A comparison of the molecular pharmacology of gold and platinum complexes.
Auranofin and cisplatinum have antiarthritic, and antineoplastic activities respectively. Because of the chemical and biological similarities of the two compounds and the extensive studies on molecular pharmacology of cisplatinum, the information about the molecular and pharmacologic effects of these agents is presented and compared. Gold and platinum complexes both can exist in several oxidation states and form coordinate complexes of varying geometry and complexity. Gold complexes interact with bases and nucleosides but relatively little is known about their interaction with polynucleotides. Extrapolating from an understanding of the interactions of platinum complexes with polynucleotides, a number of proposals for additional research on gold complexes are presented. Substantially more information is available concerning the interactions of gold complexes and various proteins. The effects of gold complexes on intracellular macromolecules and their synthesis are poorly understood and should be studied using systems employed to study platinum analogues. It is suggested that 2 dimensional gel electrophoresis of various cellular proteins be employed to determine to which intracellular protein gold complexes bind.


Gene function prediction using semantic similarity clustering and enrichment analysis in the malaria parasite Plasmodium falciparum.
Functional genomics data provides a rich source of information that can be used in the annotation of the thousands of genes of unknown function found in most sequenced genomes. However, previous gene function prediction programs are mostly produced for relatively well-annotated organisms that often have a large amount of functional genomics data. Here, we present a novel method for predicting gene function that uses clustering of genes by semantic similarity, a naïve Bayes classifier and 'enrichment analysis' to predict gene function for a genome that is less well annotated but does has a severe effect on human health, that of the malaria parasite Plasmodium falciparum. Predictions for the molecular function, biological process and cellular component of P.falciparum genes were created from eight different datasets with a combined prediction also being produced. The high-confidence predictions produced by the combined prediction were compared to those produced by a simple K-nearest neighbour classifier approach and were shown to improve accuracy and coverage. Finally, two case studies are described, which investigate two biological processes in more detail, that of translation initiation and invasion of the host cell. Predictions produced are available at http://www.bioinformatics.leeds.ac.uk/∼bio5pmrt/PAGODA.


Rheumatoid arthritis among Nigerians: the first 200 patients from a rheumatology clinic.
Rheumatoid arthritis has uncommonly been reported among Africans and rarely among West Africans. Most of the reported cases have been from Southern Africa. A recent awareness of increased reports of RA among Nigerians necessitated this study. The objective of this retrospective study was to identify the clinical presentations, laboratory characteristics as well as treatment regimens of Nigerians presenting with rheumatoid arthritis to a private rheumatology clinic in Lagos, Nigeria. This is a retrospective study of consecutive rheumatoid arthritis patients seen over a period covering 7 years and 10 months diagnosed using the ARA Criteria for RA. Laboratory tests and radiographic investigations were carried out. Treatment was with NSAIDs, prednisolone, disease modifying anti-rheumatic drugs (DMARDs), and biologics. RA accounted for 12.3% of a total of 1,623 patients presenting to the clinic with rheumatologic complaints over the study period. Females were mostly affected (F:M-2.4:1) and mean age is 46.9 years. Duration of symptoms before presentation was 4-264 months with a mean of 63.4 months. The proximal interphalangeal joints were mostly involved. Subcutaneous nodules were seen in 29.5% of the cases while rheumatoid factor was found in 38.5% of the subjects. ESR was mostly elevated and radiographic changes were mostly mild with 29.2% showing erosive changes on radiographs of the hands. Treatment was variously with non-steroidal antiinflammatory drugs (NSAIDs), prednisolone, and DMARDs. Rheumatoid arthritis is not uncommon among Nigerian; and clinical, serologic acumen are necessary for early diagnosis and appropriate referral.


A study of children's taste and visual preferences in dentifrices.
Variables and gimmicks can make choosing a dentifrice for a child complicated. Various flavors, colors, shapes, consistency, labelling, and type of dispensers provide a constellation of choices for the consumer. This study sought to determine whether children actually prefer the dentifrices designed for them. Visually the child-oriented products were preferred; modern containers were preferred over the traditional. In terms of taste, however, "child-flavored" dentifrices were not preferred over the regular flavor of the same brand, when one is tasted after the other.


Patient Derived Xenografts (PDX) Models as an Avatar to Assess Personalized Therapy Options in Uveal Melanoma: A Feasibility Study.
Uveal melanoma is the most common primary intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease, usually in the liver. When metastatic, the prognosis is poor, and few treatment options exist. Here, we investigated the feasibility of establishing patient-derived xenografts (PDXs) from a patient's tumor in order to screen for therapies that the patient could benefit from. Samples obtained from 29 primary tumors and liver metastases of uveal melanoma were grafted into SCID mice. PDX models were successfully established for 35% of primary patient tumors and 67% of liver metastases. The tumor take rate was proportional to the risk of metastases. PDXs showed the same morphology, the same GNAQ/11, BAP1, and SF3B1 mutations, and the same chromosome 3 and 8q status as the corresponding patient samples. Six PDX models were challenged with two compounds for 4 weeks. We show that, for 31% of patients with high or intermediate risk of metastasis, the timing to obtain efficacy results on PDX models derived from their primary tumors was compatible with the selection of the therapy to treat the patient after relapse. PDXs could thus be a valid tool ("avatar") to select the best personalized therapy for one third of patients that are most at risk of relapse.


Interlaminar versus transforaminal epidural steroids for the treatment of subacute lumbar radicular pain: a randomized, blinded, prospective outcome study.
There is uncertainty in the literature over the relative effectiveness of lumbar epidural interlaminar (IL) steroid injection versus transforaminal (TF) steroid injection for lumbar radiculopathy. Most studies to date have been retrospective, or technically focused. To complete a randomized, blinded, prospective outcome study of the short-term benefit for IL versus TF epidural steroids for the treatment of subacute lumbar radicular pain. Prospective, randomized, blinded, subacute efficacy trial. Tertiary care pain management center, major metropolitan city, United States. After institutional review board approval, 42 age-matched patients with similar lower back pain and unilateral radicular symptoms were enrolled and randomized in a patient and evaluating physician blinded trial to IL or TF epidural steroids from 2007 through 2009. Prior to intervention and 10-16 days after injection, each participant was evaluated by questionnaire and physical exam by an independent physician. All injections were performed by the same physician. Thirty-eight participants completed the study, 18 in the IL group and 20 in the TF group. Four participants required a repeat injection, and 2 participants crossed over to the alternative injection type (IL to TF). Overall, physical exam, diagnostic testing, disability, activity, depression measures, and opioid pill use were similar between the 2 groups, both pre-injection baseline and post-injection improvement. In primary outcomes, the post-injection follow-up Numeric Rating Scale (NRS) was more greatly reduced in the TF group. The NRS decreased from 7.0 ± 1.9 to 3.9 ± 3.1 (mean values +/- standard deviation) in the IL group and 6.4 ± 2.1 to 1.7 ± 1.4 in the TF group. The Oswestry Disability Index was reduced from 37.5 ± 12.6 to 19.0 ± 16.7 in the IL group and 38.3 ± 6.4 to 21.6 ± 16.8 in the TF group. In secondary outcomes, the depression scale was reduced from 4.39 ± 3.22 to 2.28 ± 3.20 in the IL group and 4.10 ± 1.94 to 1.65 ± 1.63 in the TF group. Walking tolerance was increased from 8.1 ± 4.6 blocks to 10.6 ± 4.4 in the IL group and 8.9 ± 5.3 blocks to 11.8 ± 4.2 in the TF group. The study did not examine long-term outcomes. A single experienced interventionalist performed all injections. Results suggest that patients may experience greater subjective relief, at least initially, from TF epidural steroid injections over IL. However, more objective, and likely subacute, therapeutic effects are similar.


Understanding the evolutionary relationship of hemagglutinin protein from influenza viruses using phylogenetic and molecular modeling studies.
The existing H1N1 (2009) swine flu is pandemic in nature and is responsible for global economic losses and fatalities. Among the eight gene segments of H1N1, hemagglutinin (HA) plays a major role in the attachment of the virus to the host cell surface and entry of viral RNA into the host cell leads to infection. In this study, sequence and phylogenetic analysis of the H1N1 (2009) HA, from Mexico City along with 1952 sequences, from different subtypes of pandemic influenza A virus were studied and results showed that the closest relationship of H1N1 (2009) Mexico strain was with the H1N1 (2007) Mallard Norway strain. Analysis of secondary structures predicted from the protein sequence revealed that diminishing of alpha helixes was observed in many areas of the sequences between the years 2005 to 2010. Conversely, analysis at the structural level is necessary to critically assess the functional significance. Structural level investigation was therefore done for the above said proteins by constructing the 3D structure of these proteins through homology modeling. The models were validated and structural level similarities were evaluated through superimposition. Subsequently, docking studies were done to find the binding mode of the sialic acid (SA) with influenza HA. Molecular dynamics simulations were executed to study the interactions of SA molecule with the HA. Energetic analysis reveals that van der Waal interaction is more favorable for binding of HA with SA of the whole influenza virus. Binding pocket analysis shows that intensities of H-bond donor and acceptor are more in H1N1 (2009).


A case of primary cutaneous extranodal natural killer/t-cell lymphoma, nasal type, with a 22-year indolent clinical course.
Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a rare type of cytotoxic lymphoma involving mainly the upper aerodigestive tract and associated with Epstein-Barr virus. The disease has usually a poor prognosis related to several factors. The skin is the second most common affected organ, and cases may be localized to the skin only without any other extracutaneous manifestations. Although primary cutaneous cases may have a better prognosis, survival usually is still poor. We report a case of primary cutaneous extranodal NK/T-cell lymphoma, nasal type, in a 77-year-old woman with an indolent course for more than 22 years and still limited to the skin.


ISO-66, a novel inhibitor of macrophage migration, shows efficacy in melanoma and colon cancer models.
Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine, which possesses a contributing role in cancer progression and metastasis and, thus, is now considered a promising anticancer drug target. Many MIF-inactivating strategies have proven successful in delaying cancer growth. Here, we report on the synthesis of ISO-66, a novel, highly stable, small-molecule MIF inhibitor, an analog of ISO-1 with improved characteristics. The MIF:ISO-66 co-crystal structure demonstrated that ISO-66 ligates the tautomerase active site of MIF, which has previously been shown to play an important role in its biological functions. In vitro, ISO-66 enhanced specific and non-specific anticancer immune responses, whereas prolonged administration of ISO-66 in mice with established syngeneic melanoma or colon cancer was non-toxic and resulted in a significant decrease in tumor burden. Subsequent ex vivo analysis of mouse splenocytes revealed that the observed decrease in tumor growth rates was likely mediated by the selective in vivo expansion of antitumor-reactive effector cells induced by ISO-66. Compared to other MIF-inactivating strategies employed in vivo, the anticancer activity of ISO-66 is demonstrated to be of equal or better efficacy. Our findings suggest that targeting MIF, via highly specific and stable compounds, such as ISO-66, may be effective for cancer treatment and stimulation of anticancer immune responses.


Risk factors for cardiovascular disease in a Portuguese university population.
To characterize the distribution of risk factors for cardiovascular disease among university students, through calculating the prevalence of hypercholesterolemia, hyperhomocysteinemia, hyperglycemia, hypertension, overweight, and sedentarism, as well as nutrient intake. Cross-sectional study in a random stratified sample of 378 students from Aveiro University in the 2005/2006 academic year. Lifestyle questionnaires were completed on dietary habits and physical activity. The following were assessed: anthropometric measures, blood pressure, lipids, glycemia and homocysteine. Homocysteine was measured in 32 (25.2%) males and 95 (74.8%) females. A high prevalence of sedentarism was found (0.55, 95% CI: 0.50 to 0.60). The prevalence of overweight was 12.2% (0.122, 95% CI: 0.09 to 0.16) and of obesity 3.2% (0.032, 95% CI: 0.02 to 0.06). Hypercholesterolemia was found in 17.7% (0.177, 95% CI, 0.14 to 0.2) of the students and hypertension in 13.7% of males and 3.5% of females (p<0.001). High levels of homocysteine were found in 15.6% of males. The prevalence of hypercholesterolemia among health sciences students was higher than in technical and natural sciences (20.2% vs. 13.7%). Human and social sciences was the area with the highest prevalence of risk factors for non-communicable diseases (NCDs) (38.1%). The high prevalence of risk factors for NCDs in higher education highlights the need for nutritional and health promotion programs, emphasizing the harmful effects of sedentary behavior. Longitudinal study of this cohort will enable analysis of the impact of such behavior in early life on subsequent development of health problems.


Anatomic investigation of the lumbosacral plexus of the helmeted guinea fowl (Numida meleagris).
The study was conducted for the determination of the main nerves of the lumbosacral plexus in the helmeted guineafowl. Five helmeted guineafowls were used. Fowls were anaesthetised and the a. carotis communis was cut for blood drainage. Body cavities were revealed and were fixated with 10% formaldehyde. Nerves forming the lumbosacral plexus were dissected and photographed. Results were named according to the Nomina Anatomica Avium. It was determined that the lumbosacral plexus forms by 8 synsacral ventral rami from the ventrolateral side of synsacrum which include (2-9) synsacral spinal nerves. It was seen that the lumbar plexus was formed by the ventral rami of the 2nd, 3rd and 4th spinal nerves, and the sacral plexus was formed by the ventral rami of the 5th, 6th, 7th, 8th and 9th synsacral spinal nerves. It was observed that following nerves of n. pubicus (ilioinguinalis), r. cutaneous femoris lateralis, r. cutaneous femoris medialis (n. saphenus), n. femoralis and n. obturatorius originate from the lumbar plexus, and following nerves of n. ischiadicus, the common branch of n. fibularis and n. tibialis originate from the sacral plexus. It was determined that the n. ischiadicus was formed by the truncus cranialis, medianus and caudalis. In conclusion, it was determined that there are macro anatomical differences between different avian species in the quantity, thickness and distribution of the spinal nerves that form the lumbosacral plexus, and in formations of the plexus, and in separations of nerve branches.


Asymptotic behavior of irreducible excitatory networks of analog graded-response neurons.
In irreducible excitatory networks of analog graded-response neurons, the trajectories of most solutions tend to the equilibria. We derive sufficient conditions for such networks to be globally asymptotically stable. When the network possesses several locally stable equilibria, their location in the phase space is discussed and a description of their attraction basin is given. The results hold even when interunit transmission is delayed.


Postoperative radiation therapy for parotid pleomorphic adenoma with close or positive margins: treatment outcomes and toxicities.
To evaluate the locoregional control and treatment toxicity of patients with pleomorphic adenoma after resection with close or positive margins followed by postoperative radiation therapy (PORT). Between 2002 and 2011, twenty-one patients underwent PORT at the Mount Sinai Beth Israel Medical Center for pleomorphic adenoma of the parotid with close or positive margins. Four out of the 21 patients (19%) had recurrent lesions. The median dose was 57.6 Gy (range 55.8-69.96) delivered at 1.8-2.12 Gy/fraction. Treatment and follow-up data were retrospectively analyzed for locoregional control as well as acute- and late-treatment toxicities. Actuarial survival analysis was also performed. Twelve women and 9 men with a median age of 46 (26-65) at PORT were included in this study. Eighty-one percent of the cohort had positive resection margins while 19% had close margins. At a median follow-up of 92 months, 19/21 patients (90%) had locoregional control. Two patients who failed had primary lesions which recurred locally, and initially had positive margins. The two recurrences occurred at 8 months and 12 months. Acute Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicities were experienced by 11 (52%) and 4 (19%) patients, respectively, while 2 (10%) experienced late RTOG grade 1 toxicities. No patients experienced any grade 2-4 late toxicities. Actuarial survival was 100%. PORT for patients with pleomorphic adenoma of the parotid gland after resection with close or positive margins results in excellent locoregional control and low treatment-related morbidity.


[The morbidity after sepsis motivates person-centred clinical follow-up].
The documented morbidity problems after sepsis motivated inclusion of routine clinical follow-up at 2-6 weeks after sepsis care in the national patient-centred clinical pathway for sepsis in Sweden. This routine has been evaluated in a pilot study, in which a nurse at a department of infectious diseases performed a structured telephone follow-up after sepsis care. The pilot study showed that the routine was resource demanding and illustrated that it is not optimal to use a uniform follow-up routine in a broad sepsis population. Thus, the clinical follow-up recommendations within the patient-centred clinical pathway for sepsis should be updated, adapted for broadly available health-care structures, and more person-centred.


F-doping of nanostructured ZnO: a way to modify structural, electronic, and surface properties.
Polycrystalline ZnO is a material often used in heterogeneous catalysis. Its properties can be altered by the addition of dopants. We used gaseous fluorine (F2(g)) as direct way to incorporate fluoride in ZnO as anionic dopants. Here, the consequences of this treatment on the structural and electronic properties, as well as on the acidic/basic sites of the surface, are investigated. It is shown that the amount of F incorporation into the structure can be controlled by the synthesis parameters (t, T, p). While the surface of ZnO was altered as shown by, e.g., IR spectroscopy, XPS, and STEM/EDX measurements, the F2 treatment also influenced the electronic properties (optical band gap, conductivity) of ZnO. Furthermore, the Lewis acidity/basicity of the surface was affected which is evidenced by using, e.g., different probe molecules (CO2, NH3). In situ investigations of the fluorination process offer valuable insights on the fluorination process itself.


Functional reserve: The residual variance in instrumental activities of daily living not explained by brain structure, cognition, and demographics.
Cognitive reserve is a concept that explains individual differences in resilience to brain pathology and susceptibility to poor late-life cognitive outcomes. We evaluate the analogous concept of "Functional Reserve," defined as the difference between observed functional abilities and those predicted by brain structure, cognitive performance, and demographics. This study aims to validate the construct of functional reserve by testing its utility in predicting clinical outcomes and exploring its predictors. Longitudinal data collected annually for up to 7 years from 1,084 older adults (ndementia = 163; nMCI = 333; nCN = 523) were analyzed. Functional reserve was operationalized as the residual variance in the Lawton-Brody Instrumental Activities of Daily Living (IADL) Scale after accounting for demographics (sex/gender, race, ethnicity, education), neuropathology (gray matter, hippocampal, and white matter hyperintensity volumes), and cognition (executive function, verbal episodic memory, semantic memory, and spatial function). Structural equation models estimated (a) functional reserve's associations with 7-year changes in clinical diagnosis and disease severity and (b) predictors of functional reserve. Functional reserve was lower in dementia versus cognitively normal individuals. Higher baseline functional reserve was associated with lower concurrent dementia severity and slower clinical progression and attenuated the association of cognition with concurrent dementia severity. Physical function and apathy were the strongest predictors of functional reserve. Results provide preliminary validation of functional reserve for explaining individual differences in susceptibility to IADL dysfunction independent of neuropathology, cognition, and demographics. Physical functioning and apathy are promising modifiable intervention targets to enhance functional reserve in the context of brain atrophy and cognitive decline. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Investigating Drought Tolerance in Chickpea Using Genome-Wide Association Mapping and Genomic Selection Based on Whole-Genome Resequencing Data.
Drought tolerance is a complex trait that involves numerous genes. Identifying key causal genes or linked molecular markers can facilitate the fast development of drought tolerant varieties. Using a whole-genome resequencing approach, we sequenced 132 chickpea varieties and advanced breeding lines and found more than 144,000 single nucleotide polymorphisms (SNPs). We measured 13 yield and yield-related traits in three drought-prone environments of Western Australia. The genotypic effects were significant for all traits, and many traits showed highly significant correlations, ranging from 0.83 between grain yield and biomass to -0.67 between seed weight and seed emergence rate. To identify candidate genes, the SNP and trait data were incorporated into the SUPER genome-wide association study (GWAS) model, a modified version of the linear mixed model. We found that several SNPs from auxin-related genes, including auxin efflux carrier protein (PIN3), p-glycoprotein, and nodulin MtN21/EamA-like transporter, were significantly associated with yield and yield-related traits under drought-prone environments. We identified four genetic regions containing SNPs significantly associated with several different traits, which was an indication of pleiotropic effects. We also investigated the possibility of incorporating the GWAS results into a genomic selection (GS) model, which is another approach to deal with complex traits. Compared to using all SNPs, application of the GS model using subsets of SNPs significantly associated with the traits under investigation increased the prediction accuracies of three yield and yield-related traits by more than twofold. This has important implication for implementing GS in plant breeding programs.


Slow magnetic relaxation in Ni-Ln (Ln = Ce, Gd, Dy) dinuclear complexes.
Three new isomorphous complexes [Ni(o-van-en)LnCl3(H2O)] [H2(o-van-en) = N,N'-ethylene-bis(3-methoxysalicylaldiminate; Ln = Ce (1), Gd (2), Dy (3)] were prepared by a stepwise reaction using mild conditions and were structurally characterised as dinuclear molecules in which Ni and Ln are coordinated by the compartmental Schiff base ligand (o-van-en)= and doubly bridged by O atoms. While the nickel(ii) centre is diamagnetic within the N2O2 square-planar coordination of the Schiff base ligand, the lanthanide atoms are octa-coordinated to give an {LnCl3O5} chromophore with a fac-arrangement of the chlorido ligands. AC magnetic measurements revealed that all three complexes, including the nominally isotropic Gd(iii) system, show field induced slow magnetic relaxation with two or three relaxation channels: at T = 1.9 K the low-frequency relaxation time is τLF(1) = 0.060 s at BDC = 0.5 T, τLF(2) = 0.37 s at BDC = 0.3 T, and τLF(3) = 1.29 s at BDC = 0.15 T.


Antihypertensive activity of isradipine in humans: a new dihydropyridine calcium channel antagonist.
Isradipine (Sandoz PN 200-110), a new dihydropyridine calcium channel antagonist, was evaluated in a randomized, double-blind, placebo-controlled trial for antihypertensive efficacy in 24 patients with essential hypertension. Two groups were studied: one received placebo throughout the entire study (n = 12) and the other received isradipine (n = 12), 2.5 mg b.i.d., for the first week, 5 mg b.i.d. the second week, and 10 mg b.i.d. the third week after an initial 3-week baseline placebo period. Blood pressure was measured approximately 3 hours after dosing. Isradipine, at a total daily dose of 10 mg, lowered average supine diastolic blood pressure 11.8 mm Hg, with only a 3.5 mm Hg decrease in systolic blood pressure compared with baseline. At a total daily dose of 20 mg, average supine diastolic blood pressure decreased 14.8 mm Hg and supine systolic blood pressure declined 13.9 mm Hg; both were significantly decreased compared with placebo or baseline. Heart rate was increased only minimally by isradipine. Renin level activity was increased slightly by isradipine. No serious adverse clinical or laboratory experiences were noted. Isradipine appears to be effective in lowering blood pressure without reflex tachycardia.


Growth and physiological responses of neotropical mangrove seedlings to root zone hypoxia.
Seedlings of Rhizophora mangle L., Avicennia germinans (L.) Stearn., and Laguncularia racemosa (L.) Gaertn. f. were cultured in aerated or N(2)-purged solution for 12 weeks to assess their relative responses to low oxygen tensions. All three species responded to low oxygen treatment by modifying physiological and morphological patterns to decrease carbon loss by root respiration. However, the extent to which seedling physiology and morphology were altered by low oxygen treatment differed among species. Maintenance of root oxygen concentrations, root respiration rates and root extension rates by R. mangle demonstrated an ability to avoid low oxygen stress with minimal changes in root morphology and physiology. In contrast, oxygen concentrations in A. germinans and L. racemosa roots declined from 16 to 5% or lower within 6 h of treatment. Root hypoxia led to significant decreases in respiration rates of intact root systems (31 and 53% below controls) and root extension rates (38 and 76% below controls) by A. germinans and L. racemosa, respectively, indicating a greater vulnerability of these species to low oxygen tensions in the root zone compared with R. mangle. I conclude that the relative performance of mangrove seedlings growing in anaerobic soils is influenced by interspecific differences in root aeration and concomitant effects on root morphology and physiology.


Age, abdominal obesity, and baseline high-sensitivity C-reactive protein are associated with low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B responses to ezetimibe/simvastatin and atorvastatin in patients with metabolic syndrome.
Treatment response to lipid-lowering therapy can vary in patients with the metabolic syndrome (MetS) due to various patient demographic and baseline characteristics. This study assessed the relationships between baseline characteristics and changes in lipid variables, high-sensitivity C-reactive protein (hs-CRP) and attainment of prespecified low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) levels in MetS patients treated with ezetimibe/simvastatin and atorvastatin. This is a post-hoc analysis of a multicenter, double-blind, randomized, 6-week parallel study in >1000 hypercholesterolemic subjects (median age of 59 years) with MetS and moderately high/high coronary heart disease risk who were treated with ezetimibe/simvastatin (10/20 and 10/40 mg) or atorvastatin (10, 20, 40 mg). Factors that could affect these treatments were assessed by multivariate analysis. Increasing age, abdominal obesity (waist circumference ≥ 40/35 inches for men/women), and lower baseline hs-CRP were significant predictors of greater reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, triglycerides, and very-low-density lipoprotein cholesterol but not for changes in HDL-C or apolipoprotein AI; effects of race and baseline triglycerides, non-HDL-C, LDL-C, or HDL-C levels were more limited. Age ≥ 65 years (versus <65 years) was also associated with significantly greater attainment of all LDL-C and non-HDL-C targets, whereas abdominal obesity, gender (female > male) and lower baseline LDL-C, non-HDL-C, triglycerides, and hs-CRP were associated with improved attainment for some of these targets. Blood pressure, fasting glucose, Homeostasis Model Assessment of Insulin Resistance tertiles, and diabetes did not predict response for any efficacy variable. Ezetimibe/simvastatin treatment (versus atorvastatin) was a significant predictor for change in most efficacy variables. Treatment responses to ezetimibe/simvastatin and atorvastatin in at-risk patients with the MetS were related to age (≥ 65 years), abdominal obesity, and lower baseline hs-CRP. Ezetimibe/simvastatin treatment was found to be consistently more effective than atorvastatin at the specified dose comparisons across these subgroups. The clinical value of predictive factors requires further study in outcome trials.


Adherence to Treat-to-target Management in Rheumatoid Arthritis and Associated Factors: Data from the International RA BIODAM Cohort.
Compelling evidence supports a treat-to-target (T2T) strategy for optimal outcomes in rheumatoid arthritis (RA). There is limited knowledge regarding the factors that impede implementation of T2T, particularly in a setting where adherence to T2T is protocol-specified. We aimed to assess clinical factors that associate with failure to adhere to T2T. Patients with RA from 10 countries who were starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required per protocol to adhere to the T2T strategy. Factors influencing adherence to T2T low disease activity (T2T-LDA; 44-joint count Disease Activity Score ≤ 2.4) were analyzed in 2 types of binomial generalized estimating equations models: (1) including only baseline features (baseline model); and (2) modeling variables that inherently vary over time as such (longitudinal model). A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. Failure of adherence to T2T-LDA was noted in 1765 visits (40.5%). In the baseline multivariable model, a high number of comorbidities (OR 1.10, 95% CI 1.02-1.19), smoking (OR 1.32, 95% CI 1.08-1.63) and high number of tender joints (OR 1.03, 95% CI 1.02-1.04) were independently associated with failure to implement T2T, while anticitrullinated protein antibody/rheumatoid factor positivity (OR 0.63, 95% CI 0.50-0.80) was a significant facilitator of T2T. Results were similar in the longitudinal model. Lack of adherence to T2T in the RA BIODAM cohort was evident in a substantial proportion despite being a protocol requirement, and this could be predicted by clinical features. [Rheumatoid Arthritis (RA) BIODAM cohort; ClinicalTrials.gov: NCT01476956].


Avian Influenza A Virus Infects Swine Airway Epithelial Cells without Prior Adaptation.
Pigs play an important role in the interspecies transmission of influenza A viruses (IAV). The porcine airway epithelium contains binding sites for both swine/human IAV (α2,6-linked sialic acids) and avian IAV (α2,3-linked sialic acids) and therefore is suited for adaptation of viruses from other species as suggested by the "mixing vessel theory". Here, we applied well-differentiated swine airway epithelial cells to find out whether efficient infection by avian IAV requires prior adaption. Furthermore, we analyzed the influence of the sialic acid-binding activity and the virus-induced detrimental effects. Surprisingly, an avian IAV H1N1 strain circulating in European poultry and waterfowl shows increased and prolonged viral replication without inducing a strong innate immune response. This virus could infect the lower respiratory tract in our precision cut-lung slice model. Pretreating the cells with poly (I:C) and/or JAK/STAT pathway inhibitors revealed that the interferon-stimulated innate immune response influences the replication of avian IAV in swine airway epitheliums but not that of swine IAV. Further studies indicated that in the infection by IAVs, the binding affinity of sialic acid is not the sole factor affecting the virus infectivity for swine or human airway epithelial cells, whereas it may be crucial in well-differentiated ferret tracheal epithelial cells. Taken together, our results suggest that the role of pigs being the vessel of interspecies transmission should be reconsidered, and the potential of avian H1N1 viruses to infect mammals needs to be characterized in more detail.


Estrogen supplementation reduces whole body leucine and carbohydrate oxidation and increases lipid oxidation in men during endurance exercise.
Healthy active men exhibit higher rates of carbohydrate (CHO) and leucine oxidation and lower rates of lipid oxidation compared with their female counterparts both at rest and during moderate intensity endurance exercise. We postulated that this reduced dependence on amino acids as a fuel source in women was due to the female sex hormone estrogen. In a randomized, double-blind, placebo-controlled, cross-over design, we investigated the effect of supplementing 12 recreationally active men with estrogen on whole body substrate oxidation and leucine kinetics at rest and during moderate intensity endurance exercise. Subjects cycled for 90 min at an intensity of 65% maximum O(2) consumption after 8 d of either estrogen supplementation (2 mg 17beta-estradiol/d) or placebo (polycose). After a 2-wk washout period, they repeated the test after 8 d of the alternate treatment. On the test day, after a primed continuous infusion of l-[(13)C]leucine, O(2) consumption, CO(2) production, steady-state breath (13)CO(2), and plasma alpha-[(13)C]ketoisocaproate enrichments were measured at rest and at 60, 75, and 90 min during exercise in the postabsorptive state. Exercise increased energy expenditure more than 5-fold, CHO oxidation more than 6-fold, lipid oxidation more than 4-fold, and leucine oxidation 2.2-fold (all P < 0.0001), whereas it decreased the ratio of lipid to CHO oxidation by 50-70% (P = 0.003) compared with values at rest. Estrogen supplementation decreased respiratory exchange ratio during exercise (P = 0.03). Estrogen supplementation significantly decreased CHO oxidation by 5-16% (P = 0.04) and leucine oxidation by 16% (P = 0.01), whereas it significantly increased lipid oxidation by 22-44% (P = 0.024) at rest and during exercise. We conclude that estrogen influences fuel source selection at rest and during endurance exercise in recreationally active men, characterized by a reduced dependence on amino acids and CHO and an increased reliance on lipids as a fuel source.


High-protein diet with immediate post-exercise protein drink: Impact on appetite in middle-aged obesity.
Successful management of obesity can be challenging if individuals constantly experience cravings. The present study investigated the effects of a high-protein diet, including a high-protein drink consumed immediately after high-intensity interval training (HIIT), on appetite and weight loss in obese middle-aged individuals. A total of 52 obese middle-aged individuals (58.2 ± 4.11 years old) were randomly assigned to one of three groups: the exercise group (E, n=19), exercise and high-protein diet group (ED, n=21), and a control group (n=12). The E and ED groups engaged in cycling HIIT (comprising 90 % of peak heart rate (HRpeak) for 3 min, followed by 70 % of HRpeak for 3 min, for a total of 5 cycles) three times a week for 3 months. The ED group consumed a high-protein drink immediately after HIIT and had a daily protein intake of 1.6g/kg. Body composition and eating behavior were assessed before and after the intervention. Additionally, appetite levels were measured before and after each exercise session, before dinner, and before bedtime during three phases of the intervention: the first phase (weeks 3-4), the second phase (weeks 5-8), and the third phase (weeks 9-12). Results showed that only the ED group experienced a decrease in body mass index (from 27.4 ± 4.28 to 26.8 ± 4.09 kg/m2, p=0.04). Appetite significantly increased after exercise in both E and ED groups (p values for the three phases ranged from 0.04 to 0.001 for the E group and from 0.042 to 0.003 for the ED group). The desire to eat significantly increased after exercise in the E group (phase 1: p = 0.026; phase 2: p = 0.011; phase 3: p = 0.003), but not in the ED group. Furthermore, the frequency of late-night snacking decreased in the ED group (the score changed from 2.4 ± 0.86 to 2.7 ± 0.80, p = 0.034). Notably, the E group tended to have a higher pre-dinner appetite score than the ED group in the third phase (p = 0.063). In summary, a high daily protein intake, combined with the consumption of high-protein drinks after exercise, resulted in reduced post-exercise appetite and a decrease in the frequency of late-night snacking.


Giving patients secure << Google-like >> access to their medical record.
The main problem for the patient who wants to have access to all of the information about his health is that this information is very often spread over many medical records. Therefore, it would be convenient for the patient, after being identified and authenticated, to use a kind of specific medical search engine as one part of the solution to this main problem. The principal objective is for the patient to have access to his or her medical information at anytime and wherever it has been stored. This proposal for secure "Google Like" access requires the addition of different conditions: very strict identity checks using cryptographic techniques such as those planned for the electronic signature, which will not only ensure authentication of the patient and integrity of the file, but also protection of the confidentiality and access follow-up. The electronic medical record must also be electronically signed by the practitioner in order to provide evidence that he has given his agreement and accepted responsibility for the content. This electronic signature also prevents any kind of post-transmission falsification. New advances in technology make it possible to envisage access to medical records anywhere and anytime, thanks to Grid and watermarking methodologies.


Malignant hyperthermia-like reaction secondary to ingestion of hops in five dogs.
Five dogs, 4 of which were Greyhounds, suffered adverse effects secondary to the ingestion of spent hops. Mean time to onset of clinical signs was 3 hours, and clinical signs included marked hyperthermia, restlessness, panting, vomiting, signs of abdominal pain, and seizures. Four of the 5 dogs died despite aggressive therapeutic measures, and there was rapid onset of rigor mortis in 3. The overrepresentation of Greyhounds, coupled with the clinical signs, was suggestive of a malignant hyperthermia-like response to the ingestion of hops. It also is possible that hops contain an uncoupler of oxidative phosphorylation.


The potential for intelligent decision support systems to improve the quality and consistency of medication reviews.
Drug-related problems (DRPs) are of serious concern worldwide, particularly for the elderly who often take many medications simultaneously. Medication reviews have been demonstrated to improve medication usage, leading to reductions in DRPs and potential savings in healthcare costs. However, medication reviews are not always of a consistently high standard, and there is often room for improvement in the quality of their findings. Our aim was to produce computerized intelligent decision support software that can improve the consistency and quality of medication review reports, by helping to ensure that DRPs relevant to a patient are overlooked less frequently. A system that largely achieved this goal was previously published, but refinements have been made. This paper examines the results of both the earlier and newer systems. Two prototype multiple-classification ripple-down rules medication review systems were built, the second being a refinement of the first. Each of the systems was trained incrementally using a human medication review expert. The resultant knowledge bases were analysed and compared, showing factors such as accuracy, time taken to train, and potential errors avoided. The two systems performed well, achieving accuracies of approximately 80% and 90%, after being trained on only a small number of cases (126 and 244 cases, respectively). Through analysis of the available data, it was estimated that without the system intervening, the expert training the first prototype would have missed approximately 36% of potentially relevant DRPs, and the second 43%. However, the system appeared to prevent the majority of these potential expert errors by correctly identifying the DRPs for them, leaving only an estimated 8% error rate for the first expert and 4% for the second. These intelligent decision support systems have shown a clear potential to substantially improve the quality and consistency of medication reviews, which should in turn translate into improved medication usage if they were implemented into routine use.


Sexually segregated housing results in improved early larval survival in zebrafish.
Large-scale aquaculture facilities require highly optimized husbandry protocols that maximize fecundity and embryo health while minimizing cost and effort. Although zebrafish are being increasingly used for preclinical drug screens, functional genomic research and toxicological and behavioral studies, many of the basic husbandry procedures that are used for these fish have not been thoroughly tested. In this study, the authors compared the breeding success of zebrafish housed in sex-separated and those housed in mixed-gender arrangements. They observed a significant increase in fecundity (egg production) between the first and the third breeding and found that egg survivorship tended to increase during successive pairings. The authors also found that zebrafish had higher fecundity, egg viability and seemed to have a higher breeding success rate when males and females were housed separately than when they were housed together.


Replication profile of Saccharomyces cerevisiae chromosome VI.
An understanding of the replication programme at the genome level will require the identification and characterization of origins of replication through large, contiguous regions of DNA. As a step toward this goal, origin efficiencies and replication times were determined for 10 ARSs spanning most of the 270 kilobase (kb) chromosome VI of Saccharomyces cerevisiae. Chromosome VI shows a wide variation in the percentage of cell cycles in which different replication origins are utilized. Most of the origins are activated in only a fraction of cells, suggesting that the pattern of origin usage on chromosome VI varies greatly within the cell population. The replication times of fragments containing chromosome VI origins show a temporal pattern that has been recognized on other chromosomes--the telomeres replicate late in S phase, while the central region of the chromosome replicates early. As demonstrated here for chromosome VI, analysis of the direction of replication fork movement along a chromosome and determination of replication time by measuring a period of hemimethylation may provide an efficient means of surveying origin activity over large regions of the genome.


[The "alcohol and pregnancy" link in training in nursing or social work: A topic to reconsider?]
Alcohol consumption by pregnant women and its related dangers have been a major concern for public authorities for almost twenty years. Students finishing their training in nursing or social work are only slightly over twenty themselves. The job they are soon going to practice, as a graduate nurse, social worker, financial and family counsellor, or a specialized teacher, can lead them to come into contact with pregnant alcohol-drinking women.Based on a survey conducted in a training center for these two types of students, this study aims to understand the knowledge and representations these students have on the issue of "alcohol and pregnancy" within their future field of work.Despite having received little or no training on this topic, these students are aware of the dangers of alcohol consumption during pregnancy. As future professionals, they are poorly equipped, but they do feel able to deal with this issue. Some of them also demonstrated social misrepresentations about the people who would be affected by alcohol consumption during pregnancy. All these elements call for a rethink about the training methods that should be provided to them.


Measuring quality of life in first-episode psychosis.
Quality of life (QoL) measures are increasingly recognized as necessary parts of outcome assessments in psychosis. The present paper is a comprehensive study of patients with first-episode psychosis where QoL is measured by the commonly used Lehman Quality of Life Interview (L-QoLI). The aim is to examine if the L-QoLI maintain its original structure when used in a group of patients with first-episode psychosis, and to investigate what determines global subjective QoL with a specific emphasis on premorbid adjustment, duration of untreated psychosis (DUP) and clinical symptoms. The study indicates that the psychometric properties of the L-QoLI do not change significantly when used in first-episode samples. The patients report subjective and objective QoL in the fair to good range, with only a moderate association between the objective and subjective measures. Poor global satisfaction is predicted by being single, abusing drugs, being depressed, having a diagnosis of psychotic affective disorder, having poor premorbid social adjustment and DUP over 10 weeks. The study supports the notion that patients with first-episode psychosis construct QoL in the same way as other groups, and that longer durations of compromised function at this stage produces poor satisfaction with life rather than a downward readjustment of expectations.


Comparison of Office Blood Pressure, Automated Unattended Office Blood Pressure, Home Blood Pressure, and 24-Hour Ambulatory Blood Pressure Measurements.
Although previous studies have reported differences of blood pressure (BP) according to BP measurement methods, studies in Korean population were scarce. This study aimed to compare BP differences according to different BP measurement methods and assess hypertension phenotype. This prospective study recruited 183 individuals (mean 55.9 years; 51.4% males). The BP measurements included office BP (auscultatory attended office BP [ausAOBP], automated attended office BP [aAOBP], and automated unattended office BP [aUAOBP]) and out-of-office BP (home BP [HBP] and ambulatory BP [ABP]) measurements taken within one week of each other. The mean systolic/diastolic BP differences between ausAOBP and other BPs according to different BP measurement methods were 3.5/2.3 mmHg for aAOBP; 6.1/2.9 mmHg for aUAOBP; 15.0/7.3 mmHg for daytime ABP; and 10.6/3.4 mmHg for average HBP. The increasing disparity between ausAOBP and other BPs in multivariable regression analysis was significantly associated with increasing BP. The prevalence of white-coat hypertension and masked hypertension in 107 individuals not taking antihypertensive medication was 25.4-26.8% and 30.6-33.3% based on ausAOBP, daytime ABP, and average HBP, respectively. The prevalence of white-coat uncontrolled hypertension and masked uncontrolled hypertension in 76 of those taking antihypertensive medication was 31.7-34.1% and 17.1-37.1%, respectively. This study showed a large disparity between office BP and out-of-office BP which became more pronounced when office BP by auscultation increased, suggesting that various BP measurement methods should be used to more accurately assess BP status.


Historical research in nursing: standards for research and evaluation.
Historical research, a method of inquiry that combines science and literature, often supports a common thesis that an informed understanding of nursing history provides insights that can contribute effective approaches to current professional issues. Historical research was formally recognized by the American Nurses Association (ANA) in 1965. A review of 11 recent historical research studies supports the concept that adherence to established standards of research and presentation contributes to the value of historical research. While relating an interesting story is an intrinsic element of historical research, the research gains purpose and meaning when the presentation of data includes a statement of purpose utilizing a research question, a review of literature establishing a relation to the greater nursing community, and a concluding analysis relating the research to current and future professional issues.


CD44v6 coordinates tumor matrix-triggered motility and apoptosis resistance.
Tumor progression requires a crosstalk with the tumor surrounding, where the tumor matrix plays an essential role. We recently reported that only the matrix delivered by a CD44v6-competent (ASML(wt)), but not that of a CD44v6-deficient (ASML-CD44v(kd)) rat pancreatic adenocarcinoma line supports metastasis formation. We here describe that this matrix provides an important feedback toward the tumor cell and that CD44v6 accounts for orchestrating signals received from the matrix. ASML(wt) cells contain more hyaluronan synthase-3 and secrete higher amounts of >50 kDa HA than ASML-CD44v(kd) cells, which secrete more hyaluronidase. Only the ASML(wt)-matrix supports migration and apoptosis resistance, which both can be initiated via CD44v6, c-Met, and α6β4 ligand binding and proceed via FAK, PI3K/Akt, and MAPK activation, respectively. However, c-Met- and α6β4-initiated signaling are strongly augmented by the association with CD44v6 as only very weak effects are observed in CD44v6-deficient cells. The same CD44v6-dependent convergence of motility- and apoptosis resistance-related signals also accounts for human tumor lines. Thus, CD44v6 promotes motility and apoptosis resistance via its involvement in assembling a matrix that, in turn, triggers activation of signaling cascades, which proceeds, independent of the initiating receptor-ligand interaction, in a concerted action via CD44v6.


[Results of surgical treatment of rectal cancer].
The results of radical surgery for rectal cancer performed in 223 cases are presented. Preoperative angiographic examination of the vascular system of terminal part of the large bowel (lower selective pneumopharmacomesentericography) contributed to the selection of optimal surgical procedure in 30 cases. Mortality rate following radical surgery ranged 3.6--14.5% depending on a procedure used and patient's age. Early postoperative complications occurred in 53.4% depending on the type of surgery. Five-year survival was registered in 57.1%. Survival time appeared to be a function of tumor stage, site and the extent of invasion into the rectal wall.


Annealing by simulating the coherent Ising machine.
The coherent Ising machine (CIM) enables efficient sampling of low-lying energy states of the Ising Hamiltonian with all-to-all connectivity by encoding the spins in the amplitudes of pulsed modes in an optical parametric oscillator (OPO). The interaction between the pulses is realized by means of measurement-based optoelectronic feedforward, which enhances the gain for lower-energy spin configurations. We present an efficient method of simulating the CIM on a classical computer that outperforms the CIM itself, as well as the noisy mean-field annealer in terms of both the quality of the samples and the computational speed. It is furthermore advantageous with respect to the CIM in that it can handle Ising Hamiltonians with arbitrary real-valued node coupling strengths. These results illuminate the nature of the faster performance exhibited by the CIM and may give rise to a new class of quantum-inspired algorithms of classical annealing that can successfully compete with existing methods.


Genetic predisposition to adiposity is associated with increased objectively assessed sedentary time in young children.
Increased sedentariness has been linked to the growing prevalence of obesity in children, but some longitudinal studies suggest that sedentariness may be a consequence rather than a cause of increased adiposity. We used Mendelian randomization to examine the causal relations between body mass index (BMI) and objectively assessed sedentary time and physical activity in 3-8 year-old children from one Finnish and two Danish cohorts [NTOTAL=679]. A genetic risk score (GRS) comprised of 15 independent genetic variants associated with childhood BMI was used as the instrumental variable to test causal effects of BMI on sedentary time, total physical activity, and moderate-to-vigorous physical activity (MVPA). In fixed effects meta-analyses, the GRS was associated with 0.05 SD/allele increase in sedentary time (P=0.019), but there was no significant association with total physical activity (beta=0.011 SD/allele, P=0.58) or MVPA (beta=0.001 SD/allele, P=0.96), adjusting for age, sex, monitor wear-time and first three genome-wide principal components. In two-stage least squares regression analyses, each genetically instrumented one unit increase in BMI z-score increased sedentary time by 0.47 SD (P=0.072). Childhood BMI may have a causal influence on sedentary time but not on total physical activity or MVPA in young children. Our results provide important insights into the regulation of movement behaviour in childhood.


CD45 regulated signaling pathways.
CD45 is expressed on all nucleated haematopoietic cells and was originally identified as the first and prototypic transmembrane protein tyrosine phosphatase (PTPase). CD45 has been extensively studied for over two decades as a PTPase that functions in antigen receptor signaling by dephosphorylation of Src-kinases. CD45 can operate as a positive as well negative regulator of Src-family kinases. In CD45 mutant cell lines, CD45-deficient mice, and CD45-deficient human SCID patients, CD45 is required for signal transduction through antigen receptors. Our group has recently shown that CD45 can also function as a Janus kinase (JAK) tyrosine phosphatase that negatively regulates cytokine receptor signaling involved in the differentiation, proliferation, and antiviral immunity of haematopoietic cells. Moreover, a point mutation in CD45, implicated in affecting CD45 dimerization, and a genetic polymorphism that affects alternative CD45 splicing have been implicated in autoimmunity in mice and humans. CD45 is expressed in multiple isoforms and modulation of specific CD45 splice variants with antibodies can prevent transplant rejections. Moreover, loss of CD45 can affect microglia activation in a mouse model for Alzheimer's disease. Modulation of CD45 splice variants and CD45 activity might provide a unique opportunity to design drugs that turn off or turn-on antigen and cytokine receptor signaling in cancer, allergy, transplantation, or autoimmunity.


Pragmatic analysis of the electric submerged arc furnace continuum.
A transient mathematical model was developed for the description of fluid flow, heat transfer and electromagnetic phenomena involved in the production of ferronickel in electric arc furnaces. The key operating variables considered were the thermal and electrical conductivity of the slag and the shape, immersion depth and applied electric potential of the electrodes. It was established that the principal stimuli of the velocities in the slag bath were the electric potential and immersion depth of the electrodes and the thermal and electrical conductivities of the slag. Additionally, it was determined that, under the set of operating conditions examined, the maximum slag temperature ranged between 1756 and 1825 K, which is in accordance with industrial measurements. Moreover, it was affirmed that contributions to slag stirring due to Lorentz forces and momentum forces due to the release of carbon monoxide bubbles from the electrode surface were negligible.


Comorbid Influences on Generic Health-Related Quality of Life in COPD: A Systematic Review.
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and of loss of disability-adjusted life years worldwide. It often is accompanied by the presence of comorbidity. To systematically review the influence of COPD comorbidity on generic health-related quality of life (HRQoL). A systematic review approach was used to search the databases Pubmed, Embase and Cochrane Library for studies evaluating the influence of comorbidity on HRQoL in COPD. Identified studies were analyzed according to study characteristics, generic HRQoL measurement instrument, COPD severity and comorbid HRQoL impact. Studies using only non-generic instruments were excluded. 25 studies met the selection criteria. Seven studies utilized the EQ-5D, six studies each used the SF-36 or SF-12. The remaining studies used one of six other instruments each. Utilities were calculated by four EQ-5D studies and one 15D study. Patient populations covered both early and advanced stages of COPD and ranged from populations with mostly stage 1 and 2 to studies with patients classified mainly stage 3 and 4. Evidence was mainly created for cardiovascular disease, depression and anxiety as well as diabetes but also for quantitative comorbid associations. Strong evidence is pointing towards the significant negative association of depression and anxiety on reduced HRQoL in COPD patients. While all studies found the occurrence of specific comorbidities to decrease HRQoL in COPD patients, the orders of magnitude diverged. Due to different patient populations, different measurement tools and different concomitant diseases the study heterogeneity was high. Facilitating multimorbid intervention guidance, instead of applying a parsimony based single disease paradigm, should constitute an important goal for improving HRQoL of COPD patients in research and in clinical practice.


Breakthrough pain: the importance of baseline analgesic regimen with opioids.
Pain is one of the most common and often most feared symptoms in patients with cancer. Ongoing or progressive pain is physically debilitating and has a marked impact on quality of life. During their illness, at least 70% of patients will experience pain sufficiently severe to require chronic opioid treatment. Moreover, Breakthrough Pain (BTP) consists in transitory exacerbations of pain that occurs on a background of otherwise stable pain in a patient receiving chronic opioid therapy. An inadequate baseline therapy with opioids can be one of the causes of BTP. We will examine the molecular issues that influence the response of patients to opioids. Finally, we will discuss about the importance of individualizing therapy.


Identification of peptides that inhibit regulator of G protein signaling 4 function.
Regulators of G protein signaling (RGS) are a family of GTPase-activating proteins (GAP) that interact with heterotrimeric G proteins in the negative regulation of G-protein-coupled receptor (GPCR) signaling. RGS4, the first identified mammalian member of the RGS family, has been implicated in many GPCR signaling pathways involved in disease states. We report herein the identification of a 16-amino-acid peptide (P17) as an inhibitor of RGS4. The peptide was found by screening a random peptide library using RGS4 as 'bait' in a yeast two-hybrid system. This peptide inhibited RGS4 GAP activity on Galpha(i1)in a GTPase assay, and blocked the interaction between RGS4 and Galpha(i1)in a pull-down assay. The peptide displayed dose-dependent inhibition of RGS4 and Galpha-interacting protein (GAIP) GAP activities, yet showed no substantial effect on RGS7. Electrophysiological studies in Xenopus oocytes demonstrated that P17 attenuates RGS4 modulation of M(2) muscarinic receptor stimulation of GIRK (G-protein-mediated inwardly rectifying potassium) channels. Deletion of an arginine at the N terminus of P17 abolished its ability to inhibit RGS4 GAP activity, as did deletions of C-terminal residues. The P17 peptide showed no similarity to any known peptide sequence. Further investigation and optimization of the peptide may provide unique information for the development of RGS4 inhibitors for future therapeutic application.


Fostering a Diverse Pool of Global Health Academic Leaders Through Mentorship and Career Path Planning.
Established in 2011, the Global Emergency Medicine Academy (GEMA) aims "to improve the global delivery of emergency care through research, education, and mentorship." Global health remains early in its development as an academic track in emergency medicine, and there are only a small number of global emergency medicine academic faculty in most institutions. Consequently, GEMA focused its efforts at the Society for Academic Emergency Medicine (SAEM) Annual Meeting in 2019 on developing a diverse pool of global health academics and leaders in emergency medicine. Current and previous members of the GEMA Executive Committee convened to appraise and describe how current GEMA efforts situate within existing knowledge in the arenas of professional development and mentorship. The 2019 SAEM Annual Meeting unveiled the Global Emergency Medicine Roadmap, a joint venture between GEMA and the residents and medical students (RAMS) group. The roadmap guides medical students, residents, and fellows in the exploration of global emergency medicine and career development. GEMA's mentorship roundtable complemented this effort by providing a version of speed mentoring across several critical areas: work-life balance, identifying near-peer and long-distance mentoring opportunities, negotiating with your Chair, finding funding, networking, and teaching abroad. Finally, the GEMA-sponsored panel "Empowering Women through Emergency Care Development in LMICs" underscored the potential for empowering women through global emergency medicine development, including policy advocacy, inclusive research approaches, and mentorship and sponsorship. In summary, GEMA is committed to developing a diverse group of future global health leaders to guide the expansion of emergency medicine worldwide. Our work indicates critical future directions in global emergency medicine education and training including building innovative mentoring networks across institutions and countries. Further, we will continue to focus on growing faculty diversity, empowering underrepresented populations through emergency care development, and supporting rising global emergency medicine faculty in their pursuit of advancement and promotion.


Review of three magnetic resonance arthrography related infections.
We report three cases of intra-articular infection which followed injection for magnetic resonance arthrography. In an effort to reduce the risk of arthrogram related infection, representatives from radiology, infectious disease medicine, and microbiology departments convened to analyze the contributing factors. The proposed source was oral contamination from barium swallow studies which preceded the arthrogram injections in the same room. We propose safety measures to reduce incidence of arthrogram related infections.


A Sojourn on Mitochondria Targeted Drug Delivery Systems for cancer: Strategies, Clinical and Future Prospects.
Mitochondria, often referred to as the powerhouses of the cell, have emerged as promising targets for cancer therapy due to their pivotal roles in cell survival, apoptosis, and energy metabolism. This sojourn emphasizes the significance of mitochondria-targeted drug delivery systems in cancer therapeutics. The unique characteristics of cancer cell mitochondria, such as altered membrane potential and distinct lipid composition, offer an avenue for selective drug targeting. Several strategies have been explored to exploit these features, including the use of lipophilic cations, mitochondria-penetrating peptides, and nanocarriers tailored for mitochondrial delivery. Mitochondria-targeted drug delivery systems have demonstrated enhanced therapeutic efficacy and reduced systemic toxicity in preclinical models. Some of these systems have made a successful transition to clinical trials, illustrating their potential in real-world oncology settings. However, there remain challenges like intracellular barriers, potential off-target effects, and the complexity of tumor heterogeneity that must be addressed to fully harness the potential of mitochondria-targeted drug delivery systems. As research progresses, it is anticipated that innovative approaches and technologies will be developed to improve the specificity and efficacy of mitochondrial targeting, paving the way for more effective and safer cancer treatments in the future. This review serves as a comprehensive guide to the current state of mitochondria-targeted drug delivery systems for cancer, highlighting key strategies, clinical progress, and prospective avenues for future research.


Investigating the role of firing-rate normalization and dimensionality reduction in brain-machine interface robustness.
The intraday robustness of brain-machine interfaces (BMIs) is important to their clinical viability. In particular, BMIs must be robust to intraday perturbations in neuron firing rates, which may arise from several factors including recording loss and external noise. Using a state-of-the-art decode algorithm, the Recalibrated Feedback Intention Trained Kalman filter (ReFIT-KF) we introduce two novel modifications: (1) a normalization of the firing rates, and (2) a reduction of the dimensionality of the data via principal component analysis (PCA). We demonstrate in online studies that a ReFIT-KF equipped with normalization and PCA (NPC-ReFIT-KF) (1) achieves comparable performance to a standard ReFIT-KF when at least 60% of the neural variance is captured, and (2) is more robust to the undetected loss of channels. We present intuition as to how both modifications may increase the robustness of BMIs, and investigate the contribution of each modification to robustness. These advances, which lead to a decoder achieving state-of-the-art performance with improved robustness, are important for the clinical viability of BMI systems.


Current status and future prospects for new therapies for pulmonary tuberculosis.
Nowadays tuberculosis is becoming a worldwide problem, and according to the World Health Organization, which declared tuberculosis a global health emergency in 1993, each year 8 million people worldwide develop the active disease and almost 3 million die. Due to this problem there is an urgent need for new strategies and drugs to fight against this disease. In this context, this review describes promising new classes of compounds against tuberculosis that are under study, as well as promising drugs that may soon be introduced onto the market. Another subject reported in this review is inhaled therapy, an important route under study for delivering antitubercular drugs directly to the lungs. The implications of new drugs and inhaled therapy in tuberculosis treatment are fewer toxic side-effects, improved pharmacokinetics properties, extensive and potent activity against Gram-positive and Gram-negative bacteria, including resistant strains, and a reduction in the total treatment time.


Influence of metallic implants adjacent to the measurement site on DEXA measurements: a phantom study.
The use of dual-energy x-ray absorptiometry (DEXA) to measure changes in bone mineral density (BMD) at a healing fracture may be limited by the presence of a steel implant, such as an intramedullary nail or internal fixation plate. To determine the effect of steel implants adjacent to the measurement site on BMD measurements, tests were conducted on three geometries of steel and aluminium phantom. Analysis of variance performed on the BMD data from scans of the aluminium phantoms with and without steel present indicated that the steel had no effect on the results obtained at the 5% significance level. These results imply that the presence of a steel implant adjacent to an area of interest, for example a healing fracture, would not affect the reliability of DEXA scans, and that this method of monitoring healing could therefore be used with fractures stabilized by internal fixation.


Conjugates of methylated cyclodextrin derivatives and hydroxyethyl starch (HES): Synthesis, cytotoxicity and inclusion of anaesthetic actives.
The mono-6-deoxy-6-azides of 2,6-di-O-methyl-β-cyclodextrin (DIMEB) and randomly methylated-β-cyclodextrin (RAMEB) were conjugated to propargylated hydroxyethyl starch (HES) by Cu(+)-catalysed [2 + 3] cycloaddition. The resulting water soluble polymers showed lower critical solution temperatures (LCST) at 52.5 °C (DIMEB-HES) and 84.5 °C (RAMEB-HES), respectively. LCST phase separations could be completely avoided by the introduction of a small amount of carboxylate groups at the HES backbone. The methylated CDs conjugated to the HES backbone exhibited significantly lower cytotoxicities than the corresponding monomeric CD derivatives. Since the binding potentials of these CD conjugates were very high, they are promising candidates for new oral dosage forms of anaesthetic actives.


Silencing of CDK5 as potential therapy for Alzheimer's disease.
Neurodegeneration is one of the greatest public health challenges for the 21st century. Among neurodegenerative diseases, Alzheimer's disease (AD) is the most prevalent and best characterized. Nevertheless, despite the large investment in AD research, currently there is no effective therapeutic option. In the present review, we highlight a novel alternative, which takes advantage of the biotechnological outbreak deployed by the discovery of the RNA interference-based gene silencing mechanism, and its application as a tool for neurodegeneration treatment. Here, we highlight cyclin-dependent kinase 5 (CDK5) as a key candidate target for therapeutic gene silencing. Unlike other members of the cyclin-dependent kinase family, CDK5 does not seem to play a crucial role in cell cycle regulation. By contrast, CDK5 participates in multiple functions during nervous system development and has been established as a key mediator of Tau hyperphosphorylation and neurofibrillary pathology, thus serving as an optimal candidate for targeted therapy in the adult nervous system. We propose that the use of RNA interference for CDK5 silencing presents an attractive and specific therapeutic alternative for AD and perhaps against other tauopathies.


Successful pregnancy in patients with exstrophy-epispadias complex: A University of Washington experience.
With advances in genitourinary reconstructive surgery, women with exstrophy-epispadias complex (EEC) have improved health and quality of life, and may reach reproductive age and consider pregnancy. Despite literature suggesting impaired fertility and higher risk with pregnancy, childbirth is possible. Medical comorbidities, including müllerian anomalies, contribute to increased risk of obstetric and urologic complications during pregnancy. We reviewed our experience with EEC patients who achieved pregnancy to investigate (1) urological characteristics of women who achieved pregnancy; (2) pregnancy management, complications, and delivery; and (3) neonatal outcomes. We developed recommendations for managing pregnancy in women with EEC. This was a retrospective chart review of 36 female patients with EEC seen at our institution between 1996 and 2013. Female patients less than 18 years, and patients who did not have documented pregnancy were excluded. This resulted in a total of 12 patients with 22 pregnancies. All women with successful pregnancy had bladder exstrophy. The majority had undergone prior bladder augmentation (75%) and were on self-catheterization programs (92%). Thirty-six percent had symptomatic urinary tract infections (UTIs) during pregnancy. Five women had more than one pregnancy. There were four terminations of pregnancy. Of 18 desired pregnancies, there were four spontaneous abortions (SABs) (22%) and 16 live births (78%). The cesarean delivery (CD) rate was 100% (14/14), of which the majority were vertical (classical) uterine incisions with a paramedian skin incision. With the exception of one patient, there were no CD surgical complications. The mean gestational age at delivery was 36 weeks (Range 25 4/7 to 39 4/7 weeks) among eight pregnancies with known gestational age. There were no stillbirths, one neonatal death and no birth defects. Women with EEC can have successful pregnancies, though at increased risk for preterm delivery and SABs. In our cohort, the rate of SAB is similar to that described in prior studies. Symptomatic UTIs likely due to self-catheterization were common. Cesarean delivery using a paramedian skin incision and classical uterine incision were not associated with major complications in this cohort. Limitations include reliance on retrospective data and small sample size. The strength of this study is the longitudinal detailed management of pregnancies in EEC women by a single team over time. A multidisciplinary approach to providing a continuum of care from pediatrics through adolescence to adulthood optimizes successful transitions, reproductive health, and successful pregnancies. Based on our experience, an algorithm providing guidance for pregnancy management was developed.


Y-box protein-1 modulates circSPECC1 to promote glioma tumorigenesis via miR-615-5p/HIP1/AKT axis.
Y-box binding protein-1 (YB-1) is upregulated in glioma and plays an important role in its occurrence and drug resistance. However, the involved regulatory processes and downstream pathways are still unclear. Since various circular RNAs (circRNAs) and microRNAs (miRNAs) also play roles in the pathogenesis of glioma, we hypothesize that YB-1 may exert its function through a circRNA-miRNA-protein interaction network. In this study, we use the RNA binding protein immunoprecipitation assay and quantitative reverse transcription polymerase chain reaction to determine the circRNAs involved in the regulation of YB-1 and further elucidate their biological functions. The level of circSPECC1 (hsa_circ_0000745) modulated by YB-1 is significantly upregulated in the U251 and U87 glioma cell lines. Downregulation of circSPECC1 markedly inhibits the proliferation and invasiveness of U251 and U87 cells by inducing apoptosis. Bioinformatics analysis reveals that miR-615-5p could interact with circSPECC1 and huntingtin-interacting protein-1 (HIP-1). Then we determine the interactions between miR-615-5p, circSPECC1, and HIP1 using dual luciferase reporter system and pull-down assays. Mechanistic analysis indicates that the downregulation of circSPECC1 results in a decreased HIP1 expression. This study demonstrates that circSPECC1 modulated by YB-1 is increased in glioma cell lines. In addition, circSPECC1 promotes glioma growth through the upregulation of HIP1 by sponging miR-615-5p and targeting the HIP1/AKT pathway. This indicates that YB-1 and circSPECC1 may both be promising targets for glioma treatment.


Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial.
Histaminergic neurons are crucial to maintain wakefulness, but their role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients with narcolepsy. For this randomised, double-blind, placebo-controlled trial we recruited patients with narcolepsy from 16 sleep centres in nine countries (Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, and Ukraine). Patients were eligible if they were aged 18 years or older, diagnosed with narcolepsy with cataplexy according to version two of the International Classification of Sleep Disorders criteria, experienced at least three cataplexies per week, and had excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via an interactive web response system to randomly assign patients to receive either pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks of four. Participants and investigators were masked to treatment allocation. Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 mg). The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01800045. The trial was done between April 19, 2013, and Jan 28, 2015. We screened 117 patients, 106 of whom were randomly assigned to treatment (54 to pitolisant and 52 to placebo) and, after dropout, 54 patients from the pitolisant group and 51 from the placebo group were included in the intention-to-treat analysis. The WCR during the stable dosing period compared with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15; WCRfinal/baseline=0·25) in patients who received pitolisant and 38% (WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who received placebo (rate ratio 0·512; 95% CI 0·43-0·60, p<0·0001). Treatment-related adverse events were significantly more common in the pitolisant group than in the placebo group (15 [28%] of 54 vs 6 [12%] of 51; p=0·048). There were no serious adverse events, but one case of severe nausea in the pitolisant group. The most frequent adverse events in the pitolisant group (headache, irritability, anxiety, and nausea) were mild or moderate except one case of severe nausea. No withdrawal syndrome was detected following pitolisant treatment; one case was detected in the placebo group. Pitolisant was well tolerated and efficacious in reducing cataplexy. If confirmed in long-term studies, pitolisant might constitute a useful first-line therapy for cataplexy in patients with narcolepsy, for whom there are currently few therapeutic options. Bioprojet, France.


Fate of antibiotic resistance genes and class 1 integrons in soil microcosms following the application of treated residual municipal wastewater solids.
Substantial quantities of antibiotic resistance genes (ARGs) are discharged with treated residual municipal wastewater solids and subsequently applied to soil. The objective of this work was to determine the decay rates for ARGs and class 1 integrons following simulated land application of treated wastewater solids. Treated residual solids from two full-scale treatment plants were applied to sets of triplicate soil microcosms in two independent experiments. Experiment 1 investigated loading rates of 20, 40, and 100 g kg(-1) of residual solids to a sandy soil, while experiment 2 investigated a loading rate of 40 g kg(-1) to a silty-loamy soil. Five ARGs (erm(B), sul1, tet(A), tet(W), and tet(X)), the integrase of class 1 integrons (intI1), 16S rRNA genes, 16S rRNA genes of all Bacteroides spp., and 16S rRNA genes of human-specific Bacteroides spp. were quantified using real-time polymerase chain reaction. ARGs and intI1 quantities declined in most microcosms, with statistically significant (P < 0.05) half-lives varying between 13 d (erm(B), experiment 1, 100 g kg(-1)) and 81 d (intI1, experiment 1, 40 g kg(-1)). These kinetic rates were much slower than have been previously reported for unit operations used to treat wastewater solids (e.g., anaerobic digestion). This research suggests that the design and operation of municipal wastewater treatment facilities with the explicit goal of mitigating the release of ARGs should focus on using technologies within the treatment facility, rather than depending on attenuation subsequent to land application.


The relationship between breastfeeding and reported respiratory and gastrointestinal infection rates in young children.
Although breastfeeding is touted as providing many health benefits to infants, some aspects of this relationship remain poorly understood. The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective longitudinal study that follows children from birth through childhood, and collects data on illness events, breastfeeding duration, and time to introduction of formula or foods at 3 month intervals up until 4 years of age and at 6 months intervals thereafter. Exclusive and non-exclusive breastfeeding is examined in relation to the 3-month odds of a respiratory or gastrointestinal infection for 6861 children between the ages of 3-18 months, and 5666 children up to the age of 4 years. Analysis was performed using logistic regression models with generalized estimating equation methodology. All models were adjusted for potential confounding variables. At 3-6 months of age, breastfeeding was found to be inversely associated with the odds of respiratory infections with fever (OR = 0.82, 95% CI = 0.70-0.95), otitis media (OR = 0.76, 95% CI = 0.62-0.94), and infective gastroenteritis (OR = 0.55, 95% CI = 0.46-0.70), although the inverse association with respiratory illnesses was observed only for girls during the winter months. Between 6 and 18 months of age, breastfeeding within any 3 month period continued to be inversely associated with the odds of ear infection and infective gastroenteritis, and additionally with the odds of conjunctivitis, and laryngitis and tracheitis, over the same 3 month period within this age range. However, breastfeeding in this group was associated with increased reports of common cold. Duration of exclusive breastfeeding was inversely associated with the odds of otitis media up to 48 months of age (OR = 0.97, 95% CI = 0.95-0.99) after breastfeeding had stopped. This study demonstrates that breastfeeding can be protective against multiple respiratory and gastrointestinal acute illnesses in some children up to at least 6 months of age, with duration of exclusive breastfeeding being somewhat protective of otitis media even after breastfeeding has stopped. ClinicalTrials.gov Identifier: NCT00279318 . Date of registration: January 17, 2006 (proactively registered). First Posted: January 19, 2006.


Successful management of a giant dissecting aortic aneurysm in a patient with Behcet's disease.
Thoracic aortic aneurysm with subsequent dissection is a very rare but dangerous complication of Behcet's disease, which is a systemic syndrome that can involve blood vessels of all sizes. Surgical experience in dealing with this complication in patients with Behcet's disease has been limited. We report a 20-year-old patient with Behcet's disease who presented with a giant dissecting thoracic aortic aneurysm. The patient was successfully treated with an aortic root and arch replacement using a frozen elephant trunk technique. Timely surgical intervention and appropriate long-term medical management are important for these patients.


Oxazolidinones Can Replace Clarithromycin in Combination with Rifampin in a Mouse Model of Buruli Ulcer.
Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against Mycobacterium ulcerans infection in mice but has dose- and duration-dependent toxicity in humans. Sutezolid (SZD) and tedizolid (TZD) may be safer than LZD. Here, we evaluated the efficacy of these oxazolidinones in combination with rifampin in a murine BU model. Mice with M. ulcerans-infected footpads received control regimens of RIF plus either streptomycin (STR) or CLR or test regimens of RIF plus either LZD (1 of 2 doses), SZD, or TZD for up to 8 weeks. All combination regimens reduced the swelling and bacterial burden in footpads after two weeks of treatment compared with RIF alone. RIF+SZD was the most active test regimen, while RIF+LZD was also no less active than RIF+CLR. After 4 and 6 weeks of treatment, neither CLR nor the oxazolidinones added significant bactericidal activity to RIF alone. By the end of 8 weeks of treatment, all regimens rendered footpads culture negative. We conclude that SZD and LZD warrant consideration as alternative companion agents to CLR in combination with RIF to treat BU, especially when CLR is contraindicated, intolerable, or unavailable. Further evaluation could prove SZD superior to CLR in this combination.


Anti-factor Xa plasma levels in pregnant women receiving low molecular weight heparin thromboprophylaxis.
To report the incidence of prophylactic, subprophylactic, and supraprophylactic anti-factor Xa activity in pregnant patients receiving low molecular weight heparin for venous thromboembolism prophylaxis, and to evaluate whether maternal weight, body mass index, age, gestational age, or the low molecular weight heparin dose correlated with anti-factor Xa levels. We reviewed 321 anti-factor Xa levels in 77 patients from one Maternal-Fetal Medicine faculty practice. All patients were administered low molecular weight heparin that subsequently was adjusted based upon serial assessment of peak plasma (at 4 hours postinjection) anti-factor Xa levels at less than 36 weeks gestation. Targeted prophylactic range of peak plasma anti-factor Xa level was 0.2-0.4 units/mL. Only 59% of anti-Xa concentrations were in the prophylactic range, whereas 26% were subprophylactic, and 15% were supraprophylactic. Anti-Xa values were not significantly more likely to be prophylactic in early compared with late pregnancy, obese compared with nonobese patients, or in patients receiving a weight-based minimal dose compared with patients receiving less than a weight-based minimal dose. Anti-factor Xa levels did not correlate with maternal age, weight, body mass index, or gestational age, but there was a positive correlation with the percent of the minimal weight-based dose. Even with enhanced low molecular weight heparin dosing, 26% of patients have subprophylactic anti-factor Xa levels. Serial anti-factor Xa assessment for dose adjustment should be considered for all pregnant women receiving low molecular weight heparin.


Obesity in childhood and adolescence. Special problems in diagnosis and treatment.
Obesity is an emotional, physical, and social problem in search of a definition as well as an explanation for its pathogenesis and an efficacious approach to therapy. The complexities of the problem and the limitations of our knowledge are compounded by the anabolic aspects of growth and the sex-specific differences in fat deposition and energy requirements of children and adolescents. The clinician has a delicately balanced responsibility to moderate weight gain while avoiding dietary regimens that will induce catabolism. Further, the clinician must provide empathetic counseling and support, modify behavior, and encourage physical activity. All this must be undertaken with the knowledge that the objective may be unobtainable and, on those occasions when it is achieved, the recidivism rate will be high. Despite these difficulties, it is critical that the child and the family be provided with a realistic and practical regimen that has the potential to help while doing no harm.


[Study of radiation-induced change in the membrane structure using a fluorescent probe].
The effect of radiation on erythrocyte membrane structure has been investigated using fluorescent probe 4-(n-dimethyl aminostyryl)-1-methylpyridinium n-toluolsulfonate. The form of fluorescence spectra was analyzed and inhomogeneous broadening parameters of spectral components were estimated. It was shown that in erythrocyte membrane there were three types of DSM binding sites. The physico-chemical properties of DSM surrounding and probes distribution were found to change after irradiation.


Alcohol Exposure Impacts the Composition of HeLa-Derived Extracellular Vesicles.
Extracellular vesicles are nanosized vesicles that are under intense investigation for their role in intercellular communication. Extracellular vesicles have begun to be examined for their role in disease protection and their role as disease biomarkers and/or vaccine agents. The goal of this study was to investigate the effects of alcohol exposure on the biogenesis and composition of extracellular vesicles derived from the cervical cancer line, HeLa. The HeLa cells were cultured in exosome-free media and were either mock-treated (control) or treated with 50 mM or 100 mM of alcohol for 24 h and 48 h. Our results demonstrated that alcohol significantly impacts HeLa cell viability and exosome biogenesis/composition. Importantly, our studies demonstrate the critical role of alcohol on HeLa cells, as well as HeLa-derived extracellular vesicle biogenesis and composition. Specifically, these results indicate that alcohol alters extracellular vesicles' packaging of heat shock proteins and apoptotic proteins. Extracellular vesicles serve as communicators for HeLa cells, as well as biomarkers for the initiation and progression of disease.


Thermal adaptation of soil microbial growth traits in response to chronic warming.
Soils are the largest terrestrial carbon sink and the foundation of our food, fiber, and fuel systems. Healthy soils are carbon sinks, storing more carbon than they release. This reduces the amount of carbon dioxide released into the atmosphere and buffers against climate change. Soil microbes drive biogeochemical cycling and contribute to soil health through organic matter breakdown, plant growth promotion, and nutrient distribution. In this study, we determined how soil microbial growth traits respond to long-term soil warming. We found that bacterial isolates from warmed plots showed evidence of adaptation of optimum growth temperature. This suggests that increased microbial biomass and growth in a warming world could result in greater carbon storage. As temperatures increase, greater microbial activity may help reduce the soil carbon feedback loop. Our results provide insight on how atmospheric carbon cycling and soil health may respond in a warming world.


Prevalence of IgG and IgM anti-Toxoplasma antibodies in patients with HIV and acquired immunodeficiency syndrome (AIDS).
With the emergence of the human immunodeficiency virus (HIV), in patients with acquired immunodeficiency syndrome (AIDS), Toxoplasma gondii has arisen as an important opportunist pathogenic agent, especially in the central nervous system, being the most common cause of intracerebral lesions. The incidence of Toxoplasma gondii in HIV-infected patients depends principally on the existence of latent Toxoplasma parasitosis in the population affected. Through the enzyme-linked immunosorbent assay (ELISA), IgG and IgM anti-Toxoplasma antibodies were found in 92 patients of which 46 (50.0%) were IgG seropositive, and only one case (1.0%) had IgM antibodies. Of the 92 patients: 53 were HIV seropositives and 39 had AIDS. The detection and monitoring of anti-Toxoplasma antibodies in HIV patients is essential, since in this group there is a high percentage risk of developing cerebral toxoplasmosis, which is the second cause of death in this type of patients.


Intermediate cell states in epithelial-to-mesenchymal transition.
The transition of epithelial cells into a mesenchymal state (epithelial-to-mesenchymal transition or EMT) is a highly dynamic process implicated in various biological processes. During EMT, cells do not necessarily exist in 'pure' epithelial or mesenchymal states. There are cells with mixed (or hybrid) features of the two, which are termed as the intermediate cell states (ICSs). While the exact functions of ICS remain elusive, together with EMT it appears to play important roles in embryogenesis, tissue development, and pathological processes such as cancer metastasis. Recent single cell experiments and advanced mathematical modeling have improved our capability in identifying ICS and provided a better understanding of ICS in development and disease. Here, we review the recent findings related to the ICS in/or EMT and highlight the challenges in the identification and functional characterization of ICS.


Presynaptic cholinergic neuromodulation alters the temporal dynamics of short-term depression at parvalbumin-positive basket cell synapses from juvenile CA1 mouse hippocampus.
Parvalbumin-positive basket cells (PV BCs) of the CA1 hippocampus are active participants in theta (5-12 Hz) and gamma (20-80 Hz) oscillations in vivo. When PV BCs are driven at these frequencies in vitro, inhibitory postsynaptic currents (IPSCs) in synaptically connected CA1 pyramidal cells exhibit paired-pulse depression (PPD) and multiple-pulse depression (MPD). Moreover, PV BCs express presynaptic muscarinic acetylcholine receptors (mAChRs) that may be activated by synaptically released acetylcholine during learning behaviors in vivo. Using acute hippocampal slices from the CA1 hippocampus of juvenile PV-GFP mice, we performed whole cell recordings from synaptically connected PV BC-CA1 pyramidal cell pairs to investigate how bath application of 10 μM muscarine impacts PPD and MPD at CA1 PV BC-pyramidal cell synapses. In accordance with previous studies, PPD and MPD magnitude increased with stimulation frequency. mAChR activation reduced IPSC amplitude and transiently reduced PPD, but MPD was largely maintained. Consistent with a reduction in release probability (pr), MPD and mAChR activation increased both the coefficient of variation of IPSC amplitudes and the fraction of failures. Using variance-mean analysis, we converted MPD trains to pr functions and developed a kinetic model that optimally fit six distinct pr conditions. The model revealed that vesicular depletion caused MPD and that recovery from depression was dependent on calcium. mAChR activation reduced the presynaptic calcium transient fourfold and initial pr twofold, thereby reducing PPD. However, mAChR activation slowed calcium-dependent recovery from depression during sustained repetitive activity, thereby preserving MPD. Thus the activation of presynaptic mAChRs optimally protects PV BCs from vesicular depletion during short bursts of high-frequency activity.


Bacteremia complicating gram-negative urinary tract infections: a population-based study.
Urinary tract infection (UTI) is common and bacteremia complicating this infection is frequently seen. There has been limited data published that characterize bacteremic UTI in a population-based setting over an extended period. We therefore examined the incidence rate, microbiology, outcome, and in vitro antimicrobial resistance trends of bacteremic UTI due to gram-negative bacilli in Olmsted County, Minnesota, from 1/1/1998 to 12/31/2007. We used Kaplan-Meier method to estimate mortality rates, Cox proportional hazard regression to determine risk factors for mortality, and logistic regression to examine temporal changes in antimicrobial resistance rates. We identified 542 episodes of bacteremic gram-negative UTI among Olmsted County residents during the study period. The median age of patients was 71 years and 65.1% were females. The age-adjusted incidence rate per 100,000 person-years was 55.3 (95% confidence interval [CI]: 49.5-61.2) in females and 44.6 (95% CI: 38.1-51.1) in males. Escherichia coli was the most common pathogen (74.9%). The 28-day and 1-year all-cause mortality rates were 4.9% (95% CI: 3.0-6.8) and 15.6% (95% CI: 12.4-18.8), respectively. Older age was associated with higher mortality; community-acquired infection acquisition and E. coli UTI were both independently associated with lower mortality. During the study period, resistance rates increased linearly from 10% to 24% for trimethoprim-sulfamethoxazole and from 1% to 8% for ciprofloxacin. To our knowledge, this is the first population-based study of bacteremic gram-negative UTI. The linear trend of increasing antimicrobial resistance among gram-negative isolates should be considered when empiric therapy is selected.