Primary Langerhans Cell Histiocytosis of the Extrahepatic Bile Duct Occurring in an Adult Patient
Langerhans cell histiocytosis is characterized by an abnormal proliferation of neoplastic Langerhans cells. Langerhans cell histiocytosis commonly affects the pediatric population, whereas presentation in adults remains a rare event. The presentation of Langerhans cell histiocytosis is highly variable, but the involvement of skin, bone, and lung is very common. Langerhans cell histiocytosis presenting as a bile duct mass is rare and usually occurs as part of a multiorgan system disease. We present a case of Langerhans cell histiocytosis confined to the extrahepatic bile duct in a 62-year-old female patient with sclerosing cholangitis. The mass was composed of mononuclear cells with cleaved nuclei that were positive for CD68, S100, and CD1a as assessed by immunohistochemistry. This is the first report of Langerhans cell histiocytosis limited to the extrahepatic bile duct in an adult patient. We discuss the clinical manifestations and the challenges encountered in the diagnosis and treatment of this rare entity.


Revealing soil legacy phosphorus to promote sustainable agriculture in Brazil.
Exploiting native soil phosphorus (P) and the large reservoirs of residual P accumulated over decades of cultivation, namely "legacy P", has great potential to overcome the high demand of P fertilisers in Brazilian cropping systems. Long-term field experiments have shown that a large proportion (> 70%) of the surplus P added via fertilisers remains in the soil, mainly in forms not readily available to crops. An important issue is if the amount of legacy P mobilized from soil is sufficient for the crop nutritional demand and over how long this stored soil P can be effectively 'mined' by crops in a profitable way. Here we mapped the spatial-temporal distribution of legacy P over the past 50 years, and discussed possible agricultural practices that could increase soil legacy P usage by plants in Brazil. Mineral fertiliser and manure applications have resulted in ~ 33.4 Tg of legacy P accumulated in the agricultural soils from 1967 to 2016, with a current annual surplus rate of 1.6 Tg. Following this same rate, soil legacy P may reach up to 106.5 Tg by 2050. Agricultural management practices to enhance soil legacy P usage by crops includes increasing soil pH by liming, crop rotation, double-cropping, inter-season cover crops, no-tillage system and use of modern fertilisers, in addition to more efficient crop varieties and inoculation with P solubilising microorganisms. The adoption of these practices could increase the use efficiency of P, substantially reducing the new input of fertilisers and thus save up to 31.8 Tg of P fertiliser use (US$ 20.8 billion) in the coming decades. Therefore, exploring soil legacy P is imperative to reduce the demand for mineral fertilisers while promoting long-term P sustainability in Brazil.


Polypeptide-b-Poly(Phenyl Isocyanide) Hybrid Rod-Rod Copolymers: One-Pot Synthesis, Self-Assembly, and Cell Imaging.
Hybrid rod-rod diblock copolymers, poly(γ-benzyl L-glutamate)-poly(4-cyano-benzoic acid 2-isopropyl-5-methyl-cyclohexyl ester) (PBLG-PPI), with determined chirality are facilely synthesized through sequential copolymerization of γ-benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) and phenyl isocyanide monomers bearing chiral menthyl pendants using a Ni(cod)(bpy) complex as the catalyst in one-pot. Circular dichroism and absorption spectra reveal that each block of the block copolymers possesses a stable helical conformation with controlled helicity in solution due to the induction of chiral pendants. The two diastereomeric polymers self-assemble into helical nanofibrils with opposite handedness due to the different chiral induction of the L- and D-menthyl pendants, confirmed by transmission electron microscopy (TEM). Deprotection of the benzyl groups of the PBLG segment affords biocompatible amphiphilic diblock copolymers, poly(L-glutamic acid)-poly(4-cyano-benzoic acid 2-isopropyl-5-methyl-cyclohexyl ester) (PLGA-PPI), that can self-assemble into well-defined micelles by cosolvent induced aggregation. Very interestingly, a chiral rhodamine chromophores RhB(D) can be selectively encapsulated into the chiral polymeric micelles, which is efficiently internalized into living cells when directly monitored with a confocal microscope. This contribution will be useful for developing novel rod-rod biocompatible hybrid block copolymers with a controlled helicity, and may also provide unique chiral materials for potential bio-medical applications.


[Bile acids in duodenal juice of infants and children. Normal values, lognormal distribution, and age-dependence of the total quantity and the distribution of bile acids (author's transl)].
43 gastroenterologically healthy infants and children were investigated during the basic secretion period and after the injection of secretin/pankreozymin in order to establish the total quantity and also the distribution of the secreted bile acids. The total concentration and quantity were enzymatically determined while column and thin-layer chromatography were utilized to separate the bile into 34 different bile acids. Quantified results for bile salts were read directly from the thin-layer sheet with the help of a Chromatogram-Spectrophotometer Zeiss KM 3. While the total quantity of bile acids was found to be independent of age, the composition of bile changed during the first years of life. The percentage of cholic acids decreased from 50% in infants to 35% in older children. At the same time, deoxycholic acids went up from 3% to 13%, and chenodeoxycholic acids increased by 5%. The percentage of glycine and taurine conjugated bile salts, however, remained constant after to the second month of life, the former at 58% and the latter at 35%. In comparison, rather small amounts of unconjugated acids and sulfates were secreted, 0,5% and 6% respectively. The latter were distributed in the same sequence as the nonsulfated bile acids. Lithocholic acids (2,6%) and ursodeoxycholic acids (4,3%) were regularly present in the intestinal secretion.


[Update of enteral nutrition at the patient's home].
Home enteral nutrition is the administration of enteral formulae into the digestive tract using a tube, with the objective of preventing or correcting malnutrition patients who are seen at home. Home enteral nutrition is a type of nutritional support that is growing, that improves the nutritional status of the patient with a lower cost and with a greater quality of life of the family unit than enteral nutrition in the hospital. The prevalence is clearly increasing although the data of the national registers of patients with at home enteral nutrition are under estimated. Patients who are candidates for home enteral nutrition can be all those with an indication for enteral nutrition and whose underlying disease is stabilized or does not require all the technical means of the hospital in a permanent and essential manner. Neoplasias and neurological diseases are those that benefit most from at home enteral nutrition and in all registries each group varies between 30 and 40%. All access routes and all enteral nutrition formulae can be used in patients with home enteral nutrition. The use of percutaneous endoscopic gastrostomies is ever more recommended in patients who need at home enteral nutrition for a period longer than 4 weeks. Since the publication of the Ministerial Order of June 2nd 1998, home enteral nutrition is considered a health care service that can be covered by the Social Security. This order lists a series of disease that are likely to be treated with at home enteral nutrition (in our opinion the list is not complete but it is likely to be changed in the future by an Assessing Committee), and it presents some basic norms that all patients must comply with, regardless of the autonomous community in which they live. Before beginning at home enteral nutrition the training of the patient and/or the family with regard to the management of at home enteral nutrition is essential. The existence of qualified personnel with experience in this nutritional support technique, as well as the collaboration between Primary Care and Specialized Care (Clinical Nutrition Units if these exist in the health care area) is essential for the control and follow up of the patient with at home enteral nutrition.


Immunoglobulin E synthesis in parasite infection.
The infection of rats with Nippostrongylus brasiliensis (Nb) larvae enhanced IgE synthesis prior to the formation of IgE antibody specific for parasite antigens. As early as the eighth to tenth day of infection, IgE-bearing lymphocytes appeared in lymph nodes and spleen. At this time, even bone marrow contained IgE-bearing blast cells. The IgE-forming plasma cells were detected in the lymph nodes and spleen at the tenth day and their number reached maximum at the fourteenth day. The proliferation of IgE-bearing lymphocytes in the lymphoid tissues was observed in neonatally thymectomized animals, indicating that T cells are not essential for the development of IgE-B cells in the infected animals. It appears, however, that T cells are involved in the differentiation of IgE-B cells to IgE-forming plasma cells. Nonspecific proliferation of IgE-B cells and their differentiation to IgE-forming plasma cells may explain potentiation of IgE antibody formation against unrelated antigens after infection with N. brasiliensis (Nb). It was also found that T cells specific for parasite antigens were primed by infection with Nb. Evidence was obtained tht Nb-specific T cells raised by the infection collaborated with hapten-specific IgE-B cells and IgG-B cells for the secondary antihapten antibody responses. By contrast, T cells primed by immunization with parasite antigen included in alum exerted the helper function for IgG antibody response but failed to collaborate with IgE-B cells. Dissociation between the helper function for IgE and IgG antibody response indicated that parasite infection generated a favorable condition for priming T cells for the IgE antibody response.


Dietary oxalate and kidney stone formation.
Dietary oxalate is plant-derived and may be a component of vegetables, nuts, fruits, and grains. In normal individuals, approximately half of urinary oxalate is derived from the diet and half from endogenous synthesis. The amount of oxalate excreted in urine plays an important role in calcium oxalate stone formation. Large epidemiological cohort studies have demonstrated that urinary oxalate excretion is a continuous variable when indexed to stone risk. Thus, individuals with oxalate excretions >25 mg/day may benefit from a reduction of urinary oxalate output. The 24-h urine assessment may miss periods of transient surges in urinary oxalate excretion, which may promote stone growth and is a limitation of this analysis. In this review we describe the impact of dietary oxalate and its contribution to stone growth. To limit calcium oxalate stone growth, we advocate that patients maintain appropriate hydration, avoid oxalate-rich foods, and consume an adequate amount of calcium.


Amniotic fluid and fetal maturity.
The lecithin/sphingomyelin ratio in amniotic fluid is a method of predicting fetal lung maturity. The L/H ratios in certain high risk pregnancies are poorly correlated with the shake test. The L/S ratios in drug addiction methadone pregnancies and diabetic pregnancies do not have a high degree of correlation with normal L/S ratios after 36 weeks of gestation and are often low.


UV-Induced Adenine Radicals Induced in DNA A-Tracts: Spectral and Dynamical Characterization.
Adenyl radicals generated in DNA single and double strands, (dA)20 and (dA)20·(dT)20, by one- and two-photon ionization by 266 nm laser pulses decay at 600 nm with half-times of 1.0 ± 0.1 and 4 ± 1 ms, respectively. Though ionization initially forms the cation radical, the radicals detected for (dA)20 are quantitatively identified as N6-deprotonated adenyl radicals by their absorption spectrum, which is computed quantum mechanically employing TD-DFT. Theoretical calculations show that deprotonation of the cation radical induces only weak spectral changes, in line with the spectra of the adenyl radical cation and the deprotonated radical trapped in low temperature glasses.


TGFB1-induced autophagy affects the pattern of pancreatic cancer progression in distinct ways depending on SMAD4 status.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Given that macroautophagy/autophagy activation is prevalent in PDAC, the dual roles of autophagy could be involved in PDAC heterogeneity. In this work, we demonstrated that TGFB1 induced autophagic flux through SMAD4-dependent or SMAD4-independent pathways based on a distinct genetic context. In SMAD4-positive PDAC cells, TGFB1-induced autophagy promoted proliferation and inhibited migration by decreasing the nuclear translocation of SMAD4. Conversely, TGFB1-induced autophagy inhibited proliferation and promoted migration in SMAD4-negative cells through the regulation of MAPK/ERK activation. TGFB1 expression also positively correlated with LC3B expression in PDAC specimens. A high level of LC3B was associated with unfavorable overall survival (OS) and disease-free survival (DFS) in SMAD4-negative PDAC patients, although LC3B could not predict OS and DFS for the 110 PDAC patients. Thus, TGFB1-induced autophagy contributed to the different patterns of PDAC progression. This knowledge can aid in improving our understanding of the molecular classification of PDAC and might guide the development of therapeutic strategies for PDAC, especially for SMAD4-negative PDAC.Abbreviations: CDH1: cadherin 1; CDH2: cadherin 2; CI: combination index; CQ: chloroquine; DFS: disease-free survival; EMT: epithelial-to-mesenchymal transition; ERK: extracellular signal-regulated protein kinase; GFP: green fluorescent protein; IHC: immunohistochemistry; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK: mitogen-activated protein kinase; OS: overall survival; PBS: phosphate-buffered saline; PDAC: pancreatic ductal adenocarcinoma; RAP: rapamycin; RFP: red fluorescent protein; RT: room temperature; shRNA: short-hairpin RNA; SQSTM1: sequestosome 1; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TGFB1: transforming growth factor beta 1; TMA: tissue microarray.


In vitro and in vivo evaluation in dogs of a miniaturized glucose sensor.
A miniaturized glucose sensor was developed, consisting of a platinum wire entirely coated with teflon, except for a 1 mm section near its extremity where glucose oxidase is immobilized. The in vitro sensitivity to glucose of the sensors was 2.3 +/- 0.4 nA/mM, mean +/- SEM (n = 23). These sensors were implanted in the subcutaneous tissue of normal beagles. Two consecutive glucose infusions (15-30 mg/kg/min) were performed. The current generated by the sensor was used for calculation of the sensitivity coefficient (SC) (nA/mM), and the background current in the absence of glucose (lo) (nA). These parameters were used for determination of the apparent subcutaneous glucose concentration. The in vivo sensitivity was less than the in vitro sensitivity (0.5 +/- 0.1 vs. 2.2 +/- 0.2; n = 12 comparisons; p less than 0.01). Stability of sensor function was demonstrated by the absence in variation of SC and lo, calculated from the different plateaus obtained during the glucose infusions. This study provides a simple method for evaluating in vivo the function of a miniaturized sensor implanted in subcutaneous tissue.


Estrogen-receptor--DNA interaction. Difference between activation by estrogen and antiestrogen.
We have compared the interaction of the cytosol estrogen receptor with calf thymus DNA after its binding to [3H]estradiol or 4-hydroxy[3H]tamoxifen, a high-affinity antiestrogen, in an attempt to find a difference in the nature of these two complexes. The activation of the receptor and its binding to DNA were simultaneously obtained during an 18-h incubation at 0 degree C. The binding of a constant concentration of estrogen receptor to increasing concentrations of adsorbed DNA was examined. Scatchard representation of the data showed that the antiestrogen--receptor complex has a twofold lower affinity for DNA than the estradiol--receptor complex, while the proportion of receptor able to bind DNA was the same whether bound to estradiol or antiestrogen. Similar results were obtained by using soluble DNA and separation of the unbound and DNA-bound receptor on sucrose gradients. These results indicate that the estrogen receptor binds in vitro to non-specific double-stranded DNA with a lower affinity when it has been activated by an antiestrogen than when activated by estradiol.


Monte Carlo simulation of large electron fields.
Two Monte Carlo systems, EGSnrc and Geant4, the latter with two different 'physics lists,' were used to calculate dose distributions in large electron fields used in radiotherapy. Source and geometry parameters were adjusted to match calculated results to measurement. Both codes were capable of accurately reproducing the measured dose distributions of the six electron beams available on the accelerator. Depth penetration matched the average measured with a diode and parallel-plate chamber to 0.04 cm or better. Calculated depth dose curves agreed to 2% with diode measurements in the build-up region, although for the lower beam energies there was a discrepancy of up to 5% in this region when calculated results are compared to parallel-plate measurements. Dose profiles at the depth of maximum dose matched to 2-3% in the central 25 cm of the field, corresponding to the field size of the largest applicator. A 4% match was obtained outside the central region. The discrepancy observed in the bremsstrahlung tail in published results that used EGS4 is no longer evident. Simulations with the different codes and physics lists used different source energies, incident beam angles, thicknesses of the primary foils, and distance between the primary and secondary foil. The true source and geometry parameters were not known with sufficient accuracy to determine which parameter set, including the energy of the source, was closest to the truth. These results underscore the requirement for experimental benchmarks of depth penetration and electron scatter for beam energies and foils relevant to radiotherapy.


Synthesis and molecular recognition studies of the HNK-1 trisaccharide and related oligosaccharides. The specificity of monoclonal anti-HNK-1 antibodies as assessed by surface plasmon resonance and STD NMR.
The human natural killer cell carbohydrate, HNK-1, plays function-conducive roles in peripheral nerve regeneration and synaptic plasticity. It is also the target of autoantibodies in polyneuropathies. It is thus important to synthesize structurally related HNK-1 carbohydrates for optimizing its function-conducive roles, and for diagnosis and neutralization of autoantibodies in the fatal Guillain-Barré syndrome. As a first step toward these goals, we have synthesized several HNK-1 carbohydrate derivatives to assess the specificity of monoclonal HNK-1 antibodies from rodents: 2-aminoethyl glycosides of selectively O-sulfated trisaccharide corresponding to the HNK-1 antigen, its nonsulfated analogue, and modified structures containing 3-O-fucosyl or 6-O-sulfo substituents in the N-acetylglucosamine residues. These were converted, together with several related oligosaccharides, into biotin-tagged probes to analyze the precise carbohydrate specificity of two anti-HNK-1 antibodies by surface plasmon resonance that revealed a crucial role of the glucuronic acid in antibody binding. The contribution of the different oligosaccharide moieties in the interaction was shown by saturation transfer difference (STD) NMR of the complex consisting of the HNK-1 pentasaccharide and the HNK-1 412 antibody.


Fidelity of the quantum δ-kicked accelerator.
The sensitivity of the fidelity in the kicked rotor to an acceleration is experimentally and theoretically investigated. We used a Bose-Einstein condensate exposed to a sequence of pulses from a standing light wave followed by a single reversal pulse in which the standing wave was shifted by half a wavelength. The features of the fidelity "spectrum" as a function of acceleration are presented. This work may find applications in the measurement of temperature of an ultracold atomic sample.


Integrating Models to Quantify Environment-Mediated Drug Resistance.
Drug resistance is the single most important driver of cancer treatment failure for modern targeted therapies, and the dialog between tumor and stroma has been shown to modulate the response to molecularly targeted therapies through proliferative and survival signaling. In this work, we investigate interactions between a growing tumor and its surrounding stroma and their role in facilitating the emergence of drug resistance. We used mathematical modeling as a theoretical framework to bridge between experimental models and scales, with the aim of separating intrinsic and extrinsic components of resistance in BRAF-mutated melanoma; the model describes tumor-stroma dynamics both with and without treatment. Integration of experimental data into our model revealed significant variation in either the intensity of stromal promotion or intrinsic tissue carrying capacity across animal replicates. Cancer Res; 77(19); 5409-18. ©2017 AACR.


Doping is a threat to sporting excellence.
Savulescu et al have argued that the risk to athletes' welfare provides the only legitimate ground for restricting the use of performance enhancing drugs in sport. In this paper, it is argued that the idea of `sport', properly understood, provides further reason to impose such restrictions. A `balance of excellences' argument is proposed whereby doping is considered objectionable on account of its disrupting the relation between the excellences around which sporting competition is organised. We have reason to restrict the use of performance enhancing drugs in sport not only because of the threat they pose to athletes' health but also because of the threat they pose to athletes' displaying the relevant types of sporting excellence.


[Nocardia farcinica: life-threatening chorioiditis under systemic immunosuppression].
Immunosuppressed patients occasionally suffer from a multifocal infection with Nocardia. It is important to distinguish Nocardia farcinica from Nocardia asteroides, because of different sensitivity against antibiotics. A 40-year-old patient with polycystic renal disease successfully underwent a kidney transplantation without complications. Immunosuppression consisted of: corticosteroids, azathioprin and ciclosporin A. Ten weeks later he developed acute choroiditis with consecutive retinal detachment and neovascular glaucoma in one eye. In addition, 14 weeks after transplantation CT scans revealed multiple cerebral abscesses. In the course of the disease Nocardia farcinica (N. f.) was identified by cerebral stereotactic biopsy of a cerebral lesion, histological examination of the enucleated globe and sputum culture. Histologically filamentous, eosinophilic organisms were found. Microbiology identified aerobic actinomycetes in cultures and Nocardia farcinica by PCR. Therapeutically the combination of vancomycin, ampicillin, and sulbactam was successful. In immunosuppressed patients Nocardia farcinica can become life-threatening. One of the first manifestations may be a choroiditis. Infection of the respiratory tract followed by hematogenous spread is the common way of systemic nocardiosis. Biopsy followed by identification of species by PCR is recommended because of the specific therapeutic strategies associated with each species.


Evaluating the Mental Health Impacts of the COVID-19 Pandemic in Urban South Africa: Perceived Risk of COVID-19 Infection and Childhood Trauma Predict Adult Depressive Symptoms.
South Africa's national lockdown introduced serious threats to public mental health in a society where one in three individuals develop a psychiatric disorder during their life. We aimed to evaluate the mental health impacts of the COVID-19 pandemic using a mixed methods design. This longitudinal study drew from a preexisting sample of 957 adults living in Soweto, a major township near Johannesburg. Psychological assessments were administered across two waves: between August 2019-March 2020 and during the first six weeks of the lockdown (late March-early May 2020). Interviews on COVID-19 experiences were administered in the second wave. Multiple regression models examined relationships between perceived COVID-19 risk and depression. Full data on perceived COVID-19 risk, depression, and covariates were available in 221 adults. 14.5% of adults were at risk for depression. Higher perceived COVID-19 risk predicted greater depressive symptoms (p < 0.001) particularly among adults with histories of childhood trauma, though this effect was marginally significant (p = 0.062). Adults were two times more likely to experience significant depressive symptoms for every one unit increase in perceived COVID-19 risk (p = 0.016; 95% CI [1.14, 3.49]). Qualitative data identified potent experiences of anxiety, financial insecurity, fear of infection, and rumination. Higher perceived risk of COVID-19 infection is associated with greater depressive symptoms among adults with histories of childhood trauma during the first six weeks of quarantine. High rates of severe mental illness and low availability of mental healthcare amidst COVID-19 emphasize the need for immediate and accessible psychological resources in South Africa.


Antibody response to long-term and high-dose mould-exposed sawmill workers.
Exposure to moulds is thought to cause adverse health effects ranging from vague subjective symptoms to allergy and respiratory diseases. Until now, most studies have been emphasizing low levels of exposure. In Norwegian sawmills during the 1980s, extensively high spore counts up to 10(7) spores/m3 air were reported. By using serum samples obtained from sawmill workers during that period, in addition to control sera, we studied the antibody response of all classes and IgG subclasses to Rhizopus microsporus at different levels of exposure. Antigen specificity was further studied by Western blotting. Exposure to R. microsporus was accompanied by R. microsporus-specific antibody production against a wide range of antigenic components most likely of both protein and carbohydrate nature. Increasing levels of mould-specific IgG1, IgG2, IgG4 and IgA antibodies were associated with increased exposure, while the highest levels of exposure were associated with a somewhat reduced level of mould-specific IgE antibodies. In conclusion, the present study strongly suggests that high mould exposure can induce a strong IgG and IgA response in a dose-dependent manner.


Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation.
Deletion 1p36 syndrome is a recently delineated disorder, considered to be the most common subtelomeric microdeletion syndrome (1 in 5000 newborns). 1p36.3 deletions account for 0.5% to 1.2% of idiopathic mental retardation; thus, knowledge about the condition is important for pediatricians caring for such patients. Despite 100 reported cases, little is known about its natural history. Our aim was to delineate the natural history of deletion 1p36 and develop complete and accurate information with which to answer families' questions in the clinical setting. We evaluated 60 patients with the 1p36 deletion syndrome (41 female, 19 male). All underwent physical and neurologic assessments, and most received a psychological evaluation. Standard cytogenetics, fluorescence in situ hybridization of the subtelomeric regions, or array comparative genomic hybridization were used for diagnosis. Fourteen cases were detected by standard cytogenetics, and 46 were detected by fluorescence in situ hybridization of the subtelomeric regions or array comparative genomic hybridization. Occipitofrontal circumference was at < or = 2nd centile in 95%, and height and weight ranged between the < 3rd and 90th centiles. All patients had straight eyebrows, deep-set eyes, midface hypoplasia, broad nasal root/bridge, long philtrum, and pointed chin. Other features included microbrachycephaly (65%), epicanthus (50%), large, late-closing anterior fontanel (77%), and posteriorly rotated, low-set, abnormal ears (40%). Brachy/camptodactyly and short feet were prominent. Seventy-one percent exhibited heart defects, including 23% with a "noncompaction cardiomyopathy." Fifty-two percent had eye/visual abnormalities, and 64% had visual inattentiveness. Twenty-eight percent had sensorineural deafness, 41% had skeletal anomalies, 25% had abnormal genitalia, and 22% had renal abnormalities. Eighty-eight percent had central nervous system anomalies, and 44% had seizures. All patients demonstrated developmental delay with poor/absent speech; 95% had hypotonia. Twenty-six percent were able to walk alone, and 47% had a behavior disorder. Constant developmental progress was observed in all cases over time. Noncompaction cardiomyopathy and most seizures were controlled by pharmacotherapy. These 60 patients with deletion 1p36 represent the largest clinical series to date and provide new information on several aspects of this disorder, which is characterized by neurodevelopmental disability and a recognizable pattern of malformation.


CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition.
Pharmacologic expansion of endogenous β cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1A and 1B inhibition. In contrast to rat β cells, which were broadly growth responsive to compound treatment, human β-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase-3β (GSK-3β) or activin A receptor type II-like kinase/transforming growth factor-β (ALK5/TGF-β) inhibition. Prior work emphasized DYRK1A/B inhibition-dependent activation of nuclear factor of activated T cells (NFAT) as the primary mechanism of human β-cell-replication induction. However, inhibition of NFAT activity had limited effect on CC-401-induced β-cell replication. Consequently, we investigated additional effects of CC-401-dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A-dependent phosphorylation/stabilization of the β-cell-replication inhibitor p27Kip1. Additionally, CC-401 increased expression of numerous replication-promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multivulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control β-cell replication and leverage a DYRK1A/B inhibitor (CC-401) to expand our understanding of the molecular pathways that control β-cell growth.


New Cohort of Patients With CEDNIK Syndrome Expands the Phenotypic and Genotypic Spectra.
To report 6 new patients with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. Clinical exome or targeted sequencing were performed to elucidate the molecular genetic cause in patients with neurocognitive abnormalities and brain imaging findings. CEDNIK syndrome is a rare genetic condition caused by biallelic pathogenic loss-of-function variants in synaptosomal-associated protein 29 (SNAP29), which encodes a vesicular membrane fusion protein. Clinical manifestations include significant developmental delay/intellectual disability (DD/ID), brain abnormalities, failure to thrive, and skin abnormalities. To date, 19 patients from 10 unrelated families with CEDNIK syndrome have been reported. We report 5 additional patients with homozygous predicted loss-of-function variants in SNAP29 and one with compound heterozygous variants: a frameshift SNAP29 variant and a 370 kb deletion on 22q11.2. All patients exhibit DD/ID, ichthyosis and/or palmoplantar keratoderma, and hypotonia. Four of 6 subjects had hypomyelinated white matter on MRI, 2 of 6 had early puberty, and 4 of 6 had strabismus, which were previously rarely reported. Other phenotypes were variably present, including dysmorphic features, feeding difficulties, and recurrent respiratory infections. The cohort includes 2 siblings with a c.2T>C variant who have a relatively milder phenotype, a patient with the most C-terminal variant yet described (c.622G>T), and 3 patients with previously described variants (c.354dupG, c.487dupA). This cohort of 6 additional patients expands the genotypic and phenotypic spectrum of CEDNIK syndrome, highlighting previously under-recognized features such as hypomyelination, seizures, and early puberty. Owing to reduced penetrance of the skin phenotype, cerebral dysgenesis, and neuropathy, we propose renaming this syndrome SNAP29-related disorder.


Improving the filtering of false positive single nucleotide variations by combining genomic features with quality metrics.
Technical errors in sequencing or bioinformatics steps and difficulties in alignment at some genomic sites result in false positive (FP) variants. Filtering based on quality metrics is a common method for detecting FP variants, but setting thresholds to reduce FP rates may reduce the number of true positive variants by overlooking the more complex relationships between features. The goal of this study is to develop a machine learning-based model for identifying FPs that integrates quality metrics with genomic features and with the feature interpretability property to provide insights into model results. We propose a random forest-based model that utilizes genomic features to improve identification of FPs. Further examination of the features shows that the newly introduced features have an important impact on the prediction of variants misclassified by VEF, GATK-CNN, and GARFIELD, recently introduced FP detection systems. We applied cost-sensitive training to avoid errors in misclassification of true variants and developed a model that provides a robust mechanism against misclassification of true variants while increasing the prediction rate of FP variants. This model can be easily re-trained when factors such as experimental protocols might alter the FP distribution. In addition, it has an interpretability mechanism that allows users to understand the impact of features on the model's predictions. The software implementation can be found at https://github.com/ideateknoloji/FPDetect.


WSS25 inhibits growth of xenografted hepatocellular cancer cells in nude mice by disrupting angiogenesis via blocking bone morphogenetic protein (BMP)/Smad/Id1 signaling.
The highly expressed Id1 (inhibitor of DNA binding/differentiation) protein promotes angiogenesis in HCC and is a well established target for anti-angiogenesis therapeutic strategies. Heparan sulfate (HS) mimetics such as PI-88 can abrogate HS-protein interactions to inhibit angiogenesis. Id1 is the direct downstream effector of bone morphogenetic proteins (BMPs), which are angiogenic and HS-binding proteins. Thus, targeting BMPs by HS mimetics may inhibit angiogenesis via attenuating Id1 expression. We report here that a HS mimetic WSS25 potently inhibited the tube formation of HMEC-1 cells on Matrigel and their migration. Meanwhile, WSS25 (25 μg/ml) nearly completely blocked Id1 expression in the HMEC-1 cells as demonstrated by oligo-angiogenesis microarray analysis and further confirmed by RT-PCR and Western blotting. BMP/Smad/Id1 signaling also was blocked by WSS25 treatment in HMEC-1 cells. Importantly, Id1 knockdown in HMEC-1 cells caused the disruption of their tube formation on Matrigel. By employing quartz crystal microbalance analysis, we found that WSS25 strongly bound to BMP2. Moreover, WSS25 impaired BMP2-induced tube formation of HMEC-1 cells on Matrigel and angiogenesis in Matrigel transplanted into C57BL6 mice. Furthermore, WSS25 (100 mg/kg) abrogated the growth of HCC cells xenografted in male nude mice. Immunohistochemical analysis showed that both the expression of Id1 and the endothelial cell marker CD31 were lower in the WSS25-treated tumor tissue than in the control. Therefore, WSS25 is a potential drug candidate for HCC therapy as a tumor angiogenesis inhibitor.


The stereochemical configuration of Mn(II) . ADP at the active site of creatine kinase elucidated by electron paramagnetic resonance with Rp [alpha-17O]ADP and Sp [alpha-17O]ADP.
The stereochemical configuration of the Mn(II) . ADP complex at the active site of creatine kinase has been elucidated by EPR using chirally labeled [alpha-17O]ADP. Superhyperfine coupling between the 17O nucleus and Mn(II) produces a characteristic inhomogeneous broadening of the EPR signals for Mn(II) whenever the 17O is in the first coordination sphere of the metal ion. Previous experiments with ADP regio-specifically labeled with 17O in the phosphate groups had shown that Mn(II) was coordinated to the alpha and beta positions of ADP in transition state analog complexes with creatine kinase that involved enzyme, Mn(II), ADP, creatine, and anions such as formate and thiocyanate (Reed, G. H., and Leyh, T. S. (1980) Biochemistry 19, 5472-5480). The present experiments were initiated to determine the stereochemical configuration of the Mn(II) . ADP complex at the active site of the enzyme. EPR spectra for Mn(II) in transition state analog complexes with formate, thiocyanate, and nitrate as the stabilizing anions show inhomogeneous broadening from 17O in Sp [alpha-17O]ADP whereas the spectra obtained with Rp [alpha-17O]ADP are indistinguishable from those for matched samples with unlabeled ADP. The precision of the measurements indicates that the stereoselectivity of the enzyme for the delta configuration of the alpha, beta chelate of Mn(II) . ADP is greater than 15:1. The delta configuration is also preferred in fully active enzymic complexes involving the equilibrium mixture of substrates.


Design of Revolute Joints for In-Mold Assembly Using Insert Molding.
Creating highly articulated miniature structures requires assembling a large number of small parts. This is a very challenging task and increases cost of mechanical assemblies. Insert molding presents the possibility of creating a highly articulated structure in a single molding step. This can be accomplished by placing multiple metallic bearings in the mold and injecting plastic on top of them. In theory, this idea can generate a multi degree of freedom structures in just one processing step without requiring any post molding assembly operations. However, the polymer material has a tendency to shrink on top of the metal bearings and hence jam the joints. Hence, until now insert molding has not been used to create articulated structures. This paper presents a theoretical model for estimating the extent of joint jamming that occurs due to the shrinkage of the polymer on top of the metal bearings. The level of joint jamming is seen as the effective torque needed to overcome the friction in the revolute joints formed by insert molding. We then use this model to select the optimum design parameters which can be used to fabricate functional, highly articulating assemblies while meeting manufacturing constraints. Our analysis shows that the strength of weld-lines formed during the in-mold assembly process play a significant role in determining the minimum joint dimensions necessary for fabricating functional revolute joints. We have used the models and methods described in this paper to successfully fabricate the structure for a minimally invasive medical robot prototype with potential applications in neurosurgery. To the best of our knowledge, this is the first demonstration of building an articulated structure with multiple degrees of freedom using insert molding.


Proposal of a type strain for Frankia alni (Woronin 1866) Von Tubeuf 1895, emended description of Frankia alni, and recognition of Frankia casuarinae sp. nov. and Frankia elaeagni sp. nov.
Before the establishment of pure cultures, the species Frankia alni, 'Frankia casuarinae' and 'Frankia elaeagni' were proposed to encompass all causal agents of the nitrogen-fixing root nodules of dicotyledonous plants from the genera Alnus, Casuarina or Elaeagnus. The sole Frankia species with a validly published name, the type species F. alni, was described by Woronin (1866) as present in the root of alder. Until now no type strain has been designated for F. alni, even though the absence of a type strain has seriously inhibited the application of modern taxonomic methods to the genus Frankia. Thus, we propose that strain ACN14aT, isolated in pure culture from Alnus viridis ssp. crispa with morphological properties matching the original description of F. alni, be recognized as the type strain of this species according to Rule 18f of the International Code of Nomenclature of Bacteria. We compared ACN14aT to two strains, CcI3T and BMG5.12T, isolated from Casuarina cunninghamiana and Elaeagnus angustifolia, respectively, based on chemotaxonomy, phenotype microarray data and molecular data retrieved from genome sequences. All three tested strains grew as branched hyphae, produced vesicles and multilocular sporangia containing non-motile spores and metabolized short fatty acids, TCA-cycle intermediates and carbohydrates. Chemotaxonomically, the three strains were indistinguishable with respect to phospholipids (phosphatidylinositol, diphosphatidylglycerol, glycophospholipids and phosphatidylglycerol) and cell-sugar composition (glucose, mannose, ribose, rhamnose, galactose and xylose, with the latter two being diagnostic for the genus). The major fatty acids identified in all three strains were iso-C16 : 0, C17 : 1ω8c, C15 : 0, C17 : 0 and C16 : 0. ACN14aT and BMG5.12T also shared C15 : 1ω6c, while C18 : 1ω9c was found to be unique to BMG5.12T. The major menaquinones identified in all three novel type strains were MK-9(H8), MK-9(H6) and MK-9(H4). MK-9(H2) was shared by ACN14aT and BMG5.12T, while MK-10(H4) and MK-8(H4) were only found in BMG5.12T. Analysis of 16S rRNA gene sequences showed 98.1-98.9 % identity between strains ACN14aT, CcI3T and BMG5.12T. Digital DNA-DNA hybridization values between the three type strains were well below 70 %. These results confirm the separation of the strains into three distinct species, Frankia alni, Frankia casuarinae sp. nov. and Frankia elaeagni sp. nov. Thus, we propose ACN14aT (=DSM 45986T=CECT 9034T), CcI3T (=DSM 45818T=CECT 9043T) and BMG5.12T (=DSM 46783T=CECT 9031T) as the respective type strains.


The relationship among intracellular sodium activity, calcium, and strophanthidin inotropy in canine cardiac Purkinje fibers.
The role of sodium and calcium ions in strophanthidin inotropy was studied by measuring simultaneously the electrical, mechanical, and intracellular sodium ion activities in electrically driven cardiac Purkinje fibers under conditions that change the intracellular sodium or calcium level (tetrodotoxin, strophanthidin, high calcium, and norepinephrine). Tetrodotoxin (TTX; 1-5 X 10(-6)M) shifted the action potential plateau to more negative values, shortened the action potential duration, and decreased the contractile tension and the intracellular sodium ion activity (aiNa). The changes in tension and in aiNa caused by TTX appear to be related since they had similar time courses. Strophanthidin (2-5 X 10(-7)M) increased tension and aiNa less in the presence of TTX, and, for any given value of aiNa, tension was less than in the absence of TTX. Increasing extracellular calcium (from 1.8 to 3.3-3.6 mM) or adding norepinephrine (0.5-1 X 10(-6)M) increased tension and decreased aiNa less in the presence than in the absence of TTX. When two of the above procedures were combined, the results were different. Thus, during the increase in aiNa and tension caused by strophanthidin in the presence of TTX, increasing calcium or adding norepinephrine increased tension markedly but did not increase aiNa further. In a TTX-high calcium or TTX-norepinephrine solution, adding strophanthidin increased both tension and aiNa, and the increase in tension was far greater than in the presence of TTX alone. The results indicate that: (a) the contractile force in Purkinje fibers is affected by a change in aiNa; (b) a decrease in aiNa by TTX markedly reduces the inotropic effect of strophanthidin, possibly as a consequence of depletion of intracellular calcium; (c) increasing calcium influx with norepinephrine or high calcium in the TTX-strophanthidin solution produces a potentiation of tension development, even if aiNa does not increase further; and (d) when the calcium influx is already increased by high calcium or norepinephrine, strophanthidin has its usual inotropic effect even in the presence of TTX. In conclusion, the positive inotropic effect of strophanthidin requires that an increase in aiNa be associated with suitable calcium availability.


Pancreatic neuroendocrine tumors: role of novel agents. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.
Neuroendocrine tumors of pancreas (PNET) are very rare, consisting of heterogeneous histological subtypes with a variable natural history and different clinical manifestations. Although the vast majority of these neoplasms are sporadic, it is possible to be part of a genetic syndrome such as multiple endocrine neoplasia 1 (MEN-1) or tuberous sclerosis (TSC). When systemic treatment is required the options are limited and management strategy is generally based on experts' consensus or clinical experience. The prognosis is usually better than in pancreatic adenocarcinoma, though poorly differentiated PNET behave aggressively and survival is shortened. Since last year, there has been a significant advance in the management of PNET, after reported data confirmed the efficacy of everolimus, an mTOR inhibitor, in patients with advanced disease. At the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Symposium, updated results of the phase III trial (RADIANT-3) regarding the efficacy of everolimus in PNET (Abstract #158) were reported, along with the results of a subgroup analysis of the Japanese patients enrolled in this study (Abstract #289). Another agent with promising activity in PNET which will be discussed in this review is sunitinib, a biological agent with multikinase inhibitor properties (Abstract #244).


Carbonyl Profiles of Electronic Nicotine Delivery System (ENDS) Aerosols Reflect Both the Chemical Composition and the Numbers of E-Liquid Ingredients-Focus on the In Vitro Toxicity of Strawberry and Vanilla Flavors.
Propylene glycol (PG) and glycerin (G) are the most widely used humectants in electronic nicotine delivery system (ENDS) devices. Carbonyls are present in aerosols produced when ENDS devices heat PG and G. Whether aerosolized PG and G are innocuous to the lungs has not been established. Here, we determined the chemical profiles of ENDS aerosols containing three humectant ratios (30/70, 50/50 and 70/30, PG/VG), for three flavors (strawberry, vanilla and Catalan cream) containing either 12 or 18 mg/mL of nicotine. Additionally, we examined the in vitro toxicity of the strawberry- and vanilla-flavored ENDS aerosol in human lung epithelial cells (BEAS-2B) exposed at the air-liquid interface for 1 h. For strawberry- and vanilla-flavored aerosols produced by a 3rd-generation ENDS device with the same PG/G ratio, the e-liquid nicotine content of 12 and 18 mg/mL did not transfer to the aerosol with substantial differences in concentrations. Our data also indicate the presence of carbonyls in all three flavored e-cig aerosols analyzed, with levels exceeding 1 µg/puff for acetone, butyraldehyde, and acetaldehyde, in strawberry-, vanilla, and Catalan cream-flavored e-cig aerosols, respectively. Furthermore, closed-system ENDS of the fourth generation emitted trace levels of carbonyls in the aerosols (<0.3 µg/puff), while open-system tank-style ENDS of the third generation produced elevated levels of harmful chemicals, including acrolein (>1 µg/puff), formaldehyde (>5 µg/puff), and m- & p-tolualdehyde (>4 µg/puff). Moreover, under non-cytotoxic conditions, BEAS-2B cells exposed to strawberry-flavored aerosols exhibited significantly increased reactive oxygen and nitric oxide species (ROS/NOS) levels in cell media compared to air controls, while vanilla-flavored ENDS aerosols up-regulated the expression of pro-inflammatory and oxidative stress markers. Our data suggest (a) that ENDS aerosol chemical composition will vary based upon the presence and concentration of the initial e-liquid ingredients, with a pronounced impact of the flavoring components; and (b) short-term exposures to flavored ENDS aerosols may impair lung cells' redox signaling in a flavor-specific manner.


Three-dimensional Nanowire Structures for Ultra-Fast Separation of DNA, Protein and RNA Molecules.
Separation and analysis of biomolecules represent crucial processes for biological and biomedical engineering development; however, separation resolution and speed for biomolecules analysis still require improvements. To achieve separation and analysis of biomolecules in a short time, the use of highly-ordered nanostructures fabricated by top-down or bottom-up approaches have been proposed. Here, we reported on the use of three-dimensional (3D) nanowire structures embedded in microchannels fabricated by a bottom-up approach for ultrafast separation of small biomolecules, such as DNA, protein, and RNA molecules. The 3D nanowire structures could analyze a mixture of DNA molecules (50-1000 bp) within 50 s, a mixture of protein molecules (20-340 kDa) within 5 s, and a mixture of RNA molecules (100-1000 bases) within 25 s. And, we could observe the electrophoretic mobility difference of biomolecules as a function of molecular size in the 3D nanowire structures. Since the present methodology allows users to control the pore size of sieving materials by varying the number of cycles for nanowire growth, the 3D nanowire structures have a good potential for use as alternatives for other sieving materials.


Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load.
Children are an at-risk population for developing complications following influenza infection, but immunologic correlates of disease severity are not understood. We hypothesized that innate cellular immune responses at the site of infection would correlate with disease outcome. To test the immunologic basis of severe illness during natural influenza virus infection of children and adults at the site of infection. An observational cohort study with longitudinal sampling of peripheral and mucosal sites in 84 naturally influenza-infected individuals, including infants. Cellular responses, viral loads, and cytokines were quantified from nasal lavages and blood, and correlated to clinical severity. We show for the first time that although viral loads in children and adults were similar, innate responses in the airways were stronger in children and varied considerably between plasma and site of infection. Adjusting for age and viral load, an innate immune profile characterized by increased nasal lavage monocyte chemotactic protein-3, IFN-α2, and plasma IL-10 levels at enrollment predicted progression to severe disease. Increased plasma IL-10, monocyte chemotactic protein-3, and IL-6 levels predicted hospitalization. This inflammatory cytokine production correlated significantly with monocyte localization from the blood to the site of infection, with conventional monocytes positively correlating with inflammation. Increased frequencies of CD14(lo) monocytes were in the airways of participants with lower inflammatory cytokine levels. An innate profile was identified that correlated with disease progression independent of viral dynamics and age. The airways and blood displayed dramatically different immune profiles emphasizing the importance of cellular migration and localized immune phenotypes.


Evaluation of cephalometric characteristics and skeletal maturation of the cervical vertebrae and hand-wrist in girls with central precocious puberty.
This study aimed to evaluate the differences in cephalometric characteristics and skeletal maturation in girls with central precocious puberty (CPP) via lateral and hand-wrist radiographs. We also aimed to identify the indicators that are most effective for determining skeletal maturity in these patients. The study included 70 Korean girls (mean age, 8.5 ± 0.5 years) diagnosed with CPP at the Department of Pediatrics, and 48 normal healthy age-matched girls who visited the Department of Orthodontics and had no history of hormone treatment or growth problems. Skeletal maturation was evaluated using lateral cephalometric and hand-wrist radiographs using cervical vertebrae maturation indicators (CVMI) and skeletal maturity indicators (SMI). The mean mandibular plane angle was smaller in the CPP group than in the control group (35.8° ± 4.9° vs. 39.0° ± 6.5°), resulting in greater posterior facial height (p = 0.003). SMI was significantly greater in the CPP group (3.5 ± 1.4 vs. 2.0 ± 1.0) than in the control group (p = 0.001) and was significantly associated with CPP (r = 0.492; p = 0.001), whereas CVMI was not. In comparison with the control group, the CPP group exhibited a smaller mandibular plane angle, greater posterior facial height, and greater skeletal maturation. SMI may be more suitable than CVMI for determining skeletal maturation in CPP. Hand-wrist radiography is recommended in addition to lateral cephalogram for predicting growth in girls with CPP.


Smoking in pregnancy and risk of cancer among young children: A population-based study.
Smoking during pregnancy is a plausible risk factor for childhood cancer, yet previous studies have yielded conflicting results, and few prospective studies have been published. Data on maternal smoking were obtained from California birth certificates. We linked California birth certificates (births 2007-2011) with California Cancer Registry records for childhood cancer cases (diagnosed January 2007-September 2013) that were ages 5 or younger at diagnosis (N cases = 2,021). Controls (N = 40,356) were frequency-matched by birth year and randomly selected from birth certificate records. We used unconditional logistic regression to obtain odds ratios (OR) and 95% confidence intervals (CI) to assess the association between smoking during pregnancy and childhood cancer. We observed positive associations for gliomas (OR = 1.8, 95% CI: 1.0-3.4) and retinoblastoma (OR = 3.0, 95% CI: 1.4-6.6), particularly bilateral retinoblastoma (OR = 9.4, 95% CI 3.6-24.7) with maternal smoking in pregnancy. Maternal smoking during pregnancy may be a risk factor for retinoblastoma and certain types of childhood brain tumors.


Myocardial infarction, ischaemic stroke and pulmonary embolism before and after breast cancer hospitalisation. A population-based study.
We studied the occurrence of myocardial infarction (MI), ischaemic stroke (IS) and pulmonary embolism (PE) before and after breast cancer hospitalisation compared with cancer-free controls. For this, women with a first breast cancer hospitalisation during 2000-2007 were selected from the PHARMO Record Linkage System, including drug use and hospitalisations of three million inhabitants in the Netherlands, and matched 1:10 by age to cancer-free women. The occurrence of MI, IS and PE were assessed in the 12 months before and after breast cancer hospitalisation. The study included 11,473 breast cancer patients, with a mean (± SD) age of 59 (± 14) years. Breast cancer patients were two to three times as likely as their cancer-free controls to have had a hospitalisation for PE, MI or IS in the 12 months before diagnosis, though prevalence was <1% in all groups. Breast cancer patients experienced an extreme high risk of PE in the first six months after diagnosis (hazard ratio [HR] 23.5, 95% confidence interval [CI] 11.1-49.7 compared to controls), which declined gradually to a four times increased risk (HR 3.6, 95%CI 2.4-5.5) more than 12 months after breast cancer hospitalisation. However, incidence was low: less than five events per 1,000 person years during all time periods. For MI and IS we did not observe significant increased HRs after breast cancer hospitalisation compared to controls. Breast cancer patients seem to have a higher risk profile to develop MI and IS, and receive treatment that increases the risk of PE compared to cancer-free controls, although the frequency of hospitalisations was low.


Network-Based Differences in the Vaginal and Bladder Microbial Communities Between Women With and Without Urgency Urinary Incontinence.
Little is known about the relationship of proximal urogenital microbiomes in the bladder and the vagina and how this contributes to bladder health. In this study, we use a microbial ecology and network framework to understand the dynamics of interactions/co-occurrences of bacteria in the bladder and vagina in women with and without urgency urinary incontinence (UUI). We collected vaginal swabs and catheterized urine specimens from 20 women with UUI (cases) and 30 women without UUI (controls). We sequenced the V4 region of the bacterial 16S rRNA gene and evaluated using alpha and beta diversity metrics. We used microbial network analysis to detect interactions in the microbiome and the betweenness centrality measure to identify central bacteria in the microbial network. Bacteria exhibiting maximum betweenness centrality are considered central to the microbe-wide networks and likely maintain the overall microbial network structure. There were no significant differences in the vaginal or bladder microbiomes between cases and controls using alpha and beta diversity. Silhouette metric analysis identified two distinct microbiome clusters in both the bladder and vagina. One cluster was dominated by Lactobacillus genus while the other was more diverse. Network-based analyses demonstrated that vaginal and bladder microbial networks were different between cases and controls. In the vagina, there were similar numbers of genera and subgroup clusters in each network for cases and controls. However, cases tend to have more unique bacterial co-occurrences. While Bacteroides and Lactobacillus were the central bacteria with the highest betweenness centrality in controls, Aerococcus had the highest centrality in cases and correlated with bacteria commonly associated with bacterial vaginosis. In the bladder, cases have less than half as many network clusters compared to controls. Lactobacillus was the central bacteria in both groups but associated with several known uropathogens in cases. The number of shared bacterial genera between the bladder and the vagina differed between cases and controls, with cases having larger overlap (43%) compared to controls (29%). Our study shows overlaps in microbial communities of bladder and vagina, with higher overlap in cases. We also identified differences in the bacteria that are central to the overall community structure.


Isolation of a subclavian artery.
Eight patients with isolation of a subclavian artery are described. Isolation of subclavian artery is defined as a loss of continuity between the subclavian artery and aorta but with persistent connection to the homolateral pulmonary artery through a ductus arteriosus. The connecting ductus arteriosus may or may not be patent. As the pulmonary vascular resistance is usually lower than the systemic resistance, the isolated subclavian artery is perfused by subclavian steal, and if the connecting ductus arteriosus is patent, flow occurs from the subclavian artery into the pulmonary artery. In this material and in all reported cases, isolation of subclavian artery has always been associated with other anomalies of the aortic arch, such as right aortic arch or bilateral ductus. Its frequent association with intracardiac defects, usually the tetralogy of Fallot, makes its recognition clinically important. Thoracic aortography with delayed filming is the only procedure that allows consistent diagnosis of this rare anomaly during life.


Impact of Caregiver's Psychological Aspects towards Quality of Life of Children with Acute Lymphoblastic Leukemia (ALL).
Families who have children with Acute Lymphoblastic Leukemia (ALL) are at high risk of experiencing stress. Stress on the family can cause the formation of negative communication in children so that families tend to spend more time in dealing with negative emotions through negative actions. This study aimed to analyze the correlation between stress, anxiety, and depression in caregiver with pediatric ALL outcome. A cross sectional study was conducted on children with ALL and their caregivers at the Pediatric Ward, Dr. Soetomo Hospital, Surabaya. Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) questionnaire were used to measure anxiety and depression in caregivers. Previous stressful experiences in children and caregivers were assessed by The Perceived Stress Scale (PSS), Children quality of life was assessed by pediatric quality of life inventory (PedsQL™) questionnaire. Pearson and Spearman correlation strength test was performed for the statistical analysis. There is no significant correlation between stress level of caregivers with the quality of life of children with ALL (P > 0.05). There is negative correlation between the level of anxiety and depression in caregivers with the quality of life of children (P < 0.05). There is negative correlation between children stress level with the quality of life of children (P < 0.05). The psychological condition of the caregiver affects the quality of life of children. The higher the level of anxiety and depression in caregivers, the lower the quality of life of children.<br />.


Factors associated with health-related quality of life among outpatients with major depressive disorder: a STAR*D report.
Major depressive disorder (MDD) is often chronic and is often associated with significant morbidity and mortality. The importance of assessing disability and health-related quality of life (HRQOL) in patients with MDD has only recently been recognized. The aim of this study was to examine sociodemographic and clinical correlates of HRQOL in a large cohort of outpatients with MDD. Baseline assessments were completed for 1500 consecutive patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression trial, including sociodemographic characteristics and measures of depressive symptom severity, clinical features, and HRQOL. Multiple domains of HRQOL were assessed with the 12-item Short Form Health Survey, the Work and Social Adjustment Scale, and the Quality of Life Enjoyment and Satisfaction Questionnaire. The current analyses were conducted on HRQOL data available for 1397 of the 1500 subjects. Greater symptom severity was associated with reduced HRQOL by all measures. Even after age and symptom severity were controlled for, a number of clinical features and sociodemographic characteristics were independently associated with HRQOL in multiple domains, including age at onset of MDD, ethnicity, marital status, employment status, education level, insurance status, and monthly household income. Results strongly suggest the need to assess HRQOL in addition to symptoms in order to gauge the true severity of MDD. This study also highlights the necessity of measuring HRQOL in multiple domains. These results have implications for the assessment of remission and functional recovery in the treatment of MDD.


Cluster Cooperation in Wireless-Powered Sensor Networks: Modeling and Performance Analysis.
A wireless-powered sensor network (WPSN) consisting of one hybrid access point (HAP), a near cluster and the corresponding far cluster is investigated in this paper. These sensors are wireless-powered and they transmit information by consuming the harvested energy from signal ejected by the HAP. Sensors are able to harvest energy as well as store the harvested energy. We propose that if sensors in near cluster do not have their own information to transmit, acting as relays, they can help the sensors in a far cluster to forward information to the HAP in an amplify-and-forward (AF) manner. We use a finite Markov chain to model the dynamic variation process of the relay battery, and give a general analyzing model for WPSN with cluster cooperation. Though the model, we deduce the closed-form expression for the outage probability as the metric of this network. Finally, simulation results validate the start point of designing this paper and correctness of theoretical analysis and show how parameters have an effect on system performance. Moreover, it is also known that the outage probability of sensors in far cluster can be drastically reduced without sacrificing the performance of sensors in near cluster if the transmit power of HAP is fairly high. Furthermore, in the aspect of outage performance of far cluster, the proposed scheme significantly outperforms the direct transmission scheme without cooperation.


Developing and validating measures of self-reported everyday and healthcare discrimination for Aboriginal and Torres Strait Islander adults.
It is well established that racism is a fundamental contributor to poor health and inequities. There is consistent evidence of high exposure to discrimination among Aboriginal and Torres Strait Islander (Indigenous Australian) peoples, but impacts have not been fully quantified, in part due to limited measurement tools. We aim to validate instruments developed to measure interpersonal discrimination. Instruments were discussed at five focus groups and with experts, and field tested in developing Mayi Kuwayu: The National Study of Aboriginal and Torres Strait Islander Wellbeing. Data from 7501 baseline survey participants were analysed. Acceptability was assessed according to extent of missingness, construct validity using exploratory and confirmatory factor analysis, and reliability using Cronbach's alpha. Associations between each instrument and outcomes conceptually understood to be closely (community-level racism) or less closely (family wellbeing) related were quantified to test convergent and discriminant validity. An 8-item instrument captures experiences of discrimination in everyday life and a 4-item instrument experiences in healthcare, each followed by a global attribution item. Item missingness was 2.2-3.7%. Half (55.4%) of participants reported experiencing any everyday discrimination, with 65.7% attributing the discrimination to Indigeneity; healthcare discrimination figures were 34.1% and 51.1%. Items were consistent with two distinct instruments, differentiating respondents with varying experiences of discrimination. Scales demonstrated very good reliability and convergent and divergent validity. These brief instruments demonstrate face validity and robust psychometric properties in measuring Aboriginal and Torres Strait Islander adults' experiences of interpersonal discrimination in everyday life and in healthcare. They can be used to quantify population-level experiences of discrimination, and associated wellbeing consequences, and monitor change.


Solitary calcaneal metastasis in superficial bladder carcinoma.
We report a case of a solitary calcaneal metastasis in a patient with superficial bladder carcinoma. The patient underwent transurethral tumor resection twice because of local recurrence. Both histologic examinations revealed a grade 2 PT1 superficial transitional cell carcinoma of the bladder. The metastasis was detected four months after the initial cystoscopy, due to severe leg pain. The lesion was curetted and filled with bone cement. A year later, a below knee amputation was performed because of local recurrence. This case deserves special attention, for two reasons. First, metastatic carcinoma to the bones of the foot is very rare. Although bony metastasis by transitional cell carcinoma of the bladder can be seen, presenting as a symptomatic solitary lesion after superficial bladder carcinoma is extremely unusual. Second, failure to control bladder tumours by local means might be an indication for an early cystectomy, even in tumours with no evidence of muscle invasion, in order to prevent distant metastasis.


A novel digital approach for post-stroke cognitive deficits: a pilot study.
Cognitive dysfunctions after a brain stroke have a huge impact on patients' disability and activities of daily living. Prism adaptation (PA) is currently used in patients with right brain damage to improve lateralized spatial attentional deficits. Recent findings suggest that PA could also be useful for rehabilitation of other cognitive functions. In the present study, we tested for the efficacy on cognitive rehabilitation of a novel device in which the procedure of prism adaptation is digitized and followed by cognitive training of attention and executive functions using serious games. Thirty stroke patients were randomly assigned to two groups: an experimental group of 15 patients, which performed the experimental rehabilitation training using the novel device in 10 consecutive daily sessions; a control group of 15 patients, which performed the routine cognitive training in 10 consecutive daily sessions. Both groups were tested before and after the rehabilitation program on neuropsychological tests (digit and spatial span forward and backward, attentional matrices, Stroop task) and on functional scales (Barthel index and Beck Anxiety Index). The main results showed that only patients who received the experimental rehabilitation training improved their scores on tests of digit span forward, spatial span backward, attentional matrices and Stroop. Moreover, patients of the experimental but not of the control group showed a significant correlation between improvement on some tasks (mainly spatial span backward) and improvement on activities of daily living as well as with reduction of anxiety levels. These results suggest that combining digital PA with cognitive training using serious games may be added in clinical settings for cognitive rehabilitation of stroke patients, with beneficial effects extending in promoting independency in activities of daily living and reduction of psychiatric symptoms.


Histomorphometric analysis of the rat proximal tibial metaphysis by "linear scanning".
Twenty-four female Sprague-Dawley rats (10 weeks old, 200g BW) were either sham-operated (n = 6) or ovariectomized (ovx). Ovx rats were divided into 3 groups (n = 6 each): ovx; ovx + 1,25-(OH)2D3; ovx + 1,25(OH)2D3 + 1,24,25-(OH)3D3. The vitamin D metabolites were fed orally starting the day after surgery. After 7 weeks all rats were sacrificed and the proximal tibiae were processed undecalcified for quantitative histomorphometry. Conventional histomorphometric analysis of the distal zone (greater than 1 mm from the growth cartilage) of the tibial metaphysis revealed a dramatic loss of cancellous bone mass in ovx rats. Both 1,25(OH)2D3 and the combination of 1,25(OH)2D3 with 1,24,25(OH)3D3 prevented the bone loss in the distal zone in ovx animals. Measurements in the proximal zone (less than 1 mm from the growth cartilage) of the tibial metaphysis were performed with a newly developed technique that utilizes the advantages of automatic image analysis, and that we propose to name "linear scanning". This method revealed a significantly decreased hard tissue mass at about 100 microns and within 800 to 950 microns distance from the growth plate in ovx rats. However, ovx rats reached normal amounts of hard tissue within 250 to 450 microns from the growth plate. The results obtained by linear scanning suggest that the obvious loss of cancellous bone mass in the distal zone of the tibial metaphysis in growing ovx rats is not a consequence of structural changes in the proximal zone.


Re-irradiation or re-operation followed by dendritic cell vaccination? Comparison of two different salvage strategies for relapsed high-grade gliomas by means of a new prognostic model.
We aimed to compare two different salvage treatment strategies for relapsed high-grade glioma (HGG) patients by means of a new prognostic model. A simplified version of the so-called HGG-Immuno RPA model estimates the prognosis of relapsed HGG patients and distinguishes three different prognostic classes (I = good, II = intermediate, III = poor). The model has been constructed with a cohort of 117 patients whose salvage treatment consisted of re-operation followed by dendritic cell vaccination (ReOP + DCV). However, using only the predictors histology, age and performance status, the simplified HGG-Immuno RPA model is basically independent from treatment. In the present study we applied the simplified model to the cohort used to construct the original HGG-Immuno RPA model and another cohort of 165 patients who underwent re-irradiation (ReRT) at relapse. Then, we compared the outcomes achieved by the two different salvage treatments in each prognostic class. The model predicted good, intermediate and poor prognosis for 11, 31 and 75 patients of the ReOP + DCV cohort and for 20, 39 and 106 patients of the ReRT cohort, respectively. Neither of the two strategies was superior to the other. In the groups with good, intermediate and poor prognosis 12-months survival rates were 73, 59 and 25 % after ReOP + DCV and 72, 36 and 23 % after ReRT, respectively. Being easy to handle and independent from treatment, the aforementioned model is useful for therapeutic decisions. ReRT and ReOP + DVC seem to be equally effective. The choice of salvage treatment should be based on the expected side effects.


Recent advances on biocompatible and biodegradable nanoparticles as gene carriers.
Gene therapy mainly depends on the use of appropriate delivery vehicles with no induction of immune responses and toxicity. The limitations of viral gene carriers such as induction of immunogenicity, random integration in the genome of the host, limitations in the size, has led to a movement toward non-viral systems with much safer properties. Biodegradable and biocompatible polymeric nanocarriers due to several unique properties such as excellent biocompatibility, prolonged gene circulation time, prevented gene degradation, passive targeting by using the enhanced permeability and retention (EPR) effect, and possibility of modulating polymers structure to obtain desirable therapeutic efficacy, are among the most promising systems for gene delivery. However, biodegradable gene delivery systems have some limitations such as inadequate stability and slow release of therapeutics which have to be overcome. Thus, a variety of advanced functional biodegradable delivery systems with more efficient gene delivery activity has recently been introduced. This review summarizes different aspects of biodegradable and biocompatible nano carriers including formulation, mechanism of intracellular uptake, various potential applications of biodegradable nanoparticles and finally recent studies on the therapeutic efficacy of these nanoparticles in sustained delivery of genes. Biocompatible and biodegradable polymers will play a necessary and important role in developing new and safe carriers for oligonucleotide delivery. More working and the development of optimized polymers will reveal more their efficacy in the treatment of patients via helping in better gene therapy.


Brain signatures of early lexical and morphological learning of a new language.
Morphology is an important part of language processing but little is known about how adult second language learners acquire morphological rules. Using a word-picture associative learning task, we have previously shown that a brief exposure to novel words with embedded morphological structure (suffix for natural gender) is enough for language learners to acquire the hidden morphological rule. Here we used this paradigm to study the brain signatures of early morphological learning in a novel language in adults. Behavioural measures indicated successful lexical (word stem) and morphological (gender suffix) learning. A day after the learning phase, event-related brain potentials registered during a recognition memory task revealed enhanced N400 and P600 components for stem and suffix violations, respectively. An additional effect observed with combined suffix and stem violations was an enhancement of an early N2 component, most probably related to conflict-detection processes. Successful morphological learning was also evident in the ERP responses to the subsequent rule-generalization task with new stems, where violation of the morphological rule was associated with an early (250-400ms) and late positivity (750-900ms). Overall, these findings tend to converge with lexical and morphosyntactic violation effects observed in L1 processing, suggesting that even after a short exposure, adult language learners can acquire both novel words and novel morphological rules.


The degree of tongue-coating reflects lingual motor function in the elderly.
The aim of this study was to examine the relation between the degree of tongue-coating and oral function. Tongue-coating is a moss-like deposit which forms over the tongue surface, and includes micro-organisms, food residues, and abrasive epithelia. It is considered that motor function of the tongue and lips and saliva secretion decrease in the aged and have some effect on the accumulation of tongue-coating. Although saliva secretion has been reported as a factor amongst these oral functions in contributing to tongue-coating, the correlation with the motor function of oral structures is unknown. The factors that contribute to the accumulation of tongue-coating were examined in 48 subjects of advanced age (mean age 80.8 +/- 7.8 years) with no severe levels of periodontal disease. Changes in the degree of tongue-coating were also examined after oral functional training in these subjects. The frequency of oral cleaning, status of oral hygiene, motor function of the tongue, and masticatory performance were examined as potential factors associated with the degree of coating. The results showed that tongue pressure and the frequency of oral diadochokinesis measured by pronouncing the single syllable 'ka' as an indicator were statistically significantly correlated with the degree of tongue-coating. Several factors in oral function improved with training, and also the degree of tongue-coating decreased in 27 subjects. These results suggest a correlation between the degree of tongue-coating and a reduction in lingual motor function and, in addition, possible improvement in level of coating by functional training of the tongue.


Functional and clinical characterization of a novel homozygous KCNH2 missense variant in the pore region of Kv11.1 leading to a viable but severe long-QT syndrome.
Among KCNH2 missense loss of function (LOF) variants, homozygosity -at any position in the Kv11.1/hERG channel - is very rare and generally leads to intrauterine death, while heterozygous variants in the pore are responsible for severe Type 2 long-QT syndrome (LQTS). We report a novel homozygous p.Gly603Ser missense variant in the pore of Kv11.1/hERG (KCNH2 c.1807G>A) discovered in the context of a severe LQTS. We carried out a phenotypic family study combined with a functional analysis of mutated and wild-type (WT) Kv11.1 by two-electrode voltage-clamp using the Xenopus laevis oocyte heterologous expression system. The variant resulted in a severe LQTS phenotype (very prolonged corrected QT interval, T-wave alternans, multiple Torsades de pointes) with a delayed clinical expression in later childhood in the homozygous state, and in a Type 2 LQTS phenotype in the heterozygous state. Expression of KCNH2 p.Gly603Ser cRNA alone elicited detectable current in Xenopus oocytes. Inactivation kinetics and voltage dependence of activation were not significantly affected by the variant. The macroscopic slope conductance of the variant was three-fold less compared to the WT (18.5±9.01 vs 54.7±17.2 μS, p<0.001). We characterized the novel p.Gly603Ser KCNH2 missense LOF variant in the pore region of Kv11.1/hERG leading to a severe but viable LQTS in the homozygous state and an attenuated Type 2 LQTS in heterozygous carriers. To our knowledge we provide the first description of a homozygous variant in the pore-forming region of Kv11.1 with a functional impact but a delayed clinical expression.


Long-term results of parathyroidectomy for hypercalcemic crisis.
Hypercalcemic crisis is a rare complication of severe calcium intoxication usually caused by sporadic primary hyperparathyroidism that requires prompt diagnosis and definitive surgical treatment. Parathyroidectomy is essential for long-term successful treatment of hypercalcemic crisis. Retrospective case series. Tertiary referral center. Forty-three patients treated for hypercalcemic crisis during a 35-year period who had signs and symptoms of acute calcium intoxication and serum calcium levels of 15 mg/dL (3.75 mmol/L) or greater. Operative success, operative failure, and disease recurrence after surgery. Kaplan-Meier analysis was used to estimate long-term survival after parathyroidectomy. Forty-two (98%) of 43 patients were eucalcemic after initial parathyroidectomy. There was 1 postoperative death. Of 27 patients with postoperative calcium data available for 6 months or longer, operative success was achieved in 26 (96%). There was 1 operative failure in a patient with multiglandular disease requiring reoperation. There were 3 recurrences (7%) at 7, 58, and 265 months. Overall median survival after parathyroidectomy was 11.7 years (95% confidence interval, 9.2-NE [not estimable]). The mean +/- SD serum calcium level of this group at a median follow-up of 4 years after surgery was 9.1 +/- 0.9 mg/dL (2.28 +/- 0.23 mmol/L). Hypercalcemic crisis can be successfully treated by parathyroidectomy with continued normal parathyroid function and excellent long-term survival.


Muscle involvement in the scleroderma syndromes.
Muscle involvement was identified in 14 patients with scleroderma or a connective tissue disease overlap syndrome with predominant features of scleroderma. Patients presented with symmetrical proximal weakness indistinguishable from other inflammatory myopathies. Creatine kinase and electromyography were useful to demonstrate muscle involvement. Muscle histopathology demonstrated primarily the vasculopathy of scleroderma or polymyositis in similar numbers of patients. Scleroderma vasculopathy and polymyositis generally occur without specificity to diffuse scleroderma, the calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia syndrome, or an overlap syndrome with arthritis. Polymyositis also occurs when the vasculopathy of scleroderma involves other organ systems.


CP-154,526, a selective, non-peptide antagonist of the corticotropin-releasing factor1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats.
We have found that peptide antagonists of corticotropin-releasing factor (CRF) receptors attenuate reinstatement of heroin and cocaine seeking induced by footshock. Here we examined the effect of a nonpeptide, selective CRF1 receptor antagonist, CP-154,526, on reinstatement of heroin and cocaine seeking induced by footshock. Rats were trained to self-administer heroin or cocaine (0.1 and 1.0 mg/kg per infusion, i.v., respectively) for 9-12 days. Extinction sessions were given for up to 14 days, during which saline was substituted for the drugs. Tests for reinstatement were then conducted after exposure to intermittent footshock (10 or 15 min, 0.5 mA). The footshock stressor reliably reinstated extinguished cocaine- and heroin-taking behavior. Pretreatment with CP-154,526 (15 and 30 mg/kg, s.c.) significantly attenuated the reinstatement effect of the stressor in both heroin- and cocaine-trained rats. CP-154,526, administered in the absence of the footshock stressor, did not affect extinguished drug seeking. In addition, in a separate experiment, CP-154,526 was shown not to alter high rates of lever pressing for a 10% sucrose solution, suggesting that the suppression of lever pressing in stress-induced reinstatement is not caused by a performance deficit. These results extend previous reports on the role of CRF in reinstatement of drug seeking induced by stressors. The present data also suggest that, to the extent that exposure to environmental stressors provoke relapse to drug use in humans, systemically effective CRF receptor antagonists may be of use in the treatment of relapse to drug use.


A fast least-squares algorithm for population inference.
Population inference is an important problem in genetics used to remove population stratification in genome-wide association studies and to detect migration patterns or shared ancestry. An individual's genotype can be modeled as a probabilistic function of ancestral population memberships, Q, and the allele frequencies in those populations, P. The parameters, P and Q, of this binomial likelihood model can be inferred using slow sampling methods such as Markov Chain Monte Carlo methods or faster gradient based approaches such as sequential quadratic programming. This paper proposes a least-squares simplification of the binomial likelihood model motivated by a Euclidean interpretation of the genotype feature space. This results in a faster algorithm that easily incorporates the degree of admixture within the sample of individuals and improves estimates without requiring trial-and-error tuning. We show that the expected value of the least-squares solution across all possible genotype datasets is equal to the true solution when part of the problem has been solved, and that the variance of the solution approaches zero as its size increases. The Least-squares algorithm performs nearly as well as Admixture for these theoretical scenarios. We compare least-squares, Admixture, and FRAPPE for a variety of problem sizes and difficulties. For particularly hard problems with a large number of populations, small number of samples, or greater degree of admixture, least-squares performs better than the other methods. On simulated mixtures of real population allele frequencies from the HapMap project, Admixture estimates sparsely mixed individuals better than Least-squares. The least-squares approach, however, performs within 1.5% of the Admixture error. On individual genotypes from the HapMap project, Admixture and least-squares perform qualitatively similarly and within 1.2% of each other. Significantly, the least-squares approach nearly always converges 1.5- to 6-times faster. The computational advantage of the least-squares approach along with its good estimation performance warrants further research, especially for very large datasets. As problem sizes increase, the difference in estimation performance between all algorithms decreases. In addition, when prior information is known, the least-squares approach easily incorporates the expected degree of admixture to improve the estimate.


Efficacy of sublingual administration of detomidine gel for sedation of horses undergoing veterinary and husbandry procedures under field conditions.
To determine whether sublingual detomidine gel administration to horses would be effective in providing an appropriate degree of sedation and restraint to facilitate completion of veterinary and husbandry procedures under field conditions. Multicenter, prospective, randomized, blinded, placebo-controlled clinical study. 270 client-owned horses known to require sedation or strong restraint to enable veterinary and husbandry procedures to be performed. Horses randomly received a single dose of detomidine gel (0.04 mg/kg [0.018 mg/lb]) or placebo gel administered sublingually. Horses were sedated to facilitate cleaning the prepuce, cutting of hair with electric clippers, hoof trimming or application of shoes, manual dental floating (ie, rasping or filing of the teeth to remove irregularities), nasogastric passage of a stomach tube or endoscope, and radiography. The primary determinant of efficacy was an assessment by a veterinarian on the ability or inability to successfully conduct the procedure. 171 horses met all the study protocol criteria. One hundred twenty-nine horses were treated with detomidine. The procedure was completed successfully for 76% (98/129) of the detomidine-treated horses, while the procedure was completed successfully for only 7% (3/42) of the placebo-treated horses. The percentage of horses in which the procedure was successfully completed was significantly different between detomidine-treated horses and placebo-treated horses. No serious adverse effects were reported. Detomidine gel administered to horses sublingually at a dose of 0.04 mg/kg provided an appropriate degree of sedation and restraint to facilitate completion of veterinary and husbandry procedures in horses known to require sedation for such procedures.


Acylated apelin-13 amide analogues exhibit enzyme resistance and prolonged insulin releasing, glucose lowering and anorexic properties.
The adipokine, apelin has many biological functions but its activity is curtailed by rapid plasma degradation. Fatty acid derived apelin analogues represent a new and exciting avenue for the treatment of obesity-diabetes. This study explores four novel fatty acid modified apelin-13 analogues, namely, (Lys8GluPAL)apelin-13 amide, pGlu(Lys8GluPAL)apelin-13 amide, Lys8GluPAL(Tyr13)apelin-13 and Lys8GluPAL(Val13)apelin-13. Fatty acid modification extended the half-life of native apelin-13 to >24 h in vitro. pGlu(Lys8GluPAL)apelin-13 amide was the most potent insulinotropic analogue in BRIN-BD11 cells and isolated islets with maximal stimulatory effects of up to 2.7-fold (p < .001). (Lys8GluPAL)apelin-13 amide (1.9-fold) and Lys8GluPAL(Tyr13)apelin-13 (1.7-fold) were less effective, whereas Lys8GluPAL(Val13)apelin-13 had an inhibitory effect on insulin secretion. Similarly, pGlu(Lys8GluPAL)apelin-13 amide was most potent in increasing beta-cell intracellular Ca2+ concentrations (1.8-fold, p < .001) and increasing glucose uptake in 3T3-L1 adipocytes (2.3-fold, p < .01). Persistent biological action was observed with both pGlu(Lys8GluPAL)apelin-13 amide and (Lys8GluPAL)apelin-13 amide significantly reducing blood glucose (39-43%, p < .01) and enhancing insulin secretion (43-56%, p < .001) during glucose tolerance tests in diet-induced obese mice. pGlu(Lys8GluPAL)apelin-13 amide and (Lys8GluPAL)apelin-13 amide also inhibited feeding (28-40%, p < .001), whereas Lys8GluPAL(Val13)apelin-13 increased food intake (8%, p < .05) in mice. These data indicate that novel enzymatically stable analogues of apelin-13 may be suitable for future development as therapeutic agents for obesity-diabetes.


Heart and heart-lung transplantation.
Twenty-seven years of laboratory experience in cardiac transplantation at Stanford have provided the necessary background for a moderately successful clinical program which now extends over a period of 17 years. Heart-lung transplantation, again entirely a product of intensive laboratory research, is now ready for clinical use. Certainly much work remains to be done in the area of donor tissue preservation, particularly with respect to the lungs. It appears that new and more specific immunosuppressing drugs are on the horizon, so tissue transplantation in general will be increasingly safer. Heart transplantation has come of age, and combined heart-lung transplantation is well under way.


Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.
Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.


Health provider identified barriers and facilitators to weight management for individuals with spinal cord injury.
Qualitative descriptive study using semi-structured interviews OBJECTIVE: The purpose of this study was to examine the barriers and facilitators of weight management in individuals with spinal cord injury (SCI) from the perspective of SCI health care providers. Veterans Health Administration and Midwest Regional SCI Care Systems. Health care providers (n = 25) who care for individuals with SCI completed semi-structured interviews. Thematic analysis methodology was used to identify emergent themes around barriers and facilitators to weight management in SCI. Sixteen subthemes emerged for barriers and seven subthemes emerged for facilitators for weight management in SCI. Barriers included individual-level factors (e.g., physical ability/mobility limitations, lack of interest, psychological obstacles, lack of knowledge, poor dietary strategies), socio-environmental factors (e.g., challenges with family support, lack of access to weight management resources, dependency on others, difficulties obtaining weight measurement), and organizational factors (e.g., lack of integration/inconsistent weight management support from healthcare systems, pushing calorie intake early post-injury). Facilitators included individual-level factors (e.g., motivation, education/knowledge, participation in exercise and physical activity) and socio-environmental factors (e.g., positive support network, access to/use of healthy dietary strategies, access to exercise facilities/adaptive equipment, participating in weight management with others). Healthcare providers identified individual-level, socio-environmental, and organizational barriers and facilitators that influence weight management efforts in individuals with SCI. Future weight management resources and programs should consider addressing common barriers identified by healthcare providers, individuals with SCI, and their caregivers, and develop strategies to promote facilitators to enhance weight management in this population.


Tuning the Fano resonance with an intruder continuum.
Through a combination of experiment and theory we establish the possibility of achieving strong tuning of Fano resonances (FRs), by allowing their usual two-path geometry to interfere with an additional, "intruder", continuum. As the coupling strength to this intruder is varied, we predict strong modulations of the resonance line shape that, in principle at least, may exceed the amplitude of the original FR itself. For a proof-of-concept demonstration of this phenomenon, we construct a nanoscale interferometer from nonlocally coupled quantum point contacts and utilize the unique features of their density of states to realize the intruder. External control of the intruder coupling is enabled by means of an applied magnetic field, in the presence of which we demonstrate the predicted distortions of the FR. This general scheme for resonant control should be broadly applicable to a variety of wave-based systems, opening up the possibility of new applications in areas such as chemical and biological sensing and secure communications.


Correlation between thyroid peroxidase activity and histopathological and ultrastructural changes in various thyroid diseases.
A morphological and biochemical study was performed on thyroid tissue with various thyroid diseases. The thyroid peroxidase (TPO) activity of normal thyroid tissues ranged from 2.6 to 7.0 mGU/mg DNA. The activity was low in adenomas and extremely low in carcinomas, and there was no significant relationship between the histological subclassification of follicular adenomas (simple, colloid, oxyphil) and TPO activity. The activity was various in the cases of chronic thyroiditis, ranging from non-detectable to 9.8 mGU/mg DNA, and the TPO activity showed a close correlation with the degree of lymphoid cell infiltration of the diseases. In the seven cases of Graves' disease, the values were high, though the elevation was not so remarkable in three cases which had already been euthyroid or slightly hypothyroid after long-term treatment. By means of subcellular fractionation, more than 50% of peroxidase activity was shown to be localized in the microsomal pellets, and this result well coincided with the electron microscopic findings of prominent development of rER.