Ground and valence excited states of BI: a MR-CISD+Q study.
Ab initio calculations on the valence electronic states of the BI molecule have been performed by using the entirely uncontracted all-electronic aug-cc-pVQZ (for the B atom) and Sadlej-pVTZ (for the I atom) basis sets and the internally contracted multireference singles and doubles configuration interaction method with Davidson size-extensively correction and Douglas-Kroll scalar relativistic correction. The potential energy curves of all valence states and the spectroscopic constants of bound states are fitted. It is the first time that the 12 Lambda-S states of BI molecule and all of the 23 Omega states generated from the former are studied in a theoretical way. Calculation results reproduce well most of the experimental data. The effects of the spin-orbit coupling and the avoided crossing rule between Omega states of the same symmetry are analyzed. The transition properties of the A3Pi0+, B3Pi1, and C1Pi1 states to the ground-state transitions are predicted, including the transition dipole moments, the Franck-Condon factors, and the radiative lifetimes. The radiative lifetime of the C1Pi1 state of BI molecule is less than 1 micros, while that of the A3Pi0+ and B3Pi1 states are the order of 1 ms.


Dominant formation of the microsized carbon coils by a short time SF6 flow incorporation during the initial deposition stage.
By SF6 gas incorporation for relatively short time during the initial deposition stage, carbon coils could be formed on nickel catalyst layer-deposited silicon oxide substrate using C2H2 and H2 as source gases under thermal chemical vapor deposition system. The characteristics (formation density and morphology) of as-grown carbon coils were investigated as a function of SF6 flow injection time. 5-min SF6 flow injection time is appropriate to produce the dominant microsized geometry for carbon coils without the appearance of the nanosized carbon coils. The geometry for the microsized carbon coils follows a typical double-helix structure and the shape of the rings constituting the coils is a flat-type. Fluorine's intrinsic etching characteristics for the nanosized carbon coils during the initial deposition stage seems to be the cause for the dominant formation of the microsized carbon coils in the case of 5-min SF6 flow injection time.


Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.
The impact of continuous hemofiltration (CHF) using a polyacrylonitrile membrane on the kinetics of tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), and their inhibitors (soluble TNF receptors [sTNFrI, sTNFrII], interleukin-1 receptor antagonist [IL-1Ra]) was assessed in nine oliguric patients suffering from systemic inflammatory response syndrome. Blood and plasma flow (Qb, Qp), sieving coefficient (SC), plasma and ultrafiltrate clearances (Kp, Kuf), and plasma extraction rates (ERp) were calculated at different time points using standard formulas. No significant improvement of hemodynamics or gas exchange was noted following HF but a significant increase in serum bicarbonate occurred after 24 h (P < 0.05). TNF alpha was detected in plasma from all patients (153 +/- 2.3 pg/mL [mean +/- SEM]). None of the patients had detectable IL-1 beta levels. High levels of the TNF receptors (sTNFrI 20.338 +/- 2.431 pg/mL; sTNFrII 17.839 +/- 2.630 pg/mL) and IL-1Ra (19.775 +/- 3.943 pg/mL) were found in all patients. Upon initiation of hemofiltration (HF), the mean individual sTNFrI/TNF alpha ratio amounted to 269 +/- 84.6 and the sTNFrII/TNF alpha ratio to 249 +/- 91.8. Mean ultrafiltrate volume (Vuf) was 11.8 +/- 0.4 L/day. Appreciable sieving of IL-1Ra (SC 0.45 +/- 0.10), but not of the other cytokines, was noted (SC TNF alpha, sTNFrI, sTNFrII < 0.09). Despite minimal Kuf of TNF alpha, sTNFrI, and STNFrII (Kuf < 0.8 mL/min), appreciable Kp was noted, suggesting that membrane adsorption occurs (Kp approximately 8 mL/min). There was a nonsignificant increase of the ratios between both TNF receptors and TNF alpha across the filter (sTNFrI/TNF alpha ratio [pre] 231 +/- 37.9 versus [post] 312 +/- 75.3); sTNFrII/TNF alpha ratio [pre] 211 +/- 42.1 versus [post] 291 +/- 79.3). Appreciable Kp of IL-1Ra was noted (Kp 17.3 +/- 1.61 mL/min), which was only in part due to Kuf (4.0 +/- 0.86 mL/min). There was a significant decrease of IL-1Ra levels across the membrane, both overall ([pre] 20.223 +/- 2.282 versus [post] 16.637 +/- 2.039 pg/mL; P < 0.01) and at different time points (P < 0.01). Only for IL-1Ra was significant extraction from plasma noted (ERp 26 +/- 6.0%). Plasma levels of TNF alpha, sTNFrI, sTNFrII, and IL-1Ra were not altered by 24 h of CHF. In conclusion, both cytokines and cytokine inhibitors can be removed from the circulation, either by convective transport or by membrane adsorption. Using low-volume HF (Vuf approximately 12 L/day), no impact on cytokine plasma levels nor the patients hemodynamics or gas exchange was noted. The appreciable SC of IL-1Ra (0.45), however, suggests that HF with high(er) UF volumes (> 50 L/day) may be able to achieve reductions in plasma levels of some peptide (anti)mediators. However, whether this aspecific elimination of both mediators and antimediators may alter the clinical course in critically ill patients remains to be investigated.


Development and test of sets of 3D printed age-specific thyroid phantoms for 131I measurements.
In the case of a nuclear reactor accident the release contains a high proportion of iodine-131 that can be inhaled or ingested by members of the public. Iodine-131 is naturally retained in the thyroid and increases the thyroid cancer risk. Since the radiation induced thyroid cancer risk is greater for children than for adults, the thyroid dose to children should be assessed as accurately as possible. For that purpose direct measurements should be carried out with age-specific calibration factors but, currently, there is no age-specific thyroid phantoms allowing a robust measurement protocol. A set of age-specific thyroid phantoms for 5, 10, 15 year old children and for the adult has been designed and 3D printed. A realistic thyroid shape has been selected and material properties taken into account to simulate the attenuation of biological tissues. The thyroid volumes follow ICRP recommendations and the phantoms also include the trachea and a spine model. Several versions, with or without spine, with our without trachea, with or without age-specific neck have been manufactured, in order to study the influence of these elements on calibration factors. The calibration factor obtained with the adult phantom and a reference phantom are in reasonable agreement. In vivo calibration experiments with germanium detectors have shown that the difference in counting efficiency, the inverse of the calibration factor, between the 5 year and adult phantoms is 25% for measurement at contact. It is also experimentally evidenced that the inverse of the calibration factor varies linearly with the thyroid volume. The influence of scattering elements like the neck or spine is not evidenced by experimental measurements.


MicroRNAs as biomarkers of hepatotoxicity in a randomized placebo-controlled study of simvastatin and ubiquinol supplementation.
Statins are potent cholesterol-lowering drugs and are generally well tolerated. Hepatotoxicity is a rare but serious adverse effect of statins; however, its mechanisms are not clear. Coenzyme Q10 deficiency has been suggested, and supplementation of reduced coenzyme Q10 (ubiquinol) has been shown to have hepatoprotective effects. MicroRNAs (miRNAs) are small nucleotides that have been shown to be up-regulated in drug-induced liver injury. We hypothesized that circulating miRNAs may be differentially regulated after simvastatin treatment and by comparing with that of simvastatin and ubiquinol supplementation could potentially uncover signatory miRNA profile for simvastatin-induced liver injury. In this double-blind, prospective, randomized-controlled trial, miRNA profiles and liver enzymes were compared between simvastatin-treated patients, with and without ubiquinol supplementation, over 12 weeks compared to baseline. miRNA expression was further validated in HepG2 liver cell lines by real-time PCR. Changes in miR-192, miR-146a, miR-148a, miR-15a, and miR-21 were positively correlated (p<0.05) with alanine aminotransferase in simvastatin-only treated patients. In ubiquinol supplementation group, alanine aminotransferase and alkaline phosphatase were significantly down-regulated after 12 weeks and changes in miR-15a, miR-21 and miR-33a were negatively correlated with alkaline phosphatase (p < 0.05). Bioinformatics analyses predicted that miRNA regulation in simvastatin group was related to reduce proliferation and adenosine triphosphate-binding cassette transporters. Ubiquinol supplementation additionally regulated miRNAs that inhibit apoptotic and inflammatory pathways, suggesting potential hepatoprotective effects. Our results suggest that 20 mg/day of simvastatin does not have significant risk of hepatotoxicity and ubiquinol supplementation may, at the miRNA level, provide potential beneficial changes to reduce the effects of coenzyme Q10 deficiency in the liver.


Impaired function of the blood-testis barrier during aging is preceded by a decline in cell adhesion proteins and GTPases.
With increasing age comes many changes in the testis, including germ cell loss. Cell junctions in the testis tether both seminiferous epithelial and germ cells together and assist in the formation of the blood-testis barrier (BTB), which limits transport of biomolecules, ions and electrolytes from the basal to the adluminal compartment and protects post-meiotic germ cells. We hypothesize that as male rats age the proteins involved in forming the junctions decrease and that this alters the ability of the BTB to protect the germ cells. Pachytene spermatocytes were isolated from Brown Norway rat testes at 4 (young) and 18 (aged) months of age using STA-PUT velocity sedimentation technique. RNA was extracted and gene expression was assessed using Affymetrix rat 230 2.0 whole rat genome microarrays. Microarray data were confirmed by q-RT-PCR and protein expression by Western blotting. Of the genes that were significantly decreased by at least 1.5 fold, 70 were involved in cell adhesion; of these, at least 20 are known to be specifically involved in junction dynamics within the seminiferous epithelium. The mRNA and protein levels of Jam2, Ocln, cdh2 (N-cadherin), ctnna (α-catenin), and cldn11 (involved in adherens junctions), among others, were decreased by approximately 50% in aged spermatocytes. In addition, the GTPases Rac1 and cdc42, involved in the recruitment of cadherins to the adherens junctions, were similarly decreased. It is therefore not surprising that with lower expression of these proteins that the BTB becomes diminished with age. We saw, using a FITC tracer, a gradual collapse of the BTB between 18 and 24 months. This provides the opportunity for harmful substances and immune cells to cross the BTB and cause the disruption of spermatogenesis that is observed with increasing age.


Prevalence of CXCR4-tropic viruses in clustered transmission chains at the time of primary HIV-1 infection.
During 2003-2010, 555 strains isolated from sexually-infected patients at the time of primary HIV-1 infection (PHI) were characterized. Tree topology revealed that 11.7% of PHIs segregated into transmission clusters. CXCR4-usage was identified in 27 strains (4.9%) and was significantly associated with subtype B (p 0.003) and low CD4 cell count (p 0.01). In clustered and unique PHIs, the prevalence of CXCR4-tropic strains was 1.5% and 5.3%, respectively (p 0.35). Our results are in line with the hypothesis of a mucosal bottleneck contributing to the high prevalence of CCR5 variants during PHI.


Bridging the knowledge-action gap in diabetes: information technologies, physician incentives and consumer incentives converge.
The gap between current medical knowledge and its application in chronic disease management is especially apparent in diabetes care. Although research over the last decade has shown that adherence to standards of care can prevent or delay the onset of devastating diabetic complications, little more than one-third of patients achieve adequate glycaemic control. Obstacles to better care include 'system' factors such as inadequate record-keeping and reimbursement policies that reimburse amply for illness but poorly for diabetes education and interventions via telephone and computer. Disparities in healthcare compound the difficulty among vulnerable populations in urban and rural areas. Emerging healthcare delivery systems that encourage payers, providers and consumers to improve diabetes care with the use of information technology and financial incentives are described in different health management settings.


Recurrent melena in a diagnosed case of Bernard Soulier syndrome.
Bernard Soulier Syndrome is a genetically inherited platelet disorder that commonly presents with symptoms of impaired blood coagulation, such as epistaxis, menorrhagia, and petechiae formation. Here we present a case of Bernard Soulier Syndrome in which the individual has presented with melena, which is the appearance of black tarry stools due to bleeding from the upper gastrointestinal tract. This presentation is rare and should be discussed so that appearance of the less common symptoms can be caught early, leading to an early diagnosis and consequently earlier and more effective management options.


Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function.
The pharmacokinetics of mycophenolic acid (MPA), the immunosuppressant form of the prodrug mycophenolate mofetil (MMF), and the primary glucuronide metabolite, MPAG, were characterized in renal transplant patients with delayed graft function using random effects piecewise linear models. Eight patients were evaluated after receiving their first and subsequent daily oral doses of 1.5 g mycophenolate mofetil twice daily on study days 1 (n = 8), 7 (n = 8), 14 (n = 5), 21 (n = 2), and 28 (n = 7). The area under the concentration-time curve from zero to 12 hours (AUC0-12) for MPA, MPAG, MPA free fraction, and free MPA were analyzed in serial plasma samples using validated high-performance liquid chromatography and ultrafiltration procedures. Random effects piecewise linear models, fit by maximum likelihood methods, were applied to AUC0-12 of MPA and MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine concentration, the index of renal function used in this study. Two hemodialysis sessions did not lower MPA plasma concentration, although some MPAG was removed. The AUC0-12 of MPA increased as a function of time, although it was not possible to fit a statistical model to the data due to considerable among-patient variation in the pattern of increase with time. The AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA reached maximal values on day 7; each of these parameters had unique day 1 to 7 positive slope values and unique day 7 to 28 negative slope values. The average creatinine concentration was maximal at day 1 and a unique negative slope was obtained between days 7 and 28. Thus, this study provides statistical models for the alteration of AUC0-12 of MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine in renal transplant patients with delayed graft function. These results provide evidence that renal dysfunction is associated with altered pharmacokinetics of MPA, particularly increased AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA. The perturbed pharmacokinetics normalized with improving renal function.


[Proteins from Vps13 family: from molecular function to pathogenesis of neurodegenerative disorders].
The Vps (vacuolar protein sorting) group of proteins was identified in yeast Saccharomyces cerevisiae. Among the Vps proteins, there is the Vps13 family, proteins of which are present in organisms from different systematic groups. In yeast there is only one Vps13 protein, while in humans there are four Vps13 family members - hVps13A-D. These are large proteins of characteristic domain structure. Mutations in hVPS13 genes are linked to rare neurodegenerative disorders: chorea- acanthocytosis (hVPS13A), Cohen syndrome (hVPS13B), predispose to early onset into Parkinson disease (hVPS13C) and lead to ataxia/spastic paraplegia (hVPS13D). Lack of clear diagnostic criteria and broad spectrum of nonspecific symptoms cause the misdiagnosis of several patients with neurodegeneration and it is difficult to estimate the number of individuals with mutations in hVPS13 genes. The importance of Vps13 family proteins for human health turns interest of research on finding Vps13 protein function, which remains unknown. The research is mostly performed on several experimental models in which deficit of those proteins was acquired by deletions or gene expression silencing, or on cells from patients. Several changes were found in cells lacking Vps13 proteins on cellular level, such as changes in intracellular protein trafficking between Golgi apparatus, plasma membrane and endosomes, changes in mitochondria functioning and changes in organization of cytoskeletons, mainly actin cytoskeleton. However, it is unknown which alterations are primary and which secondary, compensatory. Recently research done on yeast revealed that Vps13 is a protein of the membrane contact sites, the structures involved in exchange of metabolites between different organelles. Such localization seems to be essential for Vps13 function. Based on literature we propose a hypothesis that Vps13 might actively participate in exchange of the lipids between membranes of organelles in membrane contact sites what could explain most of the phenotypes caused by lack of Vps13 protein.


Spatial complexity of mechanisms controlling a bacterial cell cycle.
Cell cycle progression in Caulobacter is governed by a multilayered regulatory network linking chromosome replication with polar morphogenesis and cell division. Temporal and spatial regulation have emerged as the central themes, with the abundance, activity and subcellular location of key structural and regulatory proteins changing over the course of the cell cycle. An additional layer of complexity was recently uncovered, showing that each segment of the chromosome is located at a specific cellular position both during and after the completion of DNA replication, raising the possibility that this positioning contributes to temporal and spatial control of gene expression.


Clinical course of cranial dural arteriovenous fistulas with long-term persistent cortical venous reflux.
The natural history of aggressive (Borden 2 and 3) cranial dural arteriovenous fistulas (DAVFs) is not well described. Reported annual mortality and hemorrhage rates vary widely and range up to 20% per year. A consecutive single-center cohort of 236 cases that presented with a cranial DAVF between June 1984 and May 2001 was reviewed for the consequences of long-term persistent cortical venous reflux (CVR). A group of 118 cranial DAVFs was selected for the presence of CVR. All patients were offered treatment aimed at the disconnection of the CVR. Patients who declined or had partial treatment with persistence of the CVR had long-term clinical and angiographic follow-up to study the disease course of this select group. Treatment was instituted in 101 of the 118 patients (85.6%). Three patients were lost to follow-up. The remaining 14 nontreated patients (11.9%) and the partially treated patients (n=6) were assessed clinically and angiographically over time. The mean follow-up in this select group was 4.3 years (86.9 patient-years). During follow-up, 7 patients suffered an intracranial hemorrhage (35%). The incidence of nonhemorrhagic neurological deficit was 30%. Nine patients (45%) died: 6 patients expired after a hemorrhage, and 3 patients died of progressive neurological deterioration. Two patients demonstrated a spontaneous closure of the DAVF (10%). Persistence of the CVR in cranial DAVFs yields an annual mortality rate of 10.4%. Excluding events at presentation, in this series the annual risk for hemorrhage or nonhemorrhagic neurological deficit during follow-up was 8.1% and 6.9%, respectively, resulting in an annual event rate of 15.0%.


Further study of the inhibition of premature labor by indomethacin. Part I.
Prematurity still remains one of the unsolved problems in obstetrics and is responsible for a majority of cases of perinatal morbidity and mortality. The use of indomethacin to stop uterine contractions and prevent premature delivery is based on the observation that indomethacin inhibits the release of prostaglandin which is assumed to play a role in the induction and continuation of labor. The effect of indomethacin as an antagonist to prostaglandin was evaluated in a series of 297 women in premature labor. The gestational age at admission varied between 24 and 34 weeks of pregnancy (120 primiparas and 177 multiparas). In 83% of cases there was complete cessation of labor for a period of 1 to 12 weeks, in 10% of cases from 2 to 7 days and in 7% there was no effect. The delay of premature labor for 2 to 7 days allowed the administration of betamethasone in an attempt to improve fetal lung maturity. The total daily dose needed for successful treatment was between 200-300 mg indomethacin. Dilation of cervix beyond 4 cm was associated with successful treatment in 58% compared to 90% if cervix was dilated 3 cm or less. In comparing women with intact membranes to women with ruptured, the success rate in suppressing premature labor was significant; 88% versus 53%. In 49 patients delivery was delayed 11-12 weeks. Fifty-one babies were born in spite of therapy, and of these 15 with birth weights of 700-1500 g suffered from respiratory distress syndrome and died. All the rest (36 premature and 246 mature infants) showed no ill effects related to the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Gastrin-releasing peptide directly releases pepsinogen from guinea pig chief cells.
Gastrin-releasing peptide (GRP) and bombesin can stimulate pepsinogen release by both gastrin-dependent and -independent mechanisms. Using isolated guinea pig gastric chief cells, we determined that GRP can act directly on the guinea pig chief cell to cause pepsinogen release. GRP and bombesin stimulated a 2.5- to 3-fold increase in pepsinogen release above basal release. Substance P also stimulated a small but significant increase in pepsinogen release. No gastrin immunoreactivity was detected in the supernatants of cells stimulated with up to 1 microM GRP or bombesin or 1 mM carbachol. GRP-stimulated pepsinogen release was completely inhibited by GRP/bombesin receptor agonists as well as substance P receptor antagonist but not by antagonists to receptors for gastrin, the octapeptide of cholecystokinin (CCK-8), secretin, vasoactive intestinal peptide (VIP), or muscarinic agents. Substance P-stimulated pepsinogen release was completely inhibited by substance P receptor antagonist but not by GRP/bombesin receptor antagonists. An additive effect on pepsinogen release was seen when GRP was combined with maximally effective concentrations of adenosine 3',5'-cyclic monophosphate (cAMP)-mediated agents (VIP, secretin, 8-BrcAMP) but not with calcium-mediated agents (carbachol, CCK-8, gastrin). These results indicate that GRP can directly stimulate pepsinogen release from guinea pig chief cells by a specific GRP receptor that mobilizes intracellular calcium.


Effectiveness of Winkler Litter Extraction and Pitfall Traps in Sampling Ant Communities and Functional Groups in a Temperate Forest.
Selection of proper sampling methods for measuring a community of interest is essential whether the study goals are to conduct a species inventory, environmental monitoring, or a manipulative experiment. Insect diversity studies often employ multiple collection methods at the expense of researcher time and funding. Ants (Formicidae) are widely used in environmental monitoring owing to their sensitivity to ecosystem changes. When sampling ant communities, two passive techniques are recommended in combination: pitfall traps and Winkler litter extraction. These recommendations are often based on studies from highly diverse tropical regions or when a species inventory is the goal. Studies in temperate regions often focus on measuring consistent community response along gradients of disturbance or among management regimes; therefore, multiple sampling methods may be unnecessary. We compared the effectiveness of pitfalls and Winkler litter extraction in an eastern temperate forest for measuring ant species richness, composition, and occurrence of ant functional groups in response to experimental manipulations of two key forest ecosystem drivers, white-tailed deer and an invasive shrub (Amur honeysuckle). We found no significant effect of sampling method on the outcome of the ecological experiment; however, we found differences between the two sampling methods in the resulting ant species richness and functional group occurrence. Litter samples approximated the overall combined species richness and composition, but pitfalls were better at sampling large-bodied (Camponotus) species. We conclude that employing both methods is essential only for species inventories or monitoring ants in the Cold-climate Specialists functional group.


Constitutive scaffolding of multiple Wnt enhanceosome components by Legless/BCL9.
Wnt/β-catenin signaling elicits context-dependent transcription switches that determine normal development and oncogenesis. These are mediated by the Wnt enhanceosome, a multiprotein complex binding to the Pygo chromatin reader and acting through TCF/LEF-responsive enhancers. Pygo renders this complex Wnt-responsive, by capturing β-catenin via the Legless/BCL9 adaptor. We used CRISPR/Cas9 genome engineering of Drosophila legless (lgs) and human BCL9 and B9L to show that the C-terminus downstream of their adaptor elements is crucial for Wnt responses. BioID proximity labeling revealed that BCL9 and B9L, like PYGO2, are constitutive components of the Wnt enhanceosome. Wnt-dependent docking of β-catenin to the enhanceosome apparently causes a rearrangement that apposes the BCL9/B9L C-terminus to TCF. This C-terminus binds to the Groucho/TLE co-repressor, and also to the Chip/LDB1-SSDP enhanceosome core complex via an evolutionary conserved element. An unexpected link between BCL9/B9L, PYGO2 and nuclear co-receptor complexes suggests that these β-catenin co-factors may coordinate Wnt and nuclear hormone responses.


Diffuse metabolic abnormalities in reversible posterior leukoencephalopathy syndrome.
Two cases of reversible posterior leukoencephalopathy syndrome were examined with proton MR spectroscopic imaging. Widespread metabolic abnormalities, consisting of increased choline and creatine levels and mildly decreased N-acetylaspartate, occurred in regions with both normal and abnormal MR imaging appearances. In one case for which proton MR spectroscopic imaging follow-up was available, all metabolite levels had returned to normal by 2 months. Proton MR spectroscopic imaging may be helpful for the diagnosis and investigation of the underlying pathophysiology of reversible posterior leukoencephalopathy syndrome.


[The Meckel syndrome (author's transl)].
The Meckel syndrome is caused by an autosomal recessive gene. The three main features are encephalocele, polycystic kidneys and polydactyly. At least two of these should be present to establish the diagnosis. Several minor symptoms are observed in various combinations. The possibility of prenatal diagnosis is explained by a case report: A neural tube defect was diagnosed by ultrasonography and AFP-assessment in amniotic fluid whereas unfortunately the presence of polycystic kidneys was not recognized sonographically. The methods of today are able to detect the polydactyly but failed in this case. One can suggest that the complete prenatal diagnosis of the Meckel syndrome is not essential for clinical management since the presence of one major symptom will lead to legal abortion. The search for Meckel syndrome is important in cases of delivery of a child with multiple malformations, indicating a genetic counseling for each subsequent pregnancy.


Nuclear chromatin patterns in 3 glucocorticoid-resistant RPMI 8226 human myeloma cell sub-lines: correlations with cell growth and immunological phenotype.
Nuclear morphological alterations associated with glucocorticoid resistance in human myeloma were evaluated by image cytometry in three human myeloma RPMI 8226 cell sub-lines. Resistance was induced by drug selection using prednisone (8226p), methylprednisolone (8226m) and dexamethasone (8226d), respectively. All these three cell sub lines displayed significant glucocorticoid-resistance without cross-resistance to doxorubicin. Nuclear geometry and texture were analyzed on G0/G1-selected cell nuclei and data compared with cell growth characteristics and membrane expression of CD23, CD38, CD44 and CD58 antigens. When compared to the parental RPMI 8226 cell line, glucocorticoid-resistant cells display a progressive chromatin condensation with heterogeneously distributed large chromatin clumps, a phenomenon not observed in the multidrug-resistant CEM-VLB cells. These alterations were correlated to the resistance index against glucocorticoids and to the expressions of CD38, and of CD44 variant forms CD44v5 and CD44v7-8 antigens. These data suggest that glucocorticoid resistance in RPMI 8226 cells could be associated with sub-visual specific higher-order chromatin organization changes. Furthermore, these alterations are correlated to the expression of membrane markers associated with tumors aggressiveness.


Characterizing heterogeneous cellular responses to perturbations.
Cellular populations have been widely observed to respond heterogeneously to perturbation. However, interpreting the observed heterogeneity is an extremely challenging problem because of the complexity of possible cellular phenotypes, the large dimension of potential perturbations, and the lack of methods for separating meaningful biological information from noise. Here, we develop an image-based approach to characterize cellular phenotypes based on patterns of signaling marker colocalization. Heterogeneous cellular populations are characterized as mixtures of phenotypically distinct subpopulations, and responses to perturbations are summarized succinctly as probabilistic redistributions of these mixtures. We apply our method to characterize the heterogeneous responses of cancer cells to a panel of drugs. We find that cells treated with drugs of (dis-)similar mechanism exhibit (dis-)similar patterns of heterogeneity. Despite the observed phenotypic diversity of cells observed within our data, low-complexity models of heterogeneity were sufficient to distinguish most classes of drug mechanism. Our approach offers a computational framework for assessing the complexity of cellular heterogeneity, investigating the degree to which perturbations induce redistributions of a limited, but nontrivial, repertoire of underlying states and revealing functional significance contained within distinct patterns of heterogeneous responses.


Survivability of Eurasian H5N1 highly pathogenic avian influenza viruses in water varies between strains.
Aquatic habitats play a critical role in the transmission and maintenance of low-pathogenic avian influenza (LPAI) viruses in wild waterfowl; however, the importance of these environments in the ecology of H5N1 highly pathogenic avian influenza (HPAI) viruses is unknown. In laboratory-based studies, LPAI viruses can remain infective for extended durations (months) in water, but the persistence is strongly dependent on water conditions (temperature, salinity, pH) and virus strain. Little is known about the stability of H5N1 HPAI viruses in water. With the use of an established laboratory model system, the persistence of 11 strains of H5N1 HPAI virus was measured in buffered distilled water (pH 7.2) at two temperatures (17 and 28 C) and three salinities (0, 15,000, and 30,000 ppm). There was extensive variation between the 11 H5N1 HPAI virus strains in the overall stability in water, with a range similar to that which has been reported for wild-bird-origin LPAI viruses. The H5N1 HPAI virus strains responded similarly to different water temperatures and salinities, with all viruses being most stable at colder temperatures and fresh to brackish salinities. These results indicate that the overall stability and response of H5N1 HPAI viruses in water is similar to LPAI viruses, and suggest there has been no increase or loss of environmental survivability in H5N1 HPAI viruses.


Hybrid reaction-diffusion and clock-and-wavefront model for the arrest of oscillations in the somitogenesis segmentation clock.
The clock and wavefront paradigm is arguably the most widely accepted model for explaining the embryonic process of somitogenesis. According to this model, somitogenesis is based upon the interaction between a genetic oscillator, known as segmentation clock, and a differentiation wavefront, which provides the positional information indicating where each pair of somites is formed. Shortly after the clock and wavefront paradigm was introduced, Meinhardt presented a conceptually different mathematical model for morphogenesis in general, and somitogenesis in particular. Recently, Cotterell et al. [A local, self-organizing reaction-diffusion model can explain somite patterning in embryos, Cell Syst. 1, 257-269 (2015)] rediscovered an equivalent model by systematically enumerating and studying small networks performing segmentation. Cotterell et al. called it a progressive oscillatory reaction-diffusion (PORD) model. In the Meinhardt-PORD model, somitogenesis is driven by short-range interactions and the posterior movement of the front is a local, emergent phenomenon, which is not controlled by global positional information. With this model, it is possible to explain some experimental observations that are incompatible with the clock and wavefront model. However, the Meinhardt-PORD model has some important disadvantages of its own. Namely, it is quite sensitive to fluctuations and depends on very specific initial conditions (which are not biologically realistic). In this work, we propose an equivalent Meinhardt-PORD model and then amend it to couple it with a wavefront consisting of a receding morphogen gradient. By doing so, we get a hybrid model between the Meinhardt-PORD and the clock-and-wavefront ones, which overcomes most of the deficiencies of the two originating models.


Kinetic analysis of FDG in rat liver: effect of dietary intervention on arterial and portal vein input.
Dietary conditions may affect liver [(18)F]FDG kinetics due to arterial and portal vein (PV) input. The purpose of this study was to evaluate kinetic models of [(18)F]FDG metabolism under a wide range of dietary interventions taking into account variations in arterial (HA) and portal vein (PV) input. The study consisted of three groups of rats maintained under different diet interventions: 12 h fasted, 24 h fasted and those fed with high fructose diet. [(15)O]H₂O PET imaging was used to characterize liver flow contribution from HA and PV to the liver's dual input function (DIF). [(18)F]FDG PET imaging was used to characterize liver metabolism. Differences in [(18)F]FDG kinetics in HA, PV and liver under different diet interventions were investigated. An arterial to PV Transfer Function (TF) was optimized in all three dietary states to noninvasively estimate PV activity. Finally, two compartment 3-parameter (2C3P), two compartment 4-parameter (2C4P), two compartment 5-parameter (2C5P), and three compartment 5-parameter (3C5P) models were evaluated and compared to describe the kinetics of [(18)F]FDG in the liver across diet interventions. Sensitivity of the compartmental models to ratios of HA to PV flow fractions was further investigated. Differences were found in HA and PV [(18)F]FDG kinetics across 12h fasted, 24h fasted and high fructose fed diet interventions. A two exponential TF model was able to estimate portal activity in all the three diet interventions. Statistical analysis suggests that a 2C3P model configuration was adequate to describe the kinetics of [(18)F]FDG in the liver under wide ranging dietary interventions. The net influx of [(18)F]FDG was lowest in the 12h fasted group, followed by 24 h fasted group, and high fructose diet. A TF was optimized to non-invasively estimate PV time activity curve in different dietary states. Several kinetic models were assessed and a 2C3P model was sufficient to describe [(18)F]FDG liver kinetics despite differences in HA and PV kinetics across wide ranging dietary interventions. The observations have broader implications for the quantification of liver metabolism in metabolic disorders and cancer, among others.


The use of music to release the ties that bind.
The purpose of this descriptive pilot study was to determine the effect of a musical intervention on the behavioural reactions of physically restrained patients. Forty patients, of whom 23 were female and 17 were males with a mean age of 77, participated in the study. Patients listened to their preferred musical selection for a period of 30 minutes while they were out of their restraining device. The findings indicated that there was an increase in observed positive behaviours while patients listened to music as compared to the pre- or post-intervention phase. Music intervention may be appropriate for some patients as an alternative to physical restraints.


[Experimental substantiation of the method of biological tissue welding in surgical hepatology].
Application of the welding method for biological tissues in hepatobiliary surgery was experimentally substantiated. In 14 pigs (25-30 kg body mass) resection of one hepatic lobe, using electric welding method, was done. In control group (4 pigs) the similar operative intervention was accomplished, using conventional method. Application of the electric welding method guarantees secure hemostasis and cholestasis, do not causes specific pathological changes in the adjacent region of affection tissues, speed of restoration of the structures damaged exceeds such in application of the suturing method.


A Role for Frizzled and Their Post-Translational Modifications in the Mammalian Central Nervous System.
The Wnt pathway is a key signalling cascade that regulates the formation and function of neuronal circuits. The main receptors for Wnts are Frizzled (Fzd) that mediate diverse functions such as neurogenesis, axon guidance, dendritogenesis, synapse formation, and synaptic plasticity. These processes are crucial for the assembly of functional neuronal circuits required for diverse functions ranging from sensory and motor tasks to cognitive performance. Indeed, aberrant Wnt-Fzd signalling has been associated with synaptic defects during development and in neurodegenerative conditions such as Alzheimer's disease. New studies suggest that the localisation and stability of Fzd receptors play a crucial role in determining Wnt function. Post-translational modifications (PTMs) of Fzd are emerging as an important mechanism that regulates these Wnt receptors. However, only phosphorylation and glycosylation have been described to modulate Fzd function in the central nervous system (CNS). In this review, we discuss the function of Fzd in neuronal circuit connectivity and how PTMs contribute to their function. We also discuss other PTMs, not yet described in the CNS, and how they might modulate the function of Fzd in neuronal connectivity. PTMs could modulate Fzd function by affecting Fzd localisation and stability at the plasma membrane resulting in local effects of Wnt signalling, a feature particularly important in polarised cells such as neurons. Our review highlights the importance of further studies into the role of PTMs on Fzd receptors in the context of neuronal connectivity.


Behavioral Changes of Some Arboviral Vectors in Zika Forest: A Concern for Emerging and Re-Emerging Diseases in Uganda.
Background: The increasing reports on emerging/re-emerging arboviral disease outbreaks or epidemics in Sub-Saharan Africa have been impacted by factors, including the changing climate plus human activities that have resulted in land cover changes. These factors influence the prevalence, incidence, behavior, and distribution of vectors and vector-borne diseases. In this study, we assessed the potential effect of land cover changes on the distribution and oviposition behavior of some arboviral vectors in Zika forest, Uganda, which has decreased by an estimated 7 hectares since 1952 due to an increase in anthropogenic activities in the forest and its periphery. Materials and Methods: Immature mosquitoes were collected using bamboo pots and placed at various levels of a steel tower in the forest and at different intervals from the forest periphery to areas among human dwellings. Collections were conducted for 20 months. Results and Conclusion: Inside the forest, 22,280 mosquitoes were collected belonging to four arboviral vectors: Aedes aegypti, Aedes africanus, Aedes apicoargenteus, and Aedes cumminsii. When compared with similar studies conducted in the forest in 1964, there was a change from a sylvatic to a tendency of peridomestic behavior in A. africanus, which was now collected among human dwellings. There was an unexpected change in the distribution of A. aegypti, which was not only collected outside the forest as in previous reports but also collected in the forest. Conversely, A. cumminsii originally collected in the forest expanded its ranges with collections outside the forest in this study. Aedes simpsoni maintained its distribution range outside the forest among agricultural sites. We suspect that land cover changes were favorable to most of the arboviral vectors hence enhancing their proliferation and habitat range. This potentially increases the transmission of arboviral diseases in the area, hence impacting the epidemiology of emerging/remerging diseases in Uganda.


Reconstruction of the ossicular chain in the middle ear with glass ionomer cement.
The aim of this study is to describe a method to repair small defects (1 to 2 mm) of the ossicular chain by means of glass ionomer cement (GIC) alone. Larger defects can be repaired with a combination of GIC and a platinum wire prosthesis. GIC is a two-component hybrid material consisting of inorganic glass particles surrounded by an insoluble hydrogel matrix. GIC has been used by dentists for many years, but only a few reports describe the use of GIC in human middle ear surgery. Many investigators have proved that most GICs are biocompatible, biostable, and well tolerated by bone and soft tissue. From 1994 to 1996 GIC was used in 97 middle ear operations. In 44 cases small defects of the ossicular chain were reconstructed with GIC alone. The observation period ranged from 1 to 4 years. Nearly all operations were performed with the patient under local analgesia. The postoperative air-bone gap was less than 20 dB in 83.3%. Compared with results from comparable operations, the GIC results are significantly better. One patient had reoperation because the cement had loosened from the bone as a result of faulty GIC operation technique. Repair of defects of the ossicular chain with GIC is an easy, efficient, quick, and inexpensive method, which ought to be kept in mind for future middle ear surgery. No complications in the middle ear were related to GIC.


Enhancing the catalytic properties of well-defined electrophilic platinum complexes.
Platinum complexes have been often considered as the least reactive of the group 10 triad metals. Slow kinetics are behind this lack of reactivity but, still, some industrially relevant catalytic process are dominated by platinum compounds and sometimes different selectivities can be found in comparison to Ni or Pd. Nevertheless, during the last years, it has been reported that the catalytic behaviour of well-defined platinum derivatives can be improved through a judicious choice of their electronic and steric properties, leading to highly electrophilic or low-electron count platinum systems. In this feature article, we highlight some catalytic processes in which well-defined electrophilic platinum complexes or coordinatively unsaturated systems play an important role in their catalytic activity.


Draft Genome Sequence of the Algicidal Bacterium Mangrovimonas yunxiaonensis Strain LY01.
Mangrovimonas yunxiaonensis LY01, a novel bacterium isolated from mangrove sediment, showed high algicidal effects on harmful algal blooms of Alexandrium tamarense. Here, we present the first draft genome sequence of this strain to further understanding of the functional genes related to algicidal activity.


Reduction of nitrates in a photocatalytic membrane reactor in the presence of organic acids.
The present study explores the capability of the Photocatalytic Membrane Reactor (PMR) technology to remove nitrates from drinking water sources in the presence of organic electron donors. A systematic investigation was performed in a laboratory-pilot PMR, employing a hybrid TiO2/UV-A catalysis-ultrafiltration process, using formic acid as the most favorable hole scavenger for nitrate reduction. The naturally occurring humic acid as well as the cheaper and harmless acetic acid were also tested as sacrificial electron donors. The performance of the PMR system was evaluated in respect of nitrate and Total Organic Carbon (TOC) percentage removal. The results demonstrate the superiority of formic acid regarding nitrate reduction, followed by acetic acid and humic acid, as well as the negligible effect of nitrates on organic mineralization. Formic acid was further used to assess the effects of molar organic/nitrate ratio, catalyst dosage and power of irradiation per unit volume (PR) on nitrate reduction. With the present laboratory-pilot, the near optimum nitrate removal was ~60 % and the TOC reduction ~85 %; selectivity to dinitrogen was in the range 65-90 %. Key issues for improving this synergistic process and related R&D directions are discussed.


Identification of Sox6 as a regulator of pancreatic cancer development.
Pancreatic cancer (PC) is an aggressive malignancy associated with a poor prognosis and low responsiveness to chemotherapy and radiotherapy. Most patients with PC have metastatic disease at diagnosis, which partly accounts for the high mortality from this disease. Here, we explored the role of the transcription factor sex-determining region Y-box (Sox) 6 in the invasiveness of PC cells. We showed that Sox6 is down-regulated in patients with PC in association with metastatic disease. Sox6 overexpression suppressed PC cell proliferation and migration in vitro and tumour growth and liver metastasis in vivo. Sox6 inhibited epithelial-mesenchymal transition (EMT), and Akt signalling. Sox6 was shown to interact with the promoter of Twist1, a helix-loop-helix transcription factor involved in the induction of EMT, and to modulate the expression of Twist1 by recruiting histone deacetylase 1 to the promoter of the Twist1 gene. Twist1 overexpression reversed the effect of Sox6 on inhibiting EMT, confirming that the effect of Sox6 on suppressing tumour invasiveness is mediated by the modulation of Twist1 expression. These results suggest a novel mechanism underlying the aggressive behaviour of PC cells and identify potential therapeutic targets for the treatment of PC.


Endovascular stroke therapy: tirofiban is associated with risk of fatal intracerebral hemorrhage and poor outcome.
To investigate the relationship between severe bleeding complications and outcome after mechanical thrombectomy with or without glycoprotein-IIb/IIIa inhibitor tirofiban treatment. The study included prospectively collected data of consecutive patients with acute ischemic stroke in whom mechanical thrombectomy was perfomed in the years 2006 to 2011. Of 162 patients, 128 patients had anterior circulation stroke, and 34 patients had posterior circulation stroke. Additional treatment with tirofiban was given to 30 of 128 patients with anterior circulation stroke and to 20 of 34 patients with posterior circulation stroke. Treatment with tirofiban did not influence recanalization rates. Fatal intracerebral hemorrhage occurred more frequently in tirofiban-treated patients in the entire cohort (12.0% vs 2.7%; P=0.03) and in tirofiban-treated patients with anterior circulation stroke (13.3% vs 3.1%; P=0.05). Logistic regression found age (odds ratio, 1.17; 95% confidence interval, 1.00-1.37; P=0.05) and tirofiban treatment (odds ratio, 3.03; 95% confidence interval, 1.50-4.05; P=0.04) to be independent predictors for fatal intracerebral hemorrhage. Tirofiban treatment was also an independent predictor for poor outcome (odds ratio, 6.60; 95% confidence interval, 1.06-41.52; P=0.04) in addition to National Institute of Health Stroke Scale (odds ratio, 1.08; 95% confidence interval, 1.00-1.17; P=0.05). In endovascular stroke therapy, additional treatment with the glycoprotein-IIb/IIIa inhibitor tirofiban is associated with increased risk of fatal intracerebral hemorrhage and poor outcome.


Evaluation of tail biopsy collection in laboratory mice (Mus musculus): vertebral ossification, DNA quantity, and acute behavioral responses.
A preferred method to genotype genetically engineered mice is through collection of distal tail tissue (tail biopsy) followed by DNA isolation. Currently, general or local anesthesia (or both) is recommended for biopsy after 3 wk of age, the time after which tail vertebrae are considered to be ossified. Our objective was to rigorously evaluate vertebral development, DNA content, and acute behavioral responses at different ages by harvesting tail biopsies of different lengths. We evaluated laboratory mice from 5 inbred strains and 1 outbred stock at each of 12 ages (3 to 42 d of age). Biopsies of 5-, 10-, and 15-mm lengths were obtained. Vertebrae were graded according to level of ossification by using complementary modalities of high-resolution microradiography, microcomputed tomography, and histology. Vertebral development progressed at different rates among the strains, with mature tail vertebrae containing endplates detectable in the tail of some strains by 10 d of age. Within the distal 2 mm of tail, end plates were not identified before 21 d of age. DNA yield (DNA weight/tissue weight) was greatest from the 5-mm biopsy harvest. Acute behavioral responses to biopsy varied by age and strain, and these differences were associated with vertebral maturation. Vertebral development progressed most rapidly in C57BL/6 mice, which also demonstrated the highest response rate to biopsy, whereas BALB/c mice had slower vertebral development and were less responsive. These findings support the collection of minimal lengths of tail tissue from mice at ages younger than 17 d, unless anesthesia or analgesia is provided.


[Clinical research of xinganbao capsule on the treatment of chronic hepatitis B liver fibrosis].
To explore the effects of Xinganbao Capsule (Cordyceps Sinensis) on the chronic hepatitis B liver fibrosis. Sixty patients with chronic hepatitis B were randomly assigned to the trail group (40 cases) and the control group (20 cases). The trail group was treated with Xinganbao Capsule, 8 capsules each time, three times a day. The control group was given Heluo Shugan Tablet, 5 pills each time, thrice daily. Six months consisted of one therapeutic course. The liver function, four indicators of serum fibrosis, liver histology, and other items were detected. Xinganbao Capsule could reduce serum ALT and AST levels, serum HA, PC-III and LN levels (all P<0.05), showing statistical difference when compared with before treatment. The HA and LN levels decreased more significantly in the control group when compared with before treatment (P<0.05). Totally 21 patients (53% of the recruited cases) in the trial group completed the liver biopsy twice. After treated with Xinganbao Capsule, 81% patients (17/21) had decreased liver inflammation 1 grade or more, 52% patients (11/21) had decreased fibrosis staging one or more, and 33% (7/21) patients had no change in fibrosis. Xinganbao Capsule could improve the liver function, reduce liver inflammation, and fight against hepatic fibrosis.


Insights into Dynamic Polymicrobial Synergy Revealed by Time-Coursed RNA-Seq.
Many bacterial infections involve polymicrobial communities in which constituent organisms are synergistically pathogenic. Periodontitis, a commonly occurring chronic inflammatory disorder, is induced by multispecies bacterial communities. The periodontal keystone pathogen Porphyromonas gingivalis and the accessory pathogen Streptococcus gordonii exhibit polymicrobial synergy in animal models of disease. Mechanisms of co-adhesion and community formation by P. gingivalis and S. gordonii are well-established; however, little is known regarding the basis for increased pathogenicity. In this study we used time-coursed RNA-Seq to comprehensively and quantitatively examine the dynamic transcriptional landscape of P. gingivalis in a model consortium with S. gordonii. Genes encoding a number of potential virulence determinants had higher relative mRNA levels in the context of dual species model communities than P. gingivalis alone, including adhesins, the Type IX secretion apparatus, and tetratricopeptide repeat (TPR) motif proteins. In contrast, genes encoding conjugation systems and many of the stress responses showed lower levels of expression in P. gingivalis. A notable exception to reduced abundance of stress response transcripts was the genes encoding components of the oxidative stress-related OxyR regulon, indicating an adaptation of P. gingivalis to detoxify peroxide produced by the streptococcus. Collectively, the results are consistent with evolutionary adaptation of P. gingivalis to a polymicrobial oral environment, one outcome of which is increased pathogenic potential.


Overexpression of heat shock factor 1 inhibits butyrate-induced differentiation in colon cancer cells.
Produced by dietary fiber, butyrate is a potential chemopreventive agent against colon cancer. It stimulates proliferation of normal colonic epithelial cells but induces growth inhibition, differentiation, apoptosis, or a combination of effects in colon carcinoma cells. In this study, we used cDNA membrane arrays and real-time reverse transcriptase-polymerase chain reaction to identify stress genes that were differentially regulated by sodium butyrate (NaB) in HT 29 human colon carcinoma cells. The results indicated that a group of heat shock protein (hsp) genes were upregulated by 3 mM NaB within the first 24 hours of exposure. Because the transcription of hsp genes is under the control of heat shock factors (HSFs), we measured the effects of overexpressed HSF-1 on the responses of HT 29 cells to NaB. Overexpression of HSF-1 inhibited NaB-induced differentiation as measured by alkaline phosphatase activity and carcinoembryonic antigen expression. These results suggest that increased expression of HSFs and Hsps might render colon carcinoma cells resistant to the chemopreventive effects of butyrate.


Dynamic Regulation of the Interfacial pH for Highly Reversible Aqueous Zinc Ion Batteries.
An electrolyte additive, with convenient operation and remarkable functions, has been regarded as an effective strategy for prolonging the cycle life of aqueous zinc ion batteries. However, it is still difficult to dynamically regulate the unstable Zn interface during long-term cycling. Herein, tricine was introduced as an efficient regulator to achieve a pH-stable and byproduct-free interface. The functional zwitterion of tricine not only inhibits interfacial pH perturbation and parasitic reactions by the trapping effect of an anionic group (-COO-) but also simultaneously creates a uniform electric field by the electrostatic shielding effect of a cationic group (-NH2+). Such synergy accordingly eliminates dendrite formation and creates a chemical equilibrium in the electrolyte, endowing the Zn||Zn cell with long-term Zn plating/stripping for 2060 h at 5 mA cm-2 and 720 h at 10 mA cm-2. As a result, the Zn||VS2 full cell under a high cathodic loading mass (8.6 mg cm-2) exhibits exceptional capacity retention of 93% after 1000 cycles.


Diets of elite athletes: has the discipline of sports nutrition made an impact?
Although numerous descriptions exist of special diets and particular foods used by Greek athletes as early as 580 B.C., survey data on diets of Olympians of the modern era are virtually nonexistent. A survey in Helsinki in 1952 reported the diets of Olympic athletes to be high energy, high fat, and high protein. The 1952 Olympians reportedly consumed an average daily energy intake of 18,841 kJ, with 40% of energy coming from carbohydrate, 20% from protein, and 40% from fat. More recent data on elite level athletes reveal wide variation in dietary intake. For example, energy intakes of athletes from four countries ranged from 7699 to 24,845 kJ. Group percentages of energy from carbohydrate, protein, and fat ranged from 33 to 57%, 12 to 26%, and 29 to 49%, respectively. Comparing dietary intake data of athletes on an absolute basis, however, is primarily a comparison of body size. When the protein and carbohydrate intakes of elite athletes are calculated as grams per kilogram body weight, the range for protein is 1.0-4.3 g/kg body wt for protein and 3.5-6.9 g/kg body wt for carbohydrate. Interestingly, variations in carbohydrate intake diminished while protein intake varied by country. Although some data on diets of Olympians exist, the most remarkable finding when reviewing the literature is the paucity of data. The discipline of sports nutrition has arguably had a positive effect on sports performance. However, many unanswered questions remain and great strides remain to be made.


Resource Competition Shapes the Response of Genetic Circuits.
A common approach to design genetic circuits is to compose gene expression cassettes together. While appealing, this modular approach is challenged by the fact that expression of each gene depends on the availability of transcriptional/translational resources, which is in turn determined by the presence of other genes in the circuit. This raises the question of how competition for resources by different genes affects a circuit's behavior. Here, we create a library of genetic activation cascades in E. coli bacteria, where we explicitly tune the resource demand by each gene. We develop a general Hill-function-based model that incorporates resource competition effects through resource demand coefficients. These coefficients lead to nonregulatory interactions among genes that reshape the circuit's behavior. For the activation cascade, such interactions result in surprising biphasic or monotonically decreasing responses. Finally, we use resource demand coefficients to guide the choice of ribosome binding site and DNA copy number to restore the cascade's intended monotonically increasing response. Our results demonstrate how unintended circuit's behavior arises from resource competition and provide a model-guided methodology to minimize the resulting effects.


Antibiotic use in the last week of life in three different palliative care settings.
The purpose of this study was to examine the frequency and types of antibiotics prescribed in the last week of life in three different palliative care settings, including an acute care hospital, tertiary palliative care unit, and three hospice units. A total of 150 consecutive patients were evaluated, 50 in each of the three settings. Twenty-nine patients (58%) in the acute hospital setting, 26 (52%) in the tertiary palliative care unit, and 11(22%) in the hospice settings were prescribed antibiotics. In the acute care and tertiary palliative care settings, the most frequent route of antibiotic administration was intravenous and, in the hospice setting, oral. We conclude that there is marked variability in the numbers and types of antibiotics prescribed in these different palliative care settings in the last week of life. The high use of intravenous antibiotics and the large number of patients who were still receiving antibiotics at the time of death indicate the need for further prospective studies.


[Morphological and functional aspects of the kidney in children].
Ultrasonography is useful and effective in the evaluation of renal diseases in pediatric age. Sonography is well established as a screening tool to evaluate the kidney for the presence of renal obstruction. Distinction of the obstructed from the non obstructed dilated collecting system is a difficult problem. Doppler Ultrasonography offers potential advantages in the evaluation of childhood genitourinary tract abnormalities.


[H+-K+-exchange in anaerobically grown Escherichia coli bacteria during use of various sugars as exogenous energy sources].
E.coli bacteria, grown in anaerobic conditions, in the medium with glucose, lactose or maltose, upon transferring into a fresh medium with the same sugar acidify it and accumulate potassium ions with a fixed stoichiometry for the N,N'-dicyclohexylcarbodiimide-inhibited cation fluxes, which is equal to 2H+ of the cytoplasm per one K+ of the medium. Such an H(+)-K(+)-exchange is sensitive to osmotic shock. In the medium with lactose or maltose cation fluxes are less and the intracellular K+ activity at the moment of maximal accumulation is lower. The H(+)-K(+)-exchange with a variable stoichiometry of cation fluxes is lost in bacteria, grown in a medium with lactose or maltose.


Chemical signaling for pollen tube guidance at a glance.
Pollen tube guidance is a unique navigating system that is required for the successful sexual reproduction of plants. As plant sperm cells are non-motile and egg cells are embedded deep inside the female tissues, a pollen tube delivers the two sperm cells that it contains by growing towards the ovule, in which the egg cell resides. Pollen tube growth towards the ovule is precisely controlled and divided into two stages, preovular and ovular guidance. In this Cell Science at a Glance article and accompanying poster, we provide a comprehensive overview of pollen tube guidance and highlight some of the attractant peptides used during ovular guidance. We further discuss the precise one-to-one guidance system that exists in multi-ovular plants. The pollen tube-blocking system, which is mediated by male-female crosstalk communication, to avoid attraction of multiple pollen tubes, is also reviewed.


Quantifying eradication success: the removal of feral pigs from Santa Cruz Island, California.
A major challenge facing pest-eradication efforts is determining when eradication has been achieved. When the pest can no longer be detected, managers have to decide whether the pest has actually been eliminated and hence to decide when to terminate the eradication program. For most eradication programs, this decision entails considerable risk and is the largest single issue facing managers of such programs. We addressed this issue for an eradication program of feral pigs (Sus scrofa) from Santa Cruz Island, California. Using a Bayesian approach, we estimated the degree of confidence in the success of the eradication program at the point when monitoring failed to detect any more pigs. Catch-effort modeling of the hunting effort required to dispatch pigs during the eradication program was used to determine the relationship between detection probability and searching effort for different hunting methods. We then used these relationships to estimate the amount of monitoring effort required to declare eradication successful with criteria that either set a threshold for the probability that pigs remained undetected (type I error) or minimized the net expected costs of the eradication program (cost of type I and II errors). For aerial and ground-based monitoring techniques, the amount of search effort required to declare eradication successful on the basis of either criterion was highly dependent on the prior belief in the success of the program unless monitoring intensities exceeded 30 km of searching effort per square kilometer of search area for aerial monitoring and, equivalently, 38 km for ground monitoring. Calculation of these criteria to gauge the success of eradication should form an essential component of any eradication program as it allows for a transparent assessment of the risks inherent in the decision to terminate the program.


Musings on ADME predictions and structure-activity relations.
The first part of the paper examines Structure-Activity Relations (SARs) and their components from a very general point of view. The various types of interpretation emerging from statistically valid relations will be examined, namely causal (mechanistic), contextual (empirical), fortuitous, and tautological correlations. Implications for ADME predictions will be seen when discussing the diversity of interactions between active compounds (e.g., drugs) and biological systems. The second part of the paper is more specific and presents the concept of molecular-property space, an all but neglected concept in SARs. Recent results from Molecular Dynamics (MD) simulations and Molecular Interaction Fields (MIF) computations of acetylcholine will be used to illustrate not only the well-known conformational space of this molecule, but also its property space as exemplified by its lipophilicity space. It will be seen that a molecule as small as acetylcholine is able to span a relatively broad property space. Most significantly in an ADME perspective, the molecule is able, within the limits of its property space, to adapt to the medium. This is equivalent to saying that the medium constrains the molecule to resemble it as much as feasible.


Bacterial symbionts induce host organ morphogenesis during early postembryonic development of the squid Euprymna scolopes.
The mutualistic association between the squid Euprymna scolopes and the bacterium Vibrio fischeri is an emerging experimental system for the study of the influence of bacteria on animal development. Taking advantage of the ability to raise both this host and its microbial partner independently under laboratory conditions, we describe the effects of bacterial interactions on morphogenesis of the juvenile host symbiotic organ. Our results show that bacteria are essential for normal postembryonic development of the symbiotic organ, which involves changes in both the surface epithelium and the epithelial tissue within the organ where the bacterial culture will take up residence. Cell death induced by exposure to symbiotic V. fischeri results in the regression of a complex ciliated surface epithelium, a tissue that apparently functions to facilitate inoculation of the juvenile organ with the appropriate specific bacterial species. Regression of this tissue begins within hours of exposure to symbiosis-competent bacteria and progresses over the next 5 days, at which time full regression is complete, resulting in a symbiotic organ whose epithelial surface resembles that of the fully mature organ. Moreover, symbiosis-competent bacteria induce modification of the epithelial cells of the crypts that will house these symbionts; these cells undergo significant changes in shape and size in response to interactions with symbiotic V. fischeri. In contrast, we find that when these tissues are not exposed to the proper bacterial symbionts they remain in a state of arrested morphogenesis, a condition that can be rescued by interactions with symbionts. The results of these studies are the first experimental data demonstrating that a specific bacterial symbiont can play an inductive role in animal development.


Abnormalities of the intestinal immune system in AIDS.
Significant abnormalities in the distribution of lymphocyte subsets have been noted in the intestinal mucosa of ARC and AIDS patients. Abnormalities are most striking among the CD4 helper-inducer T-cell subset and likely reflects the direct effects of HIV infection of those cells. A deficiency in CD4-positive T cells in the intestinal mucosa potentially could result in significant abnormalities in mucosal immune function, including defects both in cell-mediated immunity and in the secretory IgA system. Such alterations in mucosal immunity and mucosal defense may render AIDS and ARC subjects susceptible to enteric infections and systemic infections in which the intestinal tract is the portal of entry.


[Electron microscopic study of the interaction of virulent and avirulent Shigella flexneri strains with the macrophages of murine peritoneal exudate].
The electron microscopic dynamic study of the interaction of S. flexneri virulent strain 2a and S. flexneri avirulent strain, genetically related to strain 2a and having the same antigenic structure, with peritoneal macrophages of CBA mice at an early period showed differences in the cytotoxic action of these strains. Even at the early period of the interaction between macrophages and virulent shigellae structural changes were observed in macrophages: ruptures in the membranes of parasitophore phagosomes, the vacuolization of the cytoplasm, the destruction of mitochondria. These changes were indicative of the early cytotoxic action of shigellae belonging to the virulent strain. In macrophages infected with avirulent shigellae the manifestations of this cytotoxicity were less pronounced and appeared later than in macrophages infected with S. flexneri virulent strain.


Rehabilitation strategies for optimisation of functional recovery after major joint replacement.
Exercise-based interventions applied before and after total hip and knee arthroplasty (THA and TKA, respectively) have been investigated for a number of years, based on the assumption that they will enhance post-operative recovery. Although recent studies suggest that high-volume, pre-operative exercise may enhance post-operative recovery after TKA, studies of post-operative exercise-based interventions, have not found superiority of one exercise regime over another. It seems, however, that post-operative, exercise-based, rehabilitation is superior to no or minimal rehabilitation after THA and TKA.The goal of this commentary is to summarize recent evidence for the efficacy of different peri-operative exercise-based interventions to enhance recovery after THA and TKA, and to propose new strategies to further enhance post-operative recovery.There is a major need to improve functional recovery after THA and TKA. We propose a strategy of "enriched" trials where specific rehabilitation interventions are applied to different patients based on, for example, their expectations for post-operative recovery, willingness to undertake exercise and physical activity, and pre-operative functional performance.


Genetic deletion of Urocortin 3 does not prevent functional maturation of beta cells.
There is great interest in generating functionally mature beta cells from stem cells, as loss of functional beta cell mass contributes to the pathophysiology of diabetes. Identifying markers of beta cell maturity is therefore very helpful for distinguishing stem cells that have been successfully differentiated into fully mature beta cells from stem cells that did not. Urocortin 3 (UCN3) is a peptide hormone whose expression is associated with the acquisition of functional maturity in beta cells. The onset of its expression occurs after other beta cell maturity markers are already expressed and its loss marks the beginning of beta cell dedifferentiation. Its expression pattern is therefore tightly correlated with beta cell maturity. While this makes UCN3 an excellent marker of beta cell maturity, it is not established whether UCN3 is required for beta cell maturation. Here, we compared gene expression and function of beta cells from Ucn3-null mice relative to WT mice to determine whether beta cells are functionally mature in the absence of UCN3. Our results show that genetic deletion of Ucn3 does not cause a loss of beta cell maturity or an increase in beta cell dedifferentiation. Furthermore, virgin beta cells, first identified as insulin-expressing, UCN3-negative beta cells, can still be detected at the islet periphery in Ucn3-null mice. Beta cells from Ucn3-null mice also exhibit normal calcium response when exposed to high glucose. Collectively, these observations indicate that UCN3 is an excellent mature beta cell marker that is nevertheless not necessary for beta cell maturation.


Chemical Methods to Knock Down the Amyloid Proteins.
Amyloid proteins are closely related with amyloid diseases and do tremendous harm to human health. However, there is still a lack of effective strategies to treat these amyloid diseases, so it is important to develop novel methods. Accelerating the clearance of amyloid proteins is a favorable method for amyloid disease treatment. Recently, chemical methods for protein reduction have been developed and have attracted much attention. In this review, we focus on the latest progress of chemical methods that knock down amyloid proteins, including the proteolysis-targeting chimera (PROTAC) strategy, the "recognition-cleavage" strategy, the chaperone-mediated autophagy (CMA) strategy, the selectively light-activatable organic and inorganic molecules strategy and other chemical strategies.


Nonconvulsive Status Epilepticus With Generalized Spike-and-Wave Discharges: Pathophysiological and Nosological Considerations.
Absence status epilepticus (ASE) is the most common type of status epilepticus in patients with idiopathic generalized epilepsy (IGE). Like absence seizure, ASE is characterized by generalized spike-and-wave discharges (GSWDs) on the electroencephalogram (EEG). Once considered specific for IGE, GSWDs have increasingly been observed in other forms of epilepsy, as well as in patients with no prior epilepsy. Here, we report three patients with different types of nonconvulsive status epilepticus (NCSE) in which the EEG correlate was GSWDs: a 44-year-old woman with juvenile absence epilepsy who manifested ASE, a 73-year-old woman with anoxic brain injury complicated by NCSE with well-formed GSWDs (as seen in IGE and de novo ASE), and a 41-year-old woman with frontal lobe epilepsy who developed focal NCSE with impaired consciousness. Evidently, patients with generalized epilepsy, focal epilepsy, and no prior epilepsy can all manifest NCSE with similar electroclinical characteristics, i.e., GSWDs and impaired consciousness. This observation adds to the existing evidence that seizures, whether classified as focal or generalized, often involve focal and generalized elements in their pathophysiology. To fully understand seizure pathophysiology, we must steer away from the focal-versus-generalized paradigm that has dominated the nosology of seizures and epilepsy for a very long time.


Cortisol levels and adrenal reserve after successful cardiac arrest resuscitation.
The postresuscitation phase after out-of-hospital circulatory arrest shares similarities with severe sepsis. Corticosteroid replacement is beneficial in patients with septic shock and adrenal dysfunction. The goal of this study was to assess baseline cortisol and adrenal reserve of out-of-hospital circulatory arrest patients after recovery of spontaneous circulation. Thirty-three consecutive patients successfully resuscitated after cardiac arrest were prospectively included between March 2002 and June 2003. A serum cortisol assay and a corticotropin test (250 microg i.v.) were done 6 to 36 h after circulatory arrest. A cortisol increase smaller than 9 microg/dL after corticotropin (nonresponders) defined adrenal reserve insufficiency. Response status was compared in the three outcome groups: survival with full neurologic recovery (n = 4), early death from refractory shock (n = 10), or later death from neurologic dysfunction (n = 19). Patients who died of early refractory shock had lower baseline cortisol levels than patients who died of neurologic dysfunction (27 microg/dL [15-47] vs. 52 microg/dL [28-73], respectively; P < 0.01), suggesting an inadequate adrenal response to severe systemic inflammation. Corticotropin response status was not associated with standard severity markers and seemed uninfluenced by therapeutic hypothermia. In conclusion, patients who die of early refractory shock after cardiopulmonary resuscitation may have an inadequate adrenal response to the stress associated with this condition. Thresholds for cortisol levels at baseline and after corticotropin need to be determined in this clinical setting.


Altered membrane lipid composition and functional parameters of circulating cells in cockles (Cerastoderma edule) affected by disseminated neoplasia.
Membrane lipid composition and morpho-functional parameters were investigated in circulating cells of the edible cockle (Cerastoderma edule) affected by disseminated neoplasia (neoplastic cells) and compared to those from healthy cockles (hemocytes). Membrane sterol levels, phospholipid (PL) class and subclass proportions and their respective fatty acid (FA) compositions were determined. Morpho-functional parameters were evaluated through total hemocyte count (THC), mortality rate, phagocytosis ability and reactive oxygen species (ROS) production. Both morpho-functional parameters and lipid composition were profoundly affected in neoplastic cells. These dedifferentiated cells displayed higher THC (5×), mortality rate (3×) and ROS production with addition of carbonyl cyanide m-chloro phenylhydrazone (1.7×) but lower phagocytosis ability (½×), than unaffected hemocytes. Total PL amounts were higher in neoplastic cells than in hemocytes (12.3 and 5.1 nmol×10(-6) cells, respectively). However, sterols and a particular subclass of PL (plasmalogens; 1-alkenyl-2-acyl PL) were present in similar amounts in both cell type membranes. This led to a two times lower proportion of these membrane lipid constituents in neoplastic cells when compared to hemocytes (20.5% vs. 42.1% of sterols in total membrane lipids and 21.7% vs. 44.2% of plasmalogens among total PL, respectively). Proportions of non-methylene interrupted FA- and 20:1n-11-plasmalogen molecular species were the most impacted in neoplastic cells when compared to hemocytes (⅓× and ¼×, respectively). These changes in response to this leukemia-like disease in bivalves highlight the specific imbalance of plasmalogens and sterols in neoplastic cells, in comparison to the greater stability of other membrane lipid components.


Small Poultry Flocks in Alberta: Demographics and Practices.
The distribution, composition, and management characteristics of small "backyard" poultry flocks may have important implications in the spread of both avian diseases and zoonoses of public health concern. Although the prevalence of small poultry flocks has increased in Alberta, Canada, in recent years, there is minimal demographic information available for these populations. To gain initial epidemiologic insight into this growing population and potential areas of risk, a survey was conducted to characterize the sector. Information on flock demographics and bird health, as well as production and biosecurity practices, were gathered and analyzed from 206 surveys, representing respondents from 43 counties. These results revealed great diversity of both owners and flocks, characterized by wide variations in flock sizes and composition. Laying hens were the most commonly reported type of bird (93.4%), followed by ducks and geese (35.3%), turkeys, (33.8%), and broiler chickens (33.1%). Notably, 58.1% of owners reported having more than one type of bird in their flock, with many owners never, or only sometimes, separating flocks based on species or purpose. Personal consumption (81.8%) and sale of eggs (48.2%) were the most frequently cited purposes for owning a flock. Our findings suggest that owners in Alberta are predominantly new to production; most (73.1%) have kept birds for less than 5 yr and 25.6% for less than 1 yr. Flock health parameters revealed inconsistent use of medical interventions, such as vaccinations, treatments, and veterinary consultation. Data on the sourcing, housing, and movement of birds, as well as movement of people and visitors, reveal substantial potential for contact to occur directly and indirectly between flocks and humans. Additionally, basic husbandry and biosecurity practices were found to be inconsistent and often inadequate, highlighting important gaps and opportunities to improve the health of Alberta's small poultry flocks and mitigate risks to public health. These quantitative and qualitative results provide a baseline characterization of the sector and identify risks and challenges that may serve to inform the development and delivery of future study and interventions.


Emerging ideas: Shared decision making in patients with osteoarthritis of the hip and knee.
Despite the widely reported success of total joint arthroplasty (TJA) in reducing pain and improving quality of life and function for patients with hip or knee osteoarthritis, rates of TJA use vary widely throughout the United States, with broad disparities based on geographic, racial, and socioeconomic factors. Shared decision-making approaches, which require an exchange of information between patients and their physicians, can be helpful in improving patient satisfaction with their treatment decision and appropriate use of TJA. Expected-value decision analysis models incorporating evidence-based outcome data with individual patient preferences regarding health states and willingness to pay, when used in shared decision-making models, will improve satisfaction among patients with hip or knee osteoarthritis and lead to more appropriate use of TJA. Patients with hip or knee osteoarthritis will be randomized to usual care or participation in a shared decision-making intervention. Patients in the shared decision-making intervention arm will have their preferences for individual health states related to osteoarthritis and TJA measured using the time trade-off technique, and these values will be incorporated in an expected-value decision analysis model, which also will incorporate the patient's willingness to pay for a particular treatment intervention and evidence-based outcome probabilities. The patient's decision for operative versus nonoperative care and their level of satisfaction with their decision will be compared using chi square and Mann-Whitney rank-sum tests. Information regarding patient preferences for particular health states and willingness to pay can be combined with evidence-based outcome data in expected-value decision analysis models, which will help inform shared clinical decision making between surgeons and their patients with hip or knee osteoarthritis.


Computed tomographic findings in Lemierre syndrome.
Lemierre syndrome, also known as postanginal septicemia, has long been taken as an uncommon condition with life-threatening potential. It, resulting from acute oropharyngeal infection, could lead to septic thrombophlebitis of the internal jugular vein (IJV). Substantial decrease of mortality and morbidity with the introduction of antibiotics has made this syndrome into a status that is frequently forgotten or overlooked when it appears. The purpose of this article is to refresh awareness on the side of physicians of this syndrome by means of modern image tools. As such, even this dire neck infection is rare after the advent of sophisticated antibiotics, its unique computed tomography findings can facilitate the correct image diagnosis and pertinent treatment.


Evaluation of the quality and reliability of anal cancer and its precancerous lesions-related content on YouTube: a cross-sectional study.
This research aims at evaluating the quality of anal cancer and its precancerous lesions-related videos on YouTube. Cross-sectional survey design. USA. The top 150 videos on YouTube were selected for analysis based on three search terms. The duplicate, irrelevant, commercial, operation-related and audio-free videos were excluded. Finally, 105 relevant videos were included. We assessed the completeness of video content from six dimensions and marked the men having sex with men (MSM)-related videos. To measure the video quality, DISCERN, Journal of the American Medical Association (JAMA) Benchmark Criteria, Patient Education Materials Assessment Tool (PEMAT) and Global Quality Scale (GQS) were used. The correlation between DISCERN classification and duration, JAMA, PEMAT and GQS scores were recorded. The video content was mainly about the management of the disease (mean score 1.086). Overall, the quality of videos uploaded by the non-profit organisation was relatively high. A correlation existed between each other of the JAMA, DISCERN and GQS scores (p<0.001). Moreover, they were positively correlated with video duration and PEMAT scores (p<0.001). Although the overall quality of information about anal cancer and its precancerous lesions videos on YouTube is acceptable, it might not fully meet the health information needs of patients. Therefore, they should exercise caution when using YouTube as a source of anal cancer-related information, especially the MSM population.


The relationship between the prognosis of children with acute arterial stroke and polymorphisms of CDKN2B, HDAC9, NINJ2, NAA25 genes.
Ischemic stroke is a significant health condition, whose frequency in childhood is increasing day by day. Although many factors are effective in development of the stroke, it has been showed that individuals having risk factors have a genetic predisposition. The aim of the study is to determine whether distinct genetic mutations are risk factors for children with history of ischemic stroke. Our sample data is taken from 58 patients (29 male and 29 female) who applied our hospital between 2012 and 2016 with diagnosis of acute or chronic arterial stroke and from 70 healthy children (32 male and 38 female) with similar particularities in the sense of age and sex, who have not any chronical disease. Blood samples are taken from each child participated in the study to conduct genetic analysis. It has been examined whether a mutation exists in gene locations of CDKN2B-AS1 (Rs2383206), HDAC9 (Rs11984041), NINJ2 (Rs12425791), NAA25 (Rs17696736). Moreover, whether there are significant difference between patient and control group has been investigated. In the genetic analysis of patients and control groups, no significant difference has been found for any of the genes. Mutations in gene locations of CDKN2B-AS1 (Rs2383206), HDAC9 (Rs11984041), NINJ2 (Rs12425791), NAA25 (Rs17696736) are not risk factors for ischemic stroke in childhood. However this study showed us, the patients who inherit CDKN2B-AS1 and HDCA9 gene mutations had poor prognosis. However, this study should be replicated for a wider sample of patient population.


Outpatient Management of Pediatric Type 1 Diabetes.
The incidence of both type 1 and type 2 diabetes (T1DM and T2DM) continues to rise within the pediatric population. However, T1DM remains the most prevalent form diagnosed in children. It is critical that health-care professionals understand the types of diabetes diagnosed in pediatrics, especially the distinguishing features between T1DM and T2DM, to ensure proper treatment. Similar to all individuals with T1DM, lifelong administration of exogenous insulin is necessary for survival. However, children have very distinct needs and challenges compared to those in the adult diabetes population. Accordingly, treatment, goals, and age-appropriate requirements must be individually addressed. The main objectives for the treatment of pediatric T1DM include maintaining glucose levels as close to normal as possible, avoiding acute complications, and preventing long-term complications. In addition, unique to pediatrics, facilitating normal growth and development is important to comprehensive care. To achieve these goals, a careful balance of insulin therapy, medical nutrition therapy, and exercise or activity is necessary. Pharmacological treatment options consist of various insulin products aimed at mimicking prior endogenous insulin secretion while minimizing adverse effects. This review focuses on the management of pediatric T1DM in the outpatient environment, highlighting pharmacotherapy management strategies.


Angiogenesis inhibitors and the need for anti-angiogenic therapeutics.
Angiogenesis is the formation of new blood vessels from pre-existing vessels to form capillary networks, which, among other diseases, such as diabetic retinopathy and macular degeneration, is particularly important for tumor growth and metastasis. Thus, depriving a tumor of its vascular supply by means of anti-angiogenic agents has been of great interest since its proposal in the 1970s. This review looks at the common angiogenic inhibitors (angiostatin, endostatin, maspin, pigment epithelium-derived factor, bevacizumab and other monoclonal antibodies, and zoledronic acid) and their current status in clinical trials.


The intrinsic topological information of the wild-type and of up-promoter mutations of the Saccharomyces cerevisiae alcohol dehydrogenase II regulatory region.
A 569-base pair fragment encompassing the upstream regulatory region, the RNA initiation sites, and the initial part of the coding region of the Saccharomyces cerevisiae alcohol dehydrogenase II gene has been analyzed for the presence of sites which undergo conformational modification under torsional stress. Fine mapping of P1 and S1 endonuclease-sensitive sites was obtained on single topoisomers produced by in vitro ligation. It was shown that the upstream activator sequence, the TATA sequence, a region directly upstream to the RNA initiation sites, and several positions in the first segment of the transcribed region change conformation as a function of the applied torsional stress in a precisely coordinate fashion. The superhelical density optima for this coordinate modifications have been determined. Analysis of the conformational changes of the promoter sequence in several naturally occurring (Young, E. T., Williamson, V. M., Taguchi, A., Smith, M., Sledziewski, L., Russel, D., Osterman, J., Denis, C., Cox, D., and Beier, D., (1982) in Genetic Engineering of Microorganisms for Chemicals (Hollander, A., De Moss, R. D., Kaplan, S., Konisky, J., Savage, D., and Wolle, R. S., eds) pp. 335-361, Plenum Publishing Corp., New York) up-promoter constitutive mutants was performed. This analysis has shown that the conformation of functionally relevant sites changes as a function of sequence mutations that have taken place elsewhere; this shows that the conformational behavior of the whole promoter region is linked and suggests transmission in cis of topological effects in RNA polymerase II promoters.


Influence of elastin-derived peptides, glucose, LDL and oxLDL on nitric oxide synthase expression in human umbilical artery endothelial cells.
Endothelial dysfunction plays an important role in the development of atherosclerosis. Elastin-derived peptides (EDP), hyperglycemia, hypercholesterolemia and oxidized LDL have a proven proatherosclerotic potential. Nitric oxide generated by endothelial nitric oxide synthase (eNOS; EC 220.127.116.11) is an important vasorelaxant. Here we studied the influence of those proatherosclerotic factors on eNOS gene and protein expression in artery-derived endothelial cells. Human umbilical artery endothelial cells (HUAEC) were incubated with or without: glucose (270 mg/dl), LDL (200 mg/dl), oxidized LDL (oxLDL 25 mg/dl) or κ-elastin (0.5 and 2.5 µg/ml). Gene expression was assessed by real time RT-PCR, whilst the eNOS protein by ELISA. In cells incubated with 2.5 µg/ml of κ-elastin, a 31 % increase of eNOS mRNA expression was observed, but the protein level remained unchanged. OxLDL, LDL and glucose decreased the eNOS protein level by 74 %, 37 % and 29 %, respectively. OxLDL decreased eNOS mRNA by 42 %. LDL non-significantly decreased eNOS mRNA expression. An elevated glucose level did not affect the eNOS mRNA expression. Hyperglycemia and an elevated level of LDL, particularly oxLDL, decreased the level of eNOS protein in endothelial cells. As κ-elastin did not decrease the expression of eNOS gene in HUAEC, the proatherogenic properties of elastin-derived peptides are unlikely to be due to their influence on eNOS.


Neurological recovery in diabetic rats following spinal cord injury.
This study was designed to assess the effect of spinal cord injury on neurobehavioral, electrophysiological, structural, and biochemical changes in normal and diabetic rats. Experimental diabetes was induced in Sprague-Dawley male rats (weighing 250-280 g) with streptozotocin (50 mg/kg i.p.). Eight weeks after the treatment with streptozotocin the animals were anaesthetized with chloral hydrate and laminectomy was performed at T 7-8 level leaving the dura intact. A compression plate (2.2 x 5.0 mm) loaded with a weight of 35 g was placed on the exposed spinal cord for 5 min. Postoperative neurological function was assessed using inclined plane test, modified Tarlov score, and vocal and sensory score daily for 10 days. Electrophysiological changes were assessed using somatosensory and corticomotor evoked-potentials. The animals were sacrificed at different time intervals and injured site of the spinal cord was analyzed for changes in vitamin E and glutathione levels (as markers of oxidative stress). Pathological changes in spinal cord were also studied using light microscopy. The data on neurobehavioral study clearly indicated that the compression of spinal cord produced highly significant neurological deficit and poor recovery in diabetic rats as compared to nondiabetic rats. Our histopathological and electrophysiological results also confirmed that diabetic animals are more susceptible to compressive spinal cord injury as compared to nondiabetic animals. A higher depletion of antioxidant defense markers (vitamin E and glutathione) was observed in diabetic rats as compared to nondiabetic rats. These results point toward the role of free radicals in poor recovery in diabetic rats following neurotrauma. Further studies are warranted to assess the neuroprotective potential of antioxidants to retard the secondary pathophysiological events following neurotrauma and to enhance the recovery.


Efficacy of Tele-CO-OP in Children With Organic Acidemia: A Pilot Randomized Controlled Trial.
The objective of this study was to examine the efficacy of a 5-week, tele-CO-OP intervention in children with organic acidemia. Thirty-four children were randomly divided into intervention and control groups. While 17 received the home program, 17 received the CO-OP Approach with telehealth twice a week along with the home program. Children were assessed through the Canadian Occupational Performance Measure, Pediatric Evaluation of Disability Inventory, Child and Adolescent Scale of Participation, Kid-KINDL Questionnaire, and Assistance to Participate Scale. Between-group analyses show significant benefits (p < .05) for the CO-OP group compared with the control group on the Performance and Satisfaction scales of the Canadian Occupational Performance Measure, and on the total scores of the Pediatric Evaluation of Disability Inventory, Child and Adolescent Scale of Participation, KINDL, and the Assistance to Participate Scale. The findings are preliminary results of benefits as this is the first trial, and the CO-OP approach applied through telerehabilitation had positive effects on children with organic acidemia.


Spatial-chromatic interactions in C-type horizontal cells of the turtle (Mauremys caspica) retina.
Horizontal cells are second-order retinal neurons that play a key role in spatial information processing. In some cold-blooded vertebrates such as turtles, a subtype of these cells, the chromaticity horizontal cells exhibit color-opponent responses and therefore are considered to be important also for color information processing. To reveal spatial and color interactions, the receptive-field properties of Red/Green and Yellow/Blue chromaticity horizontal cells in the retina of the turtle Mauremys caspica were studied by intracellular recordings from the everted eyecup preparation. We found that the polarity of the photoresponses depended not only upon the wavelength and intensity of the stimulus, but also upon its spatial configuration. Thus, a hyperpolarizing photoresponse that was elicited by full-field stimulation with bright light of wavelength close to the "neutral" one was reversed in polarity to a pure depolarizing one when a small spot or a thin annular pattern were used for stimulation. This finding could not be explained either by different balances between depolarizing and hyperpolarizing inputs to different cells or by stray light that effectively reduced the light intensity in the center of the small spot. Rather, it was found that the depolarizing and hyperpolarizing components were characterized by different receptive-field size and that these differences could account for the dependency of response polarity upon the spatial pattern of the stimulus. These findings indicate that color information processing in turtle C-type horizontal cells is a complex process that depends upon the wavelength and intensity of the light stimulus as well as upon its spatial properties.