Treatment with belimumab restores B cell subsets and their expression of B cell activating factor receptor in patients with primary Sjogren's syndrome.
The aim of this study was to investigate the biological effects of belimumab on B cells in the first phase II open-label trial with belimumab in patients with primary SS (pSS) (BELISS). Peripheral blood B cell subsets and their B cell activating factor-receptor (BAFF-R) expression were analysed by multicolour flow cytometry in 10 pSS patients either before or after 24 and 52 weeks of therapy with belimumab. Serum BAFF levels were analysed by ELISA. At baseline, pSS patients showed a significant increase in circulating B cells compared with healthy donors matched for age and sex, with a predominant expansion of transitional and naive B cell subsets. pSS patients also showed higher serum BAFF levels and lower B cell BAFF-R expression. Therapy with belimumab in pSS patients induced a significant reduction in transitional and naive B cell subsets to levels similar to those observed in healthy donors. Furthermore, belimumab normalized BAFF-R expression in all B subsets comprised within the memory compartment. The restoration of B cell frequency and subset composition in response to belimumab was also associated with a decrease in serum levels of Ig, RF, ANAs, and with an increase in the C4 complement fraction. All of these belimumab-mediated effects were observed after 24 weeks of therapy and maintained until the end of the therapeutic protocol. Taken together, our findings show that targeting BAFF with belimumab is successful in normalizing B cell frequency, phenotype and functions in pSS. clinicaltrials.gov; https://clinicaltrials.gov/; NCT01008982.


Direct Engagement of TLR9 Ligand with T Helper Cells Leads to Cell Proliferation & Up-regulation of Cytokines.
Toll like receptor (TLR) engagement is primarily a function of the innate immune cells. The purpose of the study was to assess direct uptake of ODN 2216 in T helper cells and effects on cell proliferation and cytokine expression. We isolated CD4+ CD25- T helper cells by magnetic sorting and studied the uptake of ODN 2216 using flow cytometry and confocal microscopy. We then studied the effect of ODN 2216 engagement on cell proliferation and cytokine expression using flow cytometry and gene expression of TLR9 signaling genes using real time RT-PCR. We made a chance observation that purified T helper cells from healthy individuals consistently bind to the TLR9 ligand ODN 2216. In PBMCs, on the other hand, 98% of monocytes preferentially bound to ODN 2216 FITC, indicating that they competed with the lymphocytes. We confirmed intracellular localization of ODN 2216 FITC as well as intracellular expression of TLR9 in Thelper cells. Furthermore, ODN 2216 FITC was also co-localized with the lysosomal membrane associated protein 1. The uptake of TLR9 ligand culminated in cellular proliferation, up-regulation of cytokines and increased mRNA expression of TLR9 and IRF7 in T helper cells, in the absence of antigen presenting cells. ODN 2216 uptake was inhibited by promethazine as well as by TLR9 antagonist. Our results show a direct engagement of TLR9 ligand in T helper cells and suggest involvement of TLR9 signalling in CD4+T cells, which may envisage novel targets for TLR inhibitors.


Major genes regulating total serum immunoglobulin E levels in families with asthma.
Immunoglobulin E (IgE) has a major role in the pathogenesis of allergic disorders and asthma. Previous data from 92 families, each identified through a proband with asthma, showed evidence for two major genes regulating total serum IgE levels. One of these genes mapped to 5q31-33. In the current study, the segregation analysis was extended by the addition of 108 probands and their families, ascertained in the same manner. A mixed recessive model (i.e., major recessive gene and residual genetic effect) was the best-fitting and most-parsimonious one-locus model of the segregation analysis. A mixed two-major-gene model (i.e., two major genes and residual genetic effect) fit the data significantly better than did the mixed recessive one-major-gene model. The second gene modified the effect of the first recessive gene. Individuals with the genotype aaBB (homozygous high-risk allele at the first gene and homozygous low-risk allele at the second locus) had normal IgE levels (mean 23 IU/ml), and only individuals with genotypes aaBb and aabb had high IgE levels (mean 282 IU/ml). A genomewide screening was performed using variance-component analysis. Significant evidence for linkage was found for a novel locus at 7q, with a multipoint LOD score of 3. 36 (P=.00004). A LOD score of 3.65 (P=.00002) was obtained after genotyping additional markers in this region. Evidence for linkage was also found for two previously reported regions, 5q and 12q, with LOD scores of 2.73 (P=.0002) and 2.46 (P=.0004), respectively. These results suggest that several major genes, plus residual genetic effects, regulate total serum IgE levels.


Branching instability in expanding bacterial colonies.
Self-organization in developing living organisms relies on the capability of cells to duplicate and perform a collective motion inside the surrounding environment. Chemical and mechanical interactions coordinate such a cooperative behaviour, driving the dynamical evolution of the macroscopic system. In this work, we perform an analytical and computational analysis to study pattern formation during the spreading of an initially circular bacterial colony on a Petri dish. The continuous mathematical model addresses the growth and the chemotactic migration of the living monolayer, together with the diffusion and consumption of nutrients in the agar. The governing equations contain four dimensionless parameters, accounting for the interplay among the chemotactic response, the bacteria-substrate interaction and the experimental geometry. The spreading colony is found to be always linearly unstable to perturbations of the interface, whereas branching instability arises in finite-element numerical simulations. The typical length scales of such fingers, which align in the radial direction and later undergo further branching, are controlled by the size parameters of the problem, whereas the emergence of branching is favoured if the diffusion is dominant on the chemotaxis. The model is able to predict the experimental morphologies, confirming that compact (resp. branched) patterns arise for fast (resp. slow) expanding colonies. Such results, while providing new insights into pattern selection in bacterial colonies, may finally have important applications for designing controlled patterns.


Biosynthesis of carnitine and 4-N-trimethylaminobutyrate from lysine.
The conversion of l-[U-(14)C]lysine into carnitine was demonstrated in normal, choline-deficient and lysine-deficient rats. In other experiments in vivo radioactivity from l-[4,5-(3)H]lysine and dl-[6-(14)C]lysine was incorporated into carnitine; however, radioactivity from dl-[1-(14)C]lysine and dl-[2-(14)C]lysine was not incorporated. Administered l-[Me-(14)C]methionine labelled only the 4-N-methyl groups whereas lysine did not label these groups. Therefore lysine must be incorporated into the main carbon chain of carnitine. The methylation of lysine by a methionine source to form 6-N-trimethyl-lysine is postulated as an intermediate step in the biosynthesis of carnitine. Radioactive 4-N-trimethylaminobutyrate (butyrobetaine) was recovered from the urine of lysine-deficient rats injected with [U-(14)C]lysine. This lysine-derived label was incorporated only into the butyrate carbon chain. The specific radioactivity of the trimethylaminobutyrate was 12 times that of carnitine isolated from the urine or carcasses of the same animals. These data further support the idea that the last step in the formation of carnitine from lysine was the hydroxylation of trimethylaminobutyric acid, and are consistent with the following sequence: lysine+methionine --> 6-N-trimethyl-lysine --> --> 4-N-trimethylaminobutyrate --> carnitine.


The role of lipid peroxidation in the chemical-dependent activation of hepatic phospholipase C in vitro.
This study assessed the role of lipid peroxidation in the chemical-dependent activation of hepatic phospholipase C in vitro. Hepatocellular membranes (1000 X g) were incubated with sn-[1,3-14C] glycerol-3-P, ATP, CoA, palmitate, Ca2+, NaF and dithiothreitol to form membrane-bound, labeled phosphatidic acid. Membrane-associated phosphatidate was incubated (10-45 min) with 2 mM Fe2+SO4 or 5mM CCl4 in the presence or absence of various antioxidants. Membranes exposed to Fe2+SO4 displayed an antioxidant-sensitive, 20-fold increase in malonic dialdehyde (MDA) formation without measurable increase in phospholipase C activity. In contrast, membranes exposed to 5 mM CCl4 displayed an antioxidant-insensitive, 2-3-fold increase in phospholipase C activity without significant increase in MDA production. These results suggest that under these incubation conditions in vitro, the CCl4-dependent activation of hepatic phospholipase C is not regulated by nor dependent upon the peroxidation of membrane phospholipids.


The efficacy of soy isoflavones combined with soy protein on serum concentration of interleukin-6 and tumour necrosis factor-α among post-menopausal women? A systematic review and meta-analysis of randomized controlled trials.
The post-menopausal stage in women's life is associated with the enhancement of inflammation that may be reduced using soy isoflavones or soy protein. The present study aimed to summarize the effect of soy isoflavones plus soy protein on circulating interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) in post-menopausal women. The English-language articles were identified from the databases such as Cochrane Library, clinicaltrials.gov, Web of Science, PubMed, and Scopus until December 2020. The mean change from baseline and its standard deviation (SD) for intervention and comparison groups were used to calculate the effect size. The statistical heterogeneity of the intervention effects was computing by Cochran's Q test and I2 statistic. Nine and seven studies were selected for systematic review and meta-analysis, respectively. The results of our meta-analysis indicated a non-significant effect on the serum concentrations of IL-6 and TNF-α (weighted mean differences [WMD] = 0.07 pg/mL; 95% confidence interval [CI] = -0.03, 0.17 pg/mL; P = 0.190; WMD =0.05 pg/mL; 95% CI = -0.01, 0.12 pg/mL; P = 0.092; respectively). In subgroup analysis, soy isoflavones plus soy protein could increase the serum concentration of IL-6 in studies with soy isoflavones dose ≤87 mg/days, cross-over design, weak quality, and studies on participants who had health risk factors or diseases. The serum concentration of TNF-α increased in studies with cross-over design, intervention duration ≤56 days, and body mass index (BMI) >27, and in studies that were conducted on at-risk or sick participants. In conclusion, our meta-analysis did not confirm any significant effect on serum concentration of IL-6 and TNF-α among post-menopausal women.


Immunohistochemical distribution of isoenzymes of glutathione transferase in adult rat adrenal gland before and after hypophysectomy.
The distribution of glutathione transferase subunits 1, 2, 3, 4, 7 and 8 in the different cells of the female and male rat adrenal and the effects of hypophysectomy on these isoenzymes were studied using immunohistochemical methods. All these glutathione transferase subunits, with the exception of subunit 1, were present in the adrenal. Each subunit showed, however, its own characteristic distribution pattern. After hypophysectomy, increased staining for these isoenzymes was generally observed, and this effect was also cell-specific. Staining for subunit 2 increased in intensity in the zona fasciculata and reticularis after hypophysectomy, whereas a decrease was observed in the zona glomerulosa. Staining for subunit 8 was increased in the borderline between the capsule and zona glomerulosa, as well as in medullary chromaffin cells after hypophysectomy. The Mu subunits 3 and 4 increased markedly in fascicular and reticular cells after hypophysectomy and staining for subunit 3 was also increased in the medullary cells. A slight, but more general, increase was observed for subunit 7. We conclude from these experiments that the increases in glutathione transferase subunits observed in the rat adrenal after hypophysectomy are due to increased protein synthesis and/or increased protein stability and not to a selective destruction of cells lacking, or with low levels of, the isoenzymes.


Higher cortisol awakening response in young adolescents with persistent anxiety problems.
The aims of the present study were to test the association between current anxiety problems and basal cortisol levels in a large population sample of young preadolescents, and to test if HPA-axis activity differs between individuals with no, only current, or persistent anxiety problems. Cortisol levels of 10- to 12-year olds (n = 1,768) from the general population were measured on three time points during the day. A self-report questionnaire (RCADS) was used to assess current anxiety, a parent-report questionnaire (TPBQ) to assess anxiety problems at age 4. Associations between cortisol levels and current anxiety problems were not found. However, individuals with persistent anxiety problems had higher morning cortisol levels and a higher cortisol awakening response. Apparently, only persistent, and not current, anxiety problems are associated with higher HPA-axis activity. Alterations in HPA-axis activity might underlie persistent anxiety problems, or result from the stress accompanied by persistent anxiety problems.


Disruption of cytoplasmic and mitochondrial folylpolyglutamate synthetase activity in Saccharomyces cerevisiae.
Similar to other eukaryotes, yeasts have parallel pathways of one-carbon metabolism in the cytoplasm and mitochondria and have folylpolyglutamate synthetase activity in both compartments. The gene encoding folylpolyglutamate synthetase is MET7 (also referred to as MET23) on chromosome XV and appears to encode both the cytoplasmic and mitochondrial forms of the enzyme. In order to determine the metabolic roles of both forms of folylpolyglutamate synthetase, we disrupted the met7 gene and determined that the strain is a methionine auxotroph and an adenine and thymidine auxotroph when grown in the presence of sulfanilamide. The met7 mutant becomes petite under normal growth conditions but can be maintained with a grande phenotype if the strain is tup and all media are supplemented with dTMP. A met7 gly1 strain is auxotrophic for glycine when grown on glucose but prototrophic when grown on glycerol. A met7 ser1 strain cannot use glycine to suppress the serine auxotrophy of the ser1 phenotype. A met7 shm2 strain is nonviable. In order to disrupt just the mitochondrial folylpolyglutamate synthetase activity, we constructed mutants with an inactivated chromosomal MET7 gene complemented by genes that express only cytoplasmic folylpolyglutamate synthetase, including the Lactobacillus casei folC gene and the yeast MET7 gene with its mitochondrial leader sequence deleted (MET7Deltam). All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy as well as the synthetic lethality of the shm2 strain and the synthetic glycine auxotrophy of the gly1 strain. The strains lacking the mitochondrial folylpolyglutamate synthetase had longer doubling times than the isogenic wild-type strains but retained the function of the mitochondrial folate-dependent enzymes to produce formate, serine, and glycine. Mutants complemented by the bacterial folC gene or by the MET7Deltam gene on a 2mu plasmid remained grande without the tup mutation and supplementation and dTMP. Mutants complemented by the MET7Deltam gene integrated in single copy became petites under those conditions, indicating a deficiency in dTMP production but this is likely due to lower expression of cytoplasmic folylpolyglutamate synthetase by the MET7Deltam gene.


Inhibition of mammalian muscle differentiation by regeneration blastema extract of Sternopygus macrurus.
Tissue regeneration through stem cell activation and/or cell dedifferentiation is widely distributed across the animal kingdom. By comparison, regeneration in mammals is poor and this may reflect a limited dedifferentiation potential of mature cells. Because mammalian myotubes can dedifferentiate in the presence of newt blastema extract, the present study tested the dedifferentiation induction capability of the blastema from the teleost Sternopygus macrurus (SmBE). Our in vitro data showed that SmBE did not induce cell cycle reentry of myonuclei in myotubes. Instead, SmBE caused myotubes to detach and time-lapse imaging analyses characterized the cellular events before their detachment. Furthermore, SmBE enhanced myoblast proliferation and reversibly inhibited their differentiation. These data suggest the presence of protein factors in SmBE that regulate mammalian muscle physiology and differentiation, but do not support the conservation of a dedifferentiation induction capability by the blastema of S. macrurus.


Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma.
Melasma, also known as mask of pregnancy, is a common, acquired hypermelanosis seen in women with Fitzpatrick skin types II-V, and is often recalcitrant to treatment with depigmentation agents. Glycolic acid has been added to hydroquinone formulations in the past to enhance their depigmentation effects, but may cause irritation, leading to postinflammatory hyperpigmentation. To assess the safety and efficacy of a cream containing 4% hydroquinone, 10% buffered glycolic acid, vitamins C and E, and sunscreen (Glyquin, ICN Pharmaceuticals, Costa Mesa, USA) vs. a cream containing sunscreen alone in the depigmentation of epidermal melasma of the face. Thirty-nine Hispanic women, Fitzpatrick skin types III-V, with bilateral epidermal melasma were enrolled in a randomized controlled trial lasting 12 weeks. Patients underwent twice-daily full-face application with the study cream or with the cream containing sunscreen only. Changes in pigmentation were measured using a mexameter, the melasma area and severity index (MASI), and a global evaluation by the patient and blind investigator. Safety evaluations were performed at each follow-up visit. Thirty-five patients completed the trial. Irritation was more common with the study cream, but resolved with temporary cessation of cream application and the addition of moisturizers. Mexameter results demonstrated a significant decrease in the degree of pigmentation using the study cream compared with the cream containing sunscreen alone (P < 0.0001). Fifteen of 20 patients (75%) using the study cream improved, whereas only two of 15 patients (13%) improved using sunscreen alone. A cream containing 4% hydroquinone, 10% buffered glycolic acid, vitamins C and E, and sunscreen is safe and effective in the treatment of melasma.


2-year follow-up of Lung transplantation as a treatment of Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) - a case report.
Hemorrhagic telangiectasia (HHT) is a disease of initially mild course - manifesting with recurrent nosebleeds and increased fatigue. Nevertheless, its progression can deteriorate patient's health. Solid organ transplantation becomes the only therapeutic option to save a life. Case series describes 19 years old female patient, who was diagnosed with HHT and qualified for lung transplantation. She meets Curacao criteria for HHT (¾). Her health deteriorated significantly to the point of the referral to Covered for Blind Review. Due to her condition she was qualified for lung transplantation as one diagnosed with Pulmonary arteriovenous malformations and then transplanted at the age of 17. Direct postoperative period was complicated by HSV2 infection of the wound. 18 months after the procedure, patient underwent acute cholangitis. Presence of portal and systemic fistulas was noted and the final diagnosis of HHT was made. Despite the fact that proper diagnosis was made posttransplant, it was a good treatment. The patient is currently 2 years after the lung transplant and feels good. Lung transplantation is a viable therapeutic option for patients with HHT, as there are reports of other patients, who have benefited from lung transplantation after other therapeutic options were exhausted.


Structure-based design technology contour and its application to the design of renin inhibitors.
It is well-known that the structure-based design approach has had a measurable impact on the drug discovery process in identifying novel and efficacious therapeutic agents for a variety of disease targets. The de novo design approach has inherent potential to generate novel molecules that best fit into a protein binding site when compared to all of the computational methods applied to structure-based design. In its initial attempts, this approach did not achieve much success due to technical hurdles. More recently, the algorithmic advancements in the methodologies and clever strategies developed to design drug-like molecules have improved the success rate. We describe a state-of-the-art structure-based design technology called Contour and provide details of the algorithmic enhancements we have implemented. Contour was designed to create novel drug-like molecules by assembling synthetically viable fragments in the protein binding site using a high-resolution crystal structure of the protein. The technology consists of a sophisticated growth algorithm and a novel scoring function based on a directional model. The growth algorithm generates molecules by dynamically selecting only those fragments from the fragment library that are complementary to the binding site, and assembling them by sampling the conformational space for each attached fragment. The scoring function embodying the essential elements of the binding interactions aids in the rank ordering of grown molecules and helps identify those that have high probability of exhibiting activity against the protein target of interest. The application of Contour to identify inhibitors against human renin enzyme eventually leading to the clinical candidate VTP-27,999 will be discussed here.


Advances in Melanoma: The Rationale for the Melanoma Nursing Initiative .
This article provides an overview of this supplement, outlining the needs assessment process the Melanoma Nursing Initiative (MNI) used to determine the immunotherapy and targeted therapy topics for discussion as well as the process for developing the consensus statements. The article provides specific discussion of a unique feature of the MNI, the care step pathways (CSPs) for management of adverse events (AEs) associated with melanoma therapies, and looks to the future in terms of the potential benefits of engaging and enabling oncology nurses to adopt a standardized approach to AE management and adherence promotion for melanoma therapies.


Preventing end-stage renal disease.
Interest in evidence-based medicine is increasing greatly, with the focus on treatment that prevents organ failure and that may prolong life. Type 1 and Type 2 diabetes are conditions associated with increased mortality, mainly as a result of renal and cardiovascular diseases, and blindness. All three complications usually occur together. In recent years, more focus has been placed on treating patients early to prevent future organ damage. Microalbuminuria is an important intermediary end-point that correlates strongly with future advanced renal disease, retinopathy and mortality. Several trials have studied patients with microalbuminuria and also patients in more advanced stages of the disease who have proteinuria (termed overt nephropathy). Recent evidence indicates that achieving optimal glycaemic control reduces the risk of an increase in urinary albumin excretion before the development of microalbuminuria. Angiotensin-converting enzyme (ACE) inhibitors are effective in reducing microalbuminuria, partly independent of their blood pressure reducing effects. In Type 1 and Type 2 diabetic patients with microalbuminuria, long-term treatment with ACE inhibitors (7-8 years) prevents the predicted decrease in glomerular filtration rate (GFR); optimal glycaemic control is also important in preventing the decline in GFR. This is important because GFR is usually well preserved in Type 1 and Type 2 diabetic patients with microalbuminuria and a predicted decline in GFR can therefore be prevented. In overt renal disease, studies that focused mostly on Type 1 diabetic patients have shown that the rate of decline in GFR can be reduced. Long-term studies in Type 1 diabetic patients have also demonstrated that mortality caused by end-stage renal disease can be postponed. Mortality associated with cardiovascular diseases, e.g. myocardial infarction, is reduced more effectively in diabetic patients treated with ACE inhibitors and beta-blockers than in non-diabetic patients treated with the same drugs. Screening for microalbuminuria, the attainment of optimal glycaemic control, and early treatment with ACE inhibitors and other antihypertensive drugs are necessary to prevent progression of diabetic complications, especially diabetic nephropathy. However, there is some controversy about the initial use of calcium channel blockers. In conclusion, early achievement of improved glycaemic control is the most important factor in the prevention of diabetic complications. Antihypertensive treatment is clearly also important.


The rheumatoid factor response in the etiology of mixed cryoglobulins associated with hepatitis C virus infection.
Studies of mixed cryoglobulins (MC) from patients infected with hepatitis C virus (HCV) show that the principal constituents in cryoprecipitate are IgM rheumatoid factors (RF), polyclonal IgG anti-HCV antibodies, and HCV RNA. The HCV-induced RF response is biased to produce IgM RF encoded by a restricted set of Ig V genes, predominantly the VH/VL gene pair 51p1/kv325. The propensity of such IgM RF to cryoprecipitate is likely a coincidental property of their V region sequences, but the clinical effect of this bias is increased by the persistence of circulating HCV-IgG immune complexes. These complexes might induce production of cryoprecipitable IgM RF and furnish multi-molecular structures that favor binding by cryoprecipitable IgM RF. The V gene sequences of HCV-induced IgM RF have features seen in other RF responses, suggesting a common immunological mechanism that is independent of HCV. B cell proliferation is probably enhanced by HCV-specific properties, however, including the ability of HCV proteins to bind to CD81 on the B cell surface, and to influence intracellular regulatory functions following viral entry into B cells. The V gene bias in HCV-induced RF is most apparent among the B cells in monoclonal expansions responsible for type II cryoglobulins, but it might originate early the polyclonal RF response, before MC are detectable. Monoclonal B cell expansions and lymphomatoid bone marrow infiltrates in HCV+ patients predominantly involve CD5-negative IgM RF B cells. Non-RF B cells can also be expanded, including producers of IgG1 and IgG3 that are likely anti-HCV antibodies. The initial site of B cell clonal expansion may be in the liver, where lymphoid aggregates are abundant and RF are produced. Sorting out how MC formation is influenced by properties that are inherent to the RF response, or specific to HCV infection, will be a challenge to future HCV research.


Neuroendocrine and Cardiovascular Activation During Aggressive Reactivity in Dogs.
Our aim was to investigate cardiovascular activation by measuring changes in facial and body surface temperature using infrared thermography, and neuroendocrine activation using salivary cortisol (CORT) and serotonin concentration (SER) in dogs exhibiting aggressive reactivity in real time. Based on two factors, owner-reported past aggressive behaviors, and detailed behavioral observations collected during a Socially Acceptable Behavior test consisting of 16 subtests and, each individual was categorized as aggressive or non-aggressive. CORT and SER showed no difference in neuroendocrine activity between dogs, but aggressive dogs with higher levels of aggression were found to have lower SER. Aggressive dogs also had an increase in facial temperature from pre-test values. The discovery of a correlation between tail wagging and left tail wagging with aggression level and aggression-related behaviors in aggressive dogs is further evidence of the right hemisphere specialization for aggression previously reported in the literature. This study provides the first evidence that both cardiovascular and neuroendocrine systems are activated during an active act of aggression in dogs.


Gender medicine and oncology: report and consensus of an ESMO workshop.
The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018. Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here. Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy. Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.


Detecting computer-induced errors in remote-sensing JPEG compression algorithms.
The JPEG image compression standard is very sensitive to errors. Even though it contains error resilience features, it cannot easily cope with induced errors from computer soft faults prevalent in remote-sensing applications. Hence, new fault tolerance detection methods are developed to sense the soft errors in major parts of the system while also protecting data across the boundaries where data flow from one subsystem to the other. The design goal is to guarantee no compressed or decompressed data contain computer-induced errors without detection. Detection methods are expressed at the algorithm level so that a wide range of hardware and software implementation techniques can be covered by the fault tolerance procedures while still maintaining the JPEG output format. The major subsystems to be addressed are the discrete cosine transform, quantizer, entropy coding, and packet assembly. Each error detection method is determined by the data representations within the subsystem or across the boundaries. They vary from real number parities in the DCT to bit-level residue codes in the quantizer, cyclic redundancy check parities for entropy coding, and packet assembly. The simulation results verify detection performances even across boundaries while also examining roundoff noise effects in detecting computer-induced errors in processing steps.


Preferences for Attributes of Sodium Oxybate Treatment: A Discrete Choice Experiment in Patients with Narcolepsy.
Current US FDA-approved treatments for narcolepsy include sodium oxybate (SXB) and calcium, magnesium, potassium, and sodium oxybates (mixed-salt oxybates), which require 2 nightly doses, 1 at bedtime and another 2.5 to 4 hours later. Once-nightly SXB (ON-SXB; FT218) is under FDA review to treat adults with narcolepsy. This study quantitatively characterized attributes of SXB treatment preferred by individuals with narcolepsy via a discrete choice experiment (DCE) and evaluated preferences for the product profiles of once-nightly vs twice-nightly SXB treatment. Adults with self-reported physician-diagnosed narcolepsy for ≥1 year and current or prior twice-nightly SXB treatment were eligible for this 30-minute, web-based study capturing patient experiences and a DCE. Participants responded to a survey instrument using 9-point scales; higher scores indicated greater severity/preference/satisfaction. In the DCE, hundreds of profiles were generated, each combining attributes of twice-nightly SXB and ON-SXB based on clinical trial data. The DCE was analyzed using a hierarchical Bayesian model. Seventy-five participants were surveyed (50 current and 25 past twice-nightly SXB users). Dosing frequency was the most important attribute of SXB treatment; once nightly was significantly preferred vs twice nightly. The most common reasons for overall product preference were lack of need to wake up in the middle of the night for a second dose (48%), fewer side effects (46%), and ease of administration (32%). Number of nightly doses was the most important driver of taking the medication exactly as directed and reduced anxiety/stress. Participants were significantly more likely to prefer the blinded product profile of once-nightly SXB over twice-nightly SXB (mean rating, 7.5 vs 4.3; P<0.05). Among the choices presented, dosing frequency was the most important attribute for overall product choice, likelihood to take medication exactly as directed, and reducing anxiety/stress. The ON-SXB blinded profile was significantly preferred over twice-nightly SXB.


Gene density in the Giemsa bands of human chromosomes.
The human genome is formed by isochores belonging to five families, L1, L2, H1, H2 and H3, that are characterized by increasing GC levels and gene concentrations. In-situ hybridization of DNA from different isochore families provides, therefore, information not only on the correlation between isochores and chromosomal bands, but also on the distribution of genes in chromosomes. Three subsets of R(everse) bands were identified: H3+, H3* and H3-, that contain large, moderate, and no detectable amounts, respectively, of the gene-richest H2 and H3 isochores, and replicate very early and early, respectively, in S phase of the cell cycle. Here, we investigated the GC levels, replication timings and DNA compaction of G(iemsa) bands. We showed that G bands comprise two different subsets of bands, one of which is predominantly composed of L1 isochores, replicates at the end of the S phase, has a higher DNA compaction relative to H3+ bands and corresponds to the darkest G bands of Francke (1994). In contrast, the other subset is composed of L2 and H1 isochores, has less-extreme properties in replication and composition and corresponds to the less-dark G bands of Francke.


Vertical transmission of dengue.
Dengue, an important mosquito-borne flavivirus infection, is endemic in Southeast Asia. We describe two mothers who had acute dengue 4 and 8 days before the births of their infants. One mother had worsening of her proteinuric pregnancy-induced hypertension, liver dysfunction, and coagulopathy and required multiple transfusions of whole blood, platelets, and fresh frozen plasma. Her male infant was ill at birth, developed respiratory distress and a large uncontrollable left intracerebral hemorrhage, and died of multiorgan failure on day 6 of life. Dengue virus type 2 was isolated from the infant's blood, and IgM antibody specific to dengue virus was detected in the mother's blood. The second mother had a milder clinical course; she gave birth to a female infant who was thrombocytopenic at birth and had an uneventful hospitalization. Dengue virus type 2 was recovered from the mother's blood, and IgM antibody specific to dengue virus was detected in the infant's blood. This report highlights not only the apparently rare occurrence of vertical transmission of dengue virus in humans but also the potential risk of death for infected neonates.


Mortality and access to care among adults after state Medicaid expansions.
Several states have expanded Medicaid eligibility for adults in the past decade, and the Affordable Care Act allows states to expand Medicaid dramatically in 2014. Yet the effect of such changes on adults' health remains unclear. We examined whether Medicaid expansions were associated with changes in mortality and other health-related measures. We compared three states that substantially expanded adult Medicaid eligibility since 2000 (New York, Maine, and Arizona) with neighboring states without expansions. The sample consisted of adults between the ages of 20 and 64 years who were observed 5 years before and after the expansions, from 1997 through 2007. The primary outcome was all-cause county-level mortality among 68,012 year- and county-specific observations in the Compressed Mortality File of the Centers for Disease Control and Prevention. Secondary outcomes were rates of insurance coverage, delayed care because of costs, and self-reported health among 169,124 persons in the Current Population Survey and 192,148 persons in the Behavioral Risk Factor Surveillance System. Medicaid expansions were associated with a significant reduction in adjusted all-cause mortality (by 19.6 deaths per 100,000 adults, for a relative reduction of 6.1%; P=0.001). Mortality reductions were greatest among older adults, nonwhites, and residents of poorer counties. Expansions increased Medicaid coverage (by 2.2 percentage points, for a relative increase of 24.7%; P=0.01), decreased rates of uninsurance (by 3.2 percentage points, for a relative reduction of 14.7%; P<0.001), decreased rates of delayed care because of costs (by 2.9 percentage points, for a relative reduction of 21.3%; P=0.002), and increased rates of self-reported health status of "excellent" or "very good" (by 2.2 percentage points, for a relative increase of 3.4%; P=0.04). State Medicaid expansions to cover low-income adults were significantly associated with reduced mortality as well as improved coverage, access to care, and self-reported health.


Intraoperative Measured Electrocochleography and Fluoroscopy Video to Detect Cochlea Trauma.
Gross electrode movements detected with intraoperative, real-time X-ray fluoroscopy will correlate with fluctuations in cochlear output, as measured with intraoperative electrocochleography (ECochG). Indications for cochlear implantation (CI) are expanding to include patients with residual hearing; however, implant recipients often lose residual hearing after CI. The objective of this study was to identify probable traumatic events during implantation by combining electrophysiological monitoring of cochlear function with simultaneous X-ray monitoring. The surgical timing of these apparently traumatic events was then investigated. For 19 adult patients (21 surgeries, 2 bilateral), the ECochG responses were measured during implantation of a cochlear nucleus slim modiolar electrode (CI532/CI632, Cochlear Ltd Australia Nucleus slim modiolar). Simultaneous fluoroscopy was performed, as well as a postoperative cone-beam computed tomography (CT) scan. For all patients, pre- and postoperative audiograms were recorded up to 1 year after surgery to record the loss of residual hearing. Electrode insertions for 21 surgeries were successfully monitored. A drop in ECochG response was significantly correlated with reduced hearing preservation compared with patients with preserved responses throughout. Drops in the ECochG response were measured to occur during insertion, because of movement of the array after insertion was complete, including while sealing of the electrode array at the round window or coiling of the array lead within the mastoid cavity. In some patients, a reduction in cochlear output, resulting in poor ECochG response, was inferred to occur before the beginning of implantation. The combination of perioperative ECochG measurements, microscope video, fluoroscopy, and postoperative CT scan may inform on what causes the loss of residual hearing after implantation. These findings will be used to improve the surgical procedure in future.


[Poisoning with aluminum phospholipide used as a poison against moles].
Aluminium phosphide (AIP) is a poison used in Denmark to combat moles and vermines e.g. in granaries. On contact with water AIP releases phosphine gas, which has a strong cytotoxic action. We describe a lethal poisoning in a healthy 83 year old man, caused by ingestion of pellets containing AIP. After ingestion the primary symptoms were burning retrosternal pain, severe vomiting and diarrhoea which progressed to cardiac failure, arrhythmias and severe metabolic acidosis. The patient and his excreta smelled of garlic, ammonium carbide and decaying fish, which is characteristic of this poisoning. In spite of intensive care support the patient died in cardiac and respiratory failure 17 hours after ingestion of the pellets. Treatment is supportive. Knowledge about the toxicity of AIP is described and discussed.


Serum Thyroglobulin Measurement Following Surgery Without Radioactive Iodine for Differentiated Thyroid Cancer: A Systematic Review.
Background: The utility of serum thyroglobulin (Tg) measurement following partial thyroidectomy or total/near-total thyroidectomy without radioactive iodine (RAI) for differentiated thyroid cancer is unclear. This systematic review examines the diagnostic accuracy of serum Tg measurement for persistent, recurrent, and/or metastatic cancer in these situations. Methods: Ovid MEDLINE, Embase, and Cochrane Central were searched in October 2021 for studies on Tg measurement following partial thyroidectomy or total/near-total thyroidectomy without or before RAI. Quality assessment was performed, and evidence was synthesized qualitatively. Results: Thirty-seven studies met inclusion criteria. Four studies (N = 561) evaluated serum Tg measurement following partial thyroidectomy, five studies (N = 751) evaluated Tg measurement following total/near-total thyroidectomy without RAI, and 28 studies (N = 7618) evaluated Tg measurement following total or near-total thyroidectomy before RAI administration. Following partial thyroidectomy, Tg measurement was not accurate for diagnosing recurrence or metastasis, or estimates were imprecise. Following total/near-total thyroidectomy without RAI, evidence was limited due to few studies with very low rates of recurrence or metastasis, but indicated that Tg levels were usually stable and low. For Tg measurements before RAI administration, diagnostic accuracy for metastatic disease or persistence varied, although sensitivity appeared high (but specificity low) at a cutoff of >1 to 2.5 ng/mL. However, applicability to patients who do not undergo RAI is uncertain because patients selected for RAI are likely to represent a higher risk group. The evidence was very low quality for all scenarios. All studies had methodological limitations, and there was variability in the Tg thresholds evaluated, patient populations, outcomes assessed, and other factors. Conclusions: Very limited evidence suggests low utility of Tg measurement for identifying recurrent or metastatic disease following partial thyroidectomy. Following total/near-total thyroidectomy, Tg levels using a cutoff of 1-2.5 ng/mL might identify patients at low risk for persistent or metastatic disease. Additional research is needed to clarify the role of Tg measurement in these settings, determine optimal Tg thresholds, and determine appropriate measurement intervals.


Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements.
The spatial organization of genes in the interphase nucleus plays an important role in establishment and regulation of gene expression. Contradicting results have been reported to date, with little consensus about the dynamics of nuclear organization and the features of the contact loci. In this study, we investigated the properties and dynamics of genomic loci that are in contact with glucocorticoid receptor (GR)-responsive loci. We took a systematic approach, combining genome-wide interaction profiling by the chromosome conformation capture on chip (4C) technology with expression, protein occupancy, and chromatin accessibility profiles. This approach allowed a comprehensive analysis of how distinct features of the linear genome are organized in the three-dimensional nuclear space in the context of rapid gene regulation. We found that the transcriptional response to GR occurs without dramatic nuclear reorganization. Moreover, contrary to the view of transcription-driven organization, even genes with opposite transcriptional responses colocalize. Regions contacting GR-regulated genes are not particularly enriched for GR-regulated loci or for any functional group of genes, suggesting that these subnuclear environments are not organized to respond to a specific factor. The contact regions are, however, highly enriched for DNase I-hypersensitive sites that comprehensively mark cell-type-specific regulatory sites. These findings indicate that the nucleus is pre-organized in a conformation allowing rapid transcriptional reprogramming, and this organization is significantly correlated with cell-type-specific chromatin sites accessible to regulatory factors. Numerous open chromatin loci may be arranged in nuclear domains that are poised to respond to diverse signals in general and to permit efficient gene regulation.


Simulating the meteorology and PM10 concentrations in Arizona dust storms using the Weather Research and Forecasting model with Chemistry (Wrf-Chem).
Nine dust storms in south-central Arizona were simulated with the Weather Research and Forecasting with Chemistry model (WRF-Chem) at 2 km resolution. The windblown dust emission algorithm was the Air Force Weather Agency model. In comparison with ground-based PM10 observations, the model unevenly reproduces the dust-storm events. The model adequately estimates the location and timing of the events, but it is unable to precisely replicate the magnitude and timing of the elevated hourly concentrations of particles 10 µm and smaller ([PM10]).Furthermore, the model underestimated [PM10] in highly agricultural Pinal County because it underestimated surface wind speeds and because the model's erodible fractions of the land surface data were too coarse to effectively resolve the active and abandoned agricultural lands. In contrast, the model overestimated [PM10] in western Arizona along the Colorado River because it generated daytime sea breezes (from the nearby Gulf of California) for which the surface-layer speeds were too strong. In Phoenix, AZ, the model's performance depended on the event, with both under- and overestimations partly due to incorrect representation of urban features. Sensitivity tests indicate that [PM10] highly relies on meteorological forcing. Increasing the fraction of erodible surfaces in the Pinal County agricultural areas improved the simulation of [PM10] in that region. Both 24-hr and 1-hr measured [PM10] were, for the most part, and especially in Pinal County, extremely elevated, with the former exceeding the health standard by as much as 10-fold and the latter exceeding health-based guidelines by as much as 70-fold. Monsoonal thunderstorms not only produce elevated [PM10], but also cause urban flash floods and disrupt water resource deliveries. Given the severity and frequency of these dust storms, and conceding that the modeling system applied in this work did not produce the desired agreement between simulations and observations, additional research in both the windblown dust emissions model and the weather research/physicochemical model is called for. While many dust storms can be considered to be natural, in semi-arid climates such storms often have an anthropogenic component in their sources of dust. Applying the natural, exceptional events policy to these storms with strong signatures of anthropogenic sources would appear not only to be misguided but also to stifle genuine regulatory efforts at remediation. Those dust storms that have resulted, in part, from passage over abandoned farm land should no longer be considered "natural"; policymakers and lawmakers need to compel the owners of such land to reduce its potential for windblown dust.


[Early diagnosis of liver cancer].
Hepatocellular carcinoma is a frequent neoplasm that usually develops in patients with liver cirrhosis. Because it is the main cause of death in these patients, they should be included in a surveillance program in order to identify these tumors at an early stage and be able to indicate curative treatment (liver transplantation, surgical resection or percutaneous ablation therapy) and to reduce mortality. Surveillance should include determination of alpha-fetoprotein and abdominal ultrasound every 6 months. This strategy should only be applied to patients suitable to receive curative treatment if diagnosed of hepatocellular carcinoma. Using this approach, 40-80% of tumors identified are solitary at diagnosis, although only half of these patients can benefit from curative treatment.


Dosimetry in myeloablative (90)Y-labeled ibritumomab tiuxetan therapy: possibility of increasing administered activity on the base of biological effective dose evaluation. Preliminary results.
In our multicentric ongoing phase I activity escalation study, (90)Y-labeled ibritumomab tiuxetan (Ze-valin was administered in activity per kilo twice- and three times the maximum tolerable dose of 15 MBq/kg suggested for nonmyeloablative treatments by the U.S. registration study. The radioinduced myelodepression was overcome by stem cell autografting. The dosimetric aim was to correlate possible extramedullary toxicities to the organ-absorbed doses or to the biologic effective dose (BED). This is a conceptually more suitable parameter, as it takes into account not only the absorbed dose, but also the influence of the dose rate and of the tissue repair mechanism. Pretreatment planar dosimetry was performed on 16 patients with a median 200 MBq of (111)In-Zevalin. Conjugate view technique, background, attenuation, and partial scatter correction were adopted. Blood samples and a planar whole body scintigram were collected at least at 0.5, 48, 96, and 120 hours. Individual organ mass correction was based on a computed tomography scan. Internal dose calculation was performed by the OLINDA/EXM software. One (1) week after dosimetry, 12 patients were treated with 30 MBq/kg and 4 patients with 45 MBq/kg of (90)Y-Zevalin. The absorbed dose per unit activity (Gy/GBq) were (median and range of 16 dosimetric studies): heart wall 3.8 [0.5, 9.7]; kidneys 4.9 [2.8, 10.5]; liver 5.5 [3.9, 8.9]; lungs 2.8 [0.4, 6.8]; red marrow 1.1 [0.8, 2.1]; spleen 6.3 [1.5, 10.9]; and testes 4.6 [3.0, 16.7]. The absorbed dose (Gy) for the 4 patients administered with 45 MBq/kg were (median and range): heart wall 17.6 [9.4, 25.1]; kidneys 16.3 [7.9, 20.3]; liver 20.9 [15.4, 24.3]; lungs 7.7 [5.6, 11.4]; red marrow 3.0 [2.4, 3.3]; spleen 28.4 [18.9, 30.8]; and testes 16.5 [12.2, 17.3]. No extramedullary toxicity was observed. The administration of 45 MBq/kg of (90)Y ibritumomab tiuxetan to 4 patients with stem cell autografting was free from extramedullary toxicity. This is in agreement with both organ doses and BEDs below the corresponding toxicity thresholds. For these clinical and dosimetric reasons, a further increase in injectable activity could have been conceivable. If the more appropriate BED parameter were chosen for toxicity limit calculations, a wider margin of increase would have been possible. Our theoretical investigation demonstrates that, in this particular case of (90)Y Zevalin therapy, the uncertainty about radiobiological parameters was not a limiting factor for a BED-based calculation of the maximum injectable activity.


ATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement.
Photoreceptor degeneration (PRD) is a genetically heterogeneous retinal disorder. Although a number of genes involved in PRD have been identified, their genetic basis remains unknown in a significant number of patients. In this study, we aimed to identify novel disease-causing genes of PRD. Comprehensive ocular examinations were performed in a 2-year-old patient diagnosed with early onset PRD. Retinal capture sequencing was performed to screen causative mutations in known retinal disease-causing loci. Whole-exome sequencing (WES) and a series of variant-filtering strategies were applied for identifying novel disease-causing genes. Retina ATF6 expression was confirmed by immunohistochemistry. RT-PCR was performed to identify ATF6 mRNA in the patient. The patient showed typical PRD features, with macular involvement and ellipsoid zone irregularities. Results of retinal capture sequencing were negative. WES data led to identification of biallelic loss-of-function mutations in the ATF6 gene. The first variant generates a premature stop codon (NCBI accession no. NM_007348: c.1126C>T, p.R376*) and the second variant affects a splicing donor site (NM_007348: c.1533+1G>C). Sanger sequencing confirmed the 2 alleles are from 1 parent each. Both of the variants are extremely rare in the population. The splicing variant causes either intron inclusion or exon skipping in the patient, thus severely disrupting ATF6 functional domains. ATF6 is expressed in three neuronal cell layers of mouse retina. Our results support ATF6 as a novel disease-causing gene for PRD and suggest that disrupted protein quality control mechanisms may be a novel pathological mechanism underlying human retinal degeneration.


Microtubule organization and cell geometry.
A characteristic feature of nondividing animal cells is the radial organization of microtubules (MTs), emanating from a single microtubule organizing center (MTOC). As generically these cells are not spherically symmetric, this raises the question of the influence of cell geometry on the orientational distribution of microtubules. We present a systematic study of this question in a simplified setting where MTs are nucleated from a single fixed MTOC in the center of an elliptical cell geometry. Within this context we introduce four models of increasing complexity, each one introducing additional mechanisms that govern the interaction of the MTs with the cell boundary. In order, we consider the cases: MTs that can bind to the boundary with a fixed mean residence time (M0), force-producing MTs that can slide on the boundary towards the cell poles (MS), MTs that interact with a generic polarity factor that is transported and deposited at the boundary, and which in turn stabilizes the MTs at the boundary (MP), and a final model in which both sliding and stabilization by polarity factors is taken into account (MSP). In the baseline model (M0), the exponential length distribution of MTs causes most of the interactions at the cell boundary to occur along the shorter transverse direction in the cell, leading to transverse biaxial order. MT sliding (MS) is able to reorient the main axis of this biaxial order along the longitudinal axis. The polarization mechanism introduced in MP and MSP overrules the geometric bias towards bipolar order observed in M0 and MS, and allows the establishment of unipolar order either along the short (MP) or the long cell axis (MSP). The behavior of the latter two models can be qualitatively reproduced by a very simple toy model with discrete MT orientations.


PK 11195 blockade of benzodiazepine-induced inhibition of forskolin-stimulated adenylate cyclase activity in the striatum.
1. The effects of benzodiazepine receptor antagonists on the inhibition of forskolin-stimulated adenylate cyclase (AC) activity by various benzodiazepine (BZ) and indoleamine agonists in the rat striatum were investigated. 2. A biphasic inhibition of forskolin-stimulated AC activity by the peripheral-type agonist, Ro5-4864, and a multiphasic inhibition by the non-selective BZ, diazepam, was observed. One phase of AC inhibition is consistent with a Gi-coupled receptor-mediated action, whereas the other phases appear to involve a direct effect on the enzyme itself. 3. While the central-type antagonist, flumazenil, had no effect on the ability of Ro5-4864 to inhibit AC activity, the peripheral-type receptor ligand, PK 11195, abolished the first phase of inhibition. 4. PK 11195 and pertussis toxin were found to block the inhibitory effect of various BZs and the indoleamines, melatonin and 2-iodomelatonin, on induced AC activity. 5. Saturation binding studies, conducted at 30 degrees C with [3H]-diazepam revealed a single binding site in the rat striatum (KD = 19.3 +/- 0.80 nM) which significantly decreased in affinity in the presence of GTP (KD = 30.5 +/- 2.6 nM; P < 0.05). No significant change in Bmax was observed. 6. These findings indicate the presence of Gi-coupled BZ receptors in the rat striatum. Thus, suppression of cyclic AMP production may contribute to the diverse neuropharmacological effects of BZs, melatonin and related drugs.


Glucocerebrosidase dysfunction in neurodegenerative disease.
Parkinson's disease (PD) and related neurodegenerative disorders, termed the synucleinopathies, are characterized pathologically by the accumulation of protein aggregates containing α-synuclein (aSyn), resulting in progressive neuronal loss. There is considerable need for the development of neuroprotective strategies to halt or slow disease progression in these disorders. To this end, evaluation of genetic mutations associated with the synucleinopathies has helped to elucidate crucial mechanisms of disease pathogenesis, revealing key roles for lysosomal and mitochondrial dysfunction. The GBA1 gene, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase) is the most common genetic risk factor for PD and is also linked to other neurodegenerative disorders including dementia with Lewy bodies (DLB). Additionally, homozygous mutations in GBA1 are associated with the rare lysosomal storage disorder, Gaucher's disease (GD). In this review, we discuss the current knowledge in the field regarding the diverse roles of GCase in neurons and the multifactorial effects of loss of GCase enzymatic activity. Importantly, GCase has been shown to have a bidirectional relationship with aSyn, resulting in a pathogenic feedback loop that can lead to progressive aSyn accumulation. Alterations in GCase activity have furthermore been linked to multiple distinct pathways involved in neurodegeneration, and therefore GCase has emerged as a promising target for therapeutic drug development for PD and related neurodegenerative disorders, particularly DLB.


AI algorithms for accurate prediction of osteoporotic fractures in patients with diabetes: an up-to-date review.
Osteoporotic fractures impose a substantial burden on patients with diabetes due to their unique characteristics in bone metabolism, limiting the efficacy of conventional fracture prediction tools. Artificial intelligence (AI) algorithms have shown great promise in predicting osteoporotic fractures. This review aims to evaluate the application of traditional fracture prediction tools (FRAX, QFracture, and Garvan FRC) in patients with diabetes and osteoporosis, review AI-based fracture prediction achievements, and assess the potential efficiency of AI algorithms in this population. This comprehensive literature search was conducted in Pubmed and Web of Science. We found that conventional prediction tools exhibit limited accuracy in predicting fractures in patients with diabetes and osteoporosis due to their distinct bone metabolism characteristics. Conversely, AI algorithms show remarkable potential in enhancing predictive precision and improving patient outcomes. However, the utilization of AI algorithms for predicting osteoporotic fractures in diabetic patients is still in its nascent phase, further research is required to validate their efficacy and assess the potential advantages of their application in clinical practice.


Utility of population models to reduce uncertainty and increase value relevance in ecological risk assessments of pesticides: an example based on acute mortality data for daphnids.
Traditionally, ecological risk assessments (ERA) of pesticides have been based on risk ratios, where the predicted concentration of the chemical is compared to the concentration that causes biological effects. The concentration that causes biological effect is mostly determined from laboratory experiments using endpoints on the level of the individual (e.g., mortality and reproduction). However, the protection goals are mostly defined at the population level. To deal with the uncertainty in the necessary extrapolations, safety factors are used. Major disadvantages with this simplified approach is that it is difficult to relate a risk ratio to the environmental protection goals, and that the use of fixed safety factors can result in over- as well as underprotective assessments. To reduce uncertainty and increase value relevance in ERA, it has been argued that population models should be used more frequently. In the present study, we have used matrix population models for 3 daphnid species (Ceriodaphnia dubia, Daphnia magna, and D. pulex) to reduce uncertainty and increase value relevance in the ERA of a pesticide (spinosad). The survival rates in the models were reduced in accordance with data from traditional acute mortality tests. As no data on reproductive effects were available, the conservative assumption that no reproduction occurred during the exposure period was made. The models were used to calculate the minimum population size and the time to recovery. These endpoints can be related to the European Union (EU) protection goals for aquatic ecosystems in the vicinity of agricultural fields, which state that reversible population level effects are acceptable if there is recovery within an acceptable (undefined) time frame. The results of the population models were compared to the acceptable (according to EU documents) toxicity exposure ratio (TER) that was based on the same data. At the acceptable TER, which was based on the most sensitive species (C. dubia), the maximum reduction in population size was 13% and the maximum time to recovery was 4 d (both for D. magna). This information is clearly more informative for risk management than a risk ratio. For one of the species, D. pulex, a more complex model, which included sublethal effects on reproduction, was set up. The results of this model were in good agreement with a previous microcosm study and indicated that a traditional TER was overprotective.


Seasonal variations in the incidence of some congenital anomalies in Puerto Rico based on the timing of conception.
Birth defects represent one of the main causes of infant mortality and morbidity around the world. The purpose of this study is to identify seasonal changes in the incidence of various congenital anomalies in our population. We identified all cases of open neural tube defects, cardiac anomalies, cleft lip and palate and gastroschisis of children born in Puerto Rico and reported to the Health's Department Birth Registry Program between January 1995 and December 2005. The conception dates were determined by estimation based on the reported last menstrual period. All deliveries during this same period were recorded and their conception dates estimated in the same manner. The data for each anomaly was separated into 4 groups for each year studied corresponding to the four seasons. The sample was stratified based on the type of anomaly detected and the season when conception took place. There is a seasonal pattern in the rate of conceptions in Puerto Rico with the highest incidence during the winter and lowest during the summer months. We detected a statistically significant increase in the incidence and relative risk during the summer months (using winter as a reference) of conceiving a child with open neural tube defects (1.03/1000, RR:1.33), cardiac anomalies (5.22/1000, RR:1.39), or cleft lip and palate (1.68/1000, RR:1.89). Gastroschisis did not show a statistically significant difference in the rate of conceptions, but there was a tendency towards a higher incidence during spring (0.39/1000, RR:1.67). The reported seasonal variation in the incidence of open neural tube defects, cardiac anomalies, and cleft lip and palate may be secondary to the effect of yet to be identified teratogens acting on the population at large, or, more likely, to changes in activity and dietary patterns of the population.


Locus-specific variation in phosphorylation state of RNA polymerase II in vivo: correlations with gene activity and transcript processing.
To investigate functional differences between RNA polymerases IIA and IIO (Pol IIA and Pol IIO), with hypo- and hyperphosphorylated carboxy-terminal repeat domains (CTDs), respectively, we have visualized the in vivo distributions of the differentially phosphorylated forms of Pol II on Drosophila polytene chromosomes. Using phosphorylation state-sensitive antibodies and immunofluorescence microscopy with digital imaging, we find Pol IIA and Pol IIO arrayed in markedly different, locus- and condition-specific patterns. Major ecdysone-induced puffs, for example, stain exclusively for Pol IIO, indicating that hyperphosphorylated Pol II is the transcriptionally active form of the enzyme on these genes. In striking contrast, induced heat shock puffs stain strongly for both Pol IIA and Pol IIO, suggesting that heat shock genes are transcribed by a mixture of hypo- and hyperphosphorylated forms of Pol II. At the insertion sites of a transposon carrying a hybrid hsp70-lacZ transgene, we observe only Pol IIA before heat shock induction, consistent with the idea that Pol II arrested on the hsp70 gene is form IIA. After a 90-sec heat shock, we detect heat shock factor (HSF) at the transposon insertion sites; and after a 5-min shock its spatial distribution on the induced transgene puffs is clearly resolved from that of Pol II. Finally, using antibodies to hnRNP proteins and splicing components, we have discerned an apparent overall correlation between the presence and processing of nascent transcripts and the presence of Pol IIO.


SMART COVID Navigator, a Clinical Decision Support Tool for COVID-19 Treatment: Design and Development Study.
COVID-19 caused by SARS-CoV-2 has infected 219 million individuals at the time of writing of this paper. A large volume of research findings from observational studies about disease interactions with COVID-19 is being produced almost daily, making it difficult for physicians to keep track of the latest information on COVID-19's effect on patients with certain pre-existing conditions. In this paper, we describe the creation of a clinical decision support tool, the SMART COVID Navigator, a web application to assist clinicians in treating patients with COVID-19. Our application allows clinicians to access a patient's electronic health records and identify disease interactions from a large set of observational research studies that affect the severity and fatality due to COVID-19. The SMART COVID Navigator takes a 2-pronged approach to clinical decision support. The first part is a connection to electronic health record servers, allowing the application to access a patient's medical conditions. The second is accessing data sets with information from various observational studies to determine the latest research findings about COVID-19 outcomes for patients with certain medical conditions. By connecting these 2 data sources, users can see how a patient's medical history will affect their COVID-19 outcomes. The SMART COVID Navigator aggregates patient health information from multiple Fast Healthcare Interoperability Resources-enabled electronic health record systems. This allows physicians to see a comprehensive view of patient health records. The application accesses 2 data sets of over 1100 research studies to provide information on the fatality and severity of COVID-19 for several pre-existing conditions. We also analyzed the results of the collected studies to determine which medical conditions result in an increased chance of severity and fatality of COVID-19 progression. We found that certain conditions result in a higher likelihood of severity and fatality probabilities. We also analyze various cancer tissues and find that the probabilities for fatality vary greatly depending on the tissue being examined. The SMART COVID Navigator allows physicians to predict the fatality and severity of COVID-19 progression given a particular patient's medical conditions. This can allow physicians to determine how aggressively to treat patients infected with COVID-19 and to prioritize different patients for treatment considering their prior medical conditions.


Isolation and characterization of microsatellite markers for Carolina hemlock (Tsuga caroliniana).
We describe the isolation and characterization of 31 polymorphic di- and trinucleotide microsatellite marker loci for Carolina hemlock (Tsuga caroliniana Englem.). In addition, primer pairs for 16 loci amplified scoreable alleles in six other Tsuga species. In eastern North America, both Carolina hemlock and eastern hemlock (Tsuga canadensis [L.] Carr.) populations are declining due to infestation by hemlock woolly adelgid, Adelges tsugae. The markers described here should enhance population genetic studies of hemlocks, providing valuable information for conserving and restoring these important forest tree species.


TetL tetracycline efflux protein from Bacillus subtilis is a dimer in the membrane and in detergent solution.
The TetL antiporter from the Bacillus subtilis inner membrane is a tetracycline-divalent cation efflux protein that is energized by the electrochemical proton gradient across the membrane. In this study, we expressed tetL in Escherichia coli and investigated the oligomeric state of TetL in the membrane and in detergent solution. Evidence for an oligomeric state of TetL emerged from SDS-PAGE and Western blot analysis of membrane samples as well as purified protein samples from cells that expressed two differently tagged TetL species. Furthermore, no formation or restoration of TetL oligomers occurred upon detergent solubilization of the membrane. Rather, oligomeric forms established in vivo persisted after solubilization. Mass spectrometry of the purified protein showed the absence of proteolysis and posttranslational modifications. Analytical size-exclusion chromatography of the purified protein revealed a dimeric TetL in dodecyl-maltoside solution. In addition, TetL dimers were found in a number of other detergents and over a wide pH range. It is therefore likely that the oligomeric form of the protein in the membrane is also a dimer.


Effect of reference database on frequency estimates of polymerase chain reaction (PCR)-based DNA profiles.
A variety of general, regional, ancestral and ethnic databases is available for the polymerase chain reaction (PCR)-based loci LDLR, GYPA, HBGG, D7S8, Gc, DQA1, and D1S80. Generally, we observed greater differences in frequency estimations of DNA profiles between racial groups than between ethnic or geographic subgroups. Analysis revealed few forensically significant differences within ethnic subgroups, particularly within general United States groups, and multi-locus frequency estimates typically differ by less than a factor of ten. Using a database different from the one to which a target profile belongs tends to overestimate rarity. Implementation of the general correction of homozygote frequencies for a population substructure, advised by the 1996 National Research Council report, The Evaluation of Forensic DNA Evidence, has a minimal effect on profile frequencies. Even when it is known that both the suspect and all possible perpetrators must belong to the same isolated population, the special correction for inbreeding, which was proposed by the 1996 National Research Council report for this special case, has a relatively modest effect, typically a factor of two or less for 1% inbreeding. The effect becomes more substantial (exceeding a factor of ten) for inbreeding of 3% or more in multi-locus profiles rarer than about one in a million.


Disk diffusion and MIC quality control ranges for BC-3205 and BC-3781, two novel pleuromutilin antibiotics.
MIC and disk diffusion quality control (QC) ranges were established for two new pleuromutilin antimicrobials (BC-3205 and BC-3781) in an eight-laboratory study performed according to Clinical and Laboratory Standards Institute M23-A3 guidelines. Staphylococcus aureus ATCC 29213 and 25923, Streptococcus pneumoniae ATCC 49619, and Haemophilus influenzae ATCC 4927 strains were evaluated. The proposed QC ranges would aid clinical laboratories in testing these compounds following their development for treatment of respiratory and cutaneous infections.


Stink of Stinkpot Turtle Identified: ohgr-Phenylalkanoic Acids.
The exocrine secretion of the "stinkpot turtle," Sternotherus odoratus, discharged by the animals in response to disturbance, contains four omega-phenylalkanoic acids (phenylacetic, 3-phenylpropionic, 5-phenylpentanoic, and 7-phenylheptanoic). The last two of these are new natural products. The first two are powerfully malodorous and responsible for the stench of the fluid. Lesser components, including several aliphatic acids, are also present. Only a few milligrams of secretion are discharged by a turtle at any one time. Although bioassays with fish suggest that the secretion has the potential to serve as a feeding deterrent to predators, it is argued that Sternotherus does not ordinarily discharge enough fluid to effect this action and may employ its secretion only as an aposematic signal that warns predators of its more generalized undesirability.


Influenza and Pertussis Maternal Vaccination Coverage and Influencing Factors in Spain: A Study Based on Primary Care Records Registry.
The purpose was to determine the coverage of maternal vaccination against influenza and pertussis, and the characteristics associated with being vaccinated, in a health area of Catalonia, Spain. Some 36,032 anonymized and computerized clinical records registries of pregnant women from Primary Care Centres (e-CAP database) were analysed, from between 2015 and 2018. Vaccination coverage and the association with sociodemographic variables and clinical conditions were estimated using a Poisson regression model. Maternal vaccination coverage against influenza ranged between 11.9% in 2015 and 6.8% in 2018, following a decreasing trend (p < 0.001). Coverage with the tetanus toxoid, diphtheria toxoid, and acellular pertussis vaccine varied between 49.8% in 2016 and 79.4% in 2018, following an increasing trend (p < 0.001). Having living children and suffering from obesity were factors associated with not being vaccinated against both infections. The predictive variables of vaccination against influenza were diabetes (IRR: 2.17, 95% CI: 1.42−3.30) and asthma (IRR: 2.05, 95% CI: 1.76−2.38); and for pertussis, it was asthma (IRR: 1.10, 95% CI: 1.03−1.17). Different socio-demographic factors and chronic conditions in pregnant women were associated with maternal vaccination, and which will have to be taken into account in clinical practice when implementing strategies to improve the coverage of the programme.


Facial paralysis during air travel: case series and literature review.
We report three cases of recurrent, unilateral facial palsy associated with air travel. The three cases are presented, along with a brief literature review concerning barotrauma and its association with air travel and facial palsy. All three patients experienced unilateral facial paralysis during air travel, accompanied by additional symptoms which varied between cases. Symptoms resolved spontaneously in all cases. Two patients received ventilation tube insertion to prevent further recurrence. Computed tomography scanning revealed no bony defect in two patients, while the third exhibited dehiscence of the facial canal which may have contributed to the condition. Available evidence suggests that eustachian tube dysfunction can contribute to increased pressure within the middle ear, leading to neuropraxia of the facial nerve. Cases of facial paralysis associated with air travel are under-reported. Since there is no evidence-based management protocol for this condition, further investigation of its pathology is encouraged in order to improve our understanding.


Identification of common differentially expressed genes in urinary bladder cancer.
Current diagnosis and treatment of urinary bladder cancer (BC) has shown great progress with the utilization of microarrays. Our goal was to identify common differentially expressed (DE) genes among clinically relevant subclasses of BC using microarrays. BC samples and controls, both experimental and publicly available datasets, were analyzed by whole genome microarrays. We grouped the samples according to their histology and defined the DE genes in each sample individually, as well as in each tumor group. A dual analysis strategy was followed. First, experimental samples were analyzed and conclusions were formulated; and second, experimental sets were combined with publicly available microarray datasets and were further analyzed in search of common DE genes. The experimental dataset identified 831 genes that were DE in all tumor samples, simultaneously. Moreover, 33 genes were up-regulated and 85 genes were down-regulated in all 10 BC samples compared to the 5 normal tissues, simultaneously. Hierarchical clustering partitioned tumor groups in accordance to their histology. K-means clustering of all genes and all samples, as well as clustering of tumor groups, presented 49 clusters. K-means clustering of common DE genes in all samples revealed 24 clusters. Genes manifested various differential patterns of expression, based on PCA. YY1 and NFκB were among the most common transcription factors that regulated the expression of the identified DE genes. Chromosome 1 contained 32 DE genes, followed by chromosomes 2 and 11, which contained 25 and 23 DE genes, respectively. Chromosome 21 had the least number of DE genes. GO analysis revealed the prevalence of transport and binding genes in the common down-regulated DE genes; the prevalence of RNA metabolism and processing genes in the up-regulated DE genes; as well as the prevalence of genes responsible for cell communication and signal transduction in the DE genes that were down-regulated in T1-Grade III tumors and up-regulated in T2/T3-Grade III tumors. Combination of samples from all microarray platforms revealed 17 common DE genes, (BMP4, CRYGD, DBH, GJB1, KRT83, MPZ, NHLH1, TACR3, ACTC1, MFAP4, SPARCL1, TAGLN, TPM2, CDC20, LHCGR, TM9SF1 and HCCS) 4 of which participate in numerous pathways. The identification of the common DE genes among BC samples of different histology can provide further insight into the discovery of new putative markers.


WITHDRAWN: Manfred Zimmermann reaches 75.
This article has been withdrawn consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.


Dynamic skeletal muscle stimulation and its potential in bone adaptation.
To identify mechanotransductive signals for combating musculoskeletal deterioration, it is essential to determine the components and mechanisms critical to the anabolic processes of musculoskeletal tissues. It is hypothesized that the interaction between bone and muscle may depend on fluid exchange in these tissues by mechanical loading. It has been shown that intramedullary pressure (ImP) and low-level bone strain induced by muscle stimulation (MS) has the potential to mitigate bone loss induced by disuse osteopenia. Optimized MS signals, i.e., low-intensity and high frequency, may be critical in maintaining bone mass and mitigating muscle atrophy. The objectives for this review are to discuss the potential for MS to induce ImP and strains on bone, to regulate bone adaptation, and to identify optimized stimulation frequency in the loading regimen. The potential for MS to regulate blood and fluid flow will also be discussed. The results suggest that oscillatory MS regulates fluid dynamics with minimal mechanical strain in bone. The response was shown to be dependent on loading frequency, serving as a critical mediator in mitigating bone loss. A specific regimen of dynamic MS may be optimized in vivo to attenuate disuse osteopenia and serve as a biomechanical intervention in the clinical setting.


Kinematic determinants and physiological response of cross-country skiing at maximal speed.
The scope of the study was to a) transfer the maximal anaerobic running test (MART) to a treadmill-based cross-country roller skiing test protocol for skating and classic style, b) analyze the development and determinants of kinematic and physiological parameters from submaximal to maximal skiing speeds, c) analyze the effects of fatigue on skiing technique, and d) test the hypotheses that maximal skiing speed is related to cycle length and that the fastest skiers show shorter thrust combined with longer swing phases. Up to 24 elite skiers performed MART tests in double poling, diagonal stride and V2 skating, with roller skis on a treadmill. Anthropometrics, blood lactate, HR, and kinematics were determined. When compared with former studies, faster skiing speeds of up to 34% were reported. Skiers improved speed by increasing cycle rate while trying to maintain cycle length. In the diagonal stride and V2 skating at maximal skiing speeds, skiers used contrary technical strategies to maintain the speed, whereas in double poling, a tendency toward an optimum in cycle length and cycle rate was established. Duration for the pole thrusts was around 180 ms for V2 skating and 210 ms for double poling. Highest relation to performance was found for the duration of the swing phases of arms and legs. The increase in skiing speed and cycle length, compared with former studies and the positive relation between swing phase duration, stresses the importance of effective thrust phases within a short period. Therefore, it is recommended to increase the proportion of training aimed at the improvement of specific explosive strength and maximal power to increase the impulse of force.


Developing operator capacity estimates for supervisory control of autonomous vehicles.
This study examined operators' capacity to successfully reallocate highly autonomous in-flight missiles to time-sensitive targets while performing secondary tasks of varying complexity. Regardless of the level of autonomy for unmanned systems, humans will be necessarily involved in the mission planning, higher level operation, and contingency interventions, otherwise known as human supervisory control. As a result, more research is needed that addresses the impact of dynamic decision support systems that support rapid planning and replanning in time-pressured scenarios, particularly on operator workload. A dual screen simulation that allows a single operator the ability to monitor and control 8, 12, or 16 missiles through high level replanning was tested on 42 U.S. Navy personnel. The most significant finding was that when attempting to control 16 missiles, participants' performance on three separate objective performance metrics and their situation awareness were significantly degraded. These results mirror studies of air traffic control that demonstrate a similar decline in performance for controllers managing 17 aircraft as compared with those managing only 10 to 11 aircraft. Moreover, the results suggest that a 70% utilization (percentage busy time) score is a valid threshold for predicting significant performance decay and could be a generalizable metric that can aid in manning predictions. This research is relevant to human supervisory control of networked military and commercial unmanned vehicles in the air, on the ground, and on and under the water.


Aortoiliac CT angiography for planning transcutaneous aortic valve implantation: aortic root anatomy and frequency of clinically significant incidental findings.
The purpose of this article is to assess aortic root and iliofemoral vessel anatomy and the frequency of clinically significant incidental findings on aortoiliac CT angiography (CTA) performed for planning of transcutaneous aortic valve implantation. Aortoiliac CTA studies of 207 patients scheduled for transcutaneous aortic valve implantation were analyzed. Anatomic dimensions relevant to the interventional procedure, including diameter of the aortic annulus and sinus of Valsalva, distance between aortic annulus and coronary ostia, coronary leaflet length, left ventricular outflow tract diameter, and vessel diameter of iliac arteries, were analyzed. Clinically significant incidental findings were recorded. The mean (± SD) maximum and minimum diameters of the aortic annulus were 29 ± 3.9 mm and 23.5 ± 4.1 mm, respectively. The mean distances between aortic annulus and the ostium of the left and right coronary artery were 13.5 ± 3.2 mm and 14.8 ± 3.9 mm, respectively. The mean maximum and minimum diameters of the left ventricular outflow tract were 27 ± 4 mm and 1.9 ± 4 mm, respectively. The mean diameter of the sinus of Valsalva was 33.4 ± 5.1 mm. The mean diameters of the right and left external iliac artery were 8 ± 1 and 8 ± 2 mm, respectively. Almost half the patients (101/207) had clinically significant incidental findings, including noncalcified pulmonary nodules larger than 8 mm (n = 7), pulmonary embolism (n = 3), or aortic aneurysm (n = 12). Aortoiliac CTA provides relevant information on aortic root and iliofemoral vessel anatomy for preinterventional planning. CTA reveals clinically significant incidental findings in a high number of patients considered for transcutaneous aortic valve implantation, which may have a significant impact on patient selection.


[Regression of Hensen's node and axial growth of the embryo].
Hensen's node is the gastrulation center in the avian embryo. It is the homologue of the amphibian dorsal blastopore lip and the zebrafish shield. It contains the progeny of all midline cells (floor plate of the neural tube, notochord and dorsal endoderm). However, microsurgical experiments on Hensen's node allow to think that organizer function is due to an extremely limited region situated in the caudal part of Hensen's node which corresponds to the boundary between prospective axial mesoderm rostrally and paraxial mesoderm caudally. This interface is essential for Hensen's node regression and organization of the caudal part of the body.


Effect of oral l-Glutamine supplementation on Covid-19 treatment.
The aim of this study is to investigate the effect of oral l-Glutamine supplementation on hospitalization time, need for intensive care unit and Coronavirus Disease-19 (Covid-19) mortality. The study included 30 Covid-19 patients using l-Glutamine and 30 Covid-19 patients who did not use l-Glutamine with similar age, gender and clinical status. Diagnostic tests, laboratory examinations, clinical findings and computed thorax tomography imaging of the patients were evaluated. Hospitalization time was 10.4 ± 1.9 days in Covid-19 without L-Glutamine group and 8.9 ± 1.8 days in Covid-19 with L-Glutamine group (p = 0.005). In Covid-19 without the L-Glutamine group, four patients require the ICU though no one in the other group required that (p = 0.038). Only one mortality was observed in Covid-19 without the L-Glutamine group (p = 0.999). Nutritional supplements such as L-Glutamine boost immune system especially by inhibition of inflammatory responses. Our results suggest adding enteral L-glutamine to the normal nutrition in the early period of Covid-19 infection may lead to a shortened hospital stay and lead to less need for ICU. Larger-scale studies are needed to evaluate the effect of adding enteral L-Glutamine to the currently used treatments in the infectious diseases especially like Covid-19.


Manifold enhancement of electron beam induced deposition rate at grazing incidence.
It is shown how a significant drawback of the electron beam induced deposition technique, namely its low deposition rate, can be circumvented. By tilting a sample, a larger part of the primary electron beam energy becomes dissipated closer to the interface. This in turn increases the emission of secondary electrons, largely responsible for the deposition of the adsorbed molecule components on the surface. An order of magnitude increase in the deposition rate is reported in the fabrication of metal nanowires from organic precursor gas.


Comparing the benefits of diet and exercise in the treatment of dyslipidemia.
Lifestyle changes are advocated as a first line of treatment for dyslipidemia. However, few studies have directly compared various combinations of diets and exercise. In a randomized controlled pilot study, we compared the standard lifestyle recommendations (NCEP step I diet with regular exercise) and more intense interventions including the NCEP step I diet with a supervised aerobic exercise program and the step II diet with and without a supervised aerobic exercise program. We measured risk factors, dietary intake, time on treadmill, and health-related quality of life at baseline and after 3 months. Out of 198 eligible subjects, 47 (24%) were willing to participate and 41 completed the study. No significant change were observed with standard lifestyle recommendations. In contrast, participants in the more intense interventions lost weight (-1.7 to -3.7 kg) and reduced their total cholesterol (-4% to -6%), low-density lipoprotein cholesterol (-6%), and systolic blood pressure (-7.3 to -8.8 mmHg). Participants in the exercise program significantly increased their exercise capacity (1.6 to 1.9 METS). Overall, each 10% reduction in body weight was associated with a 7.6% reduction in low-density lipoprotein cholesterol. Standard lifestyle recommendations had little effect on blood lipid levels but more intense lifestyle interventions may be effective at improving blood lipids, other risk factors, and quality of life.


[The pathogenetic bases for chemotherapy in an experimental Salmonella infection].
The effect of etiotropic (polymyxin and adriblastin) and pathogenetic (levamisole and vitamin E) chemotherapy on lipid peroxidation (LPO), phagocyte functional activity and the process and outcomes of Salmonella infection was studied in rabbits. It was shown that development of salmonellosis was accompanied by activation of LPO which was phase-by-phase. There was synchronism in changing of LPO and neutrophilic phagocytic activity. Adriblastin and levamisole stimulated LPO and increased the neutrophilic phagocytic activity. Vitamin E inhibited LPO and had an unfavourable effect on the process and outcomes of the infection. The problem in differential use of the chemotherapeutic drugs with an account of their modulating effect on LPO is discussed.


Inhalation studies with the Göttingen minipig.
A method for inhalative exposure of minipigs to aerosols and gases has been developed. Minipigs are exposed via mask inhalation to the test substance using a computer-controlled exposure system that permits simultaneous exposure of groups of four animals in parallel to different controlled dose levels. We studied inhalation treatment of verapamil, a cardiovascular drug, and show good absorption and favorable pharmacokinetics when compared with iv drug application. The results shown in this study encourage inhalation studies with the Göttingen minipig.


Evaluation of a peer mentoring program for a mature cohort of first-year undergraduate paramedic students.
The purpose of this study was to evaluate the effectiveness of a peer-assisted study session (PASS) program for a large class of Bachelor of Health Science (Paramedic) students. This cohort was made up predominantly of mature aged students who have not undertaken any study for many years. Within a bioscience first-year core subject, student mentees attended PASS sessions on a voluntary basis, with second-year Bachelor of Health Science (Paramedic) students acting as mentors. Mentors were recruited based on their outstanding academic performance in bioscience the previous year and selected based on group and individual interviews. Successful candidates participated in a compulsory 2 days of student mentor training and were supported throughout the program to develop their mentoring skills in both face-to-face workshops and online. Mentee students were allocated to a PASS session with a maximum size of 25 students/group that was facilitated by 2 student mentors. In general, the program was viewed favorably by both mentors and mentees. There was an increase in academic performance and a decrease in the fail rate of the mentee group compared with the cohort of students that did not participate in the PASS program. Importantly, mentees believed that the program improved their study skills and gave them confidence in their approach to studying. This is a significant consideration for the improvement of student transition and retention in a mature aged student cohort.


Activation of protein kinase A-independent pathways by Gs alpha in Drosophila.
One of the best-described transmembrane signal transduction mechanisms is based on receptor activation of the alpha subunit of the heterotrimeric G protein Gs, leading to stimulation of adenylyl cyclase and the production of cAMP. Intracellular cAMP is then thought to mediate its effects largely, if not entirely, by activation of protein kinase A and the subsequent phosphorylation of substrates which in turn control diverse cellular phenomena. In this report we demonstrate, by two different methods, that reduction or elimination of protein kinase A activity had no effect on phenotypes generated by activation of Gs alpha pathways in Drosophila wing epithelial cells. These genetic studies show that the Gs alpha pathway mediates its primary effects by a novel pathway in differentiating, wing epithelial cells. This novel pathway may in part be responsible for some of the complex, cell-specific responses observed following activation of this pathway in different cell types.


The preemptive effect of regional anesthesia on post-cesarean section pain.
The treatment of post-cesarean section (C/S) pain is very important. Since no previous report discussed the preemptive effect of regional anesthesia on post-C/S pain, the present study was undertaken to evaluate the efficacy of the preemptive effect of regional anesthesia on post-C/S pain. Ninety parturients scheduled for C/S were enrolled into one of the three groups (n = 30, per each group). The parturients in group 1 and 2 received spinal anesthesia and epidural anesthesia, respectively, while those in group 3 received general anesthesia for C/S. Postoperative patient-controlled analgesia, by means of intravenous morphine, was used for all paturients to relieve post-C/S pain. The VAS of pain and total morphine consumption were evaluated in all 3 groups of patients. The results showed that groups 1 and 2 consumed less morphine than that of group 3. Also, there was no difference between groups 1 and 2 in the amount of morphine consumed. The incidence of side effects was significantly higher in group 3 than in groups 1 and 2. We demonstrated that spinal or epidural anesthesia reduced the need of parenteral morphine postoperatively when compared with general anesthesia. We suggest that the use of regional anesthesia may provide a better preemptive effect for post-C/S pain.


The oral health of children with clefts--a review.
A review of the studies of the caries prevalence and periodontal health of patients with cleft lip and palate (CLP) revealed that only five investigations of caries prevalence in CLP patients included children. One reported that CLP children did not have a higher caries prevalence in the permanent dentition, whereas more recent studies have reported a higher caries prevalence in both the primary and permanent dentitions of CLP children than in those of noncleft children. However, there is wide variation in the teeth examined and the method of presenting data on caries prevalence. Six papers have reported on the periodontal health of adult CLP patients, and only one has done so on that of children. The adult CLP patients had poorer oral hygiene and more gingivitis, but there is no conclusive evidence that they have a higher risk of developing periodontal disease. No data on the oral hygiene of CLP children were available, but it has been emphasized that they have significantly more gingivitis than noncleft children, especially in the maxillary anterior teeth.