Measuring the attention networks and quantitative-electroencephalography correlates of attention in depression.
Given the association between major depressive disorder (MDD) and cortical inefficiency related to executive control, specifically in the sense that individuals with MDD may recruit more cognitive resources to complete tasks at the same capacity as those without MDD, the current study was interested in examining the attention networks and executive functioning of those with MDD. Past research has used the Attention Network Test (ANT) to measure changes of attention in clinical vs. healthy populations; however, theoretical concerns have been raised regarding the task. The Combined Attention Systems Task (CAST) was developed to address these concerns and was used in our study in combination with quantitative-electroencephalography (QEEG) to assess both behavioural and neurophysiological changes in participants with MDD (n = 18) compared to healthy controls (HCs; n = 22). We found no behavioural differences between MDD and HC groups suggesting individuals with MDD in our sample were not experiencing the executive functioning deficits previously reported in the literature. Neurophysiological measures of attention revealed that MDD participants had greater theta and alpha1 activity relative to HCs, suggesting that although individuals with MDD do not show deficits in behavioural attention, they exhibit altered neural processing which underlies cognitive function.


Malignant tumors of the nasal cavity and ethmoid and sphenoid sinuses.
Between October 1964 and December 1983, 48 patients with malignant tumors of the nasal cavity (31), ethmoid sinus (13), or sphenoid sinus (4) were treated with curative intent by radiation therapy. There were 21 squamous cell carcinomas, 14 minor salivary gland tumors (adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma), 3 malignant melanomas, 2 soft tissue sarcomas, and 8 esthesioneuroblastomas. Forty-two patients were treated with irradiation alone and six with planned combined irradiation and surgery. The 10-year actuarial local control rate for Stage I (limited to site of origin; 7 patients) was 100%; for Stage II (extension to adjacent sites, e.g., adjacent sinuses, orbit, pterygomaxillary fossa, nasopharynx; 19 patients) was 53%; and for Stage III (destruction of skull base or pterygoid plates, or intracranial extension; 22 patients) was 30%. Of 24 failures at the primary site, 10 occurred greater than 24 months after completion of irradiation. With the exception of adenoid cystic carcinoma (17% local control at 15 years), the ultimate local control rates for all histologies were in the range of 40% to 60%. Of 7 patients with documented intracranial extension, 3 (43%) remained free from local recurrence 3.5, 4, and 9 years after treatment. The 5-, 10-, 15-, and 20-year uncorrected actuarial survival rates for all 48 patients were 52%, 30%, 22%, and 22%, respectively. Continuous disease-free survival according to stage at 10 years was 86% for Stage I, 42% for Stage II, and 22% for Stage III. The single failure in a patient with Stage I disease was a lymph node metastasis that was successfully managed by radical neck dissection. The orbit was grossly invaded by tumor prior to treatment in 22 patients (46%). Sixteen (33%) of 48 patients developed unilateral blindness secondary to radiation retinopathy or optic neuropathy; in the majority of these patients the complication was anticipated because the ipsilateral eye was irradiated to a high dose. Four patients (8%) unexpectedly developed bilateral blindness 17, 35, 46, and 90 months following treatment owing to optic nerve injury. A discussion of possible means of avoiding this latter, unacceptable complication is included.


Targeting bile acid signaling for the treatment of liver diseases: From bench to bed.
Liver diseases and related complications have become one of the leading causes of morbidity and mortality worldwide, yet effective medicine or approved treatment approach is still limited. Thus, novel therapy is urgently required to prevent or at least slow down the growing burden of liver transplantation or even death caused by malignant liver diseases. As the irreplaceable modulator of hepatic and intestinal signaling cascades, bile acids (BAs) play complex physiological as well as pathological roles in regulating energy and immune homeostasis in various liver diseases, including but not limited to metabolic diseases and cholangiopathies, making them highly attractive therapeutic targets. In the current review, recent progress in the research of enterohepatic circulation of BAs and potential therapeutic targets of BAs signaling, especially the development of currently available treatments, including agonizts of FXR and TGR5, analogs of FGF19, inhibitors of ASBT, and the regulation of gut microbiome through fecal microbiota transplantation were extensively summarized. Their protective effects, molecular mechanisms, and outcomes of clinical trials were highlighted. The structural features of these candidates and perspectives for their future development were further discussed. In conclusion, we believe that pharmacological therapies targeting BAs signaling represent promising and efficient strategies for the treatment of complex and multifactorial liver disorders.


Treatment decision-making, family influences, and cultural influences of Chinese breast cancer survivors: a qualitative study using an expressive writing method.
Among Chinese breast cancer survivors, treatment decision-making is different than that in western countries. Among Chinese women, family often plays an important role during the treatment period, and Chinese-specific cultural factors have negative influences on their psychological conditions. The aim of the present study was to explore the treatment decision making, family influences, and cultural influences of Chinese breast cancer survivors. This study used an expressive writing method to explore the experiences of breast cancer survivors who were diagnosed with stage 0 to III cancer. Participants were instructed to write 30 min per week over a period of 3 weeks. All writings were analyzed using a qualitative method. Three themes were identified: treatment decision making, family influences, and cultural influences. Treatment decision-making included the subthemes of preference for mastectomy, passive involvement, and active involvement. Family influences included the subthemes of financial burden, family expectations, and family support. Cultural influences included the subthemes of fatalism, barriers to expressing emotions, and stigma related to cancer. Information on breast cancer treatment and survivorship should be provided to patients through multiple methods to improve their knowledge of breast cancer. Family support should be maintained to ensure patients' confidence and courage during the treatment period. Necessary and appropriate psychological interventions that consider cultural influences should be administered.


A quantitative analysis of the kinetics of Gal4 activator and effector gene expression in the zebrafish.
Using a temperature-inducible hsp70:Gal4 activator and UAS:myc-notch1a-intra as effector, we determined quantitatively the kinetics of expression of both transgenes and analysed the effects of varying their expressivity on several phenotypic traits in the developing zebrafish. hsp70:Gal4 is transcribed within 15 min after temperature-mediated induction, but Gal4 RNA decays rapidly. The Gal4 protein was found to be quite stable, as functional Gal4, which was detectable 1.5 h after heat shock (HS), persisted for at least 13 h. myc-notch1a-intra RNA is expressed approximately 1.5 h after HS, but unlike the Gal4 RNA, it was found to be very stable; it continues to accumulate during the succeeding 17 h after HS. Fully penetrant phenotypic effects are obtained after a relatively long activator induction with a 30-min HS.


Three cases of methylmercury intoxication which eluded correct diagnosis.
Three casual workers engaged in the production of mercuric acetate were admitted to hospital within 22 calendar days of each other, respectively 30, 48 and 5 days after their last working day. The workers served the same reactor in which elemental mercury was oxidized by peroxide and mercuric acetate was formed by the reaction of mercuric oxide with acetic acid. The diagnosis of mercury vapour intoxication of the first two patients was made 21 and 16 days after their admission when the third patient was admitted and hospitals were informed about their exposure. This diagnosis was made without considering: (a) that the observed signs were characteristic of methylmercury intoxication and are rarely present in mercury vapour intoxication; (b) the degree of deterioration after removal from exposure implicated methylmercury; (c) that blood mercury concentrations extrapolated to the last day at work were in the range, which had been associated with severe intoxication in the Iraq methylmercury epidemic; (d) at the time of the first blood mercury estimations the blood urinary mercury concentration ratios were 11.2, 5.4 and 2.4 while this ratio is below 0.5 in mercury vapour intoxication or in workers exposed to mercury vapour.


De novo Robertsonian D/D type translocations: the Leuven experience.
In this paper we report a de novo 13/14 Robertsonian type translocation with apparent loss of band 14q11 in a mentally retarded, blind 24-year-old male. The findings in 10 other patients with a de novo Robertsonian D/D type translocation diagnosed in this center are reviewed.


Using social media and networking in health care.
Occupational health nurses must understand the benefits, risks, and consequences of participating in social media and networking.


Hyperthermic pelvic perfusion with tumor necrosis factor-α for locally advanced cancers: encouraging results of a phase II study.
To assess the efficacy of isolated pelvic perfusion (IPP) with tumor necrosis factor (TNF)-α and melphalan in patients with locally advanced cancers in the pelvic and groin area requiring mutilating surgery. A total of 27 patients were enrolled (carcinoma, n = 17; sarcoma/melanoma, n = 4; and endocrine tumor, n = 6). They were candidates for exarticulation (n = 3) or exenteration (n = 11) or were judged unresectable (n = 13). In installing IPP, tourniquets were positioned around both thighs, and an inflated pressure suit was placed at a subthoracic position. Tumor necrosis factor-α (300 μg) was injected in the perfusate, followed 5 minutes later by melphalan at 1.5 mg/kg. After 30 minutes, the remaining drugs were washed out. Leakage was assessed with technetium Tc 99m radiolabeled human serum albumin, and a pharmacokinetic study was performed. Efficacy was based on the complete response rate observed on magnetic resonance imaging. Pelvic/systemic ratios of melphalan/TNF/technetium Tc 99m were 14.2/7/3.6. Responses on magnetic resonance imaging were as follows: 30% complete, 30% partial, 19% no change, and 15% progression. Two patients were not evaluable because they did not receive the treatment. Pre-IPP/post-IPP median percentage of necrosis on magnetic resonance imaging was 10%/70%. Median follow-up was 43 months. Median overall survival was 17 months. Twelve-month survival rate, disease-free survival, and local and metastatic recurrence rates were 67%, 30%, 57%, and 26%, respectively. Isolated pelvic perfusion with TNF-α compares favorably with historical data, as it was observed in limb perfusion and could provide a chance to translate its successful combination with chemotherapy into treatment of locally advanced pelvic cancers.


Screening for mutations in the IMPDH1 gene in Japanese patients with autosomal dominant retinitis pigmentosa.
To determine the presence and frequency of mutations in the IMPDH1 gene in Japanese patients with autosomal dominant retinitis pigmentosa (ADRP), and to characterize the clinical characteristics of patients with the Lys238Arg mutation in the IMPDH1 gene. Case reports and results of DNA analysis. All 14 coding exons of the IMPDH1 gene were directly sequenced in 96 unrelated patients with ADRP. The clinical features were determined by visual acuity, slit-lamp biomicroscopy, and kinetic visual field tests. Two novel mutations, a Leu227Pro and Lys238Arg, in the IMPDH1 gene were identified in two unrelated families with ADRP. The clinical features associated with the Lys238Arg mutation were an early-onset and severe retinal degeneration. The most commonly reported Asp226Asn mutation was not found in the Japanese population, instead two novel mutations were found. These findings suggest that mutations of the IMPDH1 gene cause ADRP in the Japanese population.


Opportunities and Considerations in the Application of Artificial Intelligence to Pharmacokinetic Prediction.
The improvement in the ability of the pharmaceutical industry to predict human pharmacokinetic behavior are attributable to major technological shifts from 1990 to the present day. The opportunity for the application of AI/ML based approaches in the pharmaceutical industry is driven by the abundance of data sets that exist within individual pharmaceutical and biotech companies and the availability, within these environments, of abundant computing power. This chapter seeks to describe opportunities for artificial intelligence to contribute to the assessment and evaluation of the dug metabolism and pharmacokinetic (DMPK) properties of novel compounds across the drug discovery and development continuum. Many initiatives are already underway with respect to the application of AI/ML in predicting pharmacokinetic profiles so the question is not whether AI will influence pharmacokinetic prediction but rather how to best utilize and incorporate this and how to evaluate the value added from these applications. Since our understanding of the underlying biology of the in vitro and in vivo systems with respect to ADME, one of the key challenges to AI-based methods will be the ability to adapt to data sets that change in quality over time.


Hybrid cosine and Radon transform-based processing for digital mammogram feature extraction and classification with SVM.
A new methodology to automatically extract features from mammograms and classify them is presented. It relies on a hybrid processing system that sequentially uses the discrete cosine transform (DCT) to obtain the high frequency component of the mammogram and then applies the Radon transform to the obtained DCT image in order to extract its directional features. The features are subsequently fed to a support vector machine for classification. The approach was tested on a database of one hundred images and shows improved classification accuracy in comparison to using the discrete cosine transform or the Radon transform alone, as done in others works.


Homocysteinylation and Sulfhydration in Diseases.
Homocysteine (Hcy) is an important intermediate in methionine metabolism and generation of one-carbon units, and its dysfunction is associated with many pathological states. Although Hcy is a non-protein amino acid, many studies have demonstrated protein-related homocysteine metabolism and possible mechanisms underlying homocysteinylation. Homocysteinylated proteins lose their original biological function and have a negative effect on the various disease phenotypes. Hydrogen sulfide (H2S) has been recognized as an important gaseous signaling molecule with mounting physiological properties. H2S modifies small molecules and proteins via sulfhydration, which is supposed to be essential in the regulation of biological functions and signal transduction in human health and disorders. This review briefly introduces Hcy and H2S, further discusses pathophysiological consequences of homocysteine modification and sulfhydryl modification, and ultimately makes a prediction that H2S might exert a protective effect on the toxicity of homocysteinylation of target protein via sulfhydration. The highlighted information here yields new insights into the role of protein modification by Hcy and H2S in diseases.


Effects of mycotoxins on the immune system - is there a single comprehensive test parameter?
There is no single comprehensive parameter for the identification of immunotoxic effects of mycotoxins, since immunological processes are very complex. Different aspects of the immune response have to be studied to detect the characteristic actions of mycotoxins and to identify the most sensitive immune functions.


Experimental studies of seed predation in old-fields.
In a pair of experiments conducted in old-field habitats in southwestern Michigan (USA), we examined rates of seed loss to post-dispersal predators (ants and rodents). Seeds from 4-6 species of "biennial" plants were tested over a range of seed densities and habitat types. We found that seed removal was significantly higher in vegetated habitats than in areas of disturbed soil (both simulated small-animal diggings and a plowed field). In the undisturbed vegetation, seed losses ranged from 1-20% of seeds removed/day.An exclosure experiment demonstrated that ants and rodents foraged selectively for seeds of the six plant species tested. Rodents (Peromyscus maniculatus) fed preferentially on species producing large seeds (predominantly Tragopogon dubius). Ants (Myrmica lobicornus) foraged on smaller seeds, although their foraging preferences were not based strictly on seed size.Seed density had only a minor effect on predation rate over the range of densities tested. Predators, instead appeared to treat each experimental group of seeds as a single prey patch. Consequently, predation intensity was quite variable over distances of <20 m within a relatively homogeneous section of habitat.These field experiments provide initial estimates of seed losses to post-dispersal predators in old-field habitats. Rates of seed loss were generally less than those reported from desert or semi-arid habitats. However, for some old-field species, seed losses averaged an appreciable 10-20% day. The selective nature of the seed predators, plusthe relative patchiness of predation intensity in space, suggest that postdispersal seed predation can play a role in determining the distribution and/or abundance of old-field herbs.


The perimenopause and sexual functioning.
Sexual functioning is an important component of women's lives. Sexual functioning, however, declines with age, and there is much debate about the contribution of menopause to sexual activity and functioning...The present article covers cross-sectional and longitudinal community-based research on sexual functioning during the perimenopause. .The.article addresses the relative contributions of perimenopause and other.factors (e.g., relationship with partner, previous sexual enjoyment, psychosocial.factors and health) to sexual functioning.


Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients.
Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A4/5 isoenzymes (encoded by CYP3A4 and CYP3A5). Guidelines for adjusting tacrolimus based on CYP3A5 test results are published; however, CYP3A4 variants also contribute to the variability in tacrolimus pharmacokinetics. The effects of composite phenotypes incorporating CYP3A5 and CYP3A4 increased (*1G, *1B) and decreased (*22) function variants have not been evaluated. The objective of this study is to investigate the impact of both increased and decreased function CYP3A variants on weight and dose-adjusted tacrolimus concentration (C0/D). We performed a single-center retrospective cohort study of lung transplant recipients to evaluate the median tacrolimus C0/D by composite CYP3A phenotype groups during the index transplant hospitalization. CYP3A4 and CYP3A5 alleles were used to classify patients into four CYP3A groups from least to most CYP3A activity. Exploratory analyses of ABCB1 and additional candidate genes were also assessed. Of the 92 included individuals, most (58) were CYP3A Group 2. The median tacrolimus C0/D differed significantly between CYP3A groups (P = 0.0001). CYP3A Group 2 median tacrolimus C0/D was 190.5 (interquartile range: 147.6-267.5) (ng/ml)/(mg/kg/d) and significantly higher than Group 4 [107.9 (90.4-116.1), P = 0.0001)]. Group 2 median tacrolimus C0/D did not significantly differ from Group 1 and Group 3 [373.5 (149.2-490.3) and 81.4 (62.6-184.1), respectively]. No significant differences in tacrolimus C0/D were found for the ABCB1 diplotypes. These data indicate that a composite CYP3A phenotype incorporating both increase and decrease variant information from CYP3A4 in addition to CYP3A5 may significantly influence tacrolimus C0/D during the early postoperative period.


Clinical examination for prognostication in comatose cardiac arrest patients.
To build new algorithms for prognostication of comatose cardiac arrest patients using clinical examination, and investigate whether therapeutic hypothermia influences the value of the clinical examination. From 2000 to 2007, 500 consecutive patients in non-traumatic coma were prospectively enrolled, 200 of whom were post-cardiac arrest. Outcome was determined by modified Rankin Scale (mRS) score at 6 months, with mRS≤3 indicating good outcome. The clinical examination was performed on days 0, 1, 3 and 7 post-arrest, and clinical variables analyzed for importance in prognostication of outcome. A classification and regression tree analysis (CART) was used to develop a predictive algorithm. Good outcome was achieved in 9.9% of patients. In CART analysis, motor response was often chosen as a root node, and spontaneous eye movements, pupillary reflexes, eye opening and corneal reflexes were often chosen as splitting nodes. Over 8% of patients with absent or extensor motor response on day 3 achieved a good outcome, as did 2 patients with myoclonic status epilepticus. The odds of achieving a good outcome were lower in patients who suffered asystole (OR 0.187, 95% CI: 0.039-0.875, p=0.033) compared with ventricular fibrillation or non-perfusing ventricular tachycardia, but some still achieved good outcome. The absence of pupillary and corneal reflexes on day 3 remained highly reliable for predicting poor outcome, regardless of therapeutic hypothermia utilization. The clinical examination remains central to prognostication in comatose cardiac arrest patients in the modern area. Future studies should incorporate the clinical examination along with modern technology for accurate prognostication.


Familial unilateral ectopia lentis.
Ectopia lentis is almost always a bilateral condition, although it may be asymmetric in some cases of Marfan syndrome. Unilateral ectopia lentis has been associated with trauma and with intraocular tumors. We report two siblings with isolated unilateral ectopia lentis who had no evidence of underlying abnormality or of trauma.


[Role of vitamin D in allergic diseases: Current research status].
Recent research has focused on the relationship between vitamin D and allergy development. Results show that on the one hand a vitamin D deficiency can be responsible for the emergence of allergies, however, on the other hand a vitamin-D (over-) substitution was also seen in context with an increased allergy development. This article provides an overview on the current state of research and points at the problematic aspects that accompany the assessment of these studies. The paradoxic effect of vitamin D is currently being explained by epigenetic programming in pregnancy, by too low vitamin-D levels or excessive supplementation in newborns. Very recently, a gender-specific impact of vitamin D is also being discussed. For a final assessment of vitamin-D effects on the emergence of allergies, further research is necessary. Due to a high level of heterogeneity among current observational studies regarding central aspects of the discussion, randomised clinical trials are recommended.


Long-term exposure to cadmium and cardiovascular alterations in the rabbit.
Some mechanisms regulating cardiovascular function (CF) were investigated in male rabbits exposed for ten months to 20 micrograms/ml of cadmium (Cd) in drinking water. Cd reduced cardiac inotropism (CI), increased aortic vascular resistance (AVR) and altered cardiovascular reactivity by acting on renin-angiotensin, serotonin, sympathetic and vagal parasympathetic systems. Cd levels were higher in the aorta than in the heart. Renal Cd content was lower than that reported as critical for Cd-exposed workers. Zinc (Zn) was increased only in the kidney and copper (Cu) was unchanged in the organs studied. It was shown that humoral, neurogenic and metabolic mechanisms are involved in the Cd-induced alterations of CF.


An essential ionized acid group in sodium channels.
Several recent experiments demonstrate the presence of an essential negatively charged acid group within sodium channels. Sodium permeability titrates away at low pH as if controlled by an acid with a voltage-dependent apparent pKa in the range between 5 and 6. The alkali ion permeability sequence of the channel is best explained by interactions between the cations and a strong negative charge in the channel. Block of sodium currents by a variety of metal and organic cations again points to a cation-coordinating site in the channel. The "blocking cations" and protons also oppose the bindings of tetrodotoxin and saxitoxin. The negative charge in the channel seems to be essential in selecting appropriate cations and in lowering their activation energy for permeation. The same charge seems to form part of the toxin receptor. At present this charged group is the chemical group known to be associated with sodium channels.--Hille B. An essential ionized acid group in sodium channels.


Nucleoside analogs for management of respiratory virus infections: mechanism of action and clinical efficacy.
The COVID-19 pandemic has accelerated the development of nucleoside analogs to treat respiratory virus infections, with remdesivir being the first compound to receive worldwide authorization and three other nucleoside analogs (i.e. favipiravir, molnupiravir, and bemnifosbuvir) in the pipeline. Here, we summarize the current knowledge concerning their clinical efficacy in suppressing the virus and reducing the need for hospitalization or respiratory support. We also mention trials of favipiravir and lumicitabine, for influenza and respiratory syncytial virus, respectively. Besides, we outline how nucleoside analogs interact with the polymerases of respiratory viruses, to cause lethal virus mutagenesis or disturbance of viral RNA synthesis. In this way, we aim to convey the key findings on this rapidly evolving class of respiratory virus medication.


The expression of MYH9 in osteosarcoma and its effect on the migration and invasion abilities of tumor cell.
To determine the expression of non-muscle myosin heavy chain 9 (MYH9) in osteosarcoma and its effect on the migration and invasion abilities of tumor cell. A total of 65 cases of osteosarcoma and 20 cases with benign osteochondroma who underwent resection operation in the Orthopaedics Department of our hospital from January 1st 2009 to January 1st 2015 were selected. Their mRNA levels of MYH9 were tested by qrt-PCR. Immunohistochemical method was used to examine the expression of MYH9 in osteosarcoma and the correlation between the positive expression of MYH9 and the clinicopathological features of patients was illustrated by statistical analysis. MYH9 was compounded artificially. The expression of MYH9 in SAOS2 osteosarcoma cells was decreased by siRNA. Scratch test was used to determine the change of SAOS2 cell migration ability after MYH9 silence. Transwell assay was employed to detect the change of cell invasion ability after MYH9 silence. The expression levels of mRNA of MYH9 and protein in osteosarcoma tissues were significantly higher than those in benign osteochondroma tissues. The high expression of MYH9 in osteosarcoma tissues was apparently related to the high Enneking classification (III classification) and lung metastasis. SiRNA of MYH9 could evidently decrease the expression level of MYH9 in SAOS2. The down-regulated expression of MYH9 could inhibit the migration and invasion abilities of SAOS2 cells. MYH9 shows a trend of high expression in osteosarcoma tissues, and its high expression is associated with features such as tumor invasion and metastasis. The down-regulated MYH9 can realize an anti-tumor effect by inhibiting the migration and invasion of osteosarcoma cells.


Metagenomics Approaches for Improving Food Safety: A Review.
Advancements in next-generation sequencing technology have dramatically reduced the cost and increased the ease of microbial whole genome sequencing. This approach is revolutionizing the identification and analysis of foodborne microbial pathogens, facilitating expedited detection and mitigation of foodborne outbreaks, improving public health outcomes, and limiting costly recalls. However, next-generation sequencing is still anchored in the traditional laboratory practice of the selection and culture of a single isolate. Metagenomic-based approaches, including metabarcoding and shotgun and long-read metagenomics, are part of the next disruptive revolution in food safety diagnostics and offer the potential to directly identify entire microbial communities in a single food, ingredient, or environmental sample. In this review, metagenomic-based approaches are introduced and placed within the context of conventional detection and diagnostic techniques, and essential considerations for undertaking metagenomic assays and data analysis are described. Recent applications of the use of metagenomics for food safety are discussed alongside current limitations and knowledge gaps and new opportunities arising from the use of this technology.


Identification of bolting-related microRNAs and their targets reveals complex miRNA-mediated flowering-time regulatory networks in radish (Raphanus sativus L.).
MicroRNAs (miRNAs) play vital regulatory roles in plant growth and development. The phase transition from vegetative growth to flowering is crucial in the life cycle of plants. To date, miRNA-mediated flowering regulatory networks remain largely unexplored in radish. In this study, two small RNA libraries from radish leaves at vegetative and reproductive stages were constructed and sequenced by Solexa sequencing. A total of 94 known miRNAs representing 21 conserved and 13 non-conserved miRNA families, and 44 potential novel miRNAs, were identified from the two libraries. In addition, 42 known and 17 novel miRNAs were significantly differentially expressed and identified as bolting-related miRNAs. RT-qPCR analysis revealed that some miRNAs exhibited tissue- or developmental stage-specific expression patterns. Moreover, 154 target transcripts were identified for 50 bolting-related miRNAs, which were predominately involved in plant development, signal transduction and transcriptional regulation. Based on the characterization of bolting-related miRNAs and their target genes, a putative schematic model of miRNA-mediated bolting and flowering regulatory network was proposed. These results could provide insights into bolting and flowering regulatory networks in radish, and facilitate dissecting the molecular mechanisms underlying bolting and flowering time regulation in vegetable crops.


Anticonvulsive properties of F1933 (dulozafone) on kindled seizures in the rat.
The anticonvulsive properties of a new compound: F1933 (Dulozafone) were investigated in the amygdala kindling model and compared with those of diazepam. Both drugs protected fully kindled rats against generalized seizures but failed to suppress partial ictal events (amygdala afterdischarges and limbic seizures). The anticonvulsive action of F1933, administered at the ED100, was nearly reversed by the specific antagonist of benzodiazepines receptors; R015-1788 (Flumazenil), suggesting that the effect of F1933 is mediated by this receptor. These results also emphasize the usefulness of kindling to test antiepileptic drugs and to confirm their supposed profile of action.


Dansylated thyrotropin as a probe of hormone-receptor interactions.
A strongly fluorescent 5-dimethylamino-1-naphthalene sulfonate (dansyl) derivative of bovine thyrotropin has been prepared. The dye-conjugated hormone is bioactive and shares, essentially unchanged, the membrane binding and adenylate cyclase stimulatory activities of the native hormone. Binding of 125I-labeled dansyl-thyrotropin to thyroid plasma membranes is sensitive to inhibition by gangliosides and, as is the case for the binding of 125I-thyrotropin, galactosyl-N-acetylgalactosaminyl[N-acetylneuraminyl-N-acetylneuraminyl]-galactosylglucosylceramide (GDIb) is the most potent binding inhibitor. Gangliosides interact with dansyl-thyrotropin, causing a large increase of the quantum yield and a 5- to 10-nm blue shift of the emission maximum of the hormone-bound naphthalene chromophore; gangliosides cause no change in the fluorescent properties of the free dye. The fluorescence enhancement caused by gangliosides can be specifically reversed by unlabeled thyrotropin. The effect of gangliosides on dansyl-thyrotropin fluorescence is strongly salt-dependent; salts cannot, however, reverse the formation of the dansyl-thyrotropin.ganglioside complex once it has formed. The salt data suggest that the association of the ganglioside with dansyl-thyrotropin is dominated by electrostatic interactions, but that salt-independent, short range interactions, most likely hydrophobic, dominate the dissociation of the dansyl-thyrotropin-ganglioside adduct. Sucrose gradient centrifugation, ultracentrifugation, and fluorescence polarization data indicate that the gangliosides are micellar in nature under the conditions of these experiments. Acid titration of dansyl-thyrotropin causes a marked quenching of dansyl fluorescence which in part reflects dissociation of the hormone into its constituent alpha and beta subunits. In the presence of GDIb, but not N-acetylneuraminylgalactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide (GDIa), pH-dependent quenching and subunit dissociation are essentially eliminated. Circular dichroism results and fluorescence polarization studies support the interpretation that the ganglioside interaction causes a conformational change in the thyrotropin molecule. The acid titration data together with differences in the ability of gangliosides to influence the tyrosine fluorescence of the thyrotropin molecule indicate that different gangliosides induce different conformational perturbations in the thyrotropin molecule.


Use of 131I-19-cholesterol in functional dynamic studies of the adrenals in vivo. II. Clinical application.
Functional dynamic studies of the adrenal in vivo employing 131I-19-cholesterol were carried out as a further screening test, according to the method previously described (Pavonia and Magrini, 1977), on seven patients in whom hyperadrenocorticism was suspected on the basis of clinical symptoms. The data obtained in basal conditions, under ACTH stimulation, and under dexamethasone suppression, compared with each other and supported by the results of conventional examinations, demonstrate that the quantitative information provided by this radioisotope test is correlated with the functional state of each adrenal, thus confirming the potential value of the method for diagnostic purposes. The functional dynamic test proposed does not require a higher dose of tracer than morphologic studies and the radiation risk (approximately 2.5 rad to the ovaries or gonads) seems acceptable in adult subjects.


Development of a sulfidogenic bioreactor system for removal of co-existent selenium, iron and nitrate from drinking water sources.
The present study showed for the first time that selenium, iron, and nitrate could be simultaneously removed in a sulfidogenic bioreactor to meet drinking water standards. A bioreactor inoculated with mixed bacterial consortium was operated for around 330 days in anoxic environment at 30 °C under varying combination of influent selenate (200-1000 μg/L as selenium), and iron (3-10 mg/L) in presence of 50 mg/L of nitrate. Required amount of acetic acid (as carbon source) and sulfate were supplied and the reactor was operated at different empty bed contact time (EBCT) of 45-120 min. Along with complete removal of nitrate, the reactor removed both selenium and iron to meet the drinking water standards. Field emission transmission electron microscopy (FETEM) and X-ray diffraction (XRD) analyses confirmed the formation of selenium sulfide (SeS), achavalite (FeSe) and pyrite (FeS2), which were the possible removal mechanisms of selenium and iron. Thus, this study exhibited that selenium, iron, and nitrate can be simultaneously removed to meet the drinking water standards in a sulfidogenic bioreactor.


Landholding, wealth and risk of blinding malnutrition in rural Bangladeshi households.
The 1982-1983 Bangladesh nutritional blindness study visited 11,618 rural households and examined 18,660 preschool-age children in an effort to determine the prevalence and determinants of eye lesions and loss of sight due to vitamin A deficiency (xerophthalmia). Risk of xerophthalmia was significantly higher for children from households without any of the indicators of relative wealth used. Almost 80% of blind children from landless households, and even a very small garden reduced considerably the chances of a household having a xerophthalmic child. Poorer households with access to less than 0.3 acres land or no garden or without a tin roof, wristwatch, radio or cycle were at least twice as likely as their more fortunate neighbours to have a young child with any type of xerophthalmia. Taking account of such socio-environmental risk factor weightings would direct the scarce resources of intervention programmes to households and children who most need them.


Evaluation of preoperative administration of the cyclooxygenase-2 inhibitor rofecoxib for the treatment of postoperative pain after lumbar disc surgery.
A combination of analgesics with different mechanisms of action may improve postoperative pain control and reduce the incidence of side effects. This study was designed to assess the efficacy of preoperative administration of rofecoxib (Vioxx; Merck & Co., Inc., Somerset, NJ) in reducing pain and opioid requirements after single-level lumbar microdiscectomy. A randomized, double-blind, placebo-controlled clinical trial was performed on 61 consenting patients who were considered American Society of Anesthesiologists Class I or II and who were scheduled for elective single-level lumbar microdiscectomy. Patients received either two doses of rofecoxib 50 mg or a placebo preoperatively. The outcome measures included morphine use in the postanesthesia care unit (PACU), discharge times, and side effect profile. Data were analyzed by use of independent sample t tests for continuous variables or chi(2) tests for categorical variables. A P value of <0.05 was considered significant. The two groups were comparable with respect to patient characteristics, intraoperative opioid and hypnotic consumption, and duration of surgery. Patients in the rofecoxib group required significantly less morphine postoperatively. Significantly more patients in the placebo group reported pain scores greater than 7 at admission to the PACU. Time to first request for analgesia was shorter in the placebo group, but the difference did not reach statistical significance. There were no significant differences between groups in the incidence of nausea, time to discharge from the PACU, or hospital stay. Preoperative rofecoxib is effective in reducing postoperative narcotic consumption in patients undergoing lumbar laminectomy. The use of rofecoxib does not shorten PACU length of stay or hospital discharge time. These outcome measures depend on multiple administrative factors.


Oncopeptide MBOP Encoded by LINC01234 Promotes Colorectal Cancer through MAPK Signaling Pathway.
Colorectal cancer (CRC) ranks third in incidence rate and second in mortality rate of malignancy worldwide, and the diagnosis and therapeutics of it remain to be further studied. With the emergence of noncoding RNAs (ncRNAs) and potential peptides derived from ncRNAs across various biological processes, we here aimed to identify a ncRNA-derived peptide possible for revealing the oncogenesis of CRC. Through combined predictive analysis of the coding potential of a batch of long noncoding RNAs (lncRNAs), the existence of an 85 amino-acid-peptide, named MEK1-binding oncopeptide (MBOP) and encoded from LINC01234 was confirmed. Mass spectrometry and Western blot assays indicated the overexpression of MBOP in CRC tissues and cell lines compared to adjacent noncancerous tissues and the normal colonic epithelial cell line. In vivo and in vitro migration and proliferation assays defined MBOP as an oncogenic peptide. Immunoprecipitation trials showed that MEK1 was the key interacting protein of MBOP, and MBOP promoted the MEK1/pERK/MMP2/MMP9 axis in CRC. Two E3-ligase enzymes MAEA and RMND5A mediated the ubiquitin-protease-system-related degradation of MBOP. This study indicates that MBOP might be a candidate prognostic indicator and a potential target for clinical therapy of CRC.


A novel small-molecule inhibitor of the human papillomavirus E6-p53 interaction that reactivates p53 function and blocks cancer cells growth.
Despite prophylactic vaccination campaigns, human papillomavirus (HPV)-induced cancers still represent a major medical issue for global population, thus specific anti-HPV drugs are needed. Since the ability of HPV E6 oncoprotein to promote p53 degradation is linked to tumor progression, E6 has been proposed as an ideal target for cancer treatment. Using the crystal structure of the E6/E6AP/p53 complex, we performed an in silico screening of small-molecule libraries against a highly conserved alpha-helix in the N-terminal domain of E6 involved in the E6-p53 interaction. We discovered a compound able to inhibit the E6-mediated degradation of p53 through disruption of E6-p53 binding both in vitro and in cells. This compound could restore p53 intracellular levels and transcriptional activity, reduce the viability and proliferation of HPV-positive cancer cells, and block 3D cervospheres formation. Mechanistic studies revealed that the compound anti-tumor activity mainly relies on induction of cell cycle arrest and senescence. Our data demonstrate that the disruption of the direct E6-p53 interaction can be obtained with a small-molecule compound leading to specific antitumoral activity in HPV-positive cancer cells and thus represents a new approach for anti-HPV drug development.


Functional expression and extension of staphylococcal staphyloxanthin biosynthetic pathway in Escherichia coli.
The biosynthetic pathway for staphyloxanthin, a C(30) carotenoid biosynthesized by Staphylococcus aureus, has previously been proposed to consist of five enzymes (CrtO, CrtP, CrtQ, CrtM, and CrtN). Here, we report a missing sixth enzyme, 4,4'-diaponeurosporen-aldehyde dehydrogenase (AldH), in the staphyloxanthin biosynthetic pathway and describe the functional expression of the complete staphyloxanthin biosynthetic pathway in Escherichia coli. When we expressed the five known pathway enzymes through artificial synthetic operons and the wild-type operon (crtOPQMN) in E. coli, carotenoid aldehyde intermediates such as 4,4'-diaponeurosporen-4-al accumulated without being converted into staphyloxanthin or other intermediates. We identified an aldH gene located 670 kilobase pairs from the known staphyloxanthin gene cluster in the S. aureus genome and an aldH gene in the non-staphyloxanthin-producing Staphylococcus carnosus genome. These two putative enzymes catalyzed the missing oxidation reaction to convert 4,4'-diaponeurosporen-4-al into 4,4'-diaponeurosporenoic acid in E. coli. Deletion of the aldH gene in S. aureus abolished staphyloxanthin biosynthesis and caused accumulation of 4,4'-diaponeurosporen-4-al, confirming the role of AldH in staphyloxanthin biosynthesis. When the complete staphyloxanthin biosynthetic pathway was expressed using an artificial synthetic operon in E. coli, staphyloxanthin-like compounds, which contained altered fatty acid acyl chains, and novel carotenoid compounds were produced, indicating functional expression and coordination of the six staphyloxanthin pathway enzymes.


Pathogenesis and therapeutic targets in spinal muscular atrophy (SMA).
Autosomal-recessive spinal muscular atrophy (SMA) is characterized by the loss of specific motor neurons of the spinal cord and skeletal muscle atrophy. SMA is caused by mutations or deletions of the survival motor neuron 1 (SMN1) gene, and disease severity correlates with the expression levels of the nearly identical copy gene, SMN2. Both genes ubiquitously express SMN protein, but SMN2 generates only low levels of protein that do not fully compensate for the loss-of-function of SMN1. SMN protein forms a multiprotein complex essential for the cellular assembly of ribonucleoprotein particles involved in diverse aspects of RNA metabolism. Other studies using animal models revealed a spatio-temporal requirement of SMN that is high during the development of the neuromuscular system and later, in the general maintenance of cellular and tissues homeostasis. These observations define a period for maximum therapeutic efficiency of SMN restoration, and suggest that cells outside the central nervous system may also participate in the pathogenesis of SMA. Finally, recent innovative therapies have been shown to mitigate SMN deficiency and have been approved to treat SMA patients. We briefly review major findings from the past twenty-five years of SMA research. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.


Toll-like receptor-6 (TLR6) deficient mice are protected from myocardial fibrosis induced by high fructose feeding through anti-oxidant and inflammatory signaling pathway.
Diabetic cardiomyopathy is an essential complication of diabetes and characterized by persistent diastolic dysfunction, leading to myocardial fibrosis. Oxidative stress and inflammation lead to cell damage and are implicated in many disease states. In our study, we evaluated the effects of toll-like receptor 6 (TLR6) in cardiac remodeling. We established a mouse model of myocardial fibrosis with diabetes using 30% fructose. In comparison to HF-feeding control mice, TLR6 deficient mice developed less myocardial fibrosis with lower myocardial injury marker enzymes and AngII and aldosterone (ALD). In addition, Collagen type I/III, alpha smooth muscle-actin (α-SMA) and FSP-1, as typical markers of myocardial fibrosis formation, were found to be reduced due to TLR6 knockout in HF-induced mice. HF-feeding mice developed myocardial fibrosis with lower SOD activity, high level of MDA, O2(-) and H2O2 and increased serum pro-inflammatory cytokines, whereas TLR6 deficient mice after HF-administration were protected from myocardial fibrosis progression significantly. HF-feeding mice also displayed lower Nrf2 and higher XO levels, which was not observed in TLR6 deficient mice after HF-feeding. Furthermore, NF-κB pathway was inactivated for TLR6 knockout compared with HF-feeding mice. In vitro, fructose directly up-regulated α-SMA, TGF-β1, Collagen type I/III and FSP-1 via ROS production and NF-κB phosphorylation as well as pro-inflammatory cytokines releasing, which were inhibited for TLR6 deficiency. Taken together, TLR6 contributed to myocardial fibrosis progression, at least partly, through oxidative stress and inflammatory response, providing a potential therapeutic strategy for myocardial fibrosis treatment.


[Importance of magnetic resonance imaging/ultrasound-guided fusion biopsy for the detection and monitoring of prostate cancer].
The use of multiparametric magnetic resonance imaging (mpMRI) is becoming increasingly more important for the primary diagnostics of prostate cancer (PCa) and for monitoring under active surveillance. Current studies confirmed that the use of mpMRI can increase the detection of clinically significant PCa and reduce the detection rate of insignificant PCa as well as the rate of unnecessary biopsies. The information from mpMRI can be cognitively used for in-bore biopsy and using fusion biopsy systems. There are no clear recommendations on the access approach for fusion biopsy (e. g. transrectal or perineal), whereby higher rates of rectal bleeding and infections have been described for transrectal access compared to perineal access. The increasing rate of antibiotic resistance as well as restricted indications for the use of quinolones are a major challenge for transrectal biopsy.


Diversity in the flavonoid composition of Stellera chamaejasme in the Hengduan Mountains.
The presence of diversity in the Stellera chamaejasme population was found via their chemical composition. The eight collected samples were grouped into two chemotypes on the basis of the amount of neochamaejasmin B and chamaejasmine. Diversity was also found in the amount of afzelechin. The stereochemistry of neochamaejasmin B was confirmed by NOE experiment.


Modified S/MAR episomal vectors for stably expressing fluorescent protein-tagged transgenes with small cell-to-cell fluctuations.
We modified and tested scaffold/matrix attachment region (S/MAR) episomal vectors. The new vectors would be useful in obtaining cells stably expressing fluorescent protein-tagged transgenes with small, mostly within 10-fold cell-to-cell fluctuations. In the vectors, the same transcript directs episomal replication and expression of transgene/antibiotic marker, and only antibiotic selection without any other extra steps was sufficient to obtain desired stable cells, including those expressing two different proteins simultaneously. Furthermore, the two test cases (expression of human growth hormone in AtT20 and four protein kinase C isoforms in HEK293) would prove to be useful in visualizing and analyzing regulatory processes involving these proteins.


Impairment of fetal endothelium-dependent relaxation in a rat model of preeclampsia by chronic nitric oxide synthase inhibition.
We studied fetal endothelial function in a model of preeclampsia induced by Nomega-nitro-l-arginine methylester (L-NAME) administration in pregnant rats. Aortic segments from term fetuses and 2-day-old Wistar rats treated with L-NAME (0.5 mg/mL in drinking water) (fetuses from hypertensive rats, FH, and newborns from hypertensive rats, NH) and from untreated rats (fetuses from normotensive rats, FN, and newborns from normotensive rats, NN) were obtained. Endothelium-dependent and -independent relaxations were determined by the response to 1 microM acetylcholine (ACh) and 1 microM sodium nitroprusside (SNP), respectively, after precontraction with 3 microM prostaglandin F2alpha. The role of nitric oxide in ACh relaxation was assessed by incubation with 0.1 mM N(G)-monomethyl-l-arginine (L-NMMA) or 0.1 mM l-arginine (l-Arg). Precontraction with 50 mM potassium chloride assessed the role of hyperpolarizing mechanisms. In FH, ACh-induced relaxation was reduced (FH 34.2 +/- 4%, FN 45.8 +/- 2%, P < .05), whereas that of SNP was enhanced (FH 68.4 +/- 5%, FN 50.4 +/- 4%, P < .05). l-Arg did not reverse the impairment of ACh relaxation. L-NMMA reduced ACh relaxation in FN but increased it in FH; this increase was abolished by potassium chloride precontraction and by 1 microM capsaicine, a calcitonin-gene related peptide inhibitor. The hyperpolarizing component of ACh relaxation was reduced in FH as compared with FN. By contrast, ACh relaxation was greater in NH than in NN, with the relative participation of nitric oxide and hyperpolarizing-related components being similar in both groups. Fetal ACh relaxation was impaired in this preeclampsia-like model. This impairment is probably not exclusively an effect of L-NAME but could reflect endothelial dysfunction that disappears after birth.


Gel double immunodiffusion studies with sex human rhinoviruses.
Rabbits were immunized on six occasions during a seven month period with fluorocarbon and sucrose denstiy gradient purified preparations of human rhinovirus types 1A,2,3,4,9, OR 14. Sera collected 1 week after the final immunization formed 1 or 2 preciptin lines when reacted by immunodiffusion against fluorocarbon purified preparations of each homologous immunizing virus. Heterologous preciptin cross reactions were detected between: RV1A antigen and rabbit sera to RV2, RV9 and RV14; RV2 antigen and sera to RV1A; RV14 antigen and sera to RV3. The heterologous "group" or C-antigenic nature of the cross reactions was suggested by the merging of heterologous preciptin lines formed against rabbit sera with "group" antibody preciptin lines formed against human sera and by the location of heterologous reaction close to the antigen well. In addition, the presence of C-antigenic particles in the fluorocarbon treated RV2 preparation was suggested by the demonstration that a subpopulation of viral particles migrated to a pH of 4.4 by isoelectric focusing.


C-Reactive Protein and Skin Temperature of the lower limbs of Brazilian elite soccer players like load markers following three consecutive games.
The aim of the study was to compare the levels and relative responses of C-Reactive Protein (CRP) and Skin Temperature (Tsk) of the lower limbs (LLs) of elite soccer players following three consecutive games with short intervals (< 4 days). Eleven male professional athletes (age, 29.26 ± 4.52 years) from an Brazil elite team were evaluated, with measurements obtained before (Baseline), and at Post-Games times (24, 48 and 72h). CRP and Tsk levels at 24 h and 48 h Post-Games times were higher than Baseline levels (CRP, p < 0.001, d > 0.9; Tsk, p < 0.04, d > 0.58), additionally, the levels of these variables (CRP vs. Tsk) showed positive correlations (p < 0.05, rs = 0.60-0.88). The relative responses these variables were evaluated (Δ%CRP; Δ%Tsk). The 48h responses of Game 3 are respectively higher than 48 h responses of games 1 and 2, in Δ%CRP (p < 0.03; G3 vs. G1, r = 0.66; G3 vs. G2, r = 0.88) and in Δ%Tsk (p < 0.003; G3 vs. G1, r = 0.88; G3 vs. G2, r = 0.88). The 48 h Post-Game time seems to represent valuable contributions to understanding the development regarding the magnitude and duration of inflammatory processes associated with recovery. Additionally, the positive correlations that were verified allow an increase in the robustness of the analysis of the load of consecutive games through CRP and Tsk of the LLs. Then, these results indicate a physiological stress and a probable cumulative effect of the game loads due to short intervals (< 4 days), which is reinforced by the verified outcome of the Total Distance covered (G3 < G2, p = 0.003; r = 0.88). These findings can contribute to better load control and greater robustness of injury prevention programs.


Latissimus Dorsi and DIEP Flaps for Pharyngeal Reconstruction: A Novel Indication.
Complex pharyngeal defects after tumor resection remain a challenging dilemma for reconstructive plastic surgeons. They often benefit from pedicled or free flaps reconstruction to maintain continuity of the aerodigestive tract and protect the great vessels. While pedicle pectoralis major myocutaneous flaps or supraclavicular flaps have been described, microvascular free flaps have largely replaced the use of pedicle flaps. We describe our experience with subtotal and total pharyngeal reconstruction utilizing tubed DIEP (n = 2) and latissimus dorsi free flaps (n = 2). All four patients were smokers and received prior radiation. All patients were able to resume a regular diet and did not suffer any recipient or donor site complications. There were no fistula or total flap losses. In our experience, DIEP and latissimus dorsi free flaps can serve as a valid alternative to radial forearm, jejunal and anterolateral thigh flaps for pharyngeal reconstruction.


Fmoc solid-phase synthesis of peptide thioesters by masking as trithioortho esters.
[reaction: see text] Total chemical synthesis of proteins by chemoselective ligation relies on C-terminal peptide thioesters as building blocks. Their preparation by standard Fmoc solid-phase peptide synthesis is made difficult by the lability of thioesters to aminolysis by the secondary amines used for removal of the Fmoc group. Here we present a novel backbone amide linker (BAL) strategy for their synthesis in which the thioester functionality is masked as a trithioortho ester throughout the synthesis.


The cDNA encoding canine dihydrolipoamide dehydrogenase contains multiple termination signals.
A 2288-bp cDNA sequence encoding dihydrolipoamide dehydrogenase (DLDH; dihydrolipoamide: NAD+ oxido-reductase; EC 18.104.22.168) was obtained by isolating a 1762-bp cDNA clone from a canine skeletal muscle library in the vector, lambda UNIZAP, combined with PCR amplification of the 5' end of the mRNA. The DLDH cDNA sequence contains a 49-bp G+C-rich 5'-untranslated region (UTR), followed by 1527 bp of coding region, and 695 bp of 3'-UTR preceding a 17-bp poly(A) tail. The single open reading frame encodes a precursor DLDH of 509 amino acids (aa) that begins with a 35-aa leader sequence. The 3'-UTR includes six possible polyadenylation signals (three AATAAA, one TATAAA and two AATGAA) and one potential stem-loop region extending from bp 1969-1991. Alignment studies of the canine and human DLDH demonstrate homology within the coding region of 98% at the aa level and 94% at the nt level. Northern blot analysis using the cDNA clone as probe showed wide tissue distribution of the mRNA, with differences in the level of expression among tissues and possible utilization of different polyadenylation sites.


Experimental and theoretical study of lanthanide complexes based on linear and macrocyclic polyaminopolycarboxylic acids containing pyrazolylethyl arms.
We report the synthesis of two novel Gd(III)-complexes derived from linear and macrocyclic polyaminopolycarboxylic acids 1 and 2, which contain a 3,5- dimethylpyrazolyl-ethyl arm, and a study of their relaxivity properties. The relationships between the experimental and theoretical results have provided interesting information about the kinetic and thermodynamic stability of these complexes.


Creation of a safety culture: reducing workplace injuries in a rural hospital setting.
A newly organized employee safety program, with an 11-step design, has been introduced at Valley General Hospital in Monroe, Washington, with the intention of changing the "culture of safety." A 1-year report of the results indicates that the overall incidence of injury claims, lost-time injuries, and needlestick injuries were reduced after the program was implemented and timely reporting of claims within 24 hours was increased. The hypothesis, that by creating more visibility for the employee safety program a decrease in injury rates would occur, was confirmed.


Oncologic outcomes of immediate breast reconstruction in young women with breast cancer receiving neoadjuvant chemotherapy.
Oncologic safety of postmastectomy breast reconstruction in young women with breast cancer is not well-defined, especially in the setting of neoadjuvant chemotherapy (NACT). We retrospectively compared the oncologic outcomes following nipple-sparing (NSM)/skin-sparing mastectomy (SSM) with immediate breast reconstruction (IBR) and conventional mastectomy (CM) alone in young breast cancer patients after NACT. A total of 1266 women with primary breast cancer who underwent NACT followed by total mastectomy with or without IBR were reviewed. Of these, only young patients (age ≤ 40 years at diagnosis) were included in the outcome analysis (n = 375). After propensity score-matching by clinical T and N stage, molecular subtype, response to NACT, and adjuvant radiotherapy status, 228 patients were 1:1 matched, comprising balanced IBR group (with NSM/SSM) and CM-alone group. The 5-year locoregional recurrence-free, disease-free, distant metastasis (DM)-free, and breast cancer-specific survival (BCSS) rates for the entire cohort of young patients were 83.4%, 65.3%, 71.7%, and 85.4%, respectively. Locoregional recurrence rates between the matched groups were similar (14% vs. 15.8%; p = 0.710); however, IBR group had significantly lower DM rate (27.2% vs. 40.4%; p = 0.036) and breast cancer mortality (14.9% vs. 27.2%; p = 0.023) than CM-alone group. IBR group showed significantly improved 5-year DM-free survival (74.1% vs. 62.6%; p = 0.043) and BCSS (89.1% vs. 77.6%; p = 0.048) rates than CM-alone group. Our results indicated that IBR with NSM/SSM does not negatively affect long-term oncologic outcomes compared to CM alone in young women with breast cancer receiving NACT.


Presence of the HLADR13 allele among Mexican Mestizos suggests a protective factor against relapsing-remitting multiple sclerosis (RRMS).
Multiple sclerosis (MS) is a chronic demyelinating disease that affects the central nervous system. Researchers have looked for an association between relapsing-remitting MS (RRMS) and human leukocyte antigen (HLA) as risk or protective factor associated to ethnicity, which may add a partial explanation to disease heterogeneity and geographical variations. We described the frequency of the HLA-DR alleles in Mexican Mestizo (RRMS) patients. We included 143 RRMS patients and 377 healthy controls, both Mexican Mestizos. Previous signing informed consent, we record demographic and clinical characteristics of the participants. Genetic profile was made, and HLA frequencies in both groups were compared. RRMS patients were 39.8% male and 60.2% female, mean age was 35 years. While, controls were 48%male and 52% women, mean age was 38 years. The most frequent allele found in subjects with RRMS was DR 15 (p=0.006, OR=2.2, 95% CI: 1.3-3.6). DR 13 allele was more frequent among healthy subjects than RRMS patients (p=0.050) with a protective OR 2.6, (95% CI: 1.3-5.2, p=0.050). In our study we found HLA DR 13 was more frequent in healthy controls than in RRMS patients, suggesting a protective factor among Mexican Mestizo population.


Characterizing cannabis use in a sample of adults with multiple sclerosis and chronic pain: An observational study.
Although cannabis has become an increasingly common method for pain management among people with multiple sclerosis (PwMS), there is a dearth of knowledge regarding the types of cannabis products used as well as the characteristics of cannabis users. The current study aimed to (1) describe the prevalence of cannabis use and the routes of administration of cannabis products in adults with an existing chronic pain condition and MS, (2) to examine differences in demographic and disease-related variables between cannabis users and non-users, and (3) to examine differences between cannabis users and non-users in pain-related variables, including pain intensity, pain interference, neuropathic pain, pain medication use, and pain-related coping. Secondary analysis of baseline data from participants with multiple sclerosis (MS) and chronic pain (N = 242) enrolled in an RCT comparing mindfulness-based cognitive therapy (MBCT), cognitive-behavioral therapy (CBT), and usual care for chronic pain. Statistical methods included t-tests, Mann-Whitney tests, chi-square tests, and Fisher's exact tests to assess for differences in demographic, disease-related, and pain-related variables between cannabis users and non-users. Of the 242 participants included in the sample, 65 (27%) reported the use of cannabis for pain management. The most common route of administration was oil/tincture (reported by 42% of cannabis users), followed by vaped (22%) and edible (17%) products. Cannabis users were slightly younger than non-users (Medage 51.0 vs 55.0, p = .019) and reported higher median pain intensity scores (6.0 vs 5.0, p = .022), higher median pain interference scores (5.9 vs 5.4, p = .027), and higher median levels of neuropathic pain (20.0 vs 16.0, p = .001). The current study identified factors that may intersect with cannabis use for pain management and adds to our current knowledge of the types of cannabis products used by PwMS. Future research should continue to investigate trends in cannabis use for pain management, especially as the legality and availability of products continue to shift. Additionally, longitudinal studies are needed to examine the effects of cannabis use on pain-related outcomes over time.


What predicts unremitting suicidal ideation? A prospective examination of the role of subjective age in suicidal ideation among ex-prisoners of war.
Research has demonstrated that traumatic experiences have significant links to suicidal ideation (SI), particularly among older adults. The present study examined SI among older adults with a history of war trauma and the role of perceptions relating to one's age (subjective age) in predicting SI. Drawing from a larger longitudinal study, we analyzed data based on interviews with 125 ex-prisoners of war (ex-POWS) from Israel's 1973 Yom Kippur War and a control group of 101 veterans from the same war who did not fall captive (mean age at most recent measurement was 65.05, SDage = 5.29). Participants were interviewed in 2008 (T1) and again in 2015 (T2). Findings revealed significantly higher levels of SI among ex-POWs than evident among controls and significantly higher levels of SI and subjective age among ex-POWs with PTSD. Furthermore, a sequential mediation analysis indicated that among ex-POWs, the path from T1 PTSD symptoms to subsequent SI was mediated by subjective age at T1, and subjective age at T2, after controlling for age, self-rated health, and SI at T1. A subset of ex-POWs are exposed to continuous suicidal risk throughout their later life, more than 40 years after the war. Furthermore, an older subjective age mediated these associations, independent of the levels of T1 SI, actual age, and self-rated health. These findings suggest debilitating long-term effects of trauma for SI in later life and their connections to advanced psychological aging. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Electrical impedance and erythrocyte sedimentation rate (ESR) of blood.
The electrical impedance of blood is primarily determined by plasma resistance Rp, cell interior resistance Ri, and cell membrane capacitance Cm. These impedance parameters were measured for 62 samples with various erythrocyte sedimentation rates (ESR = 1-150 mm/h). A formula for estimating ESR by Rp and Cm was obtained by linear regression as: In (ESR) = 10.16-0.016 x f0, (r = 0.974, P < 0.001), where f0 = 10(9)/(2 pi.Rp100.Cm100) defined as the effective characteristic frequency in kHz, Rp100 = Rp/h in omega cm, Cm100 = Cm/h in pF/cm, h is the haematocrit in decimal. The 95% confidence intervals for the coefficients in the above equation were 9.73 to 10.59 and -0.017 to -0.015. The origin of the association was found reasonable since factors increasing the ESR, i.e., the concentration of some plasma proteins and the size of the blood cells, also elevate the capacitance. The results imply that the impedance measurement might be an alternative method for fast determination of the ESR.


RNA-Guided CRISPR-Cas9 System-Mediated Engineering of Acute Myeloid Leukemia Mutations.
Current acute myeloid leukemia (AML) disease models face severe limitations because most of them induce un-physiological gene expressions that do not represent conditions in AML patients and/or depend on external promoters for regulation of gene expression/repression. Furthermore, many AML models are based on reciprocal chromosomal translocations that only reflect the minority of AML patients, whereas more than 50% of patients have a normal karyotype. The majority of AML, however, is driven by somatic mutations. Thus, identification as well as a detailed molecular and functional characterization of the role of these driver mutations via improved AML models is required for better approaches toward novel targeted therapies. Using the IDH2 R140Q mutation as a model, we present a new effective methodology here using the RNA-guided clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to reproduce or remove AML-associated mutations in or from human leukemic cells, respectively, via introduction of a DNA template at the endogenous gene locus via homologous recombination. Our technology represents a precise way for AML modeling to gain insights into AML development and progression and provides a basis for future therapeutic approaches.


Benefits of Cardiac Rehabilitation in Coronary Artery Disease: DOES WEIGHT MATTER?
To evaluate the response of patients with obesity to a cardiac rehabilitation program (CRP), compared with patients without obesity. We performed a retrospective analysis of 731 patients who completed phase II of a CRP after an acute coronary syndrome. The response to the CRP was assessed using the relative changes in exercise capacity (EC), resting heart rate (HR), and chronotropic index (CI). Only 23% of patients had obesity. Patients with obesity showed lower EC and CI at baseline and at the end of phase II of the CRP. Despite that, we reported a higher relative improvement for EC in patients with obesity (median [interquartile range], 23.9% [5.2, 40.8] vs 17.6% [8.1, 35.9], P = .043) and similar improvements in CI (10.9% [-1.4 to 34.2] vs 7.1% [-7.1 to 28.2], P = .100), compared with patients without obesity. There were no significant changes in resting HR. Regardless of their lower exercise performance at baseline, patients with obesity had a remarkably positive response to the CRP compared with patients without obesity.


Ester-free thiol-ene dental restoratives--Part B: Composite development.
To assess the performance of thiol-ene dental composites based on selected ester-free thiol-ene formulations. Further, to point out the benefits/drawback of having a hydrolytically stable thiol-ene matrix within a glass filled composite. Composite samples containing 50-65wt% of functionalized glass microparticles were prepared and photopolymerized in the presence of a suitable visible light photoinitiator. Shrinkage stress measurements were conducted as a function of the irradiation time. Degrees of conversion were measured by FT-IR analysis by comparing the double bond signals before and after photopolymerization. Mechanical tests were carried out on specimens after curing as well as after extended aging in water. Dynamic mechanical analysis was employed to track the changes in storage modulus near body temperature. The properties of the thiol-ene composites were compared with those of the BisGMA/TEGDMA control. Depending on the resin type, similar or higher conversions were achieved in thiol-ene composites when compared to the dimethacrylate controls. At comparable conversions, lower shrinkage stress values were achieved. Although exhibiting lower initial elastic moduli, the thiol-ene composites' flexural strengths were found to be comparable with the controls. Contrary to the control, the mechanical properties of the ester-free thiol-ene composites were shown to be unaffected by extensive aging in water and at least equaled that of the control after aging in water for just five weeks. Employing non-degradable step-growth networks as organic matrices in dental composites will provide structurally uniform, tough materials with extended service time.


Potential of CRISPR/Cas system as emerging tools in the detection of viral hepatitis infection.
Viral hepatitis, the most common cause of inflammatory liver disease, affects hundreds of millions of people worldwide. It is most commonly associated with one of the five nominal hepatitis viruses (hepatitis A-E viruses). HBV and HCV can cause acute infections and lifelong, persistent chronic infections, while HAV and HEV cause self-limiting acute infections. HAV and HEV are predominantly transmitted through the fecal-oral route, while diseases transmitted by the other forms are blood-borne diseases. Despite the success in the treatment of viral hepatitis and the development of HAV and HBV vaccines, there is still no accurate diagnosis at the genetic level for these diseases. Timely diagnosis of viral hepatitis is a prerequisite for efficient therapeutic intervention. Due to the specificity and sensitivity of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated sequences (Cas) technology, it has the potential to meet critical needs in the field of diagnosis of viral diseases and can be used in versatile point-of-care (POC) diagnostic applications to detect viruses with both DNA and RNA genomes. In this review, we discuss recent advances in CRISPR-Cas diagnostics tools and assess their potential and prospects in rapid and effective strategies for the diagnosis and control of viral hepatitis infection.


Changes in tropospheric composition and air quality.
Reductions in stratospheric ozone (O3) cause increased penetration of ultraviolet-B (UV-B) radiation to the troposphere, and therefore increases in the chemical activity in the lower atmosphere (the troposphere). Tropospheric ozone levels are sensitive to local concentrations of nitrogen oxides (NOx) and hydrocarbons. Model studies suggest that additional UV-B radiation reduces tropospheric ozone in clean environments (low NOx), and increases tropospheric ozone in polluted areas (high NOx). Assuming other factors remain constant, additional UV-B will increase the rate at which primary pollutants are removed from the troposphere. Increased UV-B is expected to increase the concentration of hydroxyl radicals (OH) and result in faster removal of pollutants such as carbon monoxide (CO), methane (CH4), non-methane hydrocarbons (NMHCs), sulfur and nitrogen oxides, hydrochlorofluorocarbons (HCFCs), and hydrofluorocarbons (HFCs). Concentrations of peroxy radicals (both inorganic and organic) are expected to increase, leading to higher atmospheric levels of hydrogen peroxide (H2O2) and organic peroxides. The effects of UV-B increases on tropospheric O3, OH, methane, CO, and possibly other tropospheric constituents, while not negligible, will be difficult to detect because the concentrations of these species are also influenced by many other variable factors (e.g., emissions). Trifluoroacetic acid (TFA, CF3COOH) is produced in the atmosphere by the degradation of HCFC-123 (CF3CHCl2), HCFC-124 (CF3CHFCl), and HFC-134a (CF3CH2F), which are used as substitutes for ozone-depleting substances. The atmospheric oxidation mechanisms of these replacement compounds are well established. Reported measurements of TFA in rain, rivers, lakes, and oceans show it to be a ubiquitous component of the hydrosphere, present at levels much higher than can be explained by reported sources. The levels of TFA produced by the atmospheric degradation of HFCs and HCFCs emitted up to the year 2020 are estimated to be orders of magnitude below those of concern, and to make only a minor contribution to the current environmental burden of TFA. No significant effects on humans or the environment have been identified from TFA produced by atmospheric degradation of HCFCs and HFCs. Numerous standard short-term studies have shown that TFA has, at most, moderate toxicity.


Beta-D-glucopyranosyl caldarchaetidylglycerol is the main lipid of the acidophilic, mesophilic, ferrous iron-oxidising archaeon Ferroplasma acidiphilum.
Chloroform-methanol-extractable lipids account for about 5% by weight of dry cells of the acidophilic, autotrophic, mesophilic, ferrous compound-oxidising, cell wall-less archaeon Ferroplasma acidiphilum strain Y(T), about 90% of these being contributed by phospholipids and glycophospholipids. The most abundant constituent (about 55% of total lipids) was purified by DEAE cellulose and silica gel column chromatography. By means of matrix-assisted laser desorption ionisation mass spectrometry, infrared spectroscopy, (1)H-nuclear magnetic resonance spectroscopy, and chemical degradation experiments it was established to be beta-D-glucopyranosyl caldarchaetidylglycerol, the isopranyl chains of which have a cyclopentane ring each.


Unveiling the hypoxia-induced mitophagy process through two-channel real-time imaging of NTR and viscosity under the same excitation.
Mitophagy is an essential physiological process that eliminates damaged mitochondria via lysosomes. It is reported that hypoxia, inflammatory stimuli or other stress conditions could lead to mitochondrial damage and mitochondrial dysfunction, which induces the process of mitophagy. Herein, we report a novel fluorescent probe PC-NTR for imaging hypoxia-induced mitophagy by monitoring the change of nitroreductase and viscosity simultaneously. To our delight, PC-NTR could respond simultaneously to nitroreductase and viscosity at different fluorescence channels with no mutual interference under the same excitation wavelength. The fluorescence emission around 535 nm was enhanced dramatically after addition of nitroreductase while the fluorescence emission around 635 nm heightened as the viscosity increased. The probe would be able to selectively targeting of mitochondria in cells because of the positively charged pyridine salt structure of PC-NTR. The probe was successfully applied to assess the different levels of hypoxia and real-time imaging of mitochondrial autophagy in live cells. More importantly, using dual channel imaging, PC-NTR could be used to distinguish cancer cells from normal cells and was successfully applied to imaging experiments in HeLa-derived tumor-bearing nude mice. Therefore, PC-NTR would be an important molecular tool for hypoxia imaging and detecting solid tumors in vivo.


Vedolizumab use after failure of TNF-α antagonists in children and adolescents with inflammatory bowel disease.
Vedolizumab is safe and effective in adult patients with Crohn's disease (CD) and ulcerative colitis (UC); however, data in children with inflammatory bowel disease (IBD) are scarce. Therefore, we evaluated vedolizumab use in a cohort of Austrian paediatric patients with IBD. Twelve patients (7 female; 7 CD; 5 UC), aged 8-17 years (median, 15 years), with severe IBD who received vedolizumab after tumour necrosis factor α antagonist treatment were retrospectively analysed. Clinical activity scores, relevant laboratory parameters, and auxological measures were obtained at infusion visits. In the CD group, 1/7 patient discontinued therapy due to a severe systemic allergic reaction; 1/7 and 2/7 patients achieved complete and partial response, respectively, at week 14; and 3/7 patients discontinued therapy due to a primary non-response or loss of response. In the UC group, complete clinical remission was achieved at weeks 2, 6, and 14 in 2/5, 1/5 and 1/5 patients respectively; partial response was observed in one patient at week 2. CD activity scores did not significantly change from baseline to week 38 (median 47.5 vs. 40 points, p = 1,0), while median UC activity scores changed from 70 to 5 points (p < 0,001). Substantial weight gain and increased albumin and haemoglobin levels were observed in both groups. These results demonstrate that vedolizumab can be an effective treatment for individual paediatric patients with IBD who are unresponsive, intolerant, or experience a loss of efficacy in other therapies. However, vedolizumab appears to be more effective in paediatric UC than in paediatric CD.


Therapeutic targeting of interleukin-6 trans-signaling does not affect the outcome of experimental tuberculosis.
Treatment of autoreactive inflammatory diseases such as rheumatoid arthritis with anti-inflammatory drugs is associated with an increased rate of reactivation tuberculosis (TB). Interleukin-6 (IL-6) plays a pivotal role in inflammation and protection against various infectious diseases. IL-6 signals by two mechanisms via the ubiquitous transmembrane protein gp130: 'classic' signaling using the membrane-bound IL-6 receptor (IL-6R), which is expressed mainly on hepatocytes and some leukocytes, and trans-signaling using soluble IL-6R (sIL-6R). Trans-signaling by the IL-6/sIL-6R complex is selectively inhibited by natural soluble gp130 (sgp130) and by sgp130 designer proteins. As specific blockade of IL-6 trans-signaling represents a promising approach for the therapy of inflammatory diseases, we evaluated the potential risk of interfering with this alternative pathway and analyzed the outcome of experimental TB after treatment with an IgG1-Fc fusion protein of soluble gp130 (sgp130Fc) and in sgp130Fc-overexpressing transgenic (sgp130Fc(tg)) mice. In contrast to treatment with anti-tumor necrosis factor (TNF) antibodies, administration of sgp130Fc did not interfere with protective immune responses after infection with Mycobacterium tuberculosis (Mtb). Moreover, Mtb-infected sgp130Fc(tg) mice were capable of controlling mycobacterial growth. Our finding that IL-6 trans-signaling plays no role for protective immune responses against Mtb supports the superior safety of therapeutic targeting of IL-6 trans-signaling compared to anti-TNF treatment.


In vivo urothelial surface histology by microscopic chromocystoscopy.
Microscopic chromocystoscopy is a new in vivo procedure that we have developed to aid in the detection and treatment of bladder tumors. Intravesical ionic dye chromocystoscopy was introduced by our group to permit cystoscopic viewing with ordinary light of selectively stained malignant urothelial surfaces by the cationic dye, methylene blue. With the recent availability of the Hamou hysteroscope, a microscopic endoscope, we have combined intravesical ionic dye chromocystoscopy with microscopic cystoscopy to give in vivo urothelial surface histology, with resolution of cytological detail. We herein describe our new method and preliminary results with this procedure, which we have designated in vivo urothelial surface histology by microscopic chromocystoscopy.


The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein.
α-Synuclein (α-Syn) can form different fibril strains with distinct polymorphs and neuropathologies, which is associated with the clinicopathological variability in synucleinopathies. How different α-syn fibril strains are produced and selected under disease conditions remains poorly understood. In this study, we show that the hereditary mutation G51D induces α-syn to form a distinct fibril strain in vitro. The cryogenic electron microscopy (cryo-EM) structure of the G51D fibril strain was determined at 2.96 Å resolution. The G51D fibril displays a relatively small and extended serpentine fold distinct from other α-syn fibril structures. Moreover, we show by cryo-EM that wild-type (WT) α-syn can assembly into the G51D fibril strain via cross-seeding with G51D fibrils. Our study reveals a distinct structure of G51D fibril strain triggered by G51D mutation but feasibly adopted by both WT and G51D α-syn, which suggests the cross-seeding and strain selection of WT and mutant α-syn in familial Parkinson's disease (fPD).


LINC01608 activated by YY1 facilitate hepatocellular carcinoma progression by modulating the EGFR/ERK axis.
Long non-coding RNAs (LncRNAs) have been demonstrated to associate with a variety of cancers. However, the mechanisms of LncRNAs in hepatocellular carcinoma (HCC) progression are still not fully clarified. LINC01608 expression level in HCC and adjacent normal tissues was detected by real-time-quantitively PCR (RT-qPCR) in clinical samples and in situ hybridization (ISH) in tissue microarray. Several functional assays were performed to determine the biological effects of LINC01608 in HCC cells in vitro, while subcutaneous xenograft models and lung metastasis models in nude mice and immunohistochemistry (IHC) results showed the role of LINC01608 in HCC progression in vivo. The combination of LINC01608 with miR-875-5p and target genes was elucidated by dual-luciferase report assays, RNA immunoprecipitation (RIP) assays and fluorescence in situ hybridization (FISH) assays. Finally, bioinformatics analysis and chromatin immunoprecipitation (CHIP) were performed to investigate the mechanism of Yin Yang-1 (YY1) regulating LINC01608 transcription. LINC01608 was overexpressed in HCC tissues, and high LINC01608 expression predicted poor overall survival (OS) and disease-free survival (DFS) in HCC patients. LINC01608 could promote HCC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Furthermore, we demonstrated that LINC01608 could sponge to miR-875-5p and activate the EGFR/ERK pathway. Moreover, we identified transcriptional factor YY1 could bind to the promoter of LINC01608 and induce its transcription. LINC01608 could serve as a promising prognostic biomarker of HCC. YY1-activated LINC01608 could promote HCC progression by associating with miR-875-5p to induce the EGFR/ERK signalling pathway. This discovery might provide therapeutic strategies for HCC.


The NOXA-MCL1-BIM axis defines lifespan on extended mitotic arrest.
Cell death on extended mitotic arrest is considered arguably most critical for the efficacy of microtubule-targeting agents (MTAs) in anticancer therapy. While the molecular machinery controlling mitotic arrest on MTA treatment, the spindle assembly checkpoint (SAC), appears well defined, the molecular components executing cell death, as well as factors connecting both networks remain poorly understood. Here we conduct a mini screen exploring systematically the contribution of individual BCL2 family proteins at single cell resolution to death on extended mitotic arrest, and demonstrate that the mitotic phosphorylation of BCL2 and BCLX represent a priming event for apoptosis that is ultimately triggered by NOXA-dependent MCL1 degradation, enabling BIM-dependent cell death. Our findings provide a comprehensive model for the initiation of apoptosis in cells stalled in mitosis and provide a molecular basis for the increased efficacy of combinatorial treatment of cancer cells using MTAs and BH3 mimetics.


Glucose and unstructured physical activity coupling during sleep and wake in young adults with type 1 diabetes.
Glucose variations have a bidirectional relationship with the sleep/wake and circadian systems in type 1 diabetes (T1D); however, the mechanisms remain unclear. The aim of this study was to describe the coupling between glucose and unstructured physical activity over 168 h in young adults with T1D. We hypothesized that there would be differences in sleep and wake characteristics and circadian variations. Glucose was measured with a continuous glucose monitoring device every 5 min and activity with a non-dominant wrist-worn actigraph in 30-s epochs over 6-14 days. There was substantial glucose and unstructured physical activity coupling during sleep and wake, along with circadian variation based on the wavelet coherence analysis. The extent to which glucose fluctuations result in disrupted sleep over longer than one week should be examined considering the harmful effects on achieving glycemic targets. Further studies are needed to delineate the respective roles of glucose production and utilization and the potential for improved meal and insulin timing to optimize glucose and sleep in this population reliant on exogenous insulin.


A Dynamic Quantitative Systems Pharmacology Model of Inflammatory Bowel Disease: Part 2 - Application to Current Therapies in Crohn's Disease.
Inflammatory bowel disease (IBD) is a heterogeneic disease with a variety of treatments targeting different mechanisms. A multistate, mechanistic, mathematical model of IBD was developed in part 1 of this two-part article series. In this paper, application of the model to predict response of key clinical biomarkers following different treatment options for Crohn's disease was explored. Five therapies, representing four different mechanisms of action, were simulated in the model and longitudinal profiles of key clinical markers, C-reactive protein and fecal calprotectin were compared with clinical observations. Model simulations provided an accurate match with both central tendency and variability observed in biomarker profiles. We also applied the model to predict biomarker and clinical response in an experimental, combination therapy of existing therapeutic options and provide possible mechanistic basis for the increased response. Overall, we present a validated, modular, mechanistic model construct, which can be applied to explore key biomarkers and clinical outcomes in IBD.


Safety, feasibility, and quality of thulium laser en-bloc resection for treatment of non-muscle invasive bladder cancer.
Trans-Urethral Resection of Bladder Tumors (TURBT) is a critical step in diagnosis, staging and treatment of bladder tumors. Conventional TURBT (cTURBT) involves the electro-resection of the tumor into small fragments. This technique leads to concerns about the completeness of resection, under-staging, bleeding, cancer cell implantation, and most importantly, risk of tumour recurrence. To circumvent this, laser en-bloc resection of bladder tumors has been introduced. Assessment of the safety, feasibility, and quality of Thulium Laser En-bloc Resection of Tumors (TmL-ERBT) for treatment of Non-Muscle Invasive Bladder Cancer (NMIBC) in various urinary bladder walls as a primary endpoint. The secondary endpoints were to investigate the feasibility of thulium laser use in the re-staging cystoscopy and to evaluate the learning curve of TmL-ERBT. This is a prospective observational study including all newly diagnosed patients, above 18 years old, with a urinary bladder mass ≤ 4 cm in maximal dimension (measured via bladder ultrasound or CT or MRI). All patients underwent TmL-ERBT under regional anaesthesia in a lithotomy position. All intraoperative complications such as obturator nerve reflex, bladder perforation, and significant bleeding were recorded. Postoperative variables such as the mean catheterization time, bladder irrigation fluid volume and duration, and the mean of hospital stay as well as the postoperative complications were recorded. All patients were risk stratified and managed according to EUA guidelines then followed by a surveillance regimen per 3 months for 6 months. The study included 23 patients with a mean age of 53 ± 15.8 years. While 15 patients (65%) had a single tumor, the rest had multiple tumors, ranging from 2 to 3 in number with a total of 36 lesions. No cases required conversion to cTURBT and none of them experienced obturator nerve reflex or bladder perforation. Only one patient (4.3%) had an attack of clot urine retention. The mean hospitalization time was 31.2 ± 14.4 h and the mean catheterization time was 20.4 ± 13.3 h. The Detrusor muscle was present in 20 patients (87%) and the remaining 3 patients required a re-staging cystoscopy which was performed efficiently using thulium laser. None of the treated patients developed tumour recurrence during the follow-up period. In analysis, the duration of complete resection of 2-4 cm tumours was 23-27 min after the 7th case with a resection rate of 0.12-0.15 cm/min. TmL-ERBT is safe and feasible for complete resection of NMIBC with a short learning curve and adequate cancer control.


Hepatotoxicity of piperonyl butoxide in male F344 rats.
Male F344 rats were given 0, 0.6, 1.2 or 2.4% of piperonyl butoxide in the diet. At 1, 2, 4 or 12 weeks after the beginning of the experiment, liver and kidney weight and serum clinical parameters were determined and livers and kidneys were examined with light microscopy. From 1 or 2-12 weeks, distinct increase of liver weight, changes in serum clinical parameters for liver damage, oval cell proliferation, bile duct hyperplasia, single cell necrosis, enlarged and vacuolated hepatocytes, enlarged nuclei and anisonucleosis were seen in treated rats. From 4-12 weeks, cell infiltration, focal necrosis, multinucleated hepatocytes and prominent nucleoli of hepatocytes were seen in treated rats. At 12 weeks microgranulomas were seen in treated rats. Especially in rats of the 2.4% group at 12 weeks, severe enlargement of hepatocytes, severe enlargement of nuclei and multinucleated hepatocyte were seen, suggesting preneoplastic alteration. Relative kidney weights and serum urea nitrogen levels were increased in treated rats from 1 or 2-12 weeks and at 12 weeks, atrophy of proximal tubules, dilation of tubules, cell infiltration, fibrosis and accumulation of yellow-brown pigment in the proximal tubular cells were seen.


Impaired airway epithelial cell wound-healing capacity is associated with airway remodelling following RSV infection in severe preschool wheeze.
Respiratory syncytial virus (RSV) causes exacerbations of asthma and preschool wheeze (PSW). However, the anti-viral and repair responses of the bronchial epithelium in children with severe therapy-resistant asthma (STRA) and PSW are poorly understood. Children with STRA (age 12 [6-16] years), PSW (age 2 [1-5] years) and non-asthmatic controls (age 7 [2-14] years) underwent bronchoscopy with endobronchial brushings and biopsies. Anti-viral, wound injury responses were quantified in biopsies and primary bronchial epithelial cells (PBECs) in response to RSV, poly(I:C), house dust mite (HDM) or IL-33 using RT-qPCR, Luminex and live cell imaging. Collagen deposition and tissue expression of epithelial growth factor receptor (EGFR), IL-33 and receptor ST2 were investigated in bronchial biopsies. PBECs from STRA and PSW had increased TLR3 gene expression and increased secretion of anti-viral and pro-inflammatory cytokines (IFN-γ, IL-6 and IL-13) in response to RSV compared to controls. Exposure of PBECs to concomitant TLR3 agonist poly(I:C) and HDM resulted in a significant reduction in epithelial cell proliferation in PSW compared to controls. Wound-healing was also impaired in PSW compared to controls at baseline and following IL-33 stimulation. In addition, tissue EGFR expression was significantly reduced in PSW and correlated with collagen deposition in endobronchial biopsies. Despite increased anti-viral responses, preschool children with severe wheeze had impaired airway epithelial proliferative responses following damage. This might be connected to the low expression of EGFR in PSW which may affect epithelial function and contribute to asthma pathogenesis.


Using The Cancer Genome Atlas data to refine the 8th edition of the American Joint Committee on Cancer staging for papillary thyroid carcinoma.
The 8th edition of the American Joint Committee on Cancer (AJCC) staging led to a significant downstaging of well differentiated thyroid cancer patients. However, some patients who had been downstaged still experienced death. By using data from the thyroid cancer dataset of The Cancer Genome Atlas (TCGA), we aimed to find molecular features that could improve survival prediction. TCGA data were downloaded from cBioPortal. Restaging of cases was performed according to the pathological reports. Out of 496 cases, 204 (41.1%) were downstaged, and the proportion of deaths increased in stages III and IV. TERT promoter mutations were no longer enriched in stage IV only, but significantly redistributed also in stages II and III. TERT mutation was the only alteration predictive of poor survival; however, in this series it was not independent from the AJCC staging. Five proteins (4E-BP1_pT70, Chk1_pS345, Snail, STAT5 alpha and PAI-1) were significantly associated with survival, and their use as a panel refined the risk stratification independently from the AJCC staging, with a hazard ratio for a positive result of 21.2 (95%CI 3.7-122.2, P = 0.0006). In the TCGA series, the proportion of deaths is in line with the expected survival of the latest AJCC staging, with a neat separation of risk among stages. Nevertheless, the use of protein expression can be useful in refining the stratification. Finally, after the restaging, a considerable number of tumors with TERT mutations will be allocated in lower stages; hence, dedicated studies should define the prognostic usefulness of these mutations in low-stage diseases.


Radiation-induced cavernous malformation after stereotactic radiosurgery for cavernous sinus meningioma: a case report.
Radiation-induced cavernous malformation (RICM) is a rare sequela of stereotactic radiosurgery (SRS) treatment of intracranial tumors. To date, no study reported on RICM after SRS for meningiomas originating from the skull base. The relationship between locus of initial meningioma and RICM has not been studied. A 57-year-old woman presented with persistent headaches and blepharoptosis at initial episode. MRI disclosed a right parasellar lesion, diagnosed as a cavernous sinus meningioma (CSM). After receiving a single-fractionated SRS, headache relieved, but blepharoptosis did not significantly improve. Three years and three months later, she returned with headaches and dizziness. MRI showed an enlarged CSM. Moreover, a new mass-like lesion, suspected hemangioma, appeared in the nearby right temporal lobe. After surgical removal of the new lesion and the CSM, the patient's neurological symptoms significantly improved. Pathology confirmed CSM and temporal RICM. We report the first rare case of RICM occurring after SRS for CSM. The RICM may be in the same region as the initial tumor. Surgical intervention was preferred for symptomatic RICM and initial meningioma. We recommend long-term regular followup MRIs for patients with meningioma after SRS treatment.