11). Analysis of the spectrum of single-nucleotide substitutions showed a 30% frequency of transition mutations in CpG dinucleotide sequences. The overall frequency of p53 immunostaining positivity was 36% (15 of 41). There was a very good agreement between protein expression and the presence of TP53 mutation (P=0.0005). No significant correlation was found regarding age, gender, clinical stage and LDH level and TP53 mutations. Comparison of EFS curves using the log-rank test were also not significant. However, the analysis of the effects of mutations on the core p53 structure identified biological and biochemical mutants with phenotypes probably related to different response to chemotherapy. Our data suggest that some types of mutants can alter the protein distinctly and may be associated with a more aggressive phenotype. In addition, the impact of TP53 mutations on response to therapy may also be influenced by disruption of other genes.


The correlation between osteoarthrosis as seen on radiographs and on arthroscopy.
The correlation between arthroscopic and radiographic osteoarthrosis was studied in 63 patients (51 +/- 12 years) with degenerative changes in the medial compartment of the knee involving the medial meniscus with or without chondral damage. Chondral damage on arthroscopy was classified in grades 1-3 modified after Outerbridge. The radiographic evaluation was done according to Ahlbäck classification. Twenty-eight patients (44%) did not show any significant chondral damage on arthroscopy (grades 0-1). The radiographic findings in this group were usually normal. Three patients, however, showed a slight narrowing of the medial joint space (Ahlbäck I). All three had severely degenerated menisci, and two of them showed superficial fibrillation of both the tibia and the femur. Twenty-four patients (38%) showed a partial thickness chondral damage with fragmentation of the surface (grade 2). Radiographic findings were usually normal; however, patients with involvement of both the tibia and the femur often showed a joint space narrowing on radiographs. Eleven patients (18%) showed destruction of the cartilage down to subchondral bone (grade 3). The typical radiographic finding was a joint space obliteration (Ahlbäck II). Involvement also of the lateral compartment as assessed on arthroscopy was significantly more common in patients with 2nd and 3rd degree chondral disease and Ahlbäck II and III on radiographs than in those with 2nd and 3rd degree chondral damage and normal radiographs. In all but one of the patients with involvement of both compartments, the lateral compartment was considered normal on radiographic examination.


Preliminary studies on apparent mendelian psychotic disorders in consanguineous families.
Psychiatric disorders are characterized by alteration in emotions, mood and behavior. Genetics is known to play a significant role in the development of psychiatric disorders. Genome-wide association studies have identified several loci associated with psychiatric illnesses. We hypothesize the existence of rare variants following Mendelian recessive mode of inheritance. These variants can be identified in families with multiple affected individuals born to unaffected consanguineous parents. We visited psychiatric outpatient departments of multiple hospitals in Lahore, Pakistan. We focused on psychosis, as it can occur in several DSM disorders such as schizophrenia, dementia and bipolar disorder. After clinical diagnosis by an American trained psychiatrist, detailed clinical assessments using Diagnostic Interview for Genetic Studies (DIGS), Diagnostic Interview for Psychosis and Affective Disorders (DI-PAD), Positive and Negative Syndrome Scale (PANSS), Hamilton Depression and Anxiety Rating Scale (HAM-D; HAM-A) were administered to all willing affected and unaffected participants. We identified eight pedigrees with two or more psychotic individuals in each family. Clinical diagnoses determined by their psychiatrists included ten individuals with schizophrenia; four individuals with psychosis and bipolar disorder; and two patients with "unspecified psychosis." The rating instruments rigorously confirmed the diagnosis of psychosis in the affected patients from the six families as well as the absence of psychotic disorders in unaffected individuals from the six families. We obtained DNA samples from willing members of all eight families for future genetic analyses. Our research highlights an alternative approach to discovery of rare recessively inherited genetic variants causing psychiatric disorders that have remained unidentified to date. These findings could illuminate underlying biological mechanisms leading toward development of targeted therapies in future.


Urinary Biomarkers for Screening for Renal Scarring in Children with Febrile Urinary Tract Infection: Pilot Study.
Recurrent febrile urinary tract infections during infancy cause renal scarring, which is characterized by progressive focal interstitial fibrosis and may lead to renal failure. Renal scarring can be diagnosed through scintigraphy, although it seems impractical to perform renal scintigraphy for all infants with febrile urinary tract infections. Therefore, it is important to search for a biomarker to identify the presence of renal scarring. We hypothesized that urinary biomarkers of nephropathy may increase in infants with renal scarring following febrile urinary tract infections. A total of 49 infants who underwent renal scintigraphy for febrile urinary tract infections were enrolled in the study. Several measurements were performed using urine samples, including total proteins, beta2-microglobulins, N-acetyl-β-D-glucosaminidase, neutrophil gelatinase associated lipocalin, liver-type fatty acid binding protein and angiotensinogen. Values were corrected by creatinine and compared between patients with and without renal scarring. Among urinary biomarkers only angiotensinogen in patients with scarring (median 14.6 μg/gm creatinine) demonstrated significantly higher levels than in patients without scarring (3.6 μg/gm creatinine, p <0.001). Urinary angiotensinogen may be useful for diagnosing the presence of renal scarring.


Decarboxylative substitution of β-keto acids to benzylic alcohols catalyzed by molecular iodine.
An efficient method for molecular iodine catalyzed decarboxylative substitution of β-keto acids with benzylic alcohols under mild conditions has been described and valuable α-functionalized ketones were obtained in good to excellent yields.


Investigative diagnostic toxicology and the role of the veterinarian in pet food-related outbreaks.
Due to the potential implications of food-related illnesses in animals, recognition of pet food-related outbreaks is one of the many crucial roles of the veterinarian. This article describes the veterinarian's role in investigating and reporting food-related illnesses in cats and dogs. Recommendations regarding taking thorough case histories, appropriate sample collection, effective use of veterinary diagnostic laboratories, and recommendations for reporting such illnesses are described.


Properties of extruded poly(tetramethylene oxide)-polyurethane block copolymers for blood-contacting applications.
The bulk and surface properties and blood compatibility of a series of polyurethanes based on methylene bis(p-phenyl isocyanate), 1,4-butanediol, and poly(tetramethylene oxide) of molecular weight 1000 were studied. The hard-to-soft segment ratio of these multiphase polymers was varied, and the effect of substituting a poly(dimethylsiloxane)-containing polyol in place of 5% of the polyether soft segment was studied. Bulk properties such as tensile strength and modulus increased with hard segment content, as did surface wettability and ESCA nitrogen content. However, blood compatibility measured by a canine ex vivo blood-contacting experiment was not found to vary with hard/soft segment ratio. The addition of the silicone-containing polyol did not significantly lower the surface wettability, although ESCA-measured silicon content increased and physical properties were unfavourably affected by the incorporation of this co-soft segment. Incorporation of the siloxane-containing component resulted in increased platelet adhesion and fibrinogen deposition at most blood contact times in comparison with the other polyurethanes.


Description of Palleronia rufa sp. nov., a biofilm-forming and AHL-producing Rhodobacteraceae, reclassification of Hwanghaeicola aestuarii as Palleronia aestuarii comb. nov., Maribius pontilimi as Palleronia pontilimi comb. nov., Maribius salinus as Palleronia salina comb. nov., Maribius pelagius as Palleronia pelagia comb. nov. and emended description of the genus Palleronia.
Strain MOLA 401T was isolated from marine waters in the southwest lagoon of New Caledonia and was shown previously to produce an unusual diversity of quorum sensing signaling molecules. This strain was Gram-negative, formed non-motile cocci and colonies were caramel. Optimum growth conditions were 30°C, pH 8 and 3% NaCl (w/v). Based on 16S rRNA gene sequence analysis, this strain was found to be closely related to Pseudomaribius aestuariivivens NBRC 113039T (96.9% of similarity), Maribius pontilimi DSM 104950T (96.4% of similarity) and Palleronia marisminoris LMG 22959T (96.3% of similarity), belonging to the Roseobacter group within the family Rhodobacteraceae. As its closest relatives, strain MOLA 401T is able to form a biofilm on polystyrene, supporting the view of Roseobacter group strains as prolific surface colonizers. An in-depth genomic study allowed us to affiliate strain MOLA 401T as a new species of genus Palleronia and to reaffiliate some of its closest relatives in this genus. Consequently, we describe strain MOLA 401T (DSM 106827T=CIP 111607T=BBCC 401T) for which we propose the name Palleronia rufa sp. nov. We also propose to emend the description of the genus Palleronia and to reclassify Maribius and Hwanghaeicola species as Palleronia species.


Decoding of complex isothermal chromatograms recovered from space missions. Identification of molecular structure.
A chemometric approach, based on the study of the autocovariance function, is described to study isothermal GC chromatograms of multicomponent mixtures: isothermal GC analysis is the method of choice in space missions since it is, to date, the only method compatible with flight constraints. Isothermal GC chromatograms look inhomogeneous and disordered with peak density decreasing at higher retention times: a time axis transformation is proposed to make retention an homogeneous process so that CH2 addition in terms of an homologous series yields a constant retention increment. The time axis is transformed into a new scale based on the retention times of n-alkanes, as they are the basis of the universal Kovats indices procedure. The order introduced into the chromatogram by retention time linearization can be simply singled out by the experimental autocorrelation function (EACF) plot: if constant inter-distances are repeated in different regions of the chromatogram, well-shaped peaks are evident in the EACF plot. By comparison, with a standard mixture it is possible to identify peaks diagnostic of specific molecular structures: study of the EACF plot provides information on sample chemical composition. The procedure was applied to standard mixtures containing compounds representative of the planetary atmospheres that will be investigated in the near future: in particular, those related to Titan's atmosphere (Cassini-Huygens mission) and cometary's nucleus (Rosetta mission). The employed experimental conditions simulated those applied to GC instruments installed on space probes and landers in space missions. The method was applied to two specific investigations related to space research, i.e., a comparison of retention selectivity of different GC columns and identification of the chemical composition of an unknown mixture.


An automated method for generating analogic signals that embody the Markov kinetics of model ionic channels.
In this work we present an automated method for generating electrical signals which reflect the kinetics of ionic channels that have custom-tailored intermediate sub-states and intermediate reaction constants. The concept of our virtual single-channel waveform generator makes use of two software platforms, one for the numerical generation of single channel traces stemming from a pre-defined model and another for the digital-to-analog conversion of such numerical generated single channel traces. This technique of continuous generation and recording of the activity of a model ionic channel provides an efficient protocol to teach neophytes in the field of single-channel electrophysiology about its major phenomenological facets. Random analogic signals generated by using our technique can be successfully employed in a number of applications, such us: assisted learning of the single-molecule kinetic investigation via electrical recordings, impedance spectroscopy, the evaluation of linear frequency response of neurons and the study of stochastic resonance of ion channels.


Association between Smokeless Tobacco Use and Risk of Periodontitis in Asian Countries: A Systematic Review and Meta-Analysis.
Individual studies conducted in Asian countries have reported higher risk of periodontitis among smokeless tobacco (SLT) users in comparison to non-users. Therefore, a systematic review was conducted to summarize the available evidence on this topic. Prominent electronic databases were searched using pre-decided MeSH terms and keywords. Screening of titles and abstracts, full text reading, quality assessment and data extraction was done by two investigators independently. The Newcastle-Ottawa scale was used for risk of bias assessment of eligible studies. Meta-analysis was performed for four periodontal outcomes (periodontal pocket depth, loss of attachment, clinical attachment level and gingival recession). A sensitivity analysis was also performed. Of the 546 citations, 367 were screened for eligibility. Finally, 89 studies were shortlisted for full text reading, of which, 36 were found eligible for qualitative analysis. Most of the studies were conducted in India (n=22), were of cross-sectional design (n=33), utilized purposive sampling and 24 studies were included for meta-analysis (n=28) and done on hospital-based population (n=26). Only 13 (37.1%) studies achieved a score of more than 50% (5/10 stars) on quality assessment scale. SLT users had higher odds of greater periodontal pocket depth greater than 4 mm (OR=3.64), gingival recession (OR=1.71) and loss of attachment 4-5 mm (OR=2.83) and mean difference of 1.7 mm for Clinical Attachment Level compared to non-users. The studies included in this review suggests that SLT users have poorer periodontal health in comparison to non-users. But most of this evidence comes from cross-sectional studies. Longitudinal studies with rigorous methodology are required to support this elucidation. Registration: This systematic review protocol has been registered in PROSPERO (CRD42019122964).


Assignment of the human parathyroid hormone gene to chromosome 11.
A panel of human-mouse and human-Chinese hamster cell hybrid DNA's was screened for hybridisation with a fragment of the human parathyroid hormone chromosomal gene. A 7-kilobasepair Msp I restriction fragment homologous to this probe was found to segregate with the human chromosome 11.


Long-term effects of transcranial direct current stimulation in the treatment of autism spectrum disorder: A randomized controlled trial.
To compare the efficacy of 0, 5, and 20 sessions of transcranial direct current stimulation (tDCS) for reducing symptoms of autism spectrum disorder (ASD). Thirty-six male children with ASD (mean age 2 years 3 months, SD 4 months, age range 1 years 6 months-2 years 11 months) were balanced and stratified by age, sex, and baseline severity of ASD, to: (1) a control group that received 20 sessions of sham tDCS; (2) a 5-session tDCS group (5-tDCS) that received 5 sessions of active tDCS followed by 15 sessions of sham tDCS; and (3) a 20-session tDCS group (20-tDCS) that received 20 sessions of active tDCS. All groups participated in the special school activity of Khon Kaen Special Education Center, Thailand. The primary outcome was autism severity as measured by the Childhood Autism Severity Scale. The 5-tDCS and 20-tDCS groups evidenced greater reductions in autism severity than the control group at days 5 and 14, and months 6 and 12. There were no significant differences in the outcome between the 5- and 20-tDCS groups at any time point. Within-group analysis showed clinically meaningful improvements starting at month 6 for the participants in the control group, and clinically meaningful improvements starting on day 5 in both active tDCS groups, all of which were maintained to month 12. The 5- and 20-session tDCS seems to reduce autism severity faster than sham tDCS. These effects maintained at least for 1 year. Twenty sessions of transcranial direct current stimulation (tDCS) were not superior to five sessions. Sham tDCS with a special school activity can reduce autism severity starting at 6 months after treatment. The benefits observed for 5 and 20 sessions of tDCS last for at least 12 months.


Elevation and blood traits in the mesquite lizard: Are patterns repeatable between mountains?
Ecogeographical patterns describe predictable variation in phenotypic traits between ecological communities. For example, high-altitude animals are expected to show elevated hematological values as an adaptation to the lower oxygen pressure. Mountains act like ecological islands and therefore are considered natural laboratories. However, the majority of ecophysiological studies on blood traits lack replication that would allow us to infer if the pattern reported is a local event or whether it is a widespread pattern resulting from larger-scale ecological processes. In lizards, in fact, the increase of hematological values at high altitudes has received mixed support. Here, for the first time, we compare blood traits in lizards along elevational gradients with replication. We tested the repeatability of blood traits in mesquite lizards between different elevations in three different mountains from the Trans-Mexican Volcanic Belt. We measured hematocrit, hemoglobin concentration, mean corpuscular hemoglobin concentration, and erythrocyte size in blood samples of low, medium, and high-elevation lizards. We obtained similar elevational patterns between mountains, but the blood traits differed among mountains. Middle-altitude populations had greater oxygen-carrying capacity than lizards from low and high altitudes. The differences found between mountain systems could be the result of phenotypic plasticity or genetic differentiation as a consequence of abiotic factors not considered.


Breast cancer cells secreted platelet-derived growth factor-induced motility of vascular smooth muscle cells is mediated through neuropilin-1.
Motility of vascular smooth muscle cells (SMCs) is an essential step for both normal and pathologic angiogenesis. We report here that breast tumor cells, such as MCF-7 and MDA-MB-231, can modulate this SMC migration. We present evidence that the tumor cell-derived platelet-derived growth factor (PDGF) is the key regulator of vascular SMCs motility induced by breast cancer cells. PDGF significantly upregulates neuropilin-1 (NRP-1) mRNA expression and protein production in aortic smooth muscle cells (AOSMCs) and depletion of NRP-1 production by AOSMCs with specific short hairpin RNA (shRNA) prevents the PDGF-dependent migration of vascular SMCs. Moreover, we demonstrate that PDGF physically interacts with NRP-1. We propose that tumor-derived PDGF and NRP-1 of AOSMCs function as a relay system that promotes motility of vascular SMCs.


Comparative study of the mucin-type sugar chains of human chorionic gonadotropin present in the urine of patients with trophoblastic diseases and healthy pregnant women.
Human chorionic gonadotropins (hCGs) highly purified from the urine of patients with trophoblastic diseases and of healthy pregnant women contain approximately four mucin-type sugar chains in one molecule. The structures of these sugar chains were studied comparatively by using a new sensitive method to obtain mucin-type sugar chains quantitatively as radioactive oligosaccharides from a small amount of glycoproteins. The mucin-type sugar chains of all hCGs include sialylated and nonsialylated Gal beta 1----3GalNAc and Gal beta 1----4GlcNAc beta 1----6(Gal beta 1----3)GalNAc. In the case of normal hCG and hydatidiform mole hCG, oligosaccharides containing the tetrasaccharide core occupy approximately 10% of the total mucin-type sugar chains. The ratio of the tetrasaccharide containing oligosaccharides is increased prominently to approximately 60% in choriocarcinoma hCG. The proportion in invasive mole hCG was also increased, but less than the proportion of choriocarcinoma hCG.


Dependence of emotional burnout on personality typology in the COVID-19 pandemic.
Under the conditions of the COVID-19 pandemic, the problem of emotional burnout syndrome among nurses working under extremely stressful conditions has become particularly acute. It is therefore necessary to examine the characteristics of emotional burnout syndrome in nurses during the COVID-19 pandemic to develop effective measures to prevent and enhance their mental health. The study aimed to establish the features of emotional burnout syndrome and its connection with typological characteristics of the personality in nurses working with COVID-19 patients. A total of 120 female nurses who worked with COVID-19 patients were surveyed, of whom 60 (50.0%) worked in outpatient settings along with general practitioners and 60 (50.0%) worked in the intensive care unit. The average age of the participants was 40.86±3.20 years, and the average length of medical service was 13.64±1.73 years. A burnout syndrome of varying severity was present in 50.0%of outpatient nurses and 73.3%of intensive care nurses (OR = 2.44, 95%CI [1.16-5.16]; p < 0.05). The tension phase predominated in outpatient nurses (53.3%), and the resistance phase was more typical for intensive care nurses (63.3%). The practice of nurses under COVID-19 pandemic conditions is characterized by the high prevalence of emotional burnout syndrome.


An antigenic map of the haemagglutinin of the influenza Hong Kong subtype (H3N2), constructed using mouse monoclonal antibodies.
Panels of monoclonal antibodies were raised to the haemagglutinin of strains of the Hong Kong subtype of influenza (H3N2), namely Hong Kong 1968, England 1972, Port Chalmers 1973, Victoria 1975 and Texas 1977. The probable binding sites of individual antibodies in each panel were determined by correlation of cross-reactivity with 16 heterologous strains from the same subtype, and amino acid differences between their haemagglutinin molecules. This led to an approximation of the "average repertoire" of the BALB/c mouse to influenza type A haemagglutinin. Comparative data of the cross-reactivity of whole mouse sera suggested that the monoclonal panels derived from spleen cells were a fair representation of circulating antibody. Variation in the cross-reactivities of individual sera approached that of individual monoclonal antibodies. The relevance of this finding to selection of new virus variants in the human population was discussed. Heterospecific antibodies were detected in some monoclonal panels. Specific amino acid changes which could be responsible for such activity were identified.


ATP-liganded form of aspartate transcarbamoylase, the logical regulatory target for allosteric control in divergent bacterial systems.
In Escherichia coli, the mechanism for regulatory control of aspartate transcarbamoylase is clear; CTP allosterically inhibits catalysis in direct competition with ATP. However, both CTP and ATP may be activators or may have no effect on aspartate transcarbamoylases from other enteric bacteria. A common regulatory logic observed was that the ATP-activated enzymes were rendered less active as the result of competition with CTP, regardless of the independent effects.


Sulfonimidamides by Sequential Mechanochemical Chlorinations and Aminations of Sulfinamides.
Here, we report the first mechanochemical synthesis of sulfonimidamides. The one-pot, two-step method requires neither a solvent nor inert conditions. In a mixer mill, sulfinamides are rapidly converted to sulfonimidoyl chlorides by oxidative chlorination with N-chlorosuccinimide (NCS). Subsequent substitutions with amines provides a wide range of diversely substituted sulfonimidamides.


Effect of water on the molecular structure of a phosphatidylcholine hydrate. Raman spectroscopic analysis of the phosphate, carbonyl and carbon-hydrogen stretching mode regions of 1,2-dipalmitoylphosphatidylcholine dihydrate.
The Raman spectra of 1,2-dipalmitoylphosphatidylcholine (DPPC) dihydrate crystals were examined in (a) the 1250 and 1080 cm-1 PO-2 antisymmetric and symmetric stretching mode regions, (b) the 1730 cm-1 carbonyl stretching mode region and (c) the 2800-3100 cm-1 C-H stretching mode interval. No evidence was observed for hydrogen bonding effects involving the nonester phosphate oxygen atoms. Spectra of the DPPC dihydrate crystal in the 1250 cm-1 region are compared to spectra of both anhydrous and successively hydrated systems and to spectra of crystalline glycerylphosphorylcholine. The splitting pattern in the 1240 to 1280 cm-1 interval for the DPPC dihydrate was interpreted in terms of the different bonding arrangements assumed by the PO-2 groups in the two molecule asymmetric unit of the eight molecule unit cell. An unusual triplet is observed in the carbonyl stretching mode region around 1730 cm-1. These features reflect differing bond environments, relative to the polar and hydrophobic regions of the bilayer, of the 1- and 2-chain carbonyl groups. Spectra for crystalline DPPC dihydrate in the 3000 cm-1 C-H stretching mode region suggest a hybrid chain packing lattice which is analogous to the packing arrangement determined for the isostructurally similar DMPC dihydrate species.


Lack of dilator effect of leptin in the hindlimb vascular bed of conscious rats.
Leptin acts in the hypothalamus to decrease appetite and increase sympathetic nerve activity. Some in vitro studies have suggested that leptin may possess vasodilator actions that oppose sympathetically mediated vasoconstriction. We tested whether leptin is a vasodilator of the hindlimb vascular bed in vivo, and also whether it alters vasodilation to acetylcholine or sodium nitroprusside. In conscious instrumented Sprague-Dawley rats we measured iliac blood flow responses to local arterial infusion of acetylcholine (0.1 and 1 microg/min) and sodium nitroprusside (1 and 10 microg/min) before and after 2 h of intra-arterial leptin (at doses of 0.1 or 1 mg/kg, n=10 each) or vehicle (n=10). Leptin infusion over 2 h did not change mean arterial pressure, heart rate or iliac flow and conductance. In addition, leptin did not significantly alter the vasodilation (increase in the conductance ratio between infused and non-infused arteries) induced by acetylcholine, whereas pre-treatment with a nitric oxide synthesis inhibitor, N(G)-nitro-L-arginine methyl ester, significantly attenuated the vasodilation to acetylcholine. Leptin also did not affect the vasodilation to sodium nitroprusside. Lack of effect of leptin on vasodilator function could not be due to the activation of the sympathetic nervous system because lumbar sympathoactivation was obtained only 4 h after the iliac infusion of 1 mg/kg/h of leptin. These findings are in accordance with our previous results and argue against a meaningful direct dilator action of leptin on resistance vessels in vivo.


The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism.
Mice deficient in the plasminogen activator inhibitor-1 gene (PAI-1-/- mice) are relatively protected from developing pulmonary fibrosis from bleomycin administration. We hypothesized that one of the protective mechanisms may be the ability of the plasminogen system to enhance hepatocyte growth factor (HGF) effects, which have been reported to be anti-fibrotic in the lung. HGF is known to be sequestered in tissues by binding to extracellular matrix components. Following bleomycin administration, we found that HGF protein levels were higher in bronchoalveolar lavage fluid from PAI-1-/- mice compared to wild-type (PAI-1+/+) mice. This increase could be suppressed by administering tranexamic acid, which inhibits plasmin activity. Conversely, intratracheal instillation of urokinase into bleomycin-injured PAI-1+/+ mice to activate plasminogen caused a significant increase in HGF within bronchoalveolar lavage and caused less collagen accumulation in the lungs. Administration of an anti-HGF neutralizing antibody markedly increased collagen accumulation in the lungs of bleomycin-injured PAI-1-/- mice. These results support the hypothesis that increasing the availability of HGF, possibly by enhancing its release from extracellular matrix by a plasmin-dependent mechanism, is an important means by which activation of the plasminogen system can limit pulmonary fibrosis.


Multitasking of interferon regulatory factor-4 in early B cells.
Immunoglobulin heavy- and light-chain genes are rearranged in a temporally ordered manner. In this issue, Johnson et al. (2008) show that interferon regulatory factor-4 regulates light-chain gene rearrangement by activating enhancers and attenuating interleukin-7 signaling.


Tapering conventional synthetic DMARDs in patients with early arthritis in sustained remission: 2-year follow-up of the tREACH trial.
With early and intensive treatment many patients with early RA attain remission. Aims were to investigate (1) the frequency and time to sustained remission and subsequent tapering in patients initially treated with conventional synthetic disease modifying anti-rheumatic drug ((cs)DMARD) strategies and (2) the frequency and time to flare and regained remission in patients tapering csDMARDs and biological (b)DMARDs during 2 years of follow-up. Two-year follow-up data from the treatment in the Rotterdam Early Arthritis Cohort (tREACH) cohort were used. Patients were randomised to initial treatment with triple DMARD therapy (iTDT) with glucocorticoid (GC) bridging or methotrexate monotherapy (iMM) with GC bridging. Patients were evaluated every 3 months. In case Disease Activity Score (DAS) was >2.4 treatment was switched to a TNF-blocker. In case DAS<1.6 at 2 consecutive time points, tapering was initiated according to protocol. Outcomes were rates of sustained remission (DAS<1.6 at 2 consecutive time points), flare (medication increase after tapering) and remission after flare (DAS<1.6). Data were analysed using Kaplan-Meier analyses. During 2 years of follow-up, sustained remission was achieved at least once by 159 (57%) of patients, of whom 118 and 23 patients initiated tapering of csDMARDs and bDMARDs, respectively. Thirty-four patients achieved drug-free remission. Flare rates were 41% and 37% and within 1 year, respectively. After flare, 65% of patients tapering csDMARDs re-achieved remission within 6 months after treatment intensification. Regardless of initial treatment strategy, 57% of patients achieved sustained remission during 2 years of follow-up. Flare rates were 41% and 37% within 12 months in patients tapering csDMARDs and bDMARDs, respectively. ISRCTN26791028; Post-results.


Neuronal firing rate, inter-neuron correlation and synchrony in area MT are correlated with directional choices during stimulus and reward expectation.
Sensation, memories, and predictions contribute to choices in everyday life, and their relative impact should change with task constraints. To investigate how the impact from sensory cortex on decision making varies with task constraints we trained macaque monkeys in a direction discrimination task where they could maximize reward by waiting for sensory visual information early in a trial, while focusing on memory and reward prediction as a trial progressed. The task constraints caused animals to indicate decisions in complete absence of visual motion stimuli (stimulus independent decisions), as 25% of the trials were 'no stimulus' trials. On 'no stimulus' trials reward delivery depended on the current decision in relation to the decision history. Stimulus independent decisions occurred during an epoch when a stimulus could in principle have been presented, or afterwards when stimuli could not occur anymore. Stimulus independent decisions were significantly different during these two periods. Reward exploitation was more efficient late in the trial, but it was not associated with systematic activity changes in directionally selective neurons in area MT. Conversely, systematic changes of neuronal activity and firing rate correlation in directionally selective middle temporal area (MT) neurons were restricted to a short time period before early decisions. Changing task constraints in the course of a single trial thus determines how neurons in sensory areas contribute to decision making.


Toxicity domain in presynaptically toxic phospholipase A2 of snake venom.
About 42 complete amino-acid sequences of phospholipases A2 (phosphatidylcholine 2-acylhydrolase, EC 188.8.131.52) are known, including those of 13 presynaptically toxic enzymes, but the structural features responsible for the neurotoxicity and distinguishing the toxins from the non-neurotoxic enzymes are far from being clear. In this study, we examined the charged-residue distributions and hydrophobic characteristics based on the sequence data and the predicted tertiary structure and proposed a possible toxicity domain. We found that the presynaptically toxic enzymes have three or four more basic amino-acid residues than the non-neurotoxic enzymes at positions 59, 60, 65, 70-73 and 97 or 98. These residues appear to cluster near the surface region at the N-terminal side. The cationic nature of this basic cluster in the toxin is enhanced by the alpha-amino group of the N-terminus and the dipole moment of helices 96-110 and 1-10. Moreover, these toxic-site residues are usually associated with hydrophobic regions at 1-7, 64-81 and 97-109.


A randomized, controlled study evaluating effects of amlodipine addition to chelators to reduce iron loading in patients with thalassemia major.
Cardiomyopathy due to iron overload can be fatal in patients with thalassemia major. Calcium channel blockers seem to be effective to reduce iron loading. Our goal was to study effects of amlodipine addition to chelators on iron loading in patients with thalassemia major. This randomized, controlled, and single-center trial was performed on 56 patients with thalassemia major. Patients were randomized 1:1 to combined group (iron chelator plus amlodipine) or control group (iron chelator) for 1 year. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. Serum ferritin was also measured. After 12 months of treatment, myocardial T2* values had significant improvement in combined group (21.9 ± 8.0 ms to 24.5 ± 7.6 ms; P < .05); Difference between two groups was significant (P = .02). Combined treatment had no effect on hepatic T2* value (9.6 ± 2.8 ms to 9.5 ± 3.6 ms); difference between two groups was not significant (P = .2). In addition, a significant reduction was seen in serum ferritin levels in two groups. Mild gastrointestinal upset was the most common untoward effect. Addition of amlodipine to iron chelators has beneficial effects for reduction of iron loading in patients with thalassemia major. This combination therapy seems safe.


Responsiveness of sensorimotor cortex during pharmacological intervention with bromazepam.
The aim of this study was to investigate the influence of bromazepam on EEG and the motor learning process when healthy subjects were submitted to a typewriting task. We investigated bromazepam due to its abuse by various populations and its prevalent clinical use among older individuals which are more sensitive to the negative effects of long half-life benzodiazepines. A randomized double-blind design was used with subjects divided into three groups: placebo (n=13), bromazepam 3mg (n=13) and bromazepam 6 mg (n=13). EEG data comprising theta, alpha and beta bands was recorded before, during and after the motor task. Our results showed a lower relative power value in the theta band in the Br 6 mg group when compared with PL. We also observed a reduction in relative power in the beta band in the Br 3mg and Br 6 mg when compared with PL group. These findings suggest that Br can contribute to a reduced working memory load in areas related to attention processes. On the other hand, it produces a higher cortical activation in areas associated with sensory integration. Such areas are responsible for accomplishing the motor learning task. The results are an example of the usefulness of integrating electrophysiological data, sensorimotor activity and a pharmacological approach to aid in our understanding of cerebral changes produced by external agents.


Evaluating the use of zein in structuring plant-based products.
The recent interest in plant-based foods has brought upon the need to develop novel structures using plant-based proteins. However, there is still room for improvement in the development of plant-based meat and cheese alternatives. The rheological properties of self-assembled zein networks were examined to evaluate potential in animal protein replacement. These plant-based protein networks were compared to gluten networks (a common ingredient in current plant-based products), chicken muscle tissue, and cheddar cheese. All samples were analyzed using temperature, amplitude, and frequency sweeps at different time points. Zein networks exhibited unique viscous behaviour (in line with that of an entangled polymer solution), in each amplitude, frequency and temperature sweeps, however only when freshly formed. The results suggest that the bonds and interactions responsible for strengthening zein networks need at least 24 h to fully form. Analysis of the secondary structure by FTIR revealed that zein undergoes a structural reorganization from intermolecular to intramolecular β-sheets during this time, but the substantial content of α-helix structures remains unchanged. Overall, different aspects of zein network rheological behaviour can be compared to either chicken breast, or cheddar cheese, presenting opportunities for zein in plant-based food structuring.


Amino-functionalized cellulose nanoparticles: preparation, characterization, and interactions with living cells.
Spherical nanoparticles with sizes from 80 to 200 nm are obtained by self-assembly of highly functionalized 6-deoxy-6-(ω-aminoalkyl)aminocellulosecarbamates. The particles are very stable, nontoxic, and possess primary amino groups that are accessible to further modifications in aqueous suspension. The particles can be labeled with rhodamine B isothiocyanate without changing their size, stability, and shape. The nanoparticles obtained are investigated by means of photo correlation spectroscopy, zeta potential measurements, SEM and fluorescence spectroscopy. Incorporation of the nanoparticles in human foreskin fibroblasts BJ-1-htert and breast carcinoma MCF-7 cells without any transfection reagent is proved by means of confocal laser scanning microscopy.


Symmetry Detection in Autistic Adults Benefits from Local Processing in a Contour Integration Task.
Symmetry studies in autism are inconclusive possibly due to different types of stimuli used which depend on either local or global cues. Therefore, this study compared symmetry detection between 20 autistic and 18 non-autistic adults matched on age, IQ, gender and handedness, using contour integration tasks containing open and closed contours that rely more on local or global processing respectively. Results showed that the autistic group performed equally well with both stimuli and outperformed the non-autistic group only for the open contours, possibly due to a different strategy used in detecting symmetry. However, there were no group differences for the closed contour. Results explain discrepant findings in previous symmetry studies suggesting that symmetry tasks that favour a local strategy may be advantageous for autistic individuals. Implications of the findings towards understanding visual sensory issues in this group are discussed.


Transmetalation of a nucleophilic carbene fragment: from early to late transition metals.
Early transition metal nucleophilic carbene complexes have been used as stoichiometric carbene transfer agents in a transmetalation process.


Transformation and growth related changes in levels of nuclear and cytoplasmic proteins antigenically related to mammalian beta-galactoside-binding lectin.
Immunofluorescence and immunoblotting experiments, using a monoclonal antibody to the 13 kDa mammalian beta-galactoside-binding lectin have shown that human lymphocytes contain nuclear and cytoplasmic proteins of apparent molecular masses of 130, 80, 65 and 13 kDa that are antigenically related to the lectin and whose levels and patterns of expression change in association with transformation, or after stimulation with mitogens. These observations, together with the finding that the myeloid cell line K562 is also rich in the 130 kDa component, whereas the mature granulocytes of normal donors and of patients with chronic myeloid leukaemia are lacking in all of the immunoreactive forms, raise the possibility that this family of lectin-related proteins may be components of growth regulatory systems that are variously elicited in the transformed and stimulated cells.


Recreational drugs. Current trends in the 90s.
Recreational drug use continues to be prevalent in many social settings. These drugs are alleged to enhance sociability and liberate inhibitions, allowing the user to experience feelings of euphoria. This article reviews recreational drugs that have gained notoriety in the 1990s including gamma-hydroxybutyrate (GHB), flunitrazepam, and amphetamine analogues such as 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA). Topics discussed include history, drug use and misuse, clinical presentation and treatment, and laboratory analysis.


[Oropharyngeal candidiasis and radiotherapy].
The oropharyngeal candidiasis is a common condition in cancer patients treated by irradiation, during and after their treatment. For example, almost 70% of patients treated with chemoradiation for head and neck cancer are colonized, and 40% of symptomatic patients have an oropharyngeal candidiasis. Furthermore, we noticed an increase in non-albicans Candida strains, which are present in almost 50% of samples. Cancer treatments, especially radiation therapy, and comorbidities are risk factors of oropharyngeal candidiasis. Oropharyngeal candidiasis has substantial effects on quality of life, and may limit treatment. Epidemiologic data, physiopathology, clinical diagnosis criteria, consequences and treatment of oropharyngeal candidiasis will be discussed in this article.


Spark Plasma Sintering of Aluminum Nanocomposite Powders: Recent Strategy to Translate from Lab-Scale to Mass Production.
The aim of this paper focuses on presenting a recent study that describes the fundamental steps needed to effectively scale-up from lab to mass production parts produced from Al powders reinforced with 0.5 wt% of industrial multiwalled carbon nanotubes (MWCNTs), with mechanical and electrical conductivity properties higher that those measured at the lab scale. The produced material samples were produced via a Spark Plasma Sintering (SPS) process using nanocomposite aluminum powders elaborated with a planetary ball-mill at the lab scale, and high-volume attrition milling equipment in combination with controlled atmosphere sinter hardening furnace equipment, which were used to consolidate the material at the industrial level. Surprisingly, the electrical conductivity and mechanical properties of the samples produced with the reinforced nanocomposite Al powders were made with mass production equipment and were similar or higher than those samples fabricated using metallic powders prepared with ball-mill lab equipment. Experimental measurements show that the hardness and the electrical conductivity properties of the samples fabricated with the mass production Al powders are 48% and 7.5% higher than those of the produced lab samples. This paper elucidates the steps that one needs to follow during the mass production process of reinforced aluminum powders to improve the physical properties of metallic samples consolidated via the SPS process.


Nonglycemic effects of insulin.
Insulin affects multiple metabolic pathways in many tissues. Nonglycemic effects include inhibiting production of triglyceride-rich particles and platelet aggregation and increasing vasodilatation. In persons with normal insulin sensitivity, these actions are considered antiatherogenic. However, insulin's normal antiatherogenic actions are defective in persons who are insulin resistant, which results in hypertriglyceridemia, increased platelet aggregation, and endothelial dysfunction. Insulin therapy in patients with type 2 diabetes can lead to improved glycemic control, insulin sensitivity, lipid profile, and endothelial function and may impact the incidence and severity of cardiovascular disease.


Inadequate screening in patients evaluated by nongynecologists for cervical cancer: a case control analysis.
The purpose of this study was to determine the rate of unsatisfactory Papanicolaou tests between gynecology and nongynecology providers at a single institution. Vanderbilt University Medical Center data were used to obtain a list of all liquid-based cervical Papanicolaou smears that were collected between September 2002 and October 2006. Unsatisfactory samples were identified as 2 groups (gynecology vs nongynecology) for statistical comparison. There were 69,129 Papanicolaou smears that had been collected between September 2002 and October 2006; 47,165 smears were in the gynecology group, and 21,964 smears were in the nongynecology group. Of these, 1206 smears were designated to be "unsatisfactory." A nongynecology provider was more likely to have an unsatisfactory Papanicolaou test result, compared with a gynecology physician (3% [602/21,964] vs 1% [604/47,165]; P < .001). The odds of having an unsatisfactory Papanicolaou test result was 2 times higher with nongynecology, compared with gynecology, physicians (odds ratio, 2.17; 95% CI, 1.94-2.43). Rates of liquid-based smears reported as unsatisfactory are higher among nongynecology providers. Competency-based learning programs might help to address this discrepancy.


Reaching the Texas dental goals of healthy people 2010.
The U.S. Department of Health and Human Services has promoted Healthy People 2010, which is a set of national health objectives for the nation to achieve over the first decade of the new century (1). Texas has not yet met its target of 50 percent of 8-year-old children with dental sealants having been placed on their 6-year molars, which is one of the Healthy People 2010 goals. An assessment of the dental needs of children in Tarrant County, Texas, was initiated by the JPS Health Network (named after John Peter Smith). The JPS Health Network established the Healthy Smiles program to address the dental needs of the students in this county because a school based dental sealant program would be effective in reducing dental decay. Approved Title One elementary schools in Tarrant County were scheduled for dental screenings, education, and fluoride and dental sealant applications. Students were given visual dental screenings and classified as to future dental needs. First grade students received fluoride varnish and second and third grade students received fluoride and dental sealants. For the 2010-2011 school year: A total of 28,322 students were seen by dental professionals from the JPS Health Network; 8,348 dental sealants were placed; and 11,825 fluoride applications were given by dental staff. The JPS Health Network Healthy Smiles Program proved to be an effective way to deliver oral preventive care and dental education to a large number of low-income students. Dental caries prevention programs such as Healthy Smiles could help Texas reach its goals for improved oral health for the children of Texas.


Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity.
Cancers often relapse after adoptive therapy, even though specific T cells kill cells from the same cancer efficiently in vitro. We found that tumor eradication by T cells required high affinities of the targeted peptides for major histocompatibility complex (MHC) class I. Affinities of at least 10 nM were required for relapse-free regression. Only high-affinity peptide-MHC interactions led to efficient cross-presentation of antigen, thereby stimulating cognate T cells to secrete cytokines. These findings highlight the importance of targeting peptides with high affinity for MHC class I when designing T cell-based immunotherapy.


Adolescents and young adults engaged with pro-eating disorder social media: eating disorder and comorbid psychopathology, health care utilization, treatment barriers, and opinions on harnessing technology for treatment.
The purpose of this study was to examine exposure (i.e., seeing, following, posting) to body image content emphasizing a thin ideal on various social media platforms and probable eating disorder (ED) diagnoses, ED-related quality of life, and psychiatric comorbidities (i.e., depression, anxiety) among adolescents and young adult females recruited via social media who endorsed viewing and/or posting pro-ED online content. We also investigated health care utilization, treatment barriers, and opinions on harnessing technology for treatment. Participants were 405 adolescent and young adult females engaged with pro-ED social media. We reported on study constructs for the sample as a whole, as well as on differences between age groups. Eighty-four percent of participants' self-reported symptoms were consistent with a clinical/subclinical ED, and this was slightly more common among young adults. Participants endorsed reduced ED-related quality of life, as well as comorbid depression and anxiety. Among those with clinical/subclinical EDs, only 14% had received treatment. The most common treatment barriers were believing the problem was not serious enough and believing one should help themselves. The majority of participants approved of harnessing technology for treatment. Results provide support for engagement with pro-ED online content serving as a potential indicator of ED symptoms and suggest promise for facilitating linkage from social media to technology-enhanced interventions. V, cross-sectional descriptive study.


Cancerostatica. I. synthesis of some pyrazolo[1,5-a]pyrimidine and pyrazolo [3,4-b] pyridine derivatives.
In basic medium 2-phenyl-and 2-(pyridyl-4')-derivatives of 3-dimethylaminoacrlein yields with 5-aminopyrazol-3-one the corresponding pyrazolo [1,5-a] pyrimidines. However, in acid medium, 2-phenyl-3-dimethylaminoacrolein cyclised to derivatives of pyrazolo[3,4-b] pyridine. A reaction mechanism is proposed. Some of these compounds showed significant cytostatic activity against transplanted Ehrlich asc. carcinoma and Nemeth-Kellner lymphoma.


Combination of Anti-Angiogenics and Checkpoint Inhibitors for Renal Cell Carcinoma: Is the Whole Greater Than the Sum of Its Parts?
Anti-angiogenic agents, such as vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and anti-VEGF antibodies, and immune checkpoint inhibitors (CPIs) are standard treatments for advanced renal cell carcinoma (aRCC). In the past, these agents were administered as sequential monotherapies. Recently, combinations of anti-angiogenic agents and CPIs have been approved for the treatment of aRCC, based on evidence that they provide superior efficacy when compared with sunitinib monotherapy. Here we explore the possible mechanisms of action of these combinations, including a review of relevant preclinical data and clinical evidence in patients with aRCC. We also ask whether the benefit is additive or synergistic, and, thus, whether concomitant administration is preferred over sequential monotherapy. Further research is needed to understand how combinations of anti-angiogenic agents with CPIs compare with CPI monotherapy or combination therapy (e.g., nivolumab and ipilimumab), and whether the long-term benefit observed in a subset of patients treated with CPI combinations will also be realised in patients treated with an anti-angiogenic therapy and a CPI. Additional research is also needed to establish whether other elements of the tumour microenvironment also need to be targeted to optimise treatment efficacy, and to identify biomarkers of response to inform personalised treatment using combination therapies.


Mammalian growth cone turning assays identify distinct cell signalling mechanisms that underlie axon growth, guidance and regeneration.
The cell signalling mechanisms underlying mammalian central nervous system axon growth and guidance change during development, such that axons that establish appropriate connectivity in the embryo fail to regenerate after injury to the adult nervous system. The growth cone turning assay has been used in Xenopus neurons to elucidate mechanisms of axon guidance during development. Here, we describe how we have adapted this assay for rat dorsal root ganglion neurons to study the influence of extracellular secreted factors causing growth cone attraction and repulsion. Additionally, we describe how this method can be combined with small interfering RNA and cDNA transfections to manipulate protein expression in growth cones, and fluorescence resonance energy transfer to monitor the activity of signalling pathways in live neurons. This assay provides the unique ability to manipulate and visualise the internal status of growth cone signalling whilst challenged with extracellular chemotropic signalling molecules, and can be used to develop strategies to promote axon regeneration in the mature mammalian central nervous system.