Exploring the Utility of Compound-Specific Isotope Analysis for Assessing Ferrous Iron-Mediated Reduction of RDX in the Subsurface.
Subsurface contamination with the explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) at ordnance production and testing sites is a problem because of the persistence, mobility, and toxicity of RDX and the formation of toxic products under anoxic conditions. While the utility of compound-specific isotope analysis for inferring natural attenuation pathways from stable isotope ratios has been demonstrated, the stable isotope fractionation for RDX reduction by iron-bearing minerals remains unknown. Here, we evaluated N and C isotope fractionation of RDX during reduction by Fe(II) associated with Fe minerals and natural sediments and applied N isotope ratios to the assessment of mineral-catalyzed RDX reduction in a contaminant plume and in sediment columns treated by in situ chemical reduction. Laboratory studies revealed that RDX was reduced to nitroso compounds without denitration and the concomitant ring cleavage. Fe(II)/iron oxide mineral-catalyzed reactions exhibited N isotope enrichment factors, εN, between -6.3±0.3‰ and -8.2±0.2‰, corresponding to an apparent 15N kinetic isotope effect of 1.04-1.05. The observed variations of the δ15N of ∼15‰ in RDX from groundwater samples suggested an extent of reductive transformation of 85% at an ammunition plant. Conversely, we observed masking of N isotope fractionation after RDX reduction in laboratory flow-through systems, which was presumably due to limited accessibility to reactive Fe(II).


Anesthetic management of a patient with multiple sclerosis undergoing cesarean section with low dose epidural bupivacaine.
A 32-year-old Indian female 38 weeks pregnant, with a history of multiple sclerosis since 2008 was admitted in obstetric ward for safe confinement. She had a history of diminution of vision in both eyes and limb weakness, relapsing - remitting type with movement-induced muscle spasms, in all the four limbs. Her symptoms were usually diplopia, difficulty in vision and ataxic gait. Sh was then treated with methylprednisolone. She was on oral dimethyl fumarate trial, which was stopped at the beginning of pregnancy. Presently, she was completely asymptomatic. Epidural anesthesia with an indwelling catheter was administered with 15 ml of 0.25% bupivacaine in 5 ml increments. A total of 3 mg of epidural morphine was given for post-operative analgesia. The surgery evolved without any intercurrences and patient was discharged from the hospital 72 h after surgery without worsening of her symptoms. We report a safe anesthetic management of a patient with MS undergoing cesarean section with low dose epidural bupivacaine with the addition of morphine for post-operative analgesia.


Prototype-based Domain Description for one-class classification.
This work introduces the Prototype-based Domain Description rule (PDD) one-class classifier. PDD is a nearest neighbor-based classifier since it accepts objects on the basis of their nearest neighbor distances in a reference set of objects, also called prototypes. For a suitable choice of the prototype set, the PDD classifier is equivalent to another nearest neighbor-based one-class classifier, namely, the NNDD classifier. Moreover, it generalizes statistical tests for outlier detection. The concept of a PDD consistent subset is introduced, which exploits only a selected subset of the training set. It is shown that computing a minimum size PDD consistent subset is, in general, not approximable within any constant factor. A logarithmic approximation factor algorithm, called the CPDD algorithm, for computing a minimum size PDD consistent subset is then introduced. In order to efficiently manage very large data sets, a variant of the basic rule, called Fast CPDD, is also presented. Experimental results show that the CPDD rule sensibly improves over the CNNDD classifier, namely the condensed variant of NNDD, in terms of size of the subset while guaranteeing a comparable classification quality, that it is competitive over other one-class classification methods and is suitable to classify large data sets.


Cytochrome oxidase assembly in yeast requires the product of COX11, a homolog of the P. denitrificans protein encoded by ORF3.
The synthesis of cytochrome oxidase in Saccharomyces cerevisiae was recently shown to require a protein encoded by the nuclear gene COX10. This protein was found to be homologous to the putative protein product of the open reading frame ORF1 reported in one of the cytochrome oxidase operons of Paracoccus denitrificans. In the present study we demonstrate the existence in yeast of a second nuclear gene, COX11, whose encoded protein is homologous to another open reading frame (ORF3) present in the same operon of P. denitrificans. Mutations in COX11 elicit a deficiency in cytochrome oxidase. In this and in other respects cox11 and cox10 mutants have very similar phenotypes. An antibody has been obtained against the yeast COX11 protein. The antibody recognizes a 28 kd protein in yeast mitochondria, consistent with the size of the protein predicted from the sequence of COX11. The COX11 protein is tightly associated with the mitochondrial membrane but is not a component of purified cytochrome oxidase. An analysis of cytochrome oxidase subunits in wild type and in a cox11 mutant suggests that the COX11 protein is not required either for synthesis or transport of the subunit polypeptides into mitochondria. It seems more probable that COX11 protein exerts its effect at some terminal stage of enzyme synthesis, perhaps in directing assembly of the subunits.


IMRT boost dose planning on dominant intraprostatic lesions: gold marker-based three-dimensional fusion of CT with dynamic contrast-enhanced and 1H-spectroscopic MRI.
To demonstrate the theoretical feasibility of integrating two functional prostate magnetic resonance imaging (MRI) techniques (dynamic contrast-enhanced MRI [DCE-MRI] and 1H-spectroscopic MRI [MRSI]) into inverse treatment planning for definition and potential irradiation of a dominant intraprostatic lesion (DIL) as a biologic target volume for high-dose intraprostatic boosting with intensity-modulated radiotherapy (IMRT). In 5 patients, four gold markers were implanted. An endorectal balloon was inserted for both CT and MRI. A DIL volume was defined by DCE-MRI and MRSI using different prostate cancer-specific physiologic (DCE-MRI) and metabolic (MRSI) parameters. CT-MRI registration was performed automatically by matching three-dimensional gold marker surface models with the iterative closest point method. DIL-IMRT plans, consisting of whole prostate irradiation to 70 Gy and a DIL boost to 90 Gy, and standard IMRT plans, in which the whole prostate was irradiated to 78 Gy were generated. The tumor control probability and rectal wall normal tissue complication probability were calculated and compared between the two IMRT approaches. Combined DCE-MRI and MRSI yielded a clearly defined single DIL volume (range, 1.1-6.5 cm3) in all patients. In this small, selected patient population, no differences in tumor control probability were found. A decrease in the rectal wall normal tissue complication probability was observed in favor of the DIL-IMRT plan versus the plan with IMRT to 78 Gy. Combined DCE-MRI and MRSI functional image-guided high-dose intraprostatic DIL-IMRT planned as a boost to 90 Gy is theoretically feasible. The preliminary results have indicated that DIL-IMRT may improve the therapeutic ratio by decreasing the normal tissue complication probability with an unchanged tumor control probability. A larger patient population, with more variations in the number, size, and localization of the DIL, and a feasible mechanism for treatment implementation has to be studied to extend these preliminary tumor control and toxicity estimates.


[Localization of beta-glucuronidase in the kidney of the white rat after administration of the antidiuretic hormone].
Distribution of beta-glucuronidase, one of three enzymes of hyaluronate hydrolases (HH) that hydrolyze extracellular glycosamine glycans (GAG), has been studied in the intact white rat kidney and under effect of antidiuretic hormone (ADH). Renal beta-glucuronidase is revealed as discrete granules in cytoplasm of epithelial cells, in the cortex and medulla and in the interstitial cells of the papilla. ADH increase for a short time in blood results in decreasing amount of granules in cytoplasm of epithelial cells of the collecting tubules, and a prolonged increase is accompanied with practically a complete disappearance of granules both in cytoplasm of epitheliocytes of the collecting tubules and in spindle-like interstitial cells. This effect is considered as a result of the enzyme discharge under ADH effect from the cells into the interstitial space--the place of the extracellular GAG position, HH action substrate. The possibility of the enzyme presence in the renal cells in the form of two fractions is discussed.


Biocide Resistance and Transmission of Clostridium difficile Spores Spiked onto Clinical Surfaces from an American Health Care Facility.
Clostridium difficile is the primary cause of antibiotic-associated diarrhea globally. In unfavorable environments, the organism produces highly resistant spores which can survive microbicidal insult. Our previous research determined the ability of C. difficile spores to adhere to clinical surfaces, finding that spores had markedly different hydrophobic properties and adherence abilities. Investigation into the effect of the microbicide sodium dichloroisocyanurate on C. difficile spore transmission revealed that sublethal concentrations increased spore adherence without reducing viability. The present study examined the ability of spores to transmit across clinical surfaces and their response to an in-use disinfection concentration of 1,000 ppm of chlorine-releasing agent sodium dichloroisocyanurate. In an effort to understand if these surfaces contribute to nosocomial spore transmission, surgical isolation gowns, hospital-grade stainless steel, and floor vinyl were spiked with 1 × 106 spores/ml of two types of C. difficile spore preparations: crude spores and purified spores. The hydrophobicity of each spore type versus clinical surface was examined via plate transfer assay and scanning electron microscopy. The experiment was repeated, and spiked clinical surfaces were exposed to 1,000 ppm sodium dichloroisocyanurate at the recommended 10-min contact time. Results revealed that the hydrophobicity and structure of clinical surfaces can influence spore transmission and that outer spore surface structures may play a part in spore adhesion. Spores remained viable on clinical surfaces after microbicide exposure at the recommended disinfection concentration, demonstrating ineffectual sporicidal action. This study showed that C. difficile spores can transmit and survive between various clinical surfaces despite appropriate use of microbicides.IMPORTANCEClostridium difficile is a health care-acquired organism and the causative agent of antibiotic-associated diarrhea. Its spores are implicated in fecal to oral transmission from contaminated surfaces in the health care environment due to their adherent nature. Contaminated surfaces are cleaned using high-strength chemicals to remove and kill the spores; however, despite appropriate infection control measures, there is still high incidence of C. difficile infection in patients in the United States. Our research examined the effect of a high-strength biocide on spores of C. difficile which had been spiked onto a range of clinically relevant surfaces, including isolation gowns, stainless steel, and floor vinyl. This study found that C. difficile spores were able to survive exposure to appropriate concentrations of biocide, highlighting the need to examine the effectiveness of infection control measures to prevent spore transmission and to consider the prevalence of biocide resistance when decontaminating health care surfaces.


Thrombocytopenia in malaria with immunoglobulin (IgM) changes.
Of 33 cases of naturally occurring human malaria 32 were found to have significant thrombocytopenia. Only one patient showed signs of bleeding. The lowest platelet levels were found between the day of diagnosis and the fourth day of treatment. Thereafter they returned to normal values. No other factors could be found to correlate with the presence or depth of thrombocytopenia, and no evidence of intravascular coagulation was found in any case. A rise in the immunoglobulin IgM was found in all 13 cases in which it was estimated. Since thrombocytopenia can occur independently of intravascular coagulation the latter should be diagnosed and heparin given only after clotting factors have been shown to be depleted.


Public health policies as guides for local public policies: the experience of Sobral-Ceará, Brazil.
The accelerated urbanisation process that Brazil has gone through in the last 50 years has given rise to daunting challenges for public managers, especially in terms of local public policy management for the building of "healthy cities". In Sobral, a municipality of 173,000 inhabitants in Ceará in the North-eastern region of Brazil, a number of municipal policies were initiated beginning in 1997, many in partnership with the federal and state governments. They were inspired by the vision of a healthy and equitable city and were marked by strategic planning and the implementation of intersectoral projects. This article lays out some of the actions and their results, including an increase in the public supply of drinking water from 65% to 97% of households; an increase in sewage networks from 7% to 65%; an increase in public refuse collection from 42% to 90%; the expansion of green areas; the construction of nine kilometres of bicycle paths; the universalisation of integral health care through the Family Health Strategy through a network with specialised out-patient and hospital services; and a 148% increase in the number of children enrolled in primary school. These initiatives also resulted in the improvement of quality of life indicators, including a reduction in infant mortality from 61.4 to 19.0 per thousand live births, a drop in the mortality rate from traffic accidents from 33.40 per 100,000 inhabitants in 2001 to 15.25 in 2003; and a jump in literacy rates among children in the first cycle of primary school from 40 to 90.7%. In the present article, the authors describe some of the successful strategies and projects initiated between 1997 and 2003, and discuss how this experience could be reproduced in other communities across Brazil and around the world.


Molecular determinants of human T-lymphotropic virus type 1 transmission and spread.
Human T-lymphotrophic virus type-1 (HTLV-1) infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma (ATL), or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as, p30, p12, p13 and the antisense encoded HBZ. While progress has been made in the understanding of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1.


[Clinical value of morphologic and functional parameters of blood mononuclear leukocytes in patients with rheumatoid arthritis].
The immunologic study of 412 patient with rheumatoid arthritis (RA) and 52 person of control group has been carried out. The correlation was established between activity of RA and increase in morphologic and functional activity of CD4+-, CD8+- and CD19+-lymphocytes, enhancement of proliferate response and ability to Fas-induced apoptosis of T-cells (r - from 0,5 to 0,81) and between the development of severe systemic complication and increase in percentage of CD8+-lymphocytes with large homogenous nucleoli (r=+0,71+/-0,08), mean diameter of CD8+-lymphocytes nucleus (r=+0,61+/-0,08) and mononuclear leukocytes proliferate response to FGA (r=+0,56+/-0,07). The step based system of assessment of cell immunity disturbances and the criteria of the evaluation of risks of the development of systemic complication in patients with RA were established on the above mentioned parameters development prognosis based on their immune parameters.


The mechanism of lithium and beta-blocking agents in inducing and exacerbating psoriasis.
Documentation of psoriatic eruptions occurring with the initiation of various pharmacotherapy agents has been reported in the literature. Two such agents include lithium and beta-blocking drugs. By understanding the mechanism by which these drugs induce and exacerbate psoriasis, we may gain further understanding of the disease process of psoriasis as well as how to treat this side effect. This paper reviews the literature that has examined the mechanism by which lithium and beta-blockers may induce and exacerbate psoriasis. Mechanisms involving both immunologic and non-immunologic factors have been examined in various studies. No consensus has been reached and further investigation is needed. However, findings such as improvement with inositol supplementation in cases of lithium-induced and -exacerbated psoriasis and disparate histologic presentation of beta-blocker-induced psoriasis provide suggestions that both the origin and treatment of drug-induced psoriasis may be different than psoriasis that is unrelated to medications.


[The microbiological status of dry sausage in East Netherlands].
Dry fermented sausage (dfs) was the food most suspected in a number of outbreaks of salmonellosis and staphylococcal enterotoxaemia. Data on formulation and processing showed that over 75 per cent of 76 producers still manufactured dfs in a traditional manner: fermentation and drying at ambient temperature for ten days on an average, green room facilities not present. 'Modern' processes were characterised by fermentation in green rooms at elevated temperatures, thus limiting production time to six days on an average. However, precautions to prevent luxurious growth of S. aureus under these conditions were not adopted to any appreciable extent. Consequently, high S. aureus levels (greater than 10(4) cfu/g) were detected precisely in dfs from five manufacturers using rapid processes. Colony counts of Enterobacteriaceae were low in dfs (81 per cent of 151 samples less than 10(3) cfu/g), associated with relatively low pH and aw levels and a high concentration of salt. However, Salmonella was detected in 16 (11%) of the samples, both from 'traditional' and 'modern' producers. Improvement of manufacturing practices in the manufacture of dfs should be stimulated to guarantee wholesome and safe products.


[Malignant peritoneal mesothelioma in patients without occupational exposure. Case report].
Peritoneal mesothelioma is a rare malignancy that affects more women than men, with an average of 53 years old. The most important risk factor for developing the disease is chronic exposure to asbestos, becoming a disease of occupational origin. This type of cancer is difficult to diagnose, even for pathologists, with few cases reported in the literature as the most common presentation is the pleural type. We report the case of a male patient, without asbestos exposure, who presented malignantperitoneal mesothelioma.


Systolic time intervals in children: normal standards for clinical use.
Systolic time intervals were measured in 253 normal children, with careful attention to precise recording and measuring techniques, to derive regression equations which could be used as reliable standards for clinical assessment of left ventricular performance in this age group. Using stepwise regression analysis, a highly significant correlation was found for electromechanical systole (QS2) and for left ventricular ejection time (LVET) with heart rate alone in both males and females, and age was not found to be a relevant variable. Similarly, for the preejection period (PEP) in males, heart rate was the only relevant variable. PEP in females showed a small but significant influence of age in addition to heart rate; in practice, this small influence can be neglected. Regression equations relating each of the systolic time intervals to heart rate alone were therefore derived for clinical use. The PEP/LVET ratio was found to be only weakly correlated with heart rate in males and with age in females, and in practice can be considered to be independent of these variables. The mean value of the PEP/LVET ratio and its standard deviation (0.30 +/- 0.04) can therefore be used for all children. We found that satisfactory recording of systolic time intervals can be obtained with little difficulty in almost all children using the techniques described. The method is therefore practical for clinical use in children, as it is in adults, and the normal standards derived in this study can serve as a reliable basis for its application.


Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes.
Diabetes impinges upon mechanisms of cardiovascular repair. However, the biochemical adaptation of cardiac stem cells to sustained hyperglycaemia remains largely unknown. Here, we investigate the molecular targets of high glucose-induced damage in cardiac progenitor cells (CPCs) from murine and human hearts and attempt safeguarding CPC viability and function through reactivation of the pentose phosphate pathway. Type-1 diabetes was induced by streptozotocin. CPC abundance was determined by flow cytometry. Proliferating CPCs were identified in situ by immunostaining for the proliferation marker Ki67. Diabetic hearts showed marked reduction in CPC abundance and proliferation when compared with controls. Moreover, Sca-1(pos) CPCs isolated from hearts of diabetic mice displayed reduced activity of key enzymes of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD), and transketolase, increased levels of superoxide and advanced glucose end-products (AGE), and inhibition of the Akt/Pim-1/Bcl-2 signalling pathway. Similarly, culture of murine CPCs or human CD105(pos) progenitor cells in high glucose inhibits the pentose phosphate and pro-survival signalling pathways, leading to the activation of apoptosis. In vivo and in vitro supplementation with benfotiamine reactivates the pentose phosphate pathway and rescues CPC availability and function. This benefit is abrogated by either G6PD silencing by small interfering RNA (siRNA) or Akt inhibition by dominant-negative Akt. We provide new evidence of the negative impact of diabetes and high glucose on mechanisms controlling CPC redox state and survival. Boosting the pentose phosphate pathway might represent a novel mechanistic target for protection of CPC integrity.


Neurturin: an autocrine regulator of renal collecting duct development.
Urine is produced in the kidney by excretory nephrons and is drained by a tree-like system of collecting ducts to the ureter. The collecting ducts develop by arborisation of an initially unbranched epithelial rudiment, the ureteric bud, which ramifies through the surrounding mesenchyme and induces the formation of nephrons by mesenchyme-to-epithelial transition. The question of how collecting duct morphogenesis is controlled is an important one, from the points of view of both basic developmental biology and congenital renal pathology (multi- and polycystic renal disease, and some forms of renal agenesis, arise from defective collecting duct development). We report that neurturin, a neurotrophin related to glial cell line-derived neurotrophic factor and expressed in the developing kidney, acts as a collecting duct morphogen in culture. Applied in culture medium, it promotes epithelial branching and can induced branch initiation that has otherwise been blocked by depleting cultured kidneys of their sulfated proteoglycans or by antibody treatments. Applied locally on agarose beads, neurturin induces supernumerary ureteric buds to emerge from the wolffian duct and causes nearby collecting duct branches to distend to an abnormally large diameter. Like its receptors, neurturin is expressed by the developing collecting ducts themselves, suggesting that it forms an autocrine morphoregulatory control loop. This is in marked contrast to previously identified morphogens such as glial cell line derived neurotrophic factor and hepatocyte growth factor, which act in a paracrine manner.


Widespread gene duplication and adaptive evolution in the RNA interference pathways of the Drosophila obscura group.
RNA interference (RNAi) related pathways provide defense against viruses and transposable elements, and have been implicated in the suppression of meiotic drive elements. Genes in these pathways often exhibit high levels of adaptive substitution, and over longer timescales show gene duplication and loss-most likely as a consequence of their role in mediating conflict with these parasites. This is particularly striking for Argonaute 2 (Ago2), which is ancestrally the key effector of antiviral RNAi in insects, but has repeatedly formed new testis-specific duplicates in the recent history of the obscura species-group of Drosophila. Here we take advantage of publicly available genomic and transcriptomic data to identify six further RNAi-pathway genes that have duplicated in this clade of Drosophila, and examine their evolutionary history. As seen for Ago2, we observe high levels of adaptive amino-acid substitution and changes in sex-biased expression in many of the paralogs. However, our phylogenetic analysis suggests that co-duplications of the RNAi machinery were not synchronous, and our expression analysis fails to identify consistent male-specific expression. These results confirm that RNAi genes, including genes of the antiviral and piRNA pathways, have undergone multiple independent duplications and that their history has been particularly labile within the obscura group. However, they also suggest that the selective pressures driving these changes have not been consistent, implying that more than one selective agent may be responsible.


Analysis of variations in the tryptophan hydroxylase-2 (TPH2) gene in cocaine dependence.
While the exact physiological mechanisms underlying cocaine dependence remain unclear, a growing body of evidence indicates a role for the serotonergic neurotransmitter system in the pathology of this substance use disorder. The focus of the present study is to determine whether genetic variation in the tryptophan hydroxylase-2 (TPH2) gene, which encodes the enzyme responsible for synthesis of the majority of the serotonin contained in neurons of the central nervous system, contributes to the pathophysiology of cocaine dependence. To examine this hypothesis, we used a case-control study design in which the genotype and allele distributions for six single nucleotide polymorphisms (SNPs) in the TPH2 gene were compared between cocaine-dependent (n = 299) and control individuals (n = 208) of African descent. The results indicate that none of the SNPs in the TPH2 gene examined in this study associate with the cocaine-dependent phenotype. This work suggests that variations in the TPH2 gene are not a risk factor for the development of cocaine dependence, but these findings require confirmation in larger, independent samples of cocaine-dependent and control subjects.


DNA Encapsidation and Capsid Assembly Are Underexploited Antiviral Targets for the Treatment of Herpesviruses.
Although there are effective nucleoside analogs to treat HSV, VZV, and HCMV disease, herpesvirus infections continue to contribute to significant morbidity and mortality. Acyclovir is the drug of choice for HSV encephalopathy, yet there is an estimated 6-19% mortality rate with half of the survivors experiencing moderate to severe chronic neurological deficits. For VZV, current treatments are inadequate to prevent acute and persistent pain due to zoster. Treatment of HCMV with GCV requires close monitoring particularly in patients with impaired renal function and there are no approved treatments for congenital HCMV infections. New therapeutic options to control cytomegalovirus reactivation in bone marrow and stem cell transplant patients are needed to improve patient outcome. No successful chemotherapeutic options are available for EBV, HHV-6, 7, and 8. Drug resistance is a concern for HCMV, HSV, and VZV since approved drugs share common mechanisms of action. Targeting DNA encapsidation or capsid assembly provide additional options for the development of non-nucleoside, small molecule anti-herpesviral drugs.


Monte Carlo simulation and free energies of mixed oxide nanoparticles.
A Monte Carlo Exchange technique is used to study the thermodynamic properties of MgO-MnO nanoparticles ranging in size from 1728 to 21,952 ions. The solubility of Mg(2+) is much greater in MnO than the reverse, reflecting the difference in size between the two cations. The solubility, for a given temperature, diminishes with nanoparticle size. As the Mn concentration is progressively increased the Mn(2+) ions occupy the corners, edges and then surface sites of the nanoparticle before entering subsurface layers. We do not observe any pronounced ordering of the cations within the body of the nanoparticles themselves. The enthalpies of forming ternary nanoparticles from particles of MgO and MnO of the same size vary with the size of the nanoparticle and become more positive for a given concentration as the particle size increases. Free energies of mixing of the two end-member nanoparticles have been determined using the semigrand ensemble. The consolute temperature (the temperature above which there is complete miscibility) increases non-linearly with the size of the nanoparticle by approximately 70% over the size range considered.


[Severity of acquired cystic kidney disease determines improvement in chronic kidney failure anemia].
To identify a correlation between dialysis treatment duration and severity of acquired cystic disease of the end-stage kidney measured by cyst sizes; and assess its effect on spontaneous improvement of anemia. Ten patients, 6 males and 4 females were selected, who have been on hemodialytic treatment for more than 5 years. There was no patient selected with autosomal dominant polycystic kidney disease. The renal evaluation has been made through ultrasonographic studies. Acquired cystic disease of the end-stage kidney was characterized by finding four or more cysts in both kidneys. The largest cysts were measured for correlation effect. The diagnosis of anemia was established by hematocrit and hemoglobin serum values. It has also been analyzed serum urea, creatinine, albumin, iron, total iron-binding capacity and the per cent saturation of serum transferrin were tested. The patients were properly dialysed (serum urea and creatinine = 98.7 +/- 35 mg/dL e 9.7 +/- 2.7 mg/dL, respectively). There were in good nutritional shape (serum albumin = 4.5 +/- 0.5 g/dL) and had normal serum iron level (serum iron = 80 +/- 34 mg/dL). The prevalence of acquired renal cystic disease was 80%. No finding of malignancy has been detected in these cysts. There was a significant correlation between time on dialysis treatment and hematocrit values (R = 0.70; p < 0.05). Cyst sizes had a direct and significant correlation with hematocrit levels (R = 0.74; p < 0.05). These results show that spontaneous improvement on anemia seen in patients on chronic dialysis has a significant correlation with the severity of acquired cystic disease of the end-stage kidney. Our data suggest a functional role of acquired kidney cysts on endogenous erythropoietin production.


Time-Enhancement Curve of Four-Dimensional Computed Tomography Predicts Aneurysm Enlargement with Type-II Endoleak after Endovascular Aneurysm Repair.
We investigated the hemodynamic features of Type-II endoleaks after endovascular aneurysm repair (EVAR) using four-dimensional (4D) computed tomography (CT) to identify patients with aneurysm enlargement. During a 13-month period (January 2017-January 2018) at our institution, we performed 4D-CT examinations in 13 patients after EVAR because of suspected Type-II endoleaks. Three patients were excluded from the study because of other endoleaks or absence of detectable endoleaks. The ramaining 10 patients were divided into two groups: enlargement group (n = 4), in which the aneurysm volume increased, and stable group (n = 6), in which the aneurysm remained stable or shrank. A CT scanner and three-dimensional workstation were used. All images were obtained using a consistent protocol (22 phase scans using the test bolus tracking method). We analyzed the hemodynamics of the endoleak cavity (EC) relative to those of the aorta and evaluated the time-enhancement curves (TECs) using measurement protocols. The strengths of correlations between these factors in the two groups were analyzed statistically. TECs in the enlargement group showed a more gradual curve, and the upslope, the gradient of TEC in the ascending phase and the upslope index were significantly more gradual than those in the stable group (p = 0.0247, 0.0243). The EC washout and the EC washout index were also more gradual than in the stable group's (p = 0.019, 0.019). The enhancement duration was longer in the former than in the latter (80%, p = 0.0195; 70%, p = 0.0159; 60%, p = 0.0159). The CT number in the equilibrium phase was larger in the enlargement group than in the stable group (p = 0.019). The 4D-CT is useful for predicting aneurysm enlargement with Type-II endoleaks after EVAR.


Salivary and serum proteomics in head and neck carcinomas: before and after surgery and radiotherapy.
Several body fluids have been evaluated as new sources for cancer biomarker discovery. In this context, salivary and serum proteomics seem promising diagnostic and predictive tools for head and neck diseases. In the present study, we performed a proteomic analysis of saliva and serum from patients presenting head and neck squamous cell carcinoma (HNSCC) and compared the results before and after therapy. In saliva of cancer patients, we observed an altered protein profile, including over-expression of PLUNC and zinc-alpha-2-glycoprotein. Both proteins may contribute to control tumor growth and, therefore, represent targets for new analysis. We also detected serotransferrin and a modified transthyretin form with altered levels in serum from patients. Comparing preoperative and postreatment samples, the results showed that the protein profile after treatment reverted to a pattern closer to those observed for controls. These results add information on the role of secreted proteins in the cancer process and emphasize the potential of saliva and serum analysis for diagnosis and monitoring of HNSCC.


Two subgroups of HLA Bw44 defined by cell-mediated lympholysis that differ in Bw44 expression on platelets and in patterns of genetic linkage disequilibrium.
Possible immunogenic heterogeneity of the HLA-Bw44 antigen was investigated using cytotoxic T lymphocytes (CTL) generated between donors identical for HLA-A2,3,-B7,w44. Highly discriminatory CTL combinations were identified that defined two subgroups of Bw44, designated 44.1 and 44.2. Out of 47 Bw44-positive donors tested in a population study, 30 were lysed by the CTL defining 44.1, and 19 were lysed by the CTL defining 44.2. All Bw44 cells could be typed as either 44.1 or 44.2, except two Bw44-positive cells that were phenotypically homozygous for the serologically defined Bw44 antigen and were lysed by both CTL. No Bw44-negative donors (zero out of 37) expressed either 44.1 or 44.2, although cold target blocking was required to eliminate a contaminating reactivity of one CTL population on Bw35 and some Bw45 cells. CTL were also raised between responder/stimulator combinations mismatched for Bw44. These CTL lysed all Bw44-positive target cells, indicating a CML antigen shared by all Bw44 cells. But clear discrimination of the 44.1 and 44.2 subgroups was obtained when appropriate cold target blocking cells were added. All donors with 44.2 expressed high levels of serologically detectable Bw44 on their platelets, and all with 44.1 expressed low levels (p less than 0.005). Furthermore, population studies indicate that 44.1 is in positive linkage disequilibrium with HLA-A2 and possibly DR4, whereas 44.2 is in positive linkage disequilibrium with HLA-DR7 and possibly HLA-A23, -A26, and -A29. These data suggest the existence of two genetically and functionally different subgroups of Bw44 antigens.


Phenylketonuria (PKU) Urinary Metabolomic Phenotype Is Defined by Genotype and Metabolite Imbalance: Results in 51 Early Treated Patients Using Ex Vivo 1H-NMR Analysis.
Phenylketonuria (PKU) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase gene. Depending on the severity of the genetic mutation, medical treatment, and patient dietary management, elevated phenylalanine (Phe) may occur in blood and brain tissues. Research has recently shown that high Phe not only impacts the central nervous system, but also other organ systems (e.g., heart and microbiome). This study used ex vivo proton nuclear magnetic resonance (1H-NMR) analysis of urine samples from PKU patients (mean 14.9 ± 9.2 years, n = 51) to identify the impact of elevated blood Phe and PKU treatment on metabolic profiles. Our results found that 24 out of 98 urinary metabolites showed a significant difference (p < 0.05) for PKU patients compared to age-matched healthy controls (n = 51) based on an analysis of urinary metabolome. These altered urinary metabolites were related to Phe metabolism, dysbiosis, creatine synthesis or intake, the tricarboxylic acid (TCA) cycle, end products of nicotinamide-adenine dinucleotide degradation, and metabolites associated with a low Phe diet. There was an excellent correlation between the metabolome and genotype of PKU patients and healthy controls of 96.7% in a confusion matrix model. Metabolomic investigations may contribute to a better understanding of PKU pathophysiology.


Preventing Cervical Cancer in the United States: Barriers and Resolutions for HPV Vaccination.
Human papillomavirus (HPV) vaccination rates for preadolescent and adolescent girls in the United States are far behind those of other developed nations. These rates differ substantially by region and state, socioeconomic status, and insurance status. In parents and young women, a lack of awareness and a misperception of the risk of this vaccine drive low vaccination rates. In physicians, lack of comfort with discussion of sexuality and the perception that the vaccine should be delayed to a later age contribute to low vaccination rates. Patient- and physician-targeted educational campaigns, systems-based interventions, and school-based vaccine clinics offer a variety of ways to address the barriers to HPV vaccination. A diverse and culturally appropriate approach to promoting vaccine uptake has the potential to significantly improve vaccination rates in order to reach the Healthy People 2020 goal of over 80% vaccination in adolescent girls. This article reviews the disparities in HPV vaccination rates in girls in the United States, the influences of patients', physicians', and parents' attitudes on vaccine uptake, and the proposed interventions that may help the United States reach its goal for vaccine coverage.


Understanding coordination equilibria in solution and gel-phase [2]rotaxanes.
This paper describes the use of the copper(i)-catalysed azide-alkyne cycloaddition reaction in an active metal template methodology for the synthesis of [2]rotaxanes both in solution and on polymer resins. The use of TentaGel resin beads has allowed the rotaxane functionalised solid supports to be characterized by 1H HR MAS NMR. Whereas previous research in the assembly of interlocked architectures on surfaces are complicated by the concurrent attachment of large proportions of non-interlocked byproducts, in this example over 80% of the functionalization is the desired interlocked rotaxane. The inclusion of zinc metalloporphyrins in the structure of the [2]rotaxane thread allowed the position of the macrocycle to be 'switched' upon the addition of competing base, removal of the metal or appropriate choice of solvent. Investigations into the pseudocooperative effect the mechanical bond has on the metalloporphyrin-macrocycle coordination equilibrium were performed and the associated effective molarity in this [2]rotaxane was calculated to be 120 mM.


Survival and place of delivery following preterm birth: 1994-96.
To compare the survival of premature infants, adjusted for disease severity, in different types of neonatal intensive care setting. A prospective observational study in the Trent Health Region was carried out of all infants born to resident mothers at or before 32 weeks of gestation between 1 January 1994 to 31 December 1996 inclusive. The 16 neonatal units in Trent were subdivided into five relatively large units which regularly took outside referrals and 11 smaller units which provided intensive care for a variable proportion (sometimes nearly 100%) of their local population. Data regarding obstetric management, neonatal care, and outcome were collected by independent neonatal nurses who visited the units on a regular basis. Survival rates were compared with an expected rate calculated using the Clinical Risk Index for Babies (CRIB). For either setting to be abnormally good or bad actual deaths had to exceed the 95% confidence interval of the CRIB estimate. Actual survival rates for infants < or = 32 weeks gestation and for the group of babies < or = 28 weeks gestation fell within the 95% confidence interval of the rate predicted by CRIB for both the larger referral units and the smaller district units. Similarly, compared with the CRIB prediction, infants transferred in utero or postnatally were not adversely affected in terms of the number who died. Previous results from this geographical population, showing that survival of babies < or = 28 weeks gestation was better when their care was provided by referral units, are no longer sustained. Significant changes to the neonatal services over time make the current results plausible. However, the new structure poses potential threats to the teaching, training, and research base of the neonatal service as a whole.


Bilateral proximal hamstring muscle avulsion after treatment with immune checkpoint inhibitors and corticosteroids.
A 66-year-old man presented with 4 weeks of bilateral buttock pain without previous trauma or intense exercise. He had been treated with immune checkpoint inhibitors because of metastasising melanoma and experienced immune-related adverse events requiring treatment with corticosteroids. Magnetic resonance imaging of the pelvis revealed bilateral avulsion of the proximal hamstring muscles. Treatment with physical therapy and nonsteroidal anti-inflammatory drugs led to a slow but lasting relief. This is, to our knowledge, the first report of symptomatic non-traumatic bilateral hamstring muscle avulsion following treatment with immune checkpoint inhibitors and corticosteroids.


Cochlear Implantation Outcomes in Patients with Mitochondrial Hearing Loss: A Systematic Review and Narrative Synthesis.
This study's aim was to establish outcomes following cochlear implantation (CI) in patients with mitochondrial disorders associated with deafness. Systematic review and narrative synthesis. Databases searched: Medline, EMBASE, Web of Science, COCHRANE, and ClinicalTrials.gov. No limits on language or year of publication. Review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Searches identified 437 abstracts and 37 full text articles, of which 11 studies met the inclusion criteria reporting outcomes in a total of 17 patients. All implants achieved good hearing outcomes, and follow-up ranged between 1 week and 12 months. The methodological quality of the included studies was sufficient, scoring grades 3 to 4 using the Oxford Centre for Evidence Based Medicine grading system. All studies were retrospective and consisted of case reviews and case reports. All cases of CI showed positive outcomes in speech perception and detection. There is some qualitative evidence to suggest improvement in quality of life and satisfaction postoperatively. There was very limited information available on secondary outcomes such as surgical complications, quality of life, and method of cochlear implant insertion. The small sample size of our patient cohort and quality of studies suggests a need for large-scale studies with more robust methodology to assess the effectiveness of CI. There is a need for studies that assess other factors to be considered when counseling patients about cochlear implants, such as adverse events, surgical complications, and long-term benefits.


Understanding the EF-hand closing pathway using non-biased interatomic potentials.
The EF-hand superfamily of proteins is characterized by the presence of calcium binding helix-loop-helix structures. Many of these proteins undergo considerable motion responsible for a wide range of properties upon binding but the exact mechanism at the root of this motion is not fully understood. Here, we use an unbiased accelerated multiscale simulation scheme, coupled with two force fields - CHARMM-EEF1 and the extended OPEP - to explore in details the closing pathway, from the unbound holo state to the closed apo state, of two EF-hand proteins, the Calmodulin and Troponin C N-terminal nodules. Based on a number of closing simulations for these two sequences, we show that the EF-hand β-scaffold, identified as crucial by Grabarek for the EF-hand opening driven by calcium binding, is also important in closing the EF-hand. We also show the crucial importance of the phenylalanine situated at the end of first EF-hand helix, and identify an intermediate state modulating its behavior, providing a detailed picture of the closing mechanism for these two representatives of EF-hand proteins.


FTO association and interaction with time spent sitting.
Multiple studies have revealed an interaction between a variant in the FTO gene and self-reported physical activity on body mass index (BMI). Physical inactivity, such as time spent sitting (TSS) has recently gained attention as an important risk factor for obesity and related diseases. It is possible that FTO interacts with TSS to affect BMI, and/or that FTO's putative effect on BMI is mediated through TSS. We tested these hypotheses in two cohorts of the Framingham Heart Study (FHS) (Offspring: n=3430 and Third Generation: n=3888), and attempted to replicate our results in the Women's Health Initiative (WHI; n=4756). Specifically, we examined whether an association exists between FTO and self-reported TSS, and whether an interaction exists between FTO and TSS on BMI, while adjusting for several important covariates such as physical activity. In FHS, we find a significant positive association between the BMI-increasing FTO allele and TSS. We find a similar trend in WHI. Mediation analyses suggest that the effect of FTO on BMI is mediated through TSS. In FHS, we find a significant interaction of FTO and TSS on BMI, whereby the association of TSS with BMI is greatest among those with more FTO risk alleles. In WHI, we also find a significant interaction, although the direction is opposite to that in FHS. In a meta-analysis of the two data sets, there is no net interaction of FTO with TSS on BMI. Our study suggests that FTO exerts its effect on BMI, at least partly, through energy expenditure mechanisms such as TSS. Further research into the intersection of genetics, sedentary behavior and obesity-related outcomes is warranted.


Tactile perception of thermal diffusivity.
The thermal diffusivity of an object is a parameter that controls the rate at which heat is extracted from the hand when it touches that object. It is an important feature for distinguishing materials by means of touch. In order to quantitatively describe the ability of human observers to discriminate between materials on the basis of heat extraction rate, we conducted an experiment in which this heat extraction was performed in a controlled way. In different conditions, subjects were repeatedly asked to select from two stimuli the one that cooled faster. The discrimination threshold was around 43% of the extraction rate. A rate that was twice as slow also yielded twice the absolute threshold. When we halved the temperature difference between the beginning and end of the stimulus, the threshold did not change as much. In separate experiments, we investigated the different cues that were available in the stimulus: initial cooling rate and end temperature. Both cues were used for discrimination, but cooling rate seemed to be the most important.


In vitro and in vivo evaluation of electrospun nanofibers of PCL, chitosan and gelatin: a comparative study.
Many polymers have been investigated with respect to their use in skin tissue engineering. However, directly comparable data on the role played by different polymers in assisting skin wound healing requires their in vitro and in vivo evaluation under the same conditions. Therefore, we performed a study in order to compare the performance of electrospun nanofiber mats from three different polymers concerning cell-scaffold interaction and wound healing promotion. A polyester (polycaprolactone, PCL), a protein (gelatin from cold water fish skin, GEL) and a polysaccharide (chitosan, CS) were the polymers chosen. Gelatin nanofibers were crosslinked with glutaraldehyde vapor. The scaffolds were characterized physico-chemically, in vitro by seeding with human fetal fibroblasts, HFFF2, and used in vivo as skin substitutes in a rat wound model with total skin removal. In vitro tests revealed that cells adhered and proliferated in all scaffolds. However, cells deep into the scaffold were only observed in the PCL and CS scaffolds. In in vivo tests CS scaffolds had the highest impact on the healing process by decreasing the extent of wound contraction and enhancing the production of a neodermis and re-epithelialization of the wound.


High-resolution spectral domain-OCT imaging in geographic atrophy associated with age-related macular degeneration.
To describe morphologic variations in outer retinal layers in eyes with atrophic age-related macular degeneration (AMD) using high-resolution, spectral-domain optical coherence tomography (SD-OCT). SD-OCT scans were obtained with a combined confocal scanning laser ophthalmoscope (cSLO) and SD-OCT for simultaneous tomographic and topographic in vivo imaging. A total of 81 eyes of 56 patients (mean age, 77.8 +/- 7.4 years) with geographic atrophy (GA) were examined. Morphologic alterations were analyzed and classified in the perilesional zone, at the junction between GA and nonatrophic retina, and in the atrophic area itself. In the perilesional zone, distinct morphologic alterations included elevations of the outer retinal layers, thickening, and spikes of the outer hyperreflective band as well as clumps at different neurosensory retinal levels. At the junction, highly variable transitions of the outer retinal layers were present with different degrees of loss of the normal hyperreflective bands. Within the actual GA, hyperreflective clumps at different retinal levels, segmented plaques of the outer band and elevations with variable reflectivity were visualized. SD-OCT imaging in eyes with GA revealed a wide spectrum of morphologic alterations, both in the surrounding retinal tissue and in the atrophic area. These alterations may reflect different disease stages or, alternatively, heterogeneity on a cellular and molecular level. Longitudinal studies using in vivo SD-OCT imaging may allow evaluation of the relevance of these phenotypic changes as potential predictive markers for the progression of disease (i.e., enlargement rates of GA over time) and may be used for monitoring of future therapeutic interventions.


Acceleration of cell growth by xyloglucan oligosaccharides in suspension-cultured tobacco cells.
The incorporation of xyloglucan oligosaccharide (XXXG) into the walls of suspension-cultured tobacco cells accelerated cell expansion followed by cell division, changed cell shape from cylindrical to spherical, decreased cell size, and caused cell aggregation. Fluorescent XXXG added to the culture medium was found to be incorporated into the surface of the entire wall, where strong incorporation occurred not only on the surface, but also in the interface walls between cells during cell division. Cell expansion was always greater in the transverse direction than in the longitudinal direction and then, immediately, expansion led to cell division in the presence of XXXG; this process might result in the high level of cell aggregation seen in cultured tobacco cells. We concluded that the integration of this oligosaccharide into the walls could accelerate not only cell expansion, but also cell division in cultured cells.


An advisory by the association of radiation oncologists of India for radiation therapy patients and staff among COVID 19 pandemic.
Covid19 has become a major public health problem in India and the rest of the world. The dramatic rise in the incidence of COVID 19 cases has severely challenged our healthcare system and forced us to work with limited infrastructure, resources, and workforce. However, even in this time of adversity, we as oncologists cannot neglect the seriousness of cancer care and the utmost attention it requires for the timely management of our patients. Hence, the Association of Radiation Oncologists of India has come up with an advisory for radiation therapy keeping in mind such aspects.


Study of device use adjusted rates in health care-associated infections after implementation of "bundles" in a closed-model medical intensive care unit.
"Bundles" strategies improve health care-associated infection (HCAI) rates in medical intensive care units (MICUs). However, few studies have analyzed HCAI rates adjusted for the device removal component of the bundles. An observational study of adult MICU patients while using bundles to prevent HCAIs associated with endovascular catheters, mechanical ventilation, and urinary tract catheters was conducted. The HCAI rates, unadjusted and adjusted for device use, were calculated using incidence rate ratios (unadjusted IRRs [uIRR] and adjusted IRRs [aIRR], respectively). Among 4550 study patients, HCAIs declined from 47 in 2004 to 10 in 2005, 8 in 2006, and 3 in 2007. Catheter-related blood stream infection (CRBSI) rates decreased from 10.77 to 1.67 per 1000 central line days (uIRR, 0.155; 95% confidence interval [CI], 0.13-0.18; P < .0001). Foley-related urinary tract infections (CA-UTI) decreased from 6.23 to 0.63 per 1000 device days (uIRR, 0.1; 95% CI, 0.08-0.19; P < .0001). Ventilator-associated pneumonia (VAP) per 1000 ventilator days diminished from 2.17 to 0.62 (uIRR, 0.29; 95% CI, 0.21-0.38; P < .0001). After adjustment for device use, aIRRs of CRBSI (0.14; 95% CI, 0.11-0.18), UTI (0.09; 95% CI, 0.06-0.12), and VAP (0.33; 95% CI, 0.22-0.47) declined significantly (P < .00001). Implementing comprehensive bundle strategies reduces HCAI beyond the impact of device removal.


Superficial digital flexor tendon luxation repaired with abrasion calcaneoplasty and primary retinaculum repair in dogs.
Surgical treatment of a superficial digital flexor tendon luxation is the treatment of choice, since nonsurgical treatment has been shown to be unsuccessful in dogs in which it has been attempted. The objectives of this study were to report complications and short- to long-term outcomes in dogs with superficial digital flexor tendon luxation treated with abrasion calcaneoplasty, an adjunctive surgical technique, in addition to traditional repair. In total, 12 client-owned dogs with superficial digital flexor tendon luxations were examined in this retrospective case series (from 2010 to 2020) of a novel surgical technique using abrasion calcaneoplasty, in addition to retinaculum imbrication. Records were reviewed for signalment, chronicity of clinical signs, preoperative diagnostics tests, surgical techniques, postoperative complications, and outcomes. Abrasion calcaneoplasty, in addition to traditional primary retinaculum repair, was successfully performed in 12 dogs, with ultimate resolution of clinical lameness in all patients, despite short-term reluxation in 1 patient. Based on the findings of this case series, we inferred that abrasion calcaneoplasty can be considered in addition to traditional repair as an option to treat luxation of the superficial digital flexor, with a 58% short-term complication rate, and no evidence of long-term complications.


Protective factors within the family, and their role in fostering resiliency in African American adolescents.
Violence has reached epidemic proportions in the United States, with African American males residing in urban areas bearing the brunt of this epidemic. The violence permeating our society emanates from a variety of societal ills, including poverty, racism, substance abuse and exposure to violence. Traditionally, methods of research on adolescent violence have focused on an identification of associated risk factors. The majority of African American adolescents living in communities with widespread and chronic violence grow up to be law-abiding citizens. The reason for this may be due to resiliency within these adolescents. Resiliency has been defined as the ability to experience adverse circumstances and successfully overcome them. Resiliency is enhanced through three mechanisms identified as protective factors: individual characteristics/traits; familial traits; and extrafamilial relationships. The risks faced may be altered, and even ameliorated, through the presence of these protective factors. The purpose of this paper is to identify protective factors within the family that foster resiliency. Protective factors within the family may be categorized as having three broad characteristics: caring and support, high expectations, and encouragement of participation and involvement for the adolescent.


ENteric Immunity SImulator: a tool for in silico study of gastroenteric infections.
Clinical symptoms of microbial infection of the gastrointestinal (GI) tract are often exacerbated by inflammation induced pathology. Identifying novel avenues for treating and preventing such pathologies is necessary and complicated by the complexity of interacting immune pathways in the gut, where effector and inflammatory immune cells are regulated by anti-inflammatory or regulatory cells. Here we present new advances in the development of the ENteric Immunity SImulator (ENISI), a simulator of GI immune mechanisms in response to resident commensal bacteria as well as invading pathogens and the effect on the development of intestinal lesions. ENISI is a tool for identifying potential treatment strategies that reduce inflammation-induced damage and, at the same time, ensure pathogen removal by allowing one to test plausibility of in vitro observed behavior as explanations for observations in vivo, propose behaviors not yet tested in vitro that could explain these tissue-level observations, and conduct low-cost, preliminary experiments of proposed interventions/treatments. An example of such application is shown in which we simulate dysentery resulting from Brachyispira hyodysenteriae infection and identify aspects of the host immune pathways that lead to continued inflammation-induced tissue damage even after pathogen elimination.


Distribution of edge load in scale-free trees.
Node betweenness has been studied recently by a number of authors, but until now less attention has been paid to edge betweenness. In this paper, we present an exact analytic study of edge betweenness in evolving scale-free and non-scale-free trees. We aim at the probability distribution of edge betweenness under the condition that a local property, the in-degree of the "younger" node of a randomly selected edge, is known. En route to the conditional distribution of edge betweenness the exact joint distribution of cluster size and in-degree, and its one-dimensional marginal distributions have been presented in the paper as well. From the derived probability distributions the expectation values of different quantities have been calculated. Our results provide an exact solution not only for infinite, but for finite networks as well.


Vitamin D: an essential component for skeletal health.
Vitamin D deficiency is increasing worldwide. Ultraviolet rays are supposed to provide humans over 80% of our vitamin D requirement; the rest is received through diet and supplements. In addition to enhancing calcium absorption from the intestine and mineralization of the osteoid tissue, vitamin D has many other physiological effects, including neuromodulation, improving muscle strength and coordination, insulin release, immunity and prevention of infections, and curtailing cancer. Whether the increased incidence of vitamin D deficiency is related to increased incidences of nonskeletal disorders remains to be determined. Serum levels of 25-hydroxyvitamin [25(OH)D] above 30 ng/mL indicate vitamin D sufficiency. An additional 1,000 IU of vitamin D/day is sufficient for most lighter-skinned individuals, whereas an extra 2,000 IU/day is needed by the elderly and dark-skinned individuals to maintain normal 25(OH)D levels. Additional research is needed to clarify the relationship between vitamin D and the nonskeletal systems, nonclassic functions, and targets of vitamin D.


The influence of depressive symptoms on smoking cessation among African Americans in a randomized trial of bupropion.
The influence of depressive symptoms on smoking cessation was examined among 600 African American smokers who participated in a randomized, placebo-controlled trial of sustained-release bupropion hydrochloride. Depressive symptoms were assessed at baseline, at week 6 (end of treatment), and at 6-month follow-up. The study examined three separate questions: (a) Whether depressive symptom levels were related to smoking cessation, (b) whether bupropion was more effective for smokers who had higher depressive symptoms at baseline (i.e., a moderator model), and (c) whether changes in depressive symptoms would account for the efficacy of bupropion for smoking cessation (i.e., a mediator model). Depressive symptoms at baseline were not predictive of cessation; however, increases in depressive symptoms from baseline predicted reduced cessation at the end of treatment, and higher depressive symptoms at week 6 and month 6 were associated with a reduced likelihood of smoking cessation at those time points. The moderator model was not supported, but the mediation analyses indicated that alleviation of depressive symptoms partly accounted for bupropion-assisted smoking cessation at end of treatment. Results extend prior findings to African American smokers and suggest that clinicians consider increases in depressive symptoms after quitting rather than baseline depressive symptoms in predicting risk of treatment failure. Results also suggest that even though bupropion may facilitate cessation in part by reducing depressive symptoms, it appears to be no more effective for more depressed smokers, and that mechanisms other than depressive symptom alleviation account for most of its efficacy.


Negative electrostatic contribution to the bending rigidity of charged membranes and polyelectrolytes screened by multivalent counterions.
Bending rigidity of a charged membrane or polyelectrolyte screened by monovalent counterions is known to be enhanced by electrostatic effects. We show that in the case of screening by multivalent counterions the electrostatic effects reduce the bending rigidity. This inversion of the sign of the electrostatic contribution is related to the formation of two-dimensional strongly correlated liquids (SCL) of counterions at the charged surface due to strong lateral repulsion between them. When a membrane or a polyelectrolyte is bent, SCL is compressed on one side and stretched on the other so that thermodynamic properties of SCL contribute to the bending rigidity. Thermodynamic properties of SCL are similar to those of Wigner crystal and are anomalous in the sense that the pressure, compressibility and screening radius of SCL are negative. This brings about substantial negative correction to the bending rigidity. For the case of DNA this effect qualitatively agrees with experiment.


Mechanistic Insight into the Photoredox-Nickel-HAT Triple Catalyzed Arylation and Alkylation of α-Amino Csp3-H Bonds.
We report here a comprehensive computational analysis of the mechanisms of the photoredox-nickel-HAT (HAT: hydrogen atom transfer) catalyzed arylation and alkylation of α-amino Csp3-H bonds developed by MacMillan and co-workers. Different alternatives for the three catalytic cycles were tested to identify unambiguously the operative reaction mechanism. Our analysis indicated that the IrIII photoredox catalyst, upon irradiation with visible light, can be either reduced or oxidized by the HAT and nickel catalysts, respectively, indicating that both reductive and oxidative quenching catalytic cycles can be operative, although the reductive cycle is favored. Our analysis of the HAT cycle indicated that activation of a α-amino Csp3-H bond of the substrate is facile and selective relative to activation of a β-amino Csp3-H bond. Finally, our analysis of the nickel cycle indicated that both arylation and alkylation of α-amino Csp3-H bonds occurs via the sequence of nickel oxidation states NiI-NiII-NiI-NiIII and of elementary steps: radical addition-SET-oxidative addition-reductive elimination.


Role of alpha(2)-adrenoceptors in the sympathetic inhibition of motility reflexes of guinea-pig ileum.
1. Sympathetic regulation of the motility of guinea-pig ileum was investigated using mesenteric nerve (MN) stimulation to inhibit motility reflexes, in vitro. 2. Transmural electrical stimulation (5 Hz, 1 s) in intact intestinal segments, or inflation of a balloon against the mucosa in opened segments, evoked contractions of the circular and longitudinal muscles oral to the stimulus. 3. MN stimulation (10 Hz, 5 s) usually abolished contractions of the longitudinal and circular muscles evoked by either electrical or mechanical stimuli. 4. The inhibition was mimicked by UK14,304 (70-100 nM) and abolished by idazoxan (100 nM), revealing an enhancement of circular muscle contractions. There was no evidence for alpha(2)-receptors on the muscle, suggesting sympathetic inhibition was via the myenteric plexus. 5. Possible sites of action of noradrenaline released from sympathetic nerves were investigated using intracellular recordings from the circular muscle in a multichambered organ bath. 6. When in the stimulation chamber, UK14,304 depressed (by 50 %) excitatory junction potentials (EJPs) recorded oral to a distension stimulus, but did not affect inhibitory junction potentials (IJPs) recorded anal to the stimulus. When added to a chamber between the stimulus and recording chambers, UK14,304 depressed EJPs by 40 %, but did not alter IJPs. When in the recording chamber, UK14,304 depressed EJPs by 20 %, but had no effect on IJPs. IJPs were inhibited, however, when UK14,304 was applied to the whole bath. 7. It is concluded that sympathetic activity inhibits intestinal motility mainly via alpha(2)-adrenoceptors on ascending interneurons and intrinsic sensory neurons of the orally directed reflex pathway.


Orally Administered Berberine Modulates Hepatic Lipid Metabolism by Altering Microbial Bile Acid Metabolism and the Intestinal FXR Signaling Pathway.
Previous studies suggest that the lipid-lowering effect of berberine (BBR) involves actions on the low-density lipoprotein receptor and the AMP-activated protein kinase signaling pathways. However, the implication of these mechanisms is unclear because of the low bioavailability of BBR. Because the main action site of BBR is the gut and intestinal farnesoid X receptor (FXR) plays a pivotal role in the regulation of lipid metabolism, we hypothesized that the effects of BBR on intestinal FXR signaling pathway might account for its pharmacological effectiveness. Using wild type (WT) and intestine-specific FXR knockout (FXRint-/-) mice, we found that BBR prevented the development of high-fat-diet-induced obesity and ameliorated triglyceride accumulation in livers of WT, but not FXRint-/- mice. BBR increased conjugated bile acids in serum and their excretion in feces. Furthermore, BBR inhibited bile salt hydrolase (BSH) activity in gut microbiota, and significantly increased the levels of tauro-conjugated bile acids, especially tauro-cholic acid(TCA), in the intestine. Both BBR and TCA treatment activated the intestinal FXR pathway and reduced the expression of fatty-acid translocase Cd36 in the liver. These results indicate that BBR may exert its lipid-lowering effect primarily in the gut by modulating the turnover of bile acids and subsequently the ileal FXR signaling pathway. In summary, we provide the first evidence to suggest a new mechanism of BBR action in the intestine that involves, sequentially, inhibiting BSH, elevating TCA, and activating FXR, which lead to the suppression of hepatic expression of Cd36 that results in reduced uptake of long-chain fatty acids in the liver.


Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection.
It is unclear whether hepatitis C virus (HCV) has been eradicated or persists at a low level in HCV antibody-positive HCV RNA-negative individuals. The natural history and liver histology are not well characterized. One hundred seventy-two HCV antibody-positive, serum HCV RNA-negative patients underwent diagnostic liver biopsy between 1992 and 2000 and were followed a median 7 years (range, 5-12). Patients with any possible cause of liver injury other than HCV were excluded. A single histopathologist scored sections using Ishak criteria. Characterization of the inflammatory infiltrate in selected cases used a novel semiquantitative technique and compared with HCV RNA-positive patients and healthy controls. One hundred two patients were excluded because of a risk factor for liver injury other than HCV. Seventy patients met the study criteria; four (5.7%) became HCV RNA-positive during follow-up. Sixty-six cases remained HCV RNA-negative; five (7.5%) had a normal liver biopsy; 54 (82%) had fibrosis (stage 2 or 3 in 16 (24%)). Nonviremic cases revealed expanded portal tracts (P < 0.05), with fewer CD4+ (P < 0.05) and more CD8+ cells (P < 0.05) than healthy controls, but were indistinguishable from HCV RNA-positive cases for these parameters. Lobular CD4 staining, absent in healthy controls, was noted in both HCV RNA-negative and -positive cases and was more marked in the latter (P < 0.05) with a sinusoidal lining cell distribution. Nonviremic HCV antibody-positive patients have a liver biopsy that is usually abnormal. Fibrosis was present in most with similar inflammatory infiltrate to viremic cases. The presence of a CD8+ rich inflammatory infiltrate suggests an ongoing immune response in the liver, supporting the view that HCV may persist in the liver in the majority of HCV RNA-negative cases.


Excision of metastatic breast cancer from sternum and reconstruction in two patients with solitary metastatic spread.
Metastatic breast carcinoma is a relatively common clinical entity. However, the prognosis of oligometastatic and polygometastatic disease differs considerably pertaining to five-year survival. Metastatic breast carcinoma to the sternum has been described as early as 1988. We describe two cases in our institution who presented with solitary sternal metastases with a previous history of treated breast cancer. In both cases, there had been a history of previous left breast cancer treated aggressively with surgical resection and adjuvant oncological therapy and maintenance hormonal therapy. Partial sternectomy or total sternectomy for solitary metastatic sternal deposits is well established with relatively low morbidity and mortality and improvement in quality of life and possible improvement in long-term survival. Furthermore, reconstructive options are inherently dependent on extent of resection performed. These techniques can incorporate the use of sternal plates in order to approximate defects and reinforce the sternum in the setting of partial sternectomy.


Multicollinearity in Regression Analyses Conducted in Epidemiologic Studies.
The adverse impact of ignoring multicollinearity on findings and data interpretation in regression analysis is very well documented in the statistical literature. The failure to identify and report multicollinearity could result in misleading interpretations of the results. A review of epidemiological literature in PubMed from January 2004 to December 2013, illustrated the need for a greater attention to identifying and minimizing the effect of multicollinearity in analysis of data from epidemiologic studies. We used simulated datasets and real life data from the Cameron County Hispanic Cohort to demonstrate the adverse effects of multicollinearity in the regression analysis and encourage researchers to consider the diagnostic for multicollinearity as one of the steps in regression analysis.


Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade.
The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A-retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K(d)s ~2 nM and ~200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.


The effect of normal load on polytetrafluoroethylene tribology.
The tribological behavior of oriented poly(tetrafluoroethylene) (PTFE) sliding surfaces is examined as a function of sliding direction and applied normal load in classical molecular dynamics (MD) simulations. The forces are calculated with the second-generation reactive empirical bond-order potential for short-range interactions, and with a Lennard-Jones potential for long-range interactions. The range of applied normal loads considered is 5-30 nN. The displacement of interfacial atoms from their initial positions during sliding is found to vary by a factor of seven, depending on the relative orientation of the sliding chains. However, within each sliding configuration the magnitude of the interfacial atomic displacements exhibits little dependence on load over the range considered. The predicted friction coefficients are also found to vary with chain orientation and are in excellent quantitative agreement with experimental measurements.


Effect of national cultural dimensions and HIV prevalence rates on stigma towards people living with HIV/AIDS.
This paper examines the main and interactive effects of national culture dimensions and HIV prevalence rates on stigma towards people living with HIV/AIDS (PLHIVA). We examined these various relationships using data from a sample of 68,041 individuals from 49 countries, obtained from the World Values Survey. We used Hierarchical Linear Modeling to conduct our cross-level analyses. Our results indicated that collectivistic societies were positively associated while egalitarian and performance-oriented societies were negatively associated with stigma towards PLHIVA. Additionally, HIV prevalence rates interact with several cultural dimensions to worsen stigma towards PLHIVA. Our findings indicate the need to tailor stigma reduction strategies by taking the national culture dimensions of a given society into consideration when designing and implementing programs.


Postsurgical Changes in Osseous Dysmorphology of the Midface and Mandible in Unilateral Coronal Craniosynostosis.
Early management of unilateral coronal synostosis (UCS) aims to treat the cranial abnormality with the hope of improving middle and lower facial morphology. This study analyzed osseous volume and 3-dimensional distances in the midface and mandible of patients with UCS to assess changes in facial symmetry following a cranial vault procedure. Patients who underwent fronto-orbital advancement for UCS repair between 1981 and 2012 with follow-up of at least 3 years were included. Computed tomography-based 3-dimensional reconstructions of the mandible and LeFort III midface were divided by 3 midline osseous landmarks and measured for volume. Distances between 11 osseous landmarks were measured in the midface and mandible. Ratios between the measurements on synostotic and nonsynostotic sides were calculated. Presurgical to postsurgical changes were evaluated with paired samples t tests. The study was powered to detect differences between preoperative and postoperative ratios of at least 3%. Eleven patients were included. Mean age at initial imaging was 4.7 ± 3.2 months (range, 0.4-9.2 months) with postoperative follow-up of 9.0 ± 5.3 years (range, 3.3-17.0 years). Midfacial symmetry of osseous volume improved following surgery (synostotic to nonsynostotic ratio, 94.1% vs 98.9%, P = 0.044). The width (P < 0.001), height (P = 0.039), and anterior-posterior depth of the midface (P = 0.011) also became more symmetric. In the mandible, however, volumetric and linear symmetry did not improve. Symmetry of the midface, but not the mandible, improves significantly following the cranial procedure in patients with UCS.


Voltage-gated sodium channels and hyperalgesia.
Physiological and pharmacological evidence both have demonstrated a critical role for voltage-gated sodium channels (VGSCs) in many types of chronic pain syndromes because these channels play a fundamental role in the excitability of neurons in the central and peripheral nervous systems. Alterations in function of these channels appear to be intimately linked to hyperexcitability of neurons. Many types of pain appear to reflect neuronal hyperexcitability, and importantly, use-dependent sodium channel blockers are effective in the treatment of many types of chronic pain. This review focuses on the role of VGSCs in the hyperexcitability of sensory primary afferent neurons and their contribution to the inflammatory or neuropathic pain states. The discrete localization of the tetrodotoxin (TTX)-resistant channels, in particular NaV1.8, in the peripheral nerves may provide a novel opportunity for the development of a drug targeted at these channels to achieve efficacious pain relief with an acceptable safety profile.


Developing an ecologically relevant heterogeneous biofilm model for dental-unit waterlines.
This study monitored the biodiversity of microbes cultured from a heterogeneous biofilm which had formed on the lumen of a section of dental waterline tubing over a period of 910 days. By day 2 bacterial counts on the outlet-water showed that contamination of the system had occurred. After 14 days, a biofilm comparable to that of clinical waterlines, consisting of bacteria, fungi and amoebae had formed. This showed that the proprietary silver coating applied to the luminal surface of the commercial waterline tubing failed to prevent biofilm formation. Molecular barcoding of isolated culturable microorganisms showed some degree of the diversity of taxa in the biofilm, including the opportunistic pathogen Legionella pneumophila. Whilst the system used for isolation and identification of contaminating microorganisms may underestimate the diversity of organisms in the biofilm, their similarity to those found in the clinical environment makes this a promising test-bed for future biocide testing.


Current advances of stem cell-based therapy for kidney diseases.
Kidney diseases are a prevalent health problem around the world. Multidrug therapy used in the current routine treatment for kidney diseases can only delay disease progression. None of these drugs or treatments can reverse the progression to an end-stage of the disease. Therefore, it is crucial to explore novel therapeutics to improve patients' quality of life and possibly cure, reverse, or alleviate the kidney disease. Stem cells have promising potentials as a form of regenerative medicine for kidney diseases due to their unlimited replication and their ability to differentiate into kidney cells in vitro. Mounting evidences from the administration of stem cells in an experimental kidney disease model suggested that stem cell-based therapy has therapeutic or renoprotective effects to attenuate kidney damage while improving the function and structure of both glomerular and tubular compartments. This review summarises the current stem cell-based therapeutic approaches to treat kidney diseases, including the various cell sources, animal models or in vitro studies. The challenges of progressing from proof-of-principle in the laboratory to widespread clinical application and the human clinical trial outcomes reported to date are also highlighted. The success of cell-based therapy could widen the scope of regenerative medicine in the future.


Improved automatic detection and segmentation of cell nuclei in histopathology images.
Automatic segmentation of cell nuclei is an essential step in image cytometry and histometry. Despite substantial progress, there is a need to improve accuracy, speed, level of automation, and adaptability to new applications. This paper presents a robust and accurate novel method for segmenting cell nuclei using a combination of ideas. The image foreground is extracted automatically using a graph-cuts-based binarization. Next, nuclear seed points are detected by a novel method combining multiscale Laplacian-of-Gaussian filtering constrained by distance-map-based adaptive scale selection. These points are used to perform an initial segmentation that is refined using a second graph-cuts-based algorithm incorporating the method of alpha expansions and graph coloring to reduce computational complexity. Nuclear segmentation results were manually validated over 25 representative images (15 in vitro images and 10 in vivo images, containing more than 7400 nuclei) drawn from diverse cancer histopathology studies, and four types of segmentation errors were investigated. The overall accuracy of the proposed segmentation algorithm exceeded 86%. The accuracy was found to exceed 94% when only over- and undersegmentation errors were considered. The confounding image characteristics that led to most detection/segmentation errors were high cell density, high degree of clustering, poor image contrast and noisy background, damaged/irregular nuclei, and poor edge information. We present an efficient semiautomated approach to editing automated segmentation results that requires two mouse clicks per operation.


Treatment of localised renal cell carcinoma.
The increasing incidence of localised renal cell carcinoma (RCC) over the last 3 decades and controversy over mortality rates have prompted reassessment of current treatment. To critically review the recent data on the management of localised RCC to arrive at a general consensus. A Medline search was performed from January 1, 2004, to May 3, 2011, using renal cell carcinoma, nephrectomy (Medical Subject Heading [MeSH] major topic), surgical procedures, minimally invasive (MeSH major topic), nephron-sparing surgery, cryoablation, radiofrequency ablation, surveillance, and watchful waiting. Initial active surveillance (AS) should be a first treatment option for small renal masses (SRMs) <4 cm in unfit patients or those with limited life expectancy. SRMs that show fast growth or reach 4 cm in diameter while on AS should be considered for treatment. Partial nephrectomy (PN) is the established treatment for T1a tumours (<4 cm) and an emerging standard treatment for T1b tumours (4-7 cm) provided that the operation is technically feasible and the tumour can be completely removed. Radical nephrectomy (RN) should be limited to those cases where the tumour is not amenable to nephron-sparing surgery (NSS). Laparoscopic radical nephrectomy (LRN) has benefits over open RN in terms of morbidity and should be the standard of care for T1 and T2 tumours, provided that it is performed in an advanced laparoscopic centre and NSS is not applicable. Open PN, not LRN, should be performed if minimally invasive expertise is not available. At this time, there is insufficient long-term data available to adequately compare ablative techniques with surgical options. Therefore ablative therapies should be reserved for carefully selected high surgical risk patients with SRMs <4 cm. The choice of treatment for the patient with localised RCC needs to be individualised. Preservation of renal function without compromising the oncologic outcome should be the most important goal in the decision-making process.


Sex Ideologies in China: Examining Interprovince Differences.
In recent decades, premarital sex, extramarital sex, and homosexuality have become increasingly visible in China, leading scholars to claim that a national "sex revolution" is under way. However, China's internal sociocultural diversity calls this nation-level generalization into question. How do sex ideologies vary across China's distinct provinces? To what extent are interprovince variations in sex ideologies associated with distinct macrolevel social factors in China? In this research, data from the 2010 China General Social Survey and the 2011 Chinese Statistics Yearbook were analyzed using multilevel models to test four contending theories of interprovince differences in sex ideologies in China: modernization, Westernization, deindustrialization, and the "rice theory." The modernization theory was unsupported by the results, as socioeconomic development is not significantly associated with sex ideologies. Higher levels of deindustrialization and Westernization were associated with less traditional sex ideologies, but the strength of association varied across the domains of premarital sex, extramarital sex, and homosexuality. The rice theory was consistently supported, as the distinction between rice and wheat agriculture explained up to 30% of the province-level variance in sex ideologies. The findings underline the roles of both long-standing geographic differences and recent social changes in shaping China's ideational landscape of sex.


Hot mixing: Mechanistic insights into the durability of ancient Roman concrete.
Ancient Roman concretes have survived millennia, but mechanistic insights into their durability remain an enigma. Here, we use a multiscale correlative elemental and chemical mapping approach to investigating relict lime clasts, a ubiquitous and conspicuous mineral component associated with ancient Roman mortars. Together, these analyses provide new insights into mortar preparation methodologies and provide evidence that the Romans employed hot mixing, using quicklime in conjunction with, or instead of, slaked lime, to create an environment where high surface area aggregate-scale lime clasts are retained within the mortar matrix. Inspired by these findings, we propose that these macroscopic inclusions might serve as critical sources of reactive calcium for long-term pore and crack-filling or post-pozzolanic reactivity within the cementitious constructs. The subsequent development and testing of modern lime clast-containing cementitious mixtures demonstrate their self-healing potential, thus paving the way for the development of more durable, resilient, and sustainable concrete formulations.


A Review of AI-Based Radiomics and Computational Pathology Approaches in Triple-Negative Breast Cancer: Current Applications and Perspectives.
Breast cancer is one of the most common and deadly cancers worldwide. Approximately, 20% of all breast cancers are characterized as triple negative (TNBC). TNBC typically is associated with a poorer prognosis relative to other breast cancer subtypes. Due to its aggressiveness and lack of response to hormonal therapy, conventional cytotoxic chemotherapy is the usual treatment; however, this treatment is not always effective, and an important percentage of patients develop recurrence. More recently, immunotherapy has started to be used on some populations with TNBC showing promising results. Unfortunately, immunotherapy is only applicable to a minority of patients and responses in metastatic TNBC have overall been modest in comparison to other cancer types. This situation evidences the need for developing effective biomarkers that help to stratify and personalize patient management. Thanks to recent advances in artificial intelligence (AI), there has been an increasing interest in its use for medical applications aiming at supporting clinical decision making. Several works have used AI in combination with diagnostic medical imaging, more specifically radiology and digitized histopathological tissue samples, aiming to extract disease-specific information that is difficult to quantify by the human eye. These works have demonstrated that analysis of such images in the context of TNBC has great potential for (1) risk-stratifying patients to identify those patients who are more likely to experience disease recurrence or die from the disease and (2) predicting pathologic complete response. In this manuscript, we present an overview on AI and its integration with radiology and histopathological images for developing prognostic and predictive approaches for TNBC. We present state of the art approaches in the literature and discuss the opportunities and challenges with developing AI algorithms regarding further development and clinical deployment, including identifying those patients who may benefit from certain treatments (e.g., adjuvant chemotherapy) from those who may not and thereby should be directed toward other therapies, discovering potential differences between populations, and identifying disease subtypes.


Peripartal rumination dynamics and health status in cows calving in hot and cool seasons.
Our objective was to evaluate the effect of season of calving, associated with variable levels of heat stress, on the dynamics of rumination during the prepartum period and early lactation of cows that were healthy or affected by peripartal health disorders. Three weeks before the estimated due date, 210 multiparous Holstein cows at the University of Florida Dairy Unit were affixed with a neck collar containing rumination loggers, providing rumination time (RT) in 2-h periods. One blood sample was collected in a subpopulation of cows (n=76) at 12 to 48h postcalving to assess metabolic status by determining serum calcium, nonesterified fatty acid, and β-hydroxybutyrate concentrations. The occurrence of peripartal health disorders (dystocia, clinical ketosis, clinical hypocalcemia, metritis, and mastitis) was assessed by University of Florida veterinarians and trained farm personnel. We analyzed the dynamics of daily RT over ± 14d relative to parturition in cows that were healthy or affected by specific health disorders by season of calving [hot season, June to September (n=77); cool season, November to April (n=118)] using repeated measures analysis and comparison of least squares means at different time points relative to calving. Rumination was consistently reduced on the day of calving in both healthy and sick cows in both the hot and cool seasons. Only hot-season calvings had shorter average daily RT prepartum and postpartum in cows affected by severe negative energy balance and subclinical ketosis. Dystocia during the hot season was associated with shorter daily RT prepartum; for cool-season calvings, cows with dystocia had reduced RT postpartum. We also observed reduced RT in cows with ketosis prepartum and postpartum in both the hot and cool seasons. Daily RT was reduced postpartum in cows with hypocalcemia and mastitis that calved during the cool season, and it was shorter in cows with metritis in both the hot and cool seasons. Our results indicated that the effect of heat stress on changes in rumination patterns around calving for sick cows depends on the specific health disorder or metabolic condition.


Recent Advances on O-Ethoxycarbonyl and O-Acyl Protected Cyanohydrins.
Ethoxycarbonyl cyanohydrins and O-acyl cyanohydrins are examples of O-protected cyanohydrins in which the protecting group presents an electrophilic center, contributing to additional reaction pathways. The first section of this review describes recent advances on the synthesis of O-ethoxycarbonyl and O-acyl protected cyanohydrins. Reactions using KCN or alkyl cyanoformates as the cyanide ion source are described, as well as organic and transition metal catalysis used in their preparation, including asymmetric cyanation. In a second part, transformations, and synthetic applications of O-ethoxycarbonyl/acyl cyanohydrins are presented. A variety of structures has been obtained starting from such protected cyanohydrins and, in particular, the synthesis of oxazoles, 1,4-diketones, 1,3-diketones, 2-vinyl-2-cyclopentenones through various methods are discussed.


Physician receptivity to nurse practitioners: a study of the correlates of the delegation of clinical responsibility.
A survey to measure physician receptivity to nurse practitioners was conducted in North Carolina in 1973. All North Carolina physicians were asked to rate a list of 35 clinical tasks of varying levels of difficulty and responsibility according to their willingness to delegate these tasks to nurse practitioners. Using eight items from this list that were good discriminants of physician attitudes towards delegating responsibility, task delegation scores were correlated with physician characteristics and their responses to questions about recruitment, training, reimbursement, and willingness to hire nurse practitioners. Thirty-four per cent of the respondents would hire a nurse practitioner, whereas 52% approved of the concept but would not hire one. Physicians who had previously worked with a nurse practitioner were more willing to hire one and had a higher task delegation score. Sixty-eight per cent of respondents would share their load with nurse practitioners in their offices, while 6% would have them work in satellite clinics away from the physicians' offices. Most physicians wanted their own nurse trained as a nurse practitioner in a program that combined a didactic course at a medical center with on-the-job training. The authors conclude that there is a potential demand for nurse practitioners in North Carolina and that the training program must prepare the nurse practitioners for the tasks physicians are willing to delegate to them.


Weight change from childhood to adulthood and cardiovascular risk factors and outcomes in adulthood: A systematic review of the literature.
The magnitude of the associations between life-course change in weight status and health outcomes in adulthood has been inconsistent. This study aims to examine the associations between weight change from childhood to adulthood and cardiovascular disease (CVD) risk factors and outcomes in adulthood. PubMed, Embase and ISI Web of Science between 1 August 1953 and 13 July 2020 were searched, and a total of 52 eligible articles were included. The systematic review supported significant associations between the life-course increase in BMI and high odds of markers in adulthood. In the meta-analyses, normal weight in childhood but excess weight in adulthood or persistent excess weight was associated with increased odds of adult markers. However, those who had excess weight in childhood but were normal weight in adulthood did not have increased odds of nearly all adult markers. This systematic review and meta-analysis suggest that individuals who developed excess weight in adulthood or had excess weight in both periods had higher odds of developing CVD risk factors and outcomes in adulthood. In contrast, the probability of these adult markers could be limited or eliminated for children with excess weight who are able to become adults with normal weight.