Evidence that Cd101 is an autoimmune diabetes gene in nonobese diabetic mice.
We have previously proposed that sequence variation of the CD101 gene between NOD and C57BL/6 mice accounts for the protection from type 1 diabetes (T1D) provided by the insulin-dependent diabetes susceptibility region 10 (Idd10), a <1 Mb region on mouse chromosome 3. In this study, we provide further support for the hypothesis that Cd101 is Idd10 using haplotype and expression analyses of novel Idd10 congenic strains coupled to the development of a CD101 knockout mouse. Susceptibility to T1D was correlated with genotype-dependent CD101 expression on multiple cell subsets, including Foxp3(+) regulatory CD4(+) T cells, CD11c(+) dendritic cells, and Gr1(+) myeloid cells. The correlation of CD101 expression on immune cells from four independent Idd10 haplotypes with the development of T1D supports the identity of Cd101 as Idd10. Because CD101 has been associated with regulatory T and Ag presentation cell functions, our results provide a further link between immune regulation and susceptibility to T1D.


Evaluation of patients' expectations and benefits in the treatment of allergic rhinitis with a new tool: the patient benefit index - the benefica study.
Symptoms of allergic rhinitis (AR) have a detrimental effect on quality of life. The AR-Patient Benefit Index (AR-PBI), a specific self-assessment tool has been developed to assess treatment-related benefit in two separate sections: the Patient Needs Questionnaire (PNQ) which explores the patient's expectations before treatment and the Patient Benefit Questionnaire (PBQ) which evaluates treatment benefit. For the PNQ, three dimensions summarize patients' expectations: symptoms, social life and emotional state, thus covering a larger field than symptomatic relief. The aim of the study was to validate the French language version of the AR-PBI and to assess the treatment-related expectations and benefits provided in patients with allergic rhinitis treated with H1-antihistamines in a real-life study. BENEFICA was a prospective, observational study involving patients with allergic rhinitis who were starting treatment with H1-antihistamines. The Patient Needs Questionnaire (PNQ) was administered before treatment (D0) and the Patient Benefit Questionnaire (PBQ) was collected after a 14-day course of H1-antihistamines (D15). Discomfort (visual analog scale), and quality of life (miniRQLQ) were measured on D0 and D15. Three thousands and eighty-nine patients were enrolled in the study: mean age 39 ± 14 years, women 52%, 81% of patients with moderate to severe persistent rhinitis (Allergic Rhinitis and its Impact on Asthma, ARIA); 19% had (a) concomitant condition(s), 18% were asthmatic, and 12% had atopic dermatitis. Discomfort and quality of life improved between D0 and D15. AR-PBI was 2.7 ± 0.8, superior to 1 (threshold for clinically relevant benefit) for 97% of patients and greater in patients willing to continue the treatment. PBI was moderately correlated to change in miniRQLQ (r = -0.45, p < 0.0001) and change in discomfort (r = -0.38, p < 0.0001), suggesting a richer conceptual content than symptoms relief. The French version of the Allergic Rhinitis-Patient Benefit Index (AR-PBI) has been validated. It complements the discomfort and quality of life tools and assesses the needs and benefits in patients suffering from allergic rhinitis. This new tool may help physicians to better understand patients' expectations and to discuss treatment issues with their patients.


Reported contraceptive use in the month of becoming pregnant among U.S. abortion patients in 2000 and 2014.
The objective was to determine whether types of contraceptive methods used by abortion patients in the month they became pregnant changed between 2000 and 2014. We used secondary data from the 2000 (n=10,015) and 2014 (8177) Abortion Patient Surveys. Patients were asked which contraceptive methods they had last used and when they had stopped or if they were still using them. The main outcome variable was type of contraceptive method used in the month the pregnancy began. We used bivariate logistic regressions to assess changes in the demographic and contraceptive use profiles of abortion patients. In both years, slightly more than half of patients reported that they had used a contraceptive method in the month they became pregnant, though the decline from 54% in 2000 to 51% in 2014 was statistically significant (p=.011). The methods most commonly reported to have been used in the month the pregnancy began were condoms (28% and 24% in 2000 and 2014, p<.001) followed by the pill (14% and 13%, p=.12). There was a statistically significant increase in the proportion of abortion patients who reported using long-acting reversible methods in the month they got pregnant (0.1% in 2000 vs. 1% in 2014, p<.001), and the estimated number of abortions attributed to these users was greater in 2014 than in 2000 (9500 vs. 1800). Contraceptive use patterns of abortion patients were similar in both time periods, and changes in method use mirrored changes in contraceptive use among the larger population of women. Postabortion contraception counseling has the potential to help nonusers find methods that meet their preferences and to help women better use their current methods.


Uncoupled protein 3 and p38 signal pathways are involved in anti-obesity activity of Solanum tuberosum L. cv. Bora Valley.
This study was undertaken to elucidate the anti-obesity mechanism of a new purple potato variety that has been used for the prevention of metabolic diseases as a folk remedy in Korea. Proliferation assay, differentiation assay, Western blotting, were performed in 3T3-L1 adipocytes, while blood chemistry for hyperlipidemic parameters, measurement of body weight and abdominal fats, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, magnetic resonance image (MRI) scanning were carried out in high fat diet fed Sprague-Dawley rats with ethanol extract of Solanum tuberosum L. cv. Bora Valley (ESTBV). ESTBV significantly inhibited the proliferation and differentiation of 3T3-L1 cells as well as reduced the cellular leptin level. ESTBV also significantly attenuated the levels of insulin and leptin at 500mg/kg in high fat diet fed rats. In addition, ESTBV significantly reduced total fat and whole body lipid in a therapeutic experiment, which was confirmed by MRI scanning and also significantly inhibited the retroperitoneal and epididymal fats in a preventive experiment compared with control. Similarly, the levels of total cholesterol, triglyceride and low density lipoprotein (LDL) were significantly reduced at a lower dose 200mg/kg of ESTBV in a preventive experiment than at 500mg/kg in a therapeutic experiment. Furthermore, body weight gain was significantly suppressed by over 4 weeks treatment of ESTBV compared with control. Interestingly, the expression of p38 mitogen-activated protein kinase (MAPK) was significantly downregulated in 3T3-L1 cells by ESTBV and the expression of uncoupled protein 3 (UCP-3) was activated in fats and liver tissues of ESTBV treated group compared with high fat diet control. ESTBV has anti-obesity potential via inhibition of lipid metabolism through p38 MAPK and UCP-3 pathways.


High-precision detection method for the reference position in an optical encoder.
A new detection method for the reference position (zero position) of an optical encoder by using a diffraction grating with variable pitch is proposed. Movement of the diffraction grating changes the position of the grating relative to the radiating laser spot, altering the grating pitch that is illuminated by the laser and causing a change in the diffraction angle of the beam. The change is detected by two photodiodes. Our experiment shows that the method can provide highly accurate detection of the reference point in the submicrometer range.


The proteome of central and peripheral retina with progression of age-related macular degeneration.
A growing understanding of the molecular events in age-related macular degeneration (AMD) has lead to targeted therapies for a select group of patients with advanced AMD. Development of therapies for the earlier stages requires further elucidation of disease mechanisms. In this study, a proteomics approach was used to identify proteins that had altered content in human donor eyes with progression of AMD. The early molecular events associated with AMD were identified by comparing the proteome of the macular and peripheral neurosensory retina during four progressive stages of AMD. Proteins were resolved and quantified by two-dimensional gel electrophoresis. Twenty-six proteins exhibited changes in content and were identified by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. Two-dimensional (2-D) and semiquantitative one-dimensional (1-D) Western blot analyses were used to determine whether changes identified by proteomic analysis were specific for a protein subpopulation or representative of the entire protein population. Twenty-six proteins were identified that exhibited changes at disease onset or with progression (indicating potential causal mechanisms) and at end-stage disease (indicating potential secondary consequences). These proteins are involved in key functional pathways, such as microtubule regulation and protection from stress-induced protein unfolding. Approximately 60% of the proteins exhibited changes specific to either the macula or periphery, with the remaining 40% changing in both regions. These results imply that both the macula and periphery are affected by AMD. This study provides the first direct evidence of AMD stage- and region-specific changes in retinal protein levels and highlights potential novel, disease-related proteins and biochemical pathways for future studies of AMD.


MicroRNA expression in the human blastocyst.
To determine the most highly expressed microRNAs (miRNAs) in human blastocysts and to compare miRNAs in euploid versus aneuploid embryos and in male versus female embryos. Experimental study of human embryos: 14 blastocysts (four male, five female, and five aneuploid) were evaluated for miRNA expression with the use of an array-based quantitative real-time polymerase chain reaction (qPCR). Highly expressed and differentially expressed miRNAs were confirmed with the use of qPCR in an expanded set of 27 blastocysts (seven male, eleven female, and nine aneuploid). Academic IVF program. Thirteen couples donated 91 cryopreserved embryos for this study. None. Relative miRNA expression in individual blastocysts. The most highly expressed miRNA in euploid embryos was miR-372. Many of the highly expressed miRNAs have been shown to be critical to mammalian embryo development and to maintenance of stem cell pluripotency. Several differentially expressed miRNAs were discovered based on chromosomal makeup, including sex of the embryo. Human blastocysts express miRNAs, which may be important to their survival. Differential miRNA expression based on sex implies some degree of differentiation at the blastocyst stage of development. Differential miRNA expression between euploid and aneuploid embryos may be an early indicator of their prognosis or a mechanism behind their eventual fate.


Inspirations from biological optics for advanced photonic systems.
Observing systems in nature has inspired humans to create technological tools that allow us to better understand and imitate biology. Biomimetics, in particular, owes much of its current development to advances in materials science and creative optical system designs. New investigational tools, such as those for microscopic imaging and chemical analyses, have added to our understanding of biological optics. Biologically inspired optical science has become the emerging topic among researchers and scientists. This is in part due to the availability of polymers with customizable optical properties and the ability to rapidly fabricate complex designs using soft lithography and three-dimensional microscale processing techniques.


The microglial-motoneuron dialogue in ALS.
Neuroinflammation is a pathological hallmark of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), and is characterized by activated microglia at sites of neuronal injury. In ALS, neurons do not die alone; neuronal injury is noncell-autonomous and depends upon a well-orchestrated dialogue between motor neurons and microglia. Evidence from transgenic models expressing mutant superoxide dismutase 1 (SOD) suggests that the dialogue between motor neurons and microglia initially protects motor neurons. However, with increasing stress and injury within motor neurons, induced by the presence of misfolded proteins such as mSOD1, mitochondrial function and axoplasmic flow are impaired and endoplasmic reticulum stress is induced; misfolded proteins themselves or alternate signals are released from motor neurons and activate microglia. Activated microglia, in turn, switch from anti-inflammatory and neuroprotective to proinflammatory and neurotoxic. Neurotoxic signaling from motor neurons promotes microglial release of reactive oxygen species and pro-inflammatory cytokines further enhancing motor neuron stress and cell injury and initiating a self-propagating cycle of motor neuron injury and cell death. A greater understanding of how to restore the imbalance between neuroprotection and cytotoxicity will depend upon a greater understanding of the motor neuron-microglial dialogue.


Novel case of anti-synthetase syndrome.
Anti-synthetase syndrome (AS) is a heterogeneous group of systemic autoimmune diseases associated with anti-aminoacyl-transfer RNA synthetases. These inflammatory myopathies present with a constellation of symptoms including myositis, arthritis, Raynaud's phenomenon, and interstitial lung disease (ILD). We present a novel case of a 44-year-old female, who presented with Anti-OJ AS with severe myopathy and rhabdomyolysis without evidence of ILD, which, in our literature review and to the best of our knowledge, has not been previously reported. Furthermore, our patient was initially misdiagnosed, highlighting the paucity of cases and physicians' unfamiliarity with this disease. After her diagnosis was confirmed, the patient was successfully treated with high-dose steroids and transitioned to azathioprine, and she continues to do well. This case report emphasizes a novel presentation of the rarely diagnosed AS. We also discuss the significant overlap between the inflammatory myopathies and consolidate relevant pathophysiology and current trends in the management of this disease.


Epigenetic signatures of gestational diabetes mellitus on cord blood methylation.
Intrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these elevated disease susceptibilities. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies. Using Illumina's 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 associated with genes) displayed significant methylation differences between GDM and control samples. Four candidate genes, ATP5A1, MFAP4, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The effects remained significant after adjustment for the confounding factors maternal BMI, gestational week, and fetal sex in a multivariate regression model. In general, GDM effects on FCB methylation were more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM. Our study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis, prognosis, and treatment of adverse prenatal exposures.


Quantum optimal control of multiple weakly interacting molecular rotors in the time-dependent Hartree approximation.
We perform quantum optimal control simulations, based on the Time-Dependent Hartree (TDH) approximation, for systems of three to five dipole-dipole coupled OCS rotors. A control electric field is used to steer all of the individual rotors, arranged in chains and regular polygons in a plane, toward either identical or unique objectives. The goal is to explore the utility of the TDH approximation to model the field-induced dynamics of multiple interacting rotors in the weak dipole-dipole coupling regime. A stochastic hill climbing approach is employed to seek an optimal control field that achieves the desired objectives at a specified target time. We first show that multiple rotors in chain and polygon geometries can be identically oriented in the same direction; these cases do not significantly depend on the presence of the dipole-dipole interaction. Additionally, in particular geometrical arrangements, we demonstrate that individual rotors can be uniquely manipulated toward different objectives with the same field. Specifically, it is shown that for a three rotor chain, the two end rotors can be identically oriented in a specific direction while keeping the middle rotor in its ground state, and for an equilateral triangle, two rotors can be identically oriented in a specific direction while the third rotor is oriented in the opposite direction. These multirotor unique objective cases exploit the shape of the field in coordination with dipole-dipole coupling between the rotors. Comparisons to numerically exact calculations, utilizing the TDH-determined fields, are given for all optimal control studies involving systems of three rotors.


Quality of life and associated characteristics in a large national sample of adults with diabetes.
This study investigated the quality of life and the demographic, medical-history, and self-management characteristics associated with it. A diabetes self-management survey was sent to 2,800 adults with diabetes throughout the U.S. who were part of a marketing company national sample. The response rate was 73%. The final sample of 2,056 persons was heterogeneous: the average age was 59 years (range, 18-92 years); 53% had high school education or less; 86% had type II diabetes; 62% were female; and 31% reported being on an intensive management plan, such as the one used in the Diabetes Control and Complications Trial. Quality-of-life items included the social, physical, and mental health dimensions of the Short Form (SF-20) of the General Health Survey. Overall, respondents reported a moderate to low quality of life, relative to previous studies. Factors related to lower quality of life included: less education, lower income, older age, being female, type of health insurance (no medical insurance or Medicare/Medicaid recipients reported lower quality of life than those with either a health maintenance organization or private insurance), number of diabetes complications, number of comorbid illnesses, and lower levels of physical activity. Multiple regression analyses revealed that the level of self-reported exercise was the only significant self-management behavior to predict the quality of life, after controlling for demographic and medical variables. If the findings regarding physical activity are replicated, it may be that moderate-intensity physical activity programs could be initiated with diabetic individuals at risk of low quality of life. Quality of life is an important and understudied topic in diabetes that appears to be related to demographic, medical-history, and self-management factors.


Increased calcium influx in a monocytic cell line on exposure to ultrafine carbon black.
Ultrafine particles have been shown to induce pro-inflammatory effects both in vivo and in vitro. Increased expression of pro-inflammatory genes probably requires the activation of specific transcription factors such as nuclear factor kappa B (NF-kappaB) via a number of possible pathways including Ca2+ and reactive oxygen species. The fluorescent dye fura 2, was used to measure cytosolic Ca2+ in the human monocytic cell line, Monomac 6 on exposure to 66 microg x mL(-1) of either ultrafine carbon black (ufCB; diameter 14 nm), carbon black (CB; diameter 260 nm), quartz (diameter 1.45 microm), or medium alone. UfCB but not fine CB induced a 1.6-fold increase (p<0.01) in the resting cytosolic Ca2+ concentration of Monomac 6 cells. In addition ufCB induced a 2.6-fold increase (p<0.001) in the response to the endoplasmic reticulum Ca2+- adenosine triphosphatase (ATPase) inhibitor, thapsigargin, suggesting the Ca2+ release-activated Ca2+ current across the plasma membrane was enhanced. This response was inhibited by the removal of extracellular Ca2+ and by the Ca2+ channel blocker, verapamil. In addition, ufCB stimulated the entry of extracellular Mn2+. Finally, the antioxidants mannitol and nacystelin both inhibited the effects of ufCB on the response to thapsigargin. These data suggest that ultrafine carbon black particles stimulated an increase in cytosolic Ca2+, possibly through the entry of extracellular Ca2+ via Ca2+ channels in the plasma membrane. The particles may in part activate the opening of Ca2+ channels via a mechanism involving reactive oxygen species.


TESTING HIGH-DIMENSIONAL COVARIANCE MATRICES, WITH APPLICATION TO DETECTING SCHIZOPHRENIA RISK GENES.
Scientists routinely compare gene expression levels in cases versus controls in part to determine genes associated with a disease. Similarly, detecting case-control differences in co-expression among genes can be critical to understanding complex human diseases; however statistical methods have been limited by the high dimensional nature of this problem. In this paper, we construct a sparse-Leading-Eigenvalue-Driven (sLED) test for comparing two high-dimensional covariance matrices. By focusing on the spectrum of the differential matrix, sLED provides a novel perspective that accommodates what we assume to be common, namely sparse and weak signals in gene expression data, and it is closely related with Sparse Principal Component Analysis. We prove that sLED achieves full power asymptotically under mild assumptions, and simulation studies verify that it outperforms other existing procedures under many biologically plausible scenarios. Applying sLED to the largest gene-expression dataset obtained from post-mortem brain tissue from Schizophrenia patients and controls, we provide a novel list of genes implicated in Schizophrenia and reveal intriguing patterns in gene co-expression change for Schizophrenia subjects. We also illustrate that sLED can be generalized to compare other gene-gene "relationship" matrices that are of practical interest, such as the weighted adjacency matrices.


Hospital admissions before and after shipyard closure.
"To determine the effect of job loss on health an investigation was made of admissions to hospitals in 887 men five years before and three years after the closure of a Danish shipyard. The control group comprised 441 men from another shipyard. The information on hospital admissions was obtained from the Danish national register of patients. The relative risk of admission in the control group dropped significantly in terms of the number of men admitted from the study group from 1.29 four to five years before closure to 0.74 in the three years after closure. This was especially true of admissions due to accidents (1.33 to 0.46) and diseases of the digestive system (4.53 to 1.03). For diseases of the circulatory system, particularly cardiovascular diseases, the relative risk increased from 0.8 to 1.60, and from 1.0 to 2.6 respectively. These changes in risk of illness after redundancy are probably a consequence of a change from the effects of a high risk work environment to the effects of psychosocial stresses such as job insecurity and unemployment."


Negative emotionality and discipline as long-term predictors of behavioral outcomes in African American and European American children.
The present study examined the early parenting and temperament determinants of children's antisocial and positive behaviors in a low-income, diverse ethno-racial sample. Participants were from the Early Head Start Research and Evaluation Project, which included 960 European American (initial M age = 15.00 months; 51.2% female) and 880 African American mothers and their children (initial M age = 15.10 months; 49.2% female) followed from 15 months of age to 5th grade. For European American children, findings showed direct and indirect effects (via self-regulation) of early negative emotionality on later behaviors. For African American children, discipline practices in infancy had direct long-term implications for behaviors in 5th grade. Discussion highlights the interplay of parenting, temperament, and culture from infancy to late childhood. (PsycINFO Database Record


Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface.
Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free-swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic ΔcagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and ΔcagA mutants colonized iron-replete gerbils at similar levels, ΔcagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche.


Intuitive Judgments in Depression and the Role of Processing Fluency and Positive Valence: A Preregistered Replication Study.
Recent preliminary evidence indicates that depression is associated with impaired intuitive information processing. The current study aimed at replicating these findings and to move one step further by exploring whether factors known as triggering intuition (positivity, processing fluency) also affect intuition in patients with depression. We pre-registered and tested five hypotheses using data from 35 patients with depression and 35 healthy controls who performed three versions of the Judgment of Semantic Coherence Task (JSCT, Bowers et al., 1990). This task operationalizes intuition as the inexplicable and sudden detection of semantic coherence. Results revealed that depressed patients and healthy controls did not differ in their general intuitive performance (Hypothesis 1). We further found that fluency did not significantly affect depressed patients' coherence judgments (H2a) and that the assumed effect of fluency on coherence judgments was not moderated by depression (H2b). Finally, we found that triads positive in valence were more likely to be judged as coherent as compared to negative word triads in the depressed sample (H3a), but this influence of positive (vs. negative) valence on coherence judgments did not significantly differ between the two groups (H3b). Overall the current study did not replicate findings from previous research regarding intuitive semantic coherence detection deficits in depression. However, our findings suggest that enhancing positivity in depressed patients may facilitate their ability to see meaning in their environment and to take intuitive decision.


Olive leaf extract counteracts cell proliferation and cyst growth in an in vitro model of autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts, leading to chronic kidney disease. Since the available treatment for ADPKD is limited, there is emerging interest for natural compounds as potential therapeutic candidates. The aim of our study was to investigate whether an olive leaf extract may be able to counteract the cyst growth in an in vitro model of ADPKD. We treated WT9-12 cells with an olive leaf extract (OLE). In monolayer culture we evaluated cell viability by the MTT assay, protein expression by western-blot analysis and apoptosis by DNA laddering and TUNEL assays. For functional studies we used transient transfection and ChIP assays. Intracellular calcium measurement was performed with a spectrofluorimeter using a fluorescent probe. 3D-cell-culture was used for cyst growth studies. OLE reduced the WT9-12 cell growth rate and affected intracellular signaling due to high c-AMP levels, as OLE reduced PKA levels, enhanced p-AKT, restored B-Raf-inactivation and down-regulated p-ERK. We elucidated the molecular mechanism by which OLE, via Sp1, transactivates the p21WAF1/Cip1 promoter, whose levels are down-regulated by mutated PKD1. We demonstrated that p-AKT up-regulation also played a crucial role in the OLE-induced anti-apoptotic effect and that OLE ameliorated intracellular calcium levels, the primary cause of ADPKD. Finally, using a 3D-cell-culture model we observed that OLE reduced the cyst size. Therefore, multifaceted OLE may be considered a new therapeutic approach for ADPKD treatment.


Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle Glaucoma.
To evaluate the safety, tolerability, and intraocular pressure (IOP)-lowering effect of Latrunculin-B (Lat-B), a marine macrolide that disrupts the actin cytoskeleton, in patients with ocular hypertension (OHT) or early primary open-angle glaucoma (POAG). In this Phase I, multicenter, double-masked, randomized, placebo-controlled, ascending-dose study, subjects with bilateral OHT or early POAG (>22 mm Hg) received one of four concentrations of INS115644 (Lat-B ophthalmic solutions, 0.005%, 0.01%, 0.02%, or 0.05%) in one eye over 3 days (5 single-dose instillations, separated by 12 hours). One eye was randomly assigned to active drug, the other to placebo. IOP was measured prior to treatment initiation (day 0) and on days 1 and 3. Baseline IOPs were 22.9 ± 2.4 mm Hg and 23.5 + 3.1 mm Hg in the 0.02% and 0.05% dose groups, respectively. At 4 hours post instillation of the first dose, 0.02% INS115644 reduced IOP from baseline (mean ± SE) by 3.8 ± 0.7 mm Hg (P = 0.002) and 0.05% by 3.9 ± 1.0 mm Hg (P = 0.004). A maximum IOP decrease of 24% was noted at 4 hours after the fifth instillation of 0.02%. Adjusting for diurnal baseline and IOP in the contralateral, placebo-treated eye, the maximal 12-hour hypotensive effect was 4.0 ± 0.5 mm Hg (adjusted mean ± SE), a 17% decrease, following the fifth instillation of 0.02% (day 3). Adverse events were few and consisted mainly of mild redness, irritation, and a transient, clinically insignificant increase (≤2.5%) in central corneal thickness. In OHT or POAG patients, twice daily Lat-B significantly lowered IOP compared with contralateral, placebo-treated eyes, with few and mild ocular adverse events. Lat-B may be a potential therapeutic agent for glaucoma.


Intentional and unintentional nonadherence to antihypertensive medication.
Hypertension is poorly controlled in the US due to medication nonadherence. Recent evidence suggests that nonadherence can be classified as intentional or unintentional and different patient characteristics, such as the experience of adverse effects, may be associated with each. To examine associations between patient characteristics, including reported adverse effects, and both intentional and unintentional nonadherence among 588 hypertensive patients. Baseline data from a clinical trial, the Veterans' Study To Improve the Control of Hypertension, were examined. Intentional and unintentional nonadherence were assessed using a self-report measure. Participants were presented with a list of adverse effects commonly associated with antihypertensive medication and asked to indicate which symptoms they had experienced. Logistic regression analyses were used to examine adjusted associations between patient characteristics and type of nonadherence. Approximately 31% of patients reported unintentional nonadherence and 9% reported intentional nonadherence. Non-white participants, individuals without diabetes mellitus, and individuals reporting > or = 5 adverse effects were more likely to report intentional nonadherence than their counterparts. Individuals with less than a 10th-grade education and non-white participants were more likely to report unintentional nonadherence than their counterparts. When symptoms of increased urination and wheezing/shortness of breath were reported, patients were more likely to report intentional and unintentional nonadherence compared with those who were adherent. Unintentional nonadherence was also associated with reports of dizziness and rapid pulse. Both intentional and unintentional nonadherence are common and related to perceived adverse effects. Furthermore, different interventions may be necessary to improve adherence in unintentionally and intentionally nonadherent patients.


Curcumin inhibits tumor growth and angiogenesis in glioblastoma xenografts.
Among the natural products shown to possess chemopreventive and anticancer properties, curcumin is one of the most potent. In the current study, we investigated the effects of this natural product on the growth of human glioma U-87 cells xenografted into athymic mice. We show here that curcumin administration exerted significant anti-tumor effects on subcutaneous and intracerebral gliomas as demonstrated by the slower tumor growth rate and the increase of animal survival time. While investigating the mechanism of its action in vivo, we observed that curcumin decreased the gelatinolytic activities of matrix metalloproteinase-9. Furthermore, treatment with curcumin inhibited glioma-induced angiogenesis as indicated by the decrease of endothelial cell marker from newly formed vessels and by the diminution of the concentration of hemoglobin in curcumin-treated tumors. We also demonstrate, using an in vitro model of blood-brain barrier, that curcumin can cross the blood-brain barrier to a high level. These are the first results showing that curcumin suppresses tumor growth of gliomas in xenograft models. The mechanisms of the anti-tumor effects of curcumin were related, at least partly, to the inhibition of glioma-induced angiogenesis.


Aortic walls in atherosclerotic rabbits--mechanical study.
Mechanical properties of the descending thoracic aortae harvested from endothelial cell-denuded and/or cholesterol diet-fed rabbits were studied primarily with their pressure-diameter relationships. Male Japanese white rabbits having 3.1 to 3.5 kg initial body weight were divided into 4 groups. The rabbits in Groups A and C were fed a regular chow, while those in Groups B and D were given 1 percent cholesterol diet; the luminal surfaces of the descending thoracic aortae in the rabbits of Groups C and D were injured by drawing catheter-tip balloons. These animals were sacrificed after keeping for 4, 8, 16 or 32 weeks and, then, their descending thoracic aortae were excised for the studies of pressure-diameter relationships. Stiffness parameter (beta") and incremental elastic modulus (H theta theta were used to quantitatively represent the structural stiffness of the aortic wall and the elastic modulus of the wall material, respectively. Denudation of endothelial cells thickened the aortic walls in Group C, but induced no significant changes in beta" and H theta theta. Shape of the pressure-diameter curve changed gradually with time in Group D, and beta", H theta theta, and thickness to wall radius ratio increased significantly, while those in Group B showed no significant changes with a few exceptions. Averaged percent fraction of the luminal surface area stained with Sudan IV (As) was around 50 percent in Group B and 100 percent in Group D at 32 weeks. Even if As is over 80 percent in Group D, 50 percent (7/14) of the walls gave significantly higher beta"- and H theta theta-values at 100 mm Hg than the others. Significantly increased calcification and intimal hyperplasia were observed in the walls with high beta"- and H theta theta-values.


A 2 × 2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning: efficacy in a preclinical trial in murine thromboembolic stroke model.
After the failure of so many drugs and therapies for acute ischemic stroke, innovative approaches are needed to develop new treatments. One promising strategy is to test combinations of agents in the pre-hospital setting prior to the administration of intravenous tissue plasminogen activator (IV-tPA) and/ or the use of mechanical reperfusion devices in the hospital. We performed a 2 × 2 factorial design preclinical trial where we tested minocycline (MINO), remote ischemic perconditioning (RIPerC) and their combination treatment in a thromboembolic clot model of stroke in mice, without IV-tPA or later treated with IV-tPA at 4 hours post-stroke. Cerebral blood flow (CBF) was measured by laser speckle contrast imaging (LSCI), behavioral outcomes as neurological deficit score (NDS) and adhesive tape removal test, and infarct size measurement were performed at 48 hours post-stroke. Mice within the experimental sets were randomized for the different treatments, and all outcome measures were blinded. RIPerC significantly improved CBF as measured by LSCI in both with and without tPA treated mice (P < 0.001). MINO and RIPerC treatment were effective alone at reducing infarct size (p < 0.0001) and improving short-term functional outcomes (p < 0.001) in the tPA and non-tPA treated animals. The combination treatment of MINO and RIPerC significantly reduced the infarct size greater than either intervention alone (p < 0.05). There were trends in favor of improving functional outcomes after combination treatment of MINO and RIPerC; however combination treatment group was not significantly different than the individual treatments of MINO and RIPerC. There was no "statistical" interaction between minocycline and RIPerC treatments indicating that the effects of RIPerC and MINO were additive and not synergistic on the outcome measures. In the future, combining these two safe and low cost interventions in the ambulance has the potential to "freeze" the penumbra and improve outcomes in stroke patients. This pre-clinical 2 × 2 design can be easily translated into a pre-hospital clinical trial.


Diagnostic cerebral angiography affects the tonus of the major cerebral arteries.
Vascular reactions after cerebral angiography have not been hitherto extensively explored due to the lack of a simple, easily available, and safe method for the measurement of cerebral circulation. We attempted to study cerebral circulation with color Doppler transcranial sonography (TCCS) in consecutive patients before and immediately after digital subtraction angiography (DSA). TCCS examination of the major cerebral arteries was carried out in 52 patients (25 females and 27 males), mean age 50.3+/-11.5 years, before and 10-20 minutes after cerebral angiography. A Toshiba Aplio SSA 770A system with a 2.5-MHz sector transducer was used. In general terms, there was a tendency after DSA towards a slight decrease in peak systolic blood velocity and an increase in mean and end-diastolic velocity in all the major cerebral arteries which, in turn, led to a decrease in the impedance index (pulsatility index, PI). In 19 patients, the impedance index as measured in the middle cerebral artery decreased after DSA, in 29 it did not change, while in 4 patients PI increased. Discriminant analysis showed that the factors predisposing individuals to these adverse reactions were a low score on the Glasgow Coma Scale, etiological diagnosis of intracerebral bleeding, and a high value of the impedance index prior to the procedure. Contrast cerebral angiography may affect the tonus of cerebral vessels. In the majority of patients it caused vasodilatation to varying degrees and in a small sub-group vasoconstriction.


First Report of Powdery Mildew Caused by Oidium Subgenus Pseudoidium on Lonicera caprifolium in Italy.
Honeysuckle (Lonicera caprifolium L., family Caprifoliaceae) is a climbing shrub used in gardens to cover walls and supports. During the summer of 2003, severe outbreaks of a previously unknown powdery mildew were observed on this species in some gardens near Biella (northern Italy). The first symptoms included extensive chlorosis on leaves, followed by the appearance of white mycelium on the adaxial and abaxial leaf surfaces. As the disease progressed, infected leaves turned yellow and died. Conidia were hyaline, ellipsoidal, and measured 27.6 to 43.2 × 12.2 to 21.6 μm (average 35.7 × 17.6 μm). Foot cells were cylindric and appressoria lobed. Fibrosin bodies were not present. Cleistothecia were not observed during the growing season. The pathogen was identified as Oidium subgenus Pseudoidium (2). The inoculation procedure involved gently pressing diseased leaves onto leaves of healthy L. caprifolium plants. Three plants of L. caprifolium were used as replicates. Noninoculated plants served as control. Inoculated and noninoculated plants were maintained in a garden at temperatures ranging from 15 to 25°C. After 10 days, typical symptoms of powdery mildew developed on inoculated plants. Noninoculated plants did not show symptoms. To our knowledge, this is the first report of powdery mildew on L. caprifolium in Italy. The presence of powdery mildew on different species of Lonicera has been reported in several countries, particularly, Microsphaera miurae U. Braun on L. morowii A. Gray in Germany (1), M. lonicerae (DC.) Winter on L. peryclimenum L. in England (3), and M. lonicerae-ramosissimae on L. ramosissima Fr. & Sav. in Japan (4). The conidia of M. lonicerae are smaller than those of the Oidium sp. reported on L. caprifolium. Voucher specimens are available at DIVAPRA Collection at the University of Torino. References: (1) U. Braun. Mycotaxon 16:417, 1983. (2) U. Braun and S. Takamatsu. Schlechtendalia 4:1, 2000. (3) J. Robbins. Cecidology 15:15, 2000. (4) S. Tanda. Mycoscience 41:155, 2000.


Reflux-induced collagen type v sensitization: potential mediator of bronchiolitis obliterans syndrome.
Lung transplantation continues to have poor long-term survival partly because of the high incidence of bronchiolitis obliterans syndrome (BOS). Gastroesophageal reflux disease (GERD) has been implicated in BOS pathogenesis. We investigated the role of collagen type V [col(V)] sensitization in this process. Only primary lung transplant recipients were included. Reflux status was assessed with pH monitoring, impedance plethysmography, and esophagogastroduodenoscopy. Sensitivity to col(V) was determined with trans vivo delayed-type hypersensitivity reaction (DTH). Kaplan-Meier analyses were performed. Of the 54 recipients, 26 had proven GERD. There were no significant between-group differences in diagnosis; donor and recipient age; sex; ischemic time; single vs bilateral; human leukocyte antigen A, B, and DR matching cytomegalovirus status; acute rejections; or mean follow-up period. The mean DTH response in the GERD group was 25.7 x 10(-4) inches vs 18.3 x 10(-4) inches in the non-GERD group (P = .023). There was a significant reduction in BOS-free survival in the GERD group for both BOS-I (GERD+, 28.3%; GERD-, 86.6%; P = .0001) and BOS-II/III (GERD+, 66.2%; GERD-, 91.7%; P = .0374). A second cohort of 53 patients awaiting lung transplantation also was assayed. The mean DTH response in the GERD group was 24.0 x 10(-4) inches vs 13.1 x 10(-4) inches in the non-GERD group (P = .003). There were no differences in age or sex. GERD is strongly associated with the development of BOS after primary lung transplantation. Col(V) sensitization is associated with reflux and BOS and may play an intermediary role in the pathogenesis of BOS. Trials using col(V) reactivity to assess the impact of antireflux procedures in patients with lung transplantation and idiopathic pulmonary fibrosis are warranted.


Complete Genome Sequence of Bacillus amyloliquefaciens Strain BH072, Isolated from Honey.
The genome of Bacillus amyloliquefaciens strain BH072, isolated from a honey sample and showing strong antimicrobial activity against plant pathogens, is 4.07 Mb and harbors 3,785 coding sequences (CDS). Several gene clusters for nonribosomal synthesis of antimicrobial peptides and a complete gene cluster for biosynthesis of mersacidin were detected.


Prenatal exposure to methyl mercury from fish consumption and polyunsaturated fatty acids: associations with child development at 20 mo of age in an observational study in the Republic of Seychelles.
Fish is a rich source of n-3 polyunsaturated fatty acids (PUFAs) but also contains the neurotoxicant methyl mercury (MeHg). PUFAs may modify the relation between prenatal MeHg exposure and child development either directly by enhancing neurodevelopment or indirectly through the inflammatory milieu. The objective was to investigate the associations of prenatal MeHg exposure and maternal PUFA status with child development at 20 mo of age. The Seychelles Child Development Study Nutrition Cohort 2 is an observational study in the Republic of Seychelles, a high-fish-eating population. Mothers were enrolled during pregnancy and their children evaluated at 20 mo of age by using the Bayley Scales of Infant Development II (BSID-II), the MacArthur Bates Communicative Development Inventories (CDI), and the Infant Behavior Questionnaire-Revised. There were 1265 mother-child pairs with complete data. Prenatal MeHg exposure had no direct associations with neurodevelopmental outcomes. Significant interactions were found between MeHg and PUFAs on the Psychomotor Developmental Index (PDI) of the BSID-II. Increasing MeHg was associated with lower PDI but only in children of mothers with higher n-6/n-3. Among mothers with higher n-3 PUFAs, increasing MeHg was associated with improved PDI. Higher maternal docosahexaenoic acid (DHA) was associated with improved CDI total gestures (language development) but was significantly adversely associated with the Mental Development Index (MDI), both with and without MeHg adjustment. Higher n-6:n-3 ratios were associated with poorer scores on all 3 CDI outcomes. We found no overall adverse association between prenatal MeHg exposure and neurodevelopmental outcomes. However, maternal PUFA status as a putative marker of the inflammatory milieu appeared to modify the associations of prenatal MeHg exposure with the PDI. Increasing DHA status was positively associated with language development yet negatively associated with the MDI. These findings may indicate the existence of an optimal DHA balance with respect to arachidonic acid for different aspects of neurodevelopment.


Interaction of low density lipoproteins with human aortic elastin.
Interaction between lipoproteins and elastin in the arterial wall may play an important role in atherosclerotic lipid deposition, but binding affinities and other characteristics of the interaction have not been determined previously. Elastin was isolated by hot alkali treatment of human aortic tissue. At 4 degrees C, radioiodinated human low density lipoprotein (LDL) bound to more than one class of binding sites on elastin. Sites of highest affinity had an apparent dissociation constant of 3.6 x 10(-8) M. Total binding at an LDL concentration of 50 micrograms/ml ranged from 4 to 50 ng LDL protein/mg elastin. The binding was relatively specific, since binding was competitively inhibited by LDL and apo E-containing high density lipoprotein (HDL) but only modestly by HDL3. Atherosclerotic elastin exhibited a twofold to fourfold higher capacity for binding LDL, but a reduced affinity. At 37 degrees C, normal elastin exhibited an initial rapid binding of LDL, with a slower linear phase of binding over a 15-hour period, indicating an additional complex process at this temperature. Consideration of the expected LDL concentrations in the arterial intima, in comparison with binding affinities, suggests that LDL binding to elastin probably occurs in the intima and may foster atherosclerotic lipid deposition.


To a better understanding of the giardial ENTH protein function.
Epsin N-terminal homology (ENTH) domains are present at the N-terminus of either the epsin or epsin-related (epsinR) proteins. These proteins have been involved in clathrin-mediated trafficking and are critical for membrane deformation at the site of vesicle budding. While more than one type of these proteins have been described in many eukaryotic cells, the protozoa parasite Giardia lamblia contains only one member of this ENTH-protein family. In the last two years, four works have been published showing that this giardial protein might play diverse functions. This commentary gives a brief overview on the current status of the particular characteristics and functions of this unique protein.


Seeing faces and objects with the "mind's eye".
With the advent of functional brain imaging techniques and recent developments in the analysis of cortical connectivity, the focus of mental imagery studies has shifted from a semi-modular approach to a more realistic, integrated, cortical networks perspective. Recent studies of visual imagery of faces and objects suggest that activation of content-specific representations stored in the ventral visual stream is top-down modulated by parietal and frontal regions. The relation of these findings to other cognitive functions is discussed, as well as their clinical implications for patients with impaired states of conscious awareness.


Bistable behavior originating in the axon of a crustacean motor neuron.
Both vertebrate and invertebrate motor neurons can display bistable behavior in which self-sustained tonic firing results from a brief excitatory stimulus. Induction of the bistability is usually dependent on activation of intrinsic conductances located in the somatodendritic area and is commonly sensitive to action of neuromodulators. We have observed bistable behavior in a neuromuscular preparation from the foregut of the crab Cancer borealis that consists of the gastric mill 4 (gm4) muscle and the nerve that innervates it, the dorsal gastric nerve (dgn). Nerve-evoked contractions of enhanced amplitude and long duration (>30 s) were induced by extracellular stimulation when the stimulus voltage was above a certain threshold. Intracellular and extracellular recordings showed that the large contractions were accompanied by persistent firing of the dorsal gastric (DG) motor neuron that innervates gm4. The persistent firing could be induced only by stimulating a specific region of the axon and could not be triggered by depolarizing the soma, even at current amplitudes that induced high-frequency firing of the neuron. The bistable behavior was abolished in low-Ca2+ saline or when nicardipine or flufenamic acid, blockers of L-type Ca2+ and Ca2+-activated nonselective cation currents, respectively, was applied to the axonal stimulation region of the dgn. Negative immunostaining for synapsin and synaptotagmin argued against the presence of synaptic/modulatory neuropil in the dgn. Collectively, our results suggest that bistable behavior in a motor neuron can originate in the axon and may not require the action of a locally released neuromodulator.


Differences in the processing of chylomicron remnants and beta-VLDL by macrophages.
To gain a detailed understanding of those factors that govern the processing of dietary-derived lipoprotein remnants by macrophages we examined the uptake and degradation of rat triacylglycerol-rich chylomicron remnants and rat cholesterol-rich beta-very low density lipoprotein (beta-VLDL) by J774 cells and primary cultures of mouse peritoneal macrophages. The level of cell associated 125I-labeled beta-VLDL and 125I-labeled chylomicron remnants reached a similar equilibrium level within 2 h of incubation at 37 degrees C. However, the degradation of 125I-labeled beta-VLDL was two to three times greater than the degradation of 125I-labeled chylomicron remnants at each time point examined, with rates of degradation of 161.0 +/- 36.0 and 60.1 +/- 6.6 ng degraded/h per mg cell protein, respectively. At similar extracellular concentrations of protein or cholesterol, the relative rate of cholesteryl ester hydrolysis from [3H]cholesteryl oleate/cholesteryl [14C]oleate-labeled chylomicron remnants was one-third to one-half that of similarly labeled beta-VLDL. The reduction in the relative rate of chylomicron remnant degradation by macrophages occurred in the absence of chylomicron remnant-induced alterations in low density lipoprotein (LDL) receptor recycling or in retroendocytosis of either 125I-labeled lipoprotein. The rate of internalization of 125I-labeled beta-VLDL by J774 cells was greater than that of 125I-labeled chylomicron remnants, with initial rates of internalization of 0.21 ng/min per mg cell protein for 125I-labeled chylomicron remnants and 0.39 ng/min per mg cell protein for 125I-labeled beta-VLDL. The degradation of 125I-labeled chylomicron remnants and 125I-labeled beta-VLDL was dependent on lysosomal enzyme activity: preincubation of macrophages with the lysosomotropic agent monensin reduced the degradation of both lipoproteins by greater than 90%. However, the pH-dependent rate of degradation of 125I-labeled chylomicron remnants by lysosomal enzymes isolated from J774 cells was 50% that of 125I-labeled beta-VLDL. The difference in degradation rates was dependent on the ratio of lipoprotein to lysosomal protein used and was greatest at ratios greater than 50. The degradation of 125I-labeled beta-VLDL by isolated lysosomes was reduced 30-40% by preincubation of beta-VLDL with 25-50 micrograms oleic acid/ml, suggesting that released free fatty acids could cause the slower degradation of chylomicron remnants. Thus, differences in the rate of uptake and degradation of remnant lipoproteins of different compositions by macrophages are determined by at least two factors: 1) differences in the rates of lipoprotein internalization and 2) differences in the rate of lysosomal degradation.


Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision.
Adult neurogenesis arises from neural stem cells within specialized niches. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically to the neurotransmitter γ-aminobutyric acid (GABA) by means of γ2-subunit-containing GABAA receptors. Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of γ2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division. Our study identifies a niche cell–signal–receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.


Protein tyrosine phosphatase 1B regulates endothelial endoplasmic reticulum stress; role in endothelial dysfunction.
Protein tyrosine phosphatase 1B (PTP1B) impairs nitric oxide (NO) production and induces endothelial dysfunction in various diseases, including diabetes, septic shock and heart failure. In non-cardiovascular tissues, PTP1B modulates endoplasmic reticulum stress (ERS) however this role has never been assessed in endothelial cells. We evaluated the link between PTP1B, ERS and endothelial dysfunction in mice. Induction of ERS (Tunicamycin) in vivo in mice or ex vivo in mouse arteries led to severe arterial endothelial dysfunction (i.e. reduced flow-dependent, NO mediated dilatation in isolated small mesenteric arteries), and this was prevented by the PTP1B inhibitor trodusquemine and absent in PTP1B-/- mice. Trodusquemine also prevented the Tunicamycin -induced increased arterial levels of the molecular ERS actors 78 kDa glucose-regulated protein (GRP78) and Activating Transcription Factor 6 (ATF6α). Tunicamycin strongly increased the interactions of PTP1B with GRP78 and the activated forms of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and IRE1α (proximity Ligation Assay). Thus, PTP1B plays a central role in the regulation of ERS in the endothelium, and the endothelial protective effect of PTP1B inhibition appears likely due at least in part to reduction of endothelial ERS, notably by promoting PERK protective pathway. Modulation of ER stress via PTP1B inhibitors may be a promising approach to protect the endothelium in cardiovascular diseases.


Nomograms to predict serious adverse events in phase II clinical trials of molecularly targeted agents.
A tool that quantifies the risk of treatment-related toxicity based on individual patient characteristics can augment the informed consent process and safety monitoring in the setting of phase II cancer treatment trials of molecularly targeted agents (MTAs). A regression model was constructed to predict the risk of a serious adverse event (SAE) with an MTA and presented as a nomogram. Estimation of risk can be performed by integrating risk estimates from the nomogram and from a reference or average patient. Internal validation was performed using bootstrapping techniques. A total of 578 patients were treated with one of 14 MTAs given alone or in combination on one of 27 clinical trials performed by the Princess Margaret Hospital Drug Development Program between 2001 and 2006. Approximately 50% and 24% of patients experienced an SAE and an attributable SAE (SAEatt) during cycle 1, respectively. Albumin, lactate dehydrogenase (LDH), number of target lesions, prior radiotherapy, Charlson score, age, and performance status were included in the optimal model as predictors of a cycle 1 SAE, whereas the number of prior chemotherapy regimens, baseline creatinine, LDH, prior radiotherapy, Charlson score, body-surface area, and performance status were included as predictors of an SAEatt. Moderate-good internal validity was demonstrated, with area under the curve estimates ranging from 56.7% to 86.1% for all SAEs and 63.0% to 89.7% for SAEatts. A regression model was constructed that predicts the SAE and SAEatt risk for an individual patient during cycle 1 of phase II trial treatment with moderate to good internal validity. External validation is still required.


Proteomic and biological characterization of the venom of the redtail coral snake, Micrurus mipartitus (Elapidae), from Colombia and Costa Rica.
Venoms of the redtail coral snake Micrurus mipartitus from Colombia and Costa Rica were analyzed by "venomics", a proteomic strategy to determine their composition. Proteins were separated by RP-HPLC, followed by SDS-PAGE, in-gel tryptic digestion, identification by MALDI or ESI tandem mass spectrometry, and assignment to known protein families by similarity. These analyses were complemented with a characterization of venom activities in vitro and in vivo. Proteins belonging to seven families were found in Colombian M. mipartitus venom, including abundant three-finger toxins (3FTx; ~60% of total proteins) and phospholipases A(2) (PLA(2); ~30%), with the remaining ~10% distributed among l-amino acid oxidase, P-III metalloproteinase, Kunitz-type inhibitor, serine proteinase, and C-type lectin-like families. The venoms of two M. mipartitus specimens from Costa Rica, also referred to as M. multifasciatus in some taxonomic classifications, were also analyzed. Both samples were highly similar to each other, and partially resembled the chromatographic and identity profiles of M. mipartitus from Colombia, although presenting a markedly higher proportion of 3FTxs (~83.0%) in relation to PLA(2)s (~8.2%), and a small amount of acetylcholinesterase, not detected in the venom from Colombia. An equine antivenom against the Central American coral snake, M. nigrocinctus, did not recognize venom components of M. mipartitus from Colombia or Costa Rica by enzyme-immunoassay. Four major components of Colombian M. mipartitus venom were isolated and partially characterized. Venomics of Micrurus species may provide a valuable platform for the rational design of immunizing cocktails to obtain polyspecific antivenoms for this highly diverse group of American elapids.


Using acupressure and Montessori-based activities to decrease agitation for residents with dementia: a cross-over trial.
To explore the effectiveness of acupressure and Montessori-based activities in decreasing the agitated behaviors of residents with dementia. A double-blinded, randomized (two treatments and one control; three time periods) cross-over design was used. Six special care units for residents with dementia in long-term care facilities in Taiwan were the sites for the study. One hundred thirty-three institutionalized residents with dementia. Subjects were randomized into three treatment sequences: acupressure-presence-Montessori methods, Montessori methods-acupressure-presence and presence-Montessori methods-acupressure. All treatments were done once a day, 6 days per week, for a 4-week period. The Cohen-Mansfield Agitation Inventory, Ease-of-Care, and the Apparent Affect Rating Scale. After receiving the intervention, the acupressure and Montessori-based-activities groups saw a significant decrease in agitated behaviors, aggressive behaviors, and physically nonaggressive behaviors than the presence group. Additionally, the ease-of-care ratings for the acupressure and Montessori-based-activities groups were significantly better than for the presence group. In terms of apparent affect, positive affect in the Montessori-based-activities group was significantly better than in the presence group. This study confirms that a blending of traditional Chinese medicine and a Western activities program would be useful in elderly care and that in-service training for formal caregivers in the use of these interventions would be beneficial for patients


Historical public health in central europe with special reference to hungary. Long-term environmental effects of a historical cataclysm.
Hungary, in the centre of Carpathian basin grapples with numerous challenges in order to improve catastrophic indices of environmental conditions of the country, as well as the state of health of the population. Some of these problems are subjects of financial and health policy, and can be solved internally. The remaining environmental problems can only be remedied by cooperation with neighbouring younger countries. This vitally important cooperation is hampered by severe historical conflicts burdening even the present political affiliations. The authors give a short introduction and explanation of the recent sensitive situation in this central European region, as a late consequence of an historical cataclysm happened more than nine decades ago.


A prime-boost strategy using virus-like particles pseudotyped for HCV proteins triggers broadly neutralizing antibodies in macaques.
Chronic hepatitis C virus (HCV) infection, with its cohort of life-threatening complications, affects more than 200 million persons worldwide and has a prevalence of more than 10% in certain countries. Preventive and therapeutic vaccines against HCV are thus much needed. Neutralizing antibodies (NAbs) are the foundation for successful disease prevention for most established vaccines. However, for viruses that cause chronic infection such as HIV or HCV, induction of broad NAbs from recombinant vaccines has remained elusive. We developed a vaccine platform specifically aimed at inducing NAbs based on pseudotyped virus-like particles (VLPs) made with retroviral Gag. We report that VLPs pseudotyped with E2 and/or E1 HCV envelope glycoproteins induced high-titer anti-E2 and/or anti-E1 antibodies, as well as NAbs, in both mouse and macaque. The NAbs, which were raised against HCV 1a, cross-neutralized the five other genotypes tested (1b, 2a, 2b, 4, and 5). Thus, the described VLP platform, which can be pseudotyped with a vast array of virus envelope glycoproteins, represents a new approach to viral vaccine development.


Combination Therapy and Opioids: Effectiveness of Transcranial Direct-Current Stimulation (tDCS) and Emotion Regulation Training in Reducing Current Drug Craving.
Background and objectives: Craving is the main symptom of addiction that is accompanied by dependence and relapse. The present study was aimed to compare the effectiveness of combined Transcranial Direct-Current Stimulation (tDCS) and emotion regulation training with that of separate tDCS and emotion regulation training in reducing current drug craving and thoughts and fantasies about drug use. Materials and methodology: This was a quasi-experimental study with a pretest-posttest design and three intervention groups. The statistical population included all patients dependent on opioids in medium-term residential drug rehabilitation centers in Zahedan, Iran, in 2018-2019. From eight randomly selected centers, a total of 54 patients were selected based on inclusion and exclusion criteria, and randomly divided into three intervention groups. Data were gathered using the Personal Drug Use Questionnaire, Desires for Drug Questionnaire (DDQ), and Drug Use Thoughts, Fantasies, and Temptations Questionnaire. All analyses were performed using SPSS-16. Results: The Kruskal-Wallis test indicated significant differences between the three intervention groups in current drug craving and thoughts and fantasies about drug use (P ..001). In addition, examination of the mean rank showed that t significant decrease was higher for the combined tDCS and emotion regulation training group. Conclusion: Addiction is very similar to other chronic disorders. Therefore, combined (integrated) therapies can have a very important role in treating addiction, especially in relapse prevention.


Antimicrobial traits of tea- and cranberry-derived polyphenols against Streptococcus mutans.
There are over 750 species of bacteria that inhabit the human oral cavity, but only a small fraction of those are attributed to causing plaque-related diseases such as caries. Streptococcus mutans is accepted as the main cariogenic agent and there is substantial knowledge regarding the specific virulence factors that render the organism a pathogen. There has been rising interest in alternative, target-specific treatment options as opposed to nonspecific mechanical plaque removal or application of broad-spectrum antibacterials that are currently in use. The impact of diet on oral health is undeniable, and this is directly observable in populations that consume high quantities of polyphenol-rich foods or beverages. Such populations have low caries incidence and better overall oral health. Camellia sinensis, the plant from which various forms of tea are derived, and Vaccinium macrocarpon (American cranberry fruit) have received notable attention both for their prevalence in the human diet as well as for their unique composition of polyphenols. The biologically active constituents of these plants have demonstrated potent enzyme-inhibitory properties without being bactericidal, a key quality that is important in developing therapies that will not cause microorganisms to develop resistance. The aim of this review is to consider studies that have investigated the feasibility of tea, cranberry, and other select plant derivatives as a potential basis for alternative therapeutic agents against Streptococcus mutans and to evaluate their current and future clinical relevance.


Design and performance of a multiwavelength airborne polarimetric lidar for vegetation remote sensing.
The University of Nebraska has developed a multiwavelength airborne polarimetric lidar (MAPL) system to support its Airborne Remote Sensing Program for vegetation remote sensing. The MAPL design and instrumentation are described in detail. Characteristics of the MAPL system include lidar waveform capture and polarimetric measurement capabilities, which provide enhanced opportunities for vegetation remote sensing compared with current sensors. Field tests were conducted to calibrate the range measurement. Polarimetric calibration of the system is also discussed. Backscattered polarimetric returns, as well as the cross-polarization ratios, were obtained from a small forested area to validate the system's ability for vegetation canopy detection. The system has been packaged to fly abroad a Piper Saratoga aircraft for airborne vegetation remote sensing applications.


Three-dimensional photonic crystal of negative refraction achieved by interference lithography.
A three-dimensional bicontinuous photonic crystal of a bcc lattice with all-angle negative refraction that can be achieved at optical frequencies by interference lithography is proposed. A numerical simulation of the focusing imaging of a slab of this crystal was performed to verify the property of all-angle negative refraction. The dependence of the negative-refraction frequency range on the threshold of photoresist development and on the dielectric constant is also discussed.


Antiplasmodial activity and phytochemical analysis of extracts from selected Ugandan medicinal plants.
Resistance of the parasites to known antimalarial drugs has provided the necessity to find new drugs from natural products against malaria. The aim of the study was to evaluate the in vitro antiplasmodial activity of some plants used by Traditional Medical Practitioners (TMPs) of Prometra and Rukararwe in malaria treatment in Uganda to provide scientific proof of the efficacies claimed by these Herbalists. The air dried samples of Clerodendrum rotundifolium (leaves), Microglossa pyrifolia (leaves), Momordica foetida (leaves) and Zanthoxylum chalybeum (stem bark) used for malaria treatment by TMPs were successively extracted with ethyl acetate, methanol and water to yield twelve extracts. The extracts were tested against the chloroquine-sensitive (NF54) and chloroquine-resistant (FCR3) Plasmodium falciparum strains in vitro using the micro Mark III test which is based on assessing the inhibition of schizont maturation. A compound A was extracted and purified from the stem bark of Z. chalybeum and its structure was identified and confirmed by spectroscopic methods. Most of the extracts tested (92%) showed an antiplasmodial activity with IC50<50µg/mL. In spite of successive extractions with different solvents, potent anti-plasmodial activity (IC50<5µg/mL) was observed in the ethyl acetate, methanol and aqueous extracts of M. pyrifolia and C. rotundifolium. Preferential enrichments of activity into water (IC50<15µg/mL) and Ethyl acetate (IC50<5µg/mL) were seen in the case of M. foetida and Z. chalybeum respectively. The most active extracts were from C. rotundifolium and M. pyrifolia with IC50 values less than 2µg/mL. Phytochemical analysis of the extracts revealed the presence of saponins, tannins, flavonoids, alkaloids and cardiac glycocides. Fagaramide isolated from Z. chalybeum had a higher activity (IC50 2.85µg/mL) against the chloroquine-resistant strain than against the chloroquine-senstive (IC50 16.6µg/mL) strain used in the study. The plant extracts analysed in this study presented an average antiplasmodial activity (58%). This study revealed for the first time the antiplasmodial activity of the plant C. rotundofolium. It's the first time the compound fagaramide (N-isobutyl-3-(3,4-methylene dioxyphenyl)-2E-propenamide) has been isolated from Z. chalybeum as one of the compounds that contribute to the activity of this plant against P. falciparum.


Younger age-at-diagnosis for familial malignant testicular germ cell tumor.
One of the clinical hallmarks of hereditary cancer susceptibility disorders is a younger-than-usual age at diagnosis. Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but data on whether familial TGCT cases are diagnosed at an earlier age are inconclusive. Here we compared the age at diagnosis of familial TGCT cases with that of population cases in several countries. Familial TGCT is defined as affected individuals from families with >or=2 cases of TGCT. Age at diagnosis of familial cases from the United States, Canada, United Kingdom, Australia and New Zealand, Norway, and Hungary was compared to cases identified in population-based cancer registries from the respective country, using the generalized estimation equation method. Age at diagnosis was statistically significantly younger for familial TGCT cases from North America (P = 0.024), the United Kingdom (P < 0.0001), and Australia and New Zealand (P = 0.0033) compared with population cases. When stratified by histology, the difference in age at diagnosis distribution between familial and population cases was observed for seminoma cases from North America (P = 0.002) and the United Kingdom (P < 0.0001) and non-seminoma cases from the United Kingdom (P = 0.029) and Australia and New Zealand (P = 0.0023). In summary, we found that the age at diagnosis for familial TGCT cases is, on the average, 2-3 years younger than that for the population cases in North America, United Kingdom, and Australia and New Zealand. The younger age at diagnosis might be suggestive of a genetic basis for familial TGCT.


Hit or miss: the new cholesterol targets.
Drug treatment to reduce cholesterol to new target levels is now recommended in four moderate- to high-risk patient populations: patients who have already sustained a cardiovascular event, adult diabetic patients, individuals with low density lipoprotein cholesterol levels ≥190 mg/dL and individuals with an estimated 10-year cardiovascular risk ≥7.5%. Achieving these cholesterol target levels did not confer any additional benefit in a systematic review of 35 randomised controlled trials. Recommending cholesterol lowering treatment based on estimated cardiovascular risk fails to identify many high-risk patients and may lead to unnecessary treatment of low-risk individuals. The negative results of numerous cholesterol lowering randomised controlled trials call into question the validity of using low density lipoprotein cholesterol as a surrogate target for the prevention of cardiovascular disease.


Mucosal damage mediated by clostridial toxin in experimental clindamycin-associated colitis.
A toxin produced by Clostridium difficile has been implicated in the pathogenesis of antibiotic-associated colitis in humans and experimental animals. This study was undertaken in order to define the sequential evolution of caecal mucosal lesions in the hamster and to relate those lesions directly to the clostridial toxin. Sterile filtrates from a culture of C. difficile and from caecal contents of clindamycin-treated hamsters were studied with respect to their effects on the caecal mucosa and on cultured cell monolayers. The toxic filtrates both produced cellular swelling in vitro, and appeared to have a similar cytotoxic effect on caecal epithelial cells in vivo. Cellular damage was followed by extensive epithelial desquamation and the evolution of an acute pseudomembranous typhlitis. The pathogenetic sequence produced by the filtrates was identical with that previously described after direct clindamycin treatment. These findings demonstrate that intraluminal clostridial toxin can mediate development of the characteristic antibiotic-associated mucosal lesions.


[Epidemiology of burns in children and adolescents from Chile's Metropolitan Region].
To determine demographic, clinical and health care factors associated to prevalence of burns in children less than 20 years of age in the districts of Cerro Navia, Lo Prado and Pudahuel, and their comparison with incidence in 2011. Population survey based on probability and two-stage stratified complex sample of households, registering 4,968 households. In 302 of them randomly selected, the mother/adult present at the time of the injury took a survey. A questionnaire of 50 questions (20 minutes), created by 6 experts and previously validated, was conducted by 10 interviewers and 3 supervisors. People were contacted by telephone before visiting them at their homes. The non-response rate was 6%, after up to 3 home visits. Regarding prevalence, the male-to-female ratio was 1.16:1. Main reasons were hot objects (42.4%) and liquids (41.5%). 84.1% of burns occurred inside the home and in the afternoon (50.7%). 93.3% of the burns took place with an adult present. Hands were the most affected areas (46.7%). 30.2% were left with scars the first time of the accident. 34.4% of the burn victims did not require health care and 8.4% of them required hospitalizations. Over 60% of respondents reported that they poured cold water on the burn as a first step. Relevant information was obtained to be used in burn prevention in children and adolescents. Recall bias is the main limitation of the study.


Prevention and treatment of protein energy wasting in chronic kidney disease patients: a consensus statement by the International Society of Renal Nutrition and Metabolism.
Protein energy wasting (PEW) is common in patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes, especially in individuals receiving maintenance dialysis therapy. A multitude of factors can affect the nutritional and metabolic status of CKD patients requiring a combination of therapeutic maneuvers to prevent or reverse protein and energy depletion. These include optimizing dietary nutrient intake, appropriate treatment of metabolic disturbances such as metabolic acidosis, systemic inflammation, and hormonal deficiencies, and prescribing optimized dialytic regimens. In patients where oral dietary intake from regular meals cannot maintain adequate nutritional status, nutritional supplementation, administered orally, enterally, or parenterally, is shown to be effective in replenishing protein and energy stores. In clinical practice, the advantages of oral nutritional supplements include proven efficacy, safety, and compliance. Anabolic strategies such as anabolic steroids, growth hormone, and exercise, in combination with nutritional supplementation or alone, have been shown to improve protein stores and represent potential additional approaches for the treatment of PEW. Appetite stimulants, anti-inflammatory interventions, and newer anabolic agents are emerging as novel therapies. While numerous epidemiological data suggest that an improvement in biomarkers of nutritional status is associated with improved survival, there are no large randomized clinical trials that have tested the effectiveness of nutritional interventions on mortality and morbidity.


MRI reveals that early changes in cerebral blood volume precede blood-brain barrier breakdown and overt pathology in MS-like lesions in rat brain.
Magnetic resonance imaging (MRI) is an established clinical tool for diagnosing multiple sclerosis (MS), the archetypal central nervous system neuroinflammatory disease. In this study, we have used a model of delayed-type hypersensitivity in the rat brain, which bears many of the hallmarks of an MS lesion, to investigate the development of MRI-detectable changes before the appearance of conventional indices of lesion development. In addition, we have correlated the MRI-detectable changes with the developing histopathology. Significant increases in regional cerebral blood volume (rCBV) preceded overt changes in blood-brain barrier (BBB) permeability, T2 relaxation and the diffusion properties of tissue water. Thus, changes in rCBV might be a more sensitive indicator of lesion onset than the conventional indices used clinically in MS patients, such as contrast enhancement. In addition, we show that BBB breakdown, and consequent edema formation, are more closely correlated with astrogliosis than any other histopathologic changes, while regions of T1 and T2 hypointensity appear to reflect hypercellularity.


Total synthesis of nannocystin Ax.
A concise total synthesis of nannocystin Ax, a natural depsipeptide recently isolated from myxobacteria, has been accomplished. By following a convergent strategy, the target molecule was assembled from three fragments. Each fragment can be synthesized expeditiously from readily achievable compounds. The key elements in this total synthesis feature Kobayashi's remote asymmetric induction with vinylketene silyl N,O-acetal, Roush's asymmetric crotylboration of aldehyde, Mitsunobu's esterification and macrocyclization via Stille cross-coupling.


Body roll in swimming: a review.
In this article, we present a critical review of the swimming literature on body roll, for the purposes of summarizing and highlighting existing knowledge, identifying the gaps and limitations, and stimulating further research. The main research findings can be summarized as follows: swimmers roll their shoulders significantly more than their hips; swimmers increase hip roll but maintain shoulder roll when fatigued; faster swimmers roll their shoulders less than slower swimmers during a 200-m swim; roll asymmetries, temporal differences in shoulder roll and hip roll, and shoulder roll side dominance exist in front crawl swimming, but there is no evidence to suggest that they affect swimming performance; and buoyancy contributes strongly to generating body roll in front crawl swimming. Based on and stimulated by current knowledge, future research should focus on the following areas: calculation of body roll for female swimmers and for backstroke swimming; differences in body roll between breathing and non-breathing cycles; causes of body roll asymmetries and their relation to motor laterality; body roll analysis across a wide range of velocities and swimming distances; exploration of the association between body roll and the magnitude and direction of propulsive/resistive forces developed during the stroke cycle; and the influence of kicking actions on the generation of body roll.


The effects of thermal treatment and irradiation on the chemical properties of natural diamonds.
The modification of nitrogen-contaminated diamonds into color-enhanced diamonds is usually achieved by irradiation and thermal treatment (annealing). These treatments affect nitrogen contamination chemical bonding, vacancy concentration, and atom orientation centers in the diamond lattice. In this study, natural diamonds were subjected to irradiation and thermal annealing color enhancement treatments to produce green, blue, and yellow fancy diamonds. The study followed the changes that occur during treatment relying on visual assessment, fluorescence, UV-vis, FTIR, and EPR spectroscopy to characterize paramagnetic centers. The results indicated that diamonds containing high levels of nitrogen contamination presented a relatively high carbon-centered radical concentration. Two paramagnetic groups with different g-values were found, namely, low g-value centers of 2.0017-2.0027 and high g-value centers of 2.0028-2.0035. It is suggested that the 2.0017-2.0022 centers correlate with blue centers, whereas the 2.0023-2.0027 centers correlate with yellow centers. It was also found that thermal treatment was required to produce blue and yellow fancy diamonds, whereas no such treatment was needed to produce green diamonds.


Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial.
Diabetic foot wounds, particularly those secondary to amputation, are very complex and difficult to treat. We investigated whether negative pressure wound therapy (NPWT) improves the proportion and rate of wound healing after partial foot amputation in patients with diabetes. We enrolled 162 patients into a 16-week, 18-centre, randomised clinical trial in the USA. Inclusion criteria consisted of partial foot amputation wounds up to the transmetatarsal level and evidence of adequate perfusion. Patients who were randomly assigned to NPWT (n=77) received treatment with dressing changes every 48 h. Control patients (n=85) received standard moist wound care according to consensus guidelines. NPWT was delivered through the Vacuum Assisted Closure (VAC) Therapy System. Wounds were treated until healing or completion of the 112-day period of active treatment. Analysis was by intention to treat. This study has been registered with , number NCT00224796. More patients healed in the NPWT group than in the control group (43 [56%] vs 33 [39%], p=0.040). The rate of wound healing, based on the time to complete closure, was faster in the NPWT group than in controls (p=0.005). The rate of granulation tissue formation, based on the time to 76-100% formation in the wound bed, was faster in the NPWT group than in controls (p=0.002). The frequency and severity of adverse events (of which the most common was wound infection) were similar in both treatment groups. NPWT delivered by the VAC Therapy System seems to be a safe and effective treatment for complex diabetic foot wounds, and could lead to a higher proportion of healed wounds, faster healing rates, and potentially fewer re-amputations than standard care.


Early identification of frailty: Developing an international delphi consensus on pre-frailty.
Frailty is associated with a prodromal stage called pre-frailty, a potentially reversible and highly prevalent intermediate state before frailty becomes established. Despite being widely-used in the literature and increasingly in clinical practice, it is poorly understood. To establish consensus on the construct and approaches to diagnose and manage pre-frailty. We conducted a modified (electronic, two-round) Delphi consensus study. The questionnaire included statements concerning the concept, aspects and causes, types, mechanism, assessment, consequences, prevention and management of pre-frailty. Qualitative and quantitative analysis methods were employed. An agreement level of 70% was applied. Twenty-three experts with different backgrounds from 12 countries participated. In total, 70 statements were circulated in Round 1. Of these, 52.8% were accepted. Following comments, 51 statements were re-circulated in Round 2 and 92.1% were accepted. It was agreed that physical and non-physical factors including psychological and social capacity are involved in the development of pre-frailty, potentially adversely affecting health and health-related quality of life. Experts considered pre-frailty to be an age-associated multi-factorial, multi-dimensional, and non-linear process that does not inevitably lead to frailty. It can be reversed or attenuated by targeted interventions. Brief, feasible, and validated tools and multidimensional assessment are recommended to identify pre-frailty. Consensus suggests that pre-frailty lies along the frailty continuum. It is a multidimensional risk-state associated with one or more of physical impairment, cognitive decline, nutritional deficiencies and socioeconomic disadvantages, predisposing to the development of frailty. More research is needed to agree an operational definition and optimal management strategies.


Anomalous coronary artery found in the syncopal workup of an elderly man.
Syncope, defined as a transient loss of consciousness, is seen in 1% of all visits to emergency departments and urgent care clinics in the United States. Syncope is categorized as cardiogenic, neurologic, or psychogenic. Anomalies of the coronary arteries are rare, and anomalous coronary arteries present as syncope more often in the young than in the elderly; syncope rarely occurs in patients 65 years of age and older. There are 2 major variants of coronary anomalies. In the first variant, the left main coronary artery arises from the right aortic sinus. In the second variant, the right coronary artery arises from the left aortic sinus. The risk of sudden death is higher in patients with the left coronary artery arising from the right aortic sinus. We present a case of an anomalous coronary artery discovered during the syncopal workup in a 66-year-old man because no such cases have been published in the United States. We will discuss the management of anomalous coronary arteries as well as a systematic approach to the diagnosis and management of syncope.


[Psychic aspects of the premenstrual dysphoric disorders. New therapeutic strategies: our experience with Vitex agnus castus].
The premenstrual dysphoric disorder (PMDD) is one of the main problems of the premenstrual phase. It consists of symptoms that sometimes invalidate the scope of employment, social and psycho-affective of patients, requiring thus a diagnostic and therapeutic approach as detailed and accurate as possible. The therapeutic strategies available for this disease are many, but recently the emphasis has been on Vitex agnus castus (VAC), considered by many as evidence drug of choice for both PMS and for the PMDD, being with satisfactory therapeutic properties and small side effects. Our study evaluated a group of patients suffering from PMDD and the clinical efficacy of treatment with VAC (and compared the effectiveness of the results of a more homogeneous group of patients treated with fluoxetine). This study confirms the data reported in the literature regarding the effectiveness of VAC therapy with no side effects.


Surface roughness measurement by two wavelength holographic interferometry.
This paper is a theoretical presentation of a two wavelength holographic method of measuring the roughness of a surface. This method extends the range of surface roughness which can be measured to arbitrarily rough surfaces. This paper also discusses the factors that limit the accuracy of the proposed method.


Factors predisposing to abnormal pulmonary function after adenovirus type 7 pneumonia.
Adenoviruses are well known causes of respiratory illness in children. Long term sequelae reported with types 3, 7, and 21 include bronchiolitis obliterans, bronchiectasis, and the hyperlucent lung or McLeod syndrome. Twenty children admitted to hospital with adenovirus type 7 pneumonia between 1960 and 1978 were studied and compared with 20 controls admitted during the same period with adenovirus type 7 upper respiratory tract infections. Sixty five per cent of the pneumonia group had developed evidence of airways obstruction compared with 10% of controls. Young age at the time of pneumonia and a 'measles-like' illness before its onset increase the chance of developing long term pulmonary function abnormalities. Sex and family history of smoking or atopy do not influence outcome.


Cancer-associated colonic mucin in cultured human tumor cells and athymic (nude) mouse xenografts.
Mucins derived from colonic cancers differ immunologically and chemically from those in normal colonic epithelium. It has been demonstrated that the lectin from the peanut will bind to mucins present in colonic cancers and other neoplastic lesions but not to those from the normal colon. It was hypothesized, therefore, that in transformed colonic epithelium the glycosylation of mucins occurs differently than in normal epithelium. To rule out the possibility that the differences in oligosaccharide structure were due to postsecretory degradation, studies were designed to evaluate cancer-associated colonic mucins produced under more controlled conditions. We studied nine different cancer cell lines first in monolayer culture and then as xenografts in athymic or nude mice. Eight of the nine cell lines in monolayer culture synthesized glycoconjugates that were labeled by fluorescein-conjugated lectins. After injection into nude mice, eight of the nine cell lines produced tumors typical of human colonic cancer, and six of nine secreted mucin. The mucins produced by the xenografts were labeled at fluorescence microscopy by peanut lectin and other lectins, characteristic of what had been seen in other primary human colonic cancers. One cell line, LS174T, produced large amounts of mucin in the xenograft model. Mucin was purified from these tumors and characterized biochemically. It was demonstrated that mucin purified from the xenografts bound peanut lectin. Therefore, we have concluded that cancer-associated mucins are present in cultured colorectal tumor cells. The cancer-associated mucins are also found in nude mouse xenografts, indicating that they are not the result of postsecretory degradation by colonic flora or by tumor cell necrosis. The cell culture and xenograft can therefore be useful for studying the biosynthesis of cancer-associated mucins.


Elements of the HIV Care Continuum: Improving Engagement and Retention in Care.
The HIV care continuum (or treatment cascade) classifies individuals with HIV infection who are diagnosed, linked to care, retained in care, on antiretroviral therapy, and virally suppressed, to assess the effectiveness of health care and treatment from a population-level health perspective. Initially, it was estimated that only approximately 50% of individuals diagnosed with HIV infection are retained in care, and a lower percentage is virally suppressed. In an HIV clinic, retention in care should be addressed from a system perspective but focus on persons on an individual basis, and success in retention of a high proportion of individuals in care is likely to depend on collaboration with surrounding communities, local health departments, and other agencies. Two initiatives to improve engagement and retention in care undertaken at the University of Alabama at Birmingham 1917 Clinic are discussed. This article summarizes a presentation by Michael J. Mugavero, MD, MHSc, at the Ryan White HIV/AIDS Program Clinical Care Conference held in New Orleans, Louisiana, in December 2015.


Influence of hepatic dysfunction on the pharmacokinetics and safety of fimasartan.
This study was designed to assess the pharmacokinetics (PK) and safety of fimasartan, an angiotensin II type 1 receptor blocker, in hepatic impairment patients as compared with healthy subjects. An open-label, single-dose, parallel study was conducted in 6 healthy male volunteers and 12 subjects with hepatic impairment. Healthy subjects were matched with hepatic dysfunction patients on the basis of age, gender, and body weight. After a single 120-mg oral administration of fimasartan, PK parameters and safety were analyzed between the hepatic dysfunction groups and healthy group. Compared with the healthy subjects, the geometric mean ratio and 90% confidence intervals for the maximum plasma concentration and the mean area under the plasma concentration-time curve from 0 to infinity (AUC)inf were 0.77 (0.24-2.47) and 1.11 (0.50-2.46), respectively, for the mild hepatic impairment and 6.55 (3.56-12.03) and 5.17 (4.19-6.37), respectively, for moderate hepatic impairment. However, there was no significant difference in time to peak plasma concentration (t(max)) and elimination half-life, and there were no serious or severe adverse events in all subjects. Subjects with mild hepatic impairment exhibited similar bioavailability compared with healthy subjects, whereas subjects with moderate hepatic impairment seemed to exhibit a higher level of systemic exposure to fimasartan than healthy subjects. In addition, all subjects were tolerable with fimasartan.


Philasterides dicentrarchi (Ciliophora, Scuticociliatida) as the causative agent of scuticociliatosis in farmed turbot Scophthalmus maximus in Galicia (NW Spain).
Two outbreaks of scuticociliatosis affecting farmed turbot Scophthalmus maximus in Galicia are described. Moribund fish showed cutaneous ulcers, darkened skin, swimming behaviour alterations, exophthalmos, and/or abdominal distension as a result of accumulation of ascitic fluid in the body cavity. Ciliates were detected in fresh mounts of practically all organs and tissues, including the blood and ascitic fluid. Histopathological studies revealed severe encephalitis and meningitis (associated with different degrees of softening or liquefaction of the brain), necrosis of the hepatic parenchyme, severe oedema of the intestinal wall, degeneration of muscle fibres, hyperplasia of the branchial epithelium, and/or vascular and perivascular inflammation. In some cases, parasites are surrounded by abundant monocytic and lymphocytic infiltrate. We report the morphological and biometric characteristics of this ciliate, which allow identification as Philasterides dicentrarchi. We discuss possible routes of entry into the host, and environmental factors possibly facilitating infection.