Interaction of the GTPase Elongation Factor Like-1 with the Shwachman-Diamond Syndrome Protein and Its Missense Mutations.
The Shwachman-Diamond Syndrome (SDS) is a disorder arising from mutations in the genes encoding for the Shwachman-Bodian-Diamond Syndrome (SBDS) protein and the GTPase known as Elongation Factor Like-1 (EFL1). Together, these proteins remove the anti-association factor eIF6 from the surface of the pre-60S ribosomal subunit to promote the formation of mature ribosomes. SBDS missense mutations can either destabilize the protein fold or affect surface epitopes. The molecular alterations resulting from the latter remain largely unknown, although some evidence suggest that binding to EFL1 may be affected. We further explored the effect of these SBDS mutations on the interaction with EFL1, and showed that all tested mutations disrupted the binding to EFL1. Binding was either severely weakened or almost abolished, depending on the assessed mutation. In higher eukaryotes, SBDS is essential for development, and lack of the protein results in early lethality. The existence of patients whose only source of SBDS consists of that with surface missense mutations highlights the importance of the interaction with EFL1 for their function. Additionally, we studied the interaction mechanism of the proteins in solution and demonstrated that binding consists of two independent and cooperative events, with domains 2⁻3 of SBDS directing the initial interaction with EFL1, followed by docking of domain 1. In solution, both proteins exhibited large flexibility and consisted of an ensemble of conformations, as demonstrated by Small Angle X-ray Scattering (SAXS) experiments.


Quantum Dots: Synthesis, Antibody Conjugation, and HER2-Receptor Targeting for Breast Cancer Therapy.
Breast cancer is becoming one of the main lethal carcinomas in the recent era, and its occurrence rate is increasing day by day. There are different breast cancer biomarkers, and their overexpression takes place in the metastasis of cancer cells. The most prevalent breast cancer biomarker is the human epidermal growth factor receptor2 (HER2). As this biomarker is overexpressed in malignant breast tissues, it has become the main focus in targeted therapies to fight breast cancer. There is a cascade of mechanisms involved in metastasis and cell proliferation in cancer cells. Nanotechnology has become extremely advanced in targeting and imaging cancerous cells. Quantum dots (QDs) are semiconductor NPs, and they are used for bioimaging, biolabeling, and biosensing. They are synthesized by different approaches such as top-down, bottom-up, and synthetic methods. Fully human monoclonal antibodies synthesized using transgenic mice having human immunoglobulin are used to target malignant cells. For the HER2 receptor, herceptin® (trastuzumab) is the most specific antibody (Ab), and it is conjugated with QDs by using different types of coupling mechanisms. This quantum dot monoclonal antibody (QD-mAb) conjugate is localized by injecting it into the blood vessel. After the injection, it goes through a series of steps to reach the intracellular space, and bioimaging of specifically the HER2 receptor occurs, where apoptosis of the cancer cells takes place either by the liberation of Ab or the free radicals.


The role of innate lymphoid cells in airway inflammation: evolving paradigms.
Innate lymphoid cells (ILCs) act as early orchestrators of the immune response, tissue repair, and maintenance of barrier homeostasis. This review summarizes recent findings of the role of ILCs in airway disease and highlights ongoing developments in clinical applications and treatment options. On the basis of the transcription factors required for their development and cytokine profiles, ILCs have been classified into three subsets that resemble those of T-helper subtypes. ILCs produce multiple cytokines in response to signals from activated cells in their local environment. Recent studies in both humans and mice showed that ILCs are located at barrier surfaces and play critical roles in inflammatory diseases of the upper and lower airways. The discovery of ILCs and their characterization in homeostatic and diseased conditions, have brought new insights into innate and adaptive immune responses at mucosal barrier surfaces. The recent progress in understanding the role of ILCs in airway inflammation directs translation of fundamental studies into clinical applications. This knowledge can be useful for future clinical practice.


[Endothelial NO synthase and connexin 37 gene polymorphisms as a risk factor for myocardial infarction in subjects without a history of coronary artery disease].
To define a role of connexin37 (Cx37) C1019T and endothelial nitric oxide synthase (eNOS) G894T polymorphisms in the development of myocardial infarction (MI) in subjects without a history of coronary artery disease. The investigation enrolled 183 male patients, of whom 56 (18.1%) developed MI in the presence of clinically and instrumentally verified coronary heart disease (CHD) (except MI) and 127 (81.9%) patients did without any previous clinical signs of CHD. The gene polymorphisms were identified using polymerase chain reaction and restriction fragment length polymorphism analysis. The spread of the G allele in the eNOS gene was 59.8% in the patients with MI in the presence of CHD and 75.6% in those with MI without a history of coronary artery disease (p<0.01). The GG genotype was found in 32.1 and 54.3%, respectively (p=0.01; the odds ratio (OR) was 2.5 with 95% confidence interval (CI) 1.3 to 4.9). The spread of the mutant T allele in the Cx37 gene was 29.5% in the patients with MI in the presence of CHD and 59.8% in those with MI without a history of coronary artery disease (p<0.01). The TT genotype was encountered in 7.1 and 42.5% of cases, respectively (p=0.01; OR 9.6 with 95% CI 3.3 to 28.4). There was no case of a combination of GG and TT genotypes among the patients with MI in the presence of CHD whereas this was found in 23.6% of the MI cases without a history of coronary artery disease (p<0.01). Determination of Cx37 C1019T and eNOS G894T polymorphisms may be used to detect a genetic predisposition to the development of MI in patients with hemodynamically insignificant atherosclerosis and in apparently healthy individuals.


Effect of human adipose derived stem cells on scar formation and remodeling in a pig model: a pilot study.
Adipose-derived stem cells (ASCs) have positive effects in the wound healing process. To clarify whether ASCs positively mitigate scar formation in the wound remodeling process. Full-thickness skin defects were created on the dorsal skin of Yorkshire pigs. After the defects were transformed into early scars, ASCs were injected, and the same amount of phosphate buffered saline (PBS) was injected in the control group. Clinical and histologic examinations were performed. In the experimental group, the areas of scars were smaller than those of control groups. The color of scars was more similar to that of the surrounding normal tissue, and scar pliability was better. The number of mast cells decreased, and more-mature collagen arrangement was noted. In the early period of scar remodeling, the expression of transforming growth factor beta (TGF-β)3 and matrix metalloproteinase 1 (MMP1) was greater in the experimental group than in control group. In the late period, the level of alpha smooth muscle actin and tissue inhibitor of metalloproteinase 1 were dramatically less, although the level of MMP1 was lower in the experimental group than in control group. Local injection of ASCs decreases scar size and provides better color quality and scar pliability. It decreases the activity of mast cells and inhibits the action of TGF-β against fibroblasts and positively stimulates scar remodeling through greater expression of MMP molecules.


Epigenomic-basis of Preemptive Medicine for Neurodevelopmental Disorders.
Neurodevelopmental disorders (NDs) are currently thought to be caused by either genetic defects or various environmental factors. Recent studies have demonstrated that congenital NDs can result not only from changes in DNA sequence in neuronal genes but also from changes to the secondary epigenomic modifications of DNA and histone proteins. Thus, epigenomic assays, as well as genomic assays, are currently performed for diagnosis of the congenital NDs. It is recently known that the epigenomic modifications can be altered by various environmental factors, which potentially cause acquired NDs. Furthermore these alterations can potentially be restored taking advantage of use of reversibility in epigenomics. Therefore, epigenome-based early diagnosis and subsequent intervention, by using drugs that restore epigenomic alterations, will open up a new era of preemptive medicine for congenital and acquired NDs.


Respiratory and upper airways impedance responses to methacholine inhalation in spontaneously breathing cats.
The upper airways may contribute to the increase in respiratory resistance induced by methacholine (Mch). The aim of this study was to simultaneously assess the Mch response of upper airways and lower respiratory resistances (Rua, Rrs,lo) and reactances (Xua, Xrs,lo), and to test whether the change of total respiratory resistance and reactance after Mch were affected by upper airways mechanisms. Seven cats breathing spontaneously were studied under chloralose, urethane anaesthesia. Forced oscillations were generated at 20 Hz by a loud-speaker connected to the pharyngeal cavity. A pneumotachograph was placed between rostral and caudal extremities of the severed cervical trachea. Pressure drops were measured across the upper airways and across the lower respiratory system. Rua, Xua, Rrs,lo and Xrs,lo were obtained after nebulized normal saline and Mch administered directly through the tracheostomy. The analysis focused on Mch tests showing clear positive upper airways response. Volume and flow dependence of Rrs,lo and Rua were assessed during tidal inspiration using multiple linear regression analysis. After Mch, Rrs,lo increased and became negatively volume dependent, while the increase in Rua was associated with no significant change in volume dependence; Xrs,lo became negative while Xua did not change. The upper airways response to methacholine may thus contribute to the increase in total respiratory resistance but may not account for either its negative volume dependence or the decrease in total resistance. It is surmised that these features more specifically reflect alterations in respiratory mechanics occurring at the level of the intrathoracic airways.


Novel therapeutic strategies targeting tumor-stromal interactions in pancreatic cancer.
Therapy-resistance and postoperative recurrence are causes of the poor prognosis in pancreatic cancer. Conventional therapies have a limited impact on the control of pancreatic cancer, resulting in the rapid re-growth of the tumor. The indispensable role of tumor-stromal interaction, which acts as a defender of cancer cells and enhances malignant potential, is being uncovered now. For example, specific signaling pathways for desmoplasia induction have been identified, such as sonic hedgehog (Shh) or connective tissue growth factor (CTGF), whose inhibition causes desmoplasia depletion and therapeutic advantages at least in in vivo mouse models of pancreatic cancer. Revolutions in drug delivery methods have led to the establishment of novel chemotherapeutic regimens, with better patient survival. Furthermore, mechanisms of immunosuppression in the pancreatic cancer-bearing host were clarified by the identification of myeloid-derived suppressor cells (MDSCs), which also promote disease progression. Strategies to target these components of the tumor stroma revealed certain anticancer effects in vitro and in vivo, suggesting the possibility of stroma-targeting therapy. Suppression of the stromal cell function increases the sensitivity of pancreatic cancer cells to therapeutic intervention. Further study will clarify the complex nature of the tumor microenvironment, the targeting of which has the potential to improve clinical outcome.


A prospective analysis of the HOMA model. The Mexico City Diabetes Study.
Both insulin resistance (IR) and decreased insulin secretion have been shown to predict the development of NIDDM. However, methods to assess insulin sensitivity and secretion are complicated and expensive to apply in epidemiological studies. The homeostasis model assessment (HOMA) has been suggested as a method to assess IR and secretion from the fasting glucose and insulin concentrations. We applied the HOMA model in the 3.5-year follow-up of the Mexico City Diabetes Study. Out of 1,449 subjects, 97 developed diabetes. When modeled separately insulin resistance but not insulin secretion predicted NIDDM. However, when both variables were entered into the same regression model, both increased IR and decreased beta-cell function significantly predicted NIDDM. We conclude that the HOMA provides a useful model to assess beta-cell function in epidemiological studies and that it is important to take into account the degree of IR in assessing insulin secretion.


Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) for treatment of early-stage gastric diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma (DLBCL) of the stomach is a relatively common disease. Recently, chemotherapy consisting of doxorubicin, cyclophosphamide, vincristine and prednisone (CHOP) has been reported as effective treatment for early-stage gastric DLBCL. Given the fact that the application of the CD20 antibody rituximab (R) in addition to CHOP has improved outcomes in nodal DLBCL, we have analysed our experience with application of R-CHOP in patients with early-stage gastric DLBCL. Patients with histologically verified early-stage gastric DLBCL undergoing treatment with R-CHOP for initial management were analysed. Fifteen patients received a total of 79 cycles, with a median of six cycles per patient. All patients responded to therapy, 13 had a complete remission (CR) (87%) and two (13%) a partial remission. All patients in CR, except one who died unrelated to lymphoma, have remained so with a median follow-up of 15 months (range 4-42) after treatment. Subjective tolerance was moderate, and toxicities were mainly haematological, including leukocytopenia WHO grade 3 and 4 in 10 and five patients each. The addition of rituximab to the standard CHOP regimen did not appear to significantly increase toxicity. Our data indicate that R-CHOP is an effective regimen for management of early-stage gastric DLBCL. However, given the excellent results with CHOP alone in such patients, the value of adding rituximab to standard CHOP remains to be determined in a randomised trial.


Kinetics of adherence of Actinomyces viscosus to saliva-coated silica and hydroxyapatite beads.
Adherence of 14C-labelled strains of Actinomyces viscosus to uncoated and saliva-coated silica and hydroxyapatite beads had both loose and firm components, probably reflecting different subpopulations of bacteria within a single culture. Adherence was characterized by the proportion of bacteria available for each type of adherence and a constant (Kb) for each combination of bacterial strain and bead surface. Loose adherence, which was greater with silica than with hydroxyapatite beads, always involved many more bacteria than firm adherence. Firm adherence was greater with A. viscosus WVU627 than A. viscosus TF11. The association rate constants (Ka) for loose and firm adherence were similar, indicating simultaneous processes, but the dissociation rate constant (Kd) was lower for loose adherence than for firm adherence. Removal of loosely adhering bacteria by washing may only reflect their distance from the bead surface. Silica beads were convenient for studying bacterial adherence and formed an acceptable coating of salivary glycoprotein.


Does smoking reduction result in reduction of biomarkers associated with harm? A pilot study using a nicotine inhaler.
The aim of the study was to determine if smoking reduction using a nicotine inhaler in heavy cigarette smokers who wanted to reduce but not stop smoking results in decreased levels of known biomarkers of harm. The study design was a one-sample within-subject comparative open-label study of 23 (10 male and 13 female) subjects using a nicotine inhaler to reduce smoking, with follow-up at 24 weeks. A structured protocol was used with a smoking-reduction schedule from 40 or more cigarettes per day to 10 cigarettes per day by week 9. Behavioral counseling was provided by a research assistant and ad lib use of the nicotine inhaler for 12 weeks was permitted. Blood thiocyanate, cotinine, 4-aminobiphenyl hemoglobin adducts; urine NNAL and NNAL-glucuronide; and expired air carbon monoxide were measured. On average, the subjects were able to reduce their smoking by over 50% at week 12, but only two were able to reduce to 10 cigarettes per day. The reported reduction in smoking was not associated with a consistent reduction in the biomarkers. There was no reduction in the NNAL, 4-aminobiphenyl hemoglobin adducts nor carbon monoxide levels of expired air. There was a significant reduction of NNAL-glucuronide and the sum of NNAL and NNAL-glucuronide but only at week 24. Thiocyanate levels increased. Before widely promoting harm reduction as a treatment strategy for heavy smokers, more research needs to be performed to prove conclusively that such smokers who want to reduce but not stop can actually reduce and maintain their smoking rate at a level which is likely to reduce harm. It also needs to be determined whether a reduction in the smoking rate translates into reduction of harm. At the present, for heavy smokers, an abstinence approach seems to be more scientifically sound.


Effect of polyethyleneglycol 4000 (PEG4000) solution on the in vitro release profile of nifedipine from polymer matrices.
The effect of PEG4000 solution on the in vitro release of nifedipine, a calcium entry blocker and a poorly water soluble drug was evaluated. Nifedipine tablets containing 10 mg of nifedipine, 20% of one four polymers--Eudragit L-100 and Rs, ethylcellulose and carbopol 941, 2% lubritab and an adequate quantity of Encompress to yield 300 mg weight tablets--were formulated using the direct compression method. Tablets were compressed to a hardness of 5N, and an in vitro dissolution profile was performed on the tablets in 70% ethanol and in ethanolic PEG4000 solutions. The results obtained indicated enhancement of nifedipine release from two of the polymer matrices (Eudragit L-100 and ethylcellulose) in the presence of PEG4000 and a retardant effect from carbopol 941 matrix. It is suggested that carbopols may not be suitable for use in the formulation of nifedipine tablets since there are some physiological surfactants present in the gastrointestinal tract (GIT).


Prospective Investigation of Serum Metabolites, Coffee Drinking, Liver Cancer Incidence, and Liver Disease Mortality.
Coffee has been consistently associated with lower risk of liver cancer and chronic liver disease, suggesting that coffee affects mechanisms underlying disease development. We measured serum metabolites using untargeted metabolomics in 1:1 matched nested case-control studies of liver cancer (n = 221 cases) and fatal liver disease (n = 242 cases) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort (n = 29 133). Associations between baseline coffee drinking and metabolites were identified using linear regression; conditional logistic regression models were used to identify associations with subsequent outcomes. Overall, 21 metabolites were associated with coffee drinking and also each subsequent endpoint; nine metabolites and trigonelline, a known coffee biomarker, were identified. Tyrosine and two bile acids, glycochenodeoxycholic acid (GCDCA) and glycocholic acid (GCA), were inversely associated with coffee but positively associated with both outcomes; odds ratios (ORs) comparing the 90th to 10th percentile (modeled on a continuous basis) ranged from 3.93 (95% confidence interval [CI] = 2.00 to 7.74) for tyrosine to 4.95 (95% CI = 2.64 to 9.29) for GCA and from 4.00 (95% CI = 2.42 to 6.62) for GCA to 6.77 (95% CI = 3.62 to 12.65) for GCDCA for liver cancer and fatal liver disease, respectively. The remaining six metabolites and trigonelline were positively associated with coffee drinking but inversely associated with both outcomes; odds ratio ranged from 0.16 to 0.37. Associations persisted following diet adjustment and for outcomes occurring greater than 10 years after blood collection. A broad range of compounds were associated with coffee drinking, incident liver cancer, and liver disease death over 27 years of follow-up. These associations provide novel insight into chronic liver disease and liver cancer etiology and support a possible hepatoprotective effect of coffee.


Leucocytes labelled with 99mTc-HMPAO in the detection of abdominal abscesses.
To assess the value of 99mTc-HMPAO-labelled-leucocyte scintigraphy in the detection of abdominal abscesses, the results of 74 examinations in 69 patients suspected of having abscesses on clinical grounds were reviewed retrospectively. Of a final total of 29 abscesses in 28 patients, leucocyte scanning diagnosed 26, giving a sensitivity, specificity, and accuracy of 90%, 91%, and 91%, respectively. In 22 patients abscesses were diagnosed within 30 min. In 13 of the 74 examinations (18%) an infection or inflammatory lesion other than an abscess was diagnosed. 99mTc-HMPAO-labelled-leucocyte scintigraphy is an accurate and rapid method of diagnosing abscesses in acutely ill patients.


Neuroimaging of diving-related decompression illness: current knowledge and perspectives.
Diving-related decompression illness is classified into 2 main categories: arterial gas embolism and decompression sickness. The latter is further divided into types 1 and 2, depending on the clinical presentation. MR imaging is currently the most accurate neuroimaging technique available for the detection of brain and spinal cord lesions in neurologic type 2 decompression sickness. Rapid bubble formation in tissues and the bloodstream during ascent is the basic pathophysiologic mechanism in decompression illness. These bubbles can damage the central nervous system through different mechanisms, namely arterial occlusion, venous obstruction, or in situ toxicity. Neuroimaging studies of decompression sickness have reported findings associated with each of these mechanisms: some typical results are summarized and illustrated in this article. We also review the limitations of previous work and make practical methodologic suggestions for future neuroimaging studies.


Exercise-induced deep vein thrombosis of the upper extremity. 1. Literature review.
Paget-Schroetter syndrome or effort-related upper extremity deep vein thrombosis is a rare condition that usually afflicts young healthy individuals, most commonly males. The cause is multifactorial but almost always involves extrinsic compression of the subclavian vein at the thoracic inlet, causing venous stenosis from repetitive trauma. The diagnosis of this condition may be difficult, and its delay may contribute to potential complications including thrombosis progression, pulmonary embolism, thrombosis recurrence, and post-thrombotic syndrome. Similarly, the best therapeutic option has not been established and in the lack of evidence-based guidelines, treatment may be extremely challenging especially in children, in whom long-term complications can be particularly disabling.


Characterization of a membrane-associated protein implicated in visna virus binding and infection.
The identity of the cellular receptor(s) for visna virus, an ovine lentivirus, is currently unknown; however, previous studies from our laboratory have identified membrane-associated proteins expressed selectively in susceptible cells which bind visna virus. Moreover, a polyclonal antibody (2-23), raised against a 45-kDa visna virus binding protein, bound specifically to the surface of susceptible cells in immunofluorescence assays and significantly reduced binding of visna virus to cells (S. E. Crane et al., 1991, J. Virol., 65, 6137-6143). In this report we extend our studies of this antibody (2-23), showing both that 2-23 significantly reduces visna virus infection of susceptible cells and that 2-23 immunoprecipitates a putative protein complex consisting of a prominent 30-kDa protein, as well as the 45-kDa immunogen, specifically from radiolabeled virus-susceptible sheep cells. Further, we demonstrate that the 30-kDa protein is a membrane-associated proteoglycan substituted with a chondroitin sulfate glycosaminoglycan (GAG) chain(s) and that treatment of susceptible cells with an inhibitor of GAG synthesis significantly reduces visna virus production. Collectively, these data support a role for a proteoglycan in visna virus cell binding and infection.


BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma.
This trial determined the safety and efficacy of the combination regimen clarithromycin (Biaxin), lenalidomide (Revlimid), and dexamethasone (BiRD) as first-line therapy for multiple myeloma. Patients received BiRD in 28-day cycles. Dexamethasone (40 mg) was given orally once weekly, clarithromycin (500 mg) was given orally twice daily, and lenalidomide (25 mg) was given orally daily on days 1 to 21. Objective response was defined by standard criteria (ie, decrease in serum monoclonal protein [M-protein] by at least 50%, and a decrease in urine M-protein by at least 90%). Of the 72 patients enrolled, 65 had an objective response (90.3%). A combined stringent and conventional complete response rate of 38.9% was achieved, and 73.6% of the patients achieved at least a 90% decrease in M-protein levels. This regimen did not interfere with hematopoietic stem-cell harvest. Fifty-two patients who did not go on to receive transplants received continued therapy (complete response, 37%; very good partial response, 33%). The major adverse events were thromboembolic events, corticosteroid-related morbidity, and cytopenias. BiRD is an effective regimen with manageable side effects in the treatment of symptomatic, newly diagnosed multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00151203.


Can multi-cropping affect soil microbial stoichiometry and functional diversity, decreasing potential soil-borne pathogens? A study on European organic vegetable cropping systems.
Crop diversification in spatial and temporal patterns can optimize the synchronization of nutrients plant demand and availability in soils, as plant diversity and soil microbial communities are the main drivers of biogeochemical C and nutrient cycling. The introduction of multi-cropping in organic vegetable production can represent a key strategy to ensure efficient complementation mediated by soil microbiota, including beneficial mycorrhizal fungi. This study shows the effect of the introduction of multi-cropping in five European organic vegetable systems (South-West: Italy; North-West: Denmark and Belgium; North-East: Finland and Latvia) on: (i) soil physicochemical parameters; (ii) soil microbial biomass stoichiometry; (iii) crop root mycorrhization; (iv) bacterial and fungal diversity and composition in crop rhizosphere; (v) relative abundance of selected fungal pathogens species. In each site, three cropping systems were considered: (1) crop 1-monocropping; (2) crop 2-monocropping; (3) crop 1-crop 2-intercropping or strip cropping. Results showed that, just before harvest, multi-cropping can increase soil microbial biomass amount and shape microbial community toward a predominance of some bacteria or fungi phyla, in the function of soil nutrient availability. We mainly observed a selection effect of crop type on rhizosphere microbiota. Particularly, Bacteroidetes and Mortierellomycota relative abundances in rhizosphere soil resulted in suitable ecological indicators of the positive effect of plant diversity in field, the first ones attesting an improved C and P cycles in soil and the second ones a reduced soil pathogens' pressure. Plant diversity also increased the root mycorrhizal colonization between the intercropped crops that, when properly selected, can also reduce the relative abundance of potential soil-borne pathogens, with a positive effect on crop productivity in long term.


BRAIN: a universal tool for high-throughput calculations of the isotopic distribution for mass spectrometry.
This Letter presents the R-package implementation of the recently introduced polynomial method for calculating the aggregated isotopic distribution called BRAIN (Baffling Recursive Algorithm for Isotopic distributioN calculations). The algorithm is simple, easy to understand, highly accurate, fast, and memory-efficient. The method is based on the application of the Newton-Girard theorem and Viète's formulae to the polynomial coding of different aggregated isotopic variants. As a result, an elegant recursive equation is obtained for computing the occurrence probabilities of consecutive aggregated isotopic peaks. Additionally, the algorithm also allows calculating the center-masses of the aggregated isotopic variants. We propose an implementation which is suitable for high-throughput processing and easily customizable for application in different areas of mass spectral data analyses. A case study demonstrates how the R-package can be applied in the context of protein research, but the software can be also used for calculating the isotopic distribution in the context of lipidomics, metabolomics, glycoscience, or even space exploration. More materials, i.e., reference manual, vignette, and the package itself are available at Bioconductor online (http://www.bioconductor.org/packages/release/bioc/html/BRAIN.html).


An examination of stereotype threat effects on girls' mathematics performance.
Stereotype threat has been proposed as 1 potential explanation for the gender difference in standardized mathematics test performance among high-performing students. At present, it is not entirely clear how susceptibility to stereotype threat develops, as empirical evidence for stereotype threat effects across the school years is inconsistent. In a series of 3 studies, with a total sample of 931 students, we investigated stereotype threat effects during childhood and adolescence. Three activation methods were used, ranging from implicit to explicit. Across studies, we found no evidence that the mathematics performance of school-age girls was impacted by stereotype threat. In 2 of the studies, there were gender differences on the mathematics assessment regardless of whether stereotype threat was activated. Potential reasons for these findings are discussed, including the possibility that stereotype threat effects only occur in very specific circumstances or that they are in fact occurring all the time. We also address the possibility that the literature regarding stereotype threat in children is subject to publication bias.


Comparison of the structure and expression of odd-skipped and two related genes that encode a new family of zinc finger proteins in Drosophila.
The odd-skipped (odd) gene, which was identified on the basis of a pair-rule segmentation phenotype in mutant embryos, is initially expressed in the Drosophila embryo in seven pair-rule stripes, but later exhibits a segment polarity-like pattern for which no phenotypic correlate is apparent. We have molecularly characterized two embryonically expressed odd-cognate genes, sob and bowel (bowl), that encode proteins with highly conserved C2H2 zinc fingers. While the Sob and Bowl proteins each contain five tandem fingers, the Odd protein lacks a fifth (C-terminal) finger and is also less conserved among the four common fingers. Reminiscent of many segmentation gene paralogues, the closely linked odd and sob genes are expressed during embryogenesis in similar striped patterns; in contrast, the less-tightly linked bowl gene is expressed in a distinctly different pattern at the termini of the early embryo. Although our results indicate that odd and sob are more likely than bowl to share overlapping developmental roles, some functional divergence between the Odd and Sob proteins is suggested by the absence of homology outside the zinc fingers, and also by amino acid substitutions in the Odd zinc fingers at positions that appear to be constrained in Sob and Bowl


Lower extremity amputation in peripheral artery disease: improving patient outcomes.
Peripheral artery disease affects over eight million Americans and is associated with an increased risk of mortality, cardiovascular disease, functional limitation, and limb loss. In its most severe form, critical limb ischemia, patients are often treated with lower extremity (LE) amputation (LEA), although the overall incidence of LEA is declining. In the US, there is significant geographic variation in the performing of major LEA. The rate of death after major LEA in the US is approximately 48% at 1 year and 71% at 3 years. Despite this significant morbidity and mortality, the use of diagnostic testing (both noninvasive and invasive testing) in the year prior to LEA is low and varies based on patient, provider, and regional factors. In this review we discuss the significance of LEA and methods to reduce its occurrence. These methods include improved recognition of the risk factors for LEA by clinicians and patients, strong advocacy for noninvasive and/or invasive imaging prior to LEA, improved endovascular revascularization techniques, and novel therapies.


Colorectal cancer: case-control study of sociodemographic, lifestyle and anthropometric parameters in Riyadh.
This case-control study compared sociodemographic variables, lifestyle and certain anthropometric parameters of 50 patients hospitalized with colorectal cancer with those of 50 age- and sex-matched controls at a referral hospital in Riyadh. Among cases, females were generally more affected by gastrointestinal symptoms and 4% of male patients had a family history of colorectal cancer. Unlike weight and height, body mass index did not differ between cases and controls, but poor knowledge of high-fibre diets was a significant factor. Regression analysis showed low education level, unemployment and not taking exercise regularly were significant risk factors for colorectal cancer. Better education and awareness of colorectal cancer screening is recommended.


Geoacoustic inversion by mode amplitude perturbation.
This paper introduces a perturbative inversion algorithm for determining sea floor acoustic properties, which uses modal amplitudes as input data. Perturbative inverse methods have been used in the past to estimate bottom acoustic properties in sediments, but up to this point these methods have used only the modal eigenvalues as input data. As with previous perturbative inversion methods, the one developed in this paper solves the nonlinear inverse problem using a series of approximate, linear steps. Examples of the method applied to synthetic and experimental data are provided to demonstrate the method's feasibility. Finally, it is shown that modal eigenvalue and amplitude perturbation can be combined into a single inversion algorithm that uses all of the potentially available modal data.


A high-throughput method for determining chloramphenicol residues in poultry, egg, shrimp, fish, swine and bovine using LC-ESI-MS/MS.
A LC-ESI-MS/MS method for determining chloramphenicol residues in fish, shrimp, poultry, eggs, bovine and swine was developed and validated. The samples were extracted with a phosphate extraction solution followed by liquid-liquid extraction with ethyl acetate. The LC was performed on a C18 column at room temperature. For all the matrices, the analytical curves showed r values and recoveries higher than 0.99 and 50%, respectively. The accuracy values lay between 85 and 120% and the precision was lower than 20%. The LOQ was 0.1 ng/g. The method was employed to analyze samples collected in Brazil.


High-efficiency single-photon generation via large-scale active time multiplexing.
Deterministic generation of single- and multiphoton states is a key requirement for large-scale optical quantum information and communication applications. While heralded single-photon sources (HSPSs) using nonlinear optical processes have enabled proof-of-principle demonstrations in this area of research, they are not scalable as their probabilistic nature severely limits their generation efficiency. We overcome this limitation by demonstrating a substantial improvement in HSPS efficiency via large-scale time multiplexing. Using an ultra-low loss, adjustable optical delay to multiplex 40 conventional HSPS photon generation processes into each operation cycle, we have observed a factor of 9.7(5) enhancement in efficiency, yielding a 66.7(24)% probability of collecting a single photon with high indistinguishability (90%) into a single-mode fiber per cycle. We also experimentally investigate the trade-off between a high single-photon probability and unwanted multiphoton emission. Upgrading our time-multiplexed source with state-of-the-art HSPS and single-photon detector technologies will enable the generation of >30 coincident photons with unprecedented efficiency.


Different patterns of perceptual learning on spectral modulation detection between older hearing-impaired and younger normal-hearing adults.
Young adults with normal hearing (YNH) can improve their sensitivity to basic acoustic features with practice. However, it is not known to what extent the influence of the same training regimen differs between YNH listeners and older listeners with hearing impairment (OHI)--the largest population seeking treatment in audiology clinics. To examine this issue, we trained OHI listeners on a basic auditory task (spectral modulation detection) using a training regimen previously administered to YNH listeners (≈ 1 h/session for seven sessions on a single condition). For the trained conditions on which pretraining performance was not already at asymptote, the YNH listeners who received training learned more than matched controls who received none, but that learning did not generalize to any untrained spectral modulation frequency. In contrast, the OHI-trained listeners and controls learned similar amounts on the trained condition, implying no effect of the training itself. However, surprisingly the OHI-trained listeners improved over the training phase and on an untrained spectral modulation frequency. These population differences suggest that learning consolidated more slowly, and that training modified an aspect of processing that had broader tuning to spectral modulation frequency, in OHI than YNH listeners. More generally, these results demonstrate that conclusions about perceptual learning that come from examination of one population do not necessarily apply to another.


Mechanisms for high affinity mannose 6-phosphate ligand binding to the insulin-like growth factor II/mannose 6-phosphate receptor.
The two mannose 6-phosphate (Man-6-P) binding domains of the insulin-like growth factor II/mannose 6-phosphate receptor (Man-6-P/IGF2R), located in extracytoplasmic repeats 1-3 and 7-9, are capable of binding Man-6-P with low affinity and glycoproteins that contain more than one Man-6-P residue with high affinity. High affinity multivalent ligand binding sites could be formed through two possible mechanisms: the interaction of two Man-6-P binding domains within one Man-6-P/IGF2R molecule or by receptor oligomerization. To discriminate between these mechanisms, truncated FLAG epitope-tagged Man-6-P/IGF2R constructs, containing one or both of the Man-6-P binding domains, were expressed in 293T cells, and characterized for binding of pentamannose phosphate-bovine serum albumin (PMP-BSA), a pseudoglycoprotein bearing multiple Man-6-P residues. A construct containing all 15 repeats of the Man-6-P/IGF2R extracytoplasmic domain bound PMP-BSA with the same affinity as the full-length receptor (K(d) = 0.54 nm) with a curvilinear Scatchard plot. The presence of excess unlabeled PMP-BSA increased the dissociation rate of pre-formed (125)I-PMP-BSA/receptor complexes, suggesting negative cooperativity in multivalent ligand binding and affirming the role of multiple Man-6-P/IGF2R binding domains in forming high affinity binding sites. Truncated receptors containing only one Man-6-P binding domain and mutant receptor constructs, containing an Arg(1325) --> Ala mutation that eliminates binding to the repeats 7-9 binding domain, formed high affinity PMP-BSA binding, but with reduced stoichiometries. Collectively, these observations suggest that alignment of Man-6-P binding domains of separate Man-6-P/IGF2R molecules is responsible for the formation of high affinity Man-6-P binding sites and provide functional evidence for Man-6-P/IGF2R oligomerization.


[Feet dermatophytosis in soccer players].
Athletes present risk of cutaneous mycosis. A study was carried out with 23 soccer players using clinical and mycological examination (direct microscopic examination and culture) and nail clipping. Eighteen (78.26%) did not present mycosis; two (8.70%) presented tinea pedis, and three (13.04%) presented onychomycosis associated to tinea pedis, mainly for Trichophyton mentagrophytes. Infected tinea pedis has produced cellulitis in one of the athletes. It is necessary to create an educative program of skin care during sports practice.


Reexpansion pulmonary edema.
When a rapidly reexpanding lung has been in a state of collapse for more than several days, pulmonary edema sometimes occurs in it. This is called reexpansion pulmonary edema (RPE). In this article, I present my views on the history, clinical features, morphophysiological features, pathogenesis, and treatment of RPE. Histological abnormalities of the pulmonary microvessels in a chronically collapsed lung will cause RPE, as well as mechanical stress exerted during reexpansion. Although the most effective treatment method is to treat the histological abnormalities of the pulmonary microvessels formed in a chronically collapsed lung, the cause of these abnormalities is not clear, making it difficult to put forward a precise treatment method. However, reasonably good effects can be expected from a symptomatic therapy that reduces the level of mechanical stress during reexpansion. In the future, it is expected that the cause of histological changes of the pulmonary microvessels in a chronically collapsed lung will be revealed, and appropriate therapies will therefore be developed according to this cause.


Flexible design of multidimensional perfect reconstruction FIR 2-band filters using transformations of variables.
An approach to designing multidimensional linear-phase FIR diamond subband filters having the perfect reconstruction property is presented. It is based on a transformation of variables technique and is equivalent to the generalized McClellan transformation. Methods for designing a whole class of transformation are given. The approach consists of two parts; design of the transformation and design of the 1-D filters. The use of Lagrange halfband filters to design the 1-D filters is discussed. The modification of a particular Lagrange halfband filter which gives a pair of simple 1-D filters that are almost similar to each other in their frequency characteristics but still form a perfect reconstruction pair is presented. The design technique is extended to other types of two-channel sampling lattice and subband shapes, in particular, the parallelogram and the diagonally quadrant subband cases. Several numerical design examples are presented to illustrate the flexibility of the design method.


Complete mitochondrial genome and the phylogenetic position of the Leadhued skate Notoraja tobitukai (Rajiformes: Arhynchobatidae).
In this study, the complete mitochondrial genome of the Leadhued skate Notoraja tobitukai (Rajiformes: Arhynchobatidae) was determined. It was a circle molecular (16, 799 bp), consisted of 37 genes with a typical gene order in vertebrate mitogenome. In the whole mitogenome, there were 24 bp short intergenic and 26 bp overlaps. The nucleotide composition was 32.3% A, 22.6% C, 13.1% G and 32.0% T. Two start codons (GTG and ATG) and two stop codons (TAG, TAA/T) were used in the protein-coding genes. The 22 tRNA genes ranged from 65 bp (tRNA-Cys) to 75 bp (tRNA-Leu1). The phylogenetic result showed that N. tobitukai was clustered with the Pavoraja nitida.


Gastric electrical stimulation in patients with gastroparesis.
As in the heart, there is a pacemaker in the human stomach and it generates myoelectrical activity with a frequency of approximately three cycles per minute. Abnormalities in gastric myoelectrical activity may result in gastric motility disorders, such as gastroparesis. Electrical stimulation of the stomach is achieved by delivering electrical currents via electrodes attached to the smooth muscle of the stomach. Recently, a number of studies on electrical stimulation of the stomach in both humans and dogs have indicated that gastric electrical stimulation with appropriate parameters is able to entrain gastric slow waves and normalize gastric dysrhythmias. This has led some investigators to use gastric electrical stimulation to treat patients with gastroparesis. Previous studies and the current state of the field in gastric electrical stimulation in treatment of gastroparesis will be discussed and summarized.


Neuroendocrine and cytokines-induced responses to minutes, hours, and days of mental stress.
Previously, a large number of studies reported that psychological stress and psychiatric illness reduces immune responsiveness. However, it turned out that stress reduces immune responsiveness is an oversimplified statement because the interactions between central nervous system, endocrine system and the immune system are undoubtedly complex. Therefore, this study aims in reviewing mental stress models (e.g. brief and written examination stress as subacute and acute type of stressor) that have been utilized to understand the effect of stress on the neuroendocrine and immune systems. The published findings from human mental stress models on catecholamines, cortisol, prolactin levels and on T helper (Th) 1 and 2-induced cytokines are presented and discussed with respect to the in vitro and in vivo effects of glucocorticoids, catecholamines, and prolactin on the induction of cytokines. This review shows evidence that short-time (minutes) or preparation to a written examination, in those students who are stressed, induces the production of proinflammatory cytokines which may be related to Th1 response. However, longer mental stress (days) causes dysregulation in the immune function by shifting the cytokine response to Th2 response. The outcome from neuroendocrine and immune function prior to, following and after mental stress depends on multiple variables most importantly on the amount of stress, exposure time, coping behavior and adjustment of the individual. A few minutes of stress may improve immune performance but longer times of mental stress have detrimental effects that may lead to loss of immune integrity. Furthermore, studies on stress and common heath problems are necessary to increase our knowledge and understanding of the mechanisms responsible for producing neuroendocrine-induced immune changes in health and common diseases.


The relative effectiveness of three and four doses of COVID-19 vaccine in Victoria, Australia: A data linkage study.
The Coronavirus Disease 2019 (COVID-19) pandemic led to extensive vaccination campaigns worldwide, including in Australia. Immunity waning and the emergence of new viral variants pose challenges to the effectiveness of vaccines. Our study aimed to assess the relative effectiveness (rVE) of 3 and 4 compared with 2 doses of COVID-19 vaccine. The study focuses on the Victorian population, a majority of whom had no prior exposure to the virus before vaccination. We used routinely collected data for the state of Victoria, Australia, to assess rVE during an Omicron-dominant period, 1 June 2022 to 1 March 2023. Immunisation, notifications, hospitalisations and mortality data for residents aged 65 years and older were linked for analysis. Cox proportional hazard regression was used to estimate the rVE against COVID-19 hospitalisation or death, accounting for key confounders with vaccination as a time-varying covariate. In 1,070,113 people 65 years or older who had received their second dose, a third and fourth dose of a COVID-19 vaccine significantly reduced the hazard of hospitalisation or death compared to two doses. rVE was highest within two weeks from administration at 40 % (95 % CI: 0 % to 64 %) and 66 % (95 % CI: 60 % to 71 %) for a third and fourth dose, respectively. Additional protection conferred by third and fourth doses waned over time from administration. Our findings underscore the need for additional vaccine doses and updated vaccine strategies. These findings have implications for public health advice and COVID-19 vaccine strategies. Further research and monitoring of vaccine effectiveness in real-world settings are warranted to inform ongoing pandemic response efforts.


Cytology of angiosarcoma in effusions.
The cytologic and immunocytochemical findings in pleural effusions from three cases of angiosarcoma are presented. In two of the cases, the primary lesion was on the scalp; in the third case, an angiosarcoma of the small intestine developed after radiotherapy for Hodgkin's disease. Single malignant cells and small clusters of cells were seen in cytologic preparations from two cases while only single cells were seen in preparations from one case. The malignant cells had delicate, finely vacuolated cytoplasm with distinct borders. No specific morphologic features were noted. Immunoperoxidase studies revealed binding of Ulex europaeus and reactivity for vimentin in all three cases and expression of Factor VIII-related protein in two of the cases but no expression of epithelial markers. The clinical history and immunoperoxidase studies are necessary to distinguish angiosarcoma from metastatic adenocarcinoma and other malignancies in effusions.


[Conformational aspects of beta-trypsin interaction with substrates and pancreatic trypsin inhibitor. I. Conformational properties of residues in the enzyme-active center and the structure of a non-valent enzyme-substrate complex].
The theoretical conformational analysis of potential surfaces of Ser-195, His-57, Asp-102 and Gln-192 side chains in the active center of native beta-trypsin has been carried out. The above residues are shown to exist in low-energy conformational states in the free enzyme and in its nonbonded substrate complexes. Interrelations between the flexibility of the residues and their catalytical functions were revealed. Conformational aspects of interaction of trypsin with N-acetyl-L-lysine and N-acetyl-L-alanyl--L-alanyl--L-lysyl--L-alanyl methyl amide and with the Gly-12--Ile-19 BPTI fragment were analysed. The productive binding of the substrate at the nonbonded complex stage is shown to take place exclusively in the lowest energy conformation of the enzyme-substrate complex. Basing on theoretical and experimental evidence, the problems of primary and secondary specificity of trypsin, and potential properties of the native protein to form a productive nonbonded complex and to react at the subsequent stages of the catalytical act are discussed. Conformational changes in the active center and interactions with a substrate are shown to result from stabilizing enzyme-substrate interactions. Trypsin inhibition by BPTI molecule does not take place at the nonbonded complex stage.


SeqSIMLA: a sequence and phenotype simulation tool for complex disease studies.
Association studies based on next-generation sequencing (NGS) technology have become popular, and statistical association tests for NGS data have been developed rapidly. A flexible tool for simulating sequence data in either unrelated case-control or family samples with different disease and quantitative trait models would be useful for evaluating the statistical power for planning a study design and for comparing power among statistical methods based on NGS data. We developed a simulation tool, SeqSIMLA, which can simulate sequence data with user-specified disease and quantitative trait models. We implemented two disease models, in which the user can flexibly specify the number of disease loci, effect sizes or population attributable risk, disease prevalence, and risk or protective loci. We also implemented a quantitative trait model, in which the user can specify the number of quantitative trait loci (QTL), proportions of variance explained by the QTL, and genetic models. We compiled recombination rates from the HapMap project so that genomic structures similar to the real data can be simulated. SeqSIMLA can efficiently simulate sequence data with disease or quantitative trait models specified by the user. SeqSIMLA will be very useful for evaluating statistical properties for new study designs and new statistical methods using NGS. SeqSIMLA can be downloaded for free at http://seqsimla.sourceforge.net.


Effect of nitrate on anaerobic azo dye reduction.
The aim of the study was to investigate the effect of nitrate on anaerobic color removal efficiencies. For this aim, anaerobic-aerobic sequencing batch reactor (SBR) fed with a simulated textile effluent including Remazol Brilliant Violet 5R azo dye was operated with a total cycle time of 12 h, including anaerobic (6 h) and aerobic cycles (6 h). Microorganism grown under anaerobic phase of the reactor was exposed to different amounts of competitive electron acceptor (nitrate) and performance of the system was determined by monitoring color removal efficiency, nitrate removal, nitrite formation and removal, oxidation reduction potential, color removal rate, chemical oxygen demand (COD), specific anaerobic enzyme (azo reductase) and aerobic enzyme (catechol 1,2 dioxygenase), and formation and removal of aromatic amines. Variations of population dynamics of microorganisms exposed to various amount of nitrate were identified by denaturing gradient gel electrophoresis (DGGE). It was found that nitrate has adverse effect on anaerobic color removal efficiency and color removal was achieved after denitrification process was completed. It was found that nitrate stimulates the COD removal efficiency and accelerates the COD removal in the first hour of anaerobic phase. About 90 % total COD removal efficiencies were achieved in which microorganism exposed to increasing amount of nitrate. Population dynamics of microorganisms exposed to various amount of nitrate were changed and diversity was increased.


Women with autistic-spectrum disorder: magnetic resonance imaging study of brain anatomy.
Our understanding of anatomical differences in people with autistic-spectrum disorder, is based on mixed-gender or male samples. To study regional grey-matter and white-matter differences in the brains of women with autistic-spectrum disorder. We compared the brain anatomy of 14 adult women with autistic-spectrum disorder with 19 controls using volumetric magnetic resonance imaging and voxel-based morphometry. Women with autistic-spectrum disorder had a smaller density bilaterally of grey matter in the fronto-temporal cortices and limbic system, and of white matter in the temporallobes (anterior) and pons. In contrast, they had a larger white-matter density bilaterally in regions of the association and projection fibres of the frontal, parietal, posterior temporal and occipital lobes, in the commissural fibres of the corpus callosum (splenium) and cerebellum (anterior lobe). Further, we found a negative relationship between reduced grey-matter density in right limbic regions and social communication ability. Women with autistic-spectrum disorder have significant differences in brain anatomy from controls, in brain regions previously reported as abnormal in adult men with the disorder. Some anatomical differences may be related to clinical symptoms.


Metabolism of tritium- and 14C-labeled alanine in rats.
[3-3H]- and [U-14C]alanine were administered to starved rats by bolus injection and by continuous infusion. The specific activities of alanine, glucose, and lactate in blood were followed. The tracer kinetics of alanine depended on the site of tracer administration and sampling. Tracer was either administered into the aorta and blood sampled from the vena cava (A-VC mode) or tracer was administered into the vena cava and arterial blood sampled (V-A mode) (Katz, J. F. Okajima, and A. Dunn. Biochem J. 194: 513-524, 1981). When tracer was infused in the A-VC mode the plateau specific activity of alanine was about half that obtained in the V-A mode. The parameters of alanine turnover were calculated from the specific activities obtained in the A-VC mode. The calculated apparent replacement rate averaged 1.9 mg.min-1.kg-1 for [U-14C]- and 3.9 mg.min-1.kg-1 for [3-3H]alanine, indicating a carbon recycling of about 50%. The apparent contribution of alanine carbon to that of glucose is 15%. The maximal activity in plasma water is attained at about 5 min after bolus injection of [3-3H]alanine and that of [14C]glucose in blood is attained about 10 min after the injection of [U-14C]alanine. Maximal specific activity of [3H]- and [14C]lactate is attained within about 1 min after injection. The apparent mean transit time and alanine mass were calculated from the areas of washout curves after the continuous infusion was terminated. The mean transit time for [3H]alanine was 10 min and apparent total body mass of alanine of the order of 40 mg/kg. The apparent means transit time for [U-14C]alanine ranged from 33 to 66 min corresponding to a mass of the order of 100 mg/kg of alanine or 40 mg/kg of alanine carbon.


Diversity of active constituents in Cichorium endivia and Cynara cornigera extracts.
The present study attempts to explore the phytochemical constituents of different extracts from Cynara cornigera and Cichorium endivia plant materials. The two species studied are native in Egypt. Five different solvents, viz., aqueous, methylene chloride, petroleum ether, ethyl acetate, and n-butanol were used. Phytochemical analysis revealed the presence of phenols, flavonoids, sterols (stigmasterol and beta-sitosterol), terpenes (α-amyrin, ursolic and oleanolic acid), and hydrocarbons (n-alkane), the latter found in low amount. The ethyl acetate and water extracts of C. cornigera root showed lower mass fractions of phenolic compounds ranged from 20 to 81 g/100 g, and higher amounts in ethyl acetate extract of the inflorescences and butanol extract of the root where values ranged from 195 to 399 g/100 g. The β-sitosterol and stigmasterol were present in all plant extracts. Oleanolic and ursolic acids were detected in roots, leaves and inflorescences of C. cornigera and in C. endivia shoot. The ethyl acetate extracts from C. cornigera leaf and inflorescence attained higher chemical diversity than the other extracts. Alternatively, sterols and triterpenes were the major constituents. The high chemical diversity of active constituents justifies the future potential use of the two species at commercial level.


How Does the Covıd-19 Pandemıc Affect the Target 90-90-90?
In 2014, The Joint United Nations Program on HIV and AIDS (UNAIDS) has set an ambitious target code-named 90-90-90, which aims to ensure that 90% of all people living with HIV will know their state, 90% of all people diagnosed will receive sustained antiretroviral therapy, and 90% of all people receiving ART will have viral suppression by 2020. Since 2014, many tests and treatment programs have been developed to achieve the above goals worldwide. In 2019, it was reported that many developed countries can reach the target with the right strategies, as well as regions that are still far from the targets. It has been reported that the fourth 90 should be one of the targets related to HIV infection in recent years. This view, beyond virological suppression, was towards developing programs that would enable people living with HIV to live not only longer but also healthy. The socio-cultural and economic obstacles to reach the targets may vary according to geographical regions, but it is clear that COVID-19 disease, which has taken the whole world under the influence since 2019, is a major obstacle to the 90-90-90 targets worldwide. Difficulties in the diagnosis and access to ART and treatment nonadherence which may be encountered more frequently due to many factors may threaten both the health of people living with HIV and public health. The COVID-19 pandemic has disrupted many programs developed in the fight against the HIV epidemic. Considering COVID-19 disease and future epidemics that may create a chaotic environment, analyzing the difficulties experienced in the pandemic retrospectively, and determining new strategies that will bring appropriate solutions to the problems will play an important role in the proper management of future issues.


EGFR Mutation Analysis for Prospective Patient Selection in Two Phase II Registration Studies of Osimertinib.
Osimertinib is an oral, central nervous system-active, EGFR tyrosine kinase inhibitor (TKI) for the treatment of EGFR T790M-positive advanced NSCLC. Here we have evaluated EGFR mutation frequencies in two phase II studies of osimertinib (AURA extension and AURA2). After progression while receiving their latest line of therapy, patients with EGFR mutation-positive advanced NSCLC provided tumor samples for mandatory central T790M testing for the study selection criteria. Tumor tissue mutation analysis for patient selection was performed with the Roche cobas EGFR Mutation Test (European Conformity-in vitro diagnostic, labeled investigational use only) (Roche Molecular Systems, Pleasanton, CA). Patients should not have been prescreened for T790M mutation status. The cobas test results were compared with those of the MiSeq next-generation sequencing system (Illumina, San Diego, CA), which was used as a reference method. Samples from 324 and 373 patients screened for AURA extension and AURA2, respectively, produced valid cobas test results. The T790M detection rates were similar between AURA extension and AURA2 (64% and 63%, respectively). The pooled T790M rate was 63%, with no difference by ethnicity (63% for Asian and non-Asian patients alike) or immediately prior treatment with an EGFR TKI (afatinib, 69%; erlotinib, 69%; and gefitinib, 63%). A higher proportion of patients had T790M detected against a background of exon 19 deletions versus L858R mutation (73% versus 58% [p = 0.0002]). In both trials the cobas test demonstrated high sensitivity (positive percent agreement) and specificity (negative percent agreement) for T790M detection when compared with the next-generation sequencing reference method: positive percent agreement of 91% versus 89% and negative percent agreement of 97% versus 98%. In both trials, the rate of detection of T790M mutation in patients with advanced NSCLC was approximately 63% and was unaffected by immediately prior treatment with an EGFR TKI or ethnicity.


Serological analysis of antigenic heterogeneity of Giardia lamblia variant surface proteins.
Neonatal ZU.ICR mice were infected with trophozoites of Giardia lamblia clone GS/M-83-H7 expressing the variant surface protein (VSP) H7 and were subsequently investigated for their serum antibody response directed against VSPH7. Recombinant polypeptides, representing overlapping segments of VSPH7, and native Giardia proteins were used as antigenic reagents to examine the antigenic substructure of VSPH7 and the extent of antigenic variation in vivo. VSPH7 proved to be the predominant antigen of the parasite with respect to serum antibody reactivity. The data indicated that VSPH7 basically consists of two antigenically distinct parts: (i) a unique, variant-specific 314-amino-acid N-terminal region which elicits a low antibody response preferentially detectable during the early phase of the infection and (ii) a 171-amino-acid C-terminal region which elicits a high antibody response during the later phase or after resolution of the infection. The epitopes of the C-terminal region appear to be shared by other, as yet uncharacterized, variant antigens. The highly conserved 34-amino-acid stretch at the extreme C terminus of VSPH7 exhibited no immunoreactivity to any of the sera tested. Further investigations indicated that antigenic variation of the intestinal parasite population was associated with a diversification into at least six to nine new antigen types. These variant antigens were extremely heterogeneous in size ranging from approximately 50 to 115 kDa. None of these proteins shared antigenic epitopes with the 314-amino-acid N-terminal portion, but several of them cross-reacted with antibodies specific to the 171-amino-acid C-terminal portion of the VSP from the original inoculum.


Serum insulin-like growth factor I in brain function.
Insulin-like growth factor I (IGF-I) is present at high concentrations in the circulation. Tissue-specific genetic ablation has shown that the majority of serum IGF-I is secreted by liver cells, although all major organs synthesize it. IGF-I is an important signal during development, including brain growth. Although the biological role of IGF-I in organs such as muscle or ovary is reasonably well established, its biological significance in the adult brain is far from clear. In this regard, while local IGF-I synthesis decreases during brain development, protein levels remain relatively constant throughout life until old age, where a decline is found, not only in the brain but also in the bloodstream. This mismatch between declining local synthesis early after birth and steady protein levels may be explained by the ability of serum IGF-I to access the brain across the blood-brain-barrier. This peripheral IGF-I input to the brain is a physiologically meaningful process of potential impact in brain diseases. Numerous brain mechanisms are regulated by serum IGF-I. Many of these, such as cell energy modulation or growth and survival are common to other IGF-I target tissues but there are also a number of brain-specific mechanisms regulated by IGF-I which likely underlie the ability of serum IGF-I to modulate the major function of the brain: cognition. We propose that serum IGF-I forms part of the mechanisms involved in the "cognitive reserve" concept of brain responses to homeostasis breakdown. Based on IGF-I pleiotropy not only in brain but elsewhere, we consider that loss of IGF-I function is an important step towards disease.


Electrothermal flow on electrodes arrays at physiological conductivities.
AC electrothermal (ET) flow is inevitable for microfluidic systems dissipating electric energy in a conducting medium. Therefore, many practical applications of biomicrofluidics are prone to ET flow. Here, a series of observations are reported on ET flow in a microfluidic chamber that houses three electrode pairs. The observations indicate that the variations in liquid conductivity and channel height critically impact the structure and magnitude of the flow field. Observations indicate that after a critical conductivity a global ET flow is present in the chamber, while at lower conductivities a vortex is present at every electrode edge. In addition, no ET flow is observed when the chamber height is kept below a critical value at physiological conductivity (∼1.5 S/m). The experimental observations are compared with the numerical simulations of ET flow. The validity of the assumptions made in the current AC ET flow theory is also discussed in the light of the experimental data. The observations can be critical while designing microfluidic systems that involve power dissipation in conductive fluids.


TRREMS procedure (transanal repair of rectocele and rectal mucosectomy with one circular stapler): a prospective multicenter trial.
Since anorectocele is usually associated with mucosa prolapse and/or rectal intussusceptions, it was developed a stapled surgical technique using one circular stapler. To report the results of Transanal Repair of Rectocele and Rectal Mucosectomy with one Circular Stapler (TRREMS procedure) in the treatment of anorectocele with mucosa prolapse in a prospective multicenter trial. It was conducted by 14 surgeons and included 75 female patients, mean aged 49.6 years, with symptoms of obstructed defecation due to grade 2 (26.7%) and grade 3 (73.3%) anorectocele associated with mucosa prolapse and/or rectal intussusception (52.0%) and an average validated Wexner constipation score of 16. All patients were evaluated by a proctological examination, cinedefecography, anal manometry and colonic transit time. The TRREMS procedure consists of the manual removal of the rectocele wall with circumferential rectal mucosectomy performed with a circular stapler. The mean follow-up time was 21 months. All patients presented obstructed defecation and they persisted with symptoms despite conservative treatment. The mean operative time was 42 minutes. In 13 (17.3%) patients, bleeding from the stapled line required hemostatic suture. Stapling was incomplete in 2 (2.6%). Forty-nine patients (65.3%) required 1 hospitalization day, the remainder (34.7%) 2 days. Postoperatively, 3 (4.0%) patients complained of persistent rectal pain and 7 (9.3%) developed stricture on the stapled suture subsequently treated by stricturectomy under anesthesia (n = 1), endoscopic stricturectomy with hot biopsy forceps (n = 3) and digital dilatation (n = 3). Postoperative cinedefecography showed residual grade I anorectoceles in 8 (10.6%). The mean Wexner constipation score decreased significantly from 16 to 4 (0-4: n = 68) (6: n = 6) (7: n = 1) (P<0.0001). Current trial results suggest that TRREMS procedure is a safe and effective technique for the treatment of anorectocele associated with mucosa prolapse. The stapling technique is low-cost as requires the use of a single circular stapler.


Professional advice and readiness to change behavioral risk factors among members of a managed care organization.
To ascertain factors related to readiness to change behavioral risk factors in members of a managed care organization (MCO). Cross-sectional study. A telephone survey reached 4667 (73%) of 6409 adult members of a Minnesota MCO attending 2 primary care clinics. Of these, 3826 members (82%) completed an interview designed to identify behavioral risk factors (smoking, consuming a high-fat diet, and physical inactivity) and readiness to change these behaviors. Among MCO members consuming a high-fat diet, those most ready to change were older, were women, used more preventive services, and reported receiving professional advice about diet. For physical inactivity, those most ready to change were younger, women, and more educated; used more preventive services; and reported receiving professional advice about physical activity. Among smokers, those with higher readiness to change smoked fewer than 15 cigarettes a day, had higher self-efficacy, had no other smokers in the household, and reported receiving professional advice about smoking. After controlling for demographic variables and for use of preventive services, greater readiness to change for smoking (beta = 0.336, odds ratio [OR] = 1.40, P = .056), physical activity (beta = 0.651, OR = 1.92, P < .001), and diet (beta = 0.532, OR = 1.70, P < .001) was associated with having received professional advice to change these behaviors. Levels of readiness to change behaviors in MCO members who smoke, are inactive, or consume high-fat diets are similar to those reported in other populations. The association of professional advice to change behaviors with increased readiness to change for smoking, physical activity, and diet suggests that receiving professional advice on these topics might assist patients in changing adverse health-related behaviors.


Neurovegetative symptoms in multiple sclerosis: relationship to depressed mood, fatigue, and physical disability.
Some authors have suggested that when evaluating depression in multiple sclerosis (MS) patients, neurovegetative symptoms should be discounted and/or not considered, given the ostensibly high overlap between symptoms of MS (e.g., sleep disturbance, fatigue) and neurovegetative symptoms of depression. A further assertion is that inclusion of items assessing neurovegetative symptoms may artificially inflate overall depression scores and that mood scales may provide more accurate indices of depression in MS patients. The current study investigated the possibility that some neurovegetative symptoms may be specifically related to MS patients' depressed mood and are not simply indicators of physical disability and/or fatigue. Seventy-six clinically definite MS patients in the northwestern United States were administered two depression inventories and measures of physical disability and fatigue as part of a larger study. Results revealed that one neurovegetative symptom--disinterest in sex--was uniquely associated with depressed mood, and other neurovegetative symptoms were associated with both depression and fatigue but not physical disability. The present findings suggest that certain neurovegetative symptoms are differentially associated with depression, fatigue, and physical disability in MS. Routinely discounting all neurovegetative symptoms when assessing depression in MS patients may thus be unwarranted.


Evaluation by real-time PCR of the expression of S. flexneri virulence-associated genes ospB and phoN2 under different genetical backgrounds.
Under conditions of activated type III secretion Shigella flexneri up-regulates the expression of numerous genes, including the virulence plasmid (pINV)-encoded ospB and phoN2 genes. ospB and phoN2 are virulence-associated genes which are part of a bicistronic transcriptional unit encoding OspB, a protein (effector) of unknown function secreted by the type III secretion (TTS) apparatus, and PhoN2 (apyrase or ATP-diphosphohydrolase), a periplasmic protein involved in polar IcsA localization on the surface of S. flexneri. In this work we used real-time PCR to measure transcription of ospB and phoN2 of wild-type S. flexneri strain M90T as well as of derivative mutants impaired in definite virulence traits. The results obtained confirmed and extended previous reports indicating that the expression of ospB and phoN2 genes is modulated in a virB-dependent, mxiE-independent manner under conditions of non-activated secretion, while their expression is considerably induced in a mxiE-dependent manner under conditions of activated secretion. That the expression of the ospB-phoN2 operon is up-regulated in condition of activated secretion, indicates that probably the expression of these two genes might be important, especially during the later stages of infection of S. flexneri.


Preoperative prediction and quantification of septic risk caused by malnutrition.
Evaluation of the nutritional status of surgical patients was carried out by means of cluster analysis of several indicators to identify different nutritional conditions that could be considered frames of reference for the prediction of postoperative infections. Seventy-one surgical patients entered into the first phase of the study that identified four nutritional situations with a different incidence of postoperative sepsis; cluster 1 showed the lowest incidence of infectious episodes, and clusters 2 to 4 were characterized by a higher incidence of sepsis and other complications. In the second phase of the study, 28 patients were examined and compared with the four reference states by means of the determinations of the euclidean distance between the nutritional assessment of the patient and the barycenter of each of the reference states. The incidence of sepsis was similar in the two series of patients, indicating that the characterization of patients in one of the four reference states allows one to predict the risk of postoperative septic complications.


Debulking surgery for patients with diffuse large B-cell non-Hodgkin's lymphoma.
Chemotherapy and radiotherapy have been the principal modalities of treatment for diffuse large B-cell non-Hodgkin's lymphoma (B-NHL) for over 30 years. Various treatment regimens have been designed over the years to try to increase response and cure rates. The role of surgery has been generally restricted to defined and limited situations including diagnostic tissue biopsies and treating abdominal emergencies such as organ rupture or perforation. We present two cases of refractory B-NHL, where surgery was used as a part of stepwise and multi-modal treatment with curative intent. In both cases, the treatment approach included standard dose chemotherapy, eradication of residual mass by surgery, high dose chemotherapy (HDC) with stem cell support and posttransplantant immunotherapy. Currently, 2 years after completing the therapy, both patients are well with no evidence of active disease. Based on our experience with 2 patients we believe that in specific cases of residual chemo-resistant lymphomatous mass, surgery should be considered as a part of a multimodal approach.


Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients.
Mitochondrial function relies heavily on its morphology and distribution, alterations of which have been increasingly implicated in neurodegenerative diseases, such as Alzheimer's disease (AD). In this study, we found abnormal mitochondrial distribution characterized by elongated mitochondria that accumulated in perinuclear areas in 19.3% of sporadic AD (sAD) fibroblasts, which was in marked contrast to their normally even cytoplasmic distribution in the majority of human fibroblasts from normal subjects (>95%). Interestingly, levels of dynamin-like protein 1 (DLP1), a regulator of mitochondrial fission and distribution, were decreased significantly in sAD fibroblasts. To explore the potential role of DLP1 in mediating mitochondrial abnormalities in sAD fibroblasts, both the overexpression of a dominant negative DLP1 mutant and the reduced expression of DLP1 by miR RNAi in human fibroblasts from normal subjects significantly increased mitochondrial abnormalities. Moreover, overexpression of wild-type DLP1 in sAD fibroblasts rescued these mitochondrial abnormalities. Based on these data, we conclude that DLP1 reduction causes mitochondrial abnormalities in sAD fibroblasts. We further demonstrate that elevated oxidative stress and increased amyloid beta production are likely the potential pathogenic factors that cause DLP1 reduction and abnormal mitochondrial distribution in AD cells.


Rehabilitation of an Extremely Edentulous Atrophic Maxilla with a Pseudoskeletal Class III Relationship.
The skeletal class III relationship presents complex dentoalveolar problems, requiring multidisciplinary treatment. In edentulous people, severe atrophy of the jawbone simulates the clinical appearance of a skeletal class III relationship (pseudoskeletal class III), which presents major problems for rehabilitation. This article describes the rehabilitation of a 67-year-old patient with a pseudoskeletal class III relationship. The mandible was restored with two implant-supported bar-retained overdentures using clips for retention. The extremely atrophic maxilla was restored with a combination of sinus augmentation, implant placement, and classic prosthodontic treatment using an electroformed mesostructured overdenture with swivel lock attachments on an implant-supported bar. By performing minimal augmentative and implant surgeries and using the possibilities and advantages of classic prosthetic dentistry, the clinical situation described here could be managed and the atrophic maxilla could be rehabilitated.


Hidden diversity in the freshwater planktonic diatom Asterionella formosa.
Many freshwater and marine algal species are described as having cosmopolitan distributions. Whether these widely distributed morphologically similar algae also share a similar gene pool remains often unclear. In the context of island biogeography theory, stronger spatial isolation deemed typical of freshwater lakes should restrict gene flow and lead to higher genetic differentiation among lakes. Using nine microsatellite loci, we investigate the genetic diversity of a widely distributed freshwater planktonic diatom, Asterionella formosa, across different lakes in Switzerland and the Netherlands. We applied a hierarchical spatial sampling design to determine the geographical scale at which populations are structured. A subset of the isolates was additionally analysed using amplified fragment length polymorphism (AFLP) markers. Our results revealed complex and unexpected population structure in A. formosa with evidence for both restricted and moderate to high gene flow at the same time. Different genetic markers (microsatellites and AFLPs) analysed with a variety of multivariate methods consistently revealed that genetic differentiation within lakes was much stronger than among lakes, indicating the presence of cryptic species within A. formosa. We conclude that the hidden diversity found in this study is expected to have implications for the further use of A. formosa in biogeographical, conservation and ecological studies. Further research using species-level phylogenetic markers is necessary to place the observed differentiation in an evolutionary context of speciation.


[Fecundity of Thominx neopulchra (Nematoda:Capillariidae) from bats of the genus Myotis (Chiroptera:Vespertilionidae)].
Variability of absolute fecundity of nematode Thominx neopulchra from three species of genus Myotis was studies on the territory Zhiguli State Reserve in 2007, 2008. Significant differences in the fecundity of the nematode females depending on host species and sex, size of the parasite, number of the helminthes in a given host, and season of year were revealed.


Prevalence of the A and B types of Epstein-Barr virus DNA in nasopharyngeal carcinoma biopsies from southern China.
Epstein-Barr virus (EBV) exists in the human population in two genetic forms, usually referred to as type A and type B. Although many earlier studies had indicated that the A type was generally predominant, there were suggestions that the B type may exhibit a preferential tropism for nasopharyngeal epithelial cells. This study examines the prevalence of the two forms of EBV DNA present in nasopharyngeal carcinoma biopsies obtained from the high incidence area of Southern China. The results obtained by Southern blot or polymerase chain reaction analyses show that in this patient group the A type of EBV is predominant.


Role of passive T-cell death in chronic experimental autoimmune encephalomyelitis.
The mechanisms of chronic disease and recovery from relapses in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, are unknown. Deletion of myelin-specific lymphocytes by apoptosis may play a role in termination of the inflammatory response. One pathway of apoptosis is the passive cell death or "cell death by neglect" pathway, which is under the control of the Bcl family of genes. To investigate the role of passive cell death pathway in EAE, we used mice with transgenic expression of the long form of the bcl-x gene (Bcl-x(L)) targeted to the T-cell lineage. We found that mice transgenic for Bcl-x(L) have an earlier onset and a more chronic form of EAE induced by myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 compared with wild-type littermate mice. This was not due to an expanded autoreactive cell repertoire. Primed peripheral lymphocytes from Bcl-x(L) transgenic mice showed increased proliferation and cytokine production to MOG peptide in vitro compared with lymphocytes from wild-type animals. Immunohistologic studies demonstrated increased cellular infiltrates, immunoglobulin precipitation, and demyelination in the Bcl-x(L) transgenic central nervous system (CNS) compared with controls. There was also a decreased number of apoptotic cells in the CNS of Bcl-x(L) transgenic mice when compared with littermates at all time points tested. This is the first report of an autoimmune disease model in Bcl-x(L) transgenic mice. Our data indicate that the passive cell death pathway is important in the pathogenesis of chronic EAE. These findings have implications for understanding the pathogenesis of multiple sclerosis and other autoimmune diseases.


The rectal mucosa-associated microflora in patients with ulcerative colitis.
The rectal mucosa-associated flora (MAF) of patients with ulcerative colitis has been studied in 25 patients with newly diagnosed disease, 20 with relapse of existing disease, and 44 who were in remission. Patients with active disease were re-examined twice during treatment. The MAF was simpler and less dense than the microflora of faeces. Obligate anaerobes usually predominated in the MAF although the ratio of obligate anaerobes to facultative species was lower than that found in faeces. Viable counts of the total flora and of its constituent genera varied considerably between patients. Counts of the total flora, of obligate anaerobes (including bifidobacteria, eubacteria and clostridia), and facultative organisms and micro-aerobes (enterobacteria and lactobacilli) were reduced in patients with active disease compared with those with inactive disease; corresponding carriage rates were also lower. Counts and carriage rates increased during treatment and approached those found in quiescent disease. The alterations in the MAF were especially marked in patients experiencing their first attack of ulcerative colitis. The relationship between these alterations and the aetiology and pathogenesis of this disease remains unclear.


[Validation of a deep vein thrombosis prediction rule in primary care].
Suspected deep vein thrombosis (DVT) of lower limbs (LL) may require different tools to rule out or confirm the diagnosis. Clinical probability provides help to select useful tests, interpret their results, and decide to treat the patient meanwhile. Clinical prediction rules that risk stratify patients with suspected DVT can be established from inpatients, but no prediction rule not requiring laboratory tests has been established from primary care patients. We previously derived and internally validated such a prediction rule. The aim of this study is to externally validate this score. The score was applied to Optimev outpatients with suspected LL-DVT, and without suspected pulmonary embolism. Sensitivity and specificity were calculated for proximal and distal DVT, according to each score. The area under the ROC curve was calculated for each kind of DVT, in order to assess the validity of the score on predicting the presence or absence of DVT. Among 3523 outpatients prospectively included in the Optimev study for suspected LL DVT, overall prevalence of DVT was 29.7% (n=1046), ranging from 21.7% in the non-high score probability, to 61.4% in the high score probability. The area under the ROC curve was 0.79 [CI 95%, 0.77-0.80]. With subgroup analysis, the area under curve was 0.83 [CI 95%, 0.82-0.85] for proximal DVT, and 0.75 [CI 95%, 0.73-0.77] for distal DVT. This score reliably identifies primary care patients with LL DVT, whether proximal or distal.


Chemical composition, antifungal, and anti-virulence action of the stem bark of Hancornia speciosa Gomes (Apocynaceae) against Candida spp.
Hancornia speciosa Gomes is a fruit and medicinal species used for treating infectious diseases of the genitourinary system. However, its mechanism of action against microbes is still not fully understood. Infections in the genitourinary system caused by Candida spp. are associated with its fungal resistance and pathogenicity. New plant-derived compounds are an alternative to fight these Candida infections. The objective of this study was to evaluate the anti-Candida effects of extracts of the stem bark of H. speciosa. This research investigated the chemical composition of sulfuric ether (EEHS) and methanolic (MEHS) extracts, their drug-modifying action on fluconazole, and their anti-virulence action on the morphological transition of Candida species. The extracts (EEHS and MEHS) of the stem bark of H. speciosa were chemically characterized via qualitative phytochemical screening and by liquid chromatography coupled with mass spectrometry (UPLC-MS-ESI-QTOF). The extracts were evaluated regarding their antifungal effects and fluconazole-modifying activity against Candida albicans, Candida krusei, and Candida tropicalis using the broth microdilution method. Additionally, the study evaluated the inhibition of fungal virulence in Candida species through morphological transition assays. The phytochemical screening revealed the presence of anthocyanidins, anthocyanins, aurones, catechins, chalcones, flavones, flavonols, flavanones, leucoanthocyanidins, tannins (condensed and pyrogallic), and xanthones in both extracts of the stem bark of H. speciosa. The UPLC-MS-ESI-QTOF analysis identified the same compounds in both extracts, predominating phenolic compounds. Some compounds were first time recorded in this species: gluconic acid, cinchonain IIb, cinchonain Ib isomer, and lariciresinol hexoside isomers. Most of the intrinsic antifungal activity was observed for the MEHS against C. krusei (IC50: 58.41 μg/mL). At subinhibitory concentrations (MC/8), the EEHS enhanced the action of fluconazole against all Candida strains. The MEHS exhibited greater efficacy than fluconazole inhibiting C. krusei growth. The EEHS completely inhibited hyphae appearance and reduced pseudohyphae formation in C. albicans. The stem bark of H. speciosa is a rich source of bioactive compounds, especially phenolic. Phenolic compounds can have important roles in fighting infectious diseases of the genitourinary system, such as candidiasis. The extracts of H. speciosa improved the action of the drug fluconazole against Candida species, inhibited hyphae appearance, and reduced pseudohyphae formation. The results of this study can support the development of new therapeutics against resistant strains of Candida.


Is There any Relationship Between Myocardial Repolarization Parameters and the Frequency of Ventricular Premature Contractions?
Ventricular premature contractions (VPCs) may trigger lethal ventricular arrhythmias in patients with structural heart disease. However, this role of VPCs in healthy people remains controversial once that not enough clinical trials are available. Recently, some myocardial repolarization markers, such as Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios, have been reported to be useful for predicting lethal ventricular arrhythmias in various clinical disorders without structural heart disease. In this study, we aimed to investigate the relation between VPC frequent and myocardial repolarization markers in individuals without structural heart disease. This study included 100 patients who had complaints of dizziness and palpitations. Twelve-lead electrocardiography and 24-hour ambulatory Holter recordings were obtained from all patients. VPC burden was calculated as the total number of VPCs divided by the number of all QRS complexes in the total recording time. P-values < 0.05 were considered significant. Tp-e interval and Tp-e/QTc ratio were significantly higher in patients with higher VPC burden than in patients with lower VPC burden, and a positive correlation was found between these markers and VPC burden. Tp-e (β = 1.318, p = 0.043) and Tp-e/QTc (β = -405.136, p = 0.024) in the lead V5 were identified as independent predictors of increased VPC burden. Tp-e interval and Tp-e/QTc ratio increased in patients with high VPC number. Our study showed that VPCs may have a negative effect on myocardial repolarization. This interaction may lead to an increased risk of malignant arrhythmias.


Pre-ESRD Dementia and Post-ESRD Mortality in a Large Cohort of Incident Dialysis Patients.
Conservative management may be a desirable option for elderly, fragile, or demented patients who reach end-stage renal disease (ESRD), yet some patients with dementia are placed on renal replacement therapy nonetheless. From a nationwide cohort of 45,076 US veterans who transitioned to ESRD over 4 contemporary years (October 1, 2007 to September 30, 2011), we identified 1,336 (3.0%) patients with International Classification of Diseases, Ninth Revision, Clinical Modification code-based dementia diagnosis during the prelude (predialysis) period. We examined the association of prelude dementia with all-cause mortality within the first 6 months following transition to dialysis, using a propensity-matched cohort and Cox proportional hazards models. In the entire cohort, the overall mean ± standard deviation age at baseline was 72 ± 11 years, 95% were male, 23% were African-American, and 66% were diabetic. There were 8,080 (18.5%) deaths (mortality rate, 412; 95% confidence interval [CI], 403-421/1,000 patient-years) in the dementia-negative group, and 396 (29.6%) deaths (mortality rate, 708; 95% CI, 642-782/1,000 patient-years) in the dementia-positive group in the entire cohort in the first 6 months after dialysis initiation. Presence of dementia was associated with higher risk of all-cause mortality (adjusted hazard ratio, 1.25; 95% CI, 1.12-1.38) compared to dementia-free patients in the first 6 months after dialysis initiation. Pre-ESRD dementia is associated with increased risk of early post-ESRD mortality in veterans transitioning to dialysis.


Late cretaceous aquatic plant world in Patagonia, Argentina.
In this contribution, we describe latest Cretaceous aquatic plant communities from the La Colonia Formation, Patagonia, Argentina, based on their taxonomic components and paleoecological attributes. The La Colonia Formation is a geological unit deposited during a Maastrichtian-Danian transgressive episode of the South Atlantic Ocean. This event resulted in the deposition of a series of fine-grained sediments associated with lagoon systems occurring along irregular coastal plains in northern Patagonia. These deposits preserved a diverse biota, including aquatic and terrestrial plants and animals. The aquatic macrophytes can be broadly divided into two groups: free-floating and rooted, the latter with emergent or floating leaves. Free-floating macrophytes include ferns in Salviniaceae (Azolla and Paleoazolla) and a monocot (Araceae). Floating microphytes include green algae (Botryoccocus, Pediastrum and Zygnemataceae). Among the rooted components, marsileaceous water ferns (including Regnellidium and an extinct form) and the eudicot angiosperm Nelumbo (Nelumbonaceae) are the dominant groups. Terrestrial plants occurring in the vegetation surrounding the lagoons include monocots (palms and Typhaceae), ferns with affinities to Dicksoniaceae, conifers, and dicots. A reconstruction of the aquatic plant paleocommuniy is provided based on the distribution of the fossils along a freshwater horizon within the La Colonia Formation. This contribution constitutes the first reconstruction of a Cretaceous aquatic habitat for southern South America.


Flow prediction in cerebral aneurysms based on geometry reconstruction from 3D rotational angiography.
We present an immersed boundary (IB) method for the simulation of steady blood flow inside a realistic cerebral aneurysm. We reconstruct a segment of the cerebrovascular system that contains an aneurysm, by using medical images obtained with three dimensional rotational angiography (3DRA). The main focus is on evaluating the sensitivity of flow predictions to the various steps of the vascular reconstruction process. Starting from the raw medical data, we analyze the fluid-mechanical consequences of the steps needed to generate the IB masking function for our simulations. We illustrate the IB method by applying it to a realistic aneurysm and investigate the role of (i) numerical resolution of the geometry; (ii) the selection of the specific vascular segment used in the simulations; and (iii) the influence of the smoothness of the periodic vessel extension to complete the computational model. Because of an unavoidable degree of uncertainty in the medical images, the geometry of the vessels and the aneurysm can be reconstructed only approximately. We also incorporate these slight uncertainties in the masking function by introducing inner and outer 'bounding' geometries and analyze the sensitivity of the flow predictions to these variations in the masking function. The numerical solutions computed in the inner and outer bounding geometries provide practical upper and lower bounds for basic flow properties, thus quantifying the reliability of the numerical solution, subject to uncertainties in the geometry of the flow domain.


Efficient RNP-directed Human Gene Targeting Reveals SPDEF Is Required for IL-13-induced Mucostasis.
Primary human bronchial epithelial cell (HBEC) cultures are a useful model for studies of lung health and major airway diseases. However, mechanistic studies have been limited by our ability to selectively disrupt specific genes in these cells. Here we optimize methods for gene targeting in HBECs by direct delivery of single guide RNA (sgRNA) and rCas9 (recombinant Cas9) complexes by electroporation, without a requirement for plasmids, viruses, or antibiotic selection. Variations in the method of delivery, sgRNA and rCas9 concentrations, and sgRNA sequences all had effects on targeting efficiency, allowing for predictable control of the extent of gene targeting and for near-complete disruption of gene expression. To demonstrate the value of this system, we targeted SPDEF, which encodes a transcription factor previously shown to be essential for the differentiation of MUC5AC-producing goblet cells in mouse models of asthma. Targeting SPDEF led to proportional decreases in MUC5AC expression in HBECs stimulated with IL-13, a central mediator of allergic asthma. Near-complete targeting of SPDEF abolished IL-13-induced MUC5AC expression and goblet cell differentiation. In addition, targeting of SPDEF prevented IL-13-induced impairment of mucociliary clearance, which is likely to be an important contributor to airway obstruction, morbidity, and mortality in asthma. We conclude that direct delivery of sgRNA and rCas9 complexes allows for predictable and efficient gene targeting and enables mechanistic studies of disease-relevant pathways in primary HBECs.