Terahertz lenses made by compression molding of micropowders.
We present a simple and versatile approach for fabricating terahertz lenses based on compression molding of micropowder polymer materials in a tabletop hydraulic press. To demonstrate the feasibility of this approach, a biconvex lens shape is calculated using a ray-tracing algorithm and lenses based on two different micropowders are fabricated. As the powder materials have different refractive indices, the resulting lenses share the same geometric shape but differ in their respective focal length. The focusing properties of the lenses are evaluated by transversal and sagittal beam profile measurements in a fiber-coupled terahertz time-domain spectroscopy system, confirming the excellent imaging qualities of the compression molded lenses.


Cardiac titin: structure, functions and role in disease.
Titin is a giant sarcomeric protein found in both cardiac and skeletal muscle. In the heart, the structure, functions and role of titin in disease have begun to be elucidated over the last decade. Titin's N-terminus is anchored in the Z-disk while C-terminal domains are bound to the thick filament. The I-band segment is a complex molecular spring consisting of PEVK and tandem Ig segments as well as variable N2B and N2A elements. The latter determine titin's two isoforms. N2B alone is present in the smaller and stiffer N2B isoform and both N2A and N2B elements are present in the larger, more compliant N2BA isoform. Large mammals co-express both isoforms, while normal rodents have virtually exclusively N2B titin. With sarcomere stretch, titin's I-band segment elongates and develops passive tension. Titin is the predominant determinant of cardiomyocyte passive tension over the physiologic sarcomere length range. With contraction below slack length, the thick filament drags titin in the opposite direction such that extension of the spring results in generation of a restoring force resulting in elastic recoil. In addition to its mechanical properties, a role is emerging for titin as a major biomechanical sensing and signaling molecule. Moreover, recent studies indicate that titin undergoes dynamic isoform and possibly phosphorylation changes in disease.


Magnetic field controlled graphene oxide-based origami with enhanced surface area and mechanical properties.
One can utilize the folding of paper to build fascinating 3D origami architectures with extraordinary mechanical properties and surface area. Inspired by the same, the morphology of 2D graphene can be tuned by addition of magnetite (Fe3O4) nanoparticles in the presence of a magnetic field. The innovative 3D architecture with enhanced mechanical properties also shows a high surface area (∼2500 m2 g-1) which is utilized for oil absorption. Detailed microscopy and spectroscopy reveal rolling of graphene oxide (GO) sheets due to the magnetic field driven action of magnetite particles, which is further supported by molecular dynamics (MD) simulations. The macroscopic and local deformation resulting from in situ mechanical loading inside a scanning electron microscope reveals a change in the mechanical response due to a change internal morphology, which is further supported by MD simulation.


Value of breath hydrogen analysis in management of diarrheal illness in childhood: comparison with duodenal biopsy.
Breath hydrogen tests were carried out on 157 children either because they had chronic diarrhea or because they were on disaccharide-free diets. Lactose malabsorption was common in patients with postgastroenteritis syndrome (43%), and sucrose malabsorption was readily detected in patients with congenital sucrase-isomaltase deficiency. Secondary sucrose malabsorption and small bowel bacterial overgrowth were also detected. In predicting clinical response to dietary change, the breath hydrogen test, as we perform it, was clearly the most specific and sensitive and had a predictive accuracy of 96%. Duodenal biopsy results obtained from 48 of the children gave a 23% incidence of misleading disaccharidase results (16.7% falsely normal, 6.3% falsely abnormal), but biopsy remains vital in the diagnosis of congenital sucrase-isomaltase deficiency. False negative breath hydrogen results were obtained on occasions (4%) but in most instances were related to recent antimicrobial therapy or failure of the breath test mechanics (e.g., vomiting, length of sampling).


Phylogenetic and temporal dynamics of human immunodeficiency virus type 1 CRF01_AE in China.
To explore the epidemic history of HIV-1 CRF01_AE in China, 408 fragments of gag gene sequences of CRF01_AE sampled in 2002-2010 were determined from different geographical regions and risk populations in China. Phylogenetic analysis indicates that the CRF01_AE sequences can be grouped into four clusters, suggesting that at least four genetically independent CRF01_AE descendants are circulating in China, of which two were closely related to the isolates from Thailand and Vietnam. Cluster 1 has the most extensive distribution in China. In North China, cluster 1 and cluster 4 were mainly transmitted through homosexuality.The real substance of the recent HIV-1 epidemic in men who have sex with men(MSM) of North China is a rapid spread of CRF01_AE, or rather two distinctive natives CRF01_AE.The time of the most recent common ancestor (tMRCA) of four CRF01_AE clusters ranged from the years 1990.9 to 2003.8 in different regions of China. This is the first phylogenetic and temporal dynamics study of HIV-1 CRF01_AE in China.


Widely tunable fiber-coupled single-frequency Er-Yb:glass laser.
A fiber-coupled tunable Er-Yb:glass minilaser is presented with output power of 40 mW. The laser can be stepwise tuned in single-frequency operation from 1530 to 1560 nm by compressing a fiber Bragg grating that provides selective feedback. Constant output power (fluctuation < 0.8 dB) over the full tuning range is demonstrated. The relative intensity noise spectrum was measured to be < 150 dB/Hz for frequencies > 2 MHz.


Estimating test characteristics of somatic cell count to detect Staphylococcus aureus-infected dairy goats using latent class analysis.
The aim of this study was to estimate test properties of composite somatic cell count (cSCC) to detect subclinically Staphylococcus aureus-infected dairy goats. Staphylococcus aureus is the most prevalent major pathogen in goats, and responsible for the majority of clinical mastitis cases. Therefore, a diagnostic tool that detects subclinical Staph. aureus infections may be useful in decreasing the number of clinical cases. We collected samples from 384 animals in 4 herds for bacteriological culture and cSCC on 3 occasions in lactation: once in early lactation, once around peak lactation, and once in late lactation. Latent class models were used to estimate test properties of cSCC and bacteriological culture in the absence of a gold standard reference test under the assumption that both tests detect Staph. aureus intramammary infection. Estimates for test properties of cSCC in early lactation at a cut-off value of 1,500 × 10(3) cells/mL were 0.90 for sensitivity and 0.95 for specificity, making cSCC a useful screening tool for detection of Staph. aureus. An effect of lactation stage was observed, causing an increased sensitivity and decreased specificity in late lactation. The sensitivity of bacteriological culture was estimated to be very low in the latent class models and the models suggested that the true prevalence of Staph. aureus in dairy goat herds is much higher than what is commonly reported based on bacteriological culture. This implies that intramammary infection by Staph. aureus may be an underestimated problem in dairy goat herds, and that cSCC can be used to diagnose infected animals.


Inhibitors of histone deacetylases: correlation between isoform specificity and reactivation of HIV type 1 (HIV-1) from latently infected cells.
Deacetylation of histone proteins at the HIV type 1 (HIV-1) long terminal repeat (LTR) by histone deactylases (HDACs) can promote transcriptional repression and virus latency. As such, HDAC inhibitors (HDACI) could be used to deplete reservoirs of persistent, quiescent HIV-1 proviral infection. However, the development of HDACI to purge latent HIV-1 requires knowledge of the HDAC isoforms contributing to viral latency and the development of inhibitors specific to these isoforms. In this study, we identify the HDACs responsible for HIV-1 latency in Jurkat J89GFP cells using a chemical approach that correlates HDACI isoform specificity with their ability to reactivate latent HIV-1 expression. We demonstrate that potent inhibition or knockdown of HDAC1, an HDAC isoform reported to drive HIV-1 into latency, was not sufficient to de-repress the viral LTR. Instead, we found that inhibition of HDAC3 was necessary to activate latent HIV-1. Consistent with this finding, we identified HDAC3 at the HIV-1 LTR by chromatin immunoprecipitation. Interestingly, we show that valproic acid is a weak inhibitor of HDAC3 (IC(50) = 5.5 mm) relative to HDAC1 (IC(50) = 170 μm). Because the total therapeutic concentration of valproic acid ranges from 275 to 700 μm in adults, these data may explain why this inhibitor has no effect on the decay of latent HIV reservoirs in patients. Taken together, our study suggests an important role for HDAC3 in HIV-1 latency and, importantly, describes a chemical approach that can readily be used to identify the HDAC isoforms that contribute to HIV-1 latency in other cell types.


The use of agrobiodiversity for plant improvement and the intellectual property paradigm: institutional fit and legal tools for mass selection, conventional and molecular plant breeding.
Focused on the impact of stringent intellectual property mechanisms over the uses of plant agricultural biodiversity in crop improvement, the article delves into a systematic analysis of the relationship between institutional paradigms and their technological contexts of application, identified as mass selection, controlled hybridisation, molecular breeding tools and transgenics. While the strong property paradigm has proven effective in the context of major leaps forward in genetic engineering, it faces a systematic breakdown when extended to mass selection, where innovation often displays a collective nature. However, it also creates partial blockages in those innovation schemes rested between on-farm observation and genetic modification, i.e. conventional plant breeding and upstream molecular biology research tools. Neither overly strong intellectual property rights, nor the absence of well delineated protection have proven an optimal fit for these two intermediary socio-technological systems of cumulative incremental innovation. To address these challenges, the authors look at appropriate institutional alternatives which can create effective incentives for in situ agrobiodiversity conservation and the equitable distribution of technologies in plant improvement, using the flexibilities of the TRIPS Agreement, the liability rules set forth in patents or plant variety rights themselves (in the form of farmers', breeders' and research exceptions), and other ad hoc reward regimes.


Juglans Sporopollenin for High-Performance Supercapacitor Electrode Design.
Recently, plant pollen has been used as a source of activated carbon to produce carbon-containing supercapacitor electrodes. However, in this study, pollen was used as a biotemplate with a completely different approach. As a biotemplate, pollen offers a wide range of varieties in terms of exterior, porosity, shape, and size. An electrode formed by the use of metal oxide grown on the pollen exine layer (sporopollenin microcapsules) as the active substance will inevitably exhibit good electrochemical capacitive properties. Juglans male flowers have been distinguished by dissection from anthers. Isolation of pollen grains from anthers was carried out using sieving from suitable sieves (45-200 μm). Juglans sporopollenin exine microcapsules (SECs) were separated from the intine and protoplasm by acetolysis in combination with reflux. The solution containing SECs, metal ions, and Ni foam was put into a Teflon-lined hydrothermal container, and then, it was reacted at 120 °C for 15 h. The resulting precipitate, as well as the Ni foam, was heat-treated at 300 and 360 °C for 3 h in air. The raw pollen, chemically treated pollen, and cobalt-coated SEC (CoSEC) and CoSEC/Ni foam were characterized using scanning electron microscopy, Brunauer-Emmett-Teller surface area analysis, thermogravimetric analysis, and X-ray diffraction techniques. Two different types of supercapacitor electrode designs, with the use of exine microcapsules of Juglans sporopollenin, were performed for the first time. The maximum specific capacitance was up to 1691 F g-1 at 5 A g-1.


Whole genome sequence of a goose haemorrhagic polyomavirus detected in Hungary.
Goose haemorrhagic polyomavirus (GHPV) provoke haemorrhagic nephritis and enteritis of domestic geese. Outbreaks were detected in European countries and caused economic losses for goose keepers. Domestic ducks may be infected with GHPV without any signs typical for geese. The genomic organisation of some isolates was described but the gene functions and the pathomechanisms of the virus was not precisely defined. Here we describe the genome sequence and structure of GHPV of a goose from a Hungarian goose flock showing characteristics of the haemorrhagic nephritis and enteritis. The GHPV genome investigated in this study was 5252 bp long and was very similar (99% nucleotide identity) to sequences deposited in the GenBank. All the whole GHPV genomes possess the same ORFs in length, including the VP1, VP2, VP3, ORF-X, t and T tumour antigens. Amino acid changes are detected mainly in the putative ORF-X region. Data about the GHPV genome imply a conserved genomic structure among isolates from different countries. Genomic and epidemiological studies may help vaccine development efforts and identify potential heterologous reservoirs of GHPV.


Metamorphosis of the mushroom bodies; large-scale rearrangements of the neural substrates for associative learning and memory in Drosophila.
Paired brain centers known as mushroom bodies are key features of the circuitry for insect associative learning, especially when evoked by olfactory cues. Mushroom bodies have an embryonic origin, and unlike most other brain structures they exhibit developmental continuity, being prominent components of both the larval and the adult CNS. Here, we use cell-type-specific markers, provided by the P[GAL4] enhancer trap system, to follow specific subsets of mushroom body intrinsic and extrinsic neurons from the larval to the adult stage. We find marked structural differences between the larval and adult mushroom bodies, arising as the consequence of large-scale reorganization during metamorphosis. Extensive, though incomplete, degradation of the larval structure is followed by establishment of adult specific alpha and beta lobes. Kenyon cells of embryonic origin, by contrast, were found to project selectively to the adult gamma lobe. We propose that the gamma lobe stores information of relevance to both developmental stages, whereas the alpha and beta lobes have uniquely adult roles.


Clinical and histologic studies of a Qatari family with myofibrillar myopathy.
The current study reports the first family with confirmed myofibrillar myopathy MFM in the Middle East and the third family worldwide. This study highlights the importance of considering MFM in young patients presenting with idiopathic cardiomyopathy, arrhythmia or atrioventricular block in the Gulf states. This is the first report that presented 2 different types of cardiomyopathy and 2 different indications of permanent pacemaker placement in the same generation of a family with MFM. This report studies a Qatari family consisting of one brother and 3 sisters. The brother had restrictive cardiomyopathy at the age of 16 years. One sister underwent heart transplantation for severe hypertrophic cardiomyopathy at the age of 15 years, the other sister had permanent pacemaker for complete heart block at the age of 21 years. This report is focused mainly on the clinical presentation and investigations carried out for the brother including echocardiogram, cardiac catheterization, cardiac and skeletal muscle biopsy, and electromyography and electrophysiology studies. The study findings support the diagnosis of MFM.


Mechanism of hypoxia-stimulated glucose transport in rat skeletal muscle: potential role of glycogen.
We have previously reported that exercise training is associated with enhanced insulin-stimulated glucose transport activity and inhibited hypoxia-stimulated glucose transport activity in rat epitrochlearis muscle. Here we examine the potential role of muscle glycogen in the inhibited glucose transport response to hypoxia. Three days of swim training (2 x 3 h/day) produce a 100% increase in glycogen and a 70% increase in GLUT-4 in epitrochlearis muscle. Glucose transport after 1 h of hypoxia in muscles from fed exercise-trained (ET) rats is not significantly elevated above basal and is 40% lower than that in muscles from fed sedentary (SED) rats. Glycogen levels after 1 h of hypoxia are reduced by 27 and 64% in muscles from fed ET and fed SED rats, respectively. After 2 h of hypoxia, glucose transport is significantly increased above basal in muscles from fed ET rats, but this response is still 55% lower than that in muscles from fed SED rats. After 2 h of hypoxia, glycogen is reduced by 50 and 83% in muscles from fed ET and fed SED rats, respectively. After a modified overnight fast (approximately 4.5 g of chow), the glucose transport and glycogen responses to 1 h of hypoxia are not significantly different between muscles from ET and SED rats. These findings demonstrate a strong inverse relationship between glycogen and hypoxia-stimulated glucose transport activity and that high levels of glycogen contribute to the inhibited glucose transport response to hypoxia. Furthermore, failure of the overexpression of GLUT-4 after exercise training to enhance the glucose transport response to contraction/hypoxia suggests selective targeting of the additional GLUT-4 to the insulin-responsive pool.


Immune protection against Trypanosoma cruzi induced by TcVac4 in a canine model.
Chagas disease, caused by Trypanosoma cruzi, is endemic in southern parts of the American continent. Herein, we have tested the protective efficacy of a DNA-prime/T. rangeli-boost (TcVac4) vaccine in a dog (Canis familiaris) model. Dogs were immunized with two-doses of DNA vaccine (pcDNA3.1 encoding TcG1, TcG2, and TcG4 antigens plus IL-12- and GM-CSF-encoding plasmids) followed by two doses of glutaraldehyde-inactivated T. rangeli epimastigotes (TrIE); and challenged with highly pathogenic T. cruzi (SylvioX10/4) isolate. Dogs given TrIE or empty pcDNA3.1 were used as controls. We monitored post-vaccination and post-challenge infection antibody response by an ELISA, parasitemia by blood analysis and xenodiagnosis, and heart function by electrocardiography. Post-mortem anatomic and pathologic evaluation of the heart was conducted. TcVac4 induced a strong IgG response (IgG2>IgG1) that was significantly expanded post-infection, and moved to a nearly balanced IgG2/IgG1 response in chronic phase. In comparison, dogs given TrIE or empty plasmid DNA only developed high IgG titers with IgG2 predominance in response to T. cruzi infection. Blood parasitemia, tissue parasite foci, parasite transmission to triatomines, electrocardiographic abnormalities were significantly lower in TcVac4-vaccinated dogs than was observed in dogs given TrIE or empty plasmid DNA only. Macroscopic and microscopic alterations, the hallmarks of chronic Chagas disease, were significantly decreased in the myocardium of TcVac4-vaccinated dogs. We conclude that TcVac4 induced immunity was beneficial in providing resistance to T. cruzi infection, evidenced by control of chronic pathology of the heart and preservation of cardiac function in dogs. Additionally, TcVac4 vaccination decreased the transmission of parasites from vaccinated/infected animals to triatomines.


Association of hemicolectomy with survival in stage II colorectal cancer: a retrospective cohort study.
To compare the oncological survival outcomes of partial colectomy (PC) and hemicolectomy (HC) in patients with stage II colon cancer. A total of 18,795 patients with stage II colon cancer who underwent hemicolectomy (n = 12,022) or partial colectomy (n = 6773) from 2010 to 2019 were included in the the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were compared between the two groups, and the threshold of harvested lymph nodes was determined. The results showed that age, gender, race, tumor site, scope of regional lymph nodes, postoperative chemotherapy, postoperative radiotherapy, harvested lymph nodes, and tumor size were significantly different between the PC and HC groups (all P < 0.05). The OS rate was slightly lower in hemicolectomy patients than in partial colectomy patients (69.9% vs. 74.5%, respectively, P < 0.001), but CSS was similar between the two groups (87.9% vs. 88.1%, respectively, P = 0.32). After propensity score matching (PSM) was performed, the OS and CSS rates in the two groups were significantly different (CSS 84.3% vs. 88.0%, P < 0.001; OS 62.2% vs. 72.5%, P < 0.001). The survminer R package determined that the optimum threshold for the harvested lymph node count in stage II colon cancer patients was 16. CSS was significantly different between patients with ≥ 12 lymph nodes harvested and patients with ≥ 16 lymph nodes harvested (P = 0.043). Univariate and multivariate Cox regression and survival analyses of stage II colon cancer patients showed that the survival benefit of stage II colon cancer patients receiving partial colectomy was superior to that of patients receiving hemicolectomy. Partial colectomy has significant oncological benefits over hemicolectomy in the treatment of stage II colon cancer patients, even in the case of pT4b or tumor deposits. Removal of 16 lymph nodes during colectomy for stage II colon cancer correlated with improved survival, and this threshold was more effective than the standard threshold of 12 lymph nodes in distinguishing between patients with good and poor prognoses.


The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex.
Schizophrenia is a life-long, severe, and disabling brain disorder that requires chronic pharmacotherapy. Because current antipsychotic drugs do not provide optimal therapy, we have been developing novel treatments that focus on receptors for the neuropeptide neurotensin (NT). NT69L, an analog of neurotensin(8-13), acts like an atypical antipsychotic drug in several dopamine-based animal models used to study schizophrenia. Another current animal model utilizes non-competitive antagonists of the NMDA/glutamate receptor, such as the psychotomimetic phencyclidine (PCP). In the present study, we investigated the effects of NT69L on PCP-induced behavioral and biochemical changes in the rat. The top of an activity chamber was modified to allow us to perform microdialysis in rat brain, while simultaneously recording the locomotor activity of a rat. PCP injection significantly increased activity as well as the extracellular concentration of norepinephrine (NE), 5-HT, dopamine (DA), and glutamate in the medial prefrontal cortex (mPFC). Pretreating with NT69L blocked the PCP-induced hyperactivity as well as the increase of DA, 5-HT, NE, and glutamate in mPFC. Interestingly and unexpectedly, NT69L markedly increased glycine levels, while PCP was without effect on glycine levels. Thus, NT69L showed antipsychotic-like effects in this glutamate-based animal model for studying schizophrenia. Previous work from our group suggests that NT69L also has antipsychotic-like effects in dopaminergic and serotonergic rodent models. Taken together, these data suggest that NT69L in particular and NT receptor agonists in general, will be useful as broad-spectrum antipsychotic drugs.


Cysteinyl Leukotrienes in Eosinophil Biology: Functional Roles and Therapeutic Perspectives in Eosinophilic Disorders.
Cysteinyl leukotrienes (cysLTs), LTC4, and its extracellular metabolites, LTD4 and LTE4, have varied and multiple roles in mediating eosinophilic disorders including host defense against parasitic helminthes and allergic inflammation, especially in the lung and in asthma. CysLTs are known to act through at least 2 receptors termed cysLT1 receptor (CysLT1R) and cysLT2 receptor (CysLT2R). Eosinophils contain a dominant population of cytoplasmic crystalloid granules that store various preformed proteins. Human eosinophils are sources of cysLTs and are known to express the two known cysLTs receptors (CysLTRs). CysLTs can have varied functions on eosinophils, ranging from intracrine regulators of secretion of granule-derived proteins to paracrine/autocrine roles in eosinophil chemotaxis, differentiation, and survival. Lately, it has been recognized the expression of CysLTRs in the membranes of eosinophil granules. Moreover, cysLTs have been shown to evoke secretion from isolated cell-free eosinophil granules operating through their receptors expressed on granule membranes. In this work, we review the functional roles of cysLTs in eosinophil biology. We review cysLTs biosynthesis, their receptors, and argue the intracrine and paracrine/autocrine responses induced by cysLTs in eosinophils and in isolated free extracellular eosinophil granules. We also examine and speculate on the therapeutic relevance of targeting CysLTRs in the treatment of eosinophilic disorders.


[Conduction of iliac-femoral arterial reconstruction using retroperitoneal miniaccess].
There was summarized the experience of treatment of 25 patients for obliterating atherosclerosis of external iliac artery, in 10 of whom the external artery reconstruction, using the elaborated miniinvasive method, was performed. The intraoperative blood loss and postoperative complications rate reduction, the quality of life improvement, the stationary treatment period shortening and its cost lowering, the achievement of better cosmetic effect were noted.


delta-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome.
Patients with nevoid basal cell carcinoma syndrome suffer from multiple basal cell carcinomas, requiring numerous surgical procedures that over time leave them with multiple disfiguring scars. Photodynamic therapy with delta-aminolevulinic acid using red light (approximately 630 nm) sources has been reported as effective in treatment of superficial and small nodular basal cell carcinomas. To our knowledge, the blue light source (417 nm peak irradiance) approved by the FDA for treatment of actinic keratoses has not been used for photodynamic therapy with delta-aminolevulinic acid of basal cell carcinoma. We report treatment of two nevoid basal cell carcinoma syndrome patients, women aged 21 and 47, with 20%delta-aminolevulinic acid solution and 417-nm blue light source (irradiance 10 mW/cm(2)). delta-Aminolevulinic acid was applied topically on lesions 1 to 5 hr before light treatment. Lesions were illuminated with 417+/-5-nm blue light for 1000 sec (10 J/cm(2)). Two consecutive treatments 1 week apart were administered as a therapeutic course. Each patient underwent two courses of photodynamic therapy with delta-aminolevulinic acid 2 to 4 months apart. The reported assessment was made 8 months after initial treatment. In most sessions the entire face, rather than visible basal cell carcinomas only, was treated. The treated basal cell carcinomas were clinically subdivided to superficial or nodular type guided by their morphologic features. A total of 9 superficial and 16 nodular basal cell carcinomas on the face and 27 superficial basal cell carcinomas on the lower extremities were treated. Complete clinical response was observed in 8 of 9 (89%) superficial basal cell carcinomas and 5 of 16 (31%) nodular basal cell carcinomas on the face and in 18 of 27 (67%) of superficial basal cell carcinomas on the lower extremities. The remaining 21 lesions showed partial clinical resolution. No new basal cell carcinomas were observed during the 8-month follow-up period in areas treated with a broad application technique. Resolution of the lesions was accompanied by an excellent cosmetic outcome and decreased prominence of old surgical scars in the more severely affected patient. Treatments were well tolerated, but associated with moderate to severe stinging during illumination. To our knowledge this is the first use of photodynamic therapy with delta-aminolevulinic acid with 417-nm blue light for treatment of multiple basal cell carcinomas in patients with nevoid basal cell carcinoma syndrome. Our clinical results demonstrate that the blue light reduces cutaneous tumor burden in such patients. Further studies are needed to confirm that broad-area photodynamic therapy with delta-aminolevulinic acid may eradicate subclinical tumors in nevoid basal cell carcinoma syndrome sufferers, as suggested by a strikingly decreased incidence of new basal cell carcinomas in our patients.


Reduction of beta-endorphin levels in the amniotic fluid of heroin addicts.
Plasma levels of beta-endorphin and beta-lipotropin in 18 heroin addicts were found to be similar to those in pregnant control subjects at all stages of gestation. In contrast, amniotic fluid levels of beta-endorphin were significantly lower in heroin abusers than in controls in both the first and second trimesters. Amniotic fluid levels of beta-lipotropin were reduced only in the second trimester. At term, when the patients were almost drug free, the amniotic fluid levels of both peptides were in the control range. These data support the existence of a specific control mechanism for amniotic fluid levels of beta-endorphin and beta-lipotropin, independent of the maternal pituitary, and show that exogenous opiates interfere with it negatively.


Genistein induces apoptosis by the inactivation of the IGF-1R/p-Akt signaling pathway in MCF-7 human breast cancer cells.
Genistein is an estrogenic soy-derived compound belonging to the isoflavone class and shows anti-cancer effects. However, the specific cell apoptosis mechanisms of genistein have not been fully understood. In this study, we investigated the specific cell apoptosis mechanisms of genistein and the potential involvement of the IGF1R-Akt-Bcl-2 and Bax-mediated pathways in human breast cancer cells in vitro. MCF-7 human breast cancer cells were treated with various concentrations of genistein, and cell proliferation was evaluated by the MTT assay. Morphological changes in treated cells were examined by Hoechst 33258 staining, and treated cells were examined by flow cytometry. The levels of IGF-1R, p-Akt, Bcl-2, and Bax protein expression and Bcl-2 and Bax mRNA expression were evaluated by western blot and RT-PCR, respectively. Genistein inhibited the proliferation of MCF-7 cells and induced cell apoptosis, as determined by Hoechst staining and flow cytometry analysis. Furthermore, genistein induced the inactivation of IGF-1R and p-Akt and downregulated the Bcl-2/Bax protein ratio. These results suggest that genistein inhibited cell proliferation by inactivating the IGF-1R-PI3 K/Akt pathway and decreasing the Bcl-2/Bax mRNA and protein expressions. Our findings help elucidate the mechanisms by which genistein may contribute to the prevention of breast cancer carcinogenesis.


Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines.
Methcathinone and methylone, the beta-ketone analogues of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), respectively, were tested for neurotransmitter uptake inhibition in vitro. The beta-ketones were threefold less potent than the nonketo drugs at inhibiting platelet serotonin accumulation, with IC(50)'s of 34.6+/-4.8 microM and 5.8+/-0.7 microM, respectively. Methcathinone and methylone were similar in potency to methamphetamine and MDMA at catecholamine transporters individually expressed in transfected glial cells. For dopamine uptake, IC(50)'s were 0.36+/-0.06 microM and 0.82+/-0.17 microM, respectively; for noradrenaline uptake, IC(50) values were 0.51+/-0.10 microM and 1. 2+/-0.1 microM, respectively. In chromaffin granules, IC(50)'s for serotonin accumulation were 112+/-8.0 microM for methcathinone and 166+/-12 microM for methylone, 10-fold higher than the respective values for methamphetamine and MDMA. Our results indicate that methcathinone and methylone potently inhibit plasma membrane catecholamine transporters but only weakly inhibit the vesicle transporter.


A redox-mediated Kemp eliminase.
The acid/base-catalysed Kemp elimination of 5-nitro-benzisoxazole forming 2-cyano-4-nitrophenol has long served as a design platform of enzymes with non-natural reactions, providing new mechanistic insights in protein science. Here we describe an alternative concept based on redox catalysis by P450-BM3, leading to the same Kemp product via a fundamentally different mechanism. QM/MM computations show that it involves coordination of the substrate's N-atom to haem-Fe(II) with electron transfer and concomitant N-O heterolysis liberating an intermediate having a nitrogen radical moiety Fe(III)-N· and a phenoxyl anion. Product formation occurs by bond rotation and H-transfer. Two rationally chosen point mutations cause a notable increase in activity. The results shed light on the prevailing mechanistic uncertainties in human P450-catalysed metabolism of the immunomodulatory drug leflunomide, which likewise undergoes redox-mediated Kemp elimination by P450-BM3. Other isoxazole-based pharmaceuticals are probably also metabolized by a redox mechanism. Our work provides a basis for designing future artificial enzymes.


Family history of premature myocardial infarction modifies the associations between bilateral oophorectomy and cardiovascular disease mortality in a US national cohort of postmenopausal women.
To test the hypothesis that a family history of premature myocardial infarction (FHPMI) will modify the associations between bilateral salpingo-oophorectomy (BSO) and mortality due to heart disease (HD), cardiovascular disease (CVD), or all-cause mortality with stronger associations observed for BSO occurring before 45 years. We analyzed data from 2,763 postmenopausal women aged 40 years or older who participated in the National Health and Nutrition Examination Survey (1988-1994) and were followed through December 31, 2015. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality outcomes (HD, CVD, and all-cause). At baseline, the average age was 62 years. There were 610 women with BSO, 338 women with FHPMI, and 95 women with both BSO and FHPMI. During a median follow-up of 22 years, 1,713 deaths occurred of which 395 and 542 were attributed to HD and CVD, respectively. In models adjusting for CVD risk factors and hormone therapy use, HD mortality was greater among women with both BSO and FHPMI compared to those without either of these conditions (HR: 2.88, 95% CI: 1.72-4.82, PInteraction = 0.016). HD mortality was higher among women with FHPMI and BSO at an earlier age (<45 y: HR: 4.32, 95% CI: 1.95-9.50 vs ≥45 y: HR: 1.60, 95% CI: 0.63-4.09). Similar observations were seen for CVD and all-cause mortality. In this study, the risk of HD, CVD, and all-cause mortality in women with BSO was modified by an FHPMI with the risk limited to women undergoing BSO at younger ages.


Telemedicine for Hip Preservation Patients: Access, Ability and Preference.
Recent events have resulted in rapid rises in the use of telemedicine in orthopaedic surgery, despite limited evidence regarding patient preferences or concerns. The purpose of this study is to determine access to and, ability to use telemedicine technology in an adult hip preservation patient population, as well as determine associations with patient characteristics. Additionally, we seek to understand patients' perceived benefits, risks and preferences of telemedicine. We performed a cross-sectional survey administered on patients scheduled to undergo joint preservation surgery by one of three surgeons at a single academic institution. Both preoperative and postoperative established patients were included and called for a telephone administered survey if a date of surgery was scheduled between October 1, 2019 and March 30, 2020 and were 18 years or older. The survey had seven sections with 45 questions relating to demographics, technology access, videoconferencing capability, confidence using technology, telehealth experiences, perceptions. 101 patients completed the survey (48% response rate, 101/212). Overall, 99% of participants reported using the internet, 94% reporting owning a device capable of videoconferencing, and 86% of patients had participated in a video call in the past year. When asked for their preferred method for a physician visit: 79% ranked in-person as their first choice and 16% ranked a videoconference visit as their first choice. Perceived benefits of telemedicine visits included reduced travel to appointments (97% agree) and reduced cost of attending appointments (69% agree). However, patients were concerned that they would not establish the same patient-physician connection (51% agree) and would not receive the same level of care (38% agree) through telemedicine visits versus in person visits. The majority of hip preservation patients have access to and are capable of using the technology required for telemedicine visits. However, patients still prefer to have in person visits over concerns that they will not establish the same patient-physician connection and will not receive the same level of care. Telemedicine visits in hip preservation patients may be most attractive to return patients with an established doctor-patient relationship, particularly those with concerns for long distances of travel and associated costs.Level of Evidence: III.


Canola proteins for human consumption: extraction, profile, and functional properties.
Canola protein isolate has been suggested as an alternative to other proteins for human food use due to a balanced amino acid profile and potential functional properties such as emulsifying, foaming, and gelling abilities. This is, therefore, a review of the studies on the utilization of canola protein in human food, comprising the extraction processes for protein isolates and fractions, the molecular character of the extracted proteins, as well as their food functional properties. A majority of studies were based on proteins extracted from the meal using alkaline solution, presumably due to its high nitrogen yield, followed by those utilizing salt extraction combined with ultrafiltration. Characteristics of canola and its predecessor rapeseed protein fractions such as nitrogen yield, molecular weight profile, isoelectric point, solubility, and thermal properties have been reported and were found to be largely related to the extraction methods. However, very little research has been carried out on the hydrophobicity and structure profiles of the protein extracts that are highly relevant to a proper understanding of food functional properties. Alkaline extracts were generally not very suitable as functional ingredients and contradictory results about many of the measured properties of canola proteins, especially their emulsification tendencies, have also been documented. Further research into improved extraction methods is recommended, as is a more systematic approach to the measurement of desired food functional properties for valid comparison between studies.


It Is Time to Implement Primary Prevention in the Workplace to Ameliorate the Ongoing U.S. Opioid Epidemic.
The United States' opioid public health crisis continues having disastrous consequences on communities, including workers and employers. From May 2019 to May 2020, the largest number of drug overdose deaths was recorded over a twelve-month period. The "twindemics" of COVID-19 and opioids underscore the urgent need to address workers' physical and mental health. Although much has been written about the negative impacts of the opioid epidemic on the workplace, few initiatives have focused on primary prevention, addressing work-related root causes of opioid use disorders (e.g., injury, stress) that may lead to prescription or illicit opioid use. We suggest primary prevention efforts to address the connection between workplace hazards and opioid misuse, dependence, and addiction such as examining patterns of work injury and stress with records of opioid prescription. Government funding should be expanded to support primary prevention and research efforts to strengthen the evidence-base to support workplace primary prevention endeavors.


[Cellular localization of peptides derived from pro-opiocortin in the normal human adenohypophysis and in tumors of Cushing's disease].
As early as 1932, basophil cells have been considered to be involved in the corticotropic and melanotropic functions due to their proliferation during Cushing's disease. Later on, opposite opinions were held and other cells suggested to be implied in the tumor process: chromophobe, acidophil or even follicular cells. Moreover, new categories of basophil cells have been evidenced through sophisticated staining methods, in animal and human pituitaries. At the same time, the prevalent dogma 'one hormone-one cell' raised the problem of the search for both a corticotroph and a melanotroph in the human pituitary, which is devoid of an intermediate lobe. Since 1960, immunocytochemistry became a reliable method and simultaneously new peptides have been found. However, these peptides share common sequences of amino acids, thus raising questions as to the specificity of the antisera. Most authors mention the reaction to the basophil cells previously considered as melanotrophs and called beta or R [here beta(R)]. These large rounded cells, showing red granules after Alcian blue-PAS staining, are mostly located in the median area of the anterior lobe, in the cystiform zone and in cell cords invading the neural lobe. In the fetal pituitary, reactivity is observed either in some differentiated beta(R) cells or, earlier, in chromophobe cells. The question is now raised whether one cell may contain several peptides and, in this case, whether the different peptides are carried by the same granule. Technical procedures using numerous antisera on serial sections have shown associations at the level of a given cell (and of a given granule under the electron microscope). However, dissociations are also to be noticed, as far as ACTH and beta-MSH (adult) and more particularly alpha-MSH (adult and fetus) are concerned.


Role of protein kinase C in cyclic AMP-mediated suppression of T-lymphocyte activation following burn injury.
Major burn injury induces T-lymphocyte dysfunction. Previous studies suggest that prostaglandin (PG) E2, which is elevated post-burn, is the causative factor via a cyclic AMP-dependent process. The present study was conducted to elucidate the mechanism by which cAMP induces T-lymphocyte dysfunction following burn injury. Splenocytes were isolated from mice 7 days after receiving a scald burn covering 25% of their total body surface or sham procedure. ConA-induced proliferation by splenocytes from burned mice was significantly suppressed. Macrophage depletion of the splenocyte cultures abrogated the suppression. Concanavalin A-stimulated proliferation by macrophage-depleted splenocytes was suppressed by PGE2 and dibutyryl cAMP in both groups. The IC50 of these cAMP-elevating agents, however, was approximately 100-fold lower for cells from burned mice, indicating an increased sensitivity to cAMP. PGE2 did not suppress PMA/Ca2+ ionophore-induced T-lymphocyte activation. Addition of PMA to ConA-stimulated cultures prevented the suppression of proliferative responses by PGE2, whereas Ca2+ ionophore had no effect. Thus, the suppression of T-lymphocyte activation following burn injury is macrophage-dependent, related to an increased sensitivity to cAMP and due to an uncoupling of cell surface receptors from protein kinase C activation.


The fate of gamma L crystallins in rat lens during diabetic cataractogenesis as determined by a monoclonal antibody.
We developed a monoclonal antibody against HPLC purified rat lens gamma L crystallins. This antibody was specific to both the polypeptides (19,000 and 21,000 daltons) which constituted the HPLC gamma L peak. Least reactivity was shown against gamma H (24,000 daltons). This antibody was used as a probe to detect the presence of and quantitate gamma L crystallins in lens soluble, insoluble and urea-insoluble fractions during diabetes. Utilizing a direct binding immunoassay (ELISA) we calculated the absolute quantities of gamma L crystallins present in these fractions. Our results show, in normal animals there was a minimal change in total quantities of gamma L crystallins in soluble fraction from 1 month to 5 months of age, but a slow accumulation of these crystallins in insoluble and urea-insoluble fractions was seen during the same period. Diabetes resulted in a depletion of gamma L crystallins from the soluble fraction, both in terms of relative proportion and absolute quantities. In insoluble and urea-insoluble fractions the relative proportions of these crystallins were increased dramatically up until 60 days followed by a decrease during 90-120 days of diabetes, whereas, the absolute quantities remained more or less steady after reaching the maximum on 60 days. Although the relative proportions of gamma L crystallins in the insoluble fraction seem to be less when compared to urea-insoluble fraction, the total quantity of these crystallins was much higher due to abundance of this fraction.(ABSTRACT TRUNCATED AT 250 WORDS)


Magnetic state of the alpha 3 center of cytochrome c oxidase and some of its derivatives.
The temperature dependence of the magnetic susceptibility was used to investigate the nature of the coupling between cytochrome alpha 3 and CuB in resting and oxidized cyanide- and formate-bound cytochrome oxidase. Resting and formate-bound enzymes were found to have strong antiferromagnetic coupling with an S = 5/2 cytochrome alpha 3, results that were independent of the dispersing detergent and the enzyme isolation method. The cyanide-bound enzyme was heterogeneous, with a minor fraction showing intermediate strength antiferromagnetic coupling. The magnitude of this coupling was independent of the enzyme isolation method and depended moderately on the identity of the dispersing detergent. The major fraction of the cyanide-bound enzyme had a lowest energy state of Ms = 0. The coupling constant for this fraction did not depend on the isolation technique or on the identity of the dispersing detergent. The use of glucose-glucose oxidase to deoxygenate samples influenced the susceptibility behavior of some preparations of both the resting and formate-bound enzymes, with results indicating an S = 3/2 cytochrome alpha 3 in the resting enzyme samples. Retention of a 417-nm Soret band for formate-bound enzyme concomitant with peroxide-induced changes in susceptibility behavior indicates different sites of enzyme interactions for the formate ion and hydrogen peroxide.


The value of observational registry studies for the next infectious disease emergency.
During infectious disease emergencies, it may be necessary to deploy new therapies without conclusive evidence for their effectiveness. During the SARS-CoV-2 pandemic, several countries used registries to track the use of COVID-19 convalescent plasma (CCP). Those registries provided evidence that CCP was effective when used early and with high titer.


Pediatric Infectious Disease Group (GPIP) position paper on the immune debt of the COVID-19 pandemic in childhood, how can we fill the immunity gap?
Since the beginning of the COVID-19 pandemic, reduced incidence of many viral and bacterial infections has been reported in children: bronchiolitis, varicella, measles, pertussis, pneumococcal and meningococcal invasive diseases. The purpose of this opinion paper is to discuss various situations that could lead to larger epidemics when the non-pharmaceutical interventions (NPI) imposed by the SARS-CoV-2 epidemic will no longer be necessary. While NPIs limited the transmission of SARS-CoV-2, they also reduced the spread of other pathogens during and after lockdown periods, despite the re-opening of schools since June 2020 in France. This positive collateral effect in the short term is welcome as it prevents additional overload of the healthcare system. The lack of immune stimulation due to the reduced circulation of microbial agents and to the related reduced vaccine uptake induced an "immunity debt" which could have negative consequences when the pandemic is under control and NPIs are lifted. The longer these periods of "viral or bacterial low-exposure" are, the greater the likelihood of future epidemics. This is due to a growing proportion of "susceptible" people and a declined herd immunity in the population. The observed delay in vaccination program without effective catch-up and the decrease in viral and bacterial exposures lead to a rebound risk of vaccine-preventable diseases. With a vaccination schedule that does not include vaccines against rotavirus, varicella, and serogroup B and ACYW Neisseria meningitidis, France could become more vulnerable to some of these rebound effects.


Alpha-thalassemia due to the deletion of nucleotides -2 and -3 preceding the AUG initiation codon affects translation efficiency both in vitro and in vivo.
We previously hypothesized that a 2 nucleotide deletion, causing a A-greater than C change at position -3 preceding the ATG initiation codon of alpha globin gene, reduced translation efficiency of alpha globin mRNA and was responsible for a form of alpha + thalassemia displayed by an Algerian patient. We presently show that this deletion leads to a 30-45% reduction in translation efficiency of synthetic alpha globin mRNA in rabbit reticulocyte lysate. In other experiments, we constructed alpha/G gamma hybrid globin genes in which the 3' end of normal or mutated alpha globin genes downstream to the ATG initiation codon was substituted by the 3' part of a G gamma globin gene. COS cells transfected with either of these 2 hybrid genes were shown to synthesize a similar amount of alpha/G gamma hybrid mRNAs but 50% less G gamma globin when transfected with the alpha/G gamma hybrid gene carrying the deletion. These results definitively establish that the 2 nucleotide deletion reduces translation efficiency by 30-50%. This contrasts with the 93% reduction induced by a similar A-greater than C change at position -3 in the different nucleotide context preceding the ATG codon of the rat preproinsulin gene.


Homophilic interactions of chick neurofascin in trans are important for neurite induction.
Neurofascin is a member of the immunoglobulin superfamily involved in axon extension and fasciculation. Here we apply adenoviral short hairpin RNA (shRNA) expression in primary neurons, PC12-NIH/3T3 co-cultures in combination with Luminex assays, to demonstrate homophilic interactions of neurofascin for neurite outgrowth. An adenoviral vector was constructed for the expression of shRNA in primary tectal cells that inhibits gene expression similar to short interfering RNA. We demonstrate that after shRNA-mediated knockdown neuronal neurofascin expression is important for neurite outgrowth on a neurofascin substrate. Neurite outgrowth assays reveal that neurite formation of PC12 cells is increased when neurofascin is overexpressed on both outgrowing PC12 cells and substrate NIH/3T3 cells, suggesting that neurofascin expression is also sufficient for neurite induction. Luminex technology for the analysis of protein-protein interactions showed homophilic binding of neurofascin to itself.


Machine learning-based classification and risk factor analysis of frailty in Korean community-dwelling older adults.
Frailty is a dynamic reversible state, characterized by frequent transitions between frailty status over time. The timely and effective detection of frailty is important to prevent adverse health outcomes. This study aims to develop machine learning-based classification models for frailty assessment and to investigate its risk factors. A total of 1,482 subjects, 1,266 robust and 216 frail older adults, were analyzed. Sixteen frail risk factors were selected from a random forest-based feature selection method, then used for the inputs of five ML models: logistic regression, K-nearest neighbor, support vector machine, gaussian naïve bayes, and random forest. Data resampling, stratified 10-fold cross-validation, and grid search were applied to improve the classification performance. The logistic regression model using the selected features showed the best performance with an accuracy of 0.93 and an F1-score of 0.92. The results suggest that machine learning techniques are an effective method for classifying frailty status and exploring frailty-related factors.Clinical Relevance- Our approach can predict frailty using data collectable in clinical setting and can help prevent and improve by identifying variables that change frailty status.


Characterization of amber and ochre suppressors in Salmonella typhimurium.
Amber and ochre suppressor mutations in Salmonella typhimurium were selected. The amino acid insertions directed by the suppressors were inferred from suppression patterns of Escherichia coli lacI amber mutations. These amber mutations only respond to nonsense suppressors that direct the insertion of particular amino acids. Four Salmonella amber suppressors characterized insert serine, glutamine, tyrosine, and (probably) leucine. Of the three ochre suppressors characterized, two direct the insertion of tyrosine and one directs that of lysine. Of the three amber and two ochre suppressors which have been mapped by phage P22 cotransduction, all are located in the same relative position on the Salmonella map as the analogous E. coli suppressors are on the E. coli map.


Pre-B cell leukemia homeobox 1 is associated with lupus susceptibility in mice and humans.
Sle1a.1 is part of the Sle1 susceptibility locus, which has the strongest association with lupus nephritis in the NZM2410 mouse model. In this study, we show that Sle1a.1 results in the production of activated and autoreactive CD4(+) T cells. Additionally, Sle1a.1 expression reduces the peripheral regulatory T cell pool, as well as induces a defective response of CD4(+) T cells to the retinoic acid expansion of TGF-β-induced regulatory T cells. At the molecular level, Sle1a.1 corresponds to an increased expression of a novel splice isoform of Pbx1, Pbx1-d. Pbx1-d overexpression is sufficient to induce an activated/inflammatory phenotype in Jurkat T cells and to decrease their apoptotic response to retinoic acid. PBX1-d is expressed more frequently in the CD4(+) T cells from lupus patients than from healthy controls, and its presence correlates with an increased central memory T cell population. These findings indicate that Pbx1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance.


A Picture of the Moon's Atmosphere.
Atomic sodium is a useful tracer of the tenuous lunar atmosphere because of its high efficiency in scattering sunlight at the D(1) (5896 angstroms) and D(2) (5890 angstroms) wavelengths. In 1988, Earth-based instruments revealed the presence of sodium at a density of less than 50 atoms per cubic centimeter at lunar altitudes below 100 kilometers. Telescopic observations that are made with a coronograph technique to block out the disk of the moon allow a true picture of the circumiunar atmosphere to be obtained and show the presence of sodium out to a distance of several lunar radii. The distribution of sodium has a solar zenith angle dependence, suggesting that most of the sodium that reaches great altitudes is liberated from the moon's surface by solar photons (by heating or sputtering) or by solar wind impact, in contrast to a source driven by uniform micrometeor bombardment.


Evolution of neuronal and endothelial transcriptomes in primates.
The study of gene expression evolution in vertebrates has hitherto focused on the analysis of transcriptomes in tissues of different species. However, because a tissue is made up of different cell types, and cell types differ with respect to their transcriptomes, the analysis of tissues offers a composite picture of transcriptome evolution. The isolation of individual cells from tissue sections opens up the opportunity to study gene expression evolution at the cell type level. We have stained neurons and endothelial cells in human brains by antibodies against cell type-specific marker proteins, isolated the cells using laser capture microdissection, and identified genes preferentially expressed in the two cell types. We analyze these two classes of genes with respect to their expression in 62 different human tissues, with respect to their expression in 44 human "postmortem" brains from different developmental stages and with respect to between-species brain expression differences. We find that genes preferentially expressed in neurons differ less across tissues and developmental stages than genes preferentially expressed in endothelial cells. We also observe less expression differences within primate species for neuronal transcriptomes. In stark contrast, we see more gene expression differences between humans, chimpanzees, and rhesus macaques relative to within-species differences in genes expressed preferentially in neurons than in genes expressed in endothelial cells. This suggests that neuronal and endothelial transcriptomes evolve at different rates within brain tissue.


Accelerator Measurements of Magnetically Induced Radio Emission from Particle Cascades with Applications to Cosmic-Ray Air Showers.
For 50 years, cosmic-ray air showers have been detected by their radio emission. We present the first laboratory measurements that validate electrodynamics simulations used in air shower modeling. An experiment at SLAC provides a beam test of radio-frequency (rf) radiation from charged particle cascades in the presence of a magnetic field, a model system of a cosmic-ray air shower. This experiment provides a suite of controlled laboratory measurements to compare to particle-level simulations of rf emission, which are relied upon in ultrahigh-energy cosmic-ray air shower detection. We compare simulations to data for intensity, linearity with magnetic field, angular distribution, polarization, and spectral content. In particular, we confirm modern predictions that the magnetically induced emission in a dielectric forms a cone that peaks at the Cherenkov angle and show that the simulations reproduce the data within systematic uncertainties.


The need for commissioning circumcision services for non-therapeutic indications in the NHS: lessons from an incident investigation in Oxford.
Male circumcision for religious reasons is not available in the NHS. In this report, we present the results of an investigation conducted by the Thames Valley Health Protection Unit (TVHPU) at an unregulated circumcision 'camp' in Oxford in 2006. A detailed investigation was initiated following notification by a general practitioner of two children with circumcision-related complications at a 'camp'. Telephone interviews were conducted with the 'camp' organizers, the operating surgeon, GPs and paediatric surgeons. A field visit was carried out by TVHPU staff to assess implementation of infection control practices. Thirty-two children were circumcised over a 3 day period in the library of an Islamic faith school by a single, medically qualified individual. Among the 29 children with follow-up information, 13 (44.8%) developed complications requiring medical intervention. Information obtained from interviews and the field visit confirmed the lack of implementation of standard infection control practices. This incident highlights the harm associated with circumcision in young children by unregulated operators due to lack of compliance with best surgical and infection control guidance. There is an urgent need for commissioning circumcision services for religious reasons in the NHS.


[Contribution of military doctor Roman S. Chetyrkin in the formation and development of medicine in Russia].
The article deals with an extensive and diverse activities of prominent military doctor Roman Sergeyevich Chetyrkin, who contributed greatly to the development of hygiene and epidemiology in Russia. He had a lot of merit as a talented organizer of military and civilian health care. Special attention is paid to the Chetyrkin's contribution to the development of military medical expertise because of his works in this direction are fundamental for this science.


Pre-and post-HSCT use of TKI therapy for fusion-driven B-ALL: A case series of five pediatric, adolescent and young adult patients.
The development of tyrosine kinase inhibitors (TKIs) has significantly improved survival rates among patients with Philadelphia chromosome (Ph+) B cell acute lymphoblastic leukemia (B-ALL). Ph-like B-ALL patients lack the BCR::ABL1 translocation but share gene expression profiles with Ph+ B-ALL. The role of TKIs for Ph-like patients pre- and post-hematopoietic stem cell transplantation (HSCT) is not yet clear. Here we present five cases of pediatric, adolescent, and young adult patients who presented with Ph-like B-ALL or CML in B-ALL blast phase who were treated with personalized TKI regimens pre- and post-HSCT. This report describes several novel Ph-like fusions as well as combinations of TKIs with chemotherapy or immunotherapy not yet reported in the pediatric population. This case series provides real-world experience highlighting the potential application of pre- and post-HSCT use of TKIs in a subset of patients with targetable fusions.


Altered self-report of empathic responding in patients with bipolar disorder.
Despite evidence of impairments in social cognition in patients with bipolar disorder (BD), systematic investigations of empathic responding in this population have not been conducted. The objectives of the current study were to investigate empathic responding in patients with BD in varying states of illness and to determine whether course of illness variables and symptom severity predicted responding. Twenty well-characterized patients with BD and 20 matched healthy control subjects completed the Interpersonal Reactivity Index (IRI) and the Social Adjustment Scale Self-Report (SAS-SR), self-report measures of cognitive and emotional empathy and of psychosocial functioning, respectively. Patients with BD reported significantly reduced levels of cognitive empathy ('Perspective Taking') and higher levels of personal distress in response to others' negative experiences than did controls. Altered affective empathic abilities correlated significantly with reduced psychosocial functioning in family, social and occupational domains and with increased symptom severity. This study provides preliminary evidence of alterations in empathic responding in patients with BD. Alterations in the ability to adopt the perspective of others may contribute to the difficulties in social communication inherent in this patient population. Additional studies, involving larger samples, are required to determine the contribution of social cognitive performance to impaired social functioning in BD.


[The natural course of psoriasis from infancy to adulthood].
Unraveling questions concerning the etiology of psoriasis is one of the most complex problems facing researchers today. Within the last few decades, significant advances have been made with regard to the biochemical, immunologic, and genetic aspects of many disorders that have a bearing on psoriasis. Recently, we have stressed two concepts concerning the pathogenesis of psoriasis: first, that psoriasis is a disease that involves the total area of the skin and second, that psychoneuro-immunological research may be of fundamental importance to psoriasis. We have related the impact of these two observations to the course of psoriasis from infancy through adulthood. In the latter part of this paper, we emphasized that teaching patients self-help techniques may reduce their psoriasis by preventing a wide range of skin injuries.


[Natural history of pollinosis in childhood].
Out of 2.513 clinical files of allergic children, we have found 200 pollen-allergic patients, which represent 7.9% of the total allergic pathology in children, in our environment. We have studied in these 200, the most important epidemiological parameters and the influence that this can cause upon the characteristics of this disease. A male predominance has been found (70%) and it has been discovered that 52% of the total were born in spring (p less than 0.0005). An hundred per cent have shown grass-pollen sensitiveness and 52% have also shown other kinds of pollen hypersensitivity. It has been found familiar allergic background in 76.5% of the cases and in 32.5% familiar allergic history of pollinosis. Unexpectedly, those who were in lack of familiar allergic history began their clinical symptoms earlier; 51.06% before 6 years of age (p less than 0.05). Other kinds of allergic manifestations were found in 51%, being respiratory symptoms the most important (35.5%), followed by the cutaneous (23.5%) and digestive ones (10.5%). Allergy to drugs was found in 10.5%. The more frequent symptoms of pollinosis were in order of importance: rhinitis (86.5%), conjunctivitis (77%), asthma (48%), spasmodic cough (27.5%) and urticaria (4%). Asthma induced by grass-pollen hypersensitivity was equally suffered by the males as by the females, and this was more frequent among the patients who had previously suffered from non-pollinic respiratory allergies.


Low-spin pseudotetrahedral iron(I) sites in Fe₂(μ-S) complexes.
Fe(I) centers in iron-sulfide complexes have little precedent in synthetic chemistry despite a growing interest in the possible role of unusually low valent iron in metalloenzymes that feature iron-sulfur clusters. A series of three diiron [(L3Fe)2(μ-S)] complexes that were isolated and characterized in the low-valent oxidation states Fe(II)-S-Fe(II), Fe(II)-S-Fe(I), and Fe(I)-S-Fe(I) is described. This family of iron sulfides constitutes a unique redox series comprising three nearly isostructural but electronically distinct Fe2(μ-S) species. Combined structural, magnetic, and spectroscopic studies provided strong evidence that the pseudotetrahedral iron centers undergo a transition to low-spin S=1/2 states upon reduction from Fe(II) to Fe(I). The possibility of accessing low-spin, pseudotetrahedral Fe(I) sites compatible with S(2-) as a ligand was previously unknown.


Polyacrylamide gel electrophoresis in quantification of high-density lipoprotein cholesterol.
We evaluated a method for quantifying high-density lipoprotein cholesterol in plasma, based on electrophoretic migration of the prestained (with Sudan Black III) sample through a discontinuous polyacrylamide++ gel and densitometric integration of the stain associated with each class of lipoprotein. With this method, operations can be carried out on all types of lipoproteins over a broad range of concentrations. Overloading with very-low and low-density lipoproteins did not affect reliability within a wide range of HDL concentrations (0.45 to 16.60 mmol/L). Results for 22 individual plasma samples from normal and dyslipemic subjects correlated well with those by ultracentrifugal analysis (r=0.96; Student's t= 0.90, p > 0.30). We conclude that this method is reliable, sensitive, and accurate, It may be used for simultaneously typing dyslipoproteinemias and assaying HDL cholesterol.


Isolation and characterization of a new bacteriophage, Cp-1, infecting Streptococcus pneumoniae.
Several pneumococcal phages showing a morphology completely different from those of all other previously found pneumococcal bacteriophages have been isolated. Bacteriophage Cp-1, one of the phages isolated, showed an irregular hexagonal structure and a short tail of 20 nm. The virion density was 1.46 g/cm3. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the presence of nine polypeptides. The polypeptide showing a molecular weight of 39,000 accounted for more than the 90% of the total protein. The nucleic acid of Cp-1 was linear, double-stranded DNA with a mean length of 6.3 microns and a guanine-plus-cytosine content of 41%; its buoyant density was 1.699 and 1.422 g/cm3 in CsCl and CS2SO4, respectively. Its sedimentation coefficient (S20,w) was 19S. Cp-1 DNA showed a remarkable resistance to a large number of restriction endonucleases. A total of 12 fragments, ranging in molecular weight from 1.3 X 10(6) to 0.09 X 10(6), were produced by AluI, two fragments (molecular weight, 5.5 X 10(6) and 0.9 X 10(6)) were generated by HindIII, and two fragments (molecular weight, 6.0 X 10(6) and 5.7 X 10(6)) were produced by HaeIII. The easy visualization of th plaques produced by Cp-1, the small size of Cp-1 DNA (12 X 10(6) daltons), and other biological and physiochemical properties make this phage potentially useful for genetic studies.


Sexuality in Older Couples: Individual and Dyadic Characteristics.
Sexuality is a key component of health and functioning that changes with age. Although most sexual activity takes place with a partner, the majority of research on sexuality has focused on individuals. In this paper, we focused on the sexual dyad. We proposed and tested a conceptual model of the predictors of partnered sexual activity in older adulthood. This model began with the personality of each of the partners, which affects individuals' views of sex and characteristics of the partnership, which in turn affected sexual expression in the couple. We measured a key feature of personality, Positivity, which reflected the individual's tendency to present his or herself positively in social situations. This trait, we posited, increased frequency of sex through increased desire for sex, and the subjective importance of sex to each member of the couple. In this model, Positivity also impacted characteristics of the relationship that promoted dyadic sexual behavior. These processes differed for men and women in the model. We tested this model with data from the National Social Life, Health and Aging Project, which conducted personal interviews with both partners in 940 American dyads (average male age 72; average female age 69). We found that couples in which the husbands' (but not wives') were high in Positivity show higher levels of sexual activity, and that this association was partially mediated by dimensions of relationship quality, but more so by individual factors such as thinking about sex and believing sex is important.


Resistin and leptin levels in acromegaly: lack of correlation with echocardiographic findings.
To find out how resistin and leptin levels were affected in patients with acromegaly and whether there is a relation between resistin levels and cardiac parameters. We also aimed to investigate whether resistin and leptin may be a link between insulin resistance and cardiac functions as well as these affected cardiac functions in the patients with acromegaly. We included 30 subjects (15 men and 15 women) who had a diagnosis of acromegaly and 30 healthy (10 men and 20 women) subjects. Serum glucose, insulin, growth hormone, insulinlike growth factor 1 (IGF-1), resistin, and leptin levels were obtained, and insulin resistance of subjects were calculated. Echocardiographic studies of the subjects were performed. Resistin levels of the patients with acromegaly were found lower than controls. This difference was statistically significant (P = 0.001). Leptin levels were lower in the patients with acromegaly than in the controls, but this difference was not statistically significant. Resistin and leptin levels were not correlated with growth hormone, IGF-1, and with insulin-like growth factor binding protein 3 levels. Homeostasis model assessment of insulin resistance was positively correlated with resistin levels. (P = 0.03; r = 0.531) but not correlated with leptin levels. There was a positive correlation between body mass index and leptin levels in the patients with acromegaly (P = 0.007; r = 0.482). Interventricular septum thickness, posterior wall thickness, left ventricle mass index, peak early mitral inflow velocity-peak late mitral inflow velocity ratio, deceleration time, ejection time, isovolumetric relaxation time, velocity propagation, and left ventricular end-systolic volume values were significantly greater in the patients with acromegaly. Leptin levels in the acromegalic patients were not correlated with any of them. We found biventricular hypertrophy and impairment of diastolic and systolic function in the patients with acromegaly. We conclude that changes in resistin and leptin levels are unlikely to account for the insulin resistance of acromegaly. They do not also seem to be contributing factors of cardiovascular changes in patients with acromegaly.


An immunohistochemical study of normal and neoplastic canine sertoli cells.
Immunohistochemical studies of human fetal Sertoli cells (SCs) have shown transient expression of cytokeratin (CK) and desmin (DES) that is replaced after birth by expression of vimentin (VIM) and inhibin-α (INH-α). Human Sertoli cell tumours (SCTs) are characterized by re-expression of CK and DES. The aim of the present study was to evaluate immunohistochemically the expression of VIM, INH-α, CK and DES in normal and neoplastic canine SCs. Normal testicular tissue from three adult dogs, one 6-month-old puppy and two neonatal pups was examined in addition to samples from 21 canine SCTs. VIM was not expressed by neonatal SCs, but was present in SCs from the puppy, the adult dogs and in all SCTs. Conversely, INH-α was expressed by neonatal SCs and most SCTs, but not by normal SCs of adult dogs and the puppy. DES and CK were expressed only by some SCTs. These results show that, contrary to findings in man, canine SCs do not express VIM at the time of birth. SCs from neonatal dogs do express INH-α, but such expression was lost in the puppy and the adult dogs. Canine SCs therefore differ from human SCs, as expression of INH-α characterizes immature SCs, whereas the expression of VIM characterizes mature SCs. Canine SCTs may express CK and DES, suggesting that the neoplastic cells undergo de-differentiation during transformation.


Use of recipient's left hepatic artery for artery reconstruction in right lobe living donor liver transplantation with duct-to-duct anastomosis.
The hepatic arteries (HAs) in a hepatic graft are usually reconstructed using the recipient's left or right HAs in living donor liver transplantation (LDLT). There have been no apparent selection criteria concerning which of the recipient's HAs should be used. This study retrospectively investigated whether the selection of left or right HA for HA reconstruction affects the outcomes of right lobe LDLT (RL-LDLT). Ninety-nine RL-LDLT were performed between July 1998 and March 2009. After excluding 10 cases of RL-LDLT with complex HA reconstruction(s), 89 cases of RL-LDLT were divided into four groups: RL-LDLT with duct-to-duct biliary anastomosis with an HA reconstruction using the recipient's left HA (DD-L-group; n=41), the recipient's right HA (DD-R-group; n=27), RL-LDLT with hepaticojejunostomy with an HA reconstruction using the recipient's left HA (HJ-L-group; n=11), and the recipient's right HA (HJ-R-group; n=10). The outcomes of RL-LDLT were compared among these four groups. Septic complications occurred more frequently in the DD-R-group than in the DD-L-group (2.4% vs. 22.2%, P=0.013). Furthermore, 39% of the patients in the DD-R-group suffered anastomotic biliary stricture within 2 years after transplantation, in comparison with 8.1% in the DD-L-group (P=0.003). The selection of the recipient's left or right HA did not influence patient outcomes in the case of a hepaticojejunostomy. The DD-L-group patients experienced favorable outcomes in comparison with the DD-R-group patients. Therefore, recipient's left HAs should be selected for HA reconstruction in RL-LDLT when biliary reconstruction is performed by duct-to-duct anastomosis.


Accumulating research: a systematic account of how cumulative meta-analyses would have provided knowledge, improved health, reduced harm and saved resources.
"Cumulative meta-analysis" describes a statistical procedure to calculate, retrospectively, summary estimates from the results of similar trials every time the results of a further trial in the series had become available. In the early 1990 s, comparisons of cumulative meta-analyses of treatments for myocardial infarction with advice promulgated through medical textbooks showed that research had continued long after robust estimates of treatment effects had accumulated, and that medical textbooks had overlooked strong, existing evidence from trials. Cumulative meta-analyses have subsequently been used to assess what could have been known had new studies been informed by systematic reviews of relevant existing evidence and how waste might have been reduced. We used a systematic approach to identify and summarise the findings of cumulative meta-analyses of studies of the effects of clinical interventions, published from 1992 to 2012. Searches were done of PubMed, MEDLINE, EMBASE, the Cochrane Methodology Register and Science Citation Index. A total of 50 eligible reports were identified, including more than 1,500 cumulative meta-analyses. A variety of themes are illustrated with specific examples. The studies showed that initially positive results became null or negative in meta-analyses as more trials were done; that early null or negative results were over-turned; that stable results (beneficial, harmful and neutral) would have been seen had a meta-analysis been done before the new trial; and that additional trials had been much too small to resolve the remaining uncertainties. This large, unique collection of cumulative meta-analyses highlights how a review of the existing evidence might have helped researchers, practitioners, patients and funders make more informed decisions and choices about new trials over decades of research. This would have led to earlier uptake of effective interventions in practice, less exposure of trial participants to less effective treatments, and reduced waste resulting from unjustified research.


ACROSTUDY: the Italian experience.
ACROSTUDY is a world-wide non-interventional, post marketing surveillance study performed to monitor the safety and outcomes of pegvisomant (PEG) in clinical practice. We report data from acromegaly patients who have been included in the Italian ACROSTUDY registry. The data of 341 acromegaly patients (171 males) were available for analysis using data freeze (12/9/2012). Patients were enrolled in 25 Italian endocrine centres. Before and during PEG treatment IGF-I, liver enzymes, metabolic parameters, and pituitary MRI were assessed. Before PEG, 54.3% patients had been treated with medical therapy and surgery, 22.9% medical therapy only, and 15.8% medical plus radiation and surgical therapy. 199 adverse events were reported in 98 patients (28.7%). Serious adverse events were documented in 29 patients (8.5%). 71.1% of patients had no significant change in tumor volume. Central MRI reading was performed in 34 patients; in 7 patients, an increase in tumor volume was found. Hormonal efficacy progressively increased since the start of PEG. After 6 years, normal IGF-I levels were found in 70.9% of patients (mean daily dose 18.1 mg). 87.1% of patients were treated with daily PEG although in 8.8% of patients, it was administered 2-6 times per week and in 3.8% with weekly injections. 74.8% received a PEG dose 10-15 mg/daily. PEG is a drug with a favorable safety profile which is efficacious also considering that in Italy it is currently available as third-line therapy.


Effects of gibberellic acid on primary terpenoids and delta-tetrahydrocannabinol in Cannabis sativa at flowering stage.
Plants synthesize an astonishing diversity of isoprenoids, some of which play essential roles in photosynthesis, respiration, and the regulation of growth and development. Two independent pathways for the biosynthesis of isoprenoid precursors coexist within the plant cell: the cytosolic mevalonic acid (MVA) pathway and the plastidial methylerythritol phosphate (MEP) pathway. However, little is known about the effects of plant hormones on the regulation of these pathways. In the present study we investigated the effect of gibberellic acid (GA(3)) on changes in the amounts of many produced terpenoids and the activity of the key enzymes, 1-deoxy-D-xylulose 5-phosphate synthase (DXS) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), in these pathways. Our results showed GA(3) caused a decrease in DXS activity in both sexes that it was accompanied by a decrease in chlorophylls, carotenoids and Delta(9)-tetrahydrocannabinol (THC) contents and an increase in alpha-tocopherol content. The treated plants with GA(3) showed an increase in HMGR activity. This increase in HMGR activity was followed by accumulation of stigmasterol and beta-sitosterol in male and female plants and campestrol in male plants. The pattern of the changes in the amounts of sterols was exactly similar to the changes in the HMGR activity. These data suggest that GA(3) can probably influence the MEP and MVA pathways oppositely, with stimulatory and inhibitory effects on the produced primary terpenoids in MVA and DXS pathways, respectively.


Fulvic acid disturbs processing of procollagen II in articular cartilage of embryonic chicken and may also cause Kashin-Beck disease.
Kashin-Beck disease is an endemic osteoarthropathy in China which may lead to skeletal deformation and dwarfism. We have analysed articular cartilage from two patients and found an accumulation of the precursor molecule, pro-pN-collagen II (pN, peptide attached at the amino-terminus) which was not present in extracts of control fetal cartilage. In addition, collagen II isolated from the same tissue by limited pepsin digestion had a decreased electrophoretic mobility, increased proline hydroxylation and decreased thermal stability. Previously, a genetic defect in pro-pN-collagen-I processing has been described in calf and sheep (dermatosparaxis) and man (Ehlers-Danlos, type VII) which caused an extreme fragility of the skin [Lenaers, A., Ansay, M., Nusgens, B.V. & Lapière, C.M. (1971) Eur. J. Biochem. 23, 533-541; Helle, O. & Nes, N.J. (1972) Acta Vet. Scand. 13, 443-445; Lichtenstein, J.R., Martin, G.R., Kohn, L.D., Byers, P.H. & McKusick, V.A. (1973) Science 182, 298-300]. Accordingly, one may assume that the impaired conversion of pro-pN-collagen II to collagen II and the structural alteration of collagen II, presumably caused by fulvic acid and other environmental factors, play an important role in the pathogenesis of Kashin-Beck disease.


Fusion-independent expression of functional ACh receptors in mouse mesoangioblast stem cells contacting muscle cells.
Mesoangioblasts are vessel-associated fetal stem cells that can be induced to differentiate into skeletal muscle, both in vitro and in vivo. Whether this is due to fusion or to transdifferentiation into bona fide satellite cells is still an open question, for mesoangioblasts as well as for other types of stem cells. The early steps of satellite cell myogenic differentiation involve MyoD activation, membrane hyperpolarization and the appearance of ACh sensitivity and gap junctional communication. If mesoangioblasts differentiate into satellite cells, these characteristics should be observed in stem cells prior to fusion into multinucleated myotubes. We have investigated the functional properties acquired by mononucleated green fluorescent protein (GFP)-positive mesoangioblasts co-cultured with differentiating C2C12 myogenic cells, using the patch-clamp technique. Mesoangioblasts whose membrane contacted myogenic cells developed a hyperpolarized membrane resting potential and ACh-evoked current responses. Dye and electrical coupling was observed among mesoangioblasts but not between mesoangioblasts and myotubes. Mouse MyoD was detected by RT-PCR both in single, mononucleated mesoangioblasts co-cultured with C2C12 myotubes and in the total mRNA from mouse mesoangioblasts co-cultured with human myotubes, but not in human myotubes or stem cells cultured in isolation. In conclusion, when co-cultured with muscle cells, mesoangioblasts acquire many of the functional characteristics of differentiating satellite cells in the absence of cell fusion, strongly indicating that these stem cells undergo transdifferentiation into satellite cells, when exposed to a myogenic environment.


Hemospray application in nonvariceal upper gastrointestinal bleeding: results of the Survey to Evaluate the Application of Hemospray in the Luminal Tract.
Hemospray TM (TC-325) is a novel hemostatic agent licensed for use in nonvariceal upper gastrointestinal bleeding (NVUGIB) in Europe. We present the operating characteristics and performance of TC-325 in the largest registry to date of patients presenting with NVUGIB in everyday clinical practice. Prospective anonymized data of device performance and clinical outcomes were collected from 10 European centers using the multicentre SEAL survey (Survey to Evaluate the Application of Hemospray in the Luminal tract). TC-325 was used as a monotherapy or as second-line therapy in combination with other hemostatic modalities at the endoscopists' discretion. Sixty-three patients (44 men, 19 women), median age 69 (range, 21 to 98) years with NVUGIB requiring endoscopic hemostasis were treated with TC-325. There were 30 patients with bleeding ulcers and 33 with other NVUGIB pathology. Fifty-five (87%) were treated with TC-325 as monotherapy; 47 [85%; 95% confidence interval (CI), 76%-94%] of them achieved primary hemostasis, and rebleeding rate at 7 days was 15% (95% CI, 5%-25%). Primary hemostasis rate for TC-325 in patients with ulcer bleeds was 76% (95% CI, 59%-93%). Eight patients, who otherwise may have required either surgery or interventional radiology, were treated with TC-325 as second-line therapy after failure of other endoscopic treatments, all of whom achieved hemostasis following the adjunct of TC-325. This multicentre registry identifies potentially useful characteristics of Hemospray (TC-325) when used either as monotherapy or as a rescue therapy in a wide variety of ulcer and nonulcer NVUGIB.


Elementary Implantable Force Sensor: For Smart Orthopaedic Implants.
Implementing implantable sensors which are robust enough to maintain long term functionality inside the body remains a significant challenge. The ideal implantable sensing system is one which is simple and robust; free from batteries, telemetry, and complex electronics. We have developed an elementary implantable sensor for orthopaedic smart implants. The sensor requires no telemetry and no batteries to communicate wirelessly. It has no on-board signal conditioning electronics. The sensor itself has no electrical connections and thus does not require a hermetic package. The sensor is an elementary L-C resonator which can function as a simple force transducer by using a solid dielectric material of known stiffness between two parallel Archimedean coils. The operating characteristics of the sensors are predicted using a simplified, lumped circuit model. We have demonstrated sensor functionality both in air and in saline. Our preliminary data indicate that the sensor can be reasonably well modeled as a lumped circuit to predict its response to loading.


Redox-Responsive Dipeptide Nanostructures toward Targeted Cancer Therapy.
Materials that exhibit responsiveness toward biological signals are currently subjected to intense research in the field of drug delivery. In our study, we tried to develop cancer-targeted and redox-responsive nanoparticles (NPs) from disulfide-linked oxidized cysteine-phenylalanine (CFO). The NPs were conjugated with folic acid (FA) to specifically target cancer cells, and the presence of disulfide bonds would enabled the disintegration of the particles in the presence of elevated levels of glutathione (GSH) in cancer cells. Anticancer drug doxorubicin (Dox) was successfully loaded inside the disulfide-linked nanoparticles (CFO-Dox-NPs), which further demonstrated stimuli-responsive drug release in the presence of GSH. We have also demonstrated enhanced uptake of FA-derivatized NPs (FA-CFO-NPs) in cancerous cells (C6 glioma and B16F10 melanoma cells) than in normal cells (HEK293T cells) due to the overexpression of FA receptors on the surface of cancer cells. Cytotoxicity studies in C6 cells and B16F10 cells further revealed enhanced efficacy of Dox loaded (FA-CFO-Dox-NPs) as compared to the native drug. The findings of this study clearly demonstrated that the disulfide-linked nanoparticle system may provide a promising selective drug delivery platform in cancer cells.


ACOG Practice Bulletin No. 196 Summary: Thromboembolism in Pregnancy.
Women who are pregnant or in the postpartum period have a fourfold to fivefold increased risk of thromboembolism compared with nonpregnant women (1, 2). Approximately 80% of thromboembolic events in pregnancy are venous (3), with a prevalence of 0.5-2.0 per 1,000 pregnant women (4-9). Venous thromboembolism (VTE) is one of the leading causes of maternal mortality in the United States, accounting for 9.3% of all maternal deaths (10).The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. The purpose of this document is to provide information regarding the risk factors, diagnosis, management, and prevention of thromboembolism, particularly VTE in pregnancy. This Practice Bulletin has been revised to reflect updated guidance regarding screening for thromboembolism risk and management of anticoagulation around the time of delivery.


[Vasopressin and brain death].
Brain death results in the breakdown of effective central regulatory mechanisms of cardiocirculatory stability, even in patients with artificial mechanical ventilation, correction of electrolytic and acid-basic disorders and maximal conventional pharmacological support of the circulation. Recent evidences have shown that the fall of vasopressin levels in the blood circulation significantly influences the cardiocirculatory stability of patients with brain death, and its exogenous administration is defended by many authors for the management of multiorgan donor patients. In this brief review we analyse and discuss some experimental and clinical relevant studies about the role of vasopressin in the control of cardiocirculatory stability in brain death, and its potential usefulness in the management of multiorgan donor. We conclude that the role of vasopressin in the pathophysiology of brain death and its usefulness as a pharmacological agent in the management of multiorgan donor are not well elucidated, deserving further investigations.


Caring for women living with HIV: gaps in the evidence.
In the management of HIV, women and men generally undergo the same treatment pathway, with gender differences being given limited consideration. This is in spite of accumulating evidence that there are a number of potential differences between women and men which may affect response to treatment, pharmacokinetics, toxicities and coping. There are also notable psychological, behavioural, social and structural factors that may have a unique impact on women living with HIV (WLWH). Despite our increasing knowledge of HIV and advances in treatment, there are significant gaps in the data relating specifically to women. One of the factors contributing to this situation is the under-representation of women in all aspects of HIV clinical research. Furthermore, there are clinical issues unique to women, including gynaecologic and breast diseases, menopause-related factors, contraception and other topics related to women's and sexual health. Using scoping review methodology, articles from the literature from 1980 to 2012 were identified using appropriate MeSH headings reflecting the clinical status of WLWH, particularly in the areas of clinical management, sexual health, emotional wellbeing and treatment access. Titles and abstracts were scanned to determine whether they were relevant to non-reproductive health in WLWH, and papers meeting inclusion criteria were reviewed. This review summarizes our current knowledge of the clinical status of WLWH, particularly in the areas of clinical management, sexual health, emotional wellbeing and treatment access. It suggests that there are a number of gender differences in disease and treatment outcomes, and distinct women-specific issues, such as menopause and co-morbidities, that pose significant challenges to the care of WLWH. Based on a review of this evidence, outstanding questions and areas where further studies are required to determine gender differences in the efficacy and safety of treatment and other clinical and psychological issues specifically affecting WLWH have been identified. Well-controlled and adequately powered clinical studies are essential to help provide answers to these questions and to contribute to activities aimed at improving the health and wellbeing of WLWH.


Site-selective synthesis of 1,3-dioxin-3-ones via a gold(i) catalyzed cascade reaction.
A novel gold(i)-catalyzed protocol for the synthesis of 4H-1,3-dioxin-3-ones is presented. The protocol exploits a metal induced cascade sequence involving a [3,3]-sigmatropic rearrangement followed by regioselective O-annulation reactions. A wide range of oxygen-based heterocyclic scaffolds (21 examples) were achieved in excellent yield (up to 80%) and a detailed computational investigation as well as deuterium-labelling investigations enabled all the plausible reaction pathways to be mapped and the rationalization of the recorded regioselectivity.


Structural bases for the different anti-fibrillatory effects of chloroquine and quinidine.
Chloroquine, an anti-malarial quinoline, is structurally similar to quinidine. Both drugs have been shown to block ion channels. We tested the hypothesis that chloroquine's mode of interaction with the vestibule of the cytoplasmic domain of the inward rectifier potassium channel Kir2.1 makes it a more effective I(K1) blocker and anti-fibrillatory agent than quinidine. We used comparative molecular modelling and ligand docking of the three-dimensional structures of quinidine and chloroquine in the intracellular domain of Kir2.1. Simulations predicted that chloroquine effectively blocks potassium flow by binding at the centre of the ion permeation vestibule of Kir2.1. In contrast, quinidine binds the vestibular side, only partially blocking ion movement. We tested the modelling predictions in Kir2.1-expressing human embryonic kidney (HEK)-293 cells. The half-maximal inhibitory concentration for chloroquine block of I(K1) was 1.2 µM, while that of quinidine was 57 µM. Finally, we used optical mapping of Langendorff-perfused mouse hearts with cardiac-specific Kir2.1 up-regulation to compare the anti-fibrillatory effects of the drugs. In five of six hearts, 10 μM quinidine slowed the frequency but did not terminate the tachyarrhythmia. In five of five hearts, 10 μM chloroquine terminated the arrhythmia, restoring sinus rhythm. Quinidine only partially blocks I(K1). Chloroquine binds at the centre of the ion permeation vestibule of Kir2.1, which makes it a more effective I(K1) blocker and anti-fibrillatory agent than quinidine. Integrating the structural biology of drug-ion channel interactions with cellular electrophysiology and optical mapping is an excellent approach to understand the molecular mechanisms of anti-arrhythmic drug action and for drug discovery.


A Prospective Mixed-Methods Study of Decision-Making on Surgery or Active Surveillance for Low-Risk Papillary Thyroid Cancer.
Background: Active surveillance (AS) of small, low-risk papillary thyroid cancers (PTCs) is increasingly being considered. There is limited understanding of why individuals with low-risk PTC may choose AS over traditional surgical management. Methods: We present a mixed-methods analysis of a prospective observational real-life decision-making study regarding the choice of thyroidectomy or AS for management of localized, low-risk PTCs <2 cm in maximum diameter (NCT03271892). Patients were provided standardized medical information and were interviewed after making their decision (which dictated disease management). We evaluated patients' levels of decision-self efficacy (confidence in medical decision-making ability) at the time information was presented and their level of decision satisfaction after finalizing their decision (using standardized questionnaires). We asked patients to explain the reason for their choice and qualitatively analyzed the results. Results: We enrolled 74 women and 26 men of mean age 52.4 years, with a mean PTC size of 11.0 mm (interquartile range 9.0, 14.0 mm). Seventy-one patients (71.0% [95% confidence interval 60.9-79.4%]) chose AS over surgery. Ninety-four percent (94/100) of participants independently made their own disease management choice; the rest shared the decision with their physician. Participants had a high baseline level of decision self-efficacy (mean 94.3, standard deviation 9.6 on a 100-point scale). Almost all (98%, 98/100) participants reported high decision satisfaction. Factors reported by patients as influencing their decision included the following: perceived risk of thyroidectomy or the cancer, family considerations, treatment timing in the context of life circumstances, and trust in health care providers. Conclusions: In this Canadian study, ∼7 out of 10 patients with small, low-risk PTC, who were offered the choice of AS or surgery, chose AS. Personal perceptions about cancer or thyroidectomy, contextual factors, family considerations, and trust in health care providers strongly influenced patients' disease management choices.