Quantification of teicoplanin in plasma by LC-MS with online sample clean-up and comparison with QMS assay.
Teicoplanin is a glycopeptide antibiotic used for the treatment of infections caused by Gram-positive bacteria. There is a good correlation between trough levels and clinical outcome, therefore therapeutic drug monitoring is recommended. Here we present a liquid chromatography-mass spectrometry (LC-MS) method with online extraction based on turbulent flow chromatography for the quantification of the five main components of teicoplanin, A2-1, A2-2, A2-3, A2-4, and A2-5. After online extraction, analytical chromatography was performed on a Hypersil Gold C8 column under acidic conditions. As mass spectrometer, a Q Exactive hybrid instrument was used. Samples were prepared by adding internal standard and subsequent centrifugation. Patient samples (n=125) that had previously been analyzed using a commercially available immunoassay (QMS teicoplanin) were re-analyzed by LC-MS. The imprecision was <6.9%, inaccuracy between 99.6% and 109%, for both, within- and between-day analysis. The method was shown to be free of matrix effects in the relevant time ranges and was compared to a commercially available immunoassay, QMS® teicoplanin from Thermo Fisher Scientific. The LC-MS assay produced comparable results to the QMS assay, the correlation coefficient was 0.856 (95% confidence interval 0.800-0.896). LC-MS yielded lower concentrations than the immunoassay as could be demonstrated by the bias of -1.16 mg/L (95% confidence interval -1.90-0.43 mg/L) in the Bland-Altman analysis. This specific, automated, LC-MS assay for teicoplanin is suitable for therapeutic drug monitoring.


Metabolic and circulatory limitations to muscular performance at the organ level.
Within working muscle, development of conditions that directly influence exercise performance is dependent on many factors, including: intensity and duration of exercise, type of skeletal muscle fibres recruited, cardiovascular support to the working fibres and the inherent metabolic characteristics of the contracting fibres. In general, it is possible to identify factors that seem to alter exercise performance only at relatively intense exercise conditions. During prolonged moderately intense exercise (e.g. 70-80% maximal oxygen consumption for at least 60-90 min) decline in performance is related to the depletion of glycogen within the working muscle. Although the cause of muscle performance decline during very intense exercise is not known, an extreme acidosis is found, especially in fast-twitch muscle, which could significantly disrupt normal metabolic and contractile processes. During fatigue caused by intense contraction conditions, ATP content decreases (by approx. 50%) and there is a stoichiometric production of IMP and ammonia in fast-twitch muscle. This loss in adenine nucleotide content is dependent on the severity of the contraction conditions relative to the functional aerobic capacity of the muscle fibre, since fast-twitch red (high mitochondria, high blood flow) and fast-twitch white (low mitochondria, low blood flow) muscles respond differently. In contrast, during similarly intense contraction conditions, rat slow-twitch muscle fibres maintain their ATP content and do not produce significant amounts of IMP. Indirect evidence suggests that a similar contrast between fibres occurs in humans during maximal exercise. Thus, there seems to be a fundamental difference between fast- and slow-twitch muscles in the management of their adenine nucleotide contents during intense contraction conditions. Whether this is related to the known differences in the fatigue process between these fibre types is not known.


The complex task of choosing a de novo assembly: lessons from fungal genomes.
Selecting the values of parameters used by de novo genomic assembly programs, or choosing an optimal de novo assembly from several runs obtained with different parameters or programs, are tasks that can require complex decision-making. A key parameter that must be supplied to typical next generation sequencing (NGS) assemblers is the k-mer length, i.e., the word size that determines which de Bruijn graph the program should map out and use. The topic of assembly selection criteria was recently revisited in the Assemblathon 2 study (Bradnam et al., 2013). Although no clear message was delivered with regard to optimal k-mer lengths, it was shown with examples that it is sometimes important to decide if one is most interested in optimizing the sequences of protein-coding genes (the gene space) or in optimizing the whole genome sequence including the intergenic DNA, as what is best for one criterion may not be best for the other. In the present study, our aim was to better understand how the assembly of unicellular fungi (which are typically intermediate in size and complexity between prokaryotes and metazoan eukaryotes) can change as one varies the k-mer values over a wide range. We used two different de novo assembly programs (SOAPdenovo2 and ABySS), and simple assembly metrics that also focused on success in assembling the gene space and repetitive elements. A recent increase in Illumina read length to around 150 bp allowed us to attempt de novo assemblies with a larger range of k-mers, up to 127 bp. We applied these methods to Illumina paired-end sequencing read sets of fungal strains of Paracoccidioides brasiliensis and other species. By visualizing the results in simple plots, we were able to track the effect of changing k-mer size and assembly program, and to demonstrate how such plots can readily reveal discontinuities or other unexpected characteristics that assembly programs can present in practice, especially when they are used in a traditional molecular microbiology laboratory with a 'genomics corner'. Here we propose and apply a component of a first pass validation methodology for benchmarking and understanding fungal genome de novo assembly processes.


Influence of anterior segment power on the scan path and RNFL thickness using SD-OCT.
Retinal nerve fiber layer (RNFL) thickness measures with spectral domain-optical coherence tomography (SD-OCT) provide important information on the health of the optic nerve. As with most retinal imaging technologies, ocular magnification characteristics of the eye must be considered for accurate analysis. While effects of axial length have been reported, the effects of anterior segment optical power on RNFL thickness measures have not been described fully to our knowledge. The purpose of our study was to determine the influence of the optical power change at the anterior corneal surface, using contact lenses, on the location of the scan path and measurements of RNFL thickness in normal healthy eyes. We recruited 15 normal subjects with less than 6 diopters (D) of ametropia and no ocular pathology. One eye of each subject was selected randomly for scanning. Baseline SD-OCT scans included raster cubes centered on the optic nerve and macula, and a standard 12-degree diameter RNFL scan. Standard 12-degree RNFL scans were repeated with 10 separate contact lenses, (Proclear daily, Omafilcon A/60%) ranging from +8 to -12 D in 2-D steps. The extent of the retinal scan, and RNFL thickness and area measures were quantified using custom MATLAB programs that included ocular biometry measures (IOL Master). RNFL thickness decreased (0.52 μm/D, r = -0.33, P < 0.01) and the retinal region scanned increased (0.52%/D, r = 0.97, P < 0.01) with increase in contact lens power (-12 to +8). The normalized/percentage rates of change of RNFL thickness (-0.11/mm, r = -0.67, P < 0.01) and image size (0.11/mm, r = 0.96, P < 0.01) were related to axial length. Changes in the retinal region scanned were in agreement with transverse scaling, computed with a three surface schematic eye (R(2) = 0.97, P < 0.01). RNFL area measures, that incorporated the computed transverse scaling, were not related significantly to contact lens power (863 μm(2)/D, r = 0.06, P = 0.47). Measurements of RNFL thickness by SD-OCT are dependent on the optics of the eye, including anterior segment power and axial length. The relationships between RNFL thickness measures and optical power are a direct reflection of scan path location with respect to the optic nerve head rim, caused by relative magnification. An incorporation of transverse scaling to RNFL area measures, based on individualized ocular biometry, eliminated the magnification effect.


The long arm of childhood experiences on longevity: Testing midlife vulnerability and resilience pathways.
Adverse early experiences have been associated with higher mortality risk, but evidence varies by type of experiences, and relatively little is known about the role of favorable early experiences on health in later life. This study evaluated the independent contributions to longevity of favorable and unfavorable early experiences, including psychosocial stressors, childhood socioeconomic status (SES), and close relationships. We also examined 4 midlife psychosocial factors as vulnerability and resilience pathways potentially mediating these associations. The sample included 1,042 men from the VA Normative Aging Study. Early experiences were assessed retrospectively in 1961-1970 and 1995. Midlife psychosocial factors were measured in 1985-1991 and included stressful life events (SLEs), negative affect, life satisfaction, and optimism. Mortality was assessed through 2016. In multiple mediator structural equation models, which account for the overlap among pathways, higher number of SLEs in midlife mediated the association of having more childhood psychosocial stressors to reduced longevity, supporting stress continuity as a vulnerability pathway. Higher optimism in midlife also mediated the association of higher childhood SES to greater longevity. In single mediator models, higher life satisfaction in midlife transmitted the benefits of higher childhood SES and presence of close relationships onto longevity. Higher optimism also mediated the association of fewer childhood psychosocial stressors to longevity. However, these indirect effects were attenuated when accounting for shared variance among mediators, suggesting overlapping pathways. Findings offer novel evidence on unique and shared pathways linking specific dimensions of early experiences to longevity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Patient Decision Making Related to Maternal and Childhood Vaccines: Exploring the Role of Trust in Providers Through a Relational Theory of Power Approach.
Immunization is one of the most effective ways to prevent infectious diseases. However, vaccination rates are suboptimal in the United States. Obstetric providers are critical in influencing vaccine decision making among pregnant women, as trust between a patient and provider may facilitate willingness to accept vaccination. Little is known about how power between a patient and provider affects vaccine acceptance. This study explored pregnant women's trust in obstetric providers within the context of vaccines. Using concepts from the relational theory of power, we conducted 40 in-depth interviews with a purposive sample of pregnant women from four Ob-Gyn practices each in Georgia and Colorado. Results suggest that to enhance trust, providers could gain distributive power by conveying empathy. Designated power through medical experience was associated with both trust and distrust, as some women trusted their providers because of their authority and medical credentials, while others viewed authority and experience as reasons to distrust their provider. To increase acceptance, providers should acknowledge the underlying power dynamics within these interpersonal relationships and strengthen rapport with patients through empathy and dialogue.


Extracorporeal shock wave lithotripsy in the treatment of renal and ureteral stones.
The use of certain technical principles and the selection of favorable cases can optimize the results of extracorporeal shock wave lithotripsy (ESWL). The aim of this study is to review how ESWL works, its indications and contraindications, predictive factors for success, and its complications. A search was conducted on the Pubmed® database between January 1984 and October 2013 using "shock wave lithotripsy" and "stone" as key-words. Only articles with a high level of evidence, in English, and conducted in humans, such as clinical trials or review/meta-analysis, were included. To optimize the search for the ESWL results, several technical factors including type of lithotripsy device, energy and frequency of pulses, coupling of the patient to the lithotriptor, location of the calculus, and type of anesthesia should be taken into consideration. Other factors related to the patient, stone size and density, skin to stone distance, anatomy of the excretory path, and kidney anomalies are also important. Antibiotic prophylaxis is not necessary, and routine double J stent placement before the procedure is not routinely recommended. Alpha-blockers, particularly tamsulosin, are useful for stones >10mm. Minor complications may occur following ESWL, which generally respond well to clinical interventions. The relationship between ESWL and hypertension/diabetes is not well established.


Rates and Determinants of Eyecare Utilization and Eyeglass Affordability Among Individuals With Visual Impairment in a Multi-Ethnic Population-Based Study in Singapore.
The purpose of this study was to determine the rates of, and factors associated with, eyecare utilization and spectacle affordability among Singaporeans with vision impairment (VI). We included adults with VI from their second visit of the Singapore Epidemiology of Eye Disease Study. Data on eyecare utilization and spectacle affordability were collected. Low eyecare utilization was defined as no eye check ever or eye checks not even once per year in reference to at least once per year. Difficulty affording glasses was defined as glasses being rated as expensive in reference to not expensive. There were 985 adults (14.5%; 415 Malays, 260 Indian, and 310 Chinese; mean age [SD]: 69.5 [10.2] years; 55.4% women) with VI who answered the above questions, were included. Of these, 624 (63.4%) wore glasses. The rates of low eyecare utilization and difficulty affording eyeglasses were 31% and 63%, respectively. Compared to Chinese (23.8%) and Indians (18.8%), Malays (57.4%) had the highest rates of low eyecare utilization (P < 0.001), and most difficulty affording eyeglasses (47.2% vs. 26.1% and 26.6% in Chinese and Indians, respectively; P < 0.001). Younger age, low socioeconomic status, absence of diabetes, absence of self-reported eye conditions, and poor vision were independently associated with low eyecare utilization, whereas older age and female sex was associated with difficulty affording glasses. In this multi-ethnic population with VI, almost one-third had low eyecare utilization and nearly two-thirds reported difficulty affording eyeglasses. This will inform strategies, such as tailored eyecare utilization awareness campaigns and awareness of available subsidy schemes for at-risk Singaporeans, such as Malays.


Pituitary autoimmunity in patients with diabetes mellitus and other endocrine disorders.
Pituitary autoimmunity is often found in association with other endocrine autoimmune or non-autoimmune diseases. Aim of the study was to assess the prevalence of serum pituitary antibodies (PitAb) in patients with Type 1 diabetes mellitus (T1DM) or Type 2 diabetes mellitus (T2DM). In this casecontrol study 111 patients with T1DM, 110 patients with T2DM, and 214 healthy controls were enrolled in a tertiary referral center. Pituitary, thyroperoxidase, thyroglobulin, 21-hydroxylase, and parietal cell antibodies were assessed in all cases. Endocrine function was further assessed by basal hormone measurement and by dynamic tests, as well as a pituitary magnetic resonance imaging (MRI) was performed in those patients found positive for PitAb. PitAb prevalence was higher in T1DM (4 out of 111, 3.6%) than in T2DM (0 out of 110, p=0.045) and in healthy subjects (1 out of 214, 0.5% p=0.029). Prevalence of other autoimmune diseases was significantly higher in patients with T1DM (45 out of 111, 40.5%) when compared with patients with T2DM (18 out of 110 T2DM, 16.3%, p<0.001). Patients with T1DM and PitAb positivity were found with a pituitary lesion at MRI in 2 cases and pituitary dysfunction in one case. A significant association between pituitary autoimmunity and T1DM was found, in particular in subjects with one or more other endocrine autoimmune diseases.


Development and application of an objective staffing calculator for antimicrobial stewardship programs in the Veterans Health Administration.
The development and validation of a staffing calculator and its use in creating staffing guidance for antimicrobial stewardship programs (ASPs) in Veterans Health Administration (VHA) facilities are described. The Tools and Resources Work Group of the Antimicrobial Stewardship Task Force and PBM Clinical Pharmacy Practice Office of the Department of Veterans Affairs developed, tested, and validated a staffing calculator to track patient care and ASP management activities needed to maintain a comprehensive ASP. Time spent on activities was based on time-in-motion tracking studies and input from experienced antimicrobial stewards. The staffing calculator was validated across VHA facilities of varying sizes and complexities to determine the number of needed clinical pharmacist full-time equivalents (FTEs) to implement and maintain ASPs per 100 occupied beds. A total of 12 facilities completed the staffing calculator for 1 calendar week. The median number of occupied beds was 226. Most facilities had at least 100 occupied beds, and 6 of the 12 were considered high complexity facilities. The median calculated FTE personnel requirement was 2.62, or 1.01 per 100 occupied beds. The majority of FTE time (70%) was spent on patient care activities and 30% on program management activities, including infectious diseases or ASP rounds. The final recommendations indicated that in order to implement and manage a robust ASP, a pharmacist FTE investment of 1.0 per 100 occupied beds would be needed. A staffing calculator to account for the time needed to implement ASP activities and provide staffing guidance across a large health-care system was validated.


Hantavirus-Driven PD-L1/PD-L2 Upregulation: An Imperfect Viral Immune Evasion Mechanism.
Viruses often subvert antiviral immune responses by taking advantage of inhibitory immune signaling. We investigated if hantaviruses use this strategy. Hantaviruses cause viral hemorrhagic fever (VHF) which is associated with strong immune activation resulting in vigorous CD8+ T cell responses. Surprisingly, we observed that hantaviruses strongly upregulate PD-L1 and PD-L2, the ligands of checkpoint inhibitor programmed death-1 (PD-1). We detected high amounts of soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2) in sera from hantavirus-infected patients. In addition, we observed hantavirus-induced PD-L1 upregulation in mice with a humanized immune system. The two major target cells of hantaviruses, endothelial cells and monocyte-derived dendritic cells, strongly increased PD-L1 and PD-L2 surface expression upon hantavirus infection in vitro. As an underlying mechanism, we found increased transcript levels whereas membrane trafficking of PD-L1 was not affected. Further analysis revealed that hantavirus-associated inflammatory signals and hantaviral nucleocapsid (N) protein enhance PD-L1 and PD-L2 expression. Cell numbers were strongly reduced when hantavirus-infected endothelial cells were mixed with T cells in the presence of an exogenous proliferation signal compared to uninfected cells. This is compatible with the concept that virus-induced PD-L1 and PD-L2 upregulation contributes to viral immune escape. Intriguingly, however, we observed hantavirus-induced CD8+ T cell bystander activation despite strongly upregulated PD-L1 and PD-L2. This result indicates that hantavirus-induced CD8+ T cell bystander activation bypasses checkpoint inhibition allowing an early antiviral immune response upon virus infection.


Alcohol, pattern of drinking and all-cause mortality in Russia, Belarus and Hungary: a retrospective indirect cohort study based on mortality of relatives.
To assess the relationship between alcohol intake frequency and mortality among males and females in three Eastern European populations, and to estimate the additional mortality risk posed by a combination of frequent drinking, binge drinking and other hazardous drinking habits. Retrospective cohort study; the cohort consisted of close relatives of survey participants. Middle-sized settlements in Russia, Belarus and Hungary. A total of 124 150 subjects aged 35-69 years in 1998 and followed-up until 2013. Survey respondents provided information on their mothers, fathers, siblings and partners of female respondents. This information, including current vital status and dates of birth and death, was used to construct the cohort of relatives. Alcohol consumption indices, reported by survey participants, included drinking frequency, binge drinking and hazardous drinking [consuming non-beverage and/or illicitly-produced alcohol and/or heavy drinking over several days (zapoi in Russian)]. Drinking frequency was associated positively with mortality in all three countries and both genders. At each drinking frequency level, mortality risk increased among those who also engaged in binge and/or hazardous drinking. Regular male drinkers who were also binge drinkers and hazardous drinkers had the highest risk of death; their hazard ratios (HR), compared with non-binge-non-hazardous occasional drinkers, were 2.56 [95% confidence interval (CI) = 2.27-2.88], 2.14 (95% CI = 1.84-2.48) and 2.11 (95% CI = 1.90-2.35) in Russia, Belarus and Hungary, respectively. In women, the corresponding HRs (using a lower frequency cut-off) were 2.86 (95% CI = 1.99-4.12) in Russia, 3.44 (95% CI = 2.17-5.44) in Belarus and 3.01 (95% CI = 2.26-4.01) in Hungary. Drinking frequency is associated positively with mortality among men and women in Russia, Belarus and Hungary. The mortality risk is higher among frequent drinkers who exhibit binge and hazardous drinking patterns.


Cooked Red Lentils Dose-Dependently Modulate the Colonic Microenvironment in Healthy C57Bl/6 Male Mice.
Dietary pulses, including lentils, are protein-rich plant foods that are enriched in intestinal health-promoting bioactives, such as non-digestible carbohydrates and phenolic compounds. The aim of this study was to investigate the effect of diets supplemented with cooked red lentils on the colonic microenvironment (microbiota composition and activity and epithelial barrier integrity and function). C57Bl/6 male mice were fed one of five diets: a control basal diet (BD), a BD-supplemented diet with 5, 10 or 20% cooked red lentils (by weight), or a BD-supplemented diet with 0.7% pectin (equivalent soluble fiber level as found in the 20% lentil diet). Red lentil supplementation resulted in increased: (1) fecal microbiota α-diversity; (2) abundance of short-chain fatty acid (SCFA)-producing bacteria (e.g., Prevotella, Roseburia and Dorea spp.); (3) concentrations of fecal SCFAs; (4) mRNA expression of SCFA receptors (G-protein-coupled receptors (GPR 41 and 43) and tight/adherens junction proteins (Zona Occulden-1 (ZO-1), Claudin-2, E-cadherin). Overall, 20% lentil had the greatest impact on colon health outcomes, which were in part explained by a change in the soluble and insoluble fiber profile of the diet. These results support recent public health recommendations to increase consumption of plant-based protein foods for improved health, in particular intestinal health.


Final amended report on safety assessment on aminomethyl propanol and aminomethyl propanediol.
Aminomethyl propanol and aminomethyl propanediol are substituted aliphatic alcohols that function as pH adjusters in cosmetic products at concentrations less than 10%; additionally, aminomethyl propanediol is a fragrance. Extensive oral toxicity data are reviewed, with fewer inhalation toxicity data. Dermal toxicity data are presented that demonstrate, for example, that a mascara with 1.92% aminomethyl propanediol does not cause dermal irritation or allergic contact sensitization, suggesting that the maximum reported use concentration of 2% in mascara would be safe. Although these ingredients are primary amines that are not substrates for N-nitrosation, they may contain secondary amines as impurities in finished products that may undergo N-nitrosation. These ingredients should not be included in cosmetic formulations containing N-nitrosating agents. The Cosmetic Ingredient Review Expert Panel concludes that aminomethyl propanol and aminomethyl propanediol are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.


[Cephalosporin allergy and cephalosporin-penicillin cross allergies with special reference to venereologic therapy of severe anaphylactic reactions].
The newer cephalosporins are gaining more and more importance in antimicrobial chemotherapy. This also applies to venereology. Yet before widespread use, their potential for anaphylactic reactions must be defined, as they are not uncommon with penicillin. In fact, the first cephalosporins shared this drawback with penicillin. According to the experimental and clinical data available, the newer cephalosporins, however, should not give rise to severe allergic reactions of the immediate type. This at least holds true for individuals without a history of allergy to beta-lactam-antibiotics but, in fact, not even they should be endangered. This, however, still needs further confirmation.


Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes.
Flavonoids have been demonstrated to affect the activity of many mammalian enzyme systems. Their functional phenolic groups are able to mediate antioxidant effects by scavenging free radicals. Molecules of this class have been found able to modulate the activity of kinases, phospholipase A2, cyclooxygenases, lipoxygenase, glutathione S-transferase, and many others. Recently, it has been demonstrated that luteolin, in the form of Luteolin-7-O-β-d-glucoside (LUT-7G) is able to induce the keratinocyte differentiation process in vitro. This flavonoid is able to counteract the proliferative effects of IL-22/IL6 pathway by the inhibition of STAT3 activity also in vivo in a psoriatic mouse model. Observations on energy metabolism changes of differentiating cells led us to perform a complete metabolomics analysis using human primary keratinocytes treated with LUT-7G. Our results show that LUT-7G, is not only able to impair the nuclear translocation of STAT3, but it also blocks the energy metabolism pathway, depressing the glycolytic and Krebs pathway by the inhibition of hexokinase 2 activity. These data confirm that LUT-7G can be proposed as a potential candidate for the treatment of inflammatory and proliferative diseases, but its role as a hexokinase 2 (HEK2) inhibitor opens new perspectives in nutritional science, and especially in cancer therapy, in which the inhibition of the Warburg effect could be relevant.


Biomechanical assessment of anterior lumbar interbody fusion with an anterior lumbosacral fixation screw-plate: comparison to stand-alone anterior lumbar interbody fusion and anterior lumbar interbody fusion with pedicle screws in an unstable human cadaver model.
Human lumbosacral cadaveric specimens were tested in an in vitro biomechanical flexibility experiment using physiologic loads in 5 sequential conditions. To determine the biomechanical differences between anterior lumbar interbody fusion (ALIF) using cylindrical threaded cages alone or supplemented with an anterior screw-plate or posterior pedicle screws-rods. Clinically and biomechanically, stand-alone ALIF performs modestly in immobilizing the unstable spine. Pedicle screws improve fixation stiffness significantly, but supplementary anterior instrumentation has not been studied. There were 7 specimens tested: (1) intact, (2) after discectomy and facetectomy to induce moderate rotational and translational hypermobility, (3) with 2 parallel ALIF cages, (4) with cages plus a triangular anterior screw-plate, and (5) with cages plus pedicle screws-rods. Pure moments without preload induced flexion, extension, lateral bending, and axial rotation; linear shear forces induced anteroposterior translation. Angular and linear motions were measured stereophotogrammetrically, and range of motion (ROM) and stiffness were quantified. Compared to the destabilized spine, interbody cages alone reduced ROM by 77% during flexion, 53% during extension, 60% during lateral bending, 69% during axial rotation, and 71% during anteroposterior shear (P < 0.001, analysis of variance/Fisher least significant difference). Addition of an anterior plate or pedicle screws-rods, respectively, further reduced ROM by 8% or 13% during flexion (P = 0.21), 21% or 28% during extension (P = 0.15), 5% or 25% during lateral bending (P = 0.04), 11% or 18% during axial rotation (P = 0.13), and 18% or 18% during anteroposterior shear (P = 0.17). Compared to stand-alone ALIF, both the anterior screw-plate and pedicle screw-rod fixation reduced vertebral ROM to less than 1.2 degrees of rotation and less than 0.1 mm of translation. The anterior screw-plate and pedicle screws-rods both substantially reduced ROM and increased stiffness compared to stand-alone interbody cages. There was no significant difference in the amount by which the supplementary fixation devices limited flexion, extension, axial rotation, or anteroposterior shear; pedicle screws-rods better restricted lateral bending.


Development of prostate-specific antigen promoter-based gene therapy for androgen-independent human prostate cancer.
The goal of this study is to develop a tissue-specific toxic gene therapy utilizing the prostate specific antigen (PSA) promoter for both androgen-dependent (AD) and androgen-independent (AI) PSA-secreting prostate cancer cells. Ideally this gene therapy would be effective without the necessity of exposing the target cells to circulating androgens. An AI subline of LNCaP, an AD PSA-secreting human prostate cancer cell line, C4-2, was used in this study. Castrated mice bearing C4-2 tumors secrete PSA. A transient expression experiment was used to analyze the activity of two PSA promoters, a 5837 bp long PSA promoter and a 642 bp short PSA promoter, in C4-2 cells. A recombinant adenovirus (Ad-PSA-TK) carrying thymidine kinase under control of the long PSA promoter was generated. The tissue-specific activity of Ad-PSA-TK was tested in vitro and in vivo. The long PSA promoter had superior activity over short PSA promoter, and higher activity in C4-2 cells than in LNCaP cells. High activity of Ad-PSA-TK was observed in C4-2 cells in an androgen deprived condition. In vitro, Ad-PSA-TK was further demonstrated to induce marked C4-2 cell-kill by acyclovir in medium containing 5% FBS. No cell-kill was observed in control WH cells (a human bladder cancer cell line). In vivo, Ad-PSA-P-TK with acyclovir significantly inhibited subcutaneous C4-2 tumor growth and PSA production in castrated animals. The 5837 bp long PSA promoter was active in the androgen free environment and could be used to target both androgen-dependent and independent PSA-producing prostate cancer cells in vitro, and prostate tumors in castrated hosts.


A cannabinoid receptor antagonist attenuates conditioned place preference but not behavioural sensitization to morphine.
The present study compared the effects of the cannabinoid receptor antagonist SR 141716 on morphine-induced locomotor sensitization (Experiment 1) and conditioned place preference (CPP, Experiment 2) in male albino Wistar rats. In Experiment 1, rats received seven consecutive daily treatments with morphine (10 mg/kg, SC) in combination with either SR 141716 (0, 0.1, 0.5 or 3.0 mg/kg, IP), or naloxone (10 mg/kg, IP). Three days later, all rats were challenged with a lower dose of morphine (5 mg/kg, SC). Rats pre-treated with morphine showed significantly elevated locomotor activity during the challenge session compared to vehicle-pre-treated animals indicating behavioural sensitization. Prior naloxone, but not SR 141716, co-administration with morphine, significantly attenuated the locomotor sensitization observed. In Experiment 2A, SR 141716 (0.1 mg/kg, IP), co-administered during conditioning, significantly attenuated the place preference produced by morphine (4 mg/kg, SC) in a standard unbiased two compartment place conditioning task. In Experiment 2B, the timing of drug administration and drug doses used were altered to be similar to Experiment 1, such that a comparison between the sensitization and CPP paradigms could be made. Thus, rats were conditioned with morphine (10 mg/kg, SC) combined with SR 141716 (0, 0.1, 0.5 or 3.0 mg/kg, IP) and tested for place preference under the influence of morphine (5 mg/kg, SC). SR 141716 attenuated morphine place preference at a dose (3.0 mg/kg) that did not itself affect place conditioning. Morphine also induced locomotor sensitization in the drug-paired compartment in Experiment 2B which was not blocked by any dose of SR 141716. We conclude that CB1 receptor antagonism modulates the rewarding value of opioids, but not the behavioural sensitization induced by chronic opioid administration.


Clinical assessment of mineral trioxide aggregate (MTA) as direct pulp capping in young permanent teeth.
Carious pulp exposure in permanent molars of children is a common incident. Mineral trioxide aggregate is a new material that possesses numerous exciting possibilities for pulp therapy. The purpose of this study was to evaluate the efficiency of MTA as a direct pulp capping agent in young permanent teeth. Thirty asymptomatic permanent molars with pulp exposures were treated by pulp capping using MTA. At each recall (6 12, 18 and 24 months), the teeth were assessed clinically, through pulpal sensitivity tests, as well as radiographically to evaluate periapical healing. None of the cases reported spontaneous pain at the six months follow up and the pulp showed signs of vitality and absence of periapical radiolucency. At 24 months, the clinical and radiographic success rate was 93% with evidence of continued root growth. Pulp capping with MTA is recommended for teeth with carious pulp exposures specially immature teeth with high potential for healing.


Adsorption and desorption characteristics of semiconductor volatile organic compounds on the thermal swing honeycomb zeolite concentrator.
The use of a honeycomb zeolite concentrator and an oxidation process is one of the most popular methods demonstrated to control volatile organic compound (VOCs) emissions from waste gases in semiconductor manufacturing plants. This study attempts to characterize the performance of a concentrator in terms of the removal efficiencies of semiconductor VOCs (isopropyl alcohol [IPA], acetone, propylene glycol methyl ether [PGME], and propylene glycol monomethyl ether acetate [PGMEA]) under several parameters that govern the actual operations. Experimental results indicated that at inlet temperatures of under 40 degrees C and a relative humidity of under 80%, the removal efficiency of a zeolite concentrator can be maintained well over 90%. The optimal rotation speed of the concentrator is between 3 and 4.5 rph in this study. The optimal rotation speed increases with the VOCs inlet concentration. Furthermore, reducing the concentration ratio helps to increase the removal efficiency, but it also increases the incineration cost. With reference to competitive adsorption, PGMEA and PGME are more easily adsorbed on a zeolite concentrator than are IPA and acetone because of their high boiling points and molecular weights.


Clinical Reasoning: A 77-Year-Old Man With Involuntary Movements, Sleep Changes, Falls, Bulbar Symptoms, and Cognitive Complaints.
A 77 year-old-man presents with chorea, parasomnias, dysarthria and dysphagia, and cognitive issues. A broad work-up reveals positive anti-IgLON5 antibody. This case report represents a "textbook" example of anti-IgLON5 syndrome.


High-Resolution Imaging of a Single Gliding Protofilament of Tubulins by HS-AFM.
In vitro gliding assay of microtubules (MTs) on kinesins has provided us with valuable biophysical and chemo-mechanical insights of this biomolecular motor system. Visualization of MTs in an in vitro gliding assay has been mainly dependent on optical microscopes, limited resolution of which often render them insufficient sources of desired information. In this work, using high speed atomic force microscopy (HS-AFM), which allows imaging with higher resolution, we monitored MTs and protofilaments (PFs) of tubulins while gliding on kinesins. Moreover, under the HS-AFM, we also observed splitting of gliding MTs into single PFs at their leading ends. The split single PFs interacted with kinesins and exhibited translational motion, but with a slower velocity than the MTs. Our investigation at the molecular level, using the HS-AFM, would provide new insights to the mechanics of MTs in dynamic systems and their interaction with motor proteins.


Three Studies Evaluating the Potential for Lidocaine, Bupivacaine or Procaine to Reduce Pain-Related Behaviors following Ring Castration and/or Tail Docking in Lambs.
The use of local anesthesia at the time of ring castration and tail docking can improve lamb welfare. However, few local anesthetics are registered for sheep, and data on their duration of effect is limited. Three studies were conducted to evaluate the efficacy of procaine (P), lidocaine (L), and bupivacaine (B) in terms of observed alleviation of behavioral responses to castration and/or tail docking in 10-min blocks in the first 60 min post-treatment. In each study, comparisons were made between two groups of lambs castrated and/or tail docked with rubber rings and either receiving the agent using the NUMNUTS® instrument (N) or receiving no anesthetic agent (RR). Acute pain behavior was lower in NL (n = 28) than RRL (n = 15) males in the first 10 min post-procedure (p < 0.05); lower in NB (n = 16) than RRB (n = 16) males in periods 10-20 min (0.05 < p < 0.01), 20-30 min (p < 0.05) and 40-50 min (0.05 < p < 0.01); lower in NB (n = 16) than RRB (n = 16) females between 20 and 40 min post-procedure (0.05 < p < 0.01); lower in NP (n = 8) than RRP (n = 7) males in period 10-20 min (0.05 < p < 0.01), and lower in NP (n = 9) than RRP (n = 9) females in periods 0-10 min (0.05 < p < 0.01), and 10-40 min (p < 0.05). Benefits were modest, and the effects of procaine appear to last longer than lidocaine, while bupivacaine is slower to take effect than either procaine or lidocaine but may provide longer-lasting pain relief. The duration of action of local anesthetics is short in sheep, and detailed behavioral evaluations are required in the first hour post-procedure to establish efficacy.


A comparative study of silver electrodeposition from pyrophosphate-cyanide and high concentration cyanide electrolytes in the presence of brighteners.
A study of the electrodeposition of silver from 2 different types of electrolytes; (1) neutral pyrophosphatecyanide electrolyte and (2) alkaline high concentrated cyanide electrolyte in the presence of a variety of additives such as 2-mercaptobenzothiazole, potassium selenocyanate, and potassium antimony tartrate was performed. Influence of additives and cyanide concentration on microstructure and kinetics of the cathodic processes were studied. A brightener couple, 2-mercaptobenzothiazole and potassium antimony tartrate, were combined within this investigation and detected to be highly effective for silver electrodeposition. The rapid increase in current density at the same potential interval related to grain refinement effect of potassium antimony tartrate was shown. The cyclic organic compound, 2-mercaptobenzothiazole, polarizes the reduction to high cathodic potential in pyrophosphate electrolyte. However, the sufficient levelling effect required for the mirror-bright appearance seems to be related to the high polarizing effect of the high concentration cyanide content. In the case of pyrophosphate electrolytes, sufficient levelling cannot be achieved, so semigloss coatings are obtained. The low cathodic potential electrodeposition of silver in pyrophosphate electrolyte, which is found to proceed by 3D instantaneous nucleation, is polarized to high cathodic potentials and grows into 3D progressive nucleation and diffusion-controlled growth in high concentration cyanide electrolyte.


NACK kinesin is required for metaphase chromosome alignment and cytokinesis in the moss Physcomitrella patens.
The NACK kinesins (NACK1, NACK2 in tobacco and AtNACK1/HINKEL, AtNACK2/STUD/TETRASPORE in Arabidopsis), members of a plant-specific kinesin-7 family, are required for cytokinesis. Previous studies using tobacco and Arabidopsis cells showed that NACK1 and AtNACK1 at the phragmoplast midzone activate the MAP kinase cascade during the late M phase, which is critical for the cell plate formation. However, the loss-of-function phenotype has not been investigated in details in living cells and the molecular activity of this kinesin remains to be determined. Here, we report the mitotic roles and activity of the NACK kinesins in the moss Physcomitrella patens. When we simultaneously knocked down three PpNACKs by RNA-interference (RNAi) in protonemal cells, we observed a cytokinesis failure following a defect in phragmoplast expansion. In addition, misaligned chromosomes were frequently detected in the pre-anaphase spindle and the anaphase onset was significantly delayed, indicating that PpNACK also plays a role in pre-anaphase. Consistent with the appearance of early and late mitotic phenotypes, endogenous PpNACK was localised to the interpolar microtubule (MT) overlap from prometaphase through telophase. In vitro MT gliding assay and single motor motility assay showed that PpNACK-b is a processive, plus-end-directed motor, suggesting that PpNACK is capable of transporting cargoes along the spindle/phragmoplast MT. Our study using Physcomitrella patens demonstrated that PpNACK is an active motor protein and identified unexpected and conserved roles of PpNACK during the mitosis of P. patens.


Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation.
In efforts to minimize the chronic administration of immunosuppression (IS) drugs in transplantation and autoimmune disease, various cell-based tolerogenic therapies, including the use of regulatory or tolerogenic dendritic cells (tolDC) have been developed. These DC-based therapies aim to harness the inherent immunoregulatory potential of these professional antigen-presenting cells. In this short review, we describe both the demonstrated tolerogenic properties, and current limitations of rapamycin-conditioned DC (RAPA-DC). RAPA-DC are generated through inhibition of the integrative kinase mammalian target of rapamycin (mTOR) by the immunosuppressive macrolide rapamycin during propagation of monocyte-derived DC. Consistent with the characteristics of tolDC, murine RAPA-DC display resistance to phenotypic maturation induced by pro-inflammatory stimuli; exhibit the ability to migrate to secondary lymphoid tissue (important for 'cross-presentation' of antigen to T cells), and enrich for naturally-occurring CD4+ regulatory T cells. In rodent models, delivery of recipient-derived RAPA-DC pulsed with donor antigen prior to organ transplantation can prolong allogeneic heart-graft survival indefinitely, especially when combined with a short course of IS. These encouraging data support ongoing efforts to develop RAPA-DC for clinical testing. When compared to murine RAPA-DC however, human RAPA-DC have proven only partially resistant to maturation triggered by pro-inflammatory cytokines, and display heterogeneity in their impact on effector T-cell expansion and function. In total, the evidence suggests the need for more in-depth studies to better understand the mechanisms by which mTOR controls human DC function. These studies may facilitate the development of RAPA-DC therapy alone or together with agents that preserve/enhance their tolerogenic properties as clinical immunoregulatory vectors.


Neurobiological Commonalities and Distinctions Among Three Major Psychiatric Diagnostic Categories: A Structural MRI Study.
Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are distinct diagnostic categories in current psychiatric nosology, yet there is increasing evidence for shared clinical and biological features in these disorders. No previous studies have examined brain structural features concurrently in these 3 disorders. The aim of this study was to identify the extent of shared and distinct brain alterations in SZ, BD, and MDD. We examined gray matter (GM) volume and white matter (WM) integrity in a total of 485 individuals (135 with SZ, 86 with BD, 108 with MDD, and 156 healthy controls [HC]) who underwent high-resolution structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) at a single site. Significant 4-group (SZ, BD, MDD, and HC groups) differences (P < .05, corrected) in GM volumes were found primarily in the paralimbic and heteromodal corticies. Post hoc analyses showed that the SZ, BD, and MDD groups shared GM volume decreases in 87.9% of the total regional volume with significant 4-group differences. Significant 4-group differences in WM integrity (P < .05 corrected) were found in callosal, limbic-paralimbic-hetermodal, cortico-cortical, thalamocortical and cerebellar WM. Post hoc analyses revealed that the SZ and BD groups shared WM alterations in all regions, while WM alterations were not observed with MDD. Our findings of common alterations in SZ, BD, and MDD support the presence of core neurobiological disruptions in these disorders and suggest that neural structural distinctions between these disorders may be less prominent than initially postulated, particularly between SZ and BD.


An electrochemical biosensor to assay Trop-2 of breast cancer cells fabricated by methylene blue-assisted assembly of DNA nanoparticles.
Human trophoblast surface cell antigen 2 (Trop-2) on the tumor cell membrane can not only serve as the target for chemotherapy drugs, but also as a biomarker for typing and prognosis of breast cancer; however, assay of Trop-2 is seriously hampered due to the limitations of available tool. Herein, we have designed and fabricated an electrochemical biosensor for the assay of Trop-2 based on methylene blue (MB)-assisted assembly of DNA nanocomposite particles (DNPs). Specially, the recognition between Trop-2 and its aptamer may activate the primer exchange reaction (PER) on an electrode surface to produce long single-strand DNA (ssDNA) which can be self-assembled into DNPs by electrostatic interaction between negative charged DNA and positive charged and electro-active MB molecules which can also be used to give electrochemical signal. By using this electrochemical biosensor, ultrasensitive detection of tumor cells with high Trop-2 expressions can be conducted, with the limit of detection (LOD) of 1 cell/mL. Moreover, this biosensor can be further used for accurately profiling Trop-2 expression of tumor cells in mouse tissues, suggesting its great potential in the precise definition of breast cancer.


Dentistry's oxymorons.
Confusion in language results in perplexity in relationships between doctor and patient, as well as threatening the consanguinity of the doctor to his fellow doctor. This article explores the common use of self-contradictory terms in the field of dental orthopedics and anesthesia-sedation in particular, and the unethical, verbal de-specialization of the dental specialist in general. It scrutinizes common dental advertising malpractices.


Managing HIV. Part 7: Professional issues. 7.6 Legal issues in HIV medicine.
The mortality, stigma and publicity surrounding HIV/AIDS have brought into focus many legal and ethical issues arising in the practice of medicine. Three important aspects of the practice of HIV medicine are the obligation to notify health authorities of HIV diagnoses, special obligations to inform and counsel patients who have or may have HIV and the duty of confidentiality.


Acrocyanosis induced by interferon alpha(2a).
A 56-year-old woman with mycosis fungoides developed acrocyanosis each time treatment with interferon alpha(2a) was started. Acrocyanosis disappeared after discontinuing therapy. Immunological study performed while acrocyanosis was present showed elevated antinuclear antibody (ANA) titers and circulating immune-complex levels. Long-term interferon treatment has been related to autoimmune side effects. Raynaud's phenomenon has been observed in patients undergoing interferon treatment associated with elevated ANA titers, to cryoglobulinemia or to arterial occlusion. Acrocyanosis has never before been described as side effect in patients undergoing this treatment. We believe that our patient's acrocyanosis must be considered a side effect of interferon.


Fatal mishap report: first SPH-4B flight helmet recovered from a U.S. Army helicopter mishap.
The most common cause of death in helicopter accidents is head injury. Flight helmets can be designed to distribute and attenuate crash forces to the head. Experience derived from crashes using the U.S. Army SPH-4 flight helmet has led to modifications to improve protection. Within the past year, the Army has introduced the SPH-4B flight helmet which includes several new features to reduce injury in future mishaps. The first SPH-4B flight helmet recovered from a fatal mishap is described and correlated with the injuries to the wearer. The new shell and liner reduced the impact forces to the head. There were no side impacts to determine the performance of the crushable earcups in the helmet. The new SPH-4B flight helmet has several new and distinctive features that should improve survival in future helicopter crashes. Careful study of life support equipment retrieved from crashes is important to understand how the equipment performs in the crash environment.


Validation of the Postnatal Growth and Retinopathy of Prematurity (GROP) screening criteria.
Retinopathy of prematurity (ROP) is a leading cause of irreversible blindness in infants. The Postnatal Growth and ROP (G-ROP) study proposed new screening criteria for ROP. This study aimed to validate the G-ROP screening criteria in a group of Iranian premature infants who were treated in the neonatal intensive care unit (NICU) for at least 40 days. In this retrospective study, we extracted the data pertaining to infants admitted to the NICU from January 2020 to December 2021. We screened all the included infants for ROP based on the Iranian national screening criteria. We applied the G-ROP criteria to our study population, and if no criterion was met, the infant was exempted from ROP screening. We determined the sensitivity and specificity of the G-ROP guidelines for ROP detection, along with its capacity for predicting the requirement for ROP treatment. Moreover, we compared the G-ROP guidelines with the Iranian and North American guidelines for ROP screening. A total of 166 premature infants with complete datasets were included: 130 had ROP, of whom 61 were treated. There were 109 female infants (65.7%). The mean (standard deviation [SD]) birth weight and gestational age were 1080 (256) g and 28.28 (1.97) weeks, respectively. Applying the G-ROP criteria, 127 of 130 infants with ROP were identified (sensitivity, 97.69%; 95% confidence interval [CI], 95.11% - 100%), and of 36 infants without ROP, three were correctly excluded (specificity, 8.33%; 95% CI, 0% - 17.36%). The G-ROP criteria did not fail to identify infants who required treatment for ROP (sensitivity, 100%; 95% CI, 98.29 - 100) and had a specificity of 8.69% (95% CI, 2.04% - 15.34%). Although the Iranian and North American criteria had 100% sensitivity for infants with any stage of ROP, they could not detect infants without ROP (0% specificity). The G-ROP screening criteria had a sensitivity of 100% in identifying infants requiring treatment for ROP in our high-risk group; however, specificity was not sufficiently high. Further studies with larger numbers of referred infants could confirm a decrease in the burden of retinal examinations using these criteria.


Costs associated with low birth weight in a rural area of Southern Mozambique.
Low Birth Weight (LBW) is prevalent in low-income countries. Even though the economic evaluation of interventions to reduce this burden is essential to guide health policies, data on costs associated with LBW are scarce. This study aims to estimate the costs to the health system and to the household and the Disability Adjusted Life Years (DALYs) arising from infant deaths associated with LBW in Southern Mozambique. Costs incurred by the households were collected through exit surveys. Health system costs were gathered from data obtained onsite and from published information. DALYs due to death of LBW babies were based on local estimates of prevalence of LBW (12%), very low birth weight (VLBW) (1%) and of case fatality rates compared to non-LBW weight babies [for LBW (12%) and VLBW (80%)]. Costs associated with LBW excess morbidity were calculated on the incremental number of hospital admissions in LBW babies compared to non-LBW weight babies. Direct and indirect household costs for routine health care were 24.12 US$ (CI 95% 21.51; 26.26). An increase in birth weight of 100 grams would lead to a 53% decrease in these costs. Direct and indirect household costs for hospital admissions were 8.50 US$ (CI 95% 6.33; 10.72). Of the 3,322 live births that occurred in one year in the study area, health system costs associated to LBW (routine health care and excess morbidity) and DALYs were 169,957.61 US$ (CI 95% 144,900.00; 195,500.00) and 2,746.06, respectively. This first cost evaluation of LBW in a low-income country shows that reducing the prevalence of LBW would translate into important cost savings to the health system and the household. These results are of relevance for similar settings and should serve to promote interventions aimed at improving maternal care.


An Original HPLC Method with Coulometric Detection to Monitor Hydroxyl Radical Generation via Fenton Chemistry.
Hydroxyl radicals (•OH) can be generated via Fenton chemistry catalyzed by transition metals. An in vitro Fenton system was developed to test both the inhibition and stimulation of •OH formation, by monitoring salicylate aromatic hydroxylation derivatives as markers of •OH production. The reaction was optimized with either iron or copper, and target analytes were determined by means of an original HPLC method coupled to coulometric detection. The method granted good sensitivity and precision, while method applicability was tested on antioxidant compounds with and without chelating properties in different substance to metal ratios. This analytical approach shows how Fenton's reaction can be monitored by HPLC coupled to coulometric detection, as a powerful tool for studying molecules' redox behavior.


An unusual angiosarcoma. A case report.
To document a retroperitoneal angiosarcoma with a 12-year disease-free period. A 50-year-old farmer was referred to the Urology Clinic, Al-Sabah Hospital, Kuwait, with a 1-year history of recurrent left renal colic. Radiological investigations revealed 2 renal cysts at the lower pole and an extrarenal soft tissue mass, presumably of adrenal origin, at the upper pole. Laparotomy confirmed both the renal cysts and a circumscribed soft tissue mass. The latter was separate from the adrenal gland but had a vascular connection with an adrenal vessel. Pathological examination showed an encapsulated angiosarcoma. The patient did not have any adjuvant therapy after surgery but was followed up with annual radiological investigations for 12 years. No evidence of recurrence or metastasis was seen. The 12-year disease-free period in this case is exceptional for angiosarcomas, which is a high-grade sarcoma.


Intact indoleamine 2,3-dioxygenase activity in human chronic granulomatous disease.
Chronic granulomatous disease (CGD) is characterized by a disability to produce reactive oxygen intermediates (ROI) caused by a defect of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. A hyperinflammatory response to immune activation has been reported to contribute to the pathology of CGD. The tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is considered critical for regulating immune responses and suppression of inflammation. IDO is generally believed to require ROI for enzymatic activity and was found to be inactive in murine CGD. Here, we report that, strikingly, in human CGD IDO metabolic activity is intact. Monocyte-derived dendritic cells generated from CGD patients, harbouring X-linked and autosomal recessive forms of CGD, and from healthy controls produced similar amounts of the tryptophan metabolite kynurenine upon activation with lipopolysaccharide and interferon-γ. Thus, in humans, ROI apparently are dispensable for IDO activity. Hyperinflammation in human CGD cannot be attributed to disabled IDO activation.


Gyrations in African Mortality and their Effect on Economic Growth.
I examine recent changes in African mortality and discuss their potential economic and demographic effects. Growth in life expectancy sharply departed from its trend after 1990, and then experienced a sharp acceleration after 2005. This latter acceleration was due overwhelmingly to improvements in HIV and malaria. Economists differ in their estimates of how large the structural effect of health on income is, with many estimates being relatively small. Taking seriously the delays built into many plausible causal channels would lead one to expect that any economic effects of these mortality changes, if they are detectable at all, will not appear for several decades. By contrast, the effect of declining mortality, especially from malaria, should soon be visible in data on population age structure in some countries.


[The adequacy and safety of low epidural anesthesia in urological operations on patients with concomitant ischemic heart disease].
An electrocardiographic evaluation of the functional state of the myocardium in patients operated upon for urological diseases under conditions of low epidural anesthesia has shown that in the absence of a cardiovascular pathology the method of anesthesia fails to exert a substantial influence on the circulation homeokinesis and functional state of the myocardium. The following use of the low epidural anesthesia in 105 patients with a coexistent ischemic heart disease during urological operative interventions results in two times less amount of cardiovascular complications, lethality and duration of the postoperative period.


The Protective and Immunomodulatory Effects of Fucoidan Against 7,12-Dimethyl benz[a]anthracene-Induced Experimental Mammary Carcinogenesis Through the PD1/PDL1 Signaling Pathway in Rats.
Fucoidan is a sulfated polysaccharide that is extracted from brown algae seaweed. This study was designed to evaluate the protective and immunomodulatory effects of dietary fucoidan on 7,12-dimethyl benz[a]anthracene (DMBA)-induced experimental mammary carcinogenesis in rats. Sixty Sprague-Dawley rats were randomly assigned to four equal groups: the control group (control group), the cancer model group (model group), and the F1 and F2 groups, which were fed fucoidan at concentrations of 200 and 400 mg/kg·body weight, respectively. We found that fucoidan treatment decreased the tumor incidence and mean tumor weight and prolonged the tumor latency. Flow cytometric analyses revealed that the number of blood natural killer cells was higher after fucoidan treatment and that the proportions of CD4 and CD8 T cells were also increased. The serum levels of interleukin (IL)-6, IL-12p40, and interferon (IFN)-γ were higher in the rats treated with fucoidan compared to those of model rats. Moreover, the percentage of CD3+ Foxp3+ regulatory T cells in the blood and the levels of IL-10 and transforming growth factor β in the serum were lower in the rats treated with fucoidan. Furthermore, fucoidan treatment decreased the expression of Foxp3 and programmed cell death 1 ligand 1 (PDL1) in tumor tissues. The levels of p-phosphatidyl inositol kinase 3 and p-AKT in tumor tissues were also lower than those of model rats. These results suggest that a fucoidan-supplemented diet can inhibit DMBA-induced tumors in rats. This study provides experimental evidence toward elucidating the immune enhancement induced by fucoidan through the programmed cell death 1/PDL1 signaling pathway. The immunomodulatory effect is one of the possible mechanisms of the protective effect of fucoidan against mammary carcinogenesis.


Late urinary morbidity and quality of life after radical prostatectomy and salvage radiotherapy for prostate cancer.
There is a paucity of knowledge of long-term urinary morbidity in patients treated for prostate cancer (PCa) with radical prostatectomy (RP) and salvage radiotherapy (SRT). Improved long-term survival calls for heightened awareness of late effects from radiotherapy after RP. The purpose of this study was to assess late urinary morbidity and its potential impact on quality of life (QoL) in patients treated with RP plus SRT compared with patients treated with RP alone. Long-term morbidity and QoL were evaluated using a cross-sectional design with validated questionnaires in urinary morbidity [Danish Prostatic Symptom Score (DAN-PSS)] and QoL [European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)]. Included were a total of 227 patients treated with SRT and 192 treated with RP in the periods 2006-2010 and 2005-2007, respectively. Weak stream, straining, frequency and nocturia were significantly more prevalent in patients treated with RP + SRT than in patients treated with RP alone. Patients treated with RP + SRT generally suffered from more severe urinary symptoms. The QoL scores of the two treatment groups were not statistically significantly different, but a high level of urinary morbidity was significantly related to decreased QoL (p = 0.000). Patients treated with SRT have a higher rate of urinary morbidity than do patients treated with RP alone. Severe urinary morbidity was significantly related to decreased QoL, but did not differ between the two treatment groups.


A comparison of prognoses of FIGO stage IB adenocarcinoma and squamous cell carcinoma.
The objective of this study was to compare clinical and pathologic variables and prognosis of FIGO stage IB adenocarcinoma and squamous cell carcinoma of uterine cervix. A retrospective review was performed of 521 patients with stage IB squamous cell carcinoma and adenocarcinoma of cervix who treated primarily by type 3 hysterectomy and pelvic and/or para-aortic lymphadenectomy at Hacettepe University Hospitals between 1980 and 1997. Age, tumor size, grade, depth of invasion, lymph node metastasis, parametrial, vaginal, and lymphvascular space involvement (LVSI) were not different between two cell types except number of the lymph nodes involved. Metastasis to three or more lymph nodes was significantly higher in adenocarcinoma. Overall and disease-free survival were 87.7%, 84.0% versus 86.4%, 83.1% for squamous cell carcinoma and adenocarcinoma, respectively (P > 0.05). The rate and site of recurrence were not different between two cell types. Multivariate analysis of disease-free and overall survival revealed independent prognostic factors as tumor size, LVSI, number of involved lymph node, and vaginal involvement. Prognosis of FIGO stage IB cervical cancer patients who were treated by primarily radical surgery was found to be same for those with adenocarcinoma and squamous cell carcinoma.


Molecular assessment of bacterial vaginosis by Lactobacillus abundance and species diversity.
To date, women are most often diagnosed with bacterial vaginosis (BV) using microscopy based Nugent scoring or Amsel criteria. However, the accuracy is less than optimal. The aim of the present study was to confirm the identity of known BV-associated composition profiles and evaluate indicators for BV using three molecular methods. Evaluation of indicators for BV was carried out by 16S rRNA amplicon sequencing of the V5-V7 region, a tailor-made 16S rRNA oligonucleotide-based microarray, and a PCR-based profiling technique termed IS-profiling, which is based on fragment variability of the 16S-23S rRNA intergenic spacer region. An inventory of vaginal bacterial species was obtained from 40 females attending a Dutch sexually transmitted infection outpatient clinic, of which 20 diagnosed with BV (Nugent score 7-10), and 20 BV negative (Nugent score 0-3). Analysis of the bacterial communities by 16S rRNA amplicon sequencing revealed two clusters in the BV negative women, dominated by either Lactobacillus iners or Lactobacillus crispatus and three distinct clusters in the BV positive women. In the former, there was a virtually complete, negative correlation between L. crispatus and L. iners. BV positive subjects showed cluster profiles that were relatively high in bacterial species diversity and dominated by anaerobic species, including Gardnerella vaginalis, and those belonging to the Families of Lachnospiraceae and Leptotrichiaceae. Accordingly, the Gini-Simpson index of species diversity, and the relative abundance Lactobacillus species appeared consistent indicators for BV. Under the conditions used, only the 16S rRNA amplicon sequencing method was suitable to assess species diversity, while all three molecular composition profiling methods were able to indicate Lactobacillus abundance in the vaginal microbiota. An affordable and simple molecular test showing a depletion of the genus Lactobacillus in combination with an increased species diversity of vaginal microbiota could serve as an alternative and practical diagnostic method for the assessment of BV.


An electrooculogram-based binary saccade sequence classification (BSSC) technique for augmentative communication and control.
In the field of assistive technology, the electrooculogram (EOG) can be used as a channel of communication and the basis of a man-machine interface. For many people with severe motor disabilities, simple actions such as changing the TV channel require assistance. This paper describes a method of detecting saccadic eye movements and the use of a saccade sequence classification algorithm to facilitate communication and control. Saccades are fast eye movements that occurs when a person's gaze jumps from one fixation point to another. The classification is based on pre-defined sequences of saccades, guided by a static visual template (e.g. a page or poster). The template, consisting of a table of symbols each having a clearly identifiable fixation point, is situated within view of the user. To execute a particular command, the user moves his or her gaze through a pre-defined path of eye movements. This results in a well-formed sequence of saccades which are translated into a command if a match is found in a library of predefined sequences. A coordinate transformation algorithm is applied to each candidate sequence of recorded saccades to mitigate the effect of changes in the user's position and orientation relative to the visual template. Upon recognition of a saccade sequence from the library, its associated command is executed. A preliminary experiment in which two subjects were instructed to perform a series of command sequences consisting of 8 different commands are presented in the final sections. The system is also shown to be extensible to facilitate convenient text entry via an alphabetic visual template.


Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome.
Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.


HTA and economics in the United States: a systematic review of ICER reports to evaluate trends, identify factors associated with recommendations, and understand implications.
BACKGROUND: The Institute for Clinical and Economic Review (ICER) is a prominent health technology assessment (HTA) entity in the United States that considers costs and applies economic analyses to derive price-based recommendations. ICER continues to adjust its value framework, yet discussion persists regarding whether ICER methodologies align with established research standards. This work evaluates ICER assessments relative to those standards, providing a benchmark with the release of ICER's most recent value framework update. OBJECTIVES: To evaluate ICER economic assessments for trends, factors related to recommendations, and quality for use in U.S. decision making. METHODS: We evaluated all ICER final evidence reports published between 2006 and August 31, 2019, with regard to base-case result trends over time, pricing sources, comparator selection, analytic perspectives, model uncertainty, how modeling results aligned with ICER's determinations of value for money, and comparison of ICER methodological approaches with established modeling standards. Analyses were stratified by time period, where appropriate, to account for changes in ICER's framework over time. RESULTS: Of 58 ICER final evidence reports, 47 used the most commonly reported outcome (cost per quality-adjusted life-year [QALY]); ICER-developed models evaluated 131 interventions and comparators with 238 base-case results. Pricing sources for ICER reports became more standardized in 2017, although sources were not associated with the likelihood of falling below ICER's cost-effectiveness thresholds. In 30% of base-case analyses (n = 72), ICER did not use a clinical comparator, although reasonable treatments were available. In modified societal perspectives scenarios applied in later assessments, 75% of analyses (n = 76) included productivity but did not specify how it was quantified. Reports did not explain how sensitivity and scenario analyses were selected or implications of results. ICER value for money determinations generally aligned with cost-effectiveness results, although 2 of 33 (6%) interventions ranked as low value and 3 of 5 (60%) interventions ranked as low-moderate value, met a $150,000 per QALY threshold, and 14 of 37 (38%) moderate-value interventions exceeded this threshold; the most common rationale was related to national budget impact. CONCLUSIONS: While some progress has been made, further improvement is needed to ensure that ICER assessments address the most relevant questions for target audiences, adhere to established research standards, and are reported in a manner that can be readily interpreted and applied to policymaking. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose.


20th-century advances in drug therapy in oncology--Part. II.
Ongoing research in cancer therapy has led to the development of antineoplastic agents which target specific components of the cell cycle. In Part II of this series, we discuss agents which target the mitotic mechanism by inhibiting microtubules. Although many of these agents are being shown to have multiple effects, the Vinca alkaloids and the taxanes are known as antimitotic drugs. They are among the most important anticancer agents currently available, and because of their unique mechanisms, can be combined with a wide variety of other antineoplastic agents in a spectrum of diseases. In addition, in part II, we are discussing agents that target DNA and prevent replication and thus cell growth by inhibiting the enzymes which protect DNA during replication, the topoisomerases. These drugs, too, have unique mechanisms of action and have become major components of combination regimens. The topoisomerase I inhibitors are new drugs derived from an older parent drug, and their full possibilities are still being explored.


Mental health challenges among adolescents living with HIV.
Mental health is a critical and neglected global health challenge for adolescents infected with HIV. The prevalence of mental and behavioural health issues among HIV-infected adolescents may not be well understood or addressed as the world scales up HIV prevention and treatment for adolescents. The objective of this narrative review is to assess the current literature related to mental health challenges faced by adolescents living with HIV, including access to mental health services, the role of mental health challenges during transition from paediatric to adult care services and responsibilities, and the impact of mental health interventions. For each of the topics included in this review, individual searches were run using Medline and PubMed, accompanied by scans of bibliographies of relevant articles. The topics on which searches were conducted for HIV-infected adolescents include depression and anxiety, transition from paediatric to adult HIV care and its impact on adherence and mental health, HIV-related, mental health services and interventions, and the measurement of mental health problems. Articles were included if the focus was consistent with one of the identified topics, involved HIV-infected adolescents, and was published in English. Mental and behavioural health challenges are prevalent in HIV-infected adolescents, including in resource-limited settings where most of them live, and they impact all aspects of HIV prevention and treatment. Too little has been done to measure the impact of mental health challenges for adolescents living with HIV, to evaluate interventions to best sustain or improve the mental health of this population, or to create healthcare systems with personnel or resources to promote mental health. Mental health issues should be addressed proactively during adolescence for all HIV-infected youth. In addition, care systems need to pay greater attention to how mental health support is integrated into the care management for HIV, particularly throughout lifespan changes from childhood to adolescence to adulthood. The lack of research and support for mental health needs in resource-limited settings presents an enormous burden for which cost-effective solutions are urgently needed.


A review of the diagnosis and geographical distribution of the recently described flea toad Brachycephalus sulfuratus in relation to B. hermogenesi (Anura: Brachycephalidae).
The flea toad Brachycephalus sulfuratus was recently described from southeastern and southern Brazil. In its description, the authors overlooked previous records of flea toads that had been identified as "Brachycephalus sp. nov." and B. hermogenesi occurring in the same regions, which could suggest the possibility of up to three flea toads coexisting in southern Brazil. In addition, B. sulfuratus is characterized by substantial phenotypic variability, to an extent that compromises its current diagnosis with respect to its congener B. hermogenesi. Therefore, the current state-of-affairs regarding the geographical distribution of these two species and the identification of previously known populations is hitherto uncertain. Our goals are to reassess previous records of flea toads attributable to B. hermogenesi, B. sulfuratus and "Brachycephalus sp. nov.", considering the description of B. sulfuratus, and to review the diagnosis of B. sulfuratus. A critical analysis of the species identity of flea toad specimens attributable to B. hermogenesi, B. sulfuratus, or to a potentially undescribed species from southeastern and southern Brazil was based either on the analysis of morphology or on their advertisement calls. These analyses include our independent examinations of specimens and, when not possible, examinations of published descriptions. To allow for a consistent comparison of advertisement calls between B. hermogenesi and B. sulfuratus, we made recordings of both species, including in the type locality of the former. We found that morphological and call characters originally proposed as diagnostic for B. sulfuratus in relation to B. hermogenesi vary intraspecifically. Live individuals with ventral yellow spots correspond to B. sulfuratus; individuals without yellow spots can be either B. sulfuratus or B. hermogenesi. In preservative, they are indistinguishable. Previous records of Brachycephalus sp. nov. correspond to B. sulfuratus. We propose that the reduced number of notes per call and the presence of only isolated notes in the call of B. sulfuratus, as opposed to a high number of notes per call with isolated notes and note groups in the call of B. hermogenesi, as the only diagnostic characters between them. Regarding their distributions and based in our assessment, only B. sulfuratus occurs in southern Brazil, without any overlap with B. hermogenesi. There is a narrow gap between the distributions of these species around the southeast of the city of São Paulo. Our revision also revealed that some records previously attributed to B. hermogenesi in Rio de Janeiro and north São Paulo represent a distinct, unidentified flea toad that is not B. sulfuratus. Both species occur side by side in Corcovado, São Paulo, a locality from where five paratypes of B. hermogenesi were obtained. Biogeographic events that might have led to vicariance between B. hermogenesi and B. sulfuratus are discussed.


Molecular epidemiology of norovirus gastroenteritis outbreaks in New Zealand from 2002-2009.
Noroviruses are the most common cause of acute non-bacterial gastroenteritis outbreaks worldwide, including New Zealand. New Zealand has a population of 4.4 million, which allows for centralized outbreak surveillance and a Norovirus Reference Laboratory, which facilitates efficient diagnosis, surveillance, and tracking of norovirus outbreaks. Norovirus outbreak strains are identified, sequenced, and compared with international reference strains. Between January 2002 and December 2009, 1,206 laboratory-confirmed norovirus outbreaks were recorded. The predominant outbreak settings were healthcare institutions for the elderly and acute care patients. Other outbreak settings included catering establishments, cruise ships, homes, community events, school camps, child-related settings, and consumption of contaminated shellfish. Of the 1,206 outbreaks, 105 (8.7%) were caused by norovirus genogroup I (GI) strains, 1,085 (89.9%) were caused by genogroup II (GII) strains, and both GI and GII strains were detected in 9 (0.8%) outbreaks. The genogroup was not identified in 7 (0.6%) outbreaks. A range of norovirus genotypes, including GI genotypes 1-6, GII genotypes 2-8, and GII.12, were associated with these outbreaks. The predominant genotype was GII.4, which was identified in 825 (68.4%) outbreaks. Norovirus GII.4 variant strains, including 2002 (Farmington Hills), 2004 (Hunter), 2006a (Laurens, Yerseke), 2006b (Minerva), and 2010 (New Orleans) implicated in overseas outbreaks also occurred in New Zealand, providing evidence of global spread.


Function of a C-rich sequence in the polypyrimidine/polypurine tract of the promoter of the chicken malic enzyme gene depends on promoter context.
The promoters of many genes contain C-rich polypyrimidine/polypurine (PPY/PPU) sequences that are important for gene expression. The promoter of the chicken malic enzyme gene contains a long PPY/PPU tract that can act as an alternative promoter. This tract can be separated functionally into a C-rich and (CT)7 sequences. The (CT)7 region together with some 3' nucleotides is essential for function of the alternative transcription start site and the C-rich sequence as a regulatory element. In constructs that contained the PPY/PPU tract or the -147/+31-bp promoter of the malic enzyme gene connected to a reporter gene, deletion of the C-rich region increased gene expression. In constructs containing 5.8-kb 5'-flanking DNA of the gene, deletion of the same C-rich region decreased expression of the reporter gene. Positive function of the C-rich sequence required two upstream DNA regions, -237 to -147 bp and -3474 to -2715 bp. To understand the mechanism(s) by which the same sequence exerts different effects, we examined the transcription start sites in the construct where the C-rich region was deleted. We directly visualized transcription start sites by performing 5'-rapid amplification of cDNA ends and a subsequent primer extension on a single-stranded template. Deletion of the C-rich region from constructs containing 5.8 kb of 5'-flanking DNA almost completely abolished transcription initiation from the PPY/PPU promoter and reduced transcription from the major endogenous start site. DEAE fractionation of hepatic nuclear extract revealed more than 10 proteins that bound specifically to C-rich DNA. These results suggest that interactions between upstream DNA elements and the C-rich sequence and the selective use of DNA-binding activities may bestow different functions on the same nucleotide sequence.


SMAD-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA4/5/6-dependent chick Nkx2.5 enhancer.
Prior work has indicated that BMP signals act in concert with FGF8, WNT11 and WNT antagonists to induce the formation of cardiac tissue in the vertebrate embryo. In an effort to understand how these signaling pathways control the expression of key cardiac regulators, we have characterized the cis-regulatory elements of the chick tinman homolog chick Nkx2.5. We find that at least three distinct cardiac activating regions (CARs) of chick Nkx2.5 cooperate to regulate early expression in the cardiac crescent and later segmental expression in the developing heart. In this report, we focus our attention on a 3' BMP-responsive enhancer, termed CAR3, which directs robust cardiac transgene expression. By systematic mutagenesis and gel shift analysis of this enhancer, we demonstrate that GATA4/5/6, YY1 and SMAD1/4 are all necessary for BMP-mediated induction and heart-specific expression of CAR3. Adjacent YY1 and SMAD-binding sites within CAR3 constitute a minimal BMP response element, and interaction of SMAD1/4 with the N terminus of YY1 is required for BMP-mediated induction of CAR3. Our data suggest that BMP-mediated activation of this regulatory region reflects both the induction of GATA genes by BMP signals, as well as modulation of the transcriptional activity of YY1 by direct interaction of this transcription factor with BMP-activated SMADs.


[Development of sustained vasodilatory shock and permanent loss of hearing after severe lithium carbonate poisoning].
A case of severe lithium carbonate self-poisoning is described, presenting with sustained vasodilatory shock, DIC and neurologic manifestations. Lengthy and repeated haemodialysis was required to lower lithemia to non-toxic levels in accordance with which the haemodynamic instability and multi organ dysfunction ceased. The patient survived with marked loss of hearing, tinnitus and vertigo as the only sequelae. We discuss the mechanism of lithium's inhibitory effect on the phosphoinositide cascade as the possible explanation for the vasodilatory shock as well as the hearing deficiency.


Appropriate and inappropriate use of psychotherapeutic medications for institutionalized mentally retarded persons.
Evaluation of psychiatric treatment in institutions must be based not only on the numbers and types of drugs prescribed but also on diagnoses and other characteristics of the patients. We crosstabulated psychotherapeutic medication regimens against diagnoses for 242 institutionalized mentally retarded adolescents and adults selected for psychiatric treatment. The drugs had generally been prescribed by nonpsychiatrists, but diagnoses were determined by consensus of evaluation teams that included fully trained psychiatrists. According to widely accepted standards for psychopharmacologic treatment, 45.4% to 60.9% of the regimens were rated as appropriate and 39.1% to 54.6% were rated as inappropriate for the conditions diagnosed.


Why do evaluative judgments affect emotion attributions? The roles of judgments about fittingness and the true self.
Past research has found that the value of a person's activities can affect observers' judgments about whether that person is experiencing certain emotions (e.g., people consider morally good agents happier than morally bad agents). One proposed explanation for this effect is that emotion attributions are influenced by judgments about fittingness (whether the emotion is merited). Another hypothesis is that emotion attributions are influenced by judgments about the agent's true self (whether the emotion reflects how the agent feels "deep down"). We tested these hypotheses in six studies. After finding that people think a wide range of emotions can be fitting and reflect a person's true self (Study 1), we tested the predictions of these two hypotheses for attributions of happiness, love, sadness, and hatred. We manipulated the emotions' fittingness (Studies 2a-b and 4) and whether the emotions reflected an agent's true self (Studies 3 and 5), measuring emotion attributions as well as fittingness judgments and true self judgments. The fittingness manipulation only impacted emotion attributions in the cases where it also impacted true self judgments, whereas the true self manipulation impacted emotion attribution in all cases, including those where it did not impact fittingness judgments. These results cast serious doubt on the fittingness hypothesis and offer some support for the true self hypothesis, which could be developed further in future work.


Evaluation of delivery of enhanced diabetes care to patients of South Asian ethnicity: the United Kingdom Asian Diabetes Study (UKADS).
We tested the hypothesis that enhanced care for diabetes, tailored to the needs of the South Asian community with Type 2 diabetes, would improve risk factors for diabetic vascular complications and ultimately reduce morbidity and mortality. The study was a cluster randomized controlled trial (RCT) with general practice the unit of randomization. Six West Midlands general practices with a high proportion of South Asian patients were randomized to 'enhanced care' using Asian link workers and extra community diabetes specialist nurse sessions (intervention) or continued standard practice care (control). Of 401 patients recruited to the study, 361 (90%), comprising 178 from Coventry and 183 from Birmingham were eligible and included in the analyses. The mean age at baseline (standard deviation, SD) was 58.9 (11.7 years) with median (interquartile range; IQR) duration of diabetes 6.5 (3-11) years. At one year follow-up there was a significant difference in reduction of systolic (4.6 mmHg, P = 0.035) and diastolic blood pressure (3.4 mmHg, P = 0.003) and total cholesterol (0.4 mmol/l, P = 0.005), comparing the intervention and control groups. After adjusting for baseline measurement and age, only differential reduction in diastolic blood pressure remained significant. There was no significant change in HbA(1c) and no difference between the groups. Using link workers and extra community diabetes specialist nurse input together with treatment protocols in primary care might prove a useful strategy in working towards NSF targets for diabetes management. In this study, small reductions in blood pressure and cholesterol were achieved. Improvement in glycaemic control may require longer and possibly different strategies. Further research is required to evaluate fully the effectiveness, including the costs and longer term sustainability of culturally sensitive initiatives.


Myosin X is a high duty ratio motor.
Myosin X is expressed in a variety of cell types and plays a role in cargo movement and filopodia extension, but its mechanoenzymatic characteristics are not fully understood. Here we analyzed the kinetic mechanism of the ATP hydrolysis cycle of acto-myosin X using a single-headed construct (M10IQ1). Myosin X was unique for the weak "strong actin binding state" (AMD) with a K(d) of 1.6 microm attributed to the large dissociation rate constant (2.1 s(-1)). V(max) and K(ATPase) of the actin-activated ATPase activity of M10IQ1 were 13.5 s(-1) and 17.4 mum, respectively. The ATP hydrolysis rate (>100 s(-1)) and the phosphate release rate from acto-myosin X (>100 s(-1)) were much faster than the entire ATPase cycle rate and, thus, not rate-limiting. The ADP off-rate from acto-myosin X was 23 s(-1), which was two times larger than the V(max). The P(i)-burst size was low (0.46 mol/mol), indicating that the equilibrium is significantly shifted toward the prehydrolysis intermediate. The steady-state ATPase rate can be explained by a combination of the unfavorable equilibrium constant of the hydrolysis step and the relatively slow ADP off-rate. The duty ratio calculated from our kinetic model, 0.6, was consistent with the duty ratio, 0.7, obtained from comparison of K(m ATPase) and K(m motility). Our results suggest that myosin X is a high duty ratio motor.


Effect of Dust Storms on the Atmospheric Microbiome in the Eastern Mediterranean.
We evaluated the impact of Saharan dust storms on the local airborne microbiome in a city in the Eastern Mediterranean area. Samples of particles with diameter less than 10 μm were collected during two spring seasons on both dusty and nondusty days. DNA was extracted, and partial 16S rRNA gene amplicons were sequenced using the Illumina platform. Bioinformatic analysis showed the effect of dust events on the diversity of the atmospheric microbiome. The relative abundance of desert soil-associated bacteria increased during dust events, while the relative abundance of anthropogenic-influenced taxa decreased. Quantitative polymerase chain reaction measurements of selected clinically significant antibiotic resistance genes (ARGs) showed that their relative abundance decreased during dust events. The ARG profiles on dust-free days were similar to those in aerosol collected in a poultry house, suggesting a strong agricultural influence on the local ambient profiles. We conclude that dust storms enrich the ambient airborne microbiome with new soil-derived bacteria that disappear as the dust settles, suggesting that the bacteria are transported attached to the dust particles. Dust storms do not seem to be an important vector for transport of probed ARGs.


Cellular factors implicated in filovirus entry.
Although filoviral infections are still occurring in different parts of the world, there are no effective preventive or treatment strategies currently available against them. Not only do filoviruses cause a deadly infection, but they also have the potential of being used as biological weapons. This makes it imperative to comprehensively study these viruses in order to devise effective strategies to prevent the occurrence of these infections. Entry is the foremost step in the filoviral replication cycle and different studies have reported the involvement of a myriad of cellular factors including plasma membrane components, cytoskeletal proteins, endosomal components, and cytosolic factors in this process. Signaling molecules such as the TAM family of receptor tyrosine kinases comprising of Tyro3, Axl, and Mer have also been implicated as putative entry factors. Additionally, filoviruses are suggested to bind to a common receptor and recent studies have proposed T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) as potential receptor candidates. This paper summarizes the existing literature on filoviral entry with a special focus on cellular factors involved in this process and also highlights some fundamental questions. Future research aimed at answering these questions could be very useful in designing novel antiviral therapeutics.


The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus.
Most systematic reviews rely substantially on the assessment of the methodological quality of the individual trials. The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of randomized clinical trials (RCTs). The invited participants were experts in the field of quality assessment of RCTs. The initial item pool contained all items from existing criteria lists. Subsequently, we reduced the number of items by using the Delphi consensus technique. Each Delphi round comprised a questionnaire, an analysis, and a feedback report. The feedback report included staff team decisions made on the basis of the analysis and their justification. A total of 33 international experts agreed to participate, of whom 21 completed all questionnaires. The initial item pool of 206 items was reduced to 9 items in three Delphi rounds. The final criteria list (the Delphi list) was satisfactory to all participants. It is a starting point on the way to a minimum reference standard for RCTs on many different research topics. This list is not intended to replace, but rather to be used alongside, existing criteria lists.


Cholinergic syndrome: a case report of acute organophosphate and carbamate poisoning.
Cholinergic syndrome is a common topic at western medical universities yet rarely observed in clinical practice. The treatment involves muscarinic antagonists, acetylcholinesterase reactivation, seizure control, and supportive measures. Here we report a case of a 52-year old Caucasian male who attempted suicide by ingesting a purple crystal powder that turned out to be a mixture of carbofuran and chlormephos. At clinical examination, the patient presented with salivation, perspiration, diarrhoea, bradypnoea, loss of consciousness, and epileptic seizures. Laboratory tests showed low plasma cholinesterase, and we started obidoxime along with supportive intensive care treatment. He was later transferred to the psychiatry department for further diagnostics and treatment.


Follicular lymphoid hyperplasia of the hard palate simulating lymphoma.
Follicular lymphoid hyperplasia of the hard palate is a slowly growing, soft, nontender swelling that may grow to involve the entire hard palate. The overlying mucosa is normal. This appearance naturally prompts biopsy, and both clinically and microscopically might be confused with lymphoma. Four case histories are presented with histologic description: normal palatal submucosal structures are replaced with benign reactive lymphoid tissue replete with well-developed germinal centers. Surrounding these centers are dense populations of small, regular, bland lymphocytes. Minor salivary glands, except for some atrophied residue, are notably absent; also absent are the epimyoepithelial islands characteristic of the benign lymphoepithelial lesion (Mikulicz's disease). Etiologic factors remain obscure. One of our patients had two recurrences following local excision; in another patient nodules of benign lymphoid hyperplasia developed in the cheek and upper neck. These four patients are alive and free of any malignant process 4, 7, 9, and 12 years after the onset of their palatal swellings. We urge caution in distinguishing these lesions from palatal lymphoma, and recommend local excision as the treatment of choice.


Allergic complications of meningococcal disease. II. Immunological investigations.
Immunological investigation of four patients with meningococcal meningitis who developed arthritis or cutaneous lesions showed circulating meningococcal antigen at the time of presentation in each patient. It was cleared from the circulation over the next few days. Circulating antibody was detectable in three of the four patients about a week after the onset of the illness. A marked fall in the serum C(3) level occurred in two patients at about that time. Deposits of meningococcal antigen, immunoglobulin, and C(3) were detected in the synovial fluid white cells of the two patients studied and in one of three skin biopsies examined. These findings suggest that the arthritis and cutaneous lesions of meningococcal meningitis may be due to immune complex formation.


Accessing the intrinsic factors of carbonyl index of microplastics: Physical and spectral properties, baseline correction, calculation methods, and their interdependence.
Carbonyl index (CI) is a measure of the degradation status of microplastics. While many studies address environmental factors of microplastic degradation, intrinsic factors like physical properties, spectral properties, baseline correction, and CI calculation methods are less explored. This research focused on these aspects using surface seawater samples. We found that color and shape have limited dependence on particle size or signal-to-noise ratio (SNR). Baseline correction can significantly alter CI values, with the direction of the shift depending on the methods used. Additionally, most CI values before and after baseline correction and those calculated using different methods tend to be strongly correlated. Using the selected CI calculation methods, we found that CI values varied significantly by shape and color. CI's relation to the similarity between the sample and its pristine form suggests an alternative degradation measure. Our findings emphasize the need for standardized CI calculation methods.