Partial sympathetic denervation of the rat epididymis permits fertilization but inhibits embryo development.
The rat cauda epididymidis receives sympathetic innervation from the inferior mesenteric ganglion (IMG). We have previously demonstrated that surgical removal of the IMG and proximal hypogastric nerves (IMG denervation) results in significant and cauda-specific changes in epididymal sperm transport, sperm motility, luminal fluid protein composition, and tissue histology. In the present study we used natural mating trials and intrauterine insemination (IUI) techniques to determine whether or not IMG denervation affects male fertility and reproductive capacity. For the initial studies, adult male Sprague Dawley rats were mated with estrous females 1 and 4 weeks following IMG denervation. Nine days after mating, uterine implantation sites and corpora lutea (CL) were counted. In females mated with sham-operated control males, 85.8% of ovulated oocytes were fertilized and subsequently implanted. In contrast, females mated with IMG-denervated males 1 or 4 weeks following surgery had 0% and 3.5%, respectively, of ovulated oocytes fertilized and implanted. For rats maintained 21 days after mating, an average of 13 +/- 1 pups were delivered by each of nine females mated with sham-operated control male rats; whereas, only seven morphologically normal pups were delivered by one of 14 females mated with IMG-denervated male rats. Additional experiments demonstrated that the decrement in offspring was, in part, due to a significant decrease in the number of spermatozoa in the female uterus following mating with IMG-denervated males. To determine whether IMG denervation exerted an additional effect directly on the fertilizing ability of spermatozoa, IUI experiments were performed. Six million cauda epididymal spermatozoa from 1- or 4-week IMG-denervated males were inseminated into the uterine horns of luteinzing hormone-releasing hormone (LHRH)-synchronized females and 9 days later implantation sites and CL were counted. Implantations were observed for 78%, 28%, and 25% of ovulated oocytes following IUI with spermatozoa from sham-operated controls and from 1- and 4-week IMG-denervated rats, respectively. To determine whether the reduction in implantation sites following IUI with spermatozoa from IMG-denervated rats resulted from impaired oocyte fertilization, studies were performed in which oocytes were retrieved and stained 24 hours after IUI. Comparable fertilization rates of 76.5% and 89.0% were observed using cauda epididymal spermatozoa from IMG-denervated and sham-operated control males, respectively, indicating that oocyte fertilization was not affected by the loss of innervation. These studies establish the importance of innervation from the IMG for ejaculatory competence and sperm reproductive capacity in the male rat. These data further suggest that sympathetic innervation in the epididymis critically influences paternal factors associated with embryonic development.


How Do People Process Different Representations of Statistical Information? Insights into Cognitive Effort, Representational Inconsistencies, and Individual Differences.
Graphical representation formats (e.g., icon arrays) have been shown to lead to better understanding of the benefits and risks of treatments compared to numbers. We investigate the cognitive processes underlying the effects of format on understanding: how much cognitive effort is required to process numerical and graphical representations, how people process inconsistent representations, and how numeracy and graph literacy affect information processing. In a preregistered between-participants experiment, 665 participants answered questions about the relative frequencies of benefits and side effects of 6 medications. First, we manipulated whether the medical information was represented numerically, graphically (as icon arrays), or inconsistently (numerically for 3 medications and graphically for the other 3). Second, to examine cognitive effort, we manipulated whether there was time pressure or not. In an additional intervention condition, participants translated graphical information into numerical information before answering questions. We also assessed numeracy and graph literacy. Processing icon arrays was more strongly affected by time pressure than processing numbers, suggesting that graphical formats required more cognitive effort. Understanding was lower when information was represented inconsistently (v. consistently) but not if there was a preceding intervention. Decisions based on inconsistent representations were biased toward graphically represented options. People with higher numeracy processed quantitative information more efficiently than people with lower numeracy did. Graph literacy was not related to processing efficiency. Our study was conducted with a nonpatient sample, and the medical information was hypothetical. Although graphical (v. numerical) formats have previously been found to lead to better understanding, they may require more cognitive effort. Therefore, the goal of risk communication may play an important role when choosing how to communicate medical information. This article investigates the cognitive processes underlying the effects of representation format on the understanding of statistical information and individual differences therein.Processing icon arrays required more cognitive effort than processing numbers did.When information was represented inconsistently (i.e., partly numerically and partly graphically), understanding was lower than with consistent representation, and decisions were biased toward the graphically represented options.People with higher numeracy processed quantitative information more efficiently than people with lower numeracy did.


The association of funding source on effect size in randomized controlled trials: 2013-2015 - a cross-sectional survey and meta-analysis.
Trials financed by for-profit organizations have been associated with favorable outcomes of new treatments, although the effect size of funding source impact on outcome is unknown. The aim of this study was to estimate the effect size for a favorable outcome in randomized controlled trials (RCTs), stratified by funding source, that have been published in general medical journals. Parallel-group RCTs published in The Lancet, New England Journal of Medicine, and JAMA between 2013 and 2015 were identified. RCTs with binary primary endpoints were included. The primary outcome was the OR of patients' having a favorable outcome in the intervention group compared with the control group. The OR of a favorable outcome in each trial was calculated by the number of positive events that occurred in the intervention and control groups. A meta-analytic technique with random effects model was used to calculate summary OR. Data were stratified by funding source as for-profit, mixed, and nonprofit. Prespecified sensitivity, subgroup, and metaregression analyses were performed. Five hundred nine trials were included. The OR for a favorable outcome in for-profit-funded RCTs was 1.92 (95% CI 1.72-2.14), which was higher than mixed source-funded RCTs (OR 1.34, 95% CI 1.25-1.43) and nonprofit-funded RCTs (OR 1.32, 95% CI 1.26-1.39). The OR for a favorable outcome was higher for both clinical and surrogate endpoints in for-profit-funded trials than in RCTs with other funding sources. Excluding drug trials lowered the OR for a favorable outcome in for-profit-funded RCTs. The OR for a favorable surrogate outcome in drug trials was higher in for-profit-funded trials than in nonprofit-funded trials. For-profit-funded RCTs have a higher OR for a favorable outcome than nonprofit- and mixed source-funded RCTs. This difference is associated mainly with the use of surrogate endpoints in for-profit-financed drug trials.


Carbon-dot-triggered aggregation/dispersion of gold nanoparticles for colorimetric detection of nucleic acids and its application in visualization of loop-mediated isothermal amplification.
In this study, cationic carbon dots (CDs) were prepared from p-phenylenediamine (pPDA) via a one-step hydrothermal method and used to trigger the aggregation and dispersion of gold nanoparticles (AuNPs) for the colorimetric detection of nucleic acids. Physicochemical characterization results revealed that the CDs are enriched with positively charged surface functional groups with an average size of ∼11 nm. The interaction between the CDs and AuNPs was confirmed via fluorescence and absorption studies. Absorption spectroscopic results revealed that the primary surface plasmon resonance (SPR) band of the AuNPs decreased upon introduction of CDs, and a new band emerged at ∼600 nm, indicating the aggregated assembly of AuNPs. Upon the introduction of double-stranded deoxyribonucleic acid (DNA), the band corresponding to the aggregated AuNPs showed a continuous decrease, accompanied by a simultaneous increase in the primary SPR band, leading to a noticeable purple-to-red color transformation. Based on this phenomenon, a colorimetric assay for DNA was developed, which relies on the interaction between negatively charged DNA and cationic CDs, leaving the AuNPs dispersed. The assay exhibited a linear response within a DNA concentration range of 0.7-14 nM with a detection limit of 1.70 nM. Selectivity results showed that colorimetric assays are specific for both DNA and single-stranded DNA (ssDNA). Smartphone-assisted detection was developed by monitoring the colorimetric response of a AuNPs/CDs probe. As a proof-of-concept experiment, the AuNPs/CDs probe was used to visualize the loop-mediated isothermal amplification (LAMP) of Escherichia coli (E. coli), a robust indicator of sewage contamination in water.


The role of estrogen in the modulation of pituitary sensitivity of LRF (luteinizing hormone-releasing factor) in men.
The role of estradiol in modulating pituitary gonadotropin release in the human male was studied by evaluating the effects of clomiphene on the pituitary gonadotropin response to synthetic LRF (150 mug) in 6 eugonadal men. Administration of clomiphene (100 mg single daily dose time 5 days) induced a significant elevation of the basal levels of LH, FSH, estradiol and testosterone. However, the pituitary release of LH and FSH in response to LRF was markedly diminished by the clomiphene treatment. This finding suggests that in men, as in women, endogenous estradiol provides feedback regulation of gonadotropin output by the pituitary.


Hepatocytes are protected by herb Phyllanthus niruri protein isolate against thioacetamide toxicity.
The herb, Phyllanthus niruri has been known to possess protective activity against various drugs and toxins induced hepatic disorders. Present study was conducted to evaluate the role of the protein isolate of the herb against thioacetamide (TAA)-induced cytotoxicity in mice hepatocytes. In vitro cell viability, lactate dehydrogenase (LDH) and alanine amino transferase (ALT) leakage were measured as the indicators of cell damage. In addition, measurement of the level of non-protein thiol, glutathione (GSH); activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) as well as the extent of lipid peroxidation were carried out to evaluate the prooxidant-antioxidant status of the cell. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay was performed to determine the radical scavenging activity of the protein isolate. Results showed that the administration of the protein isolate prior to TAA exposure significantly reduced the release of LDH and ALT leakage and enhanced the cell viability in a dose-dependent manner in hepatocytes. Besides, the protein isolate appeared to prevent the alterations in GSH levels and activities of the anti-oxidant enzymes related to prooxidant-antioxidant status of hepatocytes. It also reduced the TAA-induced lipid peroxidation significantly as demonstrated by the reduction of malondialdehyde (MDA) production. DPPH radical scavenging assay showed that the protein isolate possessed radical scavenging activity. Combining, the data suggest that the protein isolate could protect hepatocytes from TAA-induced cellular injury probably by its antioxidative and radical scavenging properties.


Multiple cutaneous leiomyomas in the perineum of a horse.
Multiple cutaneous masses developed in the perineum of a 14-year-old Saddlebred stallion over a period of approximately 5 years. Clinically, the masses ranged in size from 3- to 9-mm diameter and were not ulcerated, painful, or pruritic. Three of the masses were surgically excised and submitted for microscopic evaluation. The masses were dome shaped to nodular, located in the superficial dermis, and composed of haphazardly arranged bundles of plump spindle-shaped cells. The tumor cells immunoreacted with monoclonal antibodies directed against desmin, muscle-specific actin, and smooth muscle actin, confirming a smooth muscle origin. Multiple cutaneous leiomyomas have not been reported previously in horses.


Application of biological activated carbon as a low pH biofilter medium for gas mixture treatment.
Packing material is a crucial component of a bioreactor as it is the microbial population's habitat. This study assessed potential improvements to current biofiltration processes by investigating use of a novel support medium. Biological activated carbon (BAC) with microorganisms growing on granular activated carbon can produce a novel medium in which both adsorption and biodegradation contribute to pollutants removal. Investigation of carbon characteristics demonstrated that BAC was an ideal packing medium for biofiltration. The application of the novel packing medium for gas mixture treatment was evaluated in a low pH biofilter. Results demonstrated that BAC biofilter obtained high removal efficiency for both H(2)S and toluene. The removal mechanisms of BAC were investigated after the biofilter operation and it demonstrated that the performance of the BAC system was mainly controlled by the additive contributions of two removal mechanisms - adsorption and biodegradation. This study also indicated the potential for simultaneous treatment of hydrogen sulfide and toluene at low pH condition.


Ultrathin High-Quality SnTe Nanoplates for Fabricating Flexible Near-Infrared Photodetectors.
This work demonstrates a controlled van der Waals growth of two-dimensional SnTe nanoplates on mica substrates and their applications in flexible near-infrared photodetectors. The growth of nonlayered rock-salt structured SnTe crystals into two-dimensional SnTe nanoplate structures is mainly caused by the two-dimensional nature of the mica surface, which also results in the ultrathin nanoplates obtained (3.6 nm, equivalent to 6 monolayers). Furthermore, it is found that the shape of the SnTe nanoplates can be well engineered by changing their growth temperature due to the competition between the surface energy of the {100} crystallographic plane and that of the {111} plane. As a result of the favorable physical properties of topological crystalline insulators such as metallic surface (high electron mobility) and narrow bandgap, near-infrared photodetectors based on single SnTe nanoplate with the thickness of 3.6 nm present excellent device performance with a responsivity of 698 mA/W, a specific detectivity of 3.89 × 108 jones, and an external quantum efficiency of 88.5% under the illumination of a 980 nm laser at room temperature (300 K) without applying a gate voltage (Vg). Upon increasing the gate voltage from -30 to 30 V, the detector responsivity increases from 2.96 to 723 mA/W and the detector detectivity increases from 2.4 × 106 to 5.3 × 108 jones. Furthermore, upon increasing the thickness of SnTe nanoplate from 3.6 to 35 nm, the detector responsivity increases from 0.698 to 1.468 A/W. The device performance measured after bending for 300 times as well as after bending with different radii presents no obvious degradation, which exhibits the excellent flexibility of the SnTe nanoplate detectors. These results not only contribute to a deep understanding of the mechanisms of the van der Waals growth of nonlayered materials into two-dimensional structure but also demonstrate the immense potential of SnTe nanoplates to be used in flexible near-infrared detectors.


Rising Trends of Prescription Opioid Sales in Contemporary Brazil, 2009-2015.
To present and discuss recent patterns of prescription opioid sales throughout Brazil. We graphed linear trends of opioid prescriptions sold from registered pharmacies across Brazil from 2009 to 2015. We then calculated the change in rate of prescriptions sold per 1000 persons in 2015 compared with 2009. Opioid sales increased across Brazil from 1 601 043 prescriptions in 2009 to 9 045 945 prescriptions in 2015, corresponding to a 465% increase in 6 years. The largest absolute increase was for codeine products (rate ratio (RR) = 5.30; 95% confidence interval [CI] = 5.29, 5.31), accounting for more than 98% of prescriptions in both years. Oxycodone had the largest relative increase (RR = 11.39; 95% CI = 11.19, 11.59), and fentanyl products had the smallest absolute and relative increase (RR = 2.91; 95% CI = 2.78, 3.03). Given rapid increases in opioid sales across Brazil, it is critical to introduce effective prescribing and monitoring methods that allow patients to access necessary medications without escalating risk of opioid misuse and related consequences. Careful surveillance of supply and subsequent outcomes are needed to prevent the development of another devastating opioid epidemic in the Americas.


Effects of Single Probiotic- and Combined Probiotic-Fermented Milk on Lipid Metabolism in Hyperlipidemic Rats.
Previous studies have shown that probiotics have positive effects on hyperlipidemia by lowering the serum lipid concentration and improving the lipid profile. To explore the mechanism by which probiotic-fermented milk improves lipid metabolism, the transcription of genes regulated by liver X receptors (LXRs), 5'-AMP-activated protein kinase, and the farnesoid X receptor (FXR), which play integral roles in lipid metabolism, was investigated in hyperlipidemic rats. Compared with rats fed a high-fat diet, the administration of probiotic-fermented milk significantly lowered the levels of total cholesterol (TC) and total triglycerides (TG) in rat serum and viscera (P < 0.05) and significantly increased the level of total bile acid in the rat liver and small intestine (P < 0.05). The quantitative PCR results showed that the probiotics ameliorated the TC levels in the rats by activating the transcription of genes involved in the LXR axis, which promoted TC reverse transport and increased the conversion of TC to bile acids. The level of TG in the hyperlipidemic rats was ameliorated by the inhibition of the transcription of carbohydrate reaction element binding protein genes and activation of the transcription of PPARα genes. The regulation of lipid metabolism-related gene transcription by the single probiotic (Lactobacillus rhamnosus LV108)-fermented milk was more effective than that by the combined probiotic (L. rhamnosus LV108, Lactobacillus casei grx12, and Lactobacillus fermentum grx08)-fermented milk (P < 0.05).


Single-dose indigenous liposomal amphotericin B in the treatment of Indian visceral leishmaniasis: a phase 2 study.
Liposomal amphotericin B is an effective and safe alternative for the treatment of visceral leishmaniasis in the Indian subcontinent. In this study, we used a higher-dose regimen of an indigenously manufactured liposomal amphotericin B (FUNGISOME; L-AmBL), which was intended to improve the efficacy in terms of long-lasting cure rate. Thirty men and thirty women between 12 and 60 years old with parasitologically confirmed visceral leishmaniasis were enrolled in two cohorts of 15 patients each. Subjects in cohort I were administered one dose (10 mg/kg body weight) of L-AmBL intravenously. After the safety at this dose was confirmed in cohort I, patients were recruited in cohort II. They received one infusion of an escalated dose (15 mg/kg body weight). The safety of these two doses was evaluated over a period of 30 days, and efficacy was assessed for initial cure at day 30 and definitive cure at 6 months. FUNGISOME was found to be safe, with an initial cure rate of 100% at day 30 and a definitive cure rate of 93.3% at the 6-month follow-up in both the cohorts.


[Surgical Methods in the Treatment of Uveal Melanoma].
Significant advancements have been made in the last decades in the treatment of uveal melanoma. Radiation therapy can achieve, depending on the method, local tumour control in up to 98% of cases. Surgical modalities have been implemented in the ocular therapy for uveal melanoma either to treat/prevent radiation complications, such as so-called toxic tumour syndrome, or to primarily treat the tumour with or without adjunctive radiotherapy. These include endoresection and transscleral resection for melanomas of the choroid/ciliary body or irido-trabeculo-cyclectomy for melanomas of the iris-ciliary body. Furthermore, tumour biopsy is playing a progressively more important role in the diagnosis, treatment and follow-up planning of melanoma cases. This paper focuses on the background, the surgical technique as well as the results and complications of tumour excisional and biopsy surgery.


Eliminating Monitor Overuse (EMO) type III effectiveness-deimplementation cluster-randomized trial: Statistical analysis plan.
Deimplementing overused health interventions is essential to maximizing quality and value while minimizing harm, waste, and inefficiencies. Three national guidelines discourage continuous pulse oximetry (SpO2) monitoring in children who are not receiving supplemental oxygen, but the guideline-discordant practice remains prevalent, making it a prime target for deimplementation. This paper details the statistical analysis plan for the Eliminating Monitor Overuse (EMO) SpO2 trial, which compares the effect of two competing deimplementation strategies (unlearning only vs. unlearning plus substitution) on the sustainment of deimplementation of SpO2 monitoring in children with bronchiolitis who are in room air. The EMO Trial is a hybrid type 3 effectiveness-deimplementation trial with a longitudinal cluster-randomized design, conducted in Pediatric Research in Inpatient Settings Network hospitals. The primary outcome is deimplementation sustainment, analyzed as a longitudinal difference-in-differences comparison between study arms. This analysis will use generalized hierarchical mixed-effects models for longitudinal clustering outcomes. Secondary outcomes include the length of hospital stay and oxygen supplementation duration, modeled using linear mixed-effects regressions. Using the well-established counterfactual approach, we will also perform a mediation analysis of hospital-level mechanistic measures on the association between the deimplementation strategy and the sustainment outcome. We anticipate that the EMO Trial will advance the science of deimplementation by providing new insights into the processes, mechanisms, and likelihood of sustained practice change using rigorously designed deimplementation strategies. This pre-specified statistical analysis plan will mitigate reporting bias and support data-driven approaches. ClinicalTrials.gov NCT05132322. Registered on 24 November 2021.


Gas-producing brain abscess.
A case of a known psychiatric patient who presented with rapid neurological deterioration is reported. Neuroimaging revealed a gas-producing brain abscess in left parietal lobe with a contiguous focus of infection in the adjacent bone and scalp initiated by obsessive scalp scratching. On complete surgical excision of abscess, followed by culture-based antibiotic therapy, a good neurological recovery was achieved with minimal residual deficits at follow-up.


Specification of variables predictive of victories in the sport of boxing.
Compared to other sports, very little research has been conducted on which variables can predict victory in the sport of boxing. This investigation examined whether boxers' age, weight change from their preceding contest, country of origin, total number of wins, total number of losses, performance in their preceding contest, or the possession of a championship title was predictive of a winning performance in a given bout. A 1-mo. sample of male professional boxing records for all contests held in the USA (N = 400) were collected from the BoxRec online database. Logistic regression analysis indicated that only boxers' age, total number of wins and losses, and the performance in the preceding contest predicted significant variance in outcome.


Inhibition of phospholipase Cgamma1 and cancer cell proliferation by lignans and flavans from Machilus thunbergii.
Thirteen compounds were isolated from the CH2Cl2 fraction of Machilus thunbergii as phospholipase Cgamma1 (PLCgamma1) inhibitors. These compounds were identified as nine lignans, two neolignans, and two flavans by spectroscopic analysis. Of these, 5,7-di-O-methyl-3',4'-methylenated (-)-epicatechin (12) and 5,7,3'-tri-O-methyl (-)-epicatechin (13) have not been reported previously in this plant. In addition, seven compounds, machilin A (1), (-)-sesamin (3), machilin G (5), (+)-galbacin (9), licarin A (10), (-)-acuminatin (11) and compound 12 showed dose-dependent potent inhibitory activities against PLCgamma1 in vitro with IC50 values ranging from 8.8 to 26.0 microM. These lignans, neolignans, and flavans are presented as a new class of PLCgamma1 inhibitors. The brief study of the structure activity relationship of these compounds suggested that the benzene ring with the methylene dioxy group is responsible for the expression of inhibitory activities against PLCgamma1. Moreover, it is suggested that inhibition of PLCgamma1 may be an important mechanism for an antiproliferative effect on the human cancer cells. Therefore, these inhibitors may be utilized as cancer chemotherapeutic and chemopreventive agents.


Detection of Alphitobius diaperinus by Real-Time Polymerase Chain Reaction With a Single-Copy Gene Target.
Use of edible insects as an alternative source of proteins in food and feed is increasing. These last years, numerous companies in Europe have started producing insects for food and feed purposes. In the European Union, the use of edible insects for human consumption falls within Regulation (EU) No. 2015/2283 on novel foods. For feed, Commission Regulation (EU) 2017/893 authorizes seven insect species as processed animal proteins for aquaculture. Methods of authentication are required to check the conformity of the products. In this study, we propose a real-time polymerase chain reaction (PCR) method for the specific detection of the lesser mealworm (Alphitobius diaperinus), one of the species included in the shortlist of authorized insects. The selected target is the cadherin gene with a single-copy (per haploid genome) illustrated by our experimental evidence. The PCR test amplified a 134-bp fragment of the cadherin gene. The qualitative method was assessed toward several performance criteria. Specificity was checked against 54 insect species next to other animal and plant species. The sensitivity, efficiency, robustness, and transferability of the PCR assay were also successfully tested. Finally, the applicability of the test was assessed on real-life processed samples (industrial meals) of A. diaperinus. The study also showed that there seems to be a huge confusion on the correct labeling of the marketed mealworms. We did not succeed to get Alphitobius laevigatus samples. They all appeared to belong to the A. diaperinus taxon.


Use of CT to evaluate pleural invasion in non-small cell lung cancer: measurement of the ratio of the interface between tumor and neighboring structures to maximum tumor diameter.
To develop a simple noninvasive technique for evaluating pleural invasion by using routine preoperative computed tomography (CT). The institutional review board approved this retrospective study, and written informed consent was obtained for performing the initial and follow-up CT studies. Preoperative CT findings (169 patients with possible pleural invasion) and pathologic diagnoses after surgical resection were evaluated. The length of the interface between the primary tumor and neighboring structures (arch distance) and the maximum tumor diameter were measured on CT images, after which arch distance-to-maximum tumor diameter ratios were calculated. Receiver operating characteristic (ROC) curves were used to analyze the ratios. Median arch distance-to-maximum tumor diameter ratios for pleural invasion categories (pl1, pl2, pl3) assessed by using the Union Internationale Contre le Cancer TNM staging system were as follows: pl1, 0.206 (25th-75th percentile, 0-0.486); pl2, 0.638 (25th-75th percentile, 0.385-0.830); and pl3, 1.092 (25th-75th percentile, 1.045-1.214) (P < .001 between groups). On the basis of the ROC curves, the cut-off value for invasion was an arch distance-to-maximum tumor diameter ratio of 0.9. When the ratio was greater than 0.9, the sensitivity and specificity for thoracic invasion and area under the ROC curve were 89.7%, 96.0%, and 0.976, respectively, which represents an improvement over values obtained by using conventional criteria (radiologists A and B: 46.7% and 74.2% and 91.3% and 84.8%, respectively). When diagnosing T3 or T4 lung cancer based on arch distance-to-maximum tumor diameter ratios, a higher performance level was achieved than that with use of conventional criteria. Measurement of the ratios is a simple noninvasive technique for evaluating pleural invasion at CT.


Alpha6beta4 integrin and dystroglycan cooperate to stabilize the myelin sheath.
Schwann cells integrate signals deriving from the axon and the basal lamina to myelinate peripheral nerves. Integrin alpha6beta4 is a laminin receptor synthesized by Schwann cells and displayed apposed to the basal lamina. alpha6beta4 integrin expression in Schwann cells is induced by axons at the onset of myelination, and rises in adulthood. The beta4 chain has a uniquely long cytoplasmic domain that interacts with intermediate filaments such as dystonin, important in peripheral myelination. Furthermore, alpha6beta4 integrin binds peripheral myelin protein 22, whose alteration causes the most common demyelinating hereditary neuropathy. All these data suggest a role for alpha6beta4 integrin in peripheral nerve myelination. Here we show that ablating alpha6beta4 integrin specifically in Schwann cells of transgenic mice does not affect peripheral nerve development, myelin formation, maturation, or regeneration. However, consistent with maximal expression in adult nerves, alpha6beta4 integrin-null myelin is more prone to abnormal folding with aging. When the laminin receptor dystroglycan is also ablated, major folding abnormalities occur, associated with acute demyelination in some peripheral nervous system districts. These data indicate that, similar to its role in skin, alpha6beta4 integrin confers stability to myelin in peripheral nerves.


Occurrence of Mycoplasma spp. in wild birds: phylogenetic analysis and potential factors affecting distribution.
Different Mycoplasma species have been reported in avian hosts. However, the majority of studies focus on one particular species of Mycoplasma or one host. In our research, we screened a total of 1141 wild birds representing 55 species, 26 families, and 15 orders for the presence of mycoplasmas by conventional PCR based on the 16S rRNA gene. Selected PCR products were sequenced to perform the phylogenetic analysis. All mycoplasma-positive samples were tested for M. gallisepticum and M. synoviae, which are considered the major pathogens of commercial poultry. We also verified the influence of ecological characteristics of the tested bird species including feeding habits, habitat types, and movement patterns. The presence of Mycoplasma spp. was confirmed in 498 birds of 29 species, but none of the tested birds were positive for M. gallisepticum or M. synoviae. We found possible associations between the presence of Mycoplasma spp. and all investigated ecological factors. The phylogenetic analysis showed a high variability of Mycoplasma spp.; however, some clustering of sequences was observed regarding particular bird species. We found that wild migratory waterfowl, particularly the white-fronted goose (Anser albifrons) and mallard (Anas platyrhynchos) could be reservoirs and vectors of mycoplasmas pathogenic to commercial waterfowl.


[Regulation of glucose metabolism by insulin: dual role of protein kinase C].
The role that protein kinase C (PKC) may play on insulin regulation of glucose metabolism was investigated in rat adipocytes and Zajdela hepatoma cultured (ZHC) cells which are two cell types highly responsive to insulin. In rat adipocytes, 4 beta-phorbol 12 beta-myristate, 13 alpha-acetate (PMA, 0.1-1,000 ng/ml), a potent tumor promoter acting as a substitute for diacylglycerol which directly activates PKC, stimulated basal 2-deoxyglucose (2-DG) transport in a time- and dose-dependent manner, but decreased the activation of this process elicited by submaximal concentrations of insulin. PMA (0.1-1,000 ng/ml) also stimulated basal lipogenesis from [3-3H] glucose in a dose-dependent manner. Maximal PMA and insulin effects on both processes were not additive. The specificity of the insulin-like effects of PMA was assessed by the finding that 4 beta-phorbol 12, 13 dibutyrate (PDBu), mezerein, 1-oleyl-2-acetyl glycerol (OAG) and 1, 2 diolein, know as PKC activators, also markedly stimulated glucose metabolism whereas 4 alpha-phorbol 12, 13 didecanoate (4 alpha-PDD) and 4 beta-phorbol 13-monoacetate, shown not to activate PKC, were ineffective. PMA and insulin biological effects exhibited several similarities: both agents stimulated glucose transport and lipogenesis in a calcium-dependent manner, both activated glucose transport through an energy-requiring process, and the effects of both were markedly decreased by mellitin, a PKC inhibitor. Finally, fat cells made PKC-deficient by a chronic treatment with PMA exhibited a marked decrease in insulin responsiveness for stimulation of glucose transport and lipogenesis, with no change in either the hormone sensitivity or the insulin receptor affinity.(ABSTRACT TRUNCATED AT 250 WORDS)


Vision outcomes in children with fetal alcohol spectrum disorders.
Previous studies demonstrated that children with Fetal Alcohol Spectrum Disorders (FASD) are more likely to have vision impairments. However, existing human clinical and epidemiological investigations are few and include limited sample sizes. This study aimed to explore the association between ophthalmologic abnormalities and FASD in a sample of 5-7 year old children in the general population. This was a cross-sectional study nested in a larger study intended to estimate the prevalence of FASD in San Diego, California, conducted between 2012 and 2014. Prenatal exposure to alcohol, dysmorphology examinations, and a neurobehavioral testing battery were collected for each child and an FASD diagnosis was assigned. Parents of participating children were asked to release their child's vision screening or diagnostic records. Vision records were obtained for 424 participants in the larger prevalence study. Of these, 53 children were classified as having FASD. A statistically significant association was found between FASD and a diagnosis of strabismus; 5/42 (11.9%) of children who were classified as having FASD had strabismus compared to 6/290 (2.1%) of children who were not classified as having FASD (p = .01). All five cases of strabismus in the FASD group occurred in 19 children classified as having partial fetal alcohol syndrome (pFAS). No association was found between FASD and vision impairment (p = .23), refractive errors (p = .66), glasses/contact lens prescription (p = .30), or having one or more ophthalmological abnormalities (p = .97). An association between strabismus and FASD, specifically partial FAS, suggests that the effect of alcohol exposure on risk of strabismus must be severe enough to result in facial features consistent with FASD. This emphasizes the importance of vision screening in children with FASD.


The p16(INK4a) tumour suppressor protein inhibits alphavbeta3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alphavbeta3 to focal contacts.
Expression of full-length p16(INK4a) blocks alphavbeta3 integrin-dependent cell spreading on vitronectin but not collagen IV. Similarly, G1-associated cell cycle kinases (CDK) inhibitory (CKI) synthetic peptides derived from p16(INK4a), p18(INK4c) and p21(Cip1/Waf1), which can be delivered directly into cells from the tissue culture medium, do not affect non-alphavbeta3-dependent spreading on collagen IV, laminin and fibronectin at concentrations that inhibit cell cycle progression in late G1. The alphavbeta3 heterodimer remains intact after CKI peptide treatment but is immediately dissociated from the focal adhesion contacts. Treatment with phorbol 12-myristate 13-acetate (PMA) allows alphavbeta3 to locate to the focal adhesion contacts and the cells to spread on vitronectin in the presence of CKI peptides. The cdk6 protein is found to suppress p16(INK4a)-mediated inhibition of spreading and is also shown to localize to the ruffling edge of spreading cells, indicating a function for cdk6 in controlling matrix-dependent cell spreading. These results demonstrate a novel G1 CDK-associated integrin regulatory pathway that acts upstream of alphavbeta3-dependent activation of PKC as well as a novel function for the p16(INK4a) tumour suppressor protein in regulating matrix-dependent cell migration.


Occurrence of the microcystins MC-LW and MC-LF in Dutch surface waters and their contribution to total microcystin toxicity.
Microcystins (MCs) are the most frequently found cyanobacterial toxins in freshwater systems. Many MC variants have been identified and variants differ in their toxicity. Recent studies showed that the variants MC-LW and MC-LF might be more toxic than MC-LR, the variant that is most abundant and mostly used for risk assessments. As little is known about the presence of these two variants in The Netherlands, we determined their occurrence by analyzing 88 water samples and 10 scum samples for eight MC variants ((dm-7-)MC-RR, MC-YR, (dm-7-)MC-LR, MC-LY, MC-LW and MC-LF) by liquid chromatography with tandem mass spectrometry detection. All analyzed MC variants were detected, and MC-LW and/or MC-LF were present in 32% of the MC containing water samples. When MC-LW and MC-LF were present, they contributed to nearly 10% of the total MC concentrations, but due to their suspected high toxicity, their average contribution to the total MC toxicity was estimated to be at least 45%. Given the frequent occurrence and possible high toxicity of MC-LW and MC-LF, it seems better to base health risk assessments on the toxicity contributions of different MC variants than on MC-LR concentrations alone.


Quantitation of choline in the extracellular fluid of brain tissue with amperometric microsensors.
Amperometric microsensors for the detection of choline in the extracellular fluid of brain tissue have been prepared by immobilizing horseradish peroxidase and choline oxidase onto carbon fiber microcylinder electrodes with a cross-linkable redox polymer. The microcylinders have diameters of 7 or 10 microns and lengths of 200-400 microns. To detect choline, the microsensors are operated at an applied potential of -0.1 V vs SCE. At this potential, ascorbate and other easily oxidizable interferant molecules present in brain tissue are not detected by the electrode. Ascorbate, however, can interfere with the response to choline by acting as a reducing agent in the enzyme-containing polymer film. So, a Nafion overlayer is required in order to reliably detect choline in the presence of physiologically relevant concentrations of ascorbate (approximately 200 microM). The Nafion-coated microsensors have a detection limit of approximately 5 microM choline and give a linear response beyond 100 microM when calibrated in vitro at 37 degrees C. Exposure of the microsensors to brain tissue for several hours causes less than a 10% loss in redox polymer surface coverage and less than a 25% loss in sensitivity to choline. To assess the ability of the microsensors to monitor choline levels in brain tissue, small volumes of a choline solution were injected into brain tissue at a site about 1 mm away from a microsensor. The current arising at the microsensor was converted to choline concentration by calibrating the sensor following the in vivo experiment. The resultant choline concentrations were in excellent agreement with those predicted by appropriate diffusion equations.


Perinatal transmission of coxsackievirus B3 in mice.
Oral infection of pregnant mice with coxsackievirus B3 (CB3) late in gestation produced maternal viremia, which peaked three to four days after challenge, then rapidly diminished. Ninety percent of mice developed IgG antibody to CB3 by ten days after challenge. CB3 titers from placental tissue peaked at two to four days after maternal infection, but moderate titers persisted for at least eight days. Though virus could be recovered (less than 1.0-1.5 log10 pfu/g) from fetal tissue in only a small percentage (3%-13%) of pregnancies, virus could be found in some fetuses eight days after maternal infection. Despite the low rate of fetal infection, many pups born to dams infected one to eight days before delivery were either stillborn (4%-41%) or died from infection shortly after birth (14%-68%). The actual percentages depended on the time interval from infection of the dams to delivery. Maternal IgG antibody to CB3, which appeared at six to eight days after infection, protected against postnatal mortality, but did not protect against stillbirth.


Recognition and management of shock in the pediatric patient.
Shock continues to be a challenge for health care professionals because shock is not a single pathologic process but a complex series of interrelated events. After respiratory failure, shock is the second most common cause of death in children. The etiology of shock can be classified into three major categories: hypovolemic, cardiogenic, and distributive shock (septic shock). Despite the etiology of the shock state, if left untreated, the overwhelming response of the body to the inadequate perfusion is death. The key to successful management and treatment of shock is early recognition and rapid intervention.


PTHrP(12-48) Modulates the Bone Marrow Microenvironment and Suppresses Human Osteoclast Differentiation and Lifespan.
Bone is a common site for metastasis in breast cancer patients and is associated with a series of complications that significantly compromise patient survival, partially due to the advanced stage of disease at the time of detection. Currently, no clinically-approved biomarkers can identify or predict the development of bone metastasis. We recently identified a unique peptide fragment of parathyroid hormone-related protein (PTHrP), PTHrP(12-48), as a validated serum biomarker in breast cancer patients that correlates with and predicts the presence of bone metastases. In this study, the biological activity and mode of action of PTHrP(12-48) was investigated. Sequence-based and structure-based bioinformatics techniques predicted that the PTHrP(12-48) fragment formed an alpha helical core followed by an unstructured region after residue 40 or 42. Thereafter, detailed structure alignment and molecular docking simulations predicted a lack of interaction between PTHrP(12-48) and the cognate PTH1 receptor (PTHR1). The in silico prediction was confirmed by the lack of PTHrP(12-48)-stimulated cAMP accumulation in PTHR1-expressing human SaOS2 cells. Using a specific human PTHrP(12-48) antibody that we developed, PTHrP(12-48) was immunolocalized in primary and bone metastatic human breast cancer cells, as well as within human osteoclasts (OCLs) in bone metastasis biopsies, with little or no localization in other resident bone or bone marrow cells. In vitro, PTHrP(12-48) was internalized into cultured primary human OCLs and their precursors within 60 min. Interestingly, PTHrP(12-48) treatment dose-dependently suppressed osteoclastogenesis, via the induction of apoptosis in both OCL precursors as well as in mature OCLs, as measured by the activation of cleaved caspase 3. Collectively, these data suggest that PTHrP(12-48) is a bioactive breast cancer-derived peptide that locally regulates the differentiation of hematopoietic cells and the activity of osteoclasts within the tumor-bone marrow microenvironment, perhaps to facilitate tumor control of bone. © 2017 American Society for Bone and Mineral Research.


Is the ascending colon dispensable in resection for Crohn's disease?
Resection for chronic ileocaecal Crohn's disease may be conservative with ileo-ascending-colon anastomosis, or be extended to standard right hemicolectomy. The two operations have been compared to determine whether preservation of the ascending colon is advantageous. Stool frequency, consistency and weight were similar after the two operations. A slower stool transit time was the only clinical difference associated with preservation of the ascending colon. An adaptable and patient-acceptable technique for domicillary collection of stools is described.


Screening for speech and language disorders: the reliability, validity and accuracy of the General Language Screen.
This paper reports the reliability, validity and accuracy of the General Language Screen (GLS) as the first stage in its development as a potential screening instrument for the identification of speech and language disorder (SLD) in the primary care setting. Data reported were obtained during the Cambridge Language and Speech Project (CLASP) a longitudinal epidemiological study of primary SLD. The GLS was originally used in initial CLASP sample ascertainment when children were aged 36 months. This report utilises speech and language data collected at subsequent stages of this study (37-months, 45-months and 8-years) to determine the reliability, validity and accuracy of the GLS. The GLS demonstrated sufficient levels of reliability (internal consistency alpha = 0.74) and validity (criterion validity r = -0.55). Adequate construct validity was demonstrated by a factor analysis in which two language related factors were identified. These data therefore justified exploration of the accuracy of the GLS as a screening instrument. Analysis of accuracy in this context is complicated by lack of a generally accepted method of defining SLD case status. This report utilises data on language function at different stages of development to provide measures of GLS accuracy over time. Concurrent accuracy, measured against parental report of language function at 37-months, was good (ROC area under the curve = 0.93). Predictive accuracy measured against direct assessment of speech and language at 45-months and 8-years was, as expected, somewhat less (ROC = 0.77 and 0.68 respectively). The implications for the use of the GLS as a screening instrument are discussed. The data indicate that the GLS would function most usefully as the first stage of a two-stage screen for SLD in the primary care setting. Recommendations are made as to the nature of the second stage of such a screen and plans for future research are outlined.


Rapid electrophoresis and quantitation of haemoglobins on cellulose acetate.
A rapid and reproducible electrophoretic method for the separation and quantitation of haemoglobins on cellulose acetate is described. The accuracy of the method and its possible sources of error are discussed. The normal range for haemoglobin A(2) by this method is 1% to 3% of the total haemoglobin concentration. Blood samples from 32 thalassaemic patients showed haemoglobin A(2) values of 3.5% to 7%.


[Electrophysiologic characterization of propafenone in man].
We performed an electrophysiologic study in 10 subjects before and after administration of Propafenon in doses of 1,5 mg/Kg b.w. i.v. in 2-3 minutes. No symptoms and no significant reductions of arterial blood pressure were observed. The analysis of our data shows that Propafenon does not significantly influence the sinus node function and the sinoatrial conduction. As far the atrioventricular conduction, the drug caused a significant increase of the Wenckebach point, of St-Q interval duration and of the A-V node absolute refractory period. The H-V interval and the His-Purkinje refractory period were also increased. We conclude that P exerts a negative dromotropic effect by direct pharmacological action on the A-V node and on the intraventricular specific conduction pathways.


Antibody Profile of Colostrum and the Effect of Processing in Human Milk Banks: Implications in Immunoregulatory Properties.
When feeding preterm infants, donor milk is preferred if the mother's own milk is unavailable. Pasteurization may have detrimental effects on bioactivity, but more information is needed about its effects on the immunological compounds. Research aim: This work has two main aims: evaluate the antibody profile of colostrum and study the quantitative variations in the antibodies' level and specific reactivity after undergoing Holder pasteurization. The authors focused on immunoregulatory components of colostrum (antidietary antibodies and TGF-β2) in the neonatal gut. This is a descriptive cross-sectional study of a convenience sample of 67 donated colostrum samples at different days after delivery, both raw and pasteurized. Antibody profiles were analyzed at different times during breastfeeding, and total and specific antibodies (IgM, IgA, and IgG subclasses) were compared with tetanus toxoid and ovalbumin using enzyme-linked immunosorbent assay. The processing effect on total and specific antibodies, as well as TGF-β2, was evaluated by paired analyses. No variations in immunological compounds were observed throughout the colostrum stage. The TGF-β2, antibodies' concentrations, and antibodies' specific reactivity after pasteurization did not vary significantly as days of lactation varied. Changes in antibody levels were dependent on isotype and IgG subclass, and IgG4 showed remarkable resistance to heating. Moreover, the effect of the pasteurization on specific reactivity was antigen dependent. The supply of relevant immunological components is stable throughout the colostrum stage. The effects of pasteurization on antibodies depend on isotype, subclass, and specificity. This information is relevant to improving the immunological quality of colostrum, especially for preterm newborns.


Evaluation of CA 15-3 tumor marker in the diagnosis of breast cancer. A pilot study.
Single determinations of serum CA 15-3 levels were performed by sandwich enzyme immunoassay in 160 women: 77 patients with nonmalignant breast tumors (64 had fibrocystic disease, 11 had fibroadenoma, 2 had intraductal papilloma) and 83 patients with primary breast cancer prior to any treatment; the cut-off limit was established at 30 U/ml. The overall diagnostic sensitivity and specificity of the CA 15-3 test was 19.3% and 94.8%, respectively. The positive and negative predictive values were 80.0% and 52.1%. The mean CA 15-3 value was significantly lower in patients with benign breast tumors as compared with the breast cancer group: 16.8 +/- 8.2 vs. 23.9 +/- 20.9 U/ml (p < 0.01) as well as the percentage of positive results of the test: 5.2% vs. 19.3% (p < 0.02). Serum CA 15-3 level in breast cancer patients correlated with: (1) clinical stage: a higher percentage of positive results was observed in patients with more advanced cancer: Stage I-0%, Stage II-10.6%, Stage III-29.6%, and Stage IV-100.0% according to UICC classification; the comparison of breast cancer patients with early stage of disease (I+II) and those with more advanced cancer (III+IV) revealed statistically significant (p < 0.01) difference in the mean serum CA 15-3 value (19.7 +/- 12.8 vs. 31.5 +/- 29.2 U/ml) as well as in the percentage of positive results (9.4% vs. 36.7%, p < 0.01); (2) the histological grading according to Bloom and Richardson: 5.41% of positivity was observed in low and intermediate grade cancers (I+II) vs. 66.7% in grade III (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of bromocriptine (CB-154) treatment on copulatory behavior in hyperprolactinemic adult male rats.
Adult male rats received pituitary transplantations to induce hyperprolactinemia. Some of those had bromocriptine (CB-154) treatment, and the other had vehicle (saline) as control. The grafted animals with vehicle exhibited significantly more suppression than sham operated animals. While the hyperprolactinemic rats treated with CB-154 showed no significantly more suppression of copulatory behavior than sham operated control. In the grafted animal without CB-154 treatment, the concentration of serum PRL was significantly higher than in sham operated controls. There were no significant differences in adrenal weight and serum levels of gonadotropin between grafted and control groups. These results may imply that PRL has direct actions on central nervous system (CNS) and inhibits copulatory behavior in hyperprolactinemic male rats.


The JAK2(V617F) tyrosine kinase mutation identifies clinically latent myeloproliferative disorders in patients presenting with hepatic or portal vein thrombosis.
Clinically latent myeloproliferative disorders (MPDs) are important causes of what would otherwise be considered idiopathic hepatic (HVT) or portal vein thrombosis (PVT). They may be difficult to diagnose initially because the peripheral blood count may be normal at the time of thrombosis. A strong association between an activating mutation of the gene encoding one of the Janus kinase family of tyrosine kinases (JAK2(V617F)) and the Philadelphia chromosome-negative MPDs has been identified. We have studied 19 patients with unexplained HVT or PVT and tested for JAK2(V617F). Fourteen (74%) of the 19 patients were heterozygous for JAK2(V617F) but did not meet diagnostic criteria for a MPD at the time of presentation with thrombosis. Prolonged follow-up established the presence of an overt MPD in 13 of the 14 patients after a median duration of 38 months. We recommend testing for JAK2(V617F) in all patients with unexplained HVT or PVT, to identify latent MPDs and prevent potential complications.


The Memory Alteration Test Discriminates between Cognitively Healthy Status, Mild Cognitive Impairment and Alzheimer's Disease.
Dementia is a worldwide public health problem and there are several diagnostic tools for its assessment. The aim of this study was to evaluate the performance of the Memory Alteration Test (M@T) to discriminate between patients with early Alzheimer's disease (AD), patients with amnestic mild cognitive impairment (a-MCI), and subjects with a cognitively healthy status (CHS). The discriminative validity was assessed in a sample of 90 patients with AD, 45 patients with a-MCI, and 180 subjects with CHS. Clinical, functional, and cognitive studies were independently performed in a blinded fashion and the gold standard diagnosis was established by consensus on the basis of these results. The test performance was assessed by means of a receiver operating characteristic curve analysis as area under the curve (AUC). M@T mean scores were 17.7 (SD = 5.7) in AD, 30.8 (SD = 2.3) in a-MCI, and 44.5 (SD = 3.1) in CHS. A cutoff score of 37 points had a sensitivity of 98.3% and a specificity of 97.8% to differentiate a-MCI from CHS (AUC = 0.999). A cutoff score of 27 points had a sensitivity of 100% and a specificity of 98.9% to differentiate mild AD from a-MCI and from CHS (AUC = 1.000). The M@T had a high performance in the discrimination between early AD, a-MCI and CHS.


Higher body mass index and anti-drug antibodies predict the discontinuation of anti-TNF agents in Korean patients with axial spondyloarthritis.
The development of anti-drug antibodies against tumor necrosis factor inhibitors is a likely explanation for the failure of TNF-inhibitors in patients with spondyloarthritis. Our study determined the existence and clinical implications of ADAbs in axial spondyloarthritis patients. According to the Assessment of SpondyloArthritis International Society classification criteria for axial spondyloarthritis, patients treated with adalimumab or infliximab were recruited consecutively. Serum samples were collected at enrollment to measure anti-drug antibodies and drug levels. Of 100 patients, the mean duration of current TNF inhibitor use was 22.3±17.9 months. Anti-drug antibodies were detected in 5 of 72 adalimumab users compared to 5 of 28 infliximab users (6.9% vs. 17.9%). Anti-drug antibodies-positive patients had a significantly higher body mass index than anti-drug antibodies-negative patients among both adalimumab (28.4±5.9kg/m2 vs. 24.3±2.9kg/m2, respectively, p=0.01) and infliximab users (25.9±2.8kg/m2 vs. 22.6±2.8kg/m2, respectively, p=0.02). During the median 15-month follow-up period, drug discontinuation occurred more frequently in the anti-drug antibodies-positive group than the anti-drug antibodies-negative group (30.0% vs. 6.5%, respectively, p=0.04). In logistic regression, anti-drug antibodies positivity (OR=5.85, 95% CI 1.19-28.61, p=0.029) and body mass index (OR=4.35, 95% CI 1.01-18.69, p=0.048) were associated with a greater risk of stopping TNF inhibitor treatment. Our result suggests that the presence of anti-drug antibodies against adalimumab and infliximab as well as a higher body mass index can predict subsequent drug discontinuation in axial spondyloarthritis patients.


Tumor-Associated Macrophage (TAM) and Angiogenesis in Human Colon Carcinoma.
This study aimed to clarify how macrophages affect prognosis in cancer colon and their association with tumor angiogenesis. Forty four biopsies of colon carcinoma and 15 of benign adenomatous polyps were investigated for macrophages infiltration and microvessels density using immunohistochemistry and image morphometric analysis. Macrophages and blood vessels were stained immunohistochemically by CD68 and F-VIII markers respectively. The morphometric analysis was carried out on the immunohistochemically stained slides using the Leica Qwin 500 Image Analyzer. Both of macrophages infiltration and microvessels density were correlated with histological tumor grade, stage and lymph node metastases and were correlated with each others. Macrophage infiltration was significantly higher in malignant cases than in benign polyps. High macrophage infiltration and hypervascularity were significantly correlated with T-staging and lymph nodes metastasis. A significant correlation was found between macrophage infiltration and microvessels densitie in malignant tumors where hypervascularity was significantly correlated with high macrophages infiltration. The significant correlation between macrophage infiltration and tumor angiogenesis suggests an interaction between macrophages and cancer cells stimulating microvessels formation, tumor invasion and metastasis in colon cancer. We recommend that macrophages infiltration should be evaluated to investigate their clinical value in development of individualized therapeutic regimens for management of colon carcinoma.


Pseudosymmetry in azabicyclo[2.1.1]hexanes. A stereoselective construction of the bicyclic core of peduncularine.
Intramolecular photocycloaddition of 41 or its equivalent leads to the formation of photoadduct 25. While retro-Mannich fragmentation of the "b" bond in 25 leads to the formation of 44 (via 43), with the incorrect relative stereochemistry for the synthesis of peduncularine 5, selective fragmentation of the "a" bond in 25 leads to the formation of 42 (via 26) with the correct relative stereochemistry for the synthesis of 5.


Spotlight on necitumumab in the treatment of non-small-cell lung carcinoma.
The treatment options for metastatic non-small-cell lung cancer (NSCLC) have expanded dramatically in the last 10 years with the discovery of newer drugs and targeted therapy. Epidermal growth factor receptor (EGFR), when aberrantly activated, promotes cell growth and contributes in various ways to the malignant process. EGFR has become an important therapeutic target in a variety of malignancies. Small-molecule tyrosine kinase inhibitors (TKIs) of EGFR are being used to treat advanced NSCLC and are particularly effective in the presence of EGFR mutations. Monoclonal antibodies have also been developed that block the EGFR at the cell surface and work in conjunction with chemotherapy. Necitumumab is a second-generation fully human IgG1 monoclonal antibody that has shown promise in metastatic NSCLC. The benefit has mostly been restricted to squamous cell lung cancer in the frontline setting. Considering that the survival advantage for these patients was modest, there is a need to discover biomarkers that will predict which patients will likely have the best outcomes. This review focuses on the development and clinical trial experience with necitumumab in NSCLC.


Back pain in a previously healthy teenager.
We present the case of a 14-year-old previously healthy boy who presented to his general practitioner with back pain and fever after rugby training. He was initially treated for suspected discitis but during the course of his admission he rapidly deteriorated and developed severe necrotising pneumonia. He was intubated, ventilated and transferred to a paediatric intensive care unit. Panton-Valentine leukocidin Staphylococcus aureus was suspected and subsequently identified in blood cultures.


Transition metal-directed self-assembly of calix[4]arene based dithiocarbamate ligands.
The transition metal-directed self-assembly of dithiocarbamate ligand functionalized upper and lower rim calix[4]arenes affords novel dimeric bimetallic bis(calix[4]arene) species as determined by a combination of analytical methods including X-ray crystallography. An exception is a zinc(II) dithiocarbamate upper rim calix[4]arene assembly which is monomeric in nature. Electrochemical investigations reveal the bimetallic copper(II) bis(calix[4]arene) systems can electrochemically sense dihydrogen phosphate and carboxylate anions via significant cathodic perturbations of the respective copper(II)/(III) dithiocarbamate oxidation wave.


Wisconsin's recent BadgerCare enrollment decline: how administrative rules can set off unanticipated change.
The State Children's Health Insurance Program (SCHIP) has been intended to provide healthcare coverage to that group of children previously caught between Medicaid eligibility and adequate access to employer insurance. However, SCHIP can be implemented quite differently across the states, potentially affecting actual enrollment. We review prior studies that have attempted to dissect how the administration of SCHIP impacts enrollment, including a multivariate study by the authors that indicates presumptive eligibility, expanded parent coverage, and 12-month continuous eligibility all contribute to a reduced likelihood of being uninsured. We then detail an administrative policy change in one state, Wisconsin, that yielded unanticipated and dramatic enrollment fluctuations in its SCHIP program, BadgerCare.


NADPH oxidase 4 regulates homocysteine metabolism and protects against acetaminophen-induced liver damage in mice.
Glutathione is the major intracellular redox buffer in the liver and is critical for hepatic detoxification of xenobiotics and other environmental toxins. Hepatic glutathione is also a major systemic store for other organs and thus impacts on pathologies such as Alzheimer's disease, Sickle Cell Anaemia and chronic diseases associated with aging. Glutathione levels are determined in part by the availability of cysteine, generated from homocysteine through the transsulfuration pathway. The partitioning of homocysteine between remethylation and transsulfuration pathways is known to be subject to redox-dependent regulation, but the underlying mechanisms are not known. An association between plasma Hcy and a single nucleotide polymorphism within the NADPH oxidase 4 locus led us to investigate the involvement of this reactive oxygen species- generating enzyme in homocysteine metabolism. Here we demonstrate that NADPH oxidase 4 ablation in mice results in increased flux of homocysteine through the betaine-dependent remethylation pathway to methionine, catalysed by betaine-homocysteine-methyltransferase within the liver. As a consequence NADPH oxidase 4-null mice display significantly lowered plasma homocysteine and the flux of homocysteine through the transsulfuration pathway is reduced, resulting in lower hepatic cysteine and glutathione levels. Mice deficient in NADPH oxidase 4 had markedly increased susceptibility to acetaminophen-induced hepatic injury which could be corrected by administration of N-acetyl cysteine. We thus conclude that under physiological conditions, NADPH oxidase 4-derived reactive oxygen species is a regulator of the partitioning of the metabolic flux of homocysteine, which impacts upon hepatic cysteine and glutathione levels and thereby upon defence against environmental toxins.


Egr1 Is Necessary for Forebrain Dopaminergic Signaling during Social Behavior.
Finding the link between behaviors and their regulatory molecular pathways is a major obstacle in treating neuropsychiatric disorders. The immediate early gene (IEG) EGR1 is implicated in the etiology of neuropsychiatric disorders, and is linked to gene pathways associated with social behavior. Despite extensive knowledge of EGR1 gene regulation at the molecular level, it remains unclear how EGR1 deficits might affect the social component of these disorders. Here, we examined the social behavior of zebrafish with a mutation in the homologous gene egr1 Mutant fish exhibited reduced social approach and orienting, whereas other sensorimotor behaviors were unaffected. On a molecular level, expression of the dopaminergic biosynthetic enzyme, tyrosine hydroxylase (TH), was strongly decreased in TH-positive neurons of the anterior parvocellular preoptic nucleus. These neurons are connected with basal forebrain (BF) neurons associated with social behavior. Chemogenetic ablation of around 30% of TH-positive neurons in this preoptic region reduced social attraction to a similar extent as the egr1 mutation. These results demonstrate the requirement of Egr1 and dopamine signaling during social interactions, and identify novel circuitry underlying this behavior.


Screening and preliminary validation of T lymphocyte immunoregulation‑associated long non‑coding RNAs in diabetic foot ulcers.
The present study aimed to investigate the existence of immunoregulation‑associated long non‑coding (lnc)RNAs mediated by T lymphocytes in the wound surfaces of diabetic foot ulcers (DFUs). The wound skin tissues of patients receiving debridement for trauma or DFUs associated with infection were obtained. Dermatological histological changes were observed by pathological staining, and T lymphocyte subsets and inflammation‑associated cytokines were identified. Gene chip technology was used to screen for lncRNAs regulated by immune cells. The wound skin structure in the control group was revealed to be complete, and the inflammatory response was not marked. However, the wound skin structure in the ulcer group was disordered and exhibited a notable inflammatory response. Compared with the control group, expression levels of cluster of differentiation (CD)3 and CD8 in the wound surface tissues of the ulcer group were significantly increased, while the expression levels of interleukin (IL)‑1β, IL‑2, IL‑10, interferon‑γ and tumor necrosis factor‑α were significantly upregulated. A target regulatory association was identified between downregulated lncRNA‑ENST00000411554 and upregulated mitogen‑activated protein kinase (MAPK)1 in DFU tissues, and a negative correlation was detected between this RNA and protein. The present results suggested that an immune functional disorder of T lymphocytes may be closely associated with the development of DFUs. Furthermore, activation of the MAPK signal transduction pathway mediated by the lncRNA‑ENST00000411554/MAPK1 axis may affect the DFU immune regulatory imbalance.


DNA-assisted swarm control in a biomolecular motor system.
In nature, swarming behavior has evolved repeatedly among motile organisms because it confers a variety of beneficial emergent properties. These include improved information gathering, protection from predators, and resource utilization. Some organisms, e.g., locusts, switch between solitary and swarm behavior in response to external stimuli. Aspects of swarming behavior have been demonstrated for motile supramolecular systems composed of biomolecular motors and cytoskeletal filaments, where cross-linkers induce large scale organization. The capabilities of such supramolecular systems may be further extended if the swarming behavior can be programmed and controlled. Here, we demonstrate that the swarming of DNA-functionalized microtubules (MTs) propelled by surface-adhered kinesin motors can be programmed and reversibly regulated by DNA signals. Emergent swarm behavior, such as translational and circular motion, can be selected by tuning the MT stiffness. Photoresponsive DNA containing azobenzene groups enables switching between solitary and swarm behavior in response to stimulation with visible or ultraviolet light.


[Multiple cerebral cavernous haemangiomas in a woman with visual hallucinations].
Cerebral vascular malformations is a common condition though it remains clinically silent in the vast majority of patients. Symptoms comprise seizures, headaches, focal neurological deficits and unconsciousness due to major cerebral haemor-rhage. A 31-year-old woman was referred for assessment of intermittent visual hallucinations, headache and dizziness. A magnetic resonance imaging of the brain revealed multiple supra- and infratentorial cavernous haemangiomas. The woman suffered from simple focal seizures with visual hallucinations every twenty minutes. The biggest haemangioma was surgically removed and the epileptic condition was treated with drugs.


Effect of cholestyramine on the fecal excretion of intravenously administered cholesterol-4-14C and its degradation products in a hypercholesterolemic patient.
The effect of cholestyramine on the fecal excretion of bile acids and neutral sterols was measured in a hypercholesterolemic patient on a low fat, high polyunsaturated fatty acid-containing diet after the intravenous injection of cholesterol-4-(14)C. A significant (16%) lowering of serum cholesterol concentration was accompanied by a 3.2-fold increase in fecal bile acid excretion but no change in neutral sterol output. The increased bile acid loss was adequate to account for the observed fall in serum cholesterol level. The implications of these findings were discussed.


Influence of iron sulfides on abiotic oxidation of UO2 by nitrite and dissolved oxygen in natural sediments.
Iron sulfide precipitates formed under sulfate reducing conditions may buffer U(IV) insoluble solid phases from reoxidation after oxidants re-enter the reducing zone. In this study, sediment column experiments were performed to quantify the effect of biogenic mackinawite on U(IV) stability in the presence of nitrite or dissolved oxygen (DO). Two columns, packed with sediment from an abandoned U contaminated mill tailings site near Rifle, CO, were biostimulated for 62 days with an electron donor (3 mM acetate) in the presence (BRS+) and absence (BRS−) of 7 mM sulfate. The bioreduced sediment was supplemented with synthetic uraninite (UO2(s)), sterilized by gamma-irradiation, and then subjected to a sequential oxidation by nitrite and DO. Biogenic iron sulfides produced in the BRS+ column, mostly as mackinawite, inhibited U(IV) reoxidation and mobilization by both nitrite and oxygen. Most of the influent nitrite (0.53 mM) exited the columns without oxidizing UO2, while a small amount of nitrite was consumed by iron sulfides precipitates. An additional 10-day supply of 0.25 mM DO influent resulted in the release of about 10% and 49% of total U in BRS+ and BRS– columns, respectively. Influent DO was effectively consumed by biogenic iron sulfides in the BRS+ column, while DO and a large U spike were detected after only a brief period in the effluent in the BRS– column.


[Chikungunya and urban sprawl on Reunion Island].
The proportion of unsanitary housing in French overseas departments is much higher than in mainland France. Reunion Island is no exception to this fact. Between 80 and 90% of housing in Reunion Island was built by squatters with no legal claim or deed to the property. This has resulted in uncontrolled urban sprawl with living conditions reminiscent of those in developing countries. The absence of adequate drainage systems for sewage and rain water and the lack of properly organized garbage disposal that characterizes these sprawl areas constitutes a particularly favorable breeding ground for vector-borne diseases, especially chikungunya. Thus, implementing measures to control this type of settlement and to relocate of people out of existing sprawl areas constitutes a significant tool to control this epidemiological risk. Up to now, public officials have shown a clear reluctance to intervene in sprawl areas despite good knowledge of their location. On June 26th of this year, a law containing provisions relative to the control of urban sprawl and unsanitary housing in overseas departments and territories will come into effect. This law should provide public officials with the legal basis that has up until now been lacking to take action. Persistence in the "wait-and-see" attitude could lead to condemnation by French or European courts.


The role of vitamin D levels and vitamin D receptor polymorphism on Parkinson's disease in the Faroe Islands.
The role of vitamin D in Parkinson's disease (PD) has been proposed and both low serum 25-hydroxyvitamin D levels (25(OH)D) and vitamin D receptor polymorphisms (VDR) have been linked to PD. The aim of this study is to investigate the associations among 25(OH)D and three VDR polymorphisms and PD in the Faroese population where the prevalence of PD is high. We conducted a case-control study where 121 cases were studied for 25(OH)D levels and VDR polymorphisms against 235 randomly selected controls, matched by gender and age. No significant difference was observed in 25(OH)D levels between PD cases and controls (P=0.49), although cases had slightly lower values than controls. As well, no differences were found in genotype frequencies between cases and controls in the VDR polymorphisms studied (ApaI, BsmI, TaqI) (P=0.70, P=0.56 and P=0.54, respectively). However, we found that VDR ApaI/AC genotype was significantly associated with 25(OH)D levels (P=0.01). Although our results indicate no association between PD and vitamin D polymorphisms and/or 25(OH)D levels, the study cannot exclude a weak association. However, the known doubling in PD prevalence in the Faroe Islands cannot be explained by the polymorphisms examined in the VDR gene or the 25(OH)D levels and has to be explored further.


H-π Landscape of the Phenylacetylene-HCl System: Does This Provide the Gateway to the Markovnikov Addition?
Non covalently bonded complexes of phenylacetylene-HCl were studied using matrix isolation infrared spectroscopy and ab initio calculations. Phenylacetylene (PhAc) is an interesting hydrogen bond precursor as it has multiple sites for weak interactions, and it was therefore considered worthwhile to study PhAc-HCl landscape. The interactions in PhAc-HCl were identified using the shifts in the infrared frequencies of the precursor molecules, as a result of complex formation. Our experiments unambiguously revealed spectral signatures of two types of H-π complexes, in both of which HCl was the proton donor. In one complex, the acetylenic π cloud (H-πAc) was the proton acceptor, while in the second, the role of the proton acceptor was played by the phenyl π cloud (H-πPh). The H-πAc and H-πPh complexes were evidenced by a 124 and 80 cm-1 red shift respectively, in the fundamental HCl stretch, relative to that of the uncomplexed HCl monomer. Ab initio calculations performed at M06-2X and MP2 level of theory using 6-311++G(d,p) and aug-cc-pVDZ basis functions indicated the H-πAc complex to be the global minimum and the H-πPh complex to be a local minimum; thus corroborating our experimental results. These conclusions were also confirmed by calculations at MP2/CBS and CCSD(T)/CBS limits. Interestingly, there were two isomers for the H-πAc complex, and it appears from an analysis of the charge densities, that one of the two isomers may serve as the gateway complex for the Markovnikov addition reaction. Computations identified a number of other minima, characterized by n-σ* and possibly Cl-π bonded structures, on the PhAc-HCl potential surface. AIM, NBO, and LMO-EDA analyses were also performed to characterize the non covalent interactions in the PhAc-HCl heterodimer.


Stabilization of Dispersed Oil Droplets in Nanoemulsions by Synergistic Effects of the Gemini Surfactant, PHPA Polymer, and Silica Nanoparticle.
Nanoemulsion systems comprising n-heptane (oleic component), stabilized by the {gemini surfactant (14-6-14 GS) + polymer [partially hydrolyzed poly-acrylamide (PHPA)] + silica (SiO2) nanoparticle} shell and dispersed in aqueous phase, were synthesized by ultrasonication (high-energy method). Influence of ultrasonication time on nanoemulsion kinetics was investigated to predict the saturation droplet diameter. Morphological analysis by transmission electron cryomicroscopy imaging showed that oleic phase appears as uniformly dispersed spherical droplets in 14-6-14 GS-stabilized nanoemulsion, which on PHPA addition changes into a network structure consisting of larger oil droplets. 14-6-14 + PHPA + SiO2 nanoemulsion systems show more effective packing arrangement with irregular-shaped (nonspherical) droplets. Dynamic light scattering studies identified droplet size distribution profiles in the range 4.2-25.4 nm for the surfactant-stabilized nanoemulsion, 125.9-358.8 nm for the surfactant-polymer nanoemulsion, and 88.4-222.3 nm for the surfactant-polymer-nanoparticle-based nanoemulsion in optimal dosage(s). Statistical analyses were performed using normal, log-normal, and Cauchy-Lorentz distribution functions. A modified form of Hinze theory was employed to model droplet behavior in analyzed nanoemulsion systems. Zeta potential values of nanoemulsions were studied at different time intervals to determine kinetic stability as well as corroborate Hinze model findings. In summary, this article aims at investigating nanoemulsion droplet stability by thorough examination of electrostatic repulsive barrier and steric hindrance effects.


Early intraocular pressure after phacoemulsification combined with trabeculectomy.
To determine the efficacy of combined phacoemulsification--trabeculectomy in preventing early postoperative increases in intraocular pressure (IOP). Eighty patients were enrolled in a prospective cohort study. Thirty-six patients with cataracts and uncontrolled glaucoma underwent combined phacoemulsification--trabeculectomy, and 44 patients with cataracts underwent phacoemulsification alone. The operations were performed in a standardized manner by one surgeon. IOP was measured at 4 hours, 1 day, and 7 days after surgery. The need for intervention (digital massage, medications) and the presence of complications were documented. Four hours after surgery, 5.5% of patients undergoing the combined procedure had IOPs greater than 30 mm Hg, compared with 22.7% of phacoemulsification patients (P < .05). No significant difference in IOP was found between the groups at postoperative day 1 or day 7. These results suggest that combined phacoemulsification-trabeculectomy protects against early postoperative elevations in IOP. This finding may influence the surgical management of cataracts in patients with poorly controlled glaucoma and significant compromise of visual field or optic nerve.


Diversity among community isolates of methicillin-resistant Staphylococcus aureus in Australia.
Community methicillin-resistant Staphylococcus aureus (CMRSA) strains are being isolated with increasing frequency around the world. In Western Australia CMRSA are endemic in geographically remote communities and have been found to belong to five different contour-clamped homogeneous electric field (CHEF) electrophoretic patterns. Representatives of each of these CHEF patterns have been compared to CMRSA representative of CHEF patterns from other Australian states and New Zealand. With one exception, all of the isolates were nonmultiresistant and were not resistant to many antimicrobial agents other than the beta-lactams. With one exception, which is not believed to be a CMRSA, all of the isolates harbored a beta-lactamase plasmid. Erythromycin resistance was associated with a 2-kb plasmid. One of the beta-lactamase plasmids was found to be able to acquire additional resistance determinants to become a multiple resistance plasmid. There were 10 multilocus sequence types belonging to eight distantly related clonal complexes of S. aureus. One new sequence type was found. Although most of the CMRSA harbored the type IVa SCCmec, a type IV structural variant was found and two new SCCmec types were identified. Protein A gene (spa) typing revealed two new spa types and, with two exceptions, corresponded to multilocus sequence typing. In contrast to other reports on CMRSA, most of the CMRSA strains studied here did not contain the Panton-Valentine leukocidin genes. The results also demonstrate that nonmultiresistant hospital strains such as UK EMRSA-15 may be able to circulate in the community and could be mistaken for CMRSA based on their resistance profiles.


Reactive oxygen species selectively deplete normal T lymphocytes via a hydroxyl radical dependent mechanism.
Chronic inflammatory synovitis is characterized by both lymphocytic infiltrates and persistent polymorph exudates. Activated polymorphs release reactive oxygen species (ROS) during inflammation, but the contribution that these make to the lymphocyte abnormalities associated with RA has been little studied. We therefore investigated the cytotoxic effects of the reactive oxygen species on human peripheral blood mononuclear cells (PBMC). PBMC were exposed to RPMI 1640 medium previously irradiated for up to 60 min. Consistent dose-dependent killing was observed at 24 h. Antioxidant studies indicated that H2O2 was the effective species. Catalase, which specifically degrades H2O2, gave almost total protection against cell death, while superoxide dismutase (SOD), thiourea, and mannitol were largely ineffective. Addition of exogenous H2O2 caused an identical pattern of cell death to that observed with irradiated medium. PBMC cultures supplemented with desferrioxamine (a ferric iron chelator) also gave significant protection, suggesting that H2O2 mediated its effects via OH radicals. Analysis of lymphocyte subpopulations showed that ROS caused a selective depletion, depending on the level of H2O2 present. Low levels induced a specific loss of CD8+ cells, while higher concentrations caused significant loss of CD4+ T cells as well. sIg+ B cells were unaffected at either concentration. This selective lymphotoxic effect of ROS may be of considerable importance in the pathogenesis of autoimmune inflammatory disease.


Longitudinal Long-term Magnetic Resonance Imaging and Clinical Follow-up After Single-Row Arthroscopic Rotator Cuff Repair: Clinical Superiority of Structural Tendon Integrity.
The number of arthroscopic rotator cuff surgeries is consistently increasing. Although generally considered successful, the reported number of retears after rotator cuff repair is substantial. Short-term clinical outcomes are reported to be rarely impaired by tendon retears, whereas to our knowledge, there is no study documenting long-term clinical outcomes and tendon integrity after arthroscopic rotator cuff repair. To investigate longitudinal long-term repair integrity and clinical outcomes after arthroscopic rotator cuff reconstruction. Case series; Level of evidence, 4. Thirty patients who underwent arthroscopic rotator cuff repair with suture anchors for a full-tendon full-thickness tear of the supraspinatus or a partial-tendon full-thickness tear of the infraspinatus were included. Two and 10 years after initial arthroscopic surgery, tendon integrity was analyzed using magnetic resonance imaging (MRI). The University of California, Los Angeles (UCLA) score and Constant score as well as subjective questions regarding satisfaction with the procedure and return to normal activity were used to evaluate short- and long-term outcomes. At the early MRI follow-up, 42% of patients showed a full-thickness rerupture, while 25% had a partial rerupture, and 33% of tendons remained intact. The 10-year MRI follow-up (129 ± 11 months) showed 50% with a total rerupture, while the other half of the tendons were partially reruptured (25%) or intact (25%). The UCLA and Constant scores significantly improved from preoperatively (UCLA total: 50.6% ± 20.2%; Constant total: 44.7 ± 10.5 points) to 2 years (UCLA total: 91.4% ± 16.0% [ P < .001]; Constant total: 87.8 ± 15.3 points [ P < .001]) and remained significantly higher after 10 years (UCLA total: 89.7% ± 15.9% [ P < .001]; Constant total: 77.5 ± 15.6 points [ P < .001]). The Constant total score and Constant strength subscore, but not the UCLA score, were also significantly better at 10 years postoperatively in patients with intact tendons compared with patients with retorn tendons (Constant total: 89.0 ± 7.8 points vs 75.7 ± 14.1 points, respectively [ P = .034]; Constant strength: 18.0 ± 4.9 points vs 9.2 ± 5.2 points, respectively [ P = .006]). The majority of patients rated their satisfaction with the procedure as "excellent" (83.3%), and 87.5% returned to their normal daily activities. Arthroscopic rotator cuff repair showed good clinical long-term results despite a high rate of retears. Nonetheless, intact tendons provided significantly superior clinical long-term outcomes, making the improvement of tendon healing and repair integrity important goals of future research efforts.


Periodic fluctuation of blood pressure and its management in a patient with pheochromocytoma. Case report and review of the literature.
The case of a 69 year old man with a right adrenal pheochromocytoma who manifested cyclic fluctuations of blood pressure with a cycle length of 9 to 13 min is reported. We collected and reviewed 14 similar cases previously reported in the literature. In these cases, right adrenal pheochromocytoma was most common, while 1 case involved the left adrenal and 2 cases were of extra-adrenal origin. The incidence in males was twice that in females and the median age was 45.3 years. Although a good correlation between the blood pressure and plasma norepinephrine concentrations was observed in our patient, the exact mechanism for the cyclic fluctuations of blood pressure is not known. In our patient, both YM-09538 and bunazosin were effective in controlling severe hypertension preoperatively. YM-09538 induced significant increases in urinary norepinephrine concentrations (1327 +/- 238 micrograms/day), while bunazosin induced a significant decrement in urinary norepinephrine concentrations (475 +/- 188 micrograms/day) compared with pretreatment levels (900 +/- 42 micrograms/day) (p less than 0.01). These observations indicated that bunazosin as a postsynaptic alpha-adrenergic receptor blocker interfered with release of norepinephrine from the tumor and thus might be beneficial in the management of elevated blood pressure in patients with pheochromocytoma.


A potential trigger of nephritogenic anti-DNA antibodies in lupus nephritis.
Anti-DNA antibodies play an essential role in the pathogenesis of lupus nephritis. Mammalian DNA alone, however, is poorly immunogenic. We speculated that the antigenic trigger for the production of human nephritogenic anti-DNA antibodies is a non-DNA substance. The cDNA library from peripheral blood lymphocytes (PBLs) of a patient with active lupus nephritis was screened using the single-chain Fv of a human monoclonal nephritogenic O-81 anti-DNA antibody in a two-hybrid system. A clone containing the gene of an endoplasmic reticulum (ER) stress-inducible protein, Herp, was obtained: The O-81 antibody bound to recombinant Herp protein synthesized by Escherichia coli. Immunization with Herp elicited both anti-double-stranded DNA (anti-dsDNA) and anti-single-stranded (anti-ssDNA) antibodies in BALB/c mice and formed deposits of IgG in renal glomeruli. Anti-DNA antibodies purified from SLE sera bound to Herp. Moreover, anti-Herp antibodies showed specific binding to DNA. Herp was spontaneously expressed in PBLs of patients with active SLE, but not in PBLs of healthy subjects. These results imply that an inducible intracellular self-protein represents a candidate trigger for human nephritogenic anti-DNA autoantibodies. Any cell stress causing ER stress, such as viral infection, ultraviolet radiation, and chemicals, might be responsible for anti-DNA antibody production via Herp.


Computed Tomography-based Radiomics for Risk Stratification in Prostate Cancer.
To explore the role of Computed tomography (CT)-based radiomics features in prostate cancer risk stratification. The study population consisted of 506 patients with prostate cancer collected from a clinically annotated database. After applying exclusion criteria, 342 patients were included in the final analysis. CT-based radiomics features were extracted from planning CT scans for prostate gland-only structure, and machine learning was used to train models for Gleason score (GS) and risk group (RG) classifications. Repeated cross-validation was used. The discriminatory performance of the developed models was assessed using receiver operating characteristic area under the curve (AUC) analysis. Classifiers using CT-based radiomics features distinguished between GS ≤ 6 versus GS ≥ 7 with AUC = 0.90 and GS 7(3 + 4) versus GS 7(4 + 3) with AUC = 0.98. Developed classifiers also showed excellent performance in distinguishing low versus high RG (AUC = 0.96) and low versus intermediate RG (AUC = 1.00), but poorer performance was observed for GS 7 versus GS > 7 (AUC = 0.69). An overall modest performance was observed for validation on holdout data sets with the highest AUC of 0.75 for classifiers of low versus high RG and an AUC of 0.70 for GS 7 versus GS > 7. Our results show that radiomics features from routinely acquired planning CT scans could provide insights into prostate cancer aggressiveness in a noninvasive manner. Assessing models on training data sets, the classifiers were especially accurate in discerning high-risk from low-risk patients and in classifying GS 7 versus GS > 7 and GS 7(3 + 4) versus G7(4 + 3); however, classifiers were less adept at distinguishing high RG versus intermediate RG. External validation and prospective studies are warranted to verify the presented findings. These findings could potentially guide targeted radiation therapy strategies in radical intent radiation therapy for prostate cancer.


[Study of Coxsackie A 10 virus infection in newborn and suckling mice of the strains A2G, ICR-K and CBA].
Differences in the susceptibility to paralytogenic infection with Coxsackie A10 virus were found in neonate and suckling mice belonging to A2G, ICR-K and CBA strains and ICR-K/CBA and CBA/ICR-K hybrids in the F1 generation. At the first passage in vivo the more susceptible strains selected paralytogenic viral particles from among the cytopathogenic and non-pathogenic Coxsackie A10 virus populations. The differences in susceptibility could not be related either with the humoral immune response to virus or to the rate of fixation of virus on the neonate mouse muscle cell receptors. These differences are, however, in agreement with the data concerning the synthesis of interferon in the striated muscle, the lots with greater resistance to viral infection being also those which synthesize interferon in higher concentrations. The hybrids resulting from the parental strains more susceptible to virus, presented a resistance superior to that of the parents.


Muscle infarction in a 13 year-old female with type 1 diabetes mellitus of short duration.
A 13 year-old female with an 11-month history of type 1 diabetes mellitus (DM) was admitted to the hospital with a muscle infarction. Diagnosis of this rare complication of DM was suggested by clinical presentation, magnetic resonance imaging (MRI) and muscle biopsy. While diabetic muscle infarction (DMI) has been previously described in adult patients with long-standing DM associated with microangiopathy, it is an unexpected finding in this clinical setting.


[Hippocampal dimensions, memory and learning during rat ontogenesis].
Injury to the hippocamp disturbs learning processes and short-term memory in 20-, 50- and 110-day rats. In 50-day rats, hippocampectomy results in lesser changes in learning and memory than in 20- and 110-day animals. Anatomo-physiological characteristics of the hippocamp in 20-day rats presumably indicate a particular importance of this structure at early stages of ontogenesis, when the brain cortex is not yet sufficiently mature and its connections with other structures are not completely formed. Non-linear dependence of learning disturbance in rats of varying age after hippocampectomy suggests that in rat hippocampal function undergoes changes during individual development of animals.


Does cleanliness influence moral judgments? Response effort moderates the effect of cleanliness priming on moral judgments.
Whether cleanliness influences moral judgments has recently become a topic of debate in the psychological literature. After the initial report that activating the notion of physical purity can result in less severe moral judgments (Schnall et al., 2008a), a direct replication (Johnson et al., 2014a) with much larger sample sizes failed to yield similar findings. The current paper examines the possibility that only non-conscious activation of the cleanliness concept, as achieved in participants with low response effort on priming materials, can produce the expected effect. An online replication (Study 1, N = 214) provided evidence that, when participants exerted low (yet still acceptable) levels of response effort to the experimental material, cleanliness priming led to more lenient moral judgments than neutral priming. An online experiment (Study 2, N = 440; replicated in Study 2a, N = 436) manipulating participants' effort on the priming task (low vs. high) supported the hypothesized mechanism. Specifically, respondents in the low response effort group were instructed to complete the priming task as quickly as possible without too much attention, and the cleanliness priming resulted in less extreme moral judgments than the neutral condition as expected. In contrast, respondents in the high response effort group were instructed to perform to the best of their ability on the priming task, with a non-significant difference on moral ratings between cleanliness and neutral conditions. In addition to helping resolve the controversy regarding the cleanliness hypothesis, the current paper calls into attention the role of response effort in the execution and replication of priming studies.


Radiofrequency ablation of metastatic lesions from breast cancer.
Breast cancer (BC) is the most common malignancy in women. Various studies [5,6] have shown that surgical resection of single liver or lung metastases in patients with metastases from BC increases survival. Radiofrequency ablation (RFA) can be an alternative to resection in some patients when resection is not feasible. From January 2002 to December 2008, 491 patients with liver metastases underwent US-guided percutaneous RFA. Of these patients 5 (5/491; 1%) had BC. In the same period, 32 patients with pulmonary metastases underwent CT-guided RFA. Of these patients 3 (3/32; 9%) had BC. Mean age was 61.3 years. All patients were postmenopausal and receiving polychemotherapy according to international guidelines. Inclusion criteria for RFA treatment of metastases from BC applied are identical or in some cases more restrictive than those reported in the literature. There were no deaths or severe complications and no treatment failures. Disease free and overall median survival were respectively 7.65 and 25.7 months after US-guided RFA and 13.4 and 34.8 months after CT-guided RFA. During follow-up (mean follow-up 26 months, range 4-63 months) 5/8 (62.5%) patients exhibited recurrence: 3/5 (60%) had local recurrence and 2/5 (40%) had non-local recurrence; 4/5 patients with recurrence were re-treated. The authors' experience confirms that RFA is an effective, safe and repeatable technique in the treatment of metastases from BC. Metastatic recurrence rate confirms that metastatic BC is a disease which requires a multidisciplinary approach and that the role of chemotherapy is indisputable. Effects on survival are promising but further confirmation is needed through prospective randomized studies.


A Review of the Epidemiology, Pathophysiology, and Efficacy of Anti-diabetic Drugs Used in the Treatment of Nonalcoholic Fatty Liver Disease.
In recent years, epidemiological studies have consistently demonstrated that the coexistence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) is strongly associated with increased mortality and morbidity related to hepatic- and extrahepatic causes. Indeed, compared with the general population, patients with T2DM are more likely to be diagnosed with more severe forms of NAFLD (i.e., nonalcoholic steatohepatitis (NASH) with liver fibrosis). There is an ongoing debate whether NALFD is a consequence of diabetes or whether NAFLD is simply a component and manifestation of the metabolic syndrome, since liver fat (steatosis) and even more advanced stages of liver fibrosis can occur in the absence of diabetes. Nevertheless, insulin resistance is a key component of the mechanism of NAFLD development; furthermore, therapies that lower blood glucose concentrations also appear to be effective in the treatment of NAFLD. Here, we will discuss the pathophysiological and epidemiological associations between NAFLD and T2DM. We will also review currently available anti-diabetic agents with their regard to their efficacy of NAFLD/NASH treatment.