Evaluation and extensions of a structural equation modeling approach to the analysis of survival data.
Recently a new method for the analysis of survival data using a structural equation modeling approach has been suggested by Pickles and colleagues using twin data they demonstrated the application of this model to study the correlation in age of onset. The purpose of the current research is twofold: 1) to evaluate the statistical performance of the model as presented by Pickles and colleagues, and 2) to expand and evaluate the model in more applications, including both genetically informative data and other multivariate examples. Results evaluated from this study involve three areas of method performance: Type-I error rates, power, and parameter estimates under four different distributions (normal, Gamma-2, Gamma-6 and g-and-h) and four different sample sizes (n = 125, 250, 500 and 750). Results based on the original Pickles model indicated that in all sample size and distribution conditions the Type-I error rate was adequate, in fact below the nominal level of .05. Additionally, power was greater than .80 for sample sizes of 500 or more for all distribution conditions. Parameter estimates were upwardly biased when the population value was rho = .20. This bias varied across distributions; the g-and-h distribution showed the largest bias. Results from the expanded model indicated that Type-I error rates were adequate. Power results were not affected by distribution type; sample sizes of 500 were above the .80 level. Parameter estimates continued to be upwardly biased in this more general model, although the degree of bias was smaller.


Scalp laceration repair without prior hair removal.
The effect on the infection rate of hair removal prior to scalp laceration repair has not been studied prospectively in the outpatient setting. Concern exists that not removing skin hair may lead to an increased incidence of serious wound infections. Sixty-eight scalp lacerations were repaired without hair removal and examined prospectively for infection. No infections were noted at 5-day follow-up. The mean patient age was 21.8 +/- 19.8 years, and the mean laceration length was 2.5 +/- 2.0 cm. The mean time from injury to repair of laceration was 2.2 +/- 2.8 hours. Sixty-three lacerations (92.7%) were repaired within 3 hours of injury. A prospective, randomized study in a select patient population to examine the effect of prior hair removal on infection rate is warranted.


Localization of elevated glutaminase immunoreactivity in small DRG neurons.
Glutamate has long been considered to be a neurotransmitter candidate in vertebrate spinal sensory nerve cells. We report here the first immunohistochemical evidence in support of this hypothesis. We find that up to 30% of the moderately small dorsal root ganglion neurons in the rat contain elevated levels of glutaminase immunoreactivity. This enzyme, which mediates the synthesis of glutamate from glutamine, is not found at these high levels in large diameter neurons of the same ganglia. In contrast, another enzyme associated with glutamate metabolism, aspartate aminotransferase, is rather uniformly distributed within neurons of the sensory ganglia. These data define a subpopulation of sensory neurons which appear to contain an elevated capacity to synthesize glutamate through the glutamine cycle and suggest that glutaminase immunoreactivity may be an indicator of glutamatergic function in some nerve cells.


Operative treatment of distal radius fractures involving the volar rim-A systematic review of outcomes and complications.
Distal radius fractures involving the volar rim are a subset of unstable and extremely distal fractures involving the volar lunate and/or scaphoid facets. Volar rim fractures (VRF) are challenging to manage and different treatment options have been described. This study aimed to compare outcomes and assess the rates of complications and implant removal for different treatment methods of wrist fractures involving VRF. A systematic review of studies published in MEDLINE, EMBASE, Web of Science and Cumulative Index to Nursing and Allied Health literature (CINAHL) was conducted to assess the operative outcomes of VRF. Data on patient demographics, implant usage, postoperative outcomes, complications, and implant removal were compiled. Twenty-six studies met the inclusion criteria with a total of 617 wrists. The most commonly used implants were 2.4 mm variable-angle volar rim plate (DePuy Synthes) (17.5%), Acu-Loc II (Acumed) (14%) and standalone hook plates (13%). The average outcome measures were Q-DASH (10.9 ± 7), MWS (85.8 ± 7.5), PRWE (15.9 ± 12.1), and DASH (14 ± 8.5). The overall complication rate was 14% (n = 87), with 44% (n = 38) involving flexor tendon problems. The implant removal rate was 22%, with routine removal being performed in 54% and non-routine removal in 46% of cases. The current treatment of VRF yields favorable functional outcomes across different treatment options. However, these fractures have a high rate of complications and re-interventions, particularly for symptomatic implants. Therapeutic IV.


Facile fabrication of robust superhydrophobic epoxy film with polyamine dispersed carbon nanotubes.
Nanocomposite films of superhydrophobic surface are fabricated from the dispersion of unmodified carbon nanotubes (CNTs) and hydrophobic poly(isobutylene)-amine (PIB-amine). The PIB-amine prepared from the amidation of poly(isobutylene)-succinic anhydride and poly(oxypropylene)-amines is essential for dispersing the originally entangled CNTs into the debundled CNTs as observed by TEM. A robust CNTs/epoxy nanocomposite film with high dimensional stability is made by subsequent curing with epoxy resin. The self-standing film exhibits a superhydrophobic property, with water droplet contact angle > 152° due to the CNTs controlled alignment on the surface forming micrometer-size plateaus, as observed by SEM. The preparation of PIB-amine/CNTs dispersion and subsequently curing into a superhydrophobic CNTs/epoxy film is relatively simple and can potentially be applied to large surface coating.


Development and validation of a continuous metabolic syndrome severity score in the Tehran Lipid and Glucose Study.
Metabolic syndrome (MetS), defined as the coexistence of interrelated cardiometabolic risk factors, is limited by ignoring the severity of the disease and individuals with a pre-metabolic state. We aimed to develop the first age- and sex-specific continuous MetS severity score in the adult population using confirmatory factor analysis (CFA) based on the MetS components in the Middle East. Using data from the population-based Tehran Lipid and Glucose Study (TLGS) I and II datasets, we conducted CFA of the single factor MetS on 8933 adults (20-60 years old) totally, and in age and sex subgroups. We allowed for different factor loadings across the subgroups to formulate age- and sex-specific continuous MetS severity score equations. Thereafter, we validated these equations in the dataset of TLGS III participants. Triglyceride had the highest factor loading across age and sex subgroups, indicating the most correlation with MetS. Except for women aged 40-60 years, waist circumference was the second most significant factor contributing to MetS. Systolic blood pressure was more closely related to MetS in women than in men. Systolic blood pressure and fasting plasma glucose had the weakest correlation with MetS among the 40-60 age group. Moreover, as women age, the contribution of fasting plasma glucose to MetS tended to decline, while it remained relatively constant in men. The resulting MetS severity score was correlated with age and homeostasis model assessment of insulin resistance. Furthermore, the continuous MetS severity score well predicted the traditional MetS according to receiver operating characteristic analysis in the validation dataset. The age- and sex-specific continuous MetS severity score for the West Asian adult population provides a tangible quantitative measure of MetS enabling clinicians to screen and monitor the individuals at risk and assess their metabolic trends.


The ISOTILT software for discovering cooperative rigid-unit rotations in networks of interconnected rigid units.
A user-friendly web-based software tool called 'ISOTILT' is introduced for detecting cooperative rigid-unit modes (RUMs) in networks of interconnected rigid units (e.g. molecules, clusters or polyhedral units). This tool implements a recently described algorithm in which symmetry-mode patterns of pivot-atom rotation and displacement vectors are used to construct a linear system of equations whose null space consists entirely of RUMs. The symmetry modes are first separated into independent symmetry-mode blocks and the set of equations for each block is solved separately by singular value decomposition. ISOTILT is the newest member of the ISOTROPY Software Suite. Here, it is shown how to prepare structural and symmetry-mode information for use in ISOTILT, how to use each of ISOTILT's input fields and options, and how to use and interpret ISOTILT output.


Effects of light quantity and quality and soil nitrogen status on nitrate reductase activity in rainforest species of the genus Piper.
We studied nitrate reductase (NR) activity in six species of the genus Piper (Piperaceae) growing under a broad range of light availabilities. Field measurements were made on plants growing naturally in rainforest at the Los Tuxtlas Tropical Biological Preserve, Veracruz, Mexico at high- and lowlight extremes for each species. Foliar nitrogen on an area basis was positively related to the average daily photosynthetically active photon flux density (PFD) received by the leaf (r=0.76, p<0.01). In vivo NR activity was highly correlated with PFD (r=0.95, p<0.001) and less so with total leaf nitrogen (r=0.68, p<0.05). In vivo NR activity was always higher in high-light plants than in low-light plants within a species. Similarly, gap species such as P. auritum had much higher in vivo NR activities than shade species such as P. aequale. Soil NO 3- and NH 4+ pools and nitrogen-mineralization rates at Los Tuxtlas were similar between high- and low-light sites, indicating that the elevated NR activities in high-light plants were not the result of higher NO 3- availabilities in high-light microsites. We performed additional experiments at Stanford, California, USA on Piper plants grown at high- and low-light. Foliar NR was highly inducible by nitrate in the gap species (auritum) but not in the generalist (hispidum) or shade (aequale) species. Root NR activities were, in general, an order of magnitude lower than foliar activities. In total, these studies suggest that Piper gap species are inherently more competent to assimilate NO 3- and are better able to respond to sudden increases in NO 3- availability than are shade species.


The Temporal Association of Depression and Anxiety in Young Men With Erectile Dysfunction.
Erectile dysfunction (ED) is a multidimensional sexual disorder that is being increasingly diagnosed in younger men. Although mental illnesses such as depression and anxiety are known risk factors for ED, the association between these conditions and ED has been understudied in young men. To explore the temporal association between depression, anxiety, and ED in a population-based cohort of young men. Using 2009-2018 MarketScan Commercial Claims data, we identified all men with ED aged 18-40 years (cases). Using ICD-9/-10 codes and prescription data, we evaluated the prevalence and incidence of depression and anxiety in this cohort. Cases were matched with men without a diagnosis of ED (controls) based on age, Charlson Comorbidity Index, history of hypertension, geographic region, and year of presentation. We examined the prevalence of depression and anxiety within 12 months prior to ED diagnosis and incidence of depression and anxiety up to 36 months after ED diagnosis in cases vs controls. Differences between cases and controls were tested with Wilcoxon rank-sum test for numerical covariates, and chi-square test for categorical covariates. Significance was set at P < .05. Prevalence and incidence of depression and anxiety in young men with and without ED. Within the 12-month period preceding ED diagnosis, the prevalence of depression and anxiety in cases vs controls were 17.1% vs 12.9%, respectively (P < .001). The incidence of depression and anxiety were higher amongst cases vs controls at 12- (11.7% vs 6.3%), 24- (14.5% vs 9.0%,) and 36- (15.9% vs 10.6%) months following ED diagnosis (P < .001). High incidence and prevalence of depression and anxiety in young men diagnosed with ED highlight the importance of normalizing mental health screenings and routine psychiatric follow-up in this population. Our contemporary, case-control study utilizes a population-based cohort of young men with ED to study the temporal association between depression, anxiety, and ED, which is understudied to date. The MarketScan commercial claims database used in this analysis includes men covered by private insurers only and lacks data on symptoms and treatments. Young men with ED had significantly higher rates of depression and anxiety both before and after ED diagnosis in comparison to young men without ED. Manalo TA, Biermann HD, Patil DH, et al. The Temporal Association of Depression and Anxiety in Young Men With Erectile Dysfunction. J Sex Med 2022;19:201-206.


Gastroesophageal reflux and ascorbic acid insufficiency.
The incidental discovery of scurvy in a patient with a symptomatic hiatal hernia has led to the identification of 9 other individuals with chemically proved vitamin C deficiency secondary to an expressed aversion to "acid" food in any form. These patients were screened with capillary fragility tests and serum ascorbic acid determinations from approximately 200 hiatal hernia and reflux patients. With resumption of a normal vitamin C intake, scattered deficiency symptoms disappeared and both capillary fragility tests and serum ascorbic acid levels returned toward normal. There were no wound healing problems.


COVID-19: The disease, the vaccine and the heart.
Coronavirus SARS-CoV-2 has fundamentally affected the health, healthcare delivery and daily life in all populations and age groups in Australia. The aim of this report is to summarise how it has affected the paediatric population with an emphasis on, but not limited to, the cardiac manifestations. A literature review and appraisal of data relating to SARS-CoV-2 cardiac manifestations and vaccination in the paediatric population was undertaken.The majority of children with SARS-CoV-2 infection recover well. However, a very small proportion may develop severe acute disease. In the sub-acute phase, children may also develop a Kawasaki like illness, Paediatric Inflammatory Multisystem Syndrome temporally associated with SARS-CoV-2. Whilst not directly cardiac in nature, SARS-CoV-2 also affected children in other profound ways. Public health measures with widespread lockdowns appeared to disproportionately affect the paediatric population causing physical deconditioning and psychological harm. Vaccination against SARS-CoV-2 has proven to be safe and effective, but the small rate of complications did disproportionately affect teenage children with risks of myocarditis and pericarditis. The long term outcomes following myocarditis related to SARS-Cov-2 vaccination are yet to be clarified. When treating children in the era of SARS-CoV-2, Paediatricians need to be well aware of the risks of infection in the acute and sub-acute phases, have a good understanding of the well-established recommendations for vaccination, and also be cognisant of psychological impacts.


Errors in 14 pulse oximeters during profound hypoxia.
The accuracy of pulse oximeters from fourteen manufacturers was tested during profound brief hypoxic plateaus in 125 subject sets using 50 normal adult volunteers, of whom 29 were studied two to nine times. A data set usually consisted of 10 subjects, and 13 sets were collected between August 1987 and July 1988. In the first 6 sets, six 30-second hypoxic plateaus were obtained per subject at 55 +/- 6% oxyhemoglobin (O2Hb) (range, 40 to 70%). In the last 7 sets, three hypoxic plateaus were obtained at each of four levels, approximately 86, 74, 62, and 50% O2Hb, for the purpose of linear regression analysis. Inspired oxygen was adjusted manually breath by breath in response to arterial oxygen saturation computed on-line from end-tidal oxygen and carbon dioxide tensions. End-plateau arterial blood O2Hb was analyzed by a Radiometer OSM-3 oximeter, and plateau pulse oximeter saturation (SpO2) was read by cursor from a computer record of the analog output. Three to 13 instruments were tested simultaneously by using 1 to 3 duplicate instruments from each of one to seven manufacturers. Variations introduced by manufacturers were tested on subsequent sets in several instruments. An index of error, "ambiguity" (alpha) of oxygen saturation, was defined as the absolute sum of bias and precision (mean and SD of SpO2 - O2Hb) at O2Hb = 55.8 +/- 4.5%, preserving the sign when bias was significant at P less than 0.05. Ambiguity values for finger probes (unless specified) with latest data were: Physio-Control, 3.9 (ear, 3.3); Puritan-Bennett, -4.4; Criticare, 5.8 (forehead, 4.7); Kontron, 5.9 (infant probe) and 6.1 (ear, 5.8; forehead, 7.1); Biochem, -6.0; Datex 6.4 (ear, 6.9; forehead, 6.8); Critikon, 8.4; SiMed, 8.6; Marquest, 9.0; Novametrix, 10.2; Invivo, -12.2 (ear, -14.3); Nellcor, -15.1; Ohmeda, -21.2; and Radiometer, -21.2 (ear, -9.6). Linear regression slopes of 36 instruments from twelve manufacturers generally deviated from 1 in proportion to alpha. The data showed substantial differences in bias and precision between pulse oximeters at low saturations, the most common problems being underestimation of saturation and failing precision.


Multi-fold Sonogashira coupling: a new and convenient approach to obtain tetraalkynyl anthracenes with tunable photophysical properties.
For the first time, a direct single-step one-pot route to access nine new symmetric tetraalkynylated anthracenes via Pd(CH3CN)2Cl2/cataCXium®A catalyzed tetra-fold Sonogashira coupling is reported. Five of these tetraalkynylated anthracenes have been crystallographically characterized, with two of them exhibiting multiple interactions that significantly shorten the inter-planar distances in the solid-state structure. The rich photophysical properties exhibited by these molecules hold immense promise for future applications in sensors and optoelectronic devices. Two of the considered tetraalkynylated anthracenes comprising a D-π-A-π-D motif demonstrate solvatochromism and halochromism, with one of them showing a low bandgap of 1.79 eV. The remaining compounds demonstrate bandgaps in the range of 1.79-2.04 eV.


Semiquantitative estimations of quinacrine fluorescence in intestinal nerve fibres.
Quinacrine has been shown to bind selectively to a population of nerves and ganglion cells in the mouse, rat and guinea-pig gut. In the present report a method for semiquantitation of nervous quinacrine contents using semiquantitative estimations of fluorescence intensity and nerve fibre density is presented and evaluated. Estimation of fluorescence intensity and nerve fibre density is based on a scale with eleven steps from 0 to 5. Preparations were incubated in 14C-labelled quinacrine hydrochloride. Reliability of the scale was expressed as the correlation coefficient between two consecutive blind estimations of the same preparations with recoding and remixing specimens in between. This correlation was found to be 0.95 or higher. Validity was expressed as the correlation between the semiquantitative estimations and 14C-quinacrine uptake measurements into the same specimens. Also this correlation was found to be strongly positive. It was concluded that nervous quinacrine content and amount of quinacrine binding nerves can be reliably estimated by fluorescence microscopy.


Transcriptomic analysis of genes involved in the biosynthesis, recycling and degradation of L-ascorbic acid in pepper fruits (Capsicum annuum L.).
Sweet pepper (Capsicum annuum L.) is widely recognized among the vegetables with high content of ascorbic acid (AsA). However, the metabolic pathways involved in the biosynthesis, recycling and degradation of AsA and their relative contribution to the concentration of AsA have not been established yet. In the present work, the expression levels of selected genes involved in the AsA biosynthesis, degradation and recycling pathways were analyzed during development and ripening of pepper fruit cv. Palermo and in mature fruit of four cultivars (Lipari, C-116, Surrentino and Italverde) with different AsA concentrations. An inverse correlation was found between the expression of the biosynthetic genes and AsA concentrations, which could indicate that a feedback mechanism regulates AsA homeostasis in pepper fruits. Interestingly, analysis of mRNA levels of ascorbate oxidase, involved in the degradation of AsA, suggests that this enzyme plays a critical role in the regulation of the AsA pool during fruit development and ripening.


Chorionic villus sampling--short-term versus long-term culture in a subtle 2; 18 translocation.
Prenatal diagnosis on chorionic villous tissue was performed for a woman with the karyotype 46,XX,t(2;18)(q32;q12)--a subtle 'difficult' translocation. The case illustrates the necessity of good quality cytogenetics for accurate prenatal diagnosis. For chorionic villi this can be obtained only with long-term culture.


Novel real-time PCR assays for genomic group identification of tick-borne relapsing fever species Borrelia hermsii.
Borrelia hermsii is a non-Lyme borreliosis pathogen that is responsible for causing tick-borne relapsing fever in humans and animals in the western United States. B. hermsii has been described to encompass two divergent genomic groups, GGI and GGII, which have been suggested to maintain a unique geographical distribution and potential range of pathogenicity. Though the genomic groups have been extensively documented in the literature, a real-time PCR tool for identifying these genomic groups is lacking. This study describes the development and validation of two flaB-based quantitative real-time PCR assays for differentiating between the two genomic groups of B. hermsii while also maintaining specificity against other closely related Borrelia species. The diagnostic specificity of the assays were evaluated using a large panel of various Borrelia species, including a collection of 22 B. hermsii culture isolates purified from various hosts. The high sensitivity and specificity of the assays provide a useful tool for supporting future studies aimed at evaluating the geographical distribution as well as potential intraspecies pathogenicity within arthropod vectors and mammalian hosts.


Different informativeness of the three hypervariable mitochondrial DNA regions in the population of Bologna (Italy).
Mitochondrial DNA (mtDNA) sequence variations at hypervariable regions HVI, HVII and HVIII were analysed in 100 unrelated Italians from Bologna. The values of the statistical parameters are in agreement with the range of European populations. We suggest that the less informative HVIII region may be useful to distinguish HVI-HVII identical sequences in forensic analysis especially when nuclear DNA cannot be investigated.


Atypically Located Osteoid Osteoma: Characteristics and Therapeutic Success After Image-Guided Thermal Ablation.
While ostoeid osteomas (OO) are typically located in long tubular bones, OO occurring elsewhere are referred to as "atypical". Aim of our study was to review the characteristics of atypically located OO, course of symptoms and therapy, as well as clinical outcome, safety, and patient satisfaction of radiofrequency ablation (RFA). In the period from 04/01 to 07/13, 33 patients were treated using thermal ablation (RFA or laser), partly with low temperature and short duration technique. Clinical records were analyzed. Additionally, 23 patients were interviewed via telephone. Primary endpoints were technical success, clinical success (recurrence rates), and adverse events. Secondary endpoints were course of symptoms and therapy as well as patient satisfaction. Mean follow-up was 22.1 ± 21.5 months. Average patient age was 31.7 ± 16.3 years. Localization: Most atypical OO (61 %) were located in the lower extremity, followed by axial skeleton (26 %) and upper extremity (13 %). Pain anamnesis: 74 % of patients stated that their pain occured predominantly at night and responded to NSAID, as typical for OO. Diagnostics: Patients consulted on average 4 different doctors and in 52 % patients, ≥ 3 different radiologic imaging techniques where used before the diagnosis "OO" was made. Technical success of thermal ablation was 100 %. Primary clinical success was 91 %. Patient satisfaction was 100 %. No major complications occurred. In ¼ of cases, atypical OO did not show the typical pain characteristics of OO. Image-guided thermal ablation is a promising and safe therapy also for patients with atypical OO. · Atypical OO are challenging regarding diagnostics and therapy. · Image-guided thermal ablation is a safe and effective procedure also for patients with atypical OO. · Image-guided thermal ablation shows high patient satisfaction. · Seemann RJ, Märdian S, Schwabe P et al. Atypically Located Osteoid Osteoma: Characteristics and Therapeutic Success After Image-Guided Thermal Ablation. Fortschr Röntgenstr 2020; 192: 335 - 342.


Anatomic site-specific disparities in survival outcomes for penile squamous cell carcinoma.
To identify the predictors of cancer-specific mortality of penile squamous cell carcinoma (PSCC) using a population-based database. Using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry, we performed a time-to-event analysis to determine which clinical parameters were useful in predicting cancer-specific mortality. Our cohort consisted of 2515 cases of PSCC diagnosed from 1973 to 2007. The patients were divided into 2 groups: primary tumors of the prepuce (n = 722) and primary tumors of the glans, body, and overlapping lesions of the skin (n = 1793). The median follow-up for the cohort was 39 months (range 1-411). Compared with tumors of the prepuce, tumors of the body (hazard ratio 1.61, 95% confidence interval 1.00-2.60, P = .05) and overlapping tumors of the skin (hazard ratio 1.79, 95% confidence interval 1.13-2.83, P = .01) had a greater risk of cancer-specific mortality, even when controlling for age, Surveillance, Epidemiology, and End Results stage, and tumor grade. Furthermore, the disease-specific 10-year survival rate of those with preputial tumors was 89.4% compared with 78.7% for the other 3 groups combined (P < .0001). Anatomic site-specific disparities for PSCC survival appear to exist. Patients diagnosed with PSCC of the prepuce have greater overall long-term disease-specific survival than patients with primary tumors elsewhere.


[Medical ethics and forensic psychiatric assessment].
The legally determined role of psychiatric expert in court is described. As a necessity he always is confronted with ethical problems as regards professional discretion and instruction. In any case--proband may be ill or not--human rights and dignity have to be taken care of.


The Sendai river terraces monitored the co-seismic mega-thrusting.
We conducted a detailed geological survey of the Sendai region, covering an area of 100 × 50 km. Our survey focused on accurately mapping river terraces, identifying the source volcanoes responsible for intercalated tephras, and locating the Nagamachi-Rifu fault and associated faults. The river terraces were observed and categorized based on their elevation relative to the present river channels. These terraces are predominantly found on the hanging wall of major reverse faults. Each terrace comprises fluvial gravels at the lower levels and eolian loam intercalated with local and regional tephras at higher levels, with the contact age corresponding to the time of emergence. To determine the ages of the terrace gravels, we employed a combination of zircon U-Pb dating, sedimentation rate calculations, and extrapolation techniques. This allowed us to establish the abandonment or emergent dates of the terraces. The formation of these terraces coincided with periods of fault activity, including hanging wall uplift, footwall subsidence, and fault vertical displacement, effectively monitoring the co-seismicity of the Nagamachi-Rifu fault. While we cannot predict the exact timing of future events, it is crucial to remain vigilant regarding the potential occurrence of a significant earthquake triggered by these fault activities.


Silica coating influences the corona and biokinetics of cerium oxide nanoparticles.
The physicochemical properties of nanoparticles (NPs) influence their biological outcomes. We assessed the effects of an amorphous silica coating on the pharmacokinetics and pulmonary effects of CeO2 NPs following intratracheal (IT) instillation, gavage and intravenous injection in rats. Uncoated and silica-coated CeO2 NPs were generated by flame spray pyrolysis and later neutron-activated. These radioactive NPs were IT-instilled, gavaged, or intravenously (IV) injected in rats. Animals were analyzed over 28 days post-IT, 7 days post-gavage and 2 days post-injection. Our data indicate that silica coating caused more but transient lung inflammation compared to uncoated CeO2. The transient inflammation of silica-coated CeO2 was accompanied by its enhanced clearance. Then, from 7 to 28 days, clearance was similar although significantly more (141)Ce from silica-coated (35%) was cleared than from uncoated (19%) (141)CeO2 in 28 days. The protein coronas of the two NPs were significantly different when they were incubated with alveolar lining fluid. Despite more rapid clearance from the lungs, the extrapulmonary (141)Ce from silica-coated (141)CeO2 was still minimal (<1%) although lower than from uncoated (141)CeO2 NPs. Post-gavage, nearly 100% of both NPs were excreted in the feces consistent with very low gut absorption. Both IV-injected (141)CeO2 NP types were primarily retained in the liver and spleen. The silica coating significantly altered the plasma protein corona composition and enhanced retention of (141)Ce in other organs except the liver. We conclude that silica coating of nanoceria alters the biodistribution of cerium likely due to modifications in protein corona formation after IT and IV administration.


Radicals in 'biologically relevant' concentrations behave differently: Uncovering new radical reactions following the reaction of hydroxyl radicals with DMSO.
Methyl radicals play key roles in various chemical and biological processes. Mechanistic studies of methyl radicals with their precursor, Dimethyl Sulfoxide (DMSO), were extensively studied. Though the involved mechanisms seemed to be clarified, essentially none of the studies have been performed at conditions relevant to both biological and catalytic systems, i.e. low steady state radical concentrations. A chain-like reaction, as an inverse function of the radicals concentrations ([•CH3]ss), increases the methyl radical yields. The nature of the additional products obtained differs from those commonly observed. Furthermore it is shown that methyl radicals abstract a methyl group from DMSO to yield ethane. Herein we report a novel mechanism relevant mainly at low steady state radical concentrations, which may change the understanding of certain reaction routes present in both biological systems and catalytic chemical systems. Thus the results point out that mechanistic studies have to be carried out at dose rates forming radicals at analogous concentrations to those present in the process of interest.


Identification of ESE1 as a β-Catenin Binding Protein.
β-Catenin regulates cell-cell adhesion and gene transcription and acts as a master switch that controls proliferation in several types of cancer. ESE1 is an epithelium-restricted transcription factor and its multiple domain structure predicts its interaction with other proteins with diverse cellular functions. Here, for the first time, we report that endogenous β-catenin binds to and co-localizes with endogenous ESE1 in the cytoplasm. The binding sites were mapped to E26 transformation-specific (ETS) domain at carboxyl terminus of ESE1 and N-terminus of β-catenin. We found that C-terminus of ESE1 also binds to α-catenin and that ESE1/β-catenin interaction was abrogated by knockdown of either β-catenin or α-catenin. The data suggest that interactions between ESE1 and β-/α-catenins might be a mechanism by which the ESE1 protein determines the β-catenin function and tumorigenesis.


Comparison of utilization and cost of healthcare services and pharmacotherapy following implantation of vagus nerve stimulation vs. responsive neurostimulation or deep brain stimulation for the treatment of drug-resistant epilepsy: analyses of a large United States healthcare claims database.
Vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) all are options for drug-resistant epilepsy (DRE). However, little is known about how the choice of neurostimulation impacts subsequent healthcare costs. We used a large US healthcare claims database to identify all patients with epilepsy who underwent neurostimulation between 2012 and 2019. Eligible patients were identified and stratified based on procedure received (VNS vs. RNS/DBS). VNS patients were matched by propensity scoring to RNS/DBS patients. Use and cost of healthcare resources and pharmacotherapy were ascertained over the 24-month period following neurostimulation, incorporating all-cause and epilepsy-related measures. Disease-related care was defined based on diagnoses of claims for medical care and relevant pharmacotherapies. Seven hundred and ninety-two patients met all selection criteria. VNS patients were younger, were prescribed a higher pre-index mean number of anti-seizure medications (ASMs), and had higher pre-index levels of use and cost of epilepsy-related healthcare services. We propensity matched 148 VNS patients to an equal number of RNS/DBS patients. One year following index date (inclusive), mean total all-cause healthcare costs were 50% lower among VNS patients than RNS/DBS patients, and mean epilepsy-related costs were 55% lower; corresponding decreases at the two-year mark were 41% and 48%, respectively. Some clinical variables, such as seizure frequency and severity, quality of life, and functional status were unavailable in the database, precluding our ability to comprehensively assess differences between devices. Administrative claims data are subject to billing code errors, inaccuracies, and missing data, resulting in possible misclassification and/or unmeasured confounding. After matching, VNS was associated with significantly lower all-cause and epilepsy-related costs for the two-year period following implantation. All-cause and epilepsy-related costs remained statistically significantly lower for VNS even after costs of implantation were excluded.


A new ligand skeleton for imaging applications with d-f complexes: combined lifetime imaging and high relaxivity in an Ir/Gd dyad.
A new rigid and conjugated ligand structure connecting phenanthroline and poly(amino-carboxylate) binding sites provides d-f complexes which show high potential for use in dual (luminescence + magnetic resonance) imaging and for optimisation of d → f photoinduced energy-transfer.


Tritiated-6-beta-fluoro-6-desoxy-oxymorphone: a highly selective ligand for the opiate mu receptor whose binding is characterized by low nonspecific binding.
In this paper we examine the binding of [3H]FOXY (tritiated-6-beta-fluoro-6-desoxy-oxymorphone) to membranes of rat brain. Using the site-directed alkylating agents BIT and FIT, evidence is presented that [3H]FOXY selectively labels mu opiate binding sites in vitro. Further, BIT and FIT did not significantly affect [3H]bremazocine binding to kappa receptors. Scatchard plots of [3H]FOXY binding were somewhat curvilinear, suggesting the presence of two classes of mu binding sites. At concentrations up to 19 nM, 90 percent of the total binding was specific. The combination of high mu-selectivity and low nonspecific binding suggests the [3H]FOXY may prove to be a powerful tool for studying the opiate mu receptor.


Readiness-to-change as a moderator of a web-based brief intervention for marijuana among students identified by health center screening.
Electronic screening and brief intervention has been identified as a low cost strategy to address marijuana use among students, however there is little known about who may be most responsive to this intervention approach. This study examined whether readiness-to-change moderated the influence of a web-based intervention on frequency of use at 3-month outcomes. One-hundred twenty-three students who smoked marijuana at least monthly were identified by screening in a student health center. Baseline and 3-month outcome assessments were conducted on-line. Participants were randomly assigned to either eCHECKUP TO GO-marijuana or a control condition after completing marijuana measures and the Readiness-to-Change Questionnaire (RTCQ). Negative binomial regression analyses were conducted to examine whether the effect of the intervention on marijuana use at 3-month outcomes was moderated by the Action and Problem Recognition dimensions of the RTCQ, adjusting for baseline use. Analyses showed a significant Intervention × Action interaction. Probing of interaction effects showed that among those with high scores on the Action scale participants in the intervention group reported significantly fewer days of use than those in the control condition at follow-up (IRR=0.53, 95%CI: 0.94, 2.08). The Problem Recognition dimension did not moderate the influence of the intervention on outcomes. These results suggest that this eSBI may bolster change efforts among students who have begun taking steps toward changing their marijuana use.


Follicular helper T cells promote the effector functions of CD8+ T cells via the provision of IL-21, which is downregulated due to PD-1/PD-L1-mediated suppression in colorectal cancer.
Recent studies have demonstrated that higher expression of follicular helper T cell (Tfh)-associated genes is associated with better prognosis in breast cancer and colorectal cancer (CRC), but the underlying mechanisms remain unclear. In this study, we compared the function of Tfh cells in non-cancer (NC) controls and in CRC patients between stages II and IV. Data showed that the level of CD4+CXCR5+ Tfh cells were significantly upregulated in stage II CRC patients but was progressively reduced in stage III and stage IV patients. The frequency of PD-1+ cells in CD4+CXCR5+ Tfh cells, on the other hand, was progressively increased from NC patients to CRC patients with increasing severity. Interestingly, the CD4+CXCR5+PD-1- Tfh cells, but not the CD4+CXCR5+PD-1+ Tfh cells, promoted the CD107a expression and IFN-γ expression by CD8+ T cells. This CD8+ T cell-promoting capacity was dependent on the expression of IL-21, as this capacity was significantly impaired by IL-21 neutralization. Tfh cells from CRC patients with advanced stages presented gradual reduction in the capacity to stimulate CD8+ T cells and the capacity to produce IL-21. In addition, treatment with autologous PD-L1-expressing tumor cells further suppressed the IL-21 expression by PD-1+ Tfh cells. Together, these data demonstrated that Tfh cells potently enhanced the effector functions of CD8+ T cells in an IL-21-dependent pathway; however, this role of Tfh cells was limited in CRC patients due to PD-1/PD-L1-mediated suppression.


A synergistic promotion strategy remarkably accelerated electrochemiluminescence of SnO2 QDs for MicroRNA detection using 3D DNA walker amplification.
Developing low-cost and efficient methods to enhance the electrochemiluminescence (ECL) intensity of luminophores is highly desirable and challenging. Herein, we develop a synergistic promotion strategy based on three types of co-reaction accelerators to achieve an efficient SnO2 quantum dots (SnO2 QDs)-based ternary ECL system. Specifically, the MnO2 nanoflowers (MnO2 NFs), Ag nanoparticles (Ag NPs) and hemin/G-quadruplex were rationally selected as co-reaction accelerators. Owing to the synergistic effect, the deft integration of three types of co-reaction accelerators enabled better structural stability, more exposed catalytic active sites, and faster charge transfer, thus more effectively facilitating the reduction of co-reactant (S2O82-) compared with that of the single co-reaction accelerator. To demonstrate the practical utility of this principle, an "on-off-super on" ECL biosensor was constructed in combination with a 3D DNA walker, which showed a superior linear range (10 aM-100 pM) and a low detection limit (2.9 aM) for the highly-sensitive miRNA-21 detection. In general, this work firstly reported that three types of co-reaction accelerators were deftly integrated to remarkably amplify the ECL emission of SnO2 QDs, and provided brand-new perspectives for research on the ingenious design of the structure and component of highly efficient co-reaction accelerators.


Engineering a thermo-stable superoxide dismutase functional at sub-zero to >50°C, which also tolerates autoclaving.
Superoxide dismutase (SOD) is a critical enzyme associated with controlling oxygen toxicity arising out of oxidative stress in any living system. A hyper-thermostable SOD isolated from a polyextremophile higher plant Potentilla atrosanguinea Lodd. var. argyrophylla (Wall. ex Lehm.) was engineered by mutation of a single amino acid that enhanced the thermostability of the enzyme to twofold. The engineered enzyme was functional from sub-zero temperature to >50°C, tolerated autoclaving (heating at 121°C, at a pressure of 1.1 kg per square cm for 20 min) and was resistant to proteolysis. The present work is the first example to enhance the thermostability of a hyper-thermostable protein and has potential to application to other proteins for enhancing thermostability.


Uroflowmetric differences between standing and sitting positions for men used to void in the sitting position.
To compare the results of uroflowmetry in the standing and sitting position in men who void only in the sitting position. Two hundred patients were subjected to pelvic ultrasonography while their bladders were full, and then after voiding. Uroflowmetry was done both in sitting and standing positions and compared for all patients. Further comparisons were made according to patients' age (below and above 50) and Qmax (at or below 15 mL per second versus greater than 15 mL per second). We performed statistical analysis using Wilcoxon matched-pairs signed-ranks test. Comparison of uroflowmetric results in both positions showed no statistical differences except for significantly larger residual urine volume in the standing position (86.1 +/- 77) relative to the sitting position (73 +/- 80.2) (P = 0.04). On substratifying patients according to age, Qmax was significantly higher in the sitting position (16.6 +/- 8.94) relative to the standing position (15.2 +/- 7.5) in the young group (P = 0.02). Such a significant difference was not seen in the elder (greater than 50 years) group. In contrary to the low-flow group, cases with high flow showed significantly higher Qmax and Qave and significantly lower voiding and flow times and significantly lower residual urine volume in the sitting position. Voiding in the sitting position showed significantly better flow rates than during standing in patients with higher flow and younger age. Moreover, postvoid residual was significantly less in the sitting position in the previous two groups and in the total groups of patients. On the contrary, the presence of low flow nullifies these uroflowmetric positional differences. Uroflowmetry should be always performed in the preferred position.


Characterization of Brucella abortus sigma factor sigma54 (rpoN): genetic complementation of Sinorhizobium meliloti ntrA mutant.
The intracellular pathogen Brucella abortus has an alternative sigma factor sigma54 (RpoN) highly similar to Sinorhizobium meliloti NtrA. RpoN was described to be required for the transcription of a wide range of genes involved in diverse physiological functions including the regulation of virulence-related factors in both plants and animal pathogens. B. abortus rpoN gene restored the normal growth of an S. meliloti ntrA mutant in minimal media with succinic acid as a sole carbon source as well as the formation of functional nodules in alfalfa, thus revealing that the gene is functional. B. abortus rpoN mutant and B. abortus wild-type strain harboring a multicopy plasmid coding for a wild-type rpoN gene displayed reduced survival under stationary-phase conditions suggesting that expression of RpoN must be tightly regulated. Real-time PCR analysis revealed that B. abortus rpoN expression is downregulated during the stationary phase of growth. This regulation is absent in the rpoN mutant background, indicating that RpoN regulates its own expression. Intracellular multiplication in HeLa or J774 cells, and survival in BALB/c mice of the rpoN mutant, are not affected. However 2weeks postinfection survival of rpoN mutant complemented with a multicopy plasmid containing a wild-type rpoN gene is reduced, thus suggesting that overexpression of rpoN may misregulate the expression of genes involved in this stage of infection.


Fentanyl patch versus tramadol for the control of postoperative pain in canine ovariectomy and mastectomy.
The purpose of the present study was to evaluate the postoperative analgesic efficacy of fentanyl patches versus subcutaneous tramadol after canine ovariectomy, with and without unilateral mastectomy. A total of 40 female dogs were included in the present study, all of which were domesticated, healthy and 4-12 years of age. The animals were divided into four groups (n = 10 per group) based on the surgery and the analgesic protocol used: the TO group only underwent ovariectomy, and received postoperative tramadol; the TM group underwent both ovariectomy and mastectomy, and received postoperative tramadol; the FO group only underwent ovariectomy, and received fentanyl patches; and the FM group underwent both ovariectomy and mastectomy, and received fentanyl patches. Postoperative pain was evaluated every 4 h for 24 h using a numeric analogue scale (NAS) and a modified Glasgow Composite Measure Pain Scale Short Form (CMPS-SF). The results of the present study showed that patients in all four groups tolerated postoperative surgical stress well. Analysis of variance for repeated measures did not show significant differences in the NAS scores and in Glasgow CMPS-SF between groups in terms of pain scores or rescue analgesia. These results indicated that the analgesic effect of the fentanyl patch was similar to that of subcutaneous (SC) tramadol in female dogs after ovariectomy, with and without unilateral mastectomy, suggesting that the fentanyl patch may represent a valid supplementary tool for the control of postoperative pain in animals after surgery.


The effects of solution structure on the surface conformation and orientation of a cysteine-terminated antimicrobial peptide cecropin P1.
The surface structure of an antimicrobial peptide, cecropin P1, immobilized to a gold surface via a terminal cysteine residue was investigated. Using reflection-absorption infrared spectroscopy, surface plasmon resonance, and X-ray photoelectron spectroscopy, the effects of pH, solution conformation, and concentration on the immobilized peptide conformation, average orientation, and surface density were determined. Under all conditions investigated, the immobilized peptides were alpha-helical in a predominately flat, random orientation. The addition of the reducing agent Tris(2-carboxyethyl) phosphine hydrochloride to the buffer resulted in a twofold increase in immobilized peptide surface density.


Crystal structure of the CRISPR-Cas RNA silencing Cmr complex bound to a target analog.
In prokaryotes, Clustered regularly interspaced short palindromic repeat (CRISPR)-derived RNAs (crRNAs), together with CRISPR-associated (Cas) proteins, capture and degrade invading genetic materials. In the type III-B CRISPR-Cas system, six Cas proteins (Cmr1-Cmr6) and a crRNA form an RNA silencing Cmr complex. Here we report the 2.1 Å crystal structure of the Cmr1-deficient, functional Cmr complex bound to single-stranded DNA, a substrate analog complementary to the crRNA guide. Cmr3 recognizes the crRNA 5' tag and defines the start position of the guide-target duplex, using its idiosyncratic loops. The β-hairpins of three Cmr4 subunits intercalate within the duplex, causing nucleotide displacements with 6 nt intervals, and thus periodically placing the scissile bonds near the crucial aspartate of Cmr4. The structure reveals the mechanism for specifying the periodic target cleavage sites from the crRNA 5' tag and provides insights into the assembly of the type III interference machineries and the evolution of the Cmr and Cascade complexes.


"Cheaper and better": Societal cost savings and budget impact of changing from systemic to intralesional pentavalent antimonials as the first-line treatment for cutaneous leishmaniasis in Bolivia.
Cutaneous leishmaniasis (CL), endemic in Bolivia, mostly affects poor people in rainforest areas. The current first-line treatment consists of systemic pentavalent antimonials (SPA) for 20 days and is paid for by the Ministry of Health (MoH). Long periods of drug shortages and a lack of safe conditions to deliver treatment are challenges to implementation. Intralesional pentavalent antimonials (ILPA) are an alternative to SPA. This study aims to compare the cost of ILPA and SPA, and to estimate the health and economic impacts of changing the first-line treatment for CL in a Bolivian endemic area. The cost-per-patient treated was estimated for SPA and ILPA from the perspectives of the MoH and society. The quantity and unit costs of medications, staff time, transportation and loss of production were obtained through a health facility survey (N = 12), official documents and key informants. A one-way sensitivity analysis was conducted on key parameters to evaluate the robustness of the results. The annual number of patients treated and the budget impact of switching to ILPA as the first-line treatment were estimated under different scenarios of increasing treatment utilization. Costs were reported in 2017 international dollars (1 INT$ = 3.10 BOB). Treating CL using ILPA was associated with a cost-saving of $248 per-patient-treated from the MoH perspective, and $688 per-patient-treated from the societal perspective. Switching first-line treatment to ILPA while maintaining the current budget would allow two-and-a-half times the current number of patients to be treated. ILPA remained cost-saving compared to SPA in the sensitivity analysis. The results of this study support a shift to ILPA as the first-line treatment for CL in Bolivia and possibly in other South American countries.


Efficient removal of nitrate, manganese, and tetracycline in a novel loofah immobilized bioreactor: Performance, microbial diversity, and functional genes.
The remediation of multiple pollutants in water, for instance, nitrate, heavy metals, and antibiotics is urgent and necessary for the global water resources protection. Herein, a modified loofah bioreactor was designed for simultaneous denitrification, manganese (Mn) oxidation, and tetracycline (TC) removal. The maximum removal efficiencies of NO3--N (91.97%), Mn(II) (71.25%), and TC (57.39%) were achieved at a hydraulic retention time (HRT) of 9 h, Mn(II) concentration of 20 mg L-1, and TC concentration of 1 mg L-1. SEM and XRD were carried out to characterize the bioprecipitation in the operation of bioreactor. TC addition affected the gaseous denitrification products, dissolved organic matter, as well as reduced the OTU in the bioreactor. The Zoogloea were regarded as the dominant species in the microbial community and played an essential role in the operation of bioreactor. Metagenomic analysis proved the great potential for denitrification, manganese oxidation, and antibiotic removal of loofah bioreactor.


Characterisation of a novel class of polyamine-based neuroprotective compounds.
Prolonged cerebral ischaemia initiates complex intra- and inter-cellular signalling cascades ultimately resulting in neuronal death. Well-characterised mediators of ischaemic cell death are glutamate, free radicals and nitric oxide. Many drugs that block these mechanisms are neuroprotective in vitro, but have unfavourable side-effect profiles in man. We have recently demonstrated that the compound L-arginyl-3,4-spermidine (L-Arg3,4) is neuroprotective in vitro through an interaction with several of these mechanisms, and prevents ischaemic neurodegeneration in vivo with no gross side effects. In this study, we have used solid-phase combinatorial chemistry, to synthesise a number of analogues of L-Arg3,4, and investigate the structure-activity relationship using an in vitro, organotypic hippocampal slice culture model of cerebral ischaemia. A number of molecular features were identified which were essential for the neuroprotective activity including the requirement for a positive charge and an amino acid in the L-configuration. Relatively minor alterations to both the terminal arginine and polyamine moieties significantly attenuated neuroprotective efficacy. Our data implies that these compounds are neuroprotective through a currently undefined mechanism rather than non-specific ionic interactions described previously for other polyamine-containing compounds.


Aestival dormancy in the cabbage moth Mamestra brassicae L. (Lepidoptera: Noctuidae) : 1. Adaptive significance of variability of two traits: Day length thresholds triggering aestival dormancy and duration of aestival dormancy.
A highly specific recognition system, capable of "foreseeing" and distinguishing between two critical points in time, exists in Mamestra brassicae (Lepidoptera: Noctuidae). Both points in time, the onset of a drought period and the end of the growth season, require different growth patterns of the pupae. In order to minimize the likelihood of weather-induced mortality and to maximize fitness, individuals of M. brassicae must enter aestival dormancy or hibernal diapause, respectively, before the onset of drought or frost. This study is primarily concerned with aestival dormancy. Normally, the pupal period of dormancy-free developing individuals amounts to approximately 20 to 30 days. A modified pupal period of approximately 35 to 80 days is defined as aestival dormancy. The onset of aestival dormancy is triggered by day lengths exceeding an innate individaul-specific threshold. The results reported in this paper indicate that the photoperiodic response curve represents largely the genetic variability within a population with respect to the thresholds triggering aestival dormancy. This variability in thresholds is considered to reflect the frequency of correlation of a distinct day length with a certain onset of drought period in the past. Furthermore, the innate thresholds are characterized by a temperature dependent norm of reaction. Our results also indicate, that a strong genetical component is involved in variability of duration of the pupal period. This variability in duration of aestivation reflects the frequency of drought periods of a certain length in the past. The adaptive significance of both the variation in day length thresholds and duration of aestival dormancy is discussed with respect to the number of generations per season, and the synchronization of the individual life cycles with the seasonal changing environmental conditions.


Freezing of Fresh Wharton's Jelly From Human Umbilical Cords Yields High Post-Thaw Mesenchymal Stem Cell Numbers for Cell-Based Therapies.
Some cord blood banks freeze entire pieces of UC (mixed cord, MC) which after post-thaw yields mixed heterogeneous populations of mesenchymal stem cells (MSCs) from all its microanatomical compartments. Freezing of such entire tissues results in sub-optimal post-thaw cell recovery because of poor cryoprotectant diffusion and intracellular ice-formation, heat and water transport issues, and damage to intercellular junctions. To develop a simple method of harvesting pure homogeneous MSCs for cord blood banks, we compared the post-thaw behavior of three groups of frozen UC tissues: (i) freshly harvested WJ without cell separation; (ii) MSCs isolated from WJ (WJSC); and (iii) MC, WJ, and WJSC produced high post-thaw cell survival rates (93.52 ± 6.12% to 90.83 ± 4.51%) and epithelioid monolayers within 24 h in primary culture whereas post-thaw MC explants showed slow growth with mixed epithelioid and fibroblastic cell outgrowths after several days. Viability and proliferation rates of post-thawed WJ and hWJSC were significantly greater than MC. Post-thaw WJ and WJSC produced significantly greater CD24(+) and CD108(+) fluorescence intensities and significantly lower CD40(+) contaminants. Post-thaw WJ and WJSC produced significantly lesser annexin-V-positive and sub-G1 cells and greater degrees of osteogenic and chondrogenic differentiation compared to MC. qRT-PCR analysis of post-thaw MC showed significant decreases in anti-apoptotic gene expression (SURVIVIN, BCL2) and increases in pro-apoptotic (BAX) and cell cycle regulator genes (P53, P21, ROCK 1) compared to WJ and WJSC. We conclude that freezing of fresh WJ is a simple and reliable method of generating large numbers of clinically utilizable MSCs for cell-based therapies.


Alternative relay domains of Drosophila melanogaster myosin differentially affect ATPase activity, in vitro motility, myofibril structure and muscle function.
The relay domain of myosin is hypothesized to function as a communication pathway between the nucleotide-binding site, actin-binding site and the converter domain. In Drosophila melanogaster, a single myosin heavy chain gene encodes three alternative relay domains. Exon 9a encodes the indirect flight muscle isoform (IFI) relay domain, whereas exon 9b encodes one of the embryonic body wall isoform (EMB) relay domains. To gain a better understanding of the function of the relay domain and the differences imparted by the IFI and the EMB versions, we constructed two transgenic Drosophila lines expressing chimeric myosin heavy chains in indirect flight muscles lacking endogenous myosin. One expresses the IFI relay domain in the EMB backbone (EMB-9a), while the second expresses the EMB relay domain in the IFI backbone (IFI-9b). Our studies reveal that the EMB relay domain is functionally equivalent to the IFI relay domain when it is substituted into IFI. Essentially no differences in ATPase activity, actin-sliding velocity, flight ability at room temperature or muscle structure are observed in IFI-9b compared to native IFI. However, when the EMB relay domain is replaced with the IFI relay domain, we find a 50% reduction in actin-activated ATPase activity, a significant increase in actin affinity, abolition of actin sliding, defects in myofibril assembly and rapid degeneration of muscle structure compared to EMB. We hypothesize that altered relay domain conformational changes in EMB-9a impair intramolecular communication with the EMB-specific converter domain. This decreases transition rates involving strongly bound actomyosin states, leading to a reduced ATPase rate and loss of actin motility.


Basal weekly insulins: the way of the future!
Basal insulin treatment is indispensable for patients with type 1 diabetes and often required by many with type 2 diabetes. Incremental advances lengthening the duration of action of insulin analogs and reducing pharmacodynamic variability have resulted in truly once-daily, long-acting basal insulin analogs. In the quest for better basal insulins to facilitate improvements in glycemic control and long-term outcomes, the driving need is to remove barriers delaying timely initiation of basal insulin, to maximize treatment adherence and persistence and reduce treatment burden without increasing risk of hypoglycemia. We review the range of investigational once-weekly insulins and their molecular strategies and profiles. Currently, the two most advanced clinical development programs are: (1) basal insulin icodec, an insulin analog acylated with a C20 fatty diacid (icosanedioic acid) side chain (Novo Nordisk) and (2) basal insulin Fc, a fusion protein that combines a single-chain insulin variant with a human immunoglobulin G fragment crystallizable domain (Eli Lilly). Available phase 2 data for these two once-weekly agents show comparable glycemic control to existing once-daily insulin analogs, with no greater risk of hypoglycemia. While phase 3 data are awaited to confirm efficacy and safety, we provide future clinical perspectives on practical considerations for the potential use of once-weekly insulins.


Retroperitoneal lymph node mapping with intratesticular injected patent blue dye in rats.
Endolymphatic injection of several dyes have been previously studied to identify retroperitoneal lymphatic structure in animals and humans with malignant diseases. However, there have been no studies, to our knowledge, that demonstrate the utility of injecting patent blue dye into the testicular parenchyma to detect retroperitoneal lymphoid structure. The aim of this experimental study was to investigate whether intratesticular patent blue dye injection is feasible and is an accurate method for retroperitoneal lymph node mapping in rats. Twenty male albino Wistar rats were included in the study and divided over two equal groups. The first group underwent patent blue violet (PBV) injection into the spermatic funiculus, while the second group underwent PBV injection into the testicular parenchyma. After the injection, the color changes in the retroperitoneal lymphatic structures and the urinary bladder were anticipated. The time interval between the injection and the staining of lymphatic structures and urinary bladder was measured for each intervention. Blue stained retroperitoneal nodal tissues were dissected and removed. These nodal tissues were examined histologically. After PBV injection, intense staining of the ipsilateral spermatic cord lymphatics was seen and anticipated color changes in the retroperitoneal lymphatic structures and urinary bladder were evaluated visually. Both application routes of dye resulted in the same distribution of retroperitoneal lymph nodes in the same time frame. All retroperitoneal nodular tissues removed were noted histologically to be lymph nodes and were found to be consistent with the ipsilateral lumbar lymph and the ipsilateral suprarenal lymph nodes according to the staining order in both groups. No toxic effects were observed histologically. There were no statistically significant differences in the time intervals between the two groups. We demonstrated that both funicular and intratesticular injections of patent blue dye are feasible and accurate methods for retroperitoneal lymph node mapping in rats. This shows that intralymphatic dye injection is not absolutely necessary to detect retroperitoneal lymphatic structures and may have applications beyond testis cancer.


Facile catch and release of fullerenes using a photoresponsive molecular tube.
A novel M2L2 molecular tube capable of binding fullerene C60 was synthesized from bispyridine ligands with embedded anthracene panels and Ag(I) hinges. Unlike previous molecular cages and capsules, this open-ended tubular host can accommodate a single molecule of various C60 derivatives with large substituents. The fullerene guest can then be released by using the ideal, noninvasive external stimulus, light.


Erythrokinetic studies in hairy-cell leukaemia.
Erythrokinetics were studied in 29 patients with hairy-cell leukaemia. In all cases there was an increase in plasma volume, closely correlated to the size of the spleen, indicating that the true degree of anaemia can only be appreciated by red cell volume measurement. Moderately increased haemolysis was observed in most cases, which did not correlate with the spleen size. Simultaneous study of autologous and isologous red cell life-span suggested an extra-corpuscular mechanism for the haemolysis in most patients. A quantitative erythropoietic defect, either relative or absolute, was found in half the cases, without any qualitative defect. Only one case showed erythroid metaplasia of the spleen. Thus marrow failure appears to be largely responsible for the anaemia and granulocytopenia in hairy-cell leukaemia. A clear correlation was shown between the short-term prognosis after splenectomy and the degree of hypersplenism. However, long-term survival correlated chiefly with the degree of bone marrow failure, whether splenectomy had been carried out or not. The results indicate that isotope studies in hairy-cell leukaemia are useful both in determining the best form of treatment and predicting survival.


Cholesteryl ester hydrolytic acitivity of rat liver plasma membrane.
Cholesteryl ester hydrolyzing activity of rat liver plasma membranes was studied using acetone-dispersed [4-14-C] cholesteryl oleate as substrate. In contrast to whole liver homogenates which displayed ample activity at both acid (4.5) and neutral (6.2-7.4) pH, purified plasma membrane fractions contained little activity at neutral pH as compared to acid pH. Moreover, rate-zonal sucrose density-gradient centrifugation patterns of plasma membrane rich fractions suggested a specific association with plasma membrane only in the case of the acid activity. These findings suggest that in vivo hepatic cell surface membranes contain little or no cholesteryl ester hydrolytic activity at extracellular pH. They support the possibility that plasma lipoprotein cholesteryl esters enter hepatic parenchymal cells prior to hydrolysis.


Improvements in electron microscopy by application of superconductivity.
Resolution tests on amorphous carbon foils were carried out in an electron microscope with a superconducting system containing 4 lenses including a shielding lens at 200 kV beam voltage. Due to the mechanical and electrical stability of the system and the absence of contamination of the specimen the highest space frequencies transferred at vertically incident beam were 6 nm-1 corresponding to a resolution of 0.17 nm, a value which approaches the theoretical resolving power of the electron optical system. It should also be feasible to apply such a lens system for microprobe analysis without strongly reducing the theoretical resolution limit, if the construction of the shielding lens is slightly changed.


Effects of blue light exposure on ocular parameters and choroidal blood perfusion in Guinea pig.
To investigate the impact of different duration of blue light exposure on ocular parameters and choroidal blood perfusion in guinea pigs with lens-induced myopia. Three-week-old Guinea pigs were randomly assigned to different light-environment groups. All groups were subjected to 12-h light/dark cycle. The control (NC) group was conditioned without intervention. While lens-induced myopia (LIM) groups had a -10D lens placed in the right eye and 0D in the left eye. The guinea pigs were exposed to increasing periods of blue-light (420 nm) environment for 3,6,9,12 h per day. Changes in refraction, axial length (AL), the radius of corneal curvature (CCR), choroidal thickness (ChT), and choroidal blood perfusion (ChBP)were measured in both LIM-eye and fellow-eye during the second and fourth week of LIM duration. During the first two weeks of the experiment, blue light exposure raised ChBP and ChT, and the effect of suppressing myopia was proportional to the duration of blue light exposure. However, in the fourth week of the experiment, prolonged blue light (12BL) exposure led to a reduction in retinal thickness and the increase in ChT and ChBP ceased. Shorter blue light exposure had a better effect on myopia suppression, with all blue light groups statistically different from the LIM group. Exposure to blue-light appears to have the potential to improve ChBP and ChT, thereby inhibiting the development of myopia. we speculate that blue-light inhibits the development of myopia for reasons other than longitudinal chromatic aberration (LCA). However,long-term exposure to blue-light may have adverse effects on ocular development. The next step is to investigate in depth the mechanisms by which the rational use of blue light regulates choroidal blood flow, offering new hope for the treatment of myopia.


Frequencies of gene variant CCR5-Δ32 in 87 countries based on next-generation sequencing of 1.3 million individuals sampled from 3 national DKMS donor centers.
Homozygous carriers of CCR5-Δ32, a gene variant of CC-type chemokine receptor 5 (CCR5), are highly resistant to infections with human immunodeficiency virus type 1 (HIV-1) and therefore preferred stem cell donors for HIV-infected patients. We analyzed CCR5 typing data of 1,333,035 potential hematopoietic stem cell donors enlisted with three national DKMS donor centers. Allele and genotype frequencies were determined for 87 countries of origin as self-assessed by the donors. CCR5-Δ32 allele frequencies ranged from 16.4% in the Norwegian sample to 0 in donors from Ethiopia. The highest CCR5-Δ32/Δ32 genotype frequency was found in the sample from the Faroe Islands (2.3%), whereas in 27 samples, predominantly of donors from Africa, Asia and South America, none of the individuals carried this genotype. The characteristic CCR5-Δ32 allele frequency decline from Northern to Southeastern Eurasia supports findings of earlier studies. With available HLA haplotype frequency information for the patient's ethnicity, our data allows upfront estimation of the probability that an HLA-matched donor with CCR5-Δ32/Δ32 genotype can be found for a patient in need of hematopoietic stem cell transplantation.


Caspases activation in hyperthermia-induced stimulation of TRAIL apoptosis.
In leukemia cells, hyperthermia enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. The phenomenon is caspase-dependent and results in membrane changes leading to an increased recognition of TRAIL death receptors by TRAIL. Because either caspase-2 or an apical proteolytic event has been recently proposed to act as an initiator of the cell death mechanism induced by heat shock, we have investigated the hierarchy of caspase activation in cells exposed to the combined heat shock plus TRAIL treatment. We report here that caspases-2, -3, and -8 were the first caspases to be activated. As expected, caspase-8 is required and indispensable during the initiation of this death signaling. Caspase-2 may also participate in the phenomenon but, in contrast to caspase-8, its presence appears dispensable because its depletion by small interfering RNA is devoid of effects. Our observations also suggest a role of caspase-3 and of a particular cleaved form of this caspase during the early signals of heat shock plus TRAIL-induced apoptosis.


Retention of polysomy at 9p23-24 during karyotypic evolution in human breast cancer cell line COLO 824.
Somatic genetic alterations of 9p have been seen in a wide range of human cancers, including breast cancer. Loss of heterozygosity analysis of primary breast cancer tumors has revealed a high frequency of deletion of DNA from 9p21-22 encompassing the MTSI (P16/CDKN2A) gene. We report the approximately tenfold increase in copy number of DNA from 9p23-24, which is far distal to P16/CDKN2A in female breast cancer cell line COLO 824, as revealed by fluorescence in situ hybridization, comparative genomic hybridization, and microsatellite analysis. Amplification of DNA has been reported previously to encompass multiple sites of the genome of the breast cancer cell, but increase in DNA copy number has not been seen in distal 9p.


d-Allulose, a stereoisomer of d-fructose, extends Caenorhabditis elegans lifespan through a dietary restriction mechanism: A new candidate dietary restriction mimetic.
Dietary restriction (DR) is an effective intervention known to increase lifespan in a wide variety of organisms. DR also delays the onset of aging-associated diseases. DR mimetics, compounds that can mimic the effects of DR, have been intensively explored. d-Allulose (d-Alu), the C3-epimer of d-fructose, is a rare sugar that has various health benefits, including anti-hyperglycemia and anti-obesity effects. Here, we report that d-Alu increased the lifespan of Caenorhabditis elegans both under monoxenic and axenic culture conditions. d-Alu did not further extend the lifespan of the long-lived DR model eat-2 mutant, strongly indicating that the effect is related to DR. However, d-Alu did not reduce the food intake of wild-type C. elegans. To explore the mechanisms of the d-Alu longevity effect, we examined the lifespan of d-Alu-treated mutants deficient for nutrient sensing pathway-related genes daf-16, sir-2.1, aak-2, and skn-1. As a result, d-Alu increased the lifespan of the daf-16, sir-2.1, and skn-1 mutants, but not the aak-2 mutant, indicating that the lifespan extension was dependent on the energy sensor, AMP-activated protein kinase (AMPK). d-Alu also enhanced the mRNA expression and enzyme activities of superoxide dismutase (SOD) and catalase. From these findings, we conclude that d-Alu extends lifespan by increasing oxidative stress resistance through a DR mechanism, making it a candidate DR mimetic.


Prebiotic properties of different polysaccharide fractions from Artemisia sphaerocephala Krasch seeds evaluated by simulated digestion and in vitro fermentation by human fecal microbiota.
Artemisia sphaerocephala Krasch polysaccharide (ASKP) and its two fractions-60P (branched xylan) and 60S (branched glucomannan), were subjected to simulated gastrointestinal digestion and in vitro fermentation by human fecal microbiota. The results showed that all polysaccharide fractions could transit through gastrointestinal tract without dramatic degradation and be utilized by gut microbiota. ASKP exhibited the highest depletion rate and highest capability to decrease the pH than its fractions. Meanwhile, 60S showed the stronger capability to increase the production of propionic acid and reduce the ratio of acetic acid to propionic acid. At the phylum level, all polysaccharides efficiently reduced the Firmicutes/Bacteroidetes ratio and relative abundance of Proteobacteria, with ASKP being the most capable to suppress the proliferation of Proteobacteria. At the genus level, ASKP and 60P markedly promoted the growth of Bacteroidetes, and 60S promoted the growth of Parabacteroides and Collinsella. Prediction on metabolic function revealed that polysaccharide administration could dramatically change the metabolic profile of bacteria compared with fructooligosaccharides. Besides, all the polysaccharides dramatically promoted the bile acid metabolism. Compared with 60S, ASKP and 60P showed stronger ability to suppress the metabolisms on carbohydrate and amino acid. In summary, both ASKP and its two fractions showed the prebiotic potentials.


Growth in HIV-1-exposed but uninfected infants treated with lopinavir-ritonavir versus lamivudine: a secondary analysis of the ANRS 12174 trial.
The tolerance of antiretroviral drugs in infants must be carefully evaluated. In previous studies of children with HIV type 1 (HIV-1) less weight gain was observed in children given lopinavir-ritonavir-based combinations than those given nevirapine. We aimed to compare the effects of lopinavir-ritonavir and lamivudine on growth in HIV-exposed uninfected infants included in the ANRS 12174 trial. ANRS 12174 was a multicentre, randomised, controlled trial of infant prophylaxis to prevent HIV-1 transmission by breastfeeding done at four antenatal clinics in Burkina Faso, South Africa, Uganda, and Zambia. HIV-exposed uninfected infants born to asymptomatic mothers not eligible for antiretroviral therapy (CD4 count >350 cells per μL) were randomly assigned (1:1) to receive lopinavir-ritonavir or lamivudine 7 days after birth, with stratification by country. In a prespecified secondary analysis, we assessed the effect of lopinavir-ritonavir and lamivudine on the growth of these infants from day 7 until cessation of breastfeeding (maximum treatment time 12 months) in the modified intention-to-treat population, which included all children correctly enrolled with at least one follow-up anthropometric measurement. We compared the growth of infants, defined as children's WHO-defined length-for-age Z score (LAZ), weight-for-length Z score (WAZ), and weight-for-age Z score (WLZ). We used linear mixed effect and β spline-regression models to compare growth between the treatment groups. The trial is registered with ClinicalTrials.gov, number NCT00640263. 1273 HIV-exposed uninfected infants and their mothers were enrolled between Nov 16, 2009, and May 7, 2013, of whom 1266 (99%) infants were included in the modified intention-to-treat analysis (630 assigned to lopinavir-ritonavir, 636 assigned to lamivudine). Baseline characteristics of the infants and mothers were similar across the two treatment groups. No differences in least-squares (LS) mean LAZ were identified between the treatment groups at any timepoint. LS mean WLZ was significantly lower in the lopinavir-ritonavir group than the lamivudine group at 26 weeks (difference -0·22 [95% CI -0·34 to -0·09], p=0·0006) and 50 weeks (-0·25 [-0·47 to -0·04], p=0·02). LS mean WAZ was also significantly lower in the lopinavir-ritonavir group than the lamivudine group at 26 weeks (difference -0·18 [95% CI -0·30 to -0·05], p=0·01) and 50 weeks (-0·24 [-0·45 to -0·05], p=0·02). Linear mixed models showed that lopinavir-ritonavir was associated with decreases in WLZ and WAZ over time (p<0·0001 and p=0·002), whereas spline regression models indicated that these reductions occurred early and remained constant thereafter (p<0·0001 with a knot at 44 days for WLZ; p=0·02 with a knot at 118 days for WAZ). The difference in LS mean WLZ at 50 weeks between the treatment groups was higher among girls than boys (difference -0·29 [95% CI -0·58 to 0·01], p=0·05 for girls; -0·22 [-0·53 to 0·09], p=0·18 for boys). Less weight gain was observed in infants given lopinavir-ritonavir than those given lamivudine, which is indicative of a persistent effect that could have long-term deleterious effects. This finding merits attention considering the recommendations for early and lifelong treatment of infants with HIV. French National Agency for Research on AIDS and Viral Hepatitis, the Total Foundation, the European Developing Countries Clinical Trials Partnership, and the Research Council of Norway.


Modulation of the expression of CD4 on HL-60 cells by exposure to 1,25-dihydroxyvitamin D3.
The CD4 molecule functions as a receptor for the binding and infectivity of the human immunodeficiency virus (HIV). It is of interest, therefore, to develop procedures for its down-regulation. In the present study, the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the expression of cell surface antigens of the HL-60 promyelocytic leukemia cell line was analyzed. Exposure of HL-60 cells to 1,25(OH)2D3 resulted in down-regulation of CD4 as assessed by their staining with the Leu-3a monoclonal antibody (MoAb). This treatment increased the staining of HL-60 cells with the monocyte-specific 63D3 MoAb. In contrast to the rapid elimination of cell surface CD4 by exposure of HL-60 to phorbol myristate acetate (PMA), the maximal reduction of CD4 by 1,25(OH)2D3 was attained within 48 h after the beginning of the exposure.


New superacid synthesized (fluorinated) tertiary benzenesulfonamides acting as selective hCA IX inhibitors: toward a new mode of carbonic anhydrase inhibition by sulfonamides.
Tertiary substituted (fluorinated) benzenesulfonamides were synthesized in superacid HF/SbF5 and tested as inhibitors of human carbonic anhydrases (hCAs, EC 184.108.40.206). Strong selectivity toward tumor-associated hCA IX, without inhibiting the offtarget hCA II, was observed, pointing out to a new mechanism of action compared to classical sulfonamides.


Temporary antiretroviral treatment during primary HIV-1 infection has a positive impact on health-related quality of life: data from the Primo-SHM cohort study.
The aim of the study was to compare health-related quality of life (HRQL) over 96 weeks in patients receiving no treatment or 24 or 60 weeks of combination antiretroviral therapy (cART) during primary HIV-1 infection (PHI). A multicentre prospective cohort study of PHI patients, with an embedded randomized trial, was carried out. HRQL was assessed with the Medical Outcomes Study Health Survey for HIV (MOS-HIV) and a symptom checklist administered at weeks 0, 8, 24, 36, 48, 60, 72, 84 and 96. Mixed linear models were used for the analysis of differences in HRQL among the three groups. A total of 112 patients were included in the study: 28 received no treatment, 45 received 24 weeks of cART and 39 received 60 weeks of cART. Over 96 weeks of follow-up, the groups receiving 24 and 60 weeks of cART had better cognitive functioning than the no-treatment group (P = 0.005). Patients receiving 60 weeks of cART had less pain (P = 0.004), better role functioning (P = 0.001), better physical functioning (P = 0.02) and a better physical health summary score (P = 0.006) than the groups receiving no treatment or 24 weeks of cART. Mental health was better in patients receiving 24 weeks of cART than in patients in the no-treatment group or the group receiving 60 weeks of cART (P = 0.02). At week 8, patients in the groups receiving 24 and 60 weeks of cART reported more nausea (P = 0.002), diarrhoea (P < 0.001), abdominal pain (P = 0.02), stomach pain (P = 0.049) and dizziness (P = 0.01) than those in the no-treatment group. These differences had disappeared by week 24. Temporary cART during PHI had a significant positive impact on patients' HRQL as compared with no treatment, despite the initial, short-term occurrence of more physical symptoms, probably related to drug toxicity.


Molecular Characterization and the Antimicrobial Resistance Profile of Salmonella spp. Isolated from Ready-to-Eat Foods in Ouagadougou, Burkina Faso.
The emergence of antimicrobial-resistantfood-borne bacteria is a great challenge to public health. This study was conducted to characterize and determine the resistance profile of Salmonella strains isolated from foods including sesames, ready-to-eat (RTE) salads, mango juices, and lettuce in Burkina Faso. One hundred and forty-eight biochemically identified Salmonella isolates were characterized by molecular amplification of Salmonella marker invA and spiC, misL, orfL, and pipD virulence genes. After that, all confirmed strains were examined for susceptibility to sixteen antimicrobials, and PCR amplifications were used to identify the following resistance genes: bla TEM, temA, temB, StrA, aadA, sul1, sul2, tet(A), and tet(B). One hundred and eight isolates were genetically confirmed as Salmonella spp. Virulence genes were observed in 57.4%, 55.6%, 49.1%, and 38% isolates for pipD, SpiC, misL, and orfL, respectively. Isolates have shown moderate resistance to gentamycin (26.8%), ampicillin (22.2%), cefoxitin (19.4%), and nalidixic acid (18.5%). All isolates were sensitive to six antibiotics, including cefotaxime, ceftazidime, aztreonam, imipenem, meropenem, and ciprofloxacin. Among the 66 isolates resistant to at least one antibiotic, 11 (16.7%) were multidrug resistant. The Multiple Antimicrobial Resistance (MAR) index of Salmonella serovars ranged from 0.06 to 0.53. PCR detected 7 resistance genes (tet(A), tet(B), bla TEM, temB, sul1, sul2, and aadA) in drug-resistant isolates. These findings raise serious concerns because ready-to-eat food in Burkina Faso could serve as a reservoir for spreading antimicrobial resistance genes worldwide.


Iron Fortification through Universal Distribution of Double-Fortified Salt Can Increase Wages and Be Cost-Effective: An Ex-Ante Modeling Study in India.
The alleviation of iron deficiency through iron supplementation has not effectively reduced anemia in India, mainly due to low compliance. Food fortification with iron is considered a viable alternative, and the provision of double-fortified salt (DFS; with iron and iodine) has been mandated in public health programs. Limited evidence exists on its benefit-cost ratio. In this study we sought to estimate the economic benefit in terms of increased wages in relation to introduction of DFS in reduction of anemia and the cost of doing so. The economic benefit of introducing DFS in India was derived using a series of mathematical, statistical, and econometric models using data from national surveys capturing earnings and dietary iron intake of the population. Anemia status was predicted from data on dietary intake, sanitation, and for women, menstrual losses. The impact of iron deficiency anemia (IDA) on wages was estimated using a Heckman Selection model and 2-stage least squares procedure. Benefit of DFS was estimated through increased wages attributed to anemia reduction compared with its cost. Men and women with IDA had lower wages (by 25.9%, 95% CI: 11.3, 38.1; and by 3.9%, 95% CI: 0.0, 7.7, respectively) than those without IDA. Additional iron intake through DFS was predicted to reduce prevalence of IDA (from 10.6% to 0.7% in men and 23.8% to 20.9% in women). The economic benefit-cost ratio of introducing DFS at a national level was estimated to be 4.2:1. Iron fortification delivered through DFS under a universal program can improve wages and be sufficiently cost-effective for its implementation at scale in India.


Dental fracture and chocolate candies: case report.
A complaint by a customer to a food company claimed that the consumption of a chocolate candy fractured his anterior teeth, due to its hard consistency. Fragments of the fractured teeth and the chocolate candy that supposedly caused it were collected, examined and photographed. Fragments presented caries, large restorations, and suggested previous endodontic treatment. To evaluate causation, the food company requested a laboratory analysis, which simulated the human bite on chocolate candies of the same brand. Human teeth were assembled in a simulating device of masticatory functions of apprehension and incision. Teeth used were either sound or with non-restored endodontic accesses, to simulate previous conditions of the collected fragments. Twenty chocolate candies, cooled in a freezer to 0 °C for 2 h were used as test foods, and were positioned between the teeth of the device at the moment of the test. The set was put in a dynamometer, programmed to apply increasing forces (rate of advance of 5 mm/min), until rupture (either of the specimen or of the teeth). The applied force, in N, at the time of fracture was recorded and analyzed. The average force to fracture the test food was 233.23 N. No tooth was fractured in the experiment. Forces ranging from 191.3 to 275.2 N, applied to chocolate candies were not sufficient to neither fracture human teeth nor cause any structural damage. It was concluded that the dental fracture occurred because of previous oral health conditions of the customer.


Sarcoidosis in an Australia Aboriginal.
A case of sarcoidosis in a fullblood Aboriginal woman is reported. This condition appears not to have been recognized in Australian Aboriginals hitherto and some implications of this are discussed.


Notes on the genus Gryllacris Audinet-Serville (Orthoptera: Gryllacrididae) with description of a new species from China.
In this work we briefly reviewed the genus Gryllacris with some notes on taxonomic issues, note the taxa that have been described in and transferred to the genus and describe a new taxon, Gryllacris (Gryllacris) stylommatoprocera, from Yunnan, China. Materials are deposited in Shanghai Entomological Museum, Chinese Academy of Sciences.


Inhibition of protein kinase C by staurosporine promotes elevated accumulations of inositol trisphosphates and tetrakisphosphate in human platelets exposed to thrombin.
We have examined regulation by protein kinase C (Ca2+/phospholipid-dependent enzyme) of thrombin-induced inositol polyphosphate accumulation in human platelets. When platelets are exposed to thrombin for 10 s, the protein kinase C inhibitor staurosporine causes inositol phosphate elevations over control values of 2.7-fold (inositol 1,4,5-trisphosphate (Ins(1,4,5)P3], 1.9-fold (inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4], and 1.2-fold (inositol 1,3,4-trisphosphate). In the same period, phosphatidic acid and diacylglycerol are unaffected. The myosin light chain kinase inhibitor ML-7 has no effect on inositol phosphate accumulations. Staurosporine does not inhibit Ins(1,4,5)P3 3-kinase and 5-phosphomonoesterase activities in saponin-permeabilized platelets incubated with exogenous Ins(1,4,5)P3 unless the platelets have been exposed to thrombin and protein kinase C is consequently activated. The protein kinase C agonist beta-phorbol 12,13-dibutyrate increases the Vmax of the 3-kinase 1.8-fold, with little effect on Km. Our results provide strong evidence for a role for protein kinase C in regulating inositol phosphate levels in thrombin-activated platelets. We propose that endogenously activated protein kinase C removes Ins(1,4,5)P3 by stimulating both 5-phosphomonoesterase and Ins(1,4,5)P3 3-kinase. Initial activation of phospholipase C does not appear to be affected by such protein kinase C. Inhibition of protein kinase C by staurosporine decreases 5-phosphomonoesterase activity. The resulting elevated Ins(1,4,5)P3, as substrate for Ins(1,4,5)P3 3-kinase, promotes production of Ins(1,3,4,5)P4, which also may accumulate through decreased 5-phosphomonoesterase activity and elevated Ca2+ levels. These factors apparently counteract the inhibitory effect on 3-kinase, yielding a net increase in Ins(1,3,4,5)P4.


Causes of visual loss associated with uveitis in a singapore tertiary eye center.
To identify the causes of visual loss associated with uveitis and its risk factors. Review of 359 patients attending a uveitis service. Anterior uveitis (n = 229, 63.8%) was most common, followed by panuveitis (n = 55, 15.3%). There were 82 infective cases with 29.3% associated with tuberculosis. Visual loss occurred in 100 (27.9%) patients, of which 27 (7.5%) had severe visual loss. The main causes of visual loss were cataract (26%) and glaucoma (12%). Cystoid macular edema (14.8%) accounted for severe visual loss. Panuveitis was predictive for visual loss (p = 0.022, odds ratio (OR) 2.22) and severe visual loss (p = 0.01, OR 3.47). Posterior uveitis (p = 0.005, OR 5.01) and chronic uveitis (p = 0.008, OR 3.83) also showed higher risk for severe visual loss. With panuveitis being the second most common presentation, early specialist referral is essential in preventing visual loss.


Insights about the interaction of methotrexate loaded hydrophilic gold nanoparticles: Spectroscopic, morphological and structural characterizations.
Gold nanoparticles (AuNPs) are promising carriers in the field of nanomedicine and represent a very intriguing approach in drug delivery applications, due to their small size and enhanced properties. This work aims to highlight the interaction between functionalized AuNPs and the immune-system suppressant drug Methotrexate (MTX) at molecular level. Small and monodisperse (<2RH>5 ± 1 nm) gold nanoparticles were prepared by a simple chemical route using hydrophilic thiol 3-mercapto-1-propanesulfonate (3MPS) as a functionalizing/capping agent and act as a platform for post-synthesis conjugation of MTX via non-covalent interaction. The AuNPs-3MPS@MTX bioconjugate and the AuNPs alone were characterized to investigate their optical, chemical, and morphological properties. Moreover, NMR, AFM, SAXS, HR-TEM and SR-XPS data confirmed the spherical shape of AuNPs and allowed to determine the mechanisms behind such drug-nanoparticle physicochemical interactions. These analyses define the overall structure of drug-loaded AuNPs-3MPS and drug location on the colloidal nanoparticles surface. Based on the experimental data, it is notable to assert that MTX was successfully loaded on the negatively charged nanoparticles surface via electrostatic interactions. The physicochemical behavior leads to the formation of large clusters with close packed arrangement of AuNPs-3MPS@MTX. This self-assembling property is of importance for delivery purpose affecting the drug-loaded nanoparticle size, functionality, and morphology. Knowledge of how these systems behave will aid in increasing drug efficacy and in understanding the pharmacodynamics and pharmacokinetic properties, opening to new physicochemical insight for therapy and drug delivery systems.


[A case of poliomyelitis type 1 in Switzerland in a non-vaccinated child].
A case of paralytic poliomyelitis in an unvaccinated child is reported. Besides clinical aspects, special interest is focused on immunological and virological findings. Paralytic disease in temporal connection with poliomyelitis vaccination is also discussed.


An open-label trial of sibutramine in obese patients with binge-eating disorder.
Binge-eating disorder was recently included in Appendix B of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Binge-eating disorder is a common diagnosis among patients who seek treatment for obesity. There are scant data about the efficacy of the novel antiobesity agents for binge-eating disorder. The objective of this article is to present data from an open-label study of the efficacy and tolerability of sibutramine in a group of obese binge eaters. Ten obese patients with DSM-IV binge-eating disorder and no medical comorbidity were consecutively selected from individuals seeking treatment for obesity in our clinic. Treatment with sibutramine, 15 mg/day, was administered for 12 weeks. The number of days with binge episodes per week, the number of binge episodes per week, the Binge Eating Scale (BES), the Beck Depression Inventory, and body weight evaluation were employed for outcome assessment. Seven patients completed the trial. They showed a complete resolution of binge-eating disorder with no binge-eating episodes at the end of the treatment. The mean +/- SD number of days with binge episodes per week changed significantly from 5.2 +/- 1.8 at baseline to 0.8 +/- 1.9 at the end of the study (p < .001), and the mean BES score fell from 31.2 +/- 6.2 to 15.2 +/- 8.2. There was a reduction of body weight (mean = 4.0 kg [8.9 lb]) from baseline to the end of the study. No serious adverse effects were observed. Sibutramine might be an effective and well-tolerated agent in the treatment of binge-eating disorder in obese patients.


Betamethasone dosing interval: 12 or 24 hours apart? A randomized, noninferiority open trial.
We sought to determine whether the incidence of neonatal respiratory distress syndrome (RDS) is similar with 12- vs 24-hour dosing interval of betamethasone. This was a prospective, randomized, open, noninferiority trial. Mothers (n = 228) with a singleton or multiple pregnancies (fetuses = 260), between gestational age of 23-34 weeks, at risk for preterm delivery, received standard 2 doses of betamethasone either 12 or 24 hours apart in 2:1 ratio, respectively. Incidence of RDS was similar in the 2 cohorts (36.5% vs 37.3%; P = not significant). Women unable to receive the complete course of corticosteroids with the 24-hour interval can be reduced by half with the 12-hour interval. However, increased incidence of necrotizing enterocolitis was seen with 12-hour dosing (6.2% vs 0%; P = .03). The 12-hour dosing interval is equivalent to the 24-hour dosing interval for prevention of RDS in neonates of mothers delivering prematurely. A larger multicenter study is needed to confirm our findings.


Dietary Approaches to Stop Hypertension (DASH) intervention reduces blood pressure among hypertensive African American patients in a neighborhood health care center.
The purpose of this study was to pilot-test DASH-Dinner with Your Nutritionist, a university-neighborhood health care center intervention to promote the Dietary Approaches to Stop Hypertension (DASH) diet. Study participants were low-income African American adults (N = 82) with poorly controlled blood pressure. Six groups, each consisting of 12 to 15 participants taking antihypertensive medications, met for 1 to 2 hours per week for 8 weeks. The intervention followed constructs of Social Cognitive Theory and featured dinners based on the DASH diet plan. Blood pressure was significantly lowered (P < .05) among participants who missed no more than 2 of 8 sessions. Extension of the DASH-Dinner model could improve blood pressure control among low-income hypertensive African Americans and reduce health disparities.


Improved anticancer efficacy of methyl pyropheophorbide-a-incorporated solid lipid nanoparticles in photodynamic therapy.
Photodynamic therapy (PDT) is a promising anticancer treatment because it is patient-friendly and non-invasive. Methyl pyropheophorbide-a (MPPa), one of the chlorin class photosensitizers, is a drug with poor aqueous solubility. The purpose of this study was to synthesize MPPa and develop MPPa-loaded solid lipid nanoparticles (SLNs) with improved solubility and PDT efficacy. The synthesized MPPa was confirmed 1H nuclear magnetic resonance (1H-NMR) spectroscopy and UV-Vis spectroscopy. MPPa was encapsulated in SLN via a hot homogenization with sonication. Particle characterization was performed using particle size and zeta potential measurements. The pharmacological effect of MPPa was evaluated using the 1,3-diphenylisobenzofuran (DPBF) assay and anti-cancer effect against HeLa and A549 cell lines. The particle size and zeta potential ranged from 231.37 to 424.07 nm and - 17.37 to - 24.20 mV, respectively. MPPa showed sustained release from MPPa-loaded SLNs. All formulations improved the photostability of MPPa. The DPBF assay showed that SLNs enhanced the 1O2 generation from MPPa. In the photocytotoxicity analysis, MPPa-loaded SLNs demonstrated cytotoxicity upon photoirradiation but not in the dark. The PDT efficacy of MPPa improved following its entrapment in SLNs. This observation suggests that MPPa-loaded SLNs are suitable for the enhanced permeability and retention effect. Together, these results demonstrate that the developed MPPa-loaded SLNs are promising candidates for cancer treatment using PDT.


[Nora's Lesion: A Rare Differential Diagnosis for Benign Peripheral Bone Tumours].
We report on a bizarre parosteal osteochondromatous proliferation (BPOP), also known as Nora's lesion, in a 43-year-old female patient.