Efficacy of Sulphadoxine and Pyrimethamine, Doxycycline and their combination in the treatment of chloroquine resistant Falciparum Malaria.
The present in vivo study evaluates the efficacy of sulphadoxine/pyrimethamine, doxycycline and their combination in the treatment of Sudanese patients infected by chloroquine resistant falciparum malaria. Febrile patients with positive blood smears of Plasmodium falciparum were given chloroquine 25mg-base/kg body weight and followed up for 3 days. Patients with recrudescence due to chloroquine resistance were readmitted for test treatment. Using simple number randomization patients were divided into groups, A, B and C. These were treated with doxycycline, sulphadoxine/ pyrimethamine and a combination therapy of sulphadoxine/pyrimethamine plus doxycycline. Doxycycline was initially administered as a single dose of 200mg followed by 100mg daily for 6 days whereas sulphadoxine/pyrimethamine was given as a single dose of sulphadoxine 1500mg and pyrimethamine 75mg. Patients of group C received the combination therapy of sulphadoxine/pyrimethamine and doxycycline. Clinical observations and examination of blood films were carried out for each patient daily for 6 days and thereafter weekly for 4 weeks. A high level of chloroquine resistance (75%) was documented amongst 280 patients (age 15-53 years) visiting Omdurman Hospital of Endemic Diseases during 1996-1998. The study demonstrated that only 46% and 78% of the patients were cured after 4 days of treatment by doxycycline and sulphadoxine/pyrimethamine. Patients treated with sulphadoxine/pyrimethamine in combination with doxycycline had a cure rate of 90% and 100% after 3-4 days of treatment, a single recrudescent case was detected on day 6. No relapses occurred during the follow up period. All patients were successfully treated by all regimens with the exception of one case treated by doxycycline. All treatments were well tolerated but a few cases had complaints of nausea. The combination therapy of doxycycline/sulphadoxine/pyrimethamine appeared to be significantly effective in the treatment of patients with chloroquine resistant falciparum malaria without causing any serious side effects. Such a combination regimen has the advantages of being available at a reasonable cost and less prone to development of resistance.


Health-related quality of life in middle-aged African Americans.
In this article we explore the measurement properties of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) in 49- to 65-year-old African Americans, compare their health-related quality of life (HRQoL) with that of the nation, and evaluate the association of selected covariates with HRQoL. A probability sample of 998 African Americans in St. Louis received comprehensive in-home assessments. We used an item analysis, exploratory and confirmatory factor analysis, and internal consistency reliability to evaluate the measurement properties of the eight SF-36 scales and their interrelationships. We used a multiple linear regression analysis to characterize the effects of the demographic, socioeconomic status, psychosocial attributes, and biomedical markers. Assessments averaged 2.5 hr. Each SF-36 scale was unidimensional, all items had robust factor loadings, and all but one scale achieved excellent (alpha > or = .80) internal consistency reliability levels. The overall factor structure of the SF-36 scales was generally consistent with national norms. Substantial variance was explained by the covariates, mostly attributable to socioeconomic status and the biomedical markers. The SF-36 is a reliable and valid measure of HRQoL for use with African Americans. In this sample, the HRQoL was below national averages. Future social epidemiologic studies should include grip strength, vision, and hearing assessments, which had substantial and consistent associations with the SF-36 scale scores.


New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits.
Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.


The nuclear cofactor DOR regulates autophagy in mammalian and Drosophila cells.
The regulation of autophagy in metazoans is only partly understood, and there is a need to identify the proteins that control this process. The diabetes- and obesity-regulated gene (DOR), a recently reported nuclear cofactor of thyroid hormone receptors, is expressed abundantly in metabolically active tissues such as muscle. Here, we show that DOR shuttles between the nucleus and the cytoplasm, depending on cellular stress conditions, and re-localizes to autophagosomes on autophagy activation. We demonstrate that DOR interacts physically with autophagic proteins Golgi-associated ATPase enhancer of 16 kDa (GATE16) and microtubule-associated protein 1A/1B-light chain 3. Gain-of-function and loss-of-function studies indicate that DOR stimulates autophagosome formation and accelerates the degradation of stable proteins. CG11347, the DOR Drosophila homologue, has been predicted to interact with the Drosophila Atg8 homologues, which suggests functional conservation in autophagy. Flies lacking CG11347 show reduced autophagy in the fat body during pupal development. All together, our data indicate that DOR regulates autophagosome formation and protein degradation in mammalian and Drosophila cells.


Ethical issues in contrast-enhanced magnetic resonance imaging screening for breast cancer.
Breast magnetic resonance imaging (MRI) screening has been shown to detect early breast cancer. The main challenge ahead for breast MRI screening is to prove its effectiveness in reducing breast cancer mortality. While this challenge is commonly viewed as a scientific, technological, and clinical one, it also carries ethical components. This article is concerned with the risks and benefits of MRI screening that should be explained to screening participants and discusses the evidence needed by policy makers who ultimately will determine a just allocation of health care resources to MRI breast cancer screening.


Quantitative optical imaging of primary tumor organoid metabolism predicts drug response in breast cancer.
There is a need for technologies to predict the efficacy of cancer treatment in individual patients. Here, we show that optical metabolic imaging of organoids derived from primary tumors can predict the therapeutic response of xenografts and measure antitumor drug responses in human tumor-derived organoids. Optical metabolic imaging quantifies the fluorescence intensity and lifetime of NADH and FAD, coenzymes of metabolism. As early as 24 hours after treatment with clinically relevant anticancer drugs, the optical metabolic imaging index of responsive organoids decreased (P < 0.001) and was further reduced when effective therapies were combined (P < 5 × 10(-6)), with no change in drug-resistant organoids. Drug response in xenograft-derived organoids was validated with tumor growth measurements in vivo and staining for proliferation and apoptosis. Heterogeneous cellular responses to drug treatment were also resolved in organoids. Optical metabolic imaging shows potential as a high-throughput screen to test the efficacy of a panel of drugs to select optimal drug combinations. Cancer Res; 74(18); 5184-94. ©2014 AACR.


α-Mangostin disrupts the development of Streptococcus mutans biofilms and facilitates its mechanical removal.
α-Mangostin (αMG) has been reported to be an effective antimicrobial agent against planktonic cells of Streptococcus mutans, a biofilm-forming and acid-producing cariogenic organism. However, its anti-biofilm activity remains to be determined. We examined whether αMG, a xanthone purified from Garcinia mangostana L grown in Vietnam, disrupts the development, acidogenicity, and/or the mechanical stability of S. mutans biofilms. Treatment regimens simulating those experienced clinically (twice-daily, 60 s exposure each) were used to assess the bioactivity of αMG using a saliva-coated hydroxyapatite (sHA) biofilm model. Topical applications of early-formed biofilms with αMG (150 µM) effectively reduced further biomass accumulation and disrupted the 3D architecture of S. mutans biofilms. Biofilms treated with αMG had lower amounts of extracellular insoluble and intracellular iodophilic polysaccharides (30-45%) than those treated with vehicle control (P<0.05), while the number of viable bacterial counts was unaffected. Furthermore, αMG treatments significantly compromised the mechanical stability of the biofilm, facilitating its removal from the sHA surface when subjected to a constant shear stress of 0.809 N/m2 (>3-fold biofilm detachment from sHA vs. vehicle-treated biofilms; P<0.05). Moreover, acid production by S. mutans biofilms was disrupted following αMG treatments (vs. vehicle-control, P<0.05). The activity of enzymes associated with glucan synthesis, acid production, and acid tolerance (glucosyltransferases B and C, phosphotransferase-PTS system, and F1F0-ATPase) were significantly inhibited by αMG. The expression of manL, encoding a key component of the mannose PTS, and gtfB were slightly repressed by αMG treatment (P<0.05), while the expression of atpD (encoding F-ATPase) and gtfC genes was unaffected. Hence, this study reveals that brief exposures to αMG can disrupt the development and structural integrity of S. mutans biofilms, at least in part via inhibition of key enzymatic systems associated with exopolysaccharide synthesis and acidogenicity. αMG could be an effective anti-virulence additive for the control and/or removal of cariogenic biofilms.


KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight.
This study aims to elucidate the mechanism behind the potent weight loss induced by dual amylin and calcitonin receptor agonists (DACRA) through comparison of the novel DACRA KBP-088 with the amylinomimetic davalintide with regard to in vitro receptor pharmacology and in vivo efficacy on food intake and body weight. KBP-088 and davalintide were tested for their ability to activate the amylin and calcitonin receptors as function of dose and time. Two doses of KBP-088 (1.67 and 5.0 μg/kg) were compared with similar davalintide doses in high-fat diet (HFD)-fed rats receiving subcutaneous dosing once daily for 62 days. Glucose tolerance was assessed after 3 and 7 wk of treatment. KBP-088 demonstrated activation of amylin and calcitonin receptors and prolonged receptor activation compared with davalintide as well as a potent reduction of acute food intake. KBP-088 transiently reduced food intake and induced and notably sustained a significant ∼16% vehicle-corrected weight loss without significant weight loss in the calorie-restricted control groups. Additionally, KBP-088 reduced white adipose tissues and adipocyte hypertrophy. Finally, KBP-088 alleviated hyperinsulinemia and improved oral glucose tolerance even with significantly lower insulin levels after 3 and 7 wk of treatment. KBP-088 is a potent amylin and calcitonin receptor agonist with prolonged receptor activation compared with davalintide. Moreover, KBP-088 induced and sustained significant weight loss and reduced overall adiposity and adipocyte hypertrophy in HFD rats. Finally, KBP-088 improved oral glucose tolerance and alleviated hyperinsulinemia, underscoring the potential of KBP-088 as an antiobesity agent with benefits on glucose control.


A synthetic nanofibrillar matrix promotes in vitro hepatic differentiation of embryonic stem cells and induced pluripotent stem cells.
Embryonic stem (ES) cells recapitulate normal developmental processes and serve as an attractive source for routine access to a large number of cells for research and therapies. We previously reported that ES cells cultured on M15 cells, or a synthesized basement membrane (sBM) substratum, efficiently differentiated into an endodermal fate and subsequently adopted fates of various digestive organs, such as the pancreas and liver. Here, we established a novel hepatic differentiation procedure using the synthetic nanofiber (sNF) as a cell culture scaffold. We first compared endoderm induction and hepatic differentiation between murine ES cells grown on sNF and several other substrata. The functional assays for hepatocytes reveal that the ES cells grown on sNF were directed into hepatic differentiation. To clarify the mechanisms for the promotion of ES cell differentiation in the sNF system, we focused on the function of Rac1, which is a Rho family member protein known to regulate the actin cytoskeleton. We observed the activation of Rac1 in undifferentiated and differentiated ES cells cultured on sNF plates, but not in those cultured on normal plastic plates. We also show that inhibition of Rac1 blocked the potentiating effects of sNF on endoderm and hepatic differentiation throughout the whole differentiation stages. Taken together, our results suggest that morphological changes result in cellular differentiation controlled by Rac1 activation, and that motility is not only the consequence, but is also able to trigger differentiation. In conclusion, we believe that sNF is a promising material that might contribute to tissue engineering and drug delivery.


Biochemical Characterization of Clinical Strains of Staphylococcus spp. and Their Sensitivity to Polyphenols-Rich Extracts from Pistachio (Pistacia vera L.).
We characterized a number of clinical strains of Staphylococcus spp. and investigated their sensitivity against polyphenols-rich extracts from natural raw and roasted pistachios (NPRE and RPRE, respectively). Out of 31 clinical isolates of Staphylococcus spp., 23 were coagulase-positive and identified as S. aureus, of which 21 were MRSA. Polyphenols-rich extracts from natural pistachios and roasted pistachios were prepared: the total phenols content, expressed as gallic acid equivalent (GAE)/100 g fresh weight (FW), was higher in natural pistachios (359.04 ± 8.124 mg) than roasted pistachios (225.18 ± 5.055 mg). The higher total phenols content in natural pistachios also correlated to the higher free-radical scavenging activity found by DPPH assay: NPRE and RPRE showed IC50 values of 0.85 (C.L. 0.725⁻0.976 mg mL-1) and 1.15 (C.L. 0.920⁻1.275 mg mL-1), respectively. Both NPRE and RPRE were active against S. aureus 6538P and Staph. spp. clinical isolates, with RPRE being the most active (MIC values ranging between 31.25 and 2000 μg mL-1). The antimicrobial potential of pistachios could be used to identify novel treatments for S. aureus skin infections.


Accommodation of Helical Imperfections in Rhodobacter sphaeroides Argonaute Ternary Complexes with Guide RNA and Target DNA.
Prokaryotic Argonaute (Ago) proteins were recently shown to target foreign genetic elements, thus making them a perfect model for studies of interference mechanisms. Here, we study interactions of Rhodobacter sphaeroides Ago (RsAgo) with guide RNA (gRNA) and fully complementary or imperfect target DNA (tDNA) using biochemical and structural approaches. We show that RsAgo can specifically recognize both the first nucleotide in gRNA and complementary nucleotide in tDNA, and both interactions contribute to nucleic acid binding. Non-canonical pairs and bulges on the target strand can be accommodated by RsAgo with minimal perturbation of the duplex but significantly reduce RsAgo affinity to tDNA. Surprisingly, mismatches between gRNA and tDNA induce dissociation of the guide-target duplex from RsAgo. Our results reveal plasticity in the ability of Ago proteins to accommodate helical imperfections, show how this might affect the efficiency of RNA silencing, and suggest a potential mechanism for guide release and Ago recycling.


Predictability in community dynamics.
The coupling between community composition and climate change spans a gradient from no lags to strong lags. The no-lag hypothesis is the foundation of many ecophysiological models, correlative species distribution modelling and climate reconstruction approaches. Simple lag hypotheses have become prominent in disequilibrium ecology, proposing that communities track climate change following a fixed function or with a time delay. However, more complex dynamics are possible and may lead to memory effects and alternate unstable states. We develop graphical and analytic methods for assessing these scenarios and show that these dynamics can appear in even simple models. The overall implications are that (1) complex community dynamics may be common and (2) detailed knowledge of past climate change and community states will often be necessary yet sometimes insufficient to make predictions of a community's future state.


The p85 and p110 subunits of phosphatidylinositol 3-kinase-alpha are substrates, in vitro, for a constitutively associated protein tyrosine kinase in platelets.
Phosphatidylinositol 3-kinase (PI3K) is a heterodimer lipid kinase consisting of an 85-kD subunit bound to a 110-kD catalytic subunit that also possesses intrinsic, Mn(2+)-dependent protein serine kinase activity capable of phosphorylating the 85-kD subunit. Here, we examine the Mn(2+)-dependent protein kinase activity of PI3K alpha immunoprecipitated from normal resting or thrombin-stimulated platelets, and characterize p85/p110 phosphorylation, in vitro. Phosphoamino acid analysis of phosphorylated PI3K alpha showed p85 and p110 were phosphorylated on serine, but in contrast to previous results, were also phosphorylated on threonine and tyrosine. Wortmannin and LY294002 inhibited p85 phosphorylation; however, p110 phosphorylation was also inhibited suggesting p110 autophosphorylation on serine/threonine. The protein tyrosine kinase inhibitor, erbstatin analog, partially inhibited p85 and p110 phosphorylation but did not appear to affect PI3K lipid kinase activity. The in vitro phosphorylation of p85 alpha or p110 alpha derived from thrombin-stimulated platelets was no different than that of resting platelets, but we confirm that in thrombin receptor-stimulated platelets enhanced levels of p85 alpha and PI3K lipid kinase activity were recovered in antiphosphotyrosine antibody immunoprecipitates. These results suggest PI3K alpha can autophosphorylate on serine and threonine, and both p85 alpha and p110 alpha are substrates for a constitutively-associated protein tyrosine kinase in platelets.


Therapeutic targeting of C-terminal binding protein in human cancer.
The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable therapeutic index for cancer therapy. In human colon cancer cell peritoneal xenografts, MTOB treatment decreased tumor burden and induced tumor cell apoptosis. To verify the potential utility of CtBP as a therapeutic target in human cancer, the expression of CtBP and its negative regulator ARF was studied in a series of resected human colon adenocarcinomas. CtBP and ARF levels were inversely-correlated, with elevated CtBP levels (compared with adjacent normal tissue) observed in greater than 60% of specimens, with ARF absent in nearly all specimens exhibiting elevated CtBP levels. Targeting CtBP may represent a useful therapeutic strategy in human malignancies.


Variability in leaf optical properties among 26 species from a broad range of habitats.
Leaves from 26 species with growth forms from annual herbs to trees were collected from open, intermediate, and shaded understory habitats in Mississippi and Kansas, USA. Leaf optical properties including reflectance, transmittance, and absorptance in visible and near infrared (NIR) wavelengths were measured along with leaf thickness and specific leaf mass (SLM). These leaf properties and internal light scattering have been reported to vary with light availability in studies that have focused on a limited number of species. Our objective was to determine whether these patterns in leaf optics and light availability were consistent when a greater number of species were evaluated. Leaf thickness and SLM varied by tenfold among species sampled, but within-habitat variance was high. Although there was a strong trend toward thicker leaves in open habitats, only SLM was significantly greater in open vs. understory habitats. In contrast, leaf optical properties were strikingly similar among habitats. Reflectance and reflectance/transmittance in the NIR were used to estimate internal light scattering and there were strong relationships (r1 > 0.65) between these optical properties and leaf thickness. We concluded that leaf thickness, which did not vary consistently among habitats, was the best predictor of NIR reflectance and internal light scattering. However, because carbon allocation to leaves was lower in understory species (low SLM) yet gross optical properties were similar among all habitats, the energy investment by shade leaves required to achieve optical equivalence with sun leaves was lower. Differences in leaf longevity and growth form within a habitat may help explain the lack of consistent patterns in leaf optics as the number of species sampled increases.


Evidence of Early Language Discrimination Abilities in Infants From Bilingual Environments.
Previous research data indicate that soon after birth, infants from monolingual families can discriminate utterances drawn from languages that differ prosodically, but discrimination between rhythmically similar languages, such as English and Dutch, has not yet been established by 2 months of age. In the case of bilinguals, the question of how early they can distinguish between the languages of exposure remains unanswered. The goal of this study was to analyze language discrimination capacities in 4-month-old bilingual infants simultaneously exposed to 2 Romance languages belonging to the same rhythmic category, Spanish and Catalan. Using a familiarization-preference procedure, 2 groups of bilingual-to-be infants showed a capacity to discriminate between these 2 familial languages. Moreover, when compared with 2 groups of infants from monolingual environments, the size of the observed effects was the same. These results can be taken as initial evidence of an early capacity to distinguish languages in simultaneous bilingual exposure, thus challenging the hypothesis that language discrimination capacities are delayed in bilinguals.


Dynamic modulation of illusory and physical target size on separate and coordinated eye and hand movements.
In everyday behavior, two of the most common visually guided actions-eye and hand movements-can be performed independently, but are often synergistically coupled. In this study, we examine whether the same visual representation is used for different stages of saccades and pointing, namely movement preparation and execution, and whether this usage is consistent between independent and naturalistic coordinated eye and hand movements. To address these questions, we used the Ponzo illusion to dissociate the perceived and physical sizes of visual targets and measured the effects on movement preparation and execution for independent and coordinated saccades and pointing. During independent movements, we demonstrated that both physically and perceptually larger targets produced faster preparation for both effectors. Furthermore, participants who showed a greater influence of the illusion on saccade preparation also showed a greater influence on pointing preparation, suggesting that a shared mechanism involved in preparation across effectors is influenced by illusions. However, only physical but not perceptual target sizes influenced saccade and pointing execution. When pointing was coordinated with saccades, we observed different dynamics: pointing no longer showed modulation from illusory size, while saccades showed illusion modulation for both preparation and execution. Interestingly, in independent and coordinated movements, the illusion modulated saccade preparation more than pointing preparation, with this effect more pronounced during coordination. These results suggest a shared mechanism, dominated by the eyes, may underlie visually guided action preparation across effectors. Furthermore, the influence of illusions on action may operate within such a mechanism, leading to dynamic interactions between action modalities based on task demands.


Bax promotes neuronal cell death and is downregulated during the development of the nervous system.
The Bcl-2 and Bcl-x proteins suppress programmed cell death, whereas Bax promotes apoptosis. We investigated the pattern of expression of Bcl-2, Bax and Bcl-x during neuronal differentiation and development. All three proteins were widely expressed in neonatal rats but, in the adult, Bax levels were 20- to 140-fold lower in the cerebral cortex, cerebellum and heart muscle, whereas Bcl-x was not downregulated in any of the tissues examined. In the cerebral cortex and cerebellum, the decrease in Bax levels occurred after the period of developmental cell death. Further, microinjection of a Bax expression vector into cultured sympathetic neurons, which depend on nerve growth factor for survival, induced apoptosis in the presence of survival factor and increased the rate of cell death after nerve growth factor withdrawal. This effect could be blocked by co-injection of an expression vector for Bcl-xL or for the baculovirus p35 protein, an inhibitor of caspases (ICE-like proteases). These results suggest that, during development, the sensitivity of neurons to signals that induce apoptosis may be regulated by modulating Bax levels and that Bax-induced death requires caspase activity.


Imaging of polarimetric-phase object through scattering medium by phase shifting.
Light propagating through a scattering medium generates a random field, which is also known as a speckle. The scattering process hinders the direct retrieval of the information encoded in the light based on the randomly fluctuating field. In this study, we propose and experimentally demonstrate a method for the imaging of polarimetric-phase objects hidden behind a scattering medium based on two-point intensity correlation and phase-shifting techniques. One advantage of proposed method is that it does not require mechanical rotation of polarization elements. The method exploits the relationship between the two-point intensity correlation of the spatially fluctuating random field in the observation plane and the structure of the polarized source in the scattering plane. The polarimetric phase of the source structure is determined by replacing the interference intensity in traditional phase shift formula with the Fourier transform of the cross-covariance of the intensity. The imaging of the polarimetric-phase object is demonstrated by comparing three different phase-shifting techniques. We also evaluated the performance of the proposed technique on an unstable platform as well as using dynamic diffusers, which is implemented by replacing the diffuser with a new one during each phase-shifting step. The results were compared with that obtained with a fixed diffuser on a vibration-isolation platform during the phase-shifting process. A good match is found among the three cases, thus confirming that the proposed intensity-correlation-based technique is a useful one and should be applicable with dynamic diffusers as well as in unstable environments.


Palladium-peptide oxidative addition complexes for bioconjugation.
The synthesis of palladium oxidative addition complexes derived from unprotected peptides is described. Incorporation of 4-halophenylalanine into a peptide during solid phase peptide synthesis allows for subsequent oxidative addition at this position upon treatment with a palladium precursor and suitable ligand. The resulting palladium-peptide complexes are solid, storable, water-soluble, and easily purified via high-performance liquid chromatography. These complexes react with thiols in aqueous buffer, offering an efficient method for bioconjugation. Using this strategy, peptides can be functionalized with small molecules to prepare modified aryl thioether side-chains at low micromolar concentrations. Additionally, peptide-peptide and peptide-protein ligations are demonstrated under dilute aqueous conditions.


Efficacy and safety of topical Matricaria chamomilla L. (chamomile) oil for knee osteoarthritis: A randomized controlled clinical trial.
To assess the efficacy and safety of topical Matricaria chamomilla (Chamomile) oil in patients with knee osteoarthritis. Patients were randomized and treated with topical chamomile oil, diclofenac or placebo, 3 times/day for 3 weeks. They were allowed to use acetaminophen as analgesic. The patients were asked about their total acetaminophen use. Moreover, they were assessed in the terms of pain, physical function and stiffness by using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire at the enrolling and weekly. Chamomile oil significantly reduced the patients' need for acetaminophen (P = 0.001) compared with diclofenac and placebo. However, there were no significant differences in WOMAC questionnaire domains. The patients did not report any adverse events by using chamomile oil. Chamomile oil decreased the analgesic demand of patients with knee osteoarthritis. In addition, it may show some beneficial effects on physical function, and stiffness of the patients.


Susceptibilities of Mycoplasma hominis, Mycoplasma pneumoniae, and Ureaplasma urealyticum to new glycylcyclines in comparison with those to older tetracyclines.
The glycylcyclines are new tetracycline derivatives that include the N,N-dimethylglycylamido derivative of minocycline (DMG-MINO) and the N,N-dimethylglycylamido derivative of 6-demethyl-6-deoxytetracycline (DMG-DMDOT). The susceptibilities of Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum to DMG-MINO, DMG-DMDOT, tetracycline, doxycycline, and minocycline were determined by the agar dilution method. The glycylcyclines with MICs at which 50% of the isolates are inhibited of 0.25 to 0.5 micrograms/ml for M. pneumoniae were two- to fourfold more active than tetracycline and had the same activity as minocycline and doxycycline. Tetracycline-susceptible M. hominis strains were four- to eightfold more susceptible to the glycylcyclines (0.12 to 0.25 micrograms/ml) than to tetracycline. Strains of M. hominis known to be resistant to tetracycline, doxycycline, and minocycline because of the tet(M) determinant were as susceptible to the glycylcyclines as the tetracycline-susceptible strains. For tetracycline-susceptible U. urealyticum strains, the glycylcyclines showed the same activity as tetracycline (MICs at which 50% of the isolates are inhibited of 1 to 2 micrograms/ml). Tetracycline-resistant strains of U. urealyticum were resistant to doxycycline and minocycline and showed variable susceptibility to the glycylcyclines (range, 0.5 to 32 micrograms/ml). In view of the increasing resistance of M. hominis and U. urealyticum strains to tetracyclines, the glycylcyclines have promise, pending assessment of their pharmacokinetic and safety profiles.


Male courtship song frequency as an indicator of male genetic quality in an insect species, Drosophila montana.
Most theoretical models on evolution of male secondary sexual characters and female preferences for these characters suggest that the male characters evolve in response to female preferences that may themselves evolve in response to direct or indirect benefits of choice. In Drosophila montana (a species of the D. virilis group), females use male song in their mate choice, preferring males that produce songs with short sound pulses and a high carrier frequency. We demonstrate here that the females get indirect benefits from their choice: in our data the frequency of the male song correlated with the survival rate of the male's progeny from egg to adulthood (indirect benefit for the female), but not with the fecundity of his mating partner (no direct benefit for the female). Male wing centroid asymmetry did not correlate with male wing song characters, nor with female egg production nor the fitness of her progeny, suggesting that fluctuating asymmetry in male wings does not play a major role in sexual signalling. The fact that the male song gives the female information on the male's condition/genetic quality in D. montana suggests that in this species the evolution of female preferences for male song characters could have evolved through condition-dependent viability selection presented in some 'good genes' models.


Children exposed to a natural disaster: psychological consequences eight years after 2004 tsunami.
There is a need for studies that follow up children and adolescents for many years post disaster since earlier studies have shown that exposure during natural disasters constitutes a risk factor for poor psychological health. The main aim was to examine whether there was an association between severity of exposures during a natural disaster experienced in childhood or adolescence and posttraumatic stress symptoms, psychological distress, self-rated health, diagnosis of depression, anxiety or worry, thoughts about or attempted suicide, physical symptoms or daily functioning eight years later in young adulthood. A second aim was to compare psychological distress and self-rated health of exposed young adults with a matched population-based sample. Young adults, who experienced the 2004 tsunami as children between 10 and 15 years of age, responded to a questionnaire eight years post disaster. The results were compared to a matched population sample. The results showed that the likelihood for negative psychological outcomes was higher for those who had been exposed to several types of exposures during this natural disaster. The negative psychological impact on children and adolescents can still be present eight years post-disaster and seems to have association with the type of exposure; loss, physical presence and subjective experience. It is important for clinicians, who meet young adults seeking help, to be conscious about the impact as long as eight years post disaster and to be aware of possible clinical implications associated with severity of exposures.


[Acanthosis nigricans and cancer of the stomach].
A case of a 44 years old patient with inoperable gastric adenocarcinoma and exuberant lesions of Acanthosis Nigricans is described. He died nine months after the diagnosis, having experienced disappearance of the cutaneous manifestations after the cytostatic treatment done. The literature about Acanthosis Nigricans is reviewed and the importance of precocious search of associated malign disease is stressed. It was demonstrated by immunocytochemistry, positivity to NSE (neuron specific enolase) and ACTH, in the patient gastric tumour cells which allows them to be classified as neuroendocrine cells. It is suggested that Acanthosis Nigricans is a manifestation of a para-endocrine syndrome.


No evidence for xenotropic murine leukemia-related virus infection in Sweden using internally controlled multiepitope suspension array serology.
Many syndromes have a large number of differential diagnoses, a situation which calls for multiplex diagnostic systems. Myalgic encephalomyelitis (ME), also named chronic fatigue syndrome (CFS), is a common disease of unknown etiology. A mouse retrovirus, xenotropic murine leukemia-related virus (XMRV), was found in ME/CFS patients and blood donors, but this was not corroborated. However, the paucity of serological investigations on XMRV in humans prompted us to develop a serological assay which cover many aspects of XMRV antigenicity. It is a novel suspension array method, using a multiplex IgG assay with nine recombinant proteins from the env and gag genes of XMRV and 38 peptides based on known epitopes of vertebrate gammaretroviruses. IgG antibodies were sought in 520 blood donors and 85 ME/CFS patients and in positive- and negative-control sera from animals. We found no differences in seroreactivity between blood donors and ME/CFS patients for any of the antigens. This did not support an association between ME/CFS and XMRV infection. The multiplex serological system had several advantages: (i) biotinylated protein G allowed us to run both human and animal sera, which is essential because of a lack of XMRV-positive humans; (ii) a novel quality control was a pan-peptide positive-control rabbit serum; and (iii) synthetic XMRV Gag peptides with degenerate positions covering most of the variation of murine leukemia-like viruses did not give higher background than nondegenerate analogs. The principle may be used for creation of variant tolerant peptide serologies. Thus, our system allows rational large-scale serological assays with built-in quality control.


Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study.
Health authorities in numerous countries recommend periconceptional folic acid to pregnant women to prevent neural tube defects. The objective of this study was to examine the association of folic acid supplementation during different periods of pregnancy and of dietary folate intake with the risk of spontaneous preterm delivery (PTD). The Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 65,668 women with singleton pregnancies resulting in live births in 1999-2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until week 24 during pregnancy. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4-5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n = 1,628). The median total folate intake was 266 μg/d (interquartile range IQR 154-543) in the overall population and 540 μg/d (IQR 369-651) in the supplement users. Eighty-three percent reported any folic acid supplementation from <8 weeks before to 24 weeks after conception while 42% initiated folic acid supplementation before their pregnancy. Cox regression analysis showed that the amount of folate intake from the diet (hazard ratio HR 1.16; confidence interval CI 0.65-2.08) and from the folic acid supplements (HR 1.04; CI 0.95-1.13) was not significantly associated with the risk of PTD. The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for PTD (HR 1.19; CI 1.05-1.34) compared to no folic acid supplementation pre-conception. There was no significant association with PTD when supplementation was initiated within 8 weeks pre-conception (HR 1.01; CI 0.88-1.16). All analyses were adjusted for maternal characteristics and socioeconomic, health and dietary variables. Our findings do not support a protective effect of dietary folate intake or folic acid supplementation on spontaneous PTD. Pre-conceptional folic acid supplementation starting more than 8 weeks before conception was associated with an increased risk of PTD. These results require further investigation before discussing an expansion of folic acid supplementation guidelines.


BRAF mutation analysis is a valid tool to implement in Lynch syndrome diagnosis in patients classified according to the Bethesda guidelines.
Lynch syndrome (LS) is clinically defined by the Amsterdam criteria (AC) and by germline mutations in mismatch-repair (MMR) genes leading to microsatellite instability (MSI) at the molecular level. Patients who do not fulfil AC are considered suspected-Lynch according to the less stringent Bethesda guidelines (BG) and should be tested for MSI and MMR germline mutations. BRAF mutations have been proposed as a marker to exclude LS because they are generally absent in LS patients and present in sporadic colorectal cancer (sCRC) with MSI due to promoter hypermethylation of the MLH1 gene. Our aim was to verify whether BRAF mutations may improve the criteria to select patients for germline MMR mutation assessment. We analyzed 303 formalin-fixed paraffin-embedded CRC samples including 174 sCRC, 28 patients fulfilling AC, and 101 suspected-Lynch patients fulfilling BG. We analyzed MSI and BRAF mutations in all CRC samples. MLH1, MSH2 and MSH6 germline mutations were investigated in MSI patients fulfilling AC or BG. sCRC samples showed MSI in 20/174 (11%) cases. BRAF mutations were detected in 10/174 (6%) sCRC cases and were significantly correlated with MSI (P = 0.002). MSI was observed in 24/28 (86%) Amsterdam cases which were BRAF wild-type. MMR gene mutation was detected in 22/26 (85%) AC cases, all showing MSI. Suspected-Lynch cases carried MSI in 41/101 (40%) and BRAF mutations in 7/101 (7%) cases. MMR gene mutation was detected in 13/28 (46%) evaluable MSI patients of this group and only in cases characterized by a wild-type BRAF gene. The prevalence of BRAF mutations in CRC patients is not high but extremely correlated with MSI and risk categories as BG, whereas they are absent in LS patients. BRAF mutation detection can reduce the need for MMR gene analysis in a small (but not negligible) proportion of MSI patients (7%), with a positive impact on the financial and psychological costs of unnecessary tests.


Transoral incisionless fundoplication for gastro-esophageal reflux disease: Techniques and outcomes.
Gastro-esophageal reflux disease (GERD) is a very common disorder that results primarily from the loss of an effective antireflux barrier, which forms a mechanical obstacle to the retrograde movement of gastric content. GERD can be currently treated by medical therapy, surgical or endoscopic transoral intervention. Medical therapy is the most common approach, though concerns have been increasingly raised in recent years about the potential side effects of continuous long-term medication, drug intolerance or unresponsiveness, and the need for high dosages for long periods to treat symptoms or prevent recurrences. Surgery too may in some cases have consequences such as long-lasting dysphagia, flatulence, inability to belch or vomit, diarrhea, or functional dyspepsia related to delayed gastric emptying. In the last few years, transoral incisionless fundoplication (TIF) has proved an effective and promising therapeutic option as an alternative to medical and surgical therapy. This review describes the steps of the TIF technique, using the EsophyX(®) device and the MUSE(TM) system. Complications and their management are described in detail, and the recent literature regarding the outcomes is reviewed. TIF reconfigures the tissue to obtain a full-thickness gastro-esophageal valve from inside the stomach, by serosa-to-serosa plications which include the muscle layers. To date the procedure has achieved lasting improvement of GERD symptoms (up to six years), cessation or reduction of proton pump inhibitor medication in about 75% of patients, and improvement of functional findings, measured by either pH or impedance monitoring.


Implant-supported fixed partial prostheses: a retrospective study.
The purpose of this retrospective study was to present treatment outcome and patient reactions to rehabilitation with implant-supported fixed partial prostheses. Eighty-three patients were consecutively treated with implant-supported fixed partial prostheses (Brånemark system) from 1986 to 1995. Seventy-six of these 83 patients were examined (66 maxillary and 31 mandibular prostheses). The mean observation time was 53.9 months. In total, 285 implants were placed. Eleven implants were lost before loading. The first 41 prostheses were removed and the implants examined regarding the criteria for "success" and tightness of the screw joints. Only one implant had lost integration. The survival rate before and after loading was 96%, which included implants placed in augmented bone. All prostheses were stable at the time of examination. In prostheses with cantilevers (98 implants), 12% of the gold screws and 17% of the abutment screws showed a "not acceptable" loosening, compared to none in the prostheses without cantilevers (17 implants). The difference was not statistically significant. The mean marginal bone loss was 0.4 mm for the first year after prosthesis insertion and less than 0.1 mm per year in the following years. The most frequent prosthesis design was one pontic supported by two implants. Prostheses made in gold acrylic and titanium acrylic had more complications and showed a higher need for repair than metal-ceramic restorations. Patients reacted very positively to the esthetic results and comfort with eating, and were overall satisfied with their prostheses. Implant-supported fixed partial prostheses seem to have a very good prognosis and are well-accepted by patients.


Appraisal of patient-level health economic models of severe mental illness: systematic review.
Healthcare decision makers require accurate long-term economic models to evaluate the cost-effectiveness of new mental health interventions. To assess the suitability of current patient-level economic models to estimate long-term economic outcomes in severe mental illness. We undertook pre-specified systematic searches in MEDLINE, Embase and PsycINFO to identify reviews and stand-alone publications of economic models of interventions for schizophrenia, bipolar disorder and major depressive disorder (PROSPERO: CRD42020158243). We screened paper titles and abstracts to identify unique patient-level economic models. We conducted a structured extraction of identified models, recording the presence of key predefined model features. Model quality and validation were appraised using the 2014 ISPOR and 2016 AdViSHE model checklists. We identified 15 unique patient-level models for psychosis and major depressive disorder from 1481 non-duplicate records. Models addressed schizophrenia (n = 6), bipolar disorder (n = 2) and major depressive disorder (n = 7). The predominant model type was discrete event simulation (n = 9). Model complexity and incorporation of patient heterogeneity varied considerably, and only five models extrapolated costs and outcomes over a lifetime horizon. Key model parameters were often based on low-quality evidence, and checklist quality assessment revealed weak model verification procedures. Existing patient-level economic models of interventions for severe mental illness have considerable limitations. New modelling efforts must be supplemented by the generation of good-quality, contemporary evidence suitable for model building. Combined effort across the research community is required to build and validate economic extrapolation models suitable for accurately assessing the long-term value of new interventions from short-term clinical trial data.


Exome sequencing of prostate cancer supports the hypothesis of independent tumour origins.
Prostate cancer (PCa) is a clinically and pathologically heterogeneous disease. The rapid development of sequencing technology has the potential to deliver new biomarkers with emphasis on aggressive disease and to revolutionise personalised cancer treatment. However, a prostate harbouring cancer commonly contains multiple separate tumour foci, with the potential to aggravate tumour sampling. The level of intraprostatic tumour heterogeneity remains to be determined. To determine the level of intraprostatic tumour heterogeneity through genome-wide, high-resolution profiling of multiple tumour samples from the same individual. Multiple tumour samples were obtained from four individuals following radical prostatectomy. One individual (SWE-1) contained >70% cancer cells in all tumour samples, whereas the other three (SWE-2 to SWE-4) required the use of laser capture microdissection for tumour cell enrichment. Subsequently, DNA was extracted from all tissue samples, and exome sequencing was performed. All tumour foci of SWE-1 were also profiled using a high-resolution array for the identification of copy number alterations (CNA). Shared somatic high-frequency single nucleotide variants (SNV) and CNAs were used to infer the level of intraprostatic tumour heterogeneity. No high-frequency mutations, common for the three tumour samples of SWE-1, were identified. Ten randomly chosen positions were validated with Sanger sequencing in all foci, which verified the exome data. The high level of intraprostatic heterogeneity was consistent in all individuals. In total, three out of four individuals harboured tumours without an apparent common somatic denominator. Although we cannot exclude the presence of common structural rearrangements, a high-density array was used for the detection of deletions and amplifications in SWE-1, which agreed with the exome data. We present evidence for the presence of somatically independent tumours within the same prostate. This finding will have implications for personalised cancer treatment and biomarker discovery.


Chlamydia trachomatis Is Resistant to Inclusion Ubiquitination and Associated Host Defense in Gamma Interferon-Primed Human Epithelial Cells.
The cytokine gamma interferon (IFN-γ) induces cell-autonomous immunity to combat infections with intracellular pathogens, such as the bacterium Chlamydia trachomatis The present study demonstrates that IFN-γ-primed human cells ubiquitinate and eliminate intracellular Chlamydia-containing vacuoles, so-called inclusions. We previously described how IFN-γ-inducible immunity-related GTPases (IRGs) employ ubiquitin systems to mark inclusions for destruction in mouse cells and, furthermore, showed that the rodent pathogen Chlamydia muridarum blocks ubiquitination of its inclusions by interfering with mouse IRG function. Here, we report that ubiquitination of inclusions in human cells is independent of IRG and thus distinct from the murine pathway. We show that C. muridarum is susceptible to inclusion ubiquitination in human cells, while the closely related human pathogen C. trachomatis is resistant. C. muridarum, but not C. trachomatis, inclusions attract several markers of cell-autonomous immunity, including the ubiquitin-binding protein p62, the ubiquitin-like protein LC3, and guanylate-binding protein 1. Consequently, we find that IFN-γ priming of human epithelial cells triggers the elimination of C. muridarum, but not C. trachomatis, inclusions. This newly described defense pathway is independent of indole-2,3-dioxygenase, a known IFN-γ-inducible anti-Chlamydia resistance factor. Collectively, our observations indicate that C. trachomatis evolved mechanisms to avoid a human-specific, ubiquitin-mediated response as part of its unique adaptation to its human host. Chlamydia trachomatis is the leading cause of sexually transmitted bacterial infections and responsible for significant morbidity, including pelvic inflammatory disease, infertility, and ectopic pregnancies in women. As an obligate intracellular pathogen, C. trachomatis is in perpetual conflict with cell-intrinsic defense programs executed by its human host. Our study defines a novel anti-Chlamydia host resistance pathway active in human epithelial cells. This defense program promotes the deposition of the small antimicrobial protein ubiquitin on vacuoles containing Chlamydia We show that this ubiquitin-based resistance pathway of human cells is highly effective against a Chlamydia species adapted to rodents but ineffective against human-adapted C. trachomatis This observation indicates that C. trachomatis evolved strategies to avoid entrapment within ubiquitin-labeled vacuoles as part of its adaptation to the human innate immune system.


The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation.
Therapeutic decisions in atrial fibrillation (AF) are often influenced by assessment of bleeding risk. However, existing bleeding risk scores have limitations. We sought to develop and validate a novel bleeding risk score using routinely available clinical information to predict major bleeding in a large, community-based AF population. We analysed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), a prospective registry that enrolled incident and prevalent AF patients at 176 US sites. Using Cox proportional hazards regression, we identified factors independently associated with major bleeding among patients taking oral anticoagulation (OAC) over a median follow-up of 2 years (interquartile range = 1.6-2.5). We also created a numerical bedside risk score that included the five most predictive risk factors weighted according to their strength of association with major bleeding. The predictive performance of the full model, the simple five-item score, and two existing risk scores (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly, HAS-BLED, and anticoagulation and risk factors in atrial fibrillation, ATRIA) were then assessed in both the ORBIT-AF cohort and a separate clinical trial population, Rivaroxaban Once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET-AF). Among 7411 ORBIT-AF patients taking OAC, the rate of major bleeding was 4.0/100 person-years. The full continuous model (12 variables) and five-factor ORBIT risk score (older age [75+ years], reduced haemoglobin/haematocrit/history of anaemia, bleeding history, insufficient kidney function, and treatment with antiplatelet) both had good ability to identify those who bled vs. not (C-index 0.69 and 0.67, respectively). These scores both had similar discrimination, but markedly better calibration when compared with the HAS-BLED and ATRIA scores in an external validation population from the ROCKET-AF trial. The five-element ORBIT bleeding risk score had better ability to predict major bleeding in AF patients when compared with HAS-BLED and ATRIA risk scores. The ORBIT risk score can provide a simple, easily remembered tool to support clinical decision making.


Candida Prosthetic Joint Infection. A Review of Treatment Methods.
Fungal microorganisms are still a rare cause of bone and joint infections. We report a new case of knee prosthetic joint infection due to Candida albicans in a patient with a previous two-stage right knee arthroplasty for septic arthritis due to S. epidermidis occurred several months ago. Moreover, the treatment in 76 cases of Candida prosthetic joint infection has been discussed. Forty patients were female and mean age at diagnosis was 65.7 (± SD 18) yrs. No risk factors for candidal infection were found in 25 patients. Infection site was the knee in 38 patients and hip in 36; pain was present in 44 patients and swelling in 24. The most frequent species was C. albicans, followed by C. parapsilosis. Eleven patients were only treated with antifungal drugs being the outcome favourable in all of them. Two-stage exchange arthroplasty was performed in 30 patients, and resection arthroplasty in other 30; in three patients one-stage exchange arthroplasty was done. A favourable outcome was found in 58 patients after antifungal plus surgical treatment, in 11 after antifungal treatment alone and in one after surgery alone. The type of treatment is still not clearly defined and an algorithm for treatment in fungal PJI should be established, but various types of surgical procedures may be applied.


A stability concept for metal ion coordination to single-stranded nucleic acids and affinities of individual sites.
The three-dimensional architecture and function of nucleic acids strongly depend on the presence of metal ions, among other factors. Given the negative charge of the phosphate-sugar backbone, positively charged species, mostly metal ions, are necessary for compensation. However, these ions also allow and induce folding of complicated RNA structures. Furthermore, metal ions bind to specific sites, stabilizing local motifs and positioning themselves correctly to aid (or even enable) a catalytic mechanism, as, for example, in ribozymes. Many nucleic acids thereby exhibit large differences in folding and activity depending not only on the concentration but also on the kind of metal ion involved. As a consequence, understanding the role of metal ions in nucleic acids requires knowing not only the exact positioning and coordination sphere of each specifically bound metal ion but also its intrinsic site affinity. However, the quantification of metal ion affinities toward certain sites in a single-stranded (though folded) nucleic acid is a demanding task, and few experimental data exist. In this Account, we present a new tool for estimating the binding affinity of a given metal ion, based on its ligating sites within the nucleic acid. To this end, we have summarized the available affinity constants of Mg(2+), Ca(2+), Mn(2+), Cu(2+), Zn(2+), Cd(2+), and Pb(2+) for binding to nucleobase residues, as well as to mono- and dinucleotides. We have also estimated for these ions the stability constants for coordinating the phosphodiester bridge. In this way, stability increments for each ligand site are obtained, and a clear selectivity of the ligating atoms, as well as their discrimination by different metal ions, can thus be recognized. On the basis of these data, we propose a concept that allows one to estimate the intrinsic stabilities of nucleic acid-binding pockets for these metal ions. For example, the presence of a phosphate group has a much larger influence on the overall affinity of Mg(2+), Ca(2+), or Mn(2+) compared with, for example, that of Cd(2+) or Zn(2+). In the case of Cd(2+) and Zn(2+), the guanine N7 position is the strongest intrinsic binding site. By adding up the individual increments like building blocks, one derives an estimate not only for the overall stability of a given coordination sphere but also for the most stable complex if an excess of ligating atoms is available in a binding pocket saturating the coordination sphere of the metal ion. Hence, this empirical concept of adding up known intrinsic stabilities, like building blocks, to an estimated overall stability will help in understanding the accelerating or inhibiting effects of different metal ions in ribozymes and DNAzymes.


Concerns about medication and medication adherence in patients with chronic pain recruited from general practice.
This study examines the concerns and beliefs about medication reported by patients with nonmalignant chronic pain encountered within general practice. Two hundred thirty-nine patients with chronic pain took part in this research. Patients completed the Pain Medication Attitudes Questionnaire, a measure of patient concerns and beliefs relating to addiction, withdrawal, side effects, mistrust in doctors, perceived need of medication, scrutiny from others, and tolerance. The data revealed that patient concerns and beliefs predicted general medication nonadherence. In addition, concerns were related to the direction of nonadherence: overuse of medication was related to increased perceived need for medication and greater concern over side effects; underuse was related to decreased concerns over withdrawal and increased mistrust in the prescribing doctor. Analyses also indicated that patient attitudes and concerns about medication were more predictive of nonadherence than both level of pain and the reported frequency of experienced side effects. This research contributes to the increasing evidence that patient attitudes and beliefs about pain medication are associated with adherence behavior. Training general practitioners to identify and address these concerns may reduce concerns, improve adherence, and facilitate the doctor-patient relationship.


Group versus individual administration affects baseline neurocognitive test performance.
Computer-based tests are widely used for the purpose of documenting baseline neurocognitive function, and athletes are often tested in groups. At present, there is limited research on the effects of administering these tests in a group versus individual setting. Athletes assessed with neurocognitive tests in groups would show decreased performance compared with those assessed individually. Cohort study; Level of evidence, 3. High school athletes completed preseason baseline neurocognitive tests either in groups in their school or individually in a private neuropsychological clinic (with no significant between-group differences in sex, history of concussion, and attention deficit disorder/learning disability). All athletes completed the ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) test battery on 1 occasion, which yielded scores in the area of verbal memory, visual memory, motor processing speed, reaction time, and symptom scores. Athletes in the group setting scored significantly lower on verbal memory (mean 83.4 vs 86.5; P = .003), visual memory (mean 71.6 vs 76.7; P = .0001), motor processing speed (mean 35.6 vs 38.4; P = .0001), and reaction time (mean 0.61 vs 0.57; P = .001), but not symptom scores (mean 6.1 vs 4.4; P = .11), and exhibited a greater rate of invalid baselines. Similar results were obtained after excluding athletes with attention deficit disorder/learning disability and/or a history of concussion. Administering baseline neurocognitive testing to athletes in a group setting may introduce extraneous error, negatively affecting test performance.


The effect of quitting smoking on HDL-cholesterol - a review based on within-subject changes.
A higher concentration of high density lipoprotein cholesterol (HDL-C) in ex-smokers than smokers has consistently been observed. Better evidence of quitting effects comes from within-subject changes. We extend an earlier meta-analysis to quantify the reduction, and investigate variation by time quit and other factors. We conducted Medline and Cochrane searches for studies measuring HDL-C in subjects while still smoking and later having quit. Using unweighted and inverse-variance weighted regression analysis, we related changes (in mmol/l) to intra-measurement period, and estimated time quit, and to study type, location and start year, age, sex, product smoked, validation of quitting, baseline HDL-C, baseline and change in weight/BMI, and any study constraints on diet or exercise. Forty-five studies were identified (17 Europe, 16 North America, 11 Asia, 1 Australia). Thirteen were observational, giving changes over at least 12 months, with most involving >1000 subjects. Others were smoking cessation trials, 12 randomized and 20 non-randomized. These were often small (18 of <100 subjects) and short (14 of <10 weeks, the longest a year). Thirty studies provided results for only one time interval. From 94 estimates of HDL-C change, the unweighted mean was 0.107 (95% CI 0.085-0.128). The weighted mean 0.060 (0.044 to 0.075) was lower, due to smaller estimates in longer term studies. Weighted means varied by time quit (0.083, 0.112, 0.111, 0.072, 0.058 and 0.040 for <3, 3 to <6, 6 to <13, 13 to <27, 27 to <52 and 52+ weeks, p=0.006). After adjustment for time quit, estimates varied by study constraint on diet/exercise (p=0.003), being higher in studies requiring subjects to maintain their pre-quitting habits, but no other clear differences were seen, with significant (p<0.05) increases following quitting being evident in all subgroups studied, except where data were very limited. For both continuing and never smokers, the data are (except for two large studies atypically showing significant HDL-C declines in both groups, and a smaller decline in quitters) consistent with no change, and contrast markedly with the data for quitters. We conclude that quitting smoking increases HDL-C, and that this increase occurs rapidly after quitting, with no clear pattern of change thereafter.


Antifungal Activity of Some Constituents of Origanum vulgare L. Essential Oil Against Postharvest Disease of Peach Fruit.
Plant essential oils (EOs) can potentially replace synthetic fungicides in the management of postharvest fruit and vegetable diseases. The aim of this study was to evaluate in vitro and in vivo effectiveness of thymol, carvacrol, linalool, and trans-caryophyllene, single constituents of the EO of Origanum vulgare L. ssp. hirtum against Monilinia laxa, M. fructigena, and M. fructicola, which are important phytopathogens and causal agents of brown rot of pome and stone fruits in pre- and postharvest. Moreover, the possible phytotoxic activity of these constituents was assessed and their minimum inhibitory concentration (MIC) was determined. In vitro experiment indicated that thymol and carvacrol possess the highest antifungal activity. Results of in vivo trials confirmed the strong efficacy of thymol and carvacrol against brown rot of peach fruits. The thymol MIC resulted to be 0.16 μg/μL against M. laxa and M. fructigena and 0.12 μg/μL against M. fructicola, whereas for carvacrol they were 0.02 μg/μL against the first two Monilinia species and 0.03 μg/μL against the third. Results of this study indicated that thymol and carvacrol could be used after suitable formulation for controlling postharvest fruit diseases caused by the three studied Monilinia species.


Interactive Steering of Hierarchical Clustering.
Hierarchical clustering is an important technique to organize big data for exploratory data analysis. However, existing one-size-fits-all hierarchical clustering methods often fail to meet the diverse needs of different users. To address this challenge, we present an interactive steering method to visually supervise constrained hierarchical clustering by utilizing both public knowledge (e.g., Wikipedia) and private knowledge from users. The novelty of our approach includes 1) automatically constructing constraints for hierarchical clustering using knowledge (knowledge-driven) and intrinsic data distribution (data-driven), and 2) enabling the interactive steering of clustering through a visual interface (user-driven). Our method first maps each data item to the most relevant items in a knowledge base. An initial constraint tree is then extracted using the ant colony optimization algorithm. The algorithm balances the tree width and depth and covers the data items with high confidence. Given the constraint tree, the data items are hierarchically clustered using evolutionary Bayesian rose tree. To clearly convey the hierarchical clustering results, an uncertainty-aware tree visualization has been developed to enable users to quickly locate the most uncertain sub-hierarchies and interactively improve them. The quantitative evaluation and case study demonstrate that the proposed approach facilitates the building of customized clustering trees in an efficient and effective manner.


Red and Processed Meats and Health Risks: How Strong Is the Evidence?
Prevailing dietary guidelines have widely recommended diets relatively low in red and processed meats and high in minimally processed plant foods for the prevention of chronic diseases. However, an ad hoc research group called the Nutritional Recommendations (NutriRECS) consortium recently issued "new dietary guidelines" encouraging individuals to continue their current meat consumption habits due to "low certainty" of the evidence, difficulty of altering meat eaters' habits and preferences, and the lack of need to consider environmental impacts of red meat consumption. These recommendations are not justified, in large part because of the flawed methodologies used to review and grade nutritional evidence. The evidence evaluation was largely based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria, which are primarily designed to grade the strength of evidence for clinical interventions especially pharmacotherapy. However, the infeasibility for conducting large, long-term randomized clinical trials on most dietary, lifestyle, and environmental exposures makes the criteria inappropriate in these areas. A separate research group proposed a modified and validated system for rating the meta-evidence on nutritional studies (NutriGRADE) to address several limitations of the GRADE criteria. Applying NutriGRADE, the evidence on the positive association between red and processed meats and type 2 diabetes was rated to be of "high quality," while the evidence on the association between red and processed meats and mortality was rated to be of "moderate quality." Another important limitation is that inadequate attention was paid to what might be replacing red meat, be it plant-based proteins, refined carbohydrates, or other foods. In summary, the red/processed meat recommendations by NutriRECS suffer from important methodological limitations and involve misinterpretations of nutritional evidence. To improve human and planetary health, dietary guidelines should continue to emphasize dietary patterns low in red and processed meats and high in minimally processed plant foods such as fruits and vegetables, whole grains, nuts, and legumes.


Association between passive jobs and low levels of leisure-time physical activity: the Whitehall II cohort study.
There is mixed evidence on the association between psychosocial work exposures (ie, passive jobs) and physical activity, but previous studies did not take into account the effect of cumulative exposures nor did they examine different trajectories in exposure. We investigated whether exposure to passive jobs, measured three times over an average of 5 years, is associated with leisure-time physical activity (LTPA). Data were from working men (n = 4291) and women (n = 1794) aged 35-55 years who participated in the first three phases of the Whitehall II prospective cohort. Exposure to passive jobs was measured at each phase and LTPA at phases 1 and 3. Participants were categorised according to whether or not they worked in a passive job at each phase, leading to a scale ranging from 0 (non-passive job at all three phases) to 3 (passive job at all three phases). Poisson regression with robust variance estimates were used to assess the prevalence ratios of low LTPA. An association was found in men between exposure to passive jobs over 5 years and low LTPA at follow-up, independently of other relevant risk factors. The prevalence ratio for low LTPA in men was 1.16 (95% CI 1.01 to 1.33) times greater for employees with three reports of passive job than for those who had never worked in passive jobs. No association was observed in women. This study provides evidence that working in passive jobs may encourage a passive lifestyle in men.


Accelerated telomere shortening in response to life stress.
Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets "under the skin" remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.


Impaired phagocytosis of Staphylococcus aureus in complete tetraplegics.
Accumulating evidence implicates the sympathetic nervous system as a modulator of immune function. Immune alteration has been observed in survivors of cervical level spinal cord injury, possibly because of dysregulation of the sympathetic outflow tracts. The majority of immune studies in the spinal cord-injured population have focused on lymphocytes. Because of the high incidence of infections in this population, we hypothesized that the immune alteration would extend to the cells of the myeloid lineage. This hypothesis was tested by analyzing the phagocytic and bactericidal function of circulating neutrophils in response to Staphylococcus aureus. A group of ten individuals with complete cervical spinal cord injury, a group of eight paraplegics with injuries below the majority of sympathetic outflow (T-10 and below), and age- and gender-matched controls for each subject were studied. In addition, a psychiatric screening for depression was completed by all subjects and controls. Paired t test revealed significantly impaired phagocytic ability in the tetraplegic group compared with their controls. The paraplegic group did not demonstrate these findings. Our results suggest that individuals who have sustained complete cervical spinal cord injury have alteration in immune function compared with neurologically intact controls, whereas those with lesions at or below T-10 do not. This in vitro finding may be related to infection after cervical spinal cord injury. The mechanism may involve dysregulation of the sympathetic arm of the autonomic nervous system.


Caffeic Acid Phenethyl Ester Rescues Pulmonary Arterial Hypertension through the Inhibition of AKT/ERK-Dependent PDGF/HIF-1α In Vitro and In Vivo.
Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial proliferation and remodeling, resulting in a specific increase in right ventricle systolic pressure (RVSP) and, ultimately right ventricular failure. Recent studies have demonstrated that caffeic acid phenethyl ester (CAPE) exerts a protective role in NF-κB-mediated inflammatory diseases. However, the effect of CAPE on PAH remains to be elucidated. In this study, monocrotaline (MCT) was used to establish PAH in rats. Two weeks after the induction of PAH by MCT, CAPE was administrated by intraperitoneal injection once a day for two weeks. Pulmonary hemodynamic measurements and pulmonary artery morphological assessments were examined. Our results showed that administration of CAPE significantly suppressed MCT-induced vascular remodeling by decreasing the HIF-1α expression and PDGF-BB production, and improved in vivo RV systolic performance in rats. Furthermore, CAPE inhibits hypoxia- and PDGF-BB-induced HIF-1α expression by decreasing the activation of the AKT/ERK pathway, which results in the inhibition of human pulmonary artery smooth muscle cells (hPASMCs) proliferation and prevention of cells resistant to apoptosis. Overall, our data suggest that HIF-1α is regarded as an alternative target for CAPE in addition to NF-κB, and may represent a promising therapeutic agent for the treatment of PAH diseases.


Neurovisual Assessment in Children with Ataxia Telangiectasia.
Visual impairment is present in almost all patients with ataxia telangiectasia (AT) and, due to their early onset, constitute an important disabling aspect of the syndrome: the quality of vision is limited by dyspraxia and oculomotor abnormal movements. The purpose of this observational study was to describe visual disorders, notably oculomotor impairment, in a sample of children with AT. Fifteen AT patients (mean age 12 years and 4 months) underwent a neurovisual evaluation, particularly focused on oculomotor functions (fixation, smooth pursuit, saccades, and abnormal ocular movements). We compared the visual profile obtained with that described using the International Cooperative Ataxia Rating Scale (ICARS) subscale of oculomotor dysfunction. Refractive errors were seen in eight patients and strabismus in three. Major oculomotor findings were fixation abnormalities (6/15), saccadic impairment (15/15), and abnormal smooth pursuit (14/15). Abnormal ocular movements were seen in 13/15 (saccadic intrusion in 8 and nystagmus in 5). Using ICARS scale, 13/15 children presented gaze-evoked nystagmus, 4/15 a clearly saccadic pursuit, and 11/15 dysmetria of saccades. We propose a clinical neurovisual evaluation, which could be integrated with ICARS scores in the study of oculomotor involvement in AT pediatric patients. We strongly recommend the empowerment of visual functions to slow down progressive global disability of these patients.


Physiological responses of insects to microbial fermentation products: Insights from the interactions between Drosophila and acetic acid.
Acetic acid is a fermentation product of many microorganisms, including some that inhabit the food and guts of Drosophila. Here, we investigated the effect of dietary acetic acid on oviposition and larval performance of Drosophila. At all concentrations tested (0.34-3.4%), acetic acid promoted egg deposition by mated females in no-choice assays; and females preferred to oviposit on diet with acetic acid relative to acetic acid-free diet. However, acetic acid depressed larval performance, particularly extending the development time of both larvae colonized with the bacterium Acetobacter pomorum and axenic (microbe-free) larvae. The larvae may incur an energetic cost associated with dissipating the high acid load on acetic acid-supplemented diets. This effect was compounded by suppressed population growth of A. pomorum on the 3.4% acetic acid diet, such that the gnotobiotic Drosophila on this diet displayed traits characteristic of axenic Drosophila, specifically reduced developmental rate and elevated lipid content. It is concluded that acetic acid is deleterious to larval Drosophila, and hypothesized that acetic acid may function as a reliable cue for females to oviposit in substrates bearing microbial communities that promote larval nutrition.


Requirements for ion and solute transport, and pH regulation during enamel maturation.
Transcellular bicarbonate transport is suspected to be an important pathway used by ameloblasts to regulate extracellular pH and support crystal growth during enamel maturation. Proteins that play a role in amelogenesis include members of the ABC transporters (SLC gene family and CFTR). A number of carbonic anhydrases (CAs) have also been identified. The defined functions of these genes are likely interlinked during enamel mineralization. The purpose of this study is to quantify relative mRNA levels of individual SLC, Cftr, and CAs in enamel cells obtained from secretory and maturation stages on rat incisors. We also present novel data on the enamel phenotypes for two animal models, a mutant porcine (CFTR-ΔF508) and the NBCe1-null mouse. Our data show that two SLCs (AE2 and NBCe1), Cftr, and Car2, Car3, Car6, and Car12 are all significantly up-regulated at the onset of the maturation stage of amelogenesis when compared to the secretory stage. The remaining SLCs and CA gene transcripts showed negligible expression or no significant change in expression from secretory to maturation stages. The enamel of CFTR-ΔF508 adult pigs was hypomineralized and showed abnormal crystal growth. NBCe1-null mice enamel was structurally defective and had a marked decrease in mineral content relative to wild-type. These data demonstrate the importance of many non-matrix proteins to amelogenesis and that the expression levels of multiple genes regulating extracellular pH are modulated during enamel maturation in response to an increased need for pH buffering during hydroxyapatite crystal growth.


The Hospitalist Huddle: a 1-year experience of teaching Hospital Medicine utilizing the concept of peer teaching in medical education.
The relatively new specialty of Hospital Medicine in the USA is one of the fastest growing fields in internal medicine. Academic hospitalists are largely involved in the medical education of postgraduate residents and medical students. Little is known about the effectiveness of peer-to-peer teaching in internal medicine residency training programs and how the medical residents perceive its educational value in learning Hospital Medicine. The Hospitalist Huddle is a weekly educational activity newly established by our Hospitalist Division to facilitate the concept of peer-to-peer teaching. It requires medical residents to teach and educate their peers about the clinical topics related to Hospital Medicine. Faculty hospitalists serve as facilitators during the teaching sessions. A survey disseminated at the end of the first year of its implementation examined the residents' perception of the educational value of this new teaching activity. Most residents reported that they see the Huddle as a useful educational forum which may improve their skills in teaching, create a better educational and learning environment during their inpatient rotation, and improve their understanding of Hospital Medicine. Most residents also prefer that their peers, rather than faculty hospitalists, run the activity and do the teaching. The survey results support the notion that teaching and learning with flat hierarchies can be an appealing educational method to medical residents to help them understand Hospital Medicine during their medical wards rotation. Some areas need to be improved and others need to be continued and emphasized in order to make this novel educational activity grow and flourish in terms of its educational value and residents' satisfaction.


Chemical polyglycosylation and nanolitre detection enables single-molecule recapitulation of bacterial sugar export.
The outermost protective layer of both Gram-positive and Gram-negative bacteria is composed of bacterial capsular polysaccharides. Insights into the interactions between the capsular polysaccharide and its transporter and the mechanism of sugar export would not only increase our understanding of this key process, but would also help in the design of novel therapeutics to block capsular polysaccharide export. Here, we report a nanolitre detection system that makes use of the bilayer interface between two droplets, and we use this system to study single-molecule recapitulation of sugar export. A synthetic strategy of polyglycosylation based on tetrasaccharide monomers enables ready synthetic access to extended fragments of K30 oligosaccharides and polysaccharides. Examination of the interactions between the Escherichia coli sugar transporter Wza and very small amounts of fragments of the K30 capsular polysaccharide substrate reveal the translocation of smaller but not larger fragments. We also observe capture events that occur only on the intracellular side of Wza, which would complement coordinated feeding by adjunct biosynthetic machinery.


Patient Perceptions Correlate Weakly With Observed Patient Involvement in Decision-making in Orthopaedic Surgery.
Shared decision-making between patients and physicians involves educating the patient, providing options, eliciting patient preferences, and reaching agreement on a decision. There are different ways to measure shared decision-making, including patient involvement, but there is no consensus on the best approach. In other fields, there have been varying relationships between patient-perceived involvement and observed patient involvement in shared decision-making. The relationship between observed and patient-perceived patient involvement in decision-making has not been studied in orthopaedic surgery. (1) Does patient-perceived involvement correlate with observed measurements of patient involvement in decision-making in orthopaedic surgery? (2) Are patient demographics associated with perceived and observed measurements of patient involvement in decision-making? We performed a prospective, observational study to compare observed and perceived patient involvement in new patient consultations for eight orthopaedic surgeons in subspecialties including hand/upper extremity, total joint arthroplasty, spine, sports, trauma, foot and ankle, and tumor. We enrolled 117 English-literate patients 18 years or older over an enrollment period of 2 months. A member of the research team assessed observed patient involvement during a consultation with the Observing Patient Involvement in Decision-Making (OPTION) instrument (scaled 1-100 with higher scores representing greater involvement). After the consultation, we asked patients to complete a questionnaire with demographic information including age, sex, race, education, income, marital status, employment status, and injury type. Patients also completed the Perceived Involvement in Care Scale (PICS), which measures patient-perceived involvement (scaled 1-13 with higher scores representing greater involvement). Both instruments are validated in multiple studies in various specialties and the physicians were blinded to the instruments used. We assessed the correlation between observed and patient-perceived involvement as well as tested the association between patient demographics and patient involvement scores. There was weak correlation between observed involvement (OPTION) and patient-perceived involvement (PICS) (r = 0.37, p < 0.01) in decision-making (mean OPTION, 28.7, SD 7.7; mean PICS, 8.43, SD 2.3). We found a low degree of observed patient involvement despite a moderate to high degree of perceived involvement. No patient demographic factor had a significant association with patient involvement. Further work is needed to identify the best method for evaluating patient involvement in decision-making in the setting of discordance between observed and patient-perceived measurements. Knowing whether it is necessary for (1) actual observable patient involvement to occur; or (2) a patient to simply believe they are involved in their care can inform physicians on the best way to improve shared decision-making in their practice. Level II, therapeutic study.


Endovascular Treatment of Cavernous Sinus Dural Arteriovenous Fistula With Ipsilateral Inferior Petrosal Sinus Occlusion: A Single-Center Experience.
Although a transvenous route via the ipsilateral inferior petrosal sinus (IPS) is preferred in treating cavernous sinus dural arteriovenous fistula (CSdAVF), this option may be limited if an occluded ipsilateral IPS undermines microcatheter delivery to the cavernous sinus. To describe our experience with endovascular treatment of CSdAVF complicated by ipsilateral IPS occlusion. From January 2003 through September 2014, a total of 49 CSdAVFs with ipsilateral IPS occlusion were identified in 49 patients, who then underwent endovascular treatment. Clinical and radiologic data were retrospectively reviewed. Either transvenous (n = 38) or transarterial (n = 11) access was initially elected, the latter reserved for single-hole or dominant arterial feeder fistulas. Access via occluded ipsilateral IPS was usually attempted (n = 34) by transvenous approach, with a 54.3% success rate. Anterior (n = 3) or posterior (n = 1) facial vein was alternatively used. Direct surgical exposure of ophthalmic vein (n = 3) or radiosurgery (n = 4) was performed for access failure or unsuccessful occlusion by other means. In 46 fistulas (93.9%), complete occlusion was achieved, with no procedure-related morbidity or mortality. Postprocedural symptom improvement was noted in all but 2 patients, who separately experienced paradoxical worsening of cranial nerve palsy and access failure. In patients with CSdAVF and ipsilateral IPS occlusion, various treatment strategies may be applied (given angioanatomic suitability), resulting in excellent procedural and short-term follow-up results. Reopening of an occluded IPS is reasonable as an initial access attempt.


Risk factors for the development of albuminuria and renal impairment in type 2 diabetes--the Swedish National Diabetes Register (NDR).
The aim of this study was to identify clinical risk factors associated with the development of albuminuria and renal impairment in patients with type 2 diabetes (T2D). In addition, we evaluated if different equations to estimate renal function had an impact on interpretation of data. This was done in a nationwide population-based study using data from the Swedish National Diabetes Register. Three thousand and six hundred sixty-seven patients with T2D aged 30-74 years with no signs of renal dysfunction at baseline (no albuminuria and eGFR >60 mL/min/1.73 m(2) according to MDRD) were followed up for 5 years (2002-2007). Renal outcomes, development of albuminuria and/or renal impairment [eGFR < 60 mL/min/1.73 m(2) by MDRD or eCrCl > 60 mL/min by Cockgroft-Gault (C-G)] were assessed at follow-up. Univariate regression analyses and stepwise regression models were used to identify significant clinical risk factors for renal outcomes. Twenty percent of patients developed albuminuria, and 11% renal impairment; thus, ~6-7% of all patients developed non-albuminuric renal impairment. Development of albuminuria or renal impairment was independently associated with high age (all P < 0.001), high systolic BP (all P < 0.02) and elevated triglycerides (all P < 0.02). Additional independent risk factors for albuminuria were high BMI (P < 0.01), high HbA1c (P < 0.001), smoking (P < 0.001), HDL (P < 0.05) and male sex (P < 0.001), and for renal impairment elevated plasma creatinine at baseline and female sex (both P < 0.001). High BMI was an independent risk factor for renal impairment when defined by MDRD (P < 0.01), but low BMI was when defined by C-G (P < 0.001). Adverse effects of BMI on HbA1c, blood pressure and lipids accounted for ~50% of the increase risk for albuminuria, and for 41% of the increased risk for renal impairment (MDRD). Distinct sets of risk factors were associated with the development of albuminuria and renal impairment consistent with the concept that they are not entirely linked in patients with type 2 diabetes. Obesity and serum triglycerides are semi-novel risk factors for development of renal dysfunction and BMI accounted for a substantial proportion of the increased risk. The equations used to estimate renal function (MDRD vs. C-G) had an impact on interpretation of data, especially with regard to body composition and gender.


Factors associated with subjective quality of life in Korean patients with depressive disorders: the CRESCEND study.
A number of studies suggest that depression is associated with the significant disability and the poorer subjective quality of life (QOL). We aimed to assess subjective QOL in Korean patients with depression and explore the factors (sociodemographic characteristics and clinical features) associated with subjective QOL. We obtained the data from 808 depressive patients who entered the Clinical Research Center for Depression (CRESCEND) study and evaluated the relationship between subjective QOL and personal sociodemographics, and various clinical features, including depressive severity, and subjective QOL. We assessed subjective QOL using the 26-item abbreviated version of the World Health Organization Quality of Life (WHOQOL-BREF) instrument. Decrements in patients' physical health, psychological health, social relationships, and environment domains of subjective QOL were all strongly associated with the greater depressive symptom severity. After controlling for age and depressive symptom severity, the lower subjective QOL was independently related to being divorced or separated, the less monthly household income, and having no religious practices. Our results suggest the importance of sociodemographic characteristics in addition to symptoms for the understanding of subjective QOL in depressed patients. The prospective studies to compare the different treatments' effects on various subjective QOL domains are needed.


Surgery after drug-eluting stent implantation: it's not all doom and gloom!
Up to 15-23% of the patients with percutaneous coronary intervention (PCI) and drug-eluting stent (DES) implantation need a surgical procedure <12 months from PCI. Perioperative risk stratification in these patients is challenging and should take into account many individual clinical and anatomic variables, along with the intrinsic surgical risk for ischemic and bleeding events. The presence of DES has always been considered as a harbinger of doom. In fact, DES are associated with delayed vascular healing and require longer dual antiplatelet treatment. Perioperative pharmacologic management in those patients is intricate because of the tradeoff between the increased thrombotic risk associated with premature DAPT discontinuation and the increased risk of bleeding in the presence of antithrombotics. Whilst most of the studies agree upon the inverse relationship between time from stenting to surgery and cardiac risk, more recent data challenge the previous belief that surgery should be deferred at least 12 months after DES implantation and this safety window could be shortened to <6 months or even less with new-generation DES. The aim of this brief commentary is to critically review available data about cardiac risk associated with surgery in patients with coronary drug-eluting stents.


Nonparaxial propagation of Lorentz-Gauss beams in uniaxial crystal orthogonal to the optical axis.
Analytical expressions for the three components of nonparaxial propagation of a polarized Lorentz-Gauss beam in uniaxial crystal orthogonal to the optical axis are derived and used to investigate its propagation properties in uniaxial crystal. The influences of the initial beam parameters and the parameters of the uniaxial crystal on the evolution of the beam-intensity distribution in the uniaxial crystal are examined in detail. Results show that the statistical properties of a nonparaxial Lorentz-Gauss beam in a uniaxial crystal orthogonal to the optical axis are closely determined by the initial beam's parameters and the parameters of the crystal: the beam waist sizes-w(0), w(0x), and w(0y)-not only affect the size and shape of the beam profile in uniaxial crystal but also determine the nonparaxial effect of a Lorentz-Gauss beam; the beam profile of a Lorentz-Gauss beam in uniaxial crystal is elongated in the x or y direction, which is determined by the ratio of the extraordinary refractive index to the ordinary refractive index; with increasing deviation of the ratio from unity, the extension of the beam profile augments. The results indicate that uniaxial crystal provides an effective and convenient method for modulating the Lorentz-Gauss beams. Our results may be valuable in some fields, such as optical trapping and nonlinear optics, where a light beam with a special profile and polarization is required.


Thrombospondin and other possible related matrix proteins in malignant and benign breast disease. An immunohistochemical study.
Thrombospondin (TSP), which plays an important hemostatic role, is a 450-kd cytoadhesive protein present in the alpha granules of platelets. In vitro experiments using cultured malignant cells suggest that it may help to mediate malignant cell attachment to extracellular matrix and may be important in cancer invasiveness. The authors studied a group of malignant and benign breast tissues for the expression of TSP and provide evidence that TSP may have a role in tumor invasiveness. Using immunohistochemical techniques, the authors found in 48 fresh specimens of breast carcinoma that TSP stained strongly in the desmoplastic stroma or at the basement membrane associated with the malignant ductal epithelium. Tumor cells abutting these tissues revealed cytoplasmic staining for TSP. Stronger TSP staining was seen in the poorly differentiated tumors. These findings were compared with those of normal and benign breast tissue, which showed no TSP staining apart from reactivity in the large distended cysts of fibrocystic disease and faint staining in the stroma of fibroadenomas. Staining for integrin was positive in lymphocytes of both malignant and benign breast disease and equivocally also in the stromal cells of the breast cancer tissue. Immunoreactivity to TSP in tissues was also compared with that of fibronectin, laminin, and collagen type I, III, and IV. The overall findings suggest that thrombospondin may have a role in the tumor biology of invasiveness.