Ultrasound enhances the transfection of plasmid DNA by non-viral vectors.
Increasing attention has been paid to technology used for the delivery of genetic materials into cells for gene therapy and the generation of genetically engineered cells. So far, viral vectors have been mainly used because of their inherently high transfection efficiency of gene. However, there are some problems to be resolved for the clinical applications, such as the pathogenicity and immunogenicity of viral vectors themselves. Therefore, many research trials with non-viral vectors have been performed to enhance their efficiency to a level comparable to the viral vector. Two directions of these trials exist: material improvement of non-viral vectors and their combination with various external physical stimuli. This paper reviews the latter research trials, with special attention paid to the enhancement of gene expression by ultrasound (US). The expression level of plasmid DNA by various cationized polymers and liposomes is promoted by US irradiation in vitro as well as in vivo. This US-enhanced expression of plasmid DNA will be discussed to emphasize the technical feasibility of US in gene therapy and biotechnology.


The chromatin regulator DMAP1 modulates activity of the nuclear factor B (NF-B) transcription factor Relish in the Drosophila innate immune response.
The host defense of the model organism Drosophila is under the control of two major signaling cascades controlling transcription factors of the NF-B family, the Toll and the immune deficiency (IMD) pathways. The latter shares extensive similarities with the mammalian TNF-R pathway and was initially discovered for its role in anti-Gram-negative bacterial reactions. A previous interactome study from this laboratory reported that an unexpectedly large number of proteins are binding to the canonical components of the IMD pathway. Here, we focus on DNA methyltransferase-associated protein 1 (DMAP1), which this study identified as an interactant of Relish, a Drosophila transcription factor reminiscent of the mammalian p105 NF-B protein. We show that silencing of DMAP1 expression both in S2 cells and in flies results in a significant reduction of Escherichia coli-induced expression of antimicrobial peptides. Epistatic analysis indicates that DMAP1 acts in parallel or downstream of Relish. Co-immunoprecipitation experiments further reveal that, in addition to Relish, DMAP1 also interacts with Akirin and the Brahma-associated protein 55 kDa (BAP55). Taken together, these results reveal that DMAP1 is a novel nuclear modulator of the IMD pathway, possibly acting at the level of chromatin remodeling.


Responses to glial cell line-derived neurotrophic factor change in mice as spermatogonial stem cells form progenitor spermatogonia which replicate and give rise to more differentiated progeny.
Spermatogonial stem cells (SSCs) are the foundation of spermatogenesis. These cells are classically defined as a subset of morphologically defined A single (As) spermatogonia, which can produce more SSCs or they can give rise to nonstem As cells that, upon replication, generate A paired (Apr) and then A aligned (Aal) spermatogonia. These latter two cell types, along with the nonstem As cells, function as transit-amplifying progenitor cells. It is known that glial cell line-derived neurotrophic factor (GDNF) is essential for maintaining all of these cells, but it is unknown if or how the responses of these cells change as they progress down the pathway to differentiated type A1 spermatogonia. We address this issue by using a chemical-genetic approach to inhibit GDNF signaling in vivo and an in vitro approach to increase GDNF stimulation. We show that inhibition for 2 days suppresses replication of As, Apr, and Aal spermatogonia to an equal extent, whereas stimulation by GDNF preferentially increases replication of As and Apr spermatogonia. We also test if inhibiting GDNF signaling causes As, Apr, and Aal spermatogonia to express Kit, an essential step in their differentiation into type A1 spermatogonia. Inhibition for 3 or 7 days produces a progressive increase in the percentages of As, Apr, and Aal undergoing differentiation, with the largest increase observed in Aal spermatogonia. Finally, we demonstrate that numbers of SSCs decrease more slowly than numbers of progenitor spermatogonia when GDNF signaling is inhibited. Taken together, these data suggest that there are significant changes in the responses to GDNF as SSCs give rise to progenitor spermatogonia, which replicate and gradually differentiate into type A1 spermatogonia.


Molecular biology and immunology of cytomegalovirus.
The application of modern biochemical techniques has led to a rapid improvement in our knowledge of the molecular biology of CMV. Several coding regions of the DNA genome have been identified with certainty and major virus-coded proteins have been given provisional names. The cascade expression of the CMV genome has been shown to be controlled by mechanisms similar to those found in other herpes viruses, together with novel post-transcriptional controls which remain to be defined. The control of CMV replication by the host involves both non-specific and specific defence mechanisms. The induction of natural killer cells and interferon early after CMV infection appears to be the most important aspects of the non-specific host defence against the virus. The cell-mediated immune response, in particular the generation of Tc cells against CMV early antigens, is probably the most important facet of the specific immune defence against CMV. When intact these defence mechanisms appear to be efficient in restricting viral replication; however, when such immunity is compromised, the balance rapidly swings in favour of the virus. As our understanding of the interaction between the host and the virus increases, it may be possible to redress the balance in such cases in favour of the host.


RTEL1 is required for silencing and epigenome stability.
Transcriptional silencing is an essential mechanism for controlling the expression of genes, transgenes and heterochromatic repeats through specific epigenetic marks on chromatin that are maintained during DNA replication. In Arabidopsis, silenced transgenes and heterochromatic sequences are typically associated with high levels of DNA methylation, while silenced genes are enriched in H3K27me3. Reactivation of these loci is often correlated with decreased levels of these repressive epigenetic marks. Here, we report that the DNA helicase REGULATOR OF TELOMERE ELONGATION 1 (RTEL1) is required for transcriptional silencing. RTEL1 deficiency causes upregulation of many genes enriched in H3K27me3 accompanied by a moderate decrease in this mark, but no loss of DNA methylation at reactivated heterochromatic loci. Instead, heterochromatin exhibits DNA hypermethylation and increased H3K27me3 in rtel1. We further find that loss of RTEL1 suppresses the release of heterochromatin silencing caused by the absence of the MOM1 silencing factor. RTEL1 is conserved among eukaryotes and plays a key role in resolving DNA secondary structures during DNA replication. Inducing such aberrant DNA structures using DNA cross-linking agents also results in a loss of transcriptional silencing. These findings uncover unappreciated roles for RTEL1 in transcriptional silencing and in stabilizing DNA methylation and H3K27me3 patterns.


Shaw and Shal voltage-gated potassium channels mediate circadian changes in Drosophila clock neuron excitability.
As in mammals, Drosophila circadian clock neurons display rhythms of activity with higher action potential firing rates and more positive resting membrane potentials during the day. This rhythmic excitability has been widely observed but, critically, its regulation remains unresolved. We have characterized and modelled the changes underlying these electrical activity rhythms in the lateral ventral clock neurons (LNvs). We show that currents mediated by the voltage-gated potassium channels Shaw (Kv3) and Shal (Kv4) oscillate in a circadian manner. Disruption of these channels, by expression of dominant negative (DN) subunits, leads to changes in circadian locomotor activity and shortens lifespan. LNv whole-cell recordings then show that changes in Shaw and Shal currents drive changes in action potential firing rate and that these rhythms are abolished when the circadian molecular clock is stopped. A whole-cell biophysical model using Hodgkin-Huxley equations can recapitulate these changes in electrical activity. Based on this model and by using dynamic clamp to manipulate clock neurons directly, we can rescue the pharmacological block of Shaw and Shal, restore the firing rhythm, and thus demonstrate the critical importance of Shaw and Shal. Together, these findings point to a key role for Shaw and Shal in controlling circadian firing of clock neurons and show that changes in clock neuron currents can account for this. Moreover, with dynamic clamp we can switch the LNvs between morning-like and evening-like states of electrical activity. We conclude that changes in Shaw and Shal underlie the daily oscillation in LNv firing rate.


REM sleep function: Mythology vs. reality.
Since the discovery of REM (Rapid Eye Movement) sleep in 1953, misconceptions have arisen as to the evidence for its adaptive function and its relation to dreams. Eye movements recorded during REM sleep have not been consistently reported to mirror the eye movements predicted by dream reports. But evidence on eye movement and somatic motor expression from patients with REM sleep behavior disorder (RBD) is consistent with dream enacting behavior. The assumption that dreaming occurs only in REM sleep is incorrect, with numerous reports of nonREM dreaming. However, there may be qualitative differences between REM and nonREM dreams. Early studies that suggested a vital role for REM sleep in psychological well-being are refuted by studies of pharmacologically induced partial or complete REM sleep suppression. Studies of sleep across species show that the primitive monotreme mammals, platypus and echidna, have far more REM sleep than any other homeotherm group, whereas birds have far less REM sleep than any other homeotherm group. Human REM sleep amounts are not unusual, are correlated with nonREM sleep durations but are not correlated with intelligence. Across groups of homeotherms, REM sleep time is highly and inversely correlated (r=-0.975, P=0.02) with average core body temperature, suggesting that REM sleep cycles with nonREM sleep to regulate brain temperature during sleep. Cetacean mammals (dolphins and whales) do not have REM sleep despite their very large brain sizes and impressive cognitive abilities. Reports of "REM sleep-like states" in arachnids, cephalopods and in zebrafish larvae are lacking critical evidence that the observed behaviors are occurring during sleep and that the behaviors are homologous to mammalian REM sleep.


[Diarrhea with sequelae].
We report on a twenty-three year old woman with shifting polyarthritis after an episode with gastroenteritis. Despite normalisation of stool we could detect campylobacter jejuni one month later. After therapy with macrolide antibiotics arthritis recovered.


Rhabdomyolysis Complicated with Hyponatremia Due to Water Intoxication and Severe Aspiration Pneumonia: Description of a Patient with Chronic Schizophrenia and Literature Review.
Hyponatremia due to water intoxication is frequently observed in patients with chronic schizophrenia. We herein present a 49-year-old man who developed schizophrenia at the age of 23 and had been admitted to the closed ward of our hospital for 7 years. He was found by a round nurse standing at the bedside, covering both ears with his hands and making groaning noises. He was disoriented and immediately after being returned to bed, a general tonic-clonic seizure occurred. Severe hyponatremia (Na 104 mEq/L) was noted and intravenous sodium correction was started. A few hours later, due to glossoptosis and massive vomiting, ventilation got worse to the point where he had to be put on a ventilator. On the following day, he developed aspiration pneumonia and antimicrobial treatment was started. In addition, a blood sample taken 36 hours later revealed an extensive elevation of creatine kinase (41,286 U/L), pointing to a possibility of rhabdomyolysis as a complication. Subsequently, the general condition gradually improved with antimicrobial therapy and sodium correction. He eventually recovered without any complications including central pontine myelinolysis. He had no history of polydipsia before this event but it was later found that esophageal stricture triggered complusive fluid intake, resulting in acute hyponatremia, seizure, aspiration pneumonia and rhabdomyolysis. A brief discussion will be provided on the issues surrounding hyponatremia, rhabdomyolysis and schizophrenia.


GEOPHYSICS: Enhanced: Earth's Enigmatic Interface.
At the boundary between Earth's mantle and its core, physical properties such as density change dramatically. In their Perspective, Garnero and Jeanloz discuss the competing models of this boundary's structure. Distinguishing between the models will require more high-quality seismic data.


Validity and reliability of the Cold Discomfort Scale: a subjective judgement scale for the assessment of patient thermal state in a cold environment.
Complementary measures for the assessment of patient thermoregulatory state, such as subjective judgement scales, might be of considerable importance in field rescue scenarios where objective measures such as body core temperature, skin temperature, and oxygen consumption are difficult to obtain. The objective of this study was to evaluate, in healthy subjects, the reliability of the Cold Discomfort Scale (CDS), a subjective judgement scale for the assessment of patient thermal state in cold environments, defined as test-retest stability, and criterion validity, defined as the ability to detect a difference in cumulative cold stress over time. Twenty-two healthy subjects performed two consecutive trials (test-retest). Dressed in light clothing, the subjects remained in a climatic chamber set to -20 °C for 60 min. CDS ratings were obtained every 5 min. Reliability was analysed by test-retest stability using weighted kappa coefficient that was 0.84 including all the 5-min interval measurements. When analysed separately at each 5-min interval the weighted kappa coefficients were was 0.48-0.86. Criterion validity was analysed by comparing median CDS ratings of a moving time interval. The comparison revealed that CDS ratings were significantly increased for every interval of 10, 15, and 30 min (p < 0.001) but not for every interval of 5 min. In conclusion, in a prehospital scenario, subjective judgement scales might be a valuable measure for the assessment of patient thermal state. The results of this study indicated that, in concious patients, the CDS may be both reliable and valid for such purpose.


Self-navigated interleaved spiral (SNAILS): application to high-resolution diffusion tensor imaging.
A fat-saturated twice-refocused spin echo sequence was implemented on a GE Signa 1.5-T whole-body system for diffusion-weighted imaging. Data were acquired using an analytically designed interleaved variable-density (VD) spiral readout trajectory. This flexible design algorithm allowed real-time prescription on the scanner. Each interleaf of the VD spiral oversampled the center of k-space. The oversampling provided an inherent motion compensation capability. The resultant diffusion-weighted images showed good quality without any retrospective motion correction. An iterated motion correction algorithm was developed to further reduce the signal cancellation artifact caused by motion-induced phase error. In this algorithm, a low-resolution phase map was estimated using the oversampled data in the center of k-space in order to correct for phase error in image space. In vivo diffusion tensor imaging (DTI) studies were performed on the brains of healthy volunteers. High-quality isotropic diffusion-weighted images, trace maps, and FA maps from axial, sagittal, and coronal slices were obtained using a VD spiral readout trajectory with matrix size 256 x 256. To our knowledge, this was also the first time in vivo 512 x 512 DTI results were reported.


A 17 years retrospective study on multiple metal stents for complex malignant hilar biliary strictures: Survival, stents patency and outcomes of re-interventions for occluded metal stents.
Endoscopic placement of SEMSs for malignant hilar biliary strictures (MHBS) is well-established palliative treatment for inoperable patients. Objectives of this study were evaluation of survival and stents patency after placement of multiple SEMS for palliation of complex MHBS. Retrospective review of patients with MHBS that underwent ERCP with insertion of multiple SEMSs for palliation. Survival-associated factors and stents patency were analyzed by Cox multivariate analysis. Between January 1998 and January 2015, 740 patients with nonoperable MHBS that underwent ERCP were identified and only 18.2% of these received multiple SEMSs. Complications were observed in 7.5% of the patients with no procedure-related mortality. Palliative therapies (chemotherapy, external beam radiotherapy and high dose rate brachytherapy) were done in some patients, and outcomes were evaluated. Overall mean survival of the 134 patients was 323 days. Of these, 59% did not had stents malfunction while 41% patients had episodes of SEMSs malfunction and mean survival after re-interventions was 502.9 days. Survival was not influenced by type of tumor, sex or age. Endoscopic multiple SEMSs placement is safe and effective in patients with complex MHBS. Survival is independent from the type and complexity of MHBS while is prolonged in patients undergoing HDR brachytherapy. Prompt recognition of SEMSs malfunction is fundamental for survival.


Monoclonal antibodies as probes of epithelial membrane polarization.
Monoclonal antibodies directed against antigens in the apical plasma membrane of the toad kidney epithelial cell line A6 were produced to probe the phenomena that underlie the genesis and maintenance of epithelial polarity. Two of these antibodies, 17D7 and 18C3, were selected for detailed study here. 17D7 is directed against a 23-kD peptide found on both the apical and basolateral surfaces of the A6 epithelium whereas 18C3 recognizes a lipid localized to the apical membrane only. This novel observation of an apically localized epithelial lipid species indicates the existence of a specific sorting and insertion process for this, and perhaps other, epithelial plasma membrane lipids. The antibody-antigen complexes formed by both these monoclonal antibodies are rapidly internalized by the A6 cells, but only the 18C3-antigen complex is recycled to the plasma membrane. In contrast to the apical localization of the free antigen, however, the 18C3-antigen complex is recycled to both the apical and basolateral surface of the epithelium, which indicates that monoclonal antibody binding interferes in some way with the normal sorting process for this apical lipid antigen.


Polymorphisms of the NS3 Proteins of Hepatitis C Virus Genotype 1b Are Associated with Liver Cirrhosis.
Polymorphisms of the hepatitis C virus (HCV) core protein and NS3 have been described to be associated with liver cirrhosis (LC) and/or hepatocellular carcinoma in patients with chronic hepatitis C genotype 1b (HCV 1b). Here, we determine whether there is an association between LC and polymorphisms of viral core protein and NS3 in patients in Hubei province, China. A total of 42 patients with chronic HCV 1b (21 patients with LC and 21 with chronic hepatitis [CH]) were enrolled, amino acid sequence of the core protein and N-terminus of NS3 were obtained by direct sequencing and compared with the prototype strain HCV-J. No significant difference of amino acid polymorphisms was observed between isolates from LC and CH patients in the core protein. However, in the N-terminus of NS3, amino acid polymorphisms at positions A1072T (Ala 1072 chronic Thr 1072 cirrhosis), I1074V (Ile 1074 chronic Val 1074 cirrhosis), and T1098N/I (Thr 1098 chronic Asn or Ile 1098 cirrhosis) correlated significantly with LC. These findings indicate that the polymorphisms of HCV at these sites may be the risk factors for the development of LC in patients with chronic HCV 1b.


Bariatric Surgery in Severely Obese Kidney Donors Before Kidney Transplantation: A Retrospective Study.
Bariatric surgery (BS) is the optimal approach for sustained weight loss and may alter donation candidacy in potential donors with obesity. We evaluated the long-term effects of nephrectomy after BS on metabolic profile, including body mass index, serum lipids and diabetes, and kidney function of donors. This was a single-center retrospective study. Live kidney donors who underwent BS before nephrectomy were matched for age, gender, and body mass index with patients who underwent BS alone and with donors who underwent nephrectomy alone. Estimated glomerular filtration rate (eGFR) was calculated according to Chronic Kidney Disease Epidemiology Collaboration and adjusted to individual body surface area to create absolute eGFR. Twenty-three patients who underwent BS before kidney donation were matched to 46 controls who underwent BS alone. At the last follow-up, the study group showed significantly worse lipid profile with low-density lipoprotein of 115 ± 25 mg/dL versus the control group with low-density lipoprotein of 99 ± 29 mg/dL ( P = 0.036) and mean total cholesterol of 191 ± 32 versus 174 ± 33 mg/dL ( P = 0.046). The second control group of matched nonobese kidney donors (n = 72) had similar serum creatinine, eGFR, and absolute eGFR as the study group before nephrectomy and 1 y after the procedure. At the end of follow-up, the study group had significantly higher absolute eGFR compared with the control group (86 ± 21 versus 76 ± 18 mL/min; P = 0.02) and similar serum creatinine and eGFR. BS before live kidney donation is a safe procedure that could increase the donor pool and improve their health in the long run. Donors should be encouraged to maintain their weight and avoid adverse lipid profile and hyperfiltration.


Carbonyl reductase 1 as a novel target of (-)-epigallocatechin gallate against hepatocellular carcinoma.
Human carbonyl reductase 1 (CBR1) converts the antitumor drug and anthracycline daunorubicin (DNR) into the alcohol metabolite daunorubicinol (DNROL) with significantly reduced antitumor activity and cardiotoxicity, and this limits the clinical use of DNR. Inhibition of CBR1 can thus increase the efficacy and decrease the toxicity of DNR. Here we report that (-)-epigallocatechin gallate (EGCG) from green tea is a promising inhibitor of CBR1. EGCG directly interacts with CBR1 and acts as a noncompetitive inhibitor with respect to the cofactor reduced nicotinamide adenine dinucleotide phosphate and the substrate isatin. The inhibition is dependent on the pH, and the gallate moiety of EGCG is required for activity. Molecular modeling has revealed that EGCG occupies the active site of CBR1. Furthermore, EGCG specifically enhanced the antitumor activity of DNR against hepatocellular carcinoma SMMC7721 cells expressing high levels of CBR1 and corresponding xenografts. We also demonstrated that EGCG could overcome the resistance to DNR by Hep3B cells stably expressing CBR1 but not by RNA interference of CBR1-HepG2 cells. The level of the metabolite DNROL was negatively correlated with that of EGCG in the cell extracts. Finally, EGCG decreased the cardiotoxicity of DNR in a human carcinoma xenograft model with both SMMC7721 and Hep3B cells in mice. These results strongly suggest that EGCG can inhibit CBR1 activity and enhance the effectiveness and decrease the cardiotoxicity of the anticancer drug DNR. These findings also indicate that a combination of EGCG and DNR might represent a novel approach for hepatocellular carcinoma therapy or chemoprevention.


Health care policy evaluation using longitudinal insurance claims data: an application of the panel Tobit estimator.
The British Columbia Ministry of Health provides enhanced prescription drug insurance coverage to residents aged 65 and older. This exogenous change in the effective price of prescription drugs is used to investigate aspects of the drug use by seniors. Three sets of issues are of interest. First, what is the effect of enhanced insurance coverage on drug use and programme costs once drugs are provided free of charge? Second, is this effect permanent, or transitory? Third, are any increases in use observed concentrated among those with lower incomes? Longitudinal administrative claims payment data on 18,000 seniors over the period 1985-92 are used. All individuals in the sample turned 65 at some point and therefore became eligible for subsidized prescription drugs. Health status information is not collected; instead, health status is treated as an individual-specific fixed endowment, subject to a common rate of decay. Estimation is complicated by censoring of real drug expenditures for those under 65, rendering 'first differencing' methods invalid. A semi-parametric fixed effects Tobit estimator is used instead. For most individuals, the extension of insurance does not permanently increase drug use. Males with lower income were the exception. Little evidence of transitory effects to insurance coverage was found. Finally, the extension of insurance has made only a minor contribution to growth in seniors' drug use, relative to secular growth in drug use over time.


The role of patient-provider sexual health communication in understanding the uptake of HIV prevention services among Black men who have sex with men.
We examined factors that may be associated with whether Black men who have sex with men a) disclose their sexual orientation to healthcare providers, and b) discuss their sexual health with healthcare providers to inform interventions to improve HIV prevention efforts and reduce HIV incidence rates among Black men who have sex with men. During 2011-2012, we conducted semi-structured individual in-depth interviews with Black men who have sex with men in New York City. Interviews were audio recorded. We examined transcribed responses for main themes using a qualitative exploratory approach followed by computer-assisted thematic analyses. Twenty-nine men participated. The median age was 25.3 years; 41% (n = 12) earned an annual income of < US$10,000; 72% (n = 21) had a college degree; 86% (n = 25) reported being single; 69% (n = 20) self-identified as gay or homosexual. We identified three main themes affecting whether the men discussed their sexual orientation and sexual health with healthcare providers: 1) comfort discussing sexual health needs; 2) health literacy; and 3) trust. Identifying strategies for improved comfort, health literacy and trust between Black men who have sex with men and healthcare providers may be an important strategy for increasing sexual health patient-provider communications, increasing opportunities for HIV prevention including testing and reducing HIV-related health disparities.


Prolonged infectiousness of tuberculosis patients in a directly observed therapy short-course program with standardized therapy.
Effective tuberculosis control is compromised by a lack of clarity about the timeframe of viable Mycobacterium tuberculosis shedding after treatment initiation under programmatic conditions. This study quantifies time to conversion from smear and culture positivity to negativity in unselected tuberculosis patients receiving standardized therapy in a directly observed therapy short-course (DOTS) program. Longitudinal cohort study following up 93 adults initiating tuberculosis therapy in Lima, Peru. Baseline culture and drug susceptibility tests (DSTs) were performed using the MBBacT, proportion, and microscopic observation drug susceptibility (MODS) methods. Smear microscopy and MODS liquid culture were performed at baseline and weekly for 4 weeks then every other week for 26 weeks. Median conversion time from culture positivity to culture negativity of 38.5 days was unaffected by baseline smear status. Patients with fully susceptible tuberculosis had a median time to culture conversion of 37 days; 10% remained culture positive at day 60. Delayed culture conversion was associated with multidrug resistance, regardless of DST method used; non-multidrug resistance as defined by the proportion method and MODS (but not MBBacT) was also associated with delay. Persistent day 60 smear positivity yielded positive and negative predictive values of 67% and 92%, respectively, for detecting multidrug resistance. Smear and culture conversion in treated tuberculosis patients takes longer than is conventionally believed, even with fully susceptible disease, and must be accounted for in tuberculosis treatment and prevention programs. Persistent day 60 smear positivity is a poor predictor of multidrug resistance. The industrialized-world convention of universal baseline DST for tuberculosis patients should become the standard of care in multidrug resistance-affected resource-limited settings.


APDDD: Animal parasitic diseases and drugs database.
Animal parasitic diseases not only have an economic impact, but also have serious social and public health impacts. Although antiparasitic drugs can treat these diseases, it seems difficult for users to comprehensively utilize the information, due to incomplete and difficult data collection. Thus, there is an urgent need to establish a comprehensive database, that includes parasitic diseases and related drugs. In this paper, we develop a knowledge database dedicated to collecting and analyzing animal parasitic diseases and related drugs, named Animal Parasitic Diseases and Drugs Database (APDDD). The current version of APDDD includes animal parasitic disease data of 8 major parasite classifications that cause common parasitic diseases and 96 subclass samples mined from many literature and authoritative books, as well as 182 antiparasitic drugs. Furthermore, we utilized APDDD data to add a knowledge graph representing the relationships between parasitic diseases, drugs, and the targeted gene of drugs acting on parasites. We hope that APDDD will become a good database for animal parasitic diseases and antiparasitic drugs research and that users can gain a more intuitive understanding of the relationships between parasitic diseases, drugs, and targeted genes through the knowledge graph.


Unilateral lateral rectus recession is an effective surgery for intermittent exotropia in young children.
Different surgical methods have been suggested for the correction of intermittent exotropia. Unilateral lateral rectus recession has been described as a surgical alternative for small and moderate-angle exotropia. In general, previous studies did not focus on the outcomes of unilateral lateral rectus recession in young children with intermittent exotropia. The purpose of this study is to evaluate the surgical outcomes of unilateral lateral rectus recession in the treatment of moderate-angle exotropia (≤ 25 PD (prism diopters)) in children. The charts of all patients younger than 12 years of age with moderate-angle exotropia (up to 25 PD) who were operated during the years 2006-2018 were retrospectively reviewed. Fifty-eight patients underwent unilateral lateral rectus recession and had a minimum follow up of 6 months. The angle of exotropia (PD) before and after surgery and the success rate were documented. Mean age at surgery was 6.4 ± 1.9 (range 3.5-11.0) years. Exotropia improved from a preoperative angle of 21.4 ± 4.0 PD to 3.5 ± 5.9 PD postoperatively (p < 0.001). Success rate, defined as deviation of ≤ 10 PD, was achieved in 86.2%. There were 2 (3.4%) cases of overcorrection (consecutive esotropia). There were no intra- or postoperative complications. The mean follow-up duration after surgery was 2.3 ± 1.7 years. In children with moderate angle exotropia, good postoperative success rate was achieved by performing unilateral lateral rectus recession.


Cohort profile update: 2004 Pelotas (Brazil) Birth Cohort Study. Body composition, mental health and genetic assessment at the 6 years follow-up.
This is an update of the 2004 Pelotas Birth Cohort profile, originally published in 2011. In view of the high prevalence of overweight and mental health problems among Brazilian children, together with the availability of state-of-the-art equipment to assess body composition and diagnostic tests for mental health in childhood, the main outcomes measured in the fifth follow-up (mean age 6.8 years) included child body composition, mental health and cognitive ability. A total of 3722 (90.2%) of the original mothers/carers were interviewed and their children examined in a clinic where they underwent whole-body dual X-ray absorptiometry (DXA), air displacement plethysmography and a 3D photonic scan. Saliva samples for DNA were obtained. Clinical psychologists applied the Development and Well-Being Assessment questionnaire and the Wechsler Intelligence Scale for Children to all children. Results are being compared with those of the two earlier cohorts to assess the health effects of economic growth and full implementation of public policies aimed at reducing social inequalities in the past 30 years. For further information visit the programme website at [http://www.epidemio-ufpel.org.br/site/content/coorte_2004/questionarios.php]. Applications to use the data should be made by contacting 2004 cohort researchers and filling in the application form available at [http://www.epidemio-ufpel.org.br/site/content/estudos/formularios.php].


Aerobic Solid State Red Phosphorescence from Benzobismole Monomers and Patternable Self-Assembled Block Copolymers.
The synthesis of the first bismuth-containing macromolecules that exhibit phosphorescence in the solid state and in the presence of oxygen is reported. These red emissive high molecular weight polymers (>300 kDa) feature benzobismoles appended to a hydrocarbon scaffold, and were built via an efficient ring-opening metathesis (ROMP) protocol. Moreover, our general procedure readily allows for the formation of cross-linked networks and block copolymers. Attaining stable red phosphorescence with non-toxic elements remains a challenge and, thus, our new class of soluble (processable) polymeric phosphor is of great interest. Furthermore, the formation of bismuth-rich cores within organic-inorganic block copolymer spherical micelles is possible, leading to patterned arrays of bismuth in the film state.


Pharmacokinetics of oligonucleotides in cell culture.
Synthetic oligonucleotides offer interesting perspectives for the regulation of gene expression in normal and pathological situations. Poor uptake in many cell types, inadequate intracellular compartmentalization, often fragmentary knowledge of intracellular behaviour and mechanism of action, and lack of specificity remain major challenges. These limitations strongly urge the design of new oligonucleotide analogues and more efficient antisense strategies. Present achievements and perspectives for further developments will be discussed with emphasis on cell delivery and intracellular fate.


Simvastatin pharmacokinetics in healthy Chinese subjects and its relations with CYP2C9, CYP3A5, ABCB1, ABCG2 and SLCO1B1 polymorphisms.
A pharmacokinetic study of simvastatin (single oral dose, 40 mg) was conducted in 17 healthy Chinese volunteers. Plasma concentrations of simvastatin were determined by an LC-ESI-MS-MS method. The pharmacokinetic parameters of simvastatin were derived with a non-compartmental method. The polymorphisms of CYP2C9, CYP3A5, ABCB1 (encoding P-gp), ABCG2 (encoding BCRP) and SLCO1B1 (encoding OATP1B1) were determined by TaqMan genotyping assay and the impacts of these SNPs on the pharmacokinetics of simvastatin were analyzed. Major pharmacokinetic parameters were as follows: Tmax 1.44 +/- 0.39 h, Cmax 9.83 +/- 2.41 microg x L(-1), t1/2 4.85 +/- 1.23 h and AUC(0-infinity) 40.32 +/- 6.82 microg x h x L(-1). Effect of ABCB1 G2677T/A SNP on dispostion of simvastatin was observed. Significant differences in t1/2, but not Cmax and AUC(0-infinity), were observed between G/A, G/T or G/G carriers and non-G carriers (5.65 +/- 0.50 h vs 4.41 +/- 1.31 h, P < 0.05). There were no significant effects on simvastatin pharmacokinetics by SNPs such as CYP2C9*3 (1075A > C), CYP3A5*3 g.6986A > G, ABCB1 C3435T, ABCG2 c.34G > A, ABCG2 c.421C>A, SLCO1B1 c.388 A > G, SLCO1B1 c.521 T > C, SLCO1B1 g.11187 G > A, SLCO1B1 c.571 T > C and SLCO1B1 c.597 C > T. We conclude here that there is a small inter-subject variation in simvastatin pharmacokinetics in healthy Chinese volunteers. P-gp, OATP1 B1 and BCRP seem unlikely to play an important role in the pharmacokinetics of simvastatin. The gene-dose effects of ABCG2 c.421 C > A and CYP3A5*3 g.6986A > G on simvastatin pharmacokinetics are not strong enough in Chinese subjects.


Photoinduced tautomeric transformations of xanthurenic acid.
The properties of xanthurenic acid (XAN) in ground and photoexcited states have been studied using steady-state and time-resolved optical methods as well as quantum chemistry calculations. In neutral aqueous solution and in alcohols, XAN is present in a single tautomeric form (keto form), whereas in aprotic solvents and probably in basic aqueous solutions, more than one tautomeric form is present. UV irradiation of aqueous and alcoholic solutions of XAN results in a very rapid solvent-assisted tautomerization to the enol form, the later undergoes solvent-assisted transformation back to the keto form. The photolysis of XAN in aprotic solvents gives rise to the formation of numerous intermediate forms of XAN in both triplet and ground states. Under intense laser irradiation, XAN undergoes biphotonic ionization, the precursor for ionization being the excited singlet state.


A UK literature review of progressive long-term neurological conditions.
Progressive long-term neurological conditions are relatively rare, and policy attention has only recently been directed at community services for people with these conditions. This literature review draws together findings from 16 UK studies relating to the provision of care in the community for people with progressive long-term neurological conditions. The purpose is to identify elements of best practice which could be promoted at a national level to improve services. The findings point to the uneven coverage of services and their lack of flexibility. Multidisciplinary care delivery was considered essential and patients and carers highly valued the use of key workers. The studies also highlighted the potential for self-managed care. This evidence can be used to inform service developments for the delivery of community care for people with progressive long-term neurological conditions.


The Positive Effect of Sialendoscopy with Irrigation Lavage for Sialadenitis without Sialolithiasis or Stenosis.
The aim of the study was to evaluate different irrigation solutions during sialendoscopy to reduce complaints caused by sialodochitis. The investigators designed and implemented a retrospective study composed of 94 patients with sialodochitis but no sialolithiasis or relevant stenosis of the salivary duct system. Three different irrigations (normal saline, cortisone single-shot, and cortisone) were used. After the sialendoscopy, the patients were asked about the current status of the affected salivary gland, and the quantity and quality of the gland swelling/inflammation over a follow-up period of 11.6 months (6-24 months). At the time of follow-up, 41 patients (43.6%) no longer had any complaints with the salivary gland in question. In 75.5% of the patients, a satisfying result was achieved. In total, only 3 patients needed submandibulectomy in the course of the study due to persistent complaints. The outcome showed no statistical differences between the mean of the 3 groups (p = 0.149). Sialendoscopy with flushing/lavage seems to be a good treatment option for patients with sialodochitis lacking sialolithiasis. The results of this study suggest that the type of irrigation used during sialendoscopy seems to be secondary.


Qualifying a novel clinical trial endpoint (iBOX) predictive of long-term kidney transplant outcomes.
New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6 months to 24 months posttransplant in pivotal or exploratory drug therapeutic studies.


Target-Specific Precision of CRISPR-Mediated Genome Editing.
The CRISPR-Cas9 system has successfully been adapted to edit the genome of various organisms. However, our ability to predict the editing outcome at specific sites is limited. Here, we examined indel profiles at over 1,000 genomic sites in human cells and uncovered general principles guiding CRISPR-mediated DNA editing. We find that precision of DNA editing (i.e., recurrence of a specific indel) varies considerably among sites, with some targets showing one highly preferred indel and others displaying numerous infrequent indels. Editing precision correlates with editing efficiency and a preference for single-nucleotide homologous insertions. Precise targets and editing outcome can be predicted based on simple rules that mainly depend on the fourth nucleotide upstream of the protospacer adjacent motif (PAM). Indel profiles are robust, but they can be influenced by chromatin features. Our findings have important implications for clinical applications of CRISPR technology and reveal general patterns of broken end joining that can provide insights into DNA repair mechanisms.


A new microduplication syndrome encompassing the region of the Miller-Dieker (17p13 deletion) syndrome.
The use of array comparative genome hybridisation (CGH) analyses for investigation of children with mental retardation has led to the identification of a growing number of new microdeletion and microduplication syndromes, some of which have become clinically well characterised and some that await further delineation. This report describes three children with de novo 17p13.1 duplications encompassing the PAFAH1B1 gene, who had similar phenotypic features, including mild to moderate developmental delay, hypotonia and facial dysmorphism, and compares them to the few previously reported cases with this duplication. Multiplex ligation-dependent probe amplification (MLPA) or array-CGH was used to diagnose three developmentally delayed children with duplications of 17p13. The duplications were characterised further using Agilent array technology, revealing duplication sizes from 1.8 to 4.0 Mb, with a region of overlap corresponding to 1.8 Mb. Detailed clinical information was obtained from patient files and personal examinations. The developmental delay and similar clinical features in the three patients were most likely due to a common microduplication of 17p13. In contrast to patients with deletion of the region (Miller-Dieker syndrome) the patients reported here had mild to moderate retardation and displayed no lissencephaly or gross brain malformations. Further cases with similar duplications are expected to be diagnosed, and will contribute to the delineation of a potential new microduplication syndrome of 17p13.


Telavancin for refractory methicillin-resistant Staphylococcus aureus bacteremia and infective endocarditis.
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and infective endocarditis (IE) have become increasingly difficult to treat over the past decade, with suboptimal response rates of less than 50%. Although vancomycin and daptomycin are standard therapeutic options, treatment failures with either or both agents are common. Telavancin is a lipoglycopeptide antibiotic with activity against MRSA. In vitro, telavancin displays bactericidal activity and has lower minimum inhibitory concentrations to MRSA than vancomycin. We present a retrospective, case-series report of 14 patients treated with telavancin for refractory MRSA bacteremia with and without IE at our institution from 9 September 2010 to 2 April 2012. Of the 14 patients who received telavancin for refractory MRSA bacteremia and IE, eight survived their inpatient admission and were able to be followed for 30 days. The overall survival rate was 57% (n = 8). Of the eight surviving patients, five were diagnosed with MRSA IE and the remaining three were diagnosed with complicated MRSA bacteremia. All six patients who did not survive the inpatient admission were diagnosed with left-sided IE involving the mitral valves. This retrospective case series provides clinical evidence for the use of telavancin as a treatment option for refractory MRSA bacteremia and IE. With limited effective agents in the treatment of MRSA-complicated bacteremia and IE, telavancin represents a potential treatment option. Further randomized, controlled trials are necessary to define the optimal role of telavancin in the treatment of MRSA bacteremia and IE.


Shoulder injuries among US high school athletes, 2005/2006-2011/2012.
The objective of this study was to describe shoulder injuries in a nationally representative sample of high school athletes playing 9 sports. A national estimate of shoulder injuries among high school athletes was subsequently calculated. Injury data were collected in 9 sports (boys' football, soccer, basketball, wrestling, and baseball; girls' soccer, volleyball, basketball, and softball) during the 2005-2006 through 2011-2012 academic years from a nationally representative sample of high schools via High School Reporting Information Online. During the 2005-2006 through 2011-2012 academic years, high school athletes in this study sustained 2798 shoulder injuries during 13,002,321 athlete exposures, for an injury rate of 2.15 per 10,000 athlete exposures. This corresponds to a nationally estimated 820,691 injuries during this time period. Rates of injury were higher in competition as compared with practice (rate ratio = 3.17 [95% confidence interval: 2.94-3.41]). The highest rate of injury was in football (4.86) and the lowest in girls' soccer (0.42). The most common types of injury were strain/sprain (37.9%) and dislocation/separation (29.2%). Boys were more likely than girls to sustain their injuries after contact with another person or with the playing surface. Surgical repair was required for 7.9% of the injuries. Time loss from athletic participation varied among sports, with 40.7% of athletes returning within 1 week, whereas 8.2% were medically disqualified for their season/career. High school shoulder injury rates and patterns varied by sport and gender. Prospective epidemiologic surveillance is warranted to discern trends and patterns to develop evidence-based interventions to prevent shoulder injuries.


Anesthetic management of transcatheter aortic valve implantation.
The revolution in transcatheter aortic valve implantation (TAVI) for the treatment of aortic stenosis has been well described by the large number of randomized trials, registries, and single and multicenter experiences published during 2010-2011. The aim of this review is to describe the challenges of the anesthetic management related to TAVI. Recent data show that TAVI is clinically effective in patients with inoperable aortic stenosis when compared with standard therapy. It can be accomplished in high-risk patients with favorable outcomes compared with surgery as predicted by standard estimates of mortality and is associated with functional and hemodynamic improvement. Currently, TAVI is targeted at high-risk patients, but may be extended to lower risk groups in the near future. Outstanding questions concerning TAVI are related to its long-term durability and to procedural complications. Preprocedural, multidisciplinary assessment of the patient is essential prior to TAVI and should include a full anesthetic evaluation, consideration of patient comorbidities, and determination of technical feasibility. The role of scoring systems for risk prediction requires further scrutiny. Multidevice/multiple access approaches allow for treatment of a wide range of patients. Anesthetic techniques and supportive measures vary depending on procedural concerns, patient comorbidity, and severe, often unstable cardiac disease. Echocardiography is fundamental to preoperative evaluation, procedure guidance, and assessment of complications. Planned bailout strategies should be discussed with all members of the medical team. Postoperative standardized monitoring and management protocols are essential.


A 73-gene proliferative transcriptomic signature predicts uterine serous carcinoma patient survival and response to primary therapy.
To develop a transcriptomic signature capable of predicting overall survival (OS) for uterine serous carcinoma (USC). RNAseq data for 58 USC patients were obtained from TCGA. Expression of 73 candidate genes was measured for 67 Augusta University (AU) samples using NanoString technology. Analysis of the TCGA RNAseq data identified 73 genes that individually predict prognosis for USC patients and an elastic net model with all 73 genes (USC73) distinguishes a good OS group with low USC73 score from a poor OS group with high USC73 score (5-year OS = 83.3% and 13.3% respectively, HR = 40.1; p = 3 × 10-8). This finding was validated in the independent AU cohort (HR = 4.3; p = 0.0004). The poor prognosis group with high USC73 score consists of 37.9% and 32.8% of patients in the TCGA and AU cohort respectively. USC73 score and pathologic stage independently contribute to OS and together provide the best prognostic value. Early stage, low USC73 patients have the best prognosis (5-year OS = 85.1% in the combined dataset), while advanced stage, high USC73 patients have the worst prognosis (5-year OS = 6.4%, HR = 30.5, p = 1.2 × 10-12). Consistent with the observed poor survival, primary cell cultures from high USC73 patients had higher proliferation rate and cell cycle progression; and high USC73 patients had lower rates of complete response to standard therapy. The USC73 transcriptomic signature and stage independently predict OS of USC patients and the best prediction is achieved using USC73 and stage. USC73 may also serve as a therapeutic biomarker to guide patient care.


[Mechanism of collagen resorption in uterine postpartum involution].
Extracell and intracell mechanisms of collagen resorption were revealed electron-histochemically in the uterus of rats in its postnatal involution. Cathepsin B secreted mainly by smooth muscle cells as well as by macrophages and fibroblasts into the intracellular space takes an active part in the extracellular collagen resorption. Simultaneously with intensive extracellular lysis of collagen in the uterus there is phagocytosis and intracellular collagen resorption (due to cathepsin B and other lysosomal proteinases) by macrophages and fibroblasts and, to a lesser extent, by smooth muscle cells.


Identifying strategies that promote staff and resident influenza and COVID-19 vaccination in nursing homes: Perspectives from nursing home staff.
Resident and staff influenza and COVID-19 vaccination are critical components of infection prevention in nursing homes. Our study sought to characterize strategies that nursing home staff use to promote vaccination. Twenty-six telephone/videoconference interviews were conducted with administrators, directors of nursing, infection preventionists, and Minimum Data Set coordinators at 14 nursing homes across the US. Transcripts were analyzed using content analysis and a detailed audit trail was maintained. Staff described resident and staff influenza and COVID-19 vaccine hesitancy and confidence as well as varying approaches to promote vaccination. These included incentives, education efforts, and having a "vaccine champion" responsible for vaccine promotion. While many strategies had been in place prior to COVID-19 in support of improving influenza vaccination, participants reported implementing additional approaches to promote COVID-19 vaccination. Findings may inform future efforts to promote vaccination, which will be critical to mitigate the burden of influenza and COVID-19 in nursing homes.


[Oscar Giacchi and 'spermatic malincholy'].
Oscar Giacchi was the Director of the Psychiatric Hospital in Racconigi. In one of this works, he presented the clinical case of a malinconic patient affected by a jealousy delirium. The article analyzes the text in the light of Giacchi's scientific production and according to the principal psychiatric theories at the and of XIX century.


Applying ensemble machine learning models to predict individual response to a digitally delivered worry postponement intervention.
Generalized anxiety disorder (GAD) is a prevalent mental health disorder that often goes untreated. A core aspect of GAD is worry, which is associated with negative health outcomes, accentuating a need for simple treatments for worry. The present study leveraged pretreatment individual differences to predict personalized treatment response to a digital intervention. Linear mixed-effect models were used to model changes in daytime and nighttime worry duration and frequency for 163 participants who completed a six-day worry postponement intervention. Ensemble-based machine learning regression and classification models were implemented to predict changes in worry across the intervention. Model feature importance was derived using SHapley Additive exPlanation (SHAP). Moderate predictive performance was obtained for predicting changes in daytime worry duration (test r2 = 0.221, AUC = 0.77) and nighttime worry frequency (test r2 = 0.164, AUC = 0.72), while poor predictive performance was obtained for nighttime worry duration and daytime worry frequency. Baseline levels of worry and subjective health complaints were most important in driving model predictions. A complete-case analysis was leveraged to analyze the present data, which was collected from participants that were Dutch and majority female. This study suggests that treatment response to a digital intervention for GAD can be accurately predicted using baseline characteristics. Particularly, this worry postponement intervention may be most beneficial for individuals with high baseline worry but fewer subjective health complaints. The present findings highlight the complexities of and need for further research into daily worry dynamics and the personalizable utility of digital interventions.


Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis.
The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.


Real-time ultrasound-guided thoracentesis.
Clinicians commonly see patients with pleural effusions requiring thoracentesis. The latest evidence-based guidelines for thoracentesis recommend real-time ultrasound guidance for the safest outcomes from this procedure. This article reviews real-time ultrasound guidance for thoracentesis to help referring clinicians understand the technique and the guidelines for the performance of thoracentesis.


Regional gray matter volume deficits in adolescents with first-episode psychosis.
The current study combined baseline voxel-based morphometry and 1-year clinical follow-up assessments to examine whether and where regional gray matter (GM) volumes differed between a control group and diagnostic subgroups of early-onset first-episode psychosis (FEP). Magnetic resonance imaging brain scans were obtained from 70 patients with early-onset FEP, and 51 non-FEP controls. Early-onset FEP was defined as age younger than 18 years and a duration of positive symptoms of less than 6 months. The age range of the sample was 7 to 18 years. After a 1-year follow-up, patients were stratified into three subgroups: schizophrenia (n = 25), bipolar I disorder (n = 20), and other psychoses (n = 25). Regional GM volumes of each patient subgroup were compared with those of the control group. A follow-up diagnosis of schizophrenia was associated with GM volume deficits in the left medial and left middle frontal gyrus; bipolar I disorder was related to a GM volume deficit in the left medial frontal gyrus; and not having a follow-up diagnosis of schizophrenia or bipolar disorder was associated with smaller bilateral GM volumes in the insula and right middle occipital gyrus. Left medial frontal GM volume deficits were common in the groups with schizophrenia and bipolar I disorder, which may point to shared underlying pathological findings.


Diagnosis of attention deficit hyperactivity disorder using non-linear analysis of the EEG signal.
Attention deficit hyperactivity disorder (ADHD) is a common behavioural disorder that may be found in 5%-8% of the children. Early diagnosis of ADHD is crucial for treating the disease and reducing its harmful effects on education, employment, relationships, and life quality. On the other hand, non-linear analysis methods are widely applied in processing the electroencephalogram (EEG) signals. It has been proved that the brain neuronal activity and its related EEG signals have chaotic behaviour. Hence, chaotic indices can be employed to classify the EEG signals. In this study, a new approach is proposed based on the combination of some non-linear features to distinguish ADHD from normal children. Lyapunov exponent, fractal dimension, correlation dimension and sample, fuzzy and approximate entropies are the non-linear extracted features. For computing, the chaotic time series of obtained EEG in the brain frontal lobe (FP1, FP2, F3, F4, and Fz) need to be analysed. Experiments on a set of EEG signal obtained from 50 ADHD and 26 normal cases yielded a sensitivity, specificity, and accuracy of 98, 92.31, and 96.05%, respectively. The obtained accuracy provides a significant improvement in comparison to the other similar studies in identifying and classifying children with ADHD.


From Human Hand to Grasp Surface Detection, Tracking & Analysis.
Hands are paramount for dexterous interactions that humans exhibit in daily life. Understanding the intricacies of human hand-object interactions is therefore necessary. Unfortunately, the limitations of state-of-the-art technologies make capturing the full hand-object complexity unfeasible, giving rise to the need for new technological means to achieve this aim. In this work, we propose an end-to-end framework in which individualized hand models are derived and used to capture quantitative personalized hand-object interaction information, precisely, hand shape, kinematics, and contact surfaces. The results of this study serve as a proof of concept that such a framework can significantly deepen personalized hand-object interaction analyses, providing, in perspective, insights for medical diagnoses and rehabilitation, among others.Clinical relevance- Our work showcases the need to incorporate bespoke human hand models in individualized hand function assessment technologies, as hand-object interaction information is subject-dependent.


MRI diagnosis and follow-up of hepatic infarction in a patient with antiphospholipid syndrome in early pregnancy.
Hepatic infarction is rare in hemolysis, elevated liver enzymes, and low platelets syndrome. We described a case of a 24-year-old woman who was admitted at week 17 of pregnancy with an antiphospholipid syndrome. Magnetic resonance imaging was the imaging modality of choice for diagnosing hepatic infarction, guiding treatment, ensuring the early detection of bleeding, and monitoring liver recovery.


Tenofovir-linked hyperparathyroidism is independently associated with the presence of vitamin D deficiency.
To determine patient and treatment characteristics associated with vitamin D deficiency (VDD) in an UK inner city HIV-1-positive adult cohort. Two hundred twenty-seven HIV-positive patients attending prospectively for routine blood tests in winter had serum 25-hydroxyvitamin D and parathyroid hormone (PTH) concentrations and other routine chemistry measured. Those with and without VDD were defined as having serum 25-hydroxyvitamin D concentrations <50 nmol/L and >75 nmol/L, respectively. Characteristics were compared between patients with and without VDD. The effects of VDD, tenofovir use, and their interaction on chemical measures were investigated. VDD was found in 57% (131 of 227) of patients. Independent associations included nonwhite ethnicity [adjusted odds ratio (95% confidence interval): 7.40 (2.52 to 21.7)], higher random blood glucose [2.38 (1.24 to 4.57) per mmol/L], higher estimated glomerular filtration rate [eGFR: 1.04 (1.01 to 1.06)], and higher PTH [1.19 (1.00 to 1.42)]. PTH was higher in those receiving tenofovir (median 7.2 pmol/L) than other patients (4.3; P < 0.001) overall, but high PTH with tenofovir occurred only in the context of VDD. Tenofovir use was not associated with serum creatinine or eGFR overall but interacted with vitamin D status (P = 0.05 and P = 0.08, respectively), being linked to somewhat higher creatinine and lower eGFR among patients without VDD but higher eGFR in VDD patients. 25(OH) VDD is associated with tenofovir-linked hyperparathyroidism and also with higher eGFR.


Identification of the Streptococcus gordonii glmM gene encoding phosphoglucosamine mutase and its role in bacterial cell morphology, biofilm formation, and sensitivity to antibiotics.
Phosphoglucosamine mutase (EC 22.214.171.124) catalyzes the interconversion of glucosamine-6-phosphate into glucosamine-1-phosphate, an essential step in the biosynthetic pathway leading to the formation of peptidoglycan precursor uridine 5'-diphospho-N-acetylglucosamine. The gene (glmM) of Escherichia coli encoding the enzyme has been identified previously. We have now identified a glmM homolog in Streptococcus gordonii, an early colonizer on the human tooth and an important cause of infective endocarditis, and have confirmed that the gene encodes phosphoglucosamine mutase by assaying the enzymatic activity of the recombinant GlmM protein. Insertional glmM mutant of S. gordonii did not produce GlmM, and had a growth rate that was approximately half that of the wild type. Morphological analyses clearly indicated that the glmM mutation causes marked elongation of the streptococcal chains, enlargement of bacterial cells, and increased roughness of the bacterial cell surface. Furthermore, the glmM mutation reduces biofilm formation and increases sensitivity to penicillins relative to wild type. All of these phenotypic changes were also observed in a glmM deletion mutant, and were restored by the complementation with plasmid-borne glmM. These results suggest that, in S. gordonii, mutations in glmM appear to influence bacterial cell growth and morphology, biofilm formation, and sensitivity to penicillins.


Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents.
UV and ionizing radiation (IR) activate DNA damage checkpoints and induce Cdc25A degradation (Mailand, N., Falck, J., Lukas, C., Syljuasen, R. G., Welcker, M., Bartek, J., and Lukas, J. (2000) Science 288, 1425-1429; Falck, J., Mailand, N., Syljuasen, R. G., Bartek, J., and Lukas J. (2001) Nature 410, 842-847). The degradation of Cdc25A is abrogated by caffeine, which implicates Chk1 as the potential mediator (Mailand, N., Falck, J., Lukas, C., Syljuasen, R. G., Welcker, M., Bartek, J., and Lukas, J. (2000) Science 288, 1425-1429). However, the involvement of Chk1 is far from clear, because caffeine is a rather nonspecific inhibitor of the ATR/Chk1 signaling pathway. Additionally, it is not known whether DNA-damaging drugs commonly used in chemotherapy, which may activate different signal transduction pathways than UV or IR, also confer Cdc25A degradation. Herein, we show that camptothecin and doxorubicin, two widely used topoisomerase inhibitors conferring S and G2 arrest, respectively, cause the degradation of Cdc25A. Using a small interfering RNA that enables the specific elimination of Chk1 expression, we show that the observed proteolysis of Cdc25A is mediated through Chk1. Moreover, Cdc25A overexpression abrogates the Chk1-mediated degradation and overcomes the doxorubicin-induced G2 arrest through dephosphorylation and activation of Cdc2/Cdk1 in a dose-dependent manner. These results suggest that: (a) Cdc25A is involved in the G2/M transition in addition to its commonly accepted effect on G1/S progression, and (b) Chk1 mediates both S and G2 checkpoint and is thus a more ubiquitous cell cycle checkpoint mediator than previously thought.


The anterosuperior insertion of the temporomandibular joint capsule and condylar mobility in joints with and without internal derangement: a double-contrast arthrotomographic investigation.
The insertion of the anterior temporomandibular joint capsule at the temporal bone constitutes an anatomic boundary of the joint. When condylar translation exceeds this site, the joint is classified as hypermobile. In this study, the distance from the apex of the articular eminence to the antero-superior capsule insertion was assessed in double-contrast arthrotomograms from 192 joints with and without disc displacement. Maximum condylar translation was also measured. The insertion point of the antero-superior capsule was, on the average, located 4.4 mm (SD, 1.7 mm) anterior to the apex of the eminence, regardless of disc position. Hypermobility was present in 56 joints. Sixty-eight percent of the hypermobile joints had a reducing disc and 62% of all the joints with a reducing disc were hypermobile. In joints with permanent disc displacement, the condyle generally was halted posterior to the apex of the eminence, but could pass extensively anterior to it. Condylar hypermobility thus does not exclude the presence of a permanently displaced disc. In 71% of patients with hypermobility, the condition was bilateral. Because of the close topographic relationship between the joint and nerve branches in the anterior vicinity of the joint, a hypermobile condyle may mechanically irritate the masseteric and deep posterior temporal nerve branches.


[Relationship of kidney functions with geriatric syndromes in elderly and old women.]
Against the background of aging, there is an increase in the number of diseases associated with age, geriatric syndromes that contribute to the development of disorders of physical and functional activity, the risk of disability and mortality increases. One of the widespread diseases is chronic kidney disease (CKD), which is dangerous not only in itself, but also as a factor in the progression of other age-associated diseases and geriatric syndromes, including frailty and sarcopenia. Among patients of older age groups, CKD is more common in women than in men. A number of researchers are studying the problems of polymorbidity, the development and progression of geriatric syndromes in patients with CKD in the pre-dialysis and dialysis stages. Undoubtedly, the negative role of severe late stages of CKD in the development of senile asthenia and sarcopenia, at the same time, the relationship of these geriatric syndromes with early pre-dialysis stages of CKD has been insufficiently studied. Therefore, it is of undoubted scientific interest to identify correlations between signs of sarcopenia and frailty in elderly and senile women, depending on renal function, stage of CKD.


[Therapeutic drug monitoring of clonazepam].
Clonazepam is a 1-4 benzodiazepine mainly used to treat epilepsy and epileptiform convulsion state. Rapidly absorbed after oral administration, it is widely distributed in the organism and is extensively converted in metabolites, poorly or not active, eliminated mainly in urine (70%) and feces. Elimination half-life is long, around 40 h. In adult and child, several studies showed a concentration-effect relation. Meanwhile, a large inter-individual variability in the dose-concentration relation was observed. A 15-50 microg/L range of clonazepam blood concentrations appears to be retained as an acceptable target to control a majority of epileptic seizures. The Therapeutic Drug Monitoring (TDM) of clonazepam can be considered as possibly useful in case of association with CYP450 inducers or inhibitors, suspicion of poor observance, or toxicity signs.


Determination of Glyphosate, Maleic Hydrazide, Fosetyl Aluminum, and Ethephon in Grapes by Liquid Chromatography/Tandem Mass Spectrometry.
A simple high-throughput liquid chromatography/tandem mass spectrometry (LC-MS-MS) method was developed for the determination of maleic hydrazide, glyphosate, fosetyl aluminum, and ethephon in grapes using a reversed-phase column with weak anion-exchange and cation-exchange mixed mode. A 5 g test portion was shaken with 50 mM HOAc and 10 mM Na2EDTA in 1/3 (v/v) MeOH/H2O for 10 min. After centrifugation, the extract was passed through an Oasis HLB cartridge to retain suspended particulates and nonpolar interferences. The final solution was injected and directly analyzed in 17 min by LC-MS-MS. Two MS-MS transitions were monitored in the method for each target compound to achieve true positive identification. Four isotopically labeled internal standards corresponding to each analyte were used to correct for matrix suppression effects and/or instrument signal drift. The linearity of the detector response was demonstrated in the range from 10 to 1000 ng/mL for each analyte with a coefficient of determination (R2) of ≥0.995. The average recovery for all analytes at 100, 500, and 2000 ng/g (n = 5) ranged from 87 to 111%, with a relative standard deviation of less than 17%. The estimated LOQs for maleic hydrazide, glyphosate, fosetyl-Al, and ethephon were 38, 19, 29, and 34 ng/g, respectively.


Birdshot Retinochoroidopathy: Differences in Clinical Characteristics between Patients with Early and Late Age of Onset.
To describe differences in the clinical characteristics of birdshot retinochoroidopathy (BSRC) patients diagnosed early and later in life. This is a retrospective cohort study. Age was primarily analyzed and 50 years of age at diagnosis was selected as a cut-off point. A total of 144 patients (288 eyes) were included; 68 with early-onset and 76 with late-onset BSRC. The younger group had a statistically significant higher rate of more severe iritis (p = 0.04); an average number of non-steroidal immunosuppressants and biologic agents (NSIB) (p = 0.04); and a prolonged time to initiation of NSIB (p = 0.01). There were only four patients (3%) who had >0.5+ cells in the anterior chamber. Patients with early-onset BSRC carried a higher risk for anterior segment inflammation, had a more prolonged delay to initiation of treatment with NSIB, and required a greater number of NSIBs to achieve remission.


Polyarteritis nodosa in a cynomolgus macaque (Macaca fascicularis).
Polyarteritis nodosa (PAN) is an idiopathic necrotizing vasculitis affecting small- to medium-sized arteries. The disease is well recognized in humans, and PAN-like syndromes have been described in a number of other species. This report describes a case of PAN in a 6-year-old male cynomolgus macaque. The animal had necrotizing arteritis affecting vessels in the kidney, small intestine, colon, heart, spleen, mesentery, urinary bladder, and pancreas. The lesions were segmental in distribution and of varying severity and stage of development. A transmural mixed inflammatory cell infiltrate was present, often accompanied by fibrinoid necrosis of the tunica media and loss of the internal elastic lamina. Immunohistochemical staining showed that many of the infiltrating cells were T lymphocytes and histiocytes, suggesting a cell-mediated component to the pathogenesis.


Flaxseed Oil Alleviates Chronic HFD-Induced Insulin Resistance through Remodeling Lipid Homeostasis in Obese Adipose Tissue.
Emerging evidence suggests that higher circulating long-chain n-3 polyunsaturated fatty acids (n-3PUFA) levels were intimately associated with lower prevalence of obesity and insulin resistance. However, the understanding of bioactivity and potential mechanism of α-linolenic acid-rich flaxseed oil (ALA-FO) against insulin resistance was still limited. This study evaluated the effect of FO on high-fat diet (HFD)-induced insulin resistance in C57BL/6J mice focused on adipose tissue lipolysis. Mice after HFD feeding for 16 weeks (60% fat-derived calories) exhibited systemic insulin resistance, which was greatly attenuated by medium dose of FO (M-FO), paralleling with differential accumulation of ALA and its n-3 derivatives across serum lipid fractions. Moreover, M-FO was sufficient to effectively block the metabolic activation of adipose tissue macrophages (ATMs), thereby improving adipose tissue insulin signaling. Importantly, suppression of hypoxia-inducible factors HIF-1α and HIF-2α were involved in FO-mediated modulation of adipose tissue lipolysis, accompanied by specific reconstitution of n-3PUFA within adipose tissue lipid fractions.


Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas.
Lenalidomide, an immunomodulatory agent that enhances antibody-dependent cell-mediated cytotoxicity, has the potential to synergize with rituximab, an anti-CD20 mAb. We hypothesized that the addition of lenalidomide to rituximab would improve clinical outcomes in patients with B-cell lymphomas who were previously rituximab resistant, defined as no response to or progression of lymphoma within 6 months of rituximab-based therapy. We conducted a single-center, phase II trial in patients with indolent B-cell or mantle cell lymphomas who were previously rituximab resistant. Patients received 10 mg lenalidomide daily for 8 weeks, and then received four weekly doses of 375 mg/m(2) rituximab; lenalidomide continued during and after rituximab. Response to therapy was assessed after 8 weeks of lenalidomide and 12 weeks after first dose of rituximab. The primary endpoint was overall response rate (ORR) after lenalidomide and rituximab. Fifty patients were enrolled and 43 patients completed both response assessments. ORR after 8 weeks of lenalidomide was 30.2%; 12 weeks after the addition of rituximab to lenalidomide, ORR increased to 62.8% (N = 43). For all patients (N = 50), median progression-free survival (PFS) is 22.2 months (median follow-up, 39.2 months). PFS after lenalidomide-rituximab was significantly longer than the PFS for the antecedent regimen used to define rituximab resistance (22.2 vs. 9.13 months, P = 0.0004). This trial is the first to show that the combination of lenalidomide and rituximab overcomes prior rituximab resistance in patients with indolent B-cell and mantle cell lymphomas.


Identification of the alternative terminal oxidase of higher plant mitochondria.
In addition to cytochrome oxidase, plant mitochondria have a second terminal oxidase called the alternative oxidase. The alternative oxidase is of great interest in that energy is not conserved when electrons flow through it. The potential energy of the system is thus lost as heat, and, in plants with high levels of the alternative oxidase, this results in thermogenesis. We have purified the alternative oxidase from mitochondria of the thermogenic spadix of Sauromatum guttatum and have identified its polypeptide constituents by using polyclonal antibodies. A 166-fold purification was achieved through a combination of cation-exchange (carboxymethyl-Sepharose) and hydrophobic-interaction (phenyl-Sepharose) chromatography. Polyclonal antibodies raised to the CM-Sepharose fractions readily immunoprecipitated alternative oxidase activity and immunoprecipitated four of the proteins that copurify with the activity. These proteins have apparent molecular masses of 37, 36, 35.5, and 35 kDa. Polyclonal antibodies raised individually to the 37-, 36-, and 35.5- plus 35-kDa proteins cross-reacted with all of these proteins, indicating the presence of common antigenic sites. The 37-kDa protein appears to be constitutive in Sauromatum, whereas expression of the 36- and 35-kDa proteins was correlated with presence of alternative pathway activity. The 35.5-kDa protein appears with loss of alternative pathway activity during senescence, indicating that this protein may be a degradation product of the 36-kDa protein. Binding of anti-36-kDa protein antibodies to total mitochondrial protein blots of five plant species indicated that similar proteins were always present when alternative pathway activity was observed.


Kinetics of the coefficient of friction of elastomers.
We study theoretically and numerically the kinetics of the coefficient of friction of an elastomer due to abrupt changes of sliding velocity. Numerical simulations reveal the same qualitative behavior which has been observed experimentally on different classes of materials: the coefficient of friction first jumps and then relaxes to a new stationary value. The elastomer is modeled as a simple Kelvin body and the surface as a self-affine fractal with a Hurst exponent in the range from 0 to 1. Parameters of the jump of the coefficient of friction and the relaxation time are determined as functions of material and loading parameters. Depending on velocity and the Hurst exponent, relaxation of friction with characteristic length or characteristic time is observed.


Survival of postfledging Forster's terns in relation to mercury exposure in San Francisco Bay.
We examined factors influencing mercury concentrations in 90 fledgling Forster's terns (Sterna forsteri) and evaluated whether mercury influenced postfledging survival in San Francisco Bay, California. Mercury concentrations (+/- SE) in chicks 21-29 days old (just before fledging) were 0.33 +/- 0.01 microg g(-1) ww for blood and 6.44 +/- 0.28 microg g(-1) fw for breast feathers. Colony site had an overriding influence on fledgling contamination, however hatching date and age also affected blood, but not feather, mercury concentrations. Blood mercury concentrations decreased by 28% during the 50-day hatching period and increased with chick age by 30% during the last week prior to fledging. Using radio-telemetry, we calculated that cumulative survival during the 35-day postfledging time period was 0.81 +/- 0.09 (SE). Postfledging survival rates increased with size-adjusted mass, and cumulative survival probability was 61% lower for terns with the lowest, compared to the highest, observed masses. Conversely, survival was not influenced by blood mercury concentration, time since fledging, sex, or hatch date. Mercury concentrations in breast feathers of fledglings found dead at nesting colonies also were no different than those in live chicks. Our results indicate that colony site, hatching date, and age influenced mercury concentrations in fledgling Forster's terns, but that mercury did not influence postfledging survival.


An expected cost model of eyewitness identification.
This article presents an expected cost model for evaluating and comparing the performance of eyewitness identification procedures. The model estimates the expected cost of an identification procedure in order to quantify how well the procedure helps the police achieve the investigation goal of identifying and incriminating the culprit. We first apply the expected cost model to analyze five major procedural reforms, including showups versus lineups, filler similarity, administrator influence, lineup instruction, and presentation format. Our analysis reveals that when there is a trade-off between accurate and mistaken identifications, conclusions about procedural superiority depend on the prior probability of guilt and relative costs of different identification outcomes. We then conduct an additional analysis based on a simultaneous consideration of all identification outcomes (i.e., suspect identifications, filler identifications, and rejections). Our analysis shows that assuming different costs for filler identifications and rejections can change conclusions about procedural superiority. We conclude by discussing insights provided by the expected cost model regarding how the legal system can reduce expected costs of eyewitness identification-by changing the conditional probabilities, by reducing the costs of identification outcomes, or by increasing the prior probability of guilt. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


"Monstre". Etienne Geoffroy Saint-Hilaire and the science of monstrosity.
This article aims at analyzing the entry "Monstre", written by Etienne Geoffroy Saint-Hilaire in 1827 and included in the Dictionnaire classique d'histoire naturelle. Under Etienne Geoffroy the study of monsters brought new heuristic and theoretical approaches to the research fields of anatomy and embryology, and acquired the status of a scientific discipline having its own theoreticalfoundations and therefore its own standards for classification, seen as non-random means for revealing a groundbreaking knowledge.


Validation of gene editing efficiency with CRISPR-Cas9 system directly in rat zygotes using electroporation mediated delivery and embryo culture.
Successful use of the CRISPR-Cas9 system for gene manipulation relies on identifying effective and efficient guide RNA sequences (gRNAs). When the goal is to create transgenic animal/rodent models by knocking-in desired sequences using homology-directed repair (HDR), selecting effective guides becomes even more critical to minimize developmental time and resources. Currently, validation experiments for gRNAs for generating rat models are carried out using immortalized rat cells. However, there are several limitations with using such cell lines, including ploidy of the genome, non-predictive transfection efficiency, and the ability to identify gene modifications efficiently within diverse cell populations. Since embryos are authentic representatives of live animals compared to cell lines, validating CRISPR guides for their nuclease activity in freshly isolated embryos will provide greater accuracy of in vivo gene editing efficiency. In contrast to microinjections, delivery by electroporation is a more accessible method that can be simple and does not require special skills and equipment. We demonstrate an accessible workflow to either delete or edit target genes in vivo in rats using the efficient editing of a human mutation in alpha7 nicotinic acetylcholine receptor subunit (CHRNA7) ortholog using electroporation as a delivery method for CRISPR-Cas9 ribonucleoprotein complexes in rat embryos.•Upon identifying CRISPR targets at the desired genetic alteration site, we designed homologydriven repair (HDR) templates for effective and easy identification of gene editing by Restriction Fragment Length Polymorphism (RFLP).•Cultured rat embryos can be genotyped to assess CRISPR activity as seen by either presence of indels resulting from NHEJ or knock-in of repair template resulting from homology driven repair.•Heteroduplex mobility assay (HMA) and Restriction Fragment Length Polymorphism (RFLP) of PCR products can be performed reliably and reproducibly at a low-cost.


Activation of DREAM (downstream regulatory element antagonistic modulator), a calcium-binding protein, reduces L-DOPA-induced dyskinesias in mice.
Previous studies have implicated the cyclic adenosine monophosphate/protein kinase A pathway as well as FosB and dynorphin-B expression mediated by dopamine D1 receptor stimulation in the development of 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia. The magnitude of these molecular changes correlates with the intensity of dyskinesias. The calcium-binding protein downstream regulatory element antagonistic modulator (DREAM) binds to regulatory element sites called DRE in the DNA and represses transcription of target genes such as c-fos, fos-related antigen-2 (fra-2), and prodynorphin. This repression is released by calcium and protein kinase A activation. Dominant-active DREAM transgenic mice (daDREAM) and DREAM knockout mice (DREAM(-/-)) were used to define the involvement of DREAM in dyskinesias. Dyskinesias were evaluated twice a week in mice with 6-hydroxydopamine lesions during long-term L-DOPA (25 mg/kg) treatment. The impact of DREAM on L-DOPA efficacy was evaluated using the rotarod and the cylinder test after the establishment of dyskinesia and the molecular changes by immunohistochemistry and Western blot. In daDREAM mice, L-DOPA-induced dyskinesia was decreased throughout the entire treatment. In correlation with these behavioral results, daDREAM mice showed a decrease in FosB, phosphoacetylated histone H3, dynorphin-B, and phosphorylated glutamate receptor subunit, type 1 expression. Conversely, genetic inactivation of DREAM potentiated the intensity of dyskinesia, and DREAM(-/-) mice exhibited an increase in expression of molecular markers associated with dyskinesias. The DREAM modifications did not affect the kinetic profile or antiparkinsonian efficacy of L-DOPA therapy. The protein DREAM decreases development of L-DOPA-induced dyskinesia in mice and reduces L-DOPA-induced expression of FosB, phosphoacetylated histone H3, and dynorphin-B in the striatum. These data suggest that therapeutic approaches that activate DREAM may be useful to alleviate L-DOPA-induced dyskinesia without interfering with the therapeutic motor effects of L-DOPA.


Effect of various polymers concentrations on physicochemical properties of floating microspheres.
Floating microspheres have emerged as a potential candidate for gastroretentive drug delivery system. For developing a desired intragastric floatation system employing these microspheres, it is necessary to select an appropriate balance between buoyancy and drug releasing rate. These properties mainly depend on the polymers used in the formulation of the microspheres. Hence it is necessory to study the effect of these polymer concentrations on the various physicochemical properties of the microspheres. Floating microspheres were prepared by emulsion solvent evaporation technique utilising different polymers such as ethyl cellulose, Eudragit(®) RS and Eudragit(®) RL by dissolving them in a mixture of dichloromethane and methanol. Release modifiers studied were hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose E50 LV and Eudragit(®) EPO. Prepared microspheres were analysed for particle size, surface morphology, entrapment efficiency, buoyancy, differential scanning calorimetry and in-vitro drug release. Ethyl cellulose and Eudragit(®) EPO resulted microspheres with high percentage yield, excellent spherical shape but had very less buoyancies with a high cumulative drug release. Ethyl cellulose microspheres prepared using hydroxypropyl methylcellulose K4M showed more sustained drug release and high buoyancies than that of the microspheres formulated with the hydroxypropyl methylcellulose E50 LV. Amongst these hydroxypropyl methylcellulose E50 LV showed good balance between buoyancy and the drug release.


Electron-transfer properties of short-lived N-oxyl radicals. Kinetic study of the reactions of benzotriazole-N-oxyl radicals with ferrocenes. Comparison with the phthalimide-N-oxyl radical.
A kinetic study of the one-electron oxidation of a series of substituted ferrocenes (FcX: X = H, COCH3, CO2Et, CH2OH, Et, and Me2) by the benzotriazole-N-oxyl radical (BTNO) and of ferrocene (FcH) by a series of ring-substituted benzotriazole-N-oxyl radicals (Z-BTNO: Z = H, 6-CF(3), 6-Cl, 6-Me, 6-MeO) has been carried out in CH3CN. N-Oxyl radicals were produced by hydrogen abstraction from 1-hydroxybenzotriazoles (Z-HBT) by the cumyloxyl radical produced after 355 nm laser flash photolysis of a solution of dicumyl peroxide in CH3CN. In both systems, the rate constants exhibited a satisfactory fit with the Marcus equation allowing us to determine self-exchange reorganization energy values for the BTNO/BTNO- couple, which resulted in good agreement: 34.7 kcal mol(-1) from the oxidation of ferrocenes by BTNO and 30.5 kcal mol(-1) from the oxidation of ferrocene by aryl-substituted Z-BTNO. From the average value of 32.6 kcal mol(-1) it is possible to calculate a self-exchange rate for the BTNO/BTNO- couple of 7.6 x 10(5) M(-1 )s(-1), which is 3 orders of magnitude higher than that determined for the PINO/PINO- couple. The difference in the intrinsic barrier between the two oxidants is so large that it overcomes the thermodynamic factor and the oxidation of ferrocene by BTNO results significantly faster than that by PINO in spite of the higher reduction potential of the latter N-oxyl radical. The higher reactivity of BTNO with respect to PINO in an electron-transfer process contrasts with what is observed in hydrogen atom transfer processes where PINO is always more reactive than BTNO due to the higher NO-H bond dissociation energy in N-hydroxyphthalimide (HPI) than in HBT (88 vs. 85 kcal mol(-1), respectively). Thus, the relative reactivity of PINO and BTNO radicals might represent a criterium to help in the distinction of ET and HAT reactions promoted by these transient N-oxyl radicals.


Non-orthogonal determinants in multi-Slater-Jastrow trial wave functions for fixed-node diffusion Monte Carlo.
The accuracy and efficiency of ab initio Quantum Monte Carlo (QMC) algorithms benefit greatly from compact variational trial wave functions that accurately reproduce ground state properties of a system. We investigate the possibility of using multi-Slater-Jastrow trial wave functions with non-orthogonal determinants by optimizing identical single particle orbitals independently in separate determinants. As a test case, we compute variational and fixed-node diffusion Monte Carlo (FN-DMC) energies of a C2 molecule. For a given multi-determinant expansion, we find that this non-orthogonal orbital optimization results in a consistent improvement in the variational energy and the FN-DMC energy on the order of a few tenths of an eV. In some cases, fewer non-orthogonal determinants are required compared to orthogonal ones in order to achieve similar accuracy in FN-DMC. Our calculations indicate that trial wave functions with non-orthogonal determinants can improve computed energies in a QMC calculation when compared to their orthogonal counterparts.


Determination of measurement uncertainty for the determination of triazines in groundwater from validation data.
Laboratories are increasingly urged to submit full uncertainties of their analytical results rather than only standard deviations. The determination of measurement uncertainties in compliance with the Guide to the Expression of Uncertainty in Measurement (GUM) is demonstrated using the validation approach explicitly endorsed by the recent edition of the EURACHEM guide for the determination of measurement uncertainty. Measurement uncertainty was split into uncertainty of the sample mass, uncertainty of the concentration of the stock standard solution, uncertainty of the calibration and uncertainty connected to within- and between-series precision. Uncertainties of sample mass and of the concentration of the stock standard solution were 0.26 and 1.14% for all analytes, which is negligible compared with the contributions of precision and calibration. Uncertainty of calibration was estimated from the calibration graph. Relative uncertainty of calibration was found to be strongly concentration dependent and to be the main uncertainty contribution below 0.2 microgram L-1. Precision was split into within-series and between-series standard deviation, which dominate the combined standard uncertainty at higher concentrations. The results obtained from these calculations are compared with results for a certified reference material and with the performance in an interlaboratory comparison. It was found that all results agreed within their uncertainty with the target values, showing that the estimated uncertainties are realistic.


Relationship between motor dysfunction and chewing movement in patients with Parkinson's disease: A transversal study.
To assess the impact of chewing movement in patients with Parkinson's disease (PD), we examined the relation between chewing movement and motor dysfunction in association with PD progression. Thirty patients with PD (mean age, 68.9 ± 9.0 years; mean Hoehn and Yahr stage, 3.0 ± 0.7) were recruited. The PD condition was assessed in each patient by using the score of Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) part III score, body mass index (BMI), serum albumin (Alb), and tongue pressure, number of chews, mealtime, and chewing speed were collected. The patients were divided into two groups (mild and moderate PD groups) based on an MDS-UPDRS part III cut-off value of 32. The chewing speed positively correlated with tongue pressure (rho = 0.69, p < 0.01) in the mild group, and with BMI (rho = 0.54, p = 0.03), serum Alb (rho = 0.63, p = 0.02), and number of chews (rho = 0.69, p < 0.01) in the moderate group. The MDS-UPDRS part III scores for all participants correlated negatively with chewing speed (rho = -0.48, p < 0.01), serum Alb (rho = -0.49, p < 0.01), and positively with mealtime (rho = 0.43, p = 0.01). Tongue pressure and serum Alb were identified to be as factors affecting the chewing speed (β= 0.560, p < 0.01; β= 0.457, p < 0.01, respectively). These results indicated that the progression of motor dysfunction in patients with PD is likely to affect chewing speed and the nutritional status decline may be linked to the impairment of chewing movement in these patients.


Power and sample size of therapeutic trials in procedural dermatology: how many patients are enough?
Many new devices and therapeutic interventions are continually introduced in cutaneous surgery. The efficacy of these new techniques must be compared with that of preexisting standards so that patients can be appropriately counseled. The purpose of this article is to (1) review methods for estimating sample size and power, (2) estimate the range of sample sizes sufficient to ensure that true differences are not missed in clinical trials of new procedural dermatologic therapies, and (3) consider the reasons why the sample size may be too small in procedural dermatology trials and how this problem can be addressed. (1) Selective review of textbooks and other relevant literature, presentation of a brief tutorial describing sample size and power determination for therapeutic clinical trials comparing two groups with continuous outcomes variables; (2) implementation of standard formulae and assumptions to estimate sample size in cutaneous surgery therapeutic trials. Assuming that one group receives a standard surgical intervention and another group undergoes a new technique, to identify a moderate difference in efficacy between groups, at least 50 to 200 subjects will need to be enrolled if conventional strategies are used to reduce the likelihood of finding a difference that does not really exist (Type I error), as well as the likelihood of missing a true difference (Type II error). By face validity, it is apparent that most efficacy comparisons in procedural dermatology have low sample size and a concomitant risk of failing to detect actual differences between therapeutic arms. Owing to the limitations that restrict surgeons from frequently performing large randomized controlled trials in procedural dermatology, meta-analyses may be needed to pool the results of smaller studies. When it is critically important that differences between groups be accurately identified, dermatologic surgeons may consider eschewing smaller trials in favor of collaborating on larger trials with an adequate sample size.