Nmp4, a Regulator of Induced Osteoanabolism, Also Influences Insulin Secretion and Sensitivity.
A bidirectional and complex relationship exists between bone and glycemia. Persons with type 2 diabetes (T2D) are at risk for bone loss and fracture, however, heightened osteoanabolism may ameliorate T2D-induced deficits in glycemia as bone-forming osteoblasts contribute to energy metabolism via increased glucose uptake and cellular glycolysis. Mice globally lacking nuclear matrix protein 4 (Nmp4), a transcription factor expressed in all tissues and conserved between humans and rodents, are healthy and exhibit enhanced bone formation in response to anabolic osteoporosis therapies. To test whether loss of Nmp4 similarly impacted bone deficits caused by diet-induced obesity, male wild-type and Nmp4-/- mice (8 weeks) were fed either low-fat diet or high-fat diet (HFD) for 12 weeks. Endpoint parameters included bone architecture, structural and estimated tissue-level mechanical properties, body weight/composition, glucose-stimulated insulin secretion, glucose tolerance, insulin tolerance, and metabolic cage analysis. HFD diminished bone architecture and ultimate force and stiffness equally in both genotypes. Unexpectedly, the Nmp4-/- mice exhibited deficits in pancreatic β-cell function and were modestly glucose intolerant under normal diet conditions. Despite the β-cell deficits, the Nmp4-/- mice were less sensitive to HFD-induced weight gain, increases in % fat mass, and decreases in glucose tolerance and insulin sensitivity. We conclude that Nmp4 supports pancreatic β-cell function but suppresses peripheral glucose utilization, perhaps contributing to its suppression of induced skeletal anabolism. Selective disruption of Nmp4 in peripheral tissues may provide a strategy for improving both induced osteoanabolism and energy metabolism in comorbid patients.


"Falling-Out" in Miami and the History of Culture in American Medicine.
Turning to the case of "falling-out" in Miami, this paper locates a historical context for the incorporation of culture into medical practice. In the 1970s, after playing a leading role in the organization of medical anthropology, Hazel Weidman uncovered a condition that Miami residents called "falling-out." It was characterized by sudden collapse in situations of stress, followed by a state of semiconsciousness-and it seemed to affect only individuals of African American or Afro-Caribbean descent. Observing patients' routine mismanagement by the medical system, Weidman used the condition to advocate for greater cultural awareness among health professionals. This study finds that while anthropologists worked to change the medical community, they were also embedded in a Cold War racial politics, where health became a useful site for managing ethnic difference. Moreover, the contested nature of "falling-out" in the 1970s echoes the contested nature of "culture" in medicine that institutions continue to confront today.


[Infantile scurvy].
Infantile scurvy, today a rare disease, can be diagnosed either by recognition of a characteristic constellation of clinical features, or on the correct interpretation of nearly pathognomonic radiological signs. Dystrophy, recurrent infections, fever, anemia, hemorrhagic effusions, hematuria, tenderness of the legs, pseudo-paralysis and "frog position" and costochondral swelling or angulation are frequent signs. Radiologically, thickening of the epiphyseal plate ("scurvy line") and subepiphyseal rarefication , general osteoporosis and subperiostal hemorrhage are important diagnostic clues.


Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway.
The chiral molecule, apomorphine, is currently used for the treatment of Parkinson's disease (PD). As a potent dopamine receptor agonist, this lipophilic compound is especially effective for treating motor fluctuations in advanced PD patients. In addition to its receptor-mediated actions, apomorphine has also antioxidant and free radical scavenger activities. Neuroinflammation, oxidative stress, and microglia reactivity have emerged as central players in PD. Thus, modulating microglia activation in PD may be a valid therapeutic strategy. We previously reported that murine microglia are strongly activated upon exposure to A53T mutant α-synuclein. The present study was designed to investigate whether apomorphine enantiomers could modulate this A53T-induced microglial activation. Taken together, the results provided evidence that apomorphine enantiomers decrease A53T-induced microgliosis, through the activation of the NRF2 signalling pathway, leading to a lower pro-inflammatory state and restoring the phagocytic activity. Suppressing NRF2 recruitment (trigonelline exposure) or silencing specifically Nfe2l2 gene (siRNA treatment) abolished or strongly decreased the anti-inflammatory activity of apomorphine. In conclusion, apomorphine, which is already used in PD patients to mimic dopamine activity, may also be suitable to decrease α-synuclein-induced microglial reactivity.


Efficient and Stable Perovskite Solar Cell Achieved with Bifunctional Interfacial Layers.
The elaborate control of the surface morphologies and trap states of solution-processed perovskite films significantly governs the photovoltaic performance and moisture resistance of perovskite solar cells (PSCs). Herein, a thin layer of poly(triaryl amine) (PTAA) was unprecedentedly devised on top of perovskite quasi-film by spin-coating PTAA/chlorobenzene solution before annealing the perovskite film. This treatment induced a smooth and compact perovskite layer with passivated surface defects and grain boundaries, which result in a significantly reduced charge recombination. Besides, the time-resolved photoluminescence spectra of the PTAA-treated perovskite films confirmed a faster charge transfer and a much longer lifetime compared to the control cells without the PTAA treatment. Moreover, such a hydrophobic polymer atop the perovskite layer could effectively protect the perovskite against humidity and retain 83% of its initial efficiency in contrast to 56% of control cells stored for 1 month in ambient conditions (25 °C, 35 RH%). As a result, the PTAA-treated PSCs displayed an average efficiency of 17.77% (with a peak efficiency of 18.75%), in contrast to 16.15% of the control cells, and enhanced stability. These results demonstrate that PTAA and the method thereof constitute a promising passivation strategy for constructing stable and efficient PSCs.


miR-128 promoted adipogenic differentiation and inhibited osteogenic differentiation of human mesenchymal stem cells by suppression of VEGF pathway.
MicroRNA-128 (miR-128), a brain-enriched microRNA, has been reported to participate in the regulation of cell differentiation, but its potential roles in adipogenic and osteogenic differentiation of human mesenchymal stem cells (hMSCs) have not been addressed. The study was conducted to investigate the effects and mechanism of miR-128 on adipogenic and osteogenic differentiation of hMSCs. Morphology of hMSCs, lipid droplets and calcium nodules were observed and photographed by LSM microscopy. Expression of CCAAT/enhancer binding protein-α (C/EBPα), peroxisome proliferator-activated receptor-γ (PPARγ), miR-128, vascular endothelial growth factor (VEGF), osteocalcin (OCN) and Runt-related transcription factor 2 (RUNX2) was determined by RNA preparation and reverse transcription polymerase chain reaction (RT-PCR), protein expression of VEGF was analyzed by Western blot. It was suggested that miR-128 expression showed a 4.56-fold induction by adipogenic treatment and a 58.8% reduction by osteogenic treatment. Over-expression of miR-128, promoted adipogenic differentiation while inhibited osteogenic differentiation. In contrast, adipocyte formation was inhibited and osteogenesis was enhanced in cells slicing miR-128. Furthermore, over-expression of miR-128 down-regulated VEGF expression in adipogenically and osteogenically differentiated cells. We further identified VEGF as a key regulator in miR-128-induced adipogenic and osteogenic differentiation. Following knockdown of VEGF, the effects of over-expression of miR-128 on adipogenic and osteogenic differentiation of hMSCs were limited. It was indicated that miR-128 could regulate adipogenic and osteogenic differentiation of hMSCs significantly through the suppression of VEGF pathway.


Estrogen-inducible pS2 protein is not the key regulatory component in the proliferation of human breast cancer cells (MCF-7).
Exposure of human breast cancer cells (MCF-7) to tumor promoters such as 12-O-tetradecanoyl phorbol 13-acetate (TPA) for 24 h at concentrations of 1-100 nM resulted in marked inhibition of DNA synthesis but a 3-5-fold increase in the amount of pS2 protein in the medium. These results support our previous suggestion that pS2 protein is not involved in the mechanism controlling proliferation of MCF-7 cells. During treatment with TPA, the intracellular content of pS2 protein was constant, suggesting that TPA did not induce secretion of pS2 protein but rather de novo synthesis of the protein. The increase in the pS2 protein content of the medium by TPA was inhibited by simultaneous addition of cycloheximide, but not by that of actinomycin D. Northern-blot hybridization analysis showed that the amount of pS2 mRNA was unchanged by treatment of the cells with TPA. These results indicate that TPA does not induce transcription of the pS2 gene, and suggest that the main effect of TPA results from the induction of translation of pS2 mRNA.


Rupture of an inferior epigastric artery pseudo-aneurysm following laparoscopic port insertion.
Laparoscopic port insertion is a potential cause of trauma to the inferior epigastric artery, resulting in pseudo-aneurysm formation. Treatment of pseudo-aneurysms includes thrombin injection, coil embolisation, embolisation with N-butyl cyanoacrylate, compression therapy or surgical excision and ligation. The authors present a case of pseudo-aneurysm caused by port insertion during laparoscopic sigmoid colectomy. The pseudo-aneurysm was identified using CT and Doppler ultrasound scans, but underwent spontaneous resolution with cessation of flow prior to intervention. The patient was therefore discharged, but he presented again as an emergency with rupture of a clinically infected pseudo-aneurysm and needed emergency surgical intervention.


A Plastid Phosphatidylglycerol Lipase Contributes to the Export of Acyl Groups from Plastids for Seed Oil Biosynthesis.
The lipid composition of thylakoid membranes inside chloroplasts is conserved from leaves to developing embryos. A finely tuned lipid assembly machinery is required to build these membranes during Arabidopsis thaliana development. Contrary to thylakoid lipid biosynthetic enzymes, the functions of most predicted chloroplast lipid-degrading enzymes remain to be elucidated. Here, we explore the biochemistry and physiological function of an Arabidopsis thylakoid membrane-associated lipase, PLASTID LIPASE1 (PLIP1). PLIP1 is a phospholipase A1 In vivo, PLIP1 hydrolyzes polyunsaturated acyl groups from a unique chloroplast-specific phosphatidylglycerol that contains 16:1 Δ3trans as its second acyl group. Thus far, a specific function of this 16:1 Δ3trans -containing phosphatidylglycerol in chloroplasts has remained elusive. The PLIP1 gene is highly expressed in seeds, and plip1 mutant seeds contain less oil and exhibit delayed germination compared with the wild type. Acyl groups released by PLIP1 are exported from the chloroplast, reincorporated into phosphatidylcholine, and ultimately enter seed triacylglycerol. Thus, 16:1 Δ3trans uniquely labels a small but biochemically active plastid phosphatidylglycerol pool in developing Arabidopsis embryos, which is subject to PLIP1 activity, thereby contributing a small fraction of the polyunsaturated fatty acids present in seed oil. We propose that acyl exchange involving thylakoid lipids functions in acyl export from plastids and seed oil biosynthesis.


Use of transgenic animals to study renal acid-base transport.
Many of the transporters mediating renal acid-base homeostasis have recently been identified at the molecular level. These advances have made it possible to generate transgenic mice with deficiency or overexpression of specific transporter isoforms. Such knockout mice have served as useful experimental models to quantitate the contribution of a given transporter isoform to transtubular acid-base transport along the nephron. Studies with transgenic and knockout mice have also been used to elucidate the compensatory adaptive mechanisms in response to specific transport deficiencies. We review experiments using transgenic mice to evaluate the physiological roles in acid-base transport of NHE isoforms, vacuolar H+ pump subunits, H+, K(+)-ATPase isoforms, carbonic anhydrase, Cl(-)-base exchangers and such regulatory mediators as nitric oxide and endothelin.


Voltage-Gated Membranes Incorporating Cucurbit[n]uril Molecular Containers for Molecular Nanofiltration.
Smart voltage-gated nanofiltration membranes have enormous potential for on-demand and precise separation of similar molecules, which is an essential element of sustainable water purification and resource recovery. However, the existing voltage-gated membranes are hampered by limited selectivity, stability, and scalability due to electroactive monomer dimerization. Here, for the first time, the host-guest recognition properties of cucurbit[7]uril (CB[7]) are used to protect the viologen derivatives and promote their assembly into the membrane by interfacial polymerization. Viologen functions as a voltage switch, whereas CB[7] complexation prevents its dimerization and improves its redox stability. The inhibited diffusion of the CB[7]-viologen complex enables the precise patterning of the surface structure. The resultant voltage-gated membrane displays 80% improved rejection performance, excellent recovery accuracy for similar molecules, and anti-fouling properties. This work not only provides an innovative strategy for the preparation of voltage-gated smart nanofiltration membranes but also opens up new avenues for ion-selective transmission in water treatment, bionic ion channels, and energy conversion.


Insulator-based dielectrophoresis combined with the isomotive AC electric field and applied to single cell analysis.
We developed an insulator-based dielectrophoretic (iDEP) creek-gap device that enables the isomotive movement of cells and that is suitable for determining their DEP properties. In the iDEP creek-gap device, a pair of planar insulators forming a single fan-shaped channel allows the induction of the isomotive iDEP force on cells. Hence, the cells' behavior is characterized by straight motion at constant velocity in the longitudinal direction of the channel. Operation of the device was demonstrated using human breast epithelial cells (MCF10A) by applying an AC voltage of Vpp = 34 V peak-to-peak and frequencies of 200 kHz and 50 MHz to the device. Subsequently, the magnitude of DEP forces and the real part of the ClausiusMossotti (CM) factor, Re(β), were deduced from the measured cell velocity. The values of Re(β) were 0.14 ± 0.01 for the frequency of 200 kHz and -0.12 ± 0.01 for 50 MHz. These results demonstrated that the DEP properties of the cells could be extracted over a wide field frequency range. Therefore, the proposed iDEP creek-gap device was found to be applicable to cell analysis.


Aerobic conditioning alters the satellite cell and ribosome response to acute eccentric contractions in young men and women.
Satellite cells (SCs) and ribosomes are key determinants of the skeletal muscle adaptive response. Both are thought to increase acutely after resistance exercise and chronically with resistance training. However, the acute SC and ribosome exercise response with prior aerobic conditioning is unknown. Fourteen young men and women underwent 6 wk of single-legged aerobic conditioning followed by an acute bout of 300 eccentric contractions on each leg. Muscle biopsies were taken from the vastus lateralis of the aerobically conditioned (AC) and the control (CTL) legs before (Pre), 24 (24 h), and 48 (48 h) h post-contractions. Pre-eccentric contractions, 45S pre-rRNA and 5.8S internal transcribed spacer (ITS) expression were lower in the AC leg compared with the CTL leg. SC content (PAX7+ cells/100 fibers) in type I and mixed fibers showed a main effect of condition, where values were greater in the AC leg compared with the CTL. A main effect of condition for Pax7 and MyoD1 mRNA expression was observed where expression was greater in the AC leg compared with the CTL. AC had greater RNA concentration and mRNA expression of Ubf and Tif-1a compared with CTL. Only the AC leg increased (Pre-24h) 45S pre-rRNA, 5.8S ITS, and 28S ITS following eccentric contractions. We discovered that aerobic conditioning increased type-I SC abundance and the acute increase in ribosome content following eccentric contractions.


Joubert Syndrome in French Canadians and Identification of Mutations in CEP104.
Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.


Anxiety and depression in the first six months after stroke. A longitudinal multicentre study.
To document the prevalence, severity and time course of anxiety and depression in stroke rehabilitation patients in four European countries. At two, four and six months post-stroke, the prevalence and severity of anxiety and depression were determined in 532 consecutively recruited patients, using the Hospital Anxiety and Depression Scale. Time course of prevalence and severity was examined, using Cochran-Q and Friedman-tests, respectively. We identified whether the numbers of anxious/depressed patients at each time point comprised the same individuals. Prevalence of anxiety ranged between 22% and 25%; depression between 24% and 30%. Median severity ranged between 4 and 5. No significant differences between centres occurred (p > 0.05). Prevalence of both disorders was not significantly different over time. Severity of anxiety decreased between four and six months; severity of depression remained stable. About 40% of the patients with initial anxiety remained anxious at six months. Some 11% and 7% of those initially not anxious became anxious at four or six months after stroke, respectively. Depression showed a similar pattern. Despite differences in patient profiles and intensity of rehabilitation, no significant differences occurred between centres in prevalence and severity of both disorders. Anxiety was almost as common as depression and additional patients became anxious/depressed at each time point.


Huanglongbing and Citrus Variegated Chlorosis Integrated Management Based on Favorable Periods for Vector Population Increase and Symptom Expression.
Huanglongbing (HLB, associated with Candidatus Liberibacter asiaticus and transmitted by the Asian citrus psyllid Diaphorina citri) and citrus variegated chlorosis (CVC, caused by Xylella fastidiosa subsp. pauca and transmitted by sharpshooter species) have been managed by vector control and removal of symptomatic trees. Although vectors and new symptomatic trees can be detected year round, peaks of vector populations are higher in spring and summer, and the most symptomatic trees are found in autumn and winter. This work aimed to compare the management of both diseases during these favorable periods. The experiment was conducted during 5 years in a commercial orchard and had a three-by-two factorial design. The factor "vector control" had three levels: monthly vector control year round (VCYR), monthly vector control in spring and summer (VCSS), and vector control when a threshold level of 10% occupancy was detected (VCOT). The factor "inoculum removal" had two levels: monthly eradication year round (TEYR) and monthly eradication in autumn and winter (TEAW). Host flush, both HLB and CVC vector populations, and the number of symptomatic citrus plants were visually assessed. The level of vectors over the seasons, as measured using the average area under the curve (AUC), was similar for all treatments with the exception of psyllid abundance, which was approximately 4.5 times higher for VCSS than for other treatments. For both diseases, no difference in the average AUC of disease progress and disease final incidence was observed. VCOT or adjusted VCSS associated with TEAW could be integrated for sustainable citrus production.


Imprinting effects of proline containing dipeptides (proline-glycine, proline-leucine, proline-valine and their retro variants) in tetrahymena. Evolutionary conclusions.
Proline-glycine, proline-leucine and proline-valine dipeptides and their retro variants were used in the experiments to study the effects of pretreatment (imprinting) in Tetrahymena, by investigating fluorescein isothiocyanate (FITC)-conjugated peptide binding. The protozoan organism could differentiate between the proline-dipeptides containing different partner amino-acids and between the dipeptides having the amino acids in reversed positions. The effect of imprinting was positive or negative and this was dependent on the type of the partner amino acid and on its position. Pro-Gly and Pro-Leu induced positive imprinting (elevated FITC-dipeptide binding) and Pro-Val induced negative imprinting (decrease of FITC-peptide binding). There was positive imprinting induction in two cases for the retro FITC-peptide and in one case for the FITC-conjugate of the imprinter peptide itself. The highest positive imprinting (almost 60% increase) was induced by Pro-Gly for FITC-Gly-Pro. Considering earlier--chemotaxis--experiments, the results of the present--binding--studies run parallel with the physiological effects. The experiments call attention to the sharp differentiating ability of small peptides at a unicellular level, that could have some role in the selection of molecules for hormone formation, during evolution.


A remarkable accelerating effect of Ag-salt on intramolecular cyclization of o-(1-alkynyl)benzenesulfonamides.
Herein, we report transition metal-catalyzed intramolecular cyclization of o-(1-alkynyl)benzenesulfonamides to afford 3-substituted benzothiazines regioselectively via a C-N bond forming reaction and Cu-catalyzed sequential C-N and C-C bond formation leading to the corresponding 3,4-disubstituted derivatives.


Structural and mechanistic insights into lunatic fringe from a kinetic analysis of enzyme mutants.
The Notch receptor is critical for proper development where it orchestrates numerous cell fate decisions. The Fringe family of beta1,3-N-acetylglucosaminyltransferases are regulators of this pathway. Fringe enzymes add N-acetylglucosamine to O-linked fucose on the epidermal growth factor repeats of Notch. Here we have analyzed the reaction catalyzed by Lunatic Fringe (Lfng) in detail. A mutagenesis strategy for Lfng was guided by a multiple sequence alignment of Fringe proteins and solutions from docking an epidermal growth factor-like O-fucose acceptor substrate onto a homology model of Lfng. We targeted three main areas as follows: residues that could help resolve where the fucose binds, residues in two conserved loops not observed in the published structure of Manic Fringe, and residues predicted to be involved in UDP-N-acetylglucosamine (UDP-GlcNAc) donor specificity. We utilized a kinetic analysis of mutant enzyme activity toward the small molecule acceptor substrate 4-nitrophenyl-alpha-L-fucopyranoside to judge their effect on Lfng activity. Our results support the positioning of O-fucose in a specific orientation to the catalytic residue. We also found evidence that one loop closes off the active site coincident with, or subsequent to, substrate binding. We propose a mechanism whereby the ordering of this short loop may alter the conformation of the catalytic aspartate. Finally, we identify several residues near the UDP-GlcNAc-binding site, which are specifically permissive toward UDP-GlcNAc utilization.


Treatment of leukemia by alloreactive lymphocytes and nonmyeloablative stem cell transplantation.
Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and nonmalignant diseases, especially acute and chronic leukemias. Until recently, myeloablative regimens were considered mandatory for effective eradication of all malignant cells of host origin. Our preclinical and ongoing clinical studies indicated that eradication of host immunohematopoietic cells, including chemoradiotherapy-resistant leukemia, could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following induction of host-versus-graft transplantation tolerance mediated by engraftment of donor stem cells in the course of BMT. Thus, eradication of blood cancer cells, especially in patients with chronic myeloid leukemia and less frequently in patients with other hematologic malignancies, could be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-leukemia (GVL) effects might be a useful tool for both treatment and prevention of relapse. Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using a safer conditioning as part of the transplant procedure, with the goal in mind to induce host-versus-graft tolerance to enable subsequent induction of GVL effects rather than attempt to eliminate host cells with hazardous myeloablative chemoradiotherapy. The latter hypothesis suggested that effective BMT procedure may be accomplished without lethal conditioning of the host, using a new well-tolerated nonmyeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical observations suggest that effective treatment of leukemia may be accomplished with a well-tolerated nonmyeloablative stem cell transplantation (NST) regimen, while avoiding immediate and late toxicity and minimizing procedure-related mortality. Taken together, our cumulative data suggest that high-dose chemotherapy and radiation therapy may be successively replaced by a more effective biological tool-alloreactive donor lymphocytes-thus setting the stage for innovative immunotherapeutic procedures for more selective and effective treatment of patients in need of BMT, including those resistant to conventional chemoradiotherapy.


Development of the public information and communication technology assessment tool.
Public information and communication technologies, such as information kiosks, automated banking machines and ticket dispensers, allow people to access services in a convenient and timely manner. However, the development of these technologies has occurred largely without consideration of access by people with disabilities. Inaccessible technical features make operation of a public technology difficult and barriers in the environment create navigational challenges, limiting the opportunity of people with disabilities to use these devices and access the services they provide. This paper describes the development of a tool that individuals, disability advocacy groups, business owners, healthcare providers, and urban planners can use to evaluate the accessibility of public technologies and the surrounding environment. Evaluation results can then be used to develop recommendations and advocate for technical and environmental changes to improve access. Tool development consisted of a review of the literature and key Canadian Standards Association documents, task analysis, and consultation with accessibility experts. Studies of content validity, tool usability, inter-rater and test-retest reliability were conducted in sites across Canada. Accessibility experts verified the content validity of the tool. The current version of the tool has incorporated the findings of a usability study. Initial testing indicated excellent agreement for inter-rater and test-retest reliability scores. Social exclusion can arise when public technologies are not accessible. This newly developed instrument provides detailed information that can be used to advocate for more accessible and inclusive public information and communication technologies.


Design and kinematical performance analysis of the 7-DOF upper-limb exoskeleton toward improving human-robot interface in active and passive movement training.
Upper-limb rehabilitation robots have become an important piece of equipment in stroke rehabilitation. The design of exoskeleton mechanisms plays a key role to improve human-robot interface in the upper-limb movements under passive and active rehabilitation training. This paper proposes a novel of the 7-DOF (RR-RR-PRR) under-actuated exoskeleton mechanism based on the characteristics of the upper-limb movements in both of active and passive training. This aim of the proposed work is to improve human-robot interface in rehabilitation training with robots. Firstly, the characteristics of active and passive movement training are analyzed depending on the human upper-limb model. Then, a novel 7-DOF (RR-RR-PRR) exoskeleton mechanism is proposed based on the analyzed characteristics. After that, kinematical performances of the proposed exoskeleton are analyzed on the workspace, manipulability and manipulability ellipsoid by compared with the common exoskeleton configuration of the 7 DOFs (RRR-R-PRR) mechanism. In the end, the prototype is manufactured and tested by undergoing the experiments of single-joint passive movement training and multi-joint active movement training. The human-robot interface of the proposed exoskeleton is demonstrated by root mean square error, Pearson correlation coefficient, and the time-delay difference. The results of the kinematical performance show that the effective workspace and the flexibility of the exoskeleton with the proposed configuration are increased by 10.44% and 1.7%. In the single-joint passive movement training experiment, the root mean square errors are 6.986, 7.568, 5.846, and Pearson correlation coefficients are 0.989, 0.984, 0.988 at the shoulder joint and the elbow joint, respectively. The time-delay differences are not beyond 3.1%. In the multi-joint active movement training experiment, the root mean square errors are 9.312 and 7.677, and Pearson correlation coefficients are 0.906 and 0.968 at the shoulder joint and the elbow joint, respectively. The time-delay differences are not beyond 3.28%. The proposed 7 DOFs exoskeleton mechanism shows uniformity with that of the common exoskeleton on the same rehabilitation trajectory which is effective to improve human-robot interface under passive and active rehabilitation training.


Biobank bootstrapping: is biobank sustainability possible through cost recovery?
The pre-eminent goal of biobanks is to accelerate scientific discovery and support improvements in healthcare through the supply of high quality biospecimens to enable excellent science. Despite the need for retrospective future-proofed cancer repositories, they are presented with significant fiscal challenges. While it was once thought that biobanks could recover most, if not all, operational costs through distribution fees, biobanks have been consistently unable to fully realize this dream. Using data from three mature Canadian cancer biobanks, common attributes and assumptions related to cost recovery were evaluated. The values were entered into a simple financial model to determine the cost recovery potential for biobanks. Over a 5-year period analyzed, aliquots from almost 40% (8990) of 23055 cases collected have been distributed in whole or in part to researchers. The financial modeling demonstrates that, based on values derived from the real life experiences of three major Canadian biobanks, full cost recovery through distribution is not feasible. A more realistic, experience based, expectation of cost recovery from distribution fees is in the range of 5%-25%, and this range is lower if only academic research is supported as opposed to also supporting industry researchers. Biobanks are expensive and, to mitigate costs, are frequently challenged to operate under "self-sustainable" financial models. However, the only possible route to self-sustainability through distribution fees in today's market would require an almost exclusive targeting of commercial researchers and, even then, evidence suggests this is an impossible goal to attain. Support for biobanks should recognize that they exist to further development of personalized treatments and diagnostics essential for precision medicine. For biobanks to continue to achieve this goal, pro bono publicum, funders need to be aware of the full funding requirements of biobanks and create appropriate funding streams.


Bioimaging-based detection of mislocalized proteins in human cancers by semi-supervised learning.
There is a long-term interest in the challenging task of finding translocated and mislocated cancer biomarker proteins. Bioimages of subcellular protein distribution are new data sources which have attracted much attention in recent years because of their intuitive and detailed descriptions of protein distribution. However, automated methods in large-scale biomarker screening suffer significantly from the lack of subcellular location annotations for bioimages from cancer tissues. The transfer prediction idea of applying models trained on normal tissue proteins to predict the subcellular locations of cancerous ones is arbitrary because the protein distribution patterns may differ in normal and cancerous states. We developed a new semi-supervised protocol that can use unlabeled cancer protein data in model construction by an iterative and incremental training strategy. Our approach enables us to selectively use the low-quality images in normal states to expand the training sample space and provides a general way for dealing with the small size of annotated images used together with large unannotated ones. Experiments demonstrate that the new semi-supervised protocol can result in improved accuracy and sensitivity of subcellular location difference detection. The data and code are available at: www.csbio.sjtu.edu.cn/bioinf/SemiBiomarker/. Supplementary data are available at Bioinformatics online.


Antimicrobial Resistance and Virulence Factors of Escherichia coli in Cheese Made from Unpasteurized Milk in Three Cities in Brazil.
The production of cheeses from unpasteurized milk is still widespread in Brazil, even with a legal ban imposed on its marketing. The manufacture of this cheese is a public health problem, due to the use of raw milk and the poor hygienic conditions throughout the supply chain process. Contamination may occur from several sources and involve several different pathogenic microorganisms, such as Escherichia coli. The latter can cause different clinical manifestations depending on the pathotype involved. Furthermore, some isolates manifest antimicrobial resistance and may be a risk for public health. The purpose of the current study was to investigate the presence of potentially pathogenic E. coli in raw-milk cheese in Brazil and their possible risk to public health. A total of 83 cheeses were collected from three different cities and 169 E. coli isolates were characterized for the presence of enteropathogenic E. coli, Shigatoxigenic E. coli, enterotoxigenic E. coli, extraintestinal pathogenic E. coli (ExPEC) virulence genes, phylogenetic type, antimicrobial resistance, O serogroup, and pulsed-field gel electrophoresis. The number of samples positive for E. coli was highest in Aracaju (90.32%, 28/31). The prevalence of samples positive for potential ExPEC genes was similar for Uberaba and Aracaju (23.07%); the most prevalent ExPEC virulence genes were tsh, iucD, and papC. Isolates from Uberaba had a higher prevalence of resistance to tetracycline (38.46%), amoxicillin/clavulanic acid (58.85%), and ampicillin (61.54%) than the other cities. Overall, antimicrobial resistance genes tetB, blaTEM, and blaCMY-2 were the most prevalent genes (26.32%, 15.79%, and 28.95%, respectively) and the most prevalent serotypes were O4 (8%), 018 (12%), and O23 (8%). Clones originating from the same regions and from different regions were observed. These results emphasize the presence of a potential danger for humans in the consumption of raw-milk cheeses in three cities in Brazil due to the presence of antimicrobial resistance, which should be monitored.


How Many Patients Do You Need? Investigating Trial Designs for Anti-Seizure Treatment in Acute Brain Injury Patients.
Epileptiform activity (EA) worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized trials (RCTs) assessing anti-seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, RCTs are lacking or hindered by design constraints. We used a pharmacological model-guided simulator to design and determine feasibility of RCTs evaluating EA treatment. In a single-center cohort of adults (age >18) with aSAH and EA, we employed a mechanistic pharmacokinetic-pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size. Sample sizes ranged from 500 for levetiracetam 7 mg/kg vs placebo, to >4000 for levetiracetam 15 vs. 7 mg/kg to achieve 80% power (5% type I error). For propofol 1mg/kg/hr vs. placebo 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples >1200. Our simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo-control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and assess feasibility of future trials of EA treatment.


Probing the affinity of SecA for signal peptide in different environments.
SecA, the peripheral subunit of the Escherichia coli preprotein translocase, interacts with a number of ligands during export, including signal peptides, membrane phospholipids, and nucleotides. Using fluorescence resonance energy transfer (FRET), we studied the interactions of wild-type (WT) and mutant SecAs with IAEDANS-labeled signal peptide, and how these interactions are modified in the presence of other transport ligands. We find that residues on the third alpha-helix in the preprotein cross-linking domain (PPXD) are important for the interaction of SecA and signal peptide. For SecA in aqueous solution, saturation binding data using FRET analysis fit a single-site binding model and yielded a Kd of 2.4 microM. FRET is inhibited for SecA in lipid vesicles relative to that in aqueous solution at a low signal peptide concentration. The sigmoidal nature of the binding curve suggests that SecA in lipids has two conformational states; our results do not support different oligomeric states of SecA. Using native gel electrophoresis, we establish signal peptide-induced SecA monomerization in both aqueous solution and lipid vesicles. Whereas the affinity of SecA for signal peptide in an aqueous environment is unaffected by temperature or the presence of nucleotides, in lipids the affinity decreases in the presence of ADP or AMP-PCP but increases at higher temperature. The latter finding is consistent with SecA existing in an elongated form while inserting the signal peptide into membranes.


Targeting Tumor Necrosis Factor Alpha to Mitigate Lung Injury Induced by Mustard Vesicants and Radiation.
Pulmonary injury induced by mustard vesicants and radiation is characterized by DNA damage, oxidative stress, and inflammation. This is associated with increases in levels of inflammatory mediators, including tumor necrosis factor (TNF)α in the lung and upregulation of its receptor TNFR1. Dysregulated production of TNFα and TNFα signaling has been implicated in lung injury, oxidative and nitrosative stress, apoptosis, and necrosis, which contribute to tissue damage, chronic inflammation, airway hyperresponsiveness, and tissue remodeling. These findings suggest that targeting production of TNFα or TNFα activity may represent an efficacious approach to mitigating lung toxicity induced by both mustards and radiation. This review summarizes current knowledge on the role of TNFα in pathologies associated with exposure to mustard vesicants and radiation, with a focus on the therapeutic potential of TNFα-targeting agents in reducing acute injury and chronic disease pathogenesis.


Full Genome Sequence of a Natural Reassortant H9N2 Avian Influenza Virus Isolated from Domestic Ducks in Jiangsu Province, China.
In this study, the complete genomic sequence of a novel reassortant H9N2 avian influenza virus (AIV) from domestic ducks in eastern China was reported. Phylogenetic analysis showed that seven of the eight genes were all highly homologous to the chicken-origin H9N2 viruses, whereas the PB2 gene was homologous to the human-origin H1N1 virus, which suggested that domestic ducks might play a key role in the genetic reassortment and evolution of H9N2 AIVs in eastern China.


Prevalence of cytomegalovirus infection in patients with ulcerative colitis: a prospective cross-sectional study in Tehran, Iran.
Cytomegalovirus (CMV) infection has been reported in ulcerative colitis (UC), but limited data are available on its prevalence in Iran. The aim of this study was to evaluate the prevalence of CMV infection in patients with UC. A prospective, cross-sectional study was conducted in 86 consecutive patients with UC. Prevalence of CMV infection was determined by rectal biopsies for hematoxylin and eosin staining and PCR. CMV-positive specimens was measured for CMV loads by real-time PCR assay. In six out of 86 (7%) patients with UC, CMV was diagnosed. These patients had detectable CMV DNA in their biopsies as indicated by PCR. In all CMV-positive patients, viral load was more than 250 copy/mg. Histochemical staining did not show any CMV inclusion bodies. No significant demographic and clinical differences existed between patients with and without a CMV infection. UC and its treatment may put patients at risk of CMV infection. Real-time PCR test for the detection of CMV in UC patients may enable diagnosis of CMV infection with a high sensitivity and allow effective treatment to be administered in these patients. The impact of antiviral therapy on the clinical outcome of the UC patients with CMV remains to be elucidated.


Trauma is only part of the story: Strengths moderate the relationship between trauma and needs for older youth in foster care.
Many youth in foster care endure traumatic experiences (TE) that can lead to lasting negative outcomes. However, the identification of strengths may mitigate the impact of TE. This study examines the frequency and distribution of identified strengths; whether strengths moderate the association between TE and various outcomes; and whether certain strengths have a larger moderation effect on the association between TE and life domain functioning. Administrative and clinical data, including the Child and Adolescent Needs and Strengths (CANS) assessment, were examined for 3324 transition age youth and emerging adults in out-of-home foster care in the United States. Participants were males and females between 14.5 and 21 years old. Pearson's chi-square tests of association were conducted to determine whether identification of strengths varied significantly by sex or race/ethnicity. Negative binomial regressions were used to determine whether strengths modified the association between TE and needs domains. Of 11 measured strengths, 56% of youth had 7 or more strengths identified as centerpiece strengths, and 20% had all 11. No significant differences in identification of strengths were found across sex or race/ethnicity. All strengths significantly moderated the association of TE and outcomes across CANS domains tested. While cumulative strengths had the largest overall moderation effects, identification of education setting, coping and savoring skills, and interpersonal strengths as centerpiece strengths had the largest moderation effect among specific strengths. Findings suggest assessing, identifying, and bolstering strengths may help to promote well-being after trauma exposure.


Waterborne amino acids: uptake and functional roles in aquatic animals.
Dissolved organic matter is a ubiquitous component of freshwater and marine environments, and includes small nutrient molecules, such as amino acids, which may be available for uptake by aquatic biota. Epithelial transporters, including cotransporters, uniporters and antiporters, facilitate the absorption of dissolved amino acids (often against concentration gradients). Although there is a lack of mechanistic and molecular characterization of such transporters, pathways for the direct uptake of amino acids from the water appear to exist in a wide range of marine phyla, including Porifera, Cnidaria, Platyhelminthes, Brachiopoda, Mollusca, Nemertea, Annelida, Echinodermata, Arthropoda and Chordata. In these animals, absorbed amino acids have several putative roles, including osmoregulation, hypoxia tolerance, shell formation and metabolism. Therefore, amino acids dissolved in the water may play an important, but overlooked, role in aquatic animal nutrition.


Effectiveness of combined antibiotic ophthalmic solution in the treatment of hordeolum after incision and curettage: a randomized, placebo-controlled trial: a pilot study.
The presented pilot study compared the effectiveness of combined antibiotic ophthalmic solution (neomycin sulfate, polymyxin B sulfate and gramicidin) with a placebo (artificial tear) in the treatment of hordeolum after incision and curettage (I&C). A randomized, placebo-controlled trial with patients and investigators blinded from the start started from June 2002 to May 2003. Subjects were patients with untreated hordeolum who subsequently underwent I&C at the Ophthalmology Department. The patients were randomized into 2 groups: group A for combined antibiotic ophthalmic solution, and group B for artificial tear containing the antibiotic solution base. Pain score, mass size and duration of cure were recorded before and on the 3rd and 7th day after treatment. The study included 14 patients in each group. Two subjects in group A and three subjects in group B dropped out. There were no statistically significant differences of all outcomes in both groups, even with the intention-to-treat analysis. The conclusion is combined antibiotic ophthalmic solution is not more effective than placebo in the treatment of hordeolum after I&C.


A case study of personal exposure to nitrogen dioxide using a new high sensitive diffusive sampler.
Personal NO(2) exposure measurements were achieved during two campaigns in a large northern France city. These campaigns were following an innovating approach based on sequential exposure measurements by diffusive samplers distinguishing four categories of microenvironments ("home", "other indoor places", "transport" and "outdoors"). The objective of these campaigns was to obtain NO(2) personal exposure data in different microenvironments and to examine the determinants of personal exposure to this pollutant. Each campaign comprised two 24-h sampling periods: one during a working day and the second during the weekend. The average total NO(2) personal exposure ranged from 17 microg m(-3) for the summer weekend samplings to 38 microg m(-3) for the winter weekday samplings. The highest levels were found in transports and outdoors, the intermediate ones in other indoor places and the lowest in homes. Despite their weak levels, indoor environments contributed for more than 78% to total NO(2) personal exposure because of more time spent in these living places. A Multiple Correspondence Analysis (MCA) highlighted the determinants of NO(2) personal exposure in the "home" and "transport" microenvironments. This led to a classification of NO(2) personal exposure levels according to different means of transport: from the lowest to the highest exposure levels, train, tramway or underground, bicycle, car or motorcycle. In homes, the rise of NO(2) personal exposures is mainly due to the use of gas stoves and gas heating and the absence of automatic airing system. A classification of NO(2) personal exposure levels was set up according to the characteristics of homes. An analysis of correlations between the home NO(2) personal exposures and outdoor concentrations measured by fixed ambient air monitoring stations showed weak relations suggesting that the data of these stations are poor predictors of NO(2) personal exposures in homes.


Ten-year follow-up after in-hospital adult cardiac arrest.
The aim of the study was to determine the prevalence of in-hospital cardiac arrest and survival during 10 years of observation. patients hospitalized in the Internal Medicine Unit (including Intensive Care) in the years 1995-1997 with cardiac arrest during hospitalization. The probable reasons for the cardiac arrest were defined (cardiac or non-cardiac) as well as the mechanism (VF/VT, other). The number of deaths during the first 24 hours from the episode, during the whole stay in the hospital and after one, five and ten-years was analyzed. During the period examined, 152 cardiac arrests took place. The resuscitation was successful in 83 cases. In that group, 66% patients had cardiac cause of cardiac arrest, 50.6% in the mechanism of VF. Ninety percent of the patients died during their stay in the hospital (38.5% during the first 24 hours after the episode), 10% of the patients left the hospital alive. Only 2 of them (2.4%) survived the next 5 years. Nobody survived 10 years. Cardiac arrest within the internal ward was characterized by high in-hospital mortality risk and unsuccessful late prognosis. Non-cardiac cause of cardiac arrest, relatively common in cases of in-hospital cardiac arrest, is connected with better survival after the first 24 hours; however, it does not improve the general survival to hospital discharge.


Prolonged response times characterize cognitive performance in multiple sclerosis.
Cognitive impairment is amongst the main symptoms affecting multiple sclerosis (MS) and should be comprehensively and accurately assessed. To study the added value of a computerized neuropsychological battery enabling the measurement of response times in the cognitive domains, 58 randomly selected MS patients and 71 age-, gender- and education-matched healthy subjects were evaluated. Construct and discriminant validity were assessed for the standard Neuropsychological Screening Battery for Multiple Sclerosis (NSBMS) and the Mindstreams Computerized Cognitive Battery (MCCB). The MCCB demonstrated good construct validity in comparison with the NSBMS in memory (P < 0.001), executive function (P < 0.001), attention (P < 0.05) and information processing (P < 0.05) domains. In addition, it showed high discriminant validity most prominently for executive function, attention and motor skills (P < 0.001). Response times measured by the computerized battery were longer in all cognitive domains and varied with cognitive load, demonstrating that response time deficits in MS are associated with particular task demands. We conclude that in MS prolonged response times on a range of cognitive tasks signify abnormal conduction within demyelinative tracts.


Reversion of fruit-dependent inhibition of flowering in Citrus requires sprouting of buds with epigenetically silenced CcMADS19.
In Citrus, the response to environmental floral inductive signals is inhibited by the presence of developing fruits. The mechanism involves epigenetic activation of the CcMADS19 locus (FLC orthologue), encoding a floral repressor. To understand how this epigenetic regulation is reverted to allow flowering in the following season, we have forced precocious sprouting of axillary buds in fruit-bearing shoots, and examined the competence to floral inductive signals of old and new leaves derived from them. We have found that CcMADS19 is enriched in repressive H3K27me3 marks in young, but not old leaves, revealing that axillary buds retain a silenced version of the floral repressor that is mitotically transmitted to the newly emerging leaves, which are able to induce flowering. Therefore, we propose that flowering in Citrus is necessarily preceded by vegetative sprouting, so that the competence to respond to floral inductive signals is reset in the new leaves.


Extrachromosomal circular DNAs in interspecific mouse-rat reconstituted cells.
Several clones of reconstituted cells were isolated by fusion of karyoplasts of mouse melanoma B16 cells with cytoplasts of rat myoblastic L6 cells and processed by the mica-press-adsorption method for electron microscopy. Extrachromosomal small circular DNAs of less than 1 micron in contour length (smaller circular DNA) were present in both parental cells, and circles larger than 1 micron (larger circular DNA) were found more frequently in reconstituted cells at an early stage after the clonal isolation. Mitochondrial DNA was not released from mitochondria by this method. The new phenotypes of reconstituted cells were stable, but larger circles were lost after prolonged cultivation of the cells. The possibility that the larger circular DNAs result from intrachromosomal DNA rearrangement induced by rat cytoplasts is discussed.


Adipocytes promote nicotine-induced injury of endothelial cells via the NF-κB pathway.
Cigarette smoking is one of the most important risk factors of atherosclerosis, which can induce endothelial injury. Meanwhile, adipocytes are the main cell type of perivascular adipose tissue (PVAT), the largest endocrine and paracrine organ and direct anatomical connection to adventitia, which may play a key role in the injury of endothelial cells. We used nicotine to induce dysfunctional HUVECs and adipocytes. In addition, we used a novel model to co-culture HUVECs and adipocytes in vitro by the transwell co-culture system to determine the effect of adipocytes on endothelial injury. Cell apoptosis was detected by Annexin V-FITC. Genes and proteins involved in the nuclear factor kappa B (NF-κB) signaling pathway were detected by qRT-PCR and western blot analysis, respectively. We also investigated the nuclear translocation of NF-κB p65 using immunofluorescence staining. Our results showed that nicotine dose-dependently induces the apoptosis of HUVECs and adipocytes and is associated with increased IKKβ and NF-κB p65 expression and with IkBα degradation. Meanwhile through the co-culture system, adipocytes promoted the expression of IKKβ and NF-κB p65, as well as the translocation of NF-κB p65, and they accelerated the degradation of IkBα, resulting in increased apoptosis of HUVECs compared with that of the single cultured system. In conclusion, adipocytes could promote endothelial injury via the NF-κB pathway. Moreover, the NF-κB pathway plays pivotal roles in nicotine-induced vascular injury.


Agentic and communal narcissism in predicting different types of lies in romantic relationships.
Several studies have investigated a potential positive association between agentic narcissism and general dishonesty, revealing both supportive and contradicting evidence. Few have focused on dishonesty within romantic relationships, a phenomenon that occurs in almost all partnerships. With the present research, we first aimed to extend existing literature on narcissism by including its two complementary facets (i.e., agentic and communal narcissism). Second, we aimed to improve the understanding of narcissists' lying behavior in the context of partnerships by distinguishing between two different types of lies (i.e., self-centered and other-oriented lies). We hypothesized that both, people higher in agentic and communal narcissism, will report increased dishonesty toward their romantic partners (Hypothesis 1). Given the self-benefit function of self-centered lies and given that agentic narcissists aim to fulfill their relationship-based motives by agentic means, we predict agentic narcissism (compared with communal narcissism) will be a stronger predictor for self-centered lies (Hypothesis 1a). Given the other-benefiting function of other-oriented lies and given that communal narcissists aim to fulfill their motive of self-enhancement by communal means, we predict that communal narcissism (compared with agentic narcissism) will be a stronger predictor for other-oriented lies (Hypothesis 1b). In two preregistered online studies (N = 298: N = 256) we showed that people higher in agentic narcissism believed to be good liars, but this does not lead to higher self-reported frequencies of other-oriented and self-centered lies within romantic relationships historically; communal narcissism was also not related to self-reported deception. Limitations and directions for future research are discussed.


Identification and characterization of a fibronectin-binding protein from Clostridium difficile.
A 68 kDa fibronectin-binding protein (Fbp68) from Clostridium difficile displaying significant homology to several established or putative Fbps from other bacteria was identified. The one-copy gene is highly conserved in C. difficile isolates. Fbp68 was expressed in Escherichia coli in fusion with glutathione S-transferase; the fusion protein and the native Fbp68 were purified. Immunoblot analysis and cell fractionation experiments revealed that Fbp68 is present on the surface of the bacteria. Far-immuno dot-blotting demonstrated that Fbp68 was capable of fixing fibronectin. Indirect immunofluorescence and ELISA were employed to demonstrate that C. difficile could bind both soluble and immobilized fibronectin. With competitive adherence inhibition assays it was shown that antibodies raised against Fbp68 partially inhibited attachment of C. difficile to fibronectin and Vero cells. Furthermore, Vero cells could fix purified membrane-immobilized Fbp68. Thus Fbp68 appears to be one of the several adhesins identified to date in C. difficile.


Cortical mapping with navigated transcranial magnetic stimulation in low-grade glioma surgery.
Transcranial magnetic stimulation (TMS) is a promising method for both investigation and therapeutic treatment of psychiatric and neurologic disorders and, more recently, for brain mapping. This study describes the application of navigated TMS for motor cortex mapping in patients with a brain tumor located close to the precentral gyrus. In this prospective study, six patients with low-grade gliomas in or near the precentral gyrus underwent TMS, and their motor responses were correlated to locations in the cortex around the lesion, generating a functional map overlaid on three-dimensional magnetic resonance imaging (MRI) scans of the brain. To determine the accuracy of this new method, we compared TMS mapping with the gold standard mapping with direct cortical electrical stimulation in surgery. The same navigation system and TMS-generated map were used during the surgical resection procedure. The motor cortex could be clearly mapped using both methods. The locations corresponding to the hand and forearm, found during intraoperative mapping, showed a close spatial relationship to the homotopic areas identified by TMS mapping. The mean distance between TMS and direct cortical electrical stimulation (DES) was 4.16 ± 1.02 mm (range: 2.56-5.27 mm). Preoperative mapping of the motor cortex with navigated TMS prior to brain tumor resection is a useful presurgical planning tool with good accuracy.


Surgical outcomes and postoperative hemorrhage risk of percutaneous nephrolithotomy (PCNL) for deer horn shaped stones analyzed by Lasso regression.
To predict surgical outcomes and postoperative hemorrhage risk for percutaneous nephrolithotomy (PCNL) in cases of staghorn-shaped stones using lasso regression. We collected data from 104 patients with staghorn-shaped stones treated with PCNL between January 2019 and December 2022 at the Department of Urology Surgery, the Third People's Hospital of Gansu Province. Medical history, stone-related parameters, and lab test data were collected. Patients were categorized into stone clearance or residual groups based on postoperative stone status, and bleeding or non-bleeding groups based on post-surgery blood transfusion. The lasso model's predictive ability for post-PCNL Stone Free Rate (SFR) and hemorrhage risk was evaluated using ROC curves. The lasso model's predictive performance for post-PCNL SFR was compared to the S.T.O.N.E. score. Overall stone clearance rate was 59.29%. The lasso model identified hypertension history, calyx count at stone location, prior calyx surgeries, age, operation duration, and pre-op creatinine level as SFR predictors. The AUC of lasso model (0.867) significantly surpassed the S.T.O.N.E. model (0.748) (P=0.006) in predicting post-PCNL SFR. In addition, the AUC of lasso model in predicting the risk of postoperative bleeding was 0.779, suggesting an ability in the prediction of bleeding occurrence. A predictive model utilizing lasso algorithm was successfully established. It effectively predicts stone clearance rate and bleeding risk after PCNL for staghorn shaped kidney stones.


Dose-finding and efficacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria.
The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. In part I of the study three different artemotil dose regimens were explored in three groups of 6-9 patients for dose finding: 3.2 mg kg-1 on day 0 and 1.6 mg kg-1 on days 1-4 (treatment A), 1.6 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment B), 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment C). In part II of the study, artemotil treatments A and C were compared in three groups of 20-22 patients with standard i.m. artemether treatment: 3.2 mg kg-1 on day 0 and 0.8 mg kg-1 on days 1-4 (treatment R). Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentration-time profiles of artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial artemotil plasma concentrations. Pharmacokinetic-pharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to artemotil during approximately the first 2 days of treatment, and suggested that artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. The optimum dose regimen for artemotil in this study was identical to the standard dose regimen of artemether. The findings that artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. artemotil can be an advantage, since it may allow shorter hospitalization.


Solid-state reduction of silver nitrate with polyaniline base leading to conducting materials.
The polyaniline (PANI) base was ball-milled with silver nitrate in the solid state. Samples were prepared at various mole ratios of silver nitrate to PANI constitutional units ranging from 0 to 1.5 for three processing times, 0, 5, and 10 min. The emeraldine form of PANI was oxidized to pernigraniline, and the silver nitrate was reduced to metallic silver. Nitric acid is a byproduct, which may protonate the residual emeraldine and pernigraniline. The changes occurring in the structure of PANI are discussed on the basis of Fourier transform IR and Raman spectroscopies. Raman spectra revealed the formation of pernigraniline salt. The reaction between the two nonconducting components, emeraldine base and silver nitrate, produced a mixture of two conducting components, emeraldine or pernigraniline nitrate and metallic silver. The accompanying conductivity changes were determined. The increase in the conductivity of the original base, 10(-9) S cm(-1), up to 10(-2) S cm(-1) was found to depend on the mole ratio of silver nitrate to PANI base and on the processing time of the components in the ball mill.


The role of patient-centered outcomes in the course of chronic obstructive pulmonary disease: how long-term studies contribute to our understanding.
In chronic obstructive pulmonary disease (COPD), the rate of decline in forced expiratory volume in 1 second (FEV1) and progression to disability and death are accelerated. COPD management goals include preventing or slowing the progressive loss of lung function, relieving symptoms, improving exercise tolerance and the patient's health status, preventing and treating exacerbations and complications, minimizing side effects of treatment, and reducing mortality. Although lung function is important for diagnosis of COPD and classification of its severity, clinicians and patients are also very interested in symptoms, ability to function, and general well-being (health status). Consequently, increasing attention is being given to these patient-centered outcomes. It is possible to modify patient-centered outcomes; however, it remains to be seen whether doing so can also alter the natural course of the disease and reduce mortality. Two long-term clinical trials--Towards a Revolution in COPD Health (TORCH) and Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT)--will help to answer the question of whether pharmacologic interventions are effective in changing the clinical course of COPD. The TORCH study examines the long-term effects of combination therapy with an inhaled long-acting beta-agonist (salmeterol) and a corticosteroid (fluticasone) on reduction of all-cause mortality over 3 years. The 4-year UPLIFT study examines the effects of maintenance treatment with the once-daily anticholinergic bronchodilator tiotropium on the yearly rate of decline in trough FEV1 and the yearly rate of decline in FEV1 90 minutes after maximal or near-maximal bronchodilator administration. This article examines the rationale for each of these studies and provides an overview of study methodology as well as preliminary demographic data.


'Health-for-All' in the twenty-first century: a global perspective.
Changes in the broad determinants of health since the Alma Ata Conference in 1978 necessitate a renewed examination of the underlying principles and focus of the Primary Health Care (PHC) strategy. The PHC approach has been adopted by most countries and has led to improved access to certain basic health services. However, the health gains in other areas are less encouraging. Some elements of the PHC approach, for example, the effective implementation of equity-oriented health policies and the need to improve management principles within health services, have yet to be fully implemented. Moreover, to address the underlying determinants of health status, the World Health Organization's (WHO) renewed global health policy will have to include certain issues that were not considered at Alma Ata. For example, the health impacts of global recession and globalization and the need for human-centered sustainable development strategies were not considered at Alma Ata. A renewed global health policy will also have to consider demographic, epidemiological, environmental and technological changes that have emerged since 1978. It is important that WHO's renewed policy be based on sound evidence, a commitment to ethical principles and broad use of partnerships for health at global, national and local levels. One implication of this new context of health development for the renewed health policy will be that 'thinking globally and acting locally' will have to complemented by stronger global action to protect local and national health.


Usefulness of the capsule endoscopy Crohn's disease activity index in assessing the necessity of early additional treatment in patients with Crohn's disease in clinical remission.
The Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) was recently reported as a new scoring system to evaluate the mucosal lesions of patients with Crohn's disease (CD). We investigated whether CECDAI is useful for assessing the necessity of early additional treatment in patients with CD in clinical remission.Twenty-one patients with small intestinal CD in clinical remission underwent capsule endoscopy (CE). The CECDAI and Lewis score (LS) were used to evaluate the intestinal lesions. We analyzed the correlations between several biomarkers and CECDAI or LS and examined the changes in therapeutic regimens based on the CECDAI.CE identified intestinal abnormalities in most CD patients in clinical remission: 81.0% and 85.7%, as assessed using CECDAI and LS, respectively. A significant positive correlation was observed between the CDAI and LS (P = .025), as well as between CDAI and CECDAI (P = .014) in these cases. Compared to LS, CECDAI scores were more evenly distributed. No significant correlations were observed between endoscopic scores and serum markers, including CRP, hemoglobin, and albumin levels. Additional treatment was performed significantly more often in patients with moderate-severe disease activity (CECDAI ≥5.8) (P = .012) than in those with normal (CECDAI <3.5) and mild (3.5≤CECDAI<5.8) disease activity. Resection of the small intestine did not affect the small bowel transit time or CE score.CECDAI is useful in evaluating mucosal lesions in small bowel CD patients in clinical remission and helps in assessing the requirement for additional treatment for these patients, including those who undergo intestinal resection.


Comparison of the intakes of sugars by young children with and without dental caries experience.
Relationships among sugars and dental caries in contemporary societies are unclear. The authors describe young children's intakes of nonmilk extrinsic (NME) and intrinsic/milk sugars and relate those intakes to dental caries. The authors conducted cross-sectional analyses of dietary data collected from the Iowa Fluoride Study using three-day diaries for subjects at ages 1, 2, 3, 4 and 5 years and for subjects aged 1 through 5 years according to dental caries experience at 4.5 to 6.9 years of age. They categorized foods and beverages as containing NME or intrinsic/milk sugars. Subjects' total, NME, food NME and intrinsic/milk sugars intakes at ages studied did not differ between subjects with and without caries experience. Beverage NME sugars intakes at age 3 years predicted caries (P < .05) in logistic regression models adjusted for age at dental examination and for fluoride intake. Dental caries is a complex, multifactorial disease process dependent on the presence of oral bacteria, a fermentable carbohydrate substrate and host enamel. A simple NME-intrinsic/milk sugars categorization appears insufficient to capture the complex dietary component of the caries process. Cariogenicity is more likely a function of the food and/or beverage vehicle delivering the sugar and the nature of exposure-that is, frequency and length of eating events-than of the sugar's categorization.


[Comparison on the function of rose as interpreted by traditional Chinese medicine and medicine of Uighur ethnic group].
As a kind of edible herbal plant, rose is recorded both in the literature of Han medicine and medicine of Uighur ethnic group, yet with different understanding on its function and different clinical application as well. Both Han and Uighur medicine maintain that rose possesses the functions of improving one's look and moisturizing the skin, aromatic deodorant and invigorating spleen to treat inflammation and damage, hematemesis, pain and diarrhea etc. In addition, rose is also used to treat wind bi(impediment or migratory arthralgia), acute mastitis, breast lump and depression in Han medicine, while in Uighur medicine, it is also used to treat constipation, palpitation, flat wart and dry throat.


Skin-derived fibroblasts respond to human parathyroid hormone-like adenylate cyclase-stimulating proteins.
Human tumors and keratinocyte-conditioned medium contain PTH-like adenylate cyclase-stimulating proteins. Human dermal fibroblasts have receptors that recognize PTH and a factor associated with humoral hypercalcemia of malignancy in rats. We examined 10 human dermal fibroblast lines for an adenylate cyclase response to PTH. Six of 10 lines tested displayed a definite response (2.4- to 3.8-fold over basal) to 10(-6) M bovine PTH-(1-34). This response was inhibited by the PTH analog and antagonist Nle8,18,Tyr34-bPTH-(3-34). We also examined whether human dermal fibroblasts are capable of responding to either a human PTH-like tumor-derived factor or the PTH-like factor contained in human keratinocyte-conditioned medium. Both human humoral hypercalcemia of malignancy-associated tumor extract (2.5 X 10(-10) M) and keratinocyte-conditioned medium (8 X 10(-10) M) stimulated human dermal fibroblast adenylate cyclase. These concentrations are markedly lower than those required for PTH-induced adenylate cyclase stimulation. This activity was also inhibited by the PTH analog. The high prevalence of PTH-responsive adenylate cyclase in dermal fibroblast lines and the apparent potency of tumor-derived and keratinocyte-derived PTH-like factors in dermal fibroblasts suggest that these factors may play a role in normal dermal physiology.


Quantitative analysis of foveal retinal thickness in diabetic retinopathy with the scanning retinal thickness analyzer.
This study sought to measure foveal retinal thickness in patients with diabetic retinopathy and to investigate the relationship between foveal thickness and visual acuity, biomicroscopic findings, and angiographic features. A commercial scanning retinal thickness analyzer was used to measure retinal thickness. A laser slit was projected onto the retina and scanned in 400 milliseconds across the central area of the fundus. The image where the laser slit intersects with the retina was digitally recorded and analyzed. Retinal thickness was measured in 35 patients (35 eyes; patient age, 57 +/- 13 years) with diabetic retinopathy. Patients also were examined by fluorescein angiography and slit-lamp biomicroscopy to detect foveal thickening. Linear regression analysis indicated a significant correlation between foveal thickness and visual acuity (adjusted R2 = 0.72, P < 0.001). Foveal thickness was abnormal in 6 (100%) of 6 eyes in which foveal thickening was detected with slit-lamp biomicroscopy. Foveal thickness also was abnormal in 9 (31%) of 29 eyes that appeared normal by biomicroscopic examination. Foveal thickness was 136 +/- 65 microns in 7 eyes without leakage, 175 +/- 35 microns in 13 eyes with questionable leakage, and 291 +/- 120 microns in 7 eyes with definite leakage (P = 0.0075). Retinal thickness analysis is shown to be more sensitive than slit-lamp biomicroscopy for detecting small changes in retinal thickness. Retinal thickness analysis may prove to be a useful, noninvasive modality for the development or regression of macular edema.


Type A2 BTB Members Decrease the ABA Response during Seed Germination by Affecting the Stability of SnRK2.3 in Arabidopsis.
The Arabidopsis genome comprises eighty genes encoding BTB (broad-complex, tramtrack, and bric-a-brac) family proteins that are characterized with the BTB domain and that potentially serve as substrate adaptors for cullin-based E3-ligases. In addition to the BTB domain, most BTB proteins also contain various other interaction motifs that probably act as target recognition elements. Here, we report three members of the BTB-A2 subfamily that distinctly only contain the BTB domain, BTB-A2.1, BTB-A2.2, and BTB-A2.3, that negatively regulates abscisic acid (ABA) signaling in Arabidopsis. BTB-A2.1, BTB-A2.2, and BTB-A2.3 encoded cytoplasm- and nucleus-localized proteins and displayed highly overlapping expression patterns in Arabidopsis tissues. Disruption of these three genes, but not single or double mutants, resulted in a decrease in ABA-induced inhibition of seed germination. Further analyses demonstrated the expression levels of these three genes were up-regulated by ABA, and their mutation increased ABA signalling. Importantly, protein-protein interaction assays showed that these three BTB-A2 proteins physically interacted with SnRK2.3. Moreover, biochemical and genetic assays indicated that BTB-A2.1, BTB-A2.2, and BTB-A2.3 decreased the stability of SnRK2.3 and attenuated the SnRK2.3 responsible for the ABA hypersensitive phenotype of seed germination. This report thus reveals that BTB-A2s serve as negative regulators for balancing the intensity of ABA signaling during seed germination.


Observation of the Zero Hall Plateau in a Quantum Anomalous Hall Insulator.
We report experimental investigations on the quantum phase transition between the two opposite Hall plateaus of a quantum anomalous Hall insulator. We observe a well-defined plateau with zero Hall conductivity over a range of magnetic field around coercivity when the magnetization reverses. The features of the zero Hall plateau are shown to be closely related to that of the quantum anomalous Hall effect, but its temperature evolution exhibits a significant difference from the network model for a conventional quantum Hall plateau transition. We propose that the chiral edge states residing at the magnetic domain boundaries, which are unique to a quantum anomalous Hall insulator, are responsible for the novel features of the zero Hall plateau.


A versatile magnetic refrigeration test device.
A magnetic refrigeration test device has been built and tested. The device allows variation and control of many important experimental parameters, such as the type of heat transfer fluid, the movement of the heat transfer fluid, the timing of the refrigeration cycle, and the magnitude of the applied magnetic field. An advanced two-dimensional numerical model has previously been implemented in order to help in the optimization of the design of a refrigeration test device. Qualitative agreement between the results from model and the experimental results is demonstrated for each of the four different parameter variations mentioned above.


FTO Is Associated with Aortic Valve Stenosis in a Gender Specific Manner of Heterozygote Advantage: A Population-Based Case-Control Study.
Single nucleotide polymorphisms (SNPs) within the Fat mass and obesity associated (FTO) gene have been linked with increased body weight. However, the data on an association of FTO with cardiovascular diseases remains conflicting. Therefore, we ascertained whether FTO is associated with aortic valve stenosis (AVS), one of the most frequent cardiovascular diseases in the Western world. In this population-based case-control study the FTO SNP rs9939609 was analyzed in 300 German patients with AVS and 429 German controls of the KORA survey S4, representing a random population. Blood samples were collected prior to aortic valve replacement in AVS cases and FTO rs9939609 was genotyped via ARMS-PCR. Genotype frequencies differed significantly between AVS cases and KORA controls (p = 0.004). Separate gender-analyses uncovered an association of FTO with AVS exclusively in males; homozygote carriers for the risk-allele (A) had a higher risk to develop AVS (p = 0.017, odds ratio (OR) 1.727; 95% confidence interval (CI) 1.087-2.747, recessive model), whereas heterozygote carriers for the risk-allele showed a lower risk (p = 0.002, OR 0.565, 95% CI 0.384-0.828, overdominant model). After adjustment for multiple co-variables, the odds ratios of heterozygotes remained significant for an association with AVS (p = 0.008, OR 0.565, 95% CI 0.369-0.861). This study revealed an association of FTO rs9939609 with AVS. Furthermore, this association was restricted to men, with heterozygotes having a significantly lower chance to develop AVS. Lastly, the association between FTO and AVS was independent of BMI and other variables such as diabetes mellitus.


Chemical modification of carboxypeptidase A crystals. Nitration of tyrosine-248.
Nitration of bovine carboxypeptidase A crystals with tetranitromethane increases esterase activity, decreases peptidase activity, and modifies about one tyrosyl residue. Modification of enzyme crystals avoids the polymerization that occurs when the enzyme is nitrated in solution. Two procedures have been employed to identify the tyrosyl residues nitrated. The first involves cyanogen bromide cleavage and isolation of the fragment containing residues 104-301. After solubilization by succinylation, this fragment is digested with chymotrypsin, the peptides are fractionated by gel filtration, and the nitrotyrosyl peptides are purified by affinity chromatography on an antinitrotyrosyl antibody-Sepharose conjugate followed by ion-exchange chromatography. In the second, the nitroenzyme is heat denatured, digested by chymotrypsin, and fractionated on the affinity and ion-exchange columns. By both methods, the major mitropeptides, representing between 60 and 80% of the nitrotyrosyl label, are uniquely compatible with that segment of the sequence of carboxypeptidase containing Tyr-248. A nearby cation, either the active site zinc ion or Arg-145, would seem to be an important factor in determining the selective nitration of this residue.


A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7.
Infection with Shiga toxin (Stx)-producing Escherichia coli O157:H7, which causes diarrhea and hemorrhagic colitis in humans, often results in fatal systemic complications, such as neurological damage and hemolytic-uremic syndrome. Because Stx circulating in the blood is a major causative factor of these complications, the development of a Stx neutralizer that functions in the circulation holds promise as a viable therapy. Here we developed a series of carbosilane dendrimers, in which trisaccharides of globotriaosyl ceramide, a receptor for Stx, were variously oriented at their termini (referred to as SUPER TWIG), and identified a SUPER TWIG with six trisaccharides as a Stx neutralizer functioning in the circulation. This SUPER TWIG specifically bound to Stx with high affinity (K(d) = 1.1 x 10(-6) M) and inhibited the incorporation of the toxin into target cells. Intravenous administration of the SUPER TWIG along with Stx to mice substantially reduced the fatal brain damage and completely suppressed the lethal effect of Stx. Moreover, the SUPER TWIG protected mice from challenge with a fatal dose of E. coli O157:H7, even when administered after the establishment of the infection. The SUPER TWIG neutralized Stx in vivo by a mechanism in which the accumulation and immediate degradation of Stx by phagocytic macrophages present in the reticuloendothelial system were induced. Taken together, our findings indicate that this SUPER TWIG is therapeutic agent against infections by Stx-producing E. coli.


Gynecological cancer among adolescents and young adults (AYA).
Adolescents and young adults (AYA) patients with cancer show specific biological, sociodemographic and behavioral features, with lower survival rates than younger group. Gynecologic malignancies that occur among AYA requires a multidisciplinary management and a tailored model of care, in order to enhance the early diagnosis, the adherence to the treatment, the enrollment in clinical trials, the rate of survival and the quality of life (QoL). In this article, we review the main gynecological tumors that may occur in AYA, with a focus on the clinical signs at the diagnosis and the modality of treatment. In addition, we proposed a model of multidisciplinary and personalized care for AYA with gynecological tumors, which can help the clinicians to manage the specific gynecologic concerns, such as ovarian failure, contraception, fertility, late psychosocial effects.


Intraocular pressure response to loteprednol etabonate in known steroid responders.
The continuing development of ophthalmic steroids has resulted in compounds that have a low tendency to raise intraocular pressure (IOP). Preliminary clinical data have suggested that loteprednol etabonate (LE) 0.5% suspension may not elevate IOP while having promise as a potent topical ophthalmic steroid. This study was designed to evaluate the comparative potential of topical LE and prednisolone acetate (PA) to raise IOP in a population of individuals known to be steroid responders. The study used a double-masked, randomized, single eye, crossover design comparing LE 0.5% and PA 1.0%. Subjects instilled 1 drop of the assigned medication 4 times daily while awake, and follow-up examinations occurred on days 14, 28, and 42. Following a washout period of at least 14 days, subjects entered the second phase of the study, which was identical to the first phase, except that subjects received the alternate study medication. The mean IOP in the LE group increased from 17.4mm Hg at baseline to 21.5mm Hg at day 42 (p > 0.05), while in the PA group the mean IOP increased from 18.1mm Hg at baseline to 27.1mm Hg at day 42 (p < 0.05). There were no serious, severe, or clinically significant events in either group, and LE's effect on IOP was differentiable from that of PA. LE has less effect on IOP when compared to the IOP response induced by PA. LE may become a clinically useful ocular steroid with a favorable IOP-safety profile.


Implantable Hemodynamic Monitoring for Heart Failure Patients.
Rates of heart failure hospitalization remain unacceptably high. Such hospitalizations are associated with substantial patient, caregiver, and economic costs. Randomized controlled trials of noninvasive telemedical systems have failed to demonstrate reduced rates of hospitalization. The failure of these technologies may be due to the limitations of the signals measured. Intracardiac and pulmonary artery pressure-guided management has become a focus of hospitalization reduction in heart failure. Early studies using implantable hemodynamic monitors demonstrated the potential of pressure-based heart failure management, whereas subsequent studies confirmed the clinical utility of this approach. One large pivotal trial proved the safety and efficacy of pulmonary artery pressure-guided heart failure management, showing a marked reduction in heart failure hospitalizations in patients randomized to active pressure-guided management. "Next-generation" implantable hemodynamic monitors are in development, and novel approaches for the use of this data promise to expand the use of pressure-guided heart failure management.


The effect of baseline physical activity on cardiovascular outcomes and new-onset diabetes in patients treated for hypertension and left ventricular hypertrophy: the LIFE study.
Physical activity (PA) is a preventive strategy for cardiovascular disease and for managing cardiovascular risk factors. There is little information on the effectiveness of PA for the prevention of cardiovascular outcomes once cardiovascular disease is present. Thus, we studied the relationship between PA at baseline and cardiovascular events in a high-risk population. A prespecified analyses of observational data in a prospective, randomized hypertension study. Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Hypertension and left ventricular hypertrophy (LVH) (n = 9,193). Losartan versus atenolol. Reported level of PA: never exercise, exercise <or=30 min twice per week, or exercise >30 min twice per week at baseline and after a mean of 4.8 years of treatment with losartan- versus atenolol-based therapy. Risk reductions were calculated by level of PA for the primary composite end-point and its components cardiovascular death, stroke and myocardial infarction, and also all-cause mortality and new-onset diabetes. A modest level of PA (>30 min twice per week) was associated with significant reductions in risk for the primary composite end-point [adjusted hazard ratio (aHR) 0.70, P < 0.001) and its components, all-cause mortality (aHR 0.65, P < 0.001), and new-onset diabetes (aHR 0.66, P < 0.001). A modest level of self-reported PA (>30 min twice per week) in patients with hypertension and LVH in the LIFE study was associated with significant reductions in risk for the primary composite end-point and its components of cardiovascular death, stroke, and myocardial infarction, all-cause mortality, and new-onset diabetes.


Synthesis and aromatase inhibitory activity of novel pyridine-containing isoflavones.
Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormone-dependent breast cancer. As a result, a number of synthetic steroidal or nonsteroidal aromatase inhibitors have been successfully developed. In addition, there are several classes of natural products that exert potent activities in aromatase inhibition, with the flavonoids being most prominent. Previous studies have exploited flavone and flavanone scaffolds for the development of new aromatase inhibitors. In this paper, we describe the design, synthesis, and biological evaluation of a novel series of 2-(4'-pyridylmethyl)thioisoflavones as the first example of synthetic isoflavone-based aromatase inhibitors.


Efficiency of nitrogen and phosphorus removal by six macrophytes from eutrophic water.
Increased nitrogen and phosphorus pollution causes eutrophication in water bodies. Using aquatic plants to remove nutrients from water is an attractive phytoremediation. It is a cost-effective, environment-friendly, and efficient way that reduces water body eutrophication by the plant. It is important to choose suitable macrophytes to remove excess N and P under different nutrient conditions. In this study, six macrophyte species (Polygonum orientale, Juncus effuses, Iris pseudocorus, Phragmites australis, Iris sanguinea, Typha orientalis) were tested. Simulation experiment was conducted under five N and P levels. The removal rate, relative growth rate, and the dynamic nutrition concentration of cultivated solution were investigated. Of all the treatment, a 23-95% reduction in N removal and a 29-92% reduction in P removal were recorded. The results showed I. sanguinea is a promising species to treat various eutrophic waters and the other five species can be used specifically to treat certain types of water. The data provided a theoretical guidance to plant species selection for phytoremediation of polluted water bodies for the purpose of water quality improvement around the different reservoir in northern China.


[The production of hybrid cells producing monoclonal antibodies against Toxoplasma gondii].
Hybridomas that secrete monoclonal antibody to Toxoplasma gondii have been developed. Two groups of 10 female BALB/c mice each were immunized either over a shorter (71 d) or longer (117 d) period at first with Toxoplasma lysate antigen and afterwards with intact tachyzoites of the RH strain. Higher titres of antibody were obtained with the long-period immunization. The fusion experiments have shown that both schemes of immunization approximately result in the same number (16 and 14% respectively) of hybridoma cell lines producing antigen-specific monoclonal antibodies. Hybridoma cultures secreting antitoxoplasma monoclonal antibodies were screened parallel by indirect immunofluorescence antibody test (IFAT) and enzyme immunoassay (EIA). 16 of the hybridoma cell cultures produced positive results only in the IFAT, 112 reacted only in the EIA and 21 were positive in both tests. The monoclonal antibodies 5B10, 5G6 and 1B2, which are positive in the IFAT form a chemical compound with the major antigens on the surface of RH tachyzoites. The patterns of fluorescence produced by these monoclonal antibodies are in conformity with those produced by using polyclonal sera of Toxoplasma gondii infected hosts (mouse, rabbit, man).


Minireview: Epidemiological impact of arboviral diseases in Latin American countries, arbovirus-vector interactions and control strategies.
Mosquitoes are the most crucial insects in public health due to their vector capacity and competence to transmit pathogens, including arboviruses, bacterias and parasites. Re-emerging and emerging arboviral diseases, such as yellow fever virus (YFV), dengue virus (DENV), zika virus (ZIKV), and chikungunya virus (CHIKV), constitute one of the most critical health public concerns in Latin America. These diseases present a significant incidence within the human settlements increasing morbidity and mortality events. Likewise, among the different genus of mosquito vectors of arboviruses, those of the most significant medical importance corresponds to Aedes and Culex. In Latin America, the mosquito vector species of YFV, DENV, ZIKV, and CHIKV are mainly Aedes aegypti and Ae. Albopictus. Ae. aegypti is recognized as the primary vector in urban environments, whereas Ae. albopictus, recently introduced in the Americas, is more prone to rural settings. This minireview focuses on what is known about the epidemiological impact of mosquito-borne diseases in Latin American countries, with particular emphasis on YFV, DENV, ZIKV and CHIKV, vector mosquitoes, geographic distribution, and vector-arbovirus interactions. Besides, it was analyzed how climate change and social factors have influenced the spread of arboviruses and the control strategies developed against mosquitoes in this continent.


New palladium(II) and platinum(II) complexes with 9-aminoacridine: structures, luminiscence, theoretical calculations, and antitumor activity.
The new complexes [Pd(dmba)( N10-9AA)(PPh 3)]ClO 4 ( 1), [Pt(dmba)( N9-9AA)(PPh 3)]ClO 4 ( 2), [Pd(dmba)( N10-9AA)Cl] ( 3), and [Pd(C 6F 5)( N10-9AA)(PPh 3)Cl] ( 4) (9-AA = 9-aminoacridine; dmba = N,C-chelating 2-(dimethylaminomethyl)phenyl) have been prepared. The crystal structures have been established by X-ray diffraction. In complex 2, an anagostic C-H...Pt interaction is observed. All complexes are luminescent in the solid state at room temperature, showing important differences between the palladium and platinum complexes. Complex 2 shows two structured emission bands at high and low energies in the solid state, and the lifetimes are in agreement with excited states of triplet parentage. Density functional theory and time-dependent density functional theory calculations for complex 2 have been done. Values of IC 50 were also calculated for the new complexes 1- 4 against the tumor cell line HL-60. All of the new complexes were more active than cisplatin (up to 30-fold in some cases). The DNA adduct formation of the new complexes synthesized was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the complexes on plasmid DNA pB R322 were also obtained.