Physical Activity for Cognitive and Mental Health in Youth: A Systematic Review of Mechanisms.
Physical activity can improve cognitive and mental health, but the underlying mechanisms have not been established. To present a conceptual model explaining the mechanisms for the effect of physical activity on cognitive and mental health in young people and to conduct a systematic review of the evidence. Six electronic databases (PubMed, PsycINFO, SCOPUS, Ovid Medline, SportDiscus, and Embase) were used. School-, home-, or community-based physical activity intervention or laboratory-based exercise interventions were assessed. Studies were eligible if they reported statistical analyses of changes in the following: (1) cognition or mental health; and (2) neurobiological, psychosocial, and behavioral mechanisms. Data relating to methods, assessment period, participant characteristics, intervention type, setting, and facilitator/delivery were extracted. Twenty-five articles reporting results from 22 studies were included. Mechanisms studied were neurobiological (6 studies), psychosocial (18 studies), and behavioral (2 studies). Significant changes in at least 1 potential neurobiological mechanism were reported in 5 studies, and significant effects for at least 1 cognitive outcome were also found in 5 studies. One of 2 studies reported a significant effect for self-regulation, but neither study reported a significant impact on mental health. Small number of studies and high levels of study heterogeneity. The strongest evidence was found for improvements in physical self-perceptions, which accompanied enhanced self-esteem in the majority of studies measuring these outcomes. Few studies examined neurobiological and behavioral mechanisms, and we were unable to draw conclusions regarding their role in enhancing cognitive and mental health.


Toxoplasmosis in a post-transplant bronchoalveolar lavage: a case report.
Toxoplasma gondii usually causes an asymptomatic and then latent infection in human adults; however, a potentially fatal disseminated form can occur in immunocompromised patients. Given that the diagnosis of acute Toxoplasma infection, as opposed to latent disease, relies on finding direct evidence of T. gondii infection in tissue, pathologic examination is critical. There have only been a few reports describing the cytomorphology of Toxoplasma in exfoliative cytology, and no reports of the findings in Thin Prep. In this report, we describe a fatal case of toxoplasmosis in a cardiac transplant patient that was diagnosed by respiratory cytopathology. Although the extracellular organisms were well visualized on the Wright-Giemsa stained cytospin, they were only faintly seen on the Pap-stained cytospin trapped within mucin and were not easily appreciated on the ThinPrep slides nor the H&E stained cell block sections. An immunohistochemical stain for Toxoplasma performed on the cell block was strongly positive, and an autopsy performed on the patient confirmed disseminated infection. Our case illustrates that the diagnosis of Toxoplasma in exfoliative cytology specimens can be challenging since organisms are not well visualized on ThinPrep or Pap-stained material; therefore, Wright-Giemsa stained material can be particularly helpful.


Proptosis and hemiplegia as an initial manifestation of multiple myeloma.
Multiple myeloma (MM) is a monoclonal gammopathy, also known as the malignant proliferation of plasma cells, presenting with typical complications such as hypercalcemia, osteolytic bone lesions, anemia, renal insufficiency, and frequent infections. Central nervous system (CNS) involvement in MM in the form of parenchymal involvement is very uncommon and has been reported only in 1% of patients. CNS involvement as an initial presentation is very rare and has poor prognosis. Also specific treatment guidelines do not exist for the treatment of such patients. We present here a case of a 40-year-old female patient, with complaints of headache and left eye proptosis followed by left-sided hemiparesis, who after complete workup was diagnosed as a de novo case of stage III extramedullary MM with CNS involvement. Patient was treated with whole brain radiation followed by BCD regimen (injection of bortezomib, injection of cyclophosphamide, and tablet dexamethasone). After three cycles of chemotherapy, patient succumbed in view of consolidation and renal failure.


The abundance of alpha-tubulin mRNA increases during ciliary regeneration in Tetrahymena, and this occurs independently of the soluble tubulin content.
Control mechanisms of tubulin synthesis are analyzed during ciliary regeneration of the ciliate Tetrahymena. Titration of the alpha-tubulin mRNA concentrations during the regeneration period reveal that enhancement of tubulin synthesis is preceded and accompanied by increased concentrations of tubulin mRNA molecules. Stimulation of tubulin synthesis is independent of the pool size of soluble tubulin molecules, as suggested by at least two independent lines of evidence: First, like cells of normal phenotype a temperature sensitive size mutant enhances tubulin synthesis as well as tubulin mRNA concentration during ciliary regeneration, although these large mutant cells have a much higher concentration and amount of soluble tubulin molecules in the cytoplasm. Second, slowly regenerating cells of normal phenotype shift-up their concentration of tubulin mRNA molecules already before a time, when ciliary outgrowth might cause a significant depletion of the pool of soluble tubulin molecules. Thus, neither an induction of tubulin synthesis nor an increase in tubulin mRNA molecules is mediated via changes in the pool size of soluble tubulin molecules.


A Bacterial β1-3-Galactosyltransferase Enables Multigram-Scale Synthesis of Human Milk Lacto-N-tetraose (LNT) and Its Fucosides.
β1-3-Linked galactosides such as Galβ1‒3GlcNAcβOR are common carbohydrate motifs found in human milk oligosaccharides (HMOSs), glycolipids, and glycoproteins. Efficient and scalable enzymatic syntheses of these structures have proven challenging due to the lack of access to a highly active β1‒3-galactosyltransferase (β3GalT) in large amounts. Previously reported E. coli β3GalT (EcWbgO) has been identified as a limiting factor for producing a β1-3-galactose-terminated human milk oligosaccharide lacto-N-tetraose (LNT) by fermentation. Here we report the identification of an EcWbgO homolog from C. violaceum (Cvβ3GalT) which showed a high efficiency in catalyzing the formation of LNT from lacto-N-triose (LNT II). With the highly active Cvβ3GalT, multigram-scale (>10 gram) synthesis of LNT from lactose was achieved using a sequential one-pot multienzyme (OPME) glycosylation process. The access to Cvβ3GalT enabled enzymatic synthesis of several fucosylated HMOSs with or without further sialylation including LNFP II, S-LNF II, LNDFH I, LNFP V, and DiFuc-LNT. Among these, LNFP V and DiFuc-LNT would not be accessible by enzymatic synthesis if an active β3GalT were not available.


Depolarising primate experimentation: the good, the bad and the determined.
Until I began working at FRAME, I was not really aware of the Three Rs or FRAME's work to promote and progress them. It soon became clear to me that it made scientific sense and that it could make a difference to many thousands of laboratory animals. As an alternatives advocate, I regularly experience optimism, frustration and determination. This is illustrated most clearly by the primate research dilemma. Here, I describe the positive and negative experiences I have had whilst working toward the goal of replacing primate experiments, and how these have led me to undertake a multidisciplinary PhD project on primate use in biomedical research. The aim is to examine how research scientists view the opportunities and challenges involved in the use of primates in biomedical science, and to investigate the feasibility of phasing out their use. As a result of the research, I hope to provide a new perspective, to depolarise the debate and bring about a constructive dialogue between all parties as to how and when primate research could be replaced.


Evidence for human-mediated dispersal of exotic earthworms: support for exploring strategies to limit further spread.
As potent ecosystem engineers, non-native earthworms are altering the fundamental structure and function of previously earthworm-free cold-temperate hardwood forests in North America. Discarded earthworms used for fishing bait has been presumed to be an important vector for the continued spread of non-native earthworms because epicentres of invasion often include boat landings, lakeshores and roads. However, controversy has remained about the overall importance of human-mediated spread vs. natural expansion of established earthworm populations. In this issue of Molecular Ecology, Cameron et al. explore the continued role of humans in dispersing non-native earthworms.


Overlapping juvenile idiopathic arthritis and systemic lupus erythematosus: a case report.
Hereby, we report the case of a 12-year-old girl developing oligoarthritis and progressing into a polyarticular form. Rheumatoid factor was positive, and juvenile idiopathic arthritis (JIA) was diagnosed. After a poor response to DMARDs, an anti-TNF agent (infliximab) was initiated, but to be discontinued due to an allergic reaction. The same complication was observed with the fully human derivative, adalimumab. At the age of 22, the patient presented septicemia with severe anemia and subsequent development of leukopenia, myocarditis with heart failure, and ANA, aSm, aSS-A, aCL positives, and nephrotic syndrome. These new clinical manifestations fulfilled the classification criteria for the diagnosis of systemic lupus erythematosus. Due to the poor therapeutic responses for both diseases, alternative medical options have to be considered, such as targeted therapy with anti-CD20 or interleukin-6 receptor antagonist monoclonal antibodies. This patient may also be a candidate for autologous hemopoietic stem cell transplantation.


Adrenomedullin improves fertility and promotes pinopodes and cell junctions in the peri-implantation endometrium.
Implantation is a complex event demanding contributions from both embryo and endometrium. Despite advances in assisted reproduction, endometrial receptivity defects persist as a barrier to successful implantation in women with infertility. We previously demonstrated that maternal haploinsufficiency for the endocrine peptide adrenomedullin (AM) in mice confers a subfertility phenotype characterized by defective uterine receptivity and sparse epithelial pinopode coverage. The strong link between AM and implantation suggested the compelling hypothesis that administration of AM prior to implantation may improve fertility, protect against pregnancy complications, and ultimately lead to better maternal and fetal outcomes. Here, we demonstrate that intrauterine delivery of AM prior to blastocyst transfer improves the embryo implantation rate and spacing within the uterus. We then use genetic decrease-of-function and pharmacologic gain-of-function mouse models to identify potential mechanisms by which AM confers enhanced implantation success. In epithelium, we find that AM accelerates the kinetics of pinopode formation and water transport and that, in stroma, AM promotes connexin 43 expression, gap junction communication, and barrier integrity of the primary decidual zone. Ultimately, our findings advance our understanding of the contributions of AM to uterine receptivity and suggest potential broad use for AM as therapy to encourage healthy embryo implantation, for example, in combination with in vitro fertilization.


The deteriorating ward patient: a Swedish-Australian comparison.
Most centres in Europe have not introduced a rapid response team (RRT), partly because of concerns that data from other health-care systems may not be relevant. We tested whether patient characteristics and outcomes for deteriorating patients differ between two health-care systems separated by distance and culture. We obtained data from 3,063 RRT calls: 815 calls at Karolinska University Hospital (Sweden) and 2,248 calls at Austin Hospital (Australia) and compared demographic and clinical data, as well as outcomes for patients reviewed by a RRT. At Karolinska, 46.9% of patients were female compared with 45.1% at Austin. Mean age was 66.5 years versus 69.4 years. The unit of admission was surgical/medical in 49.1%/50.9% versus 48.8%/51.1% of patients, respectively. Overall, 56.7% versus 55.8% of the calls were out-of-hours (1700-0800 hours). There was a predominance of respiratory triggers at both centres and the "worried" criterion was frequently used in both hospitals (17.2% versus 14.4%) as a trigger for RRT activation. Overall, 30-day mortality was 27.7% versus 29.4% and allocation of Limitations of Medical Treatment (LOMT) orders was 34.2% versus 30.8%. The allocation of LOMT orders was influenced by the RRT in 14.4% versus 12.6% of cases. In two different health-care systems separated by geography, language, culture and organizational features, the characteristics of deteriorating ward patients, their disposal and outcomes were similar, suggesting that the care of the deteriorating ward patient is a global problem in modern hospitals and confirming that their hospital mortality is high.


Hormone-initiated maturation of rat liver mitochondria after birth.
1. The injection of adrenaline, glucagon or cyclic AMP into foetal rats in utero initiates the maturation of energy transduction in rat liver mitochondria before birth. 2. The injection of the beta-blocker, propranolol, prevents this maturation process. 3. The maturation of mitochondrial energy transduction is measured in terms of the increase in the respiratory control index and mitochondrial adenine nucleotide concentration. 4. It is postulated that the actions of the hormones, acting through cyclic AMP, affect glycogenolysis and glycolysis to give rise to transient localized high concentrations of ATP. 5. It is the ATP that acts as the molecular trigger, effecting mitochondrial maturation.


Functional conservation in genes and pathways linking ageing and immunity.
At first glance, longevity and immunity appear to be different traits that have not much in common except the fact that the immune system promotes survival upon pathogenic infection. Substantial evidence however points to a molecularly intertwined relationship between the immune system and ageing. Although this link is well-known throughout the animal kingdom, its genetic basis is complex and still poorly understood. To address this question, we here provide a compilation of all genes concomitantly known to be involved in immunity and ageing in humans and three well-studied model organisms, the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the house mouse Mus musculus. By analysing human orthologs among these species, we identified 7 evolutionarily conserved signalling cascades, the insulin/TOR network, three MAPK (ERK, p38, JNK), JAK/STAT, TGF-β, and Nf-κB pathways that act pleiotropically on ageing and immunity. We review current evidence for these pathways linking immunity and lifespan, and their role in the detrimental dysregulation of the immune system with age, known as immunosenescence. We argue that the phenotypic effects of these pathways are often context-dependent and vary, for example, between tissues, sexes, and types of pathogenic infection. Future research therefore needs to explore a higher temporal, spatial and environmental resolution to fully comprehend the connection between ageing and immunity.


Leprosy and social deprivation: Definition of priority areas in an endemic state Northeastern Brazil.
Leprosy is a disease that reserves close relation with social and economic conditions. Brazil is the only country that has not yet reached the goal of eliminating the disease as a public health problem. This study aimed to analyze social deprivation in the municipalities of Bahia and its relation with the detection of new cases of leprosy in the population. It is an ecological study conducted in the state of Bahia, from 2001 to 2015. Variables analyzed: detection rate of new cases, social deprivation index (SDI) and Hansen's disease in children under 15 years of age. The SDI was built on four variables: socioeconomic performance index, per capita income, proportion of extremely poor, and household density. For spatial analysis, local empirical bayesian modeling and global and local Moran statistics were used. Statistical analysis used multivariate, spatial and logistic regression, odds ratio calculation and analysis of variance. Leprosy showed heterogeneous distribution in the state, with concentration in the north-west and south axis. 60.4% (n = 252) of the municipalities presented very low life conditions. An association was observed between living conditions and the detection of leprosy, with higher coefficients in the municipality group with better living conditions (p < 0.001). It was concluded that the worst conditions acted as an impediment to the diagnosis, while increasing the risk of illness. Good conditions have the opposite effect.


Considerations on the design of lipid-based mRNA vaccines against cancer.
Throughout the last decades, mRNA vaccines have been developed as a cancer immunotherapeutic and the technology recently gained momentum during the COVID-19 pandemic. Recent promising results obtained from clinical trials investigating lipid-based mRNA vaccines in cancer therapy further highlighted the potential of this therapy. Interestingly, while the technologies being used in authorized mRNA vaccines for the prevention of COVID-19 are relatively similar, mRNA vaccines in clinical development for cancer vaccination show marked differences in mRNA modification, lipid carrier, and administration route. In this review, we describe findings on how these factors can impact the potency of mRNA vaccines in cancer therapy and provide insights into the complex interplay between them. We discuss how lipid carrier composition can affect passive targeting to immune cells to improve the efficacy and safety of mRNA vaccines. Finally, we summarize strategies that are established or still being explored to improve the efficacy of mRNA cancer vaccines and include next-generation vaccines that are on the horizon in clinical development.


Exploring the association of PM2.5 with lung cancer incidence under different climate zones and socioeconomic conditions from 2006 to 2016 in China.
Air pollution generated by urbanization and industrialization poses a significant negative impact on public health. Particularly, fine particulate matter (PM2.5) has become one of the leading causes of lung cancer mortality worldwide. The relationship between air pollutants and lung cancer has aroused global widespread concerns. Currently, the spatial agglomeration dynamic of lung cancer incidence (LCI) has been seldom discussed, and the spatial heterogeneity of lung cancer's influential factors has been ignored. Moreover, it is still unclear whether different socioeconomic levels and climate zones exhibit modification effects on the relationship between PM2.5 and LCI. In the present work, spatial autocorrelation was adopted to reveal the spatial aggregation dynamic of LCI, the emerging hot spot analysis was introduced to indicate the hot spot changes of LCI, and the geographically and temporally weighted regression (GTWR) model was used to determine the affecting factors of LCI and their spatial heterogeneity. Then, the modification effects of PM2.5 on the LCI under different socioeconomic levels and climatic zones were explored. Some findings were obtained. The LCI demonstrated a significant spatial autocorrelation, and the hot spots of LCI were mainly concentrated in eastern China. The affecting factors of LCI revealed an obvious spatial heterogeneity. PM2.5 concentration, nighttime light data, 2 m temperature, and 10 m u-component of wind represented significant positive effects on LCI, while education-related POI exhibited significant negative effects on LCI. The LCI in areas with low urbanization rates, low education levels, and extreme climate conditions was more easily affected by PM2.5 than in other areas. The results can provide a scientific basis for the prevention and control of lung cancer and related epidemics.


[Efficacy of radiotherapy of cancer of the mouth mucosa].
An analysis of 10-year experience of a radiological department (962 patients) indicated late admission of oral mucosa cancer patients for specialized treatment: 75-85% of the patients were admitted with Stage II-IV disease. The assessment of the efficacy of radiotherapy according to the 3 and 5-year survival rates showed that better results were obtained for buccal mucosa cancer and the worst for mouth fundus cancer. Three-year survival rates could be considered sufficient for the assessment of buccal cancer therapy whereas a 5-year period was necessary for the rest of the cancer sites. Therapeutic results and stage were well correlated; in all the sites the results were worse in patients with Stage III-IV disease. Regional metastases are a poor prognostic sign, particularly fixed metastases in patients with tongue and mouth fundus cancer. Combined therapy turned out to be the most effective in tongue cancer. In different variants of dose delivery in time the most favorable results were obtained with small fractionation (a conventional course). However it should be noted that a split course was usually applied to weak elderly patients with advanced stages of disease.


Price, familiarity, and availability determine the choice of drug - a population-based survey five years after generic substitution was introduced in Finland.
Mandatory generic substitution (GS) was introduced in Finland at the beginning of April 2003. However, individual patients or physicians may forbid the substitution. GS was a significant change for Finnish medicine users. It was thought it would confuse people when the names, colors, packages, etc., changed. The purpose of this study was to explore what medicine-related factors influence people's choice of prescription drugs five years after generic substitution was introduced in Finland. A population survey was carried out during the autumn of 2008. A random sample was drawn from five mainland counties. A questionnaire was mailed to 3000 people at least 18 years old and living in Finland. The questionnaire consisted of both structured and open-ended questions. Factors that influenced the subjects' choice of medicines were asked with a structured question containing 11 propositions. Descriptive statistical analyses were performed. In total, 1844 questionnaires were returned (response rate, 62%). The percentage of female respondents was 55%. Price, availability, and familiarity were the three most important factors that influenced the choice of medicines. For the people who had refused GS, the familiarity of the medicine was the most important factor. For the subjects who had allowed GS and for those who had both refused and allowed GS, price was the most important factor. The present study shows that price, familiarity, and availability were important factors in the choice of prescription medicines. The external characteristics of the medicines, for instance the color and shape of the tablet/capsule or the appearance of the package, were not significant characteristics for people.


Novel allelic variation in the Phospholipase D alpha1 gene (OsPLDα1) of wild Oryza species implies to its low expression in rice bran.
Rice bran, a by-product after milling, is a rich source of phytonutrients like oryzanols, tocopherols, tocotrienols, phytosterols, and dietary fibers. Moreover, exceptional properties of the rice bran oil make it unparalleled to other vegetable oils. However, a lipolytic enzyme Phospholipase D alpha1 (OsPLDα1) causes rancidity and 'stale flavor' in the oil, and thus limits the rice bran usage for human consumption. To improve the rice bran quality, sequence based allele mining at OsPLDα1 locus (3.6 Kb) was performed across 48 accessions representing 11 wild Oryza species, 8 accessions of African cultivated rice, and 7 Oryza sativa cultivars. From comparative sequence analysis, 216 SNPs and 30 InDels were detected at the OsPLDα1 locus. Phylogenetic analysis revealed 20 OsPLDα1 cDNA variants which further translated into 12 protein variants. The O. officinalis protein variant, when compared to Nipponbare, showed maximum variability comprising 22 amino acid substitutions and absence of two peptides and two β-sheets. Further, expression profiling indicated significant differences in transcript abundance within as well as between the OsPLDα1 variants. Also, a new OsPLDα1 transcript variant having third exon missing in it, Os01t0172400-06, has been revealed. An O. officinalis accession (IRGC101152) had lowest gene expression which suggests the presence of novel allele, named as OsPLDα1-1a (GenBank accession no. MF966931). The identified novel allele could be further deployed in the breeding programs to overcome rice bran rancidity in elite cultivars.


Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy.
We sought to determine predictors of adverse neonatal outcomes in women with intrahepatic cholestasis of pregnancy (ICP). This study was a multicenter retrospective cohort study of all women diagnosed with ICP across 5 hospital facilities from January 2009 through December 2014. Obstetric and neonatal complications were evaluated according to total bile acid (TBA) level. Multivariable logistic regression models were developed to evaluate predictors of composite neonatal outcome (neonatal intensive care unit admission, hypoglycemia, hyperbilirubinemia, respiratory distress syndrome, transient tachypnea of the newborn, mechanical ventilation use, oxygen by nasal cannula, pneumonia, and stillbirth). Predictors including TBA level, hepatic transaminase level, gestational age at diagnosis, underlying liver disease, and use of ursodeoxycholic acid were evaluated. Of 233 women with ICP, 152 women had TBA levels 10-39.9 μmol/L, 55 had TBA 40-99.9 μmol/L, and 26 had TBA ≥100 μmol/L. There was no difference in maternal age, ethnicity, or prepregnancy body mass index according to TBA level. Increasing TBA level was associated with higher hepatic transaminase and total bilirubin level (P < .05). TBA levels ≥100 μmol/L were associated with increased risk of stillbirth (P < .01). Increasing TBA level was also associated with earlier gestational age at diagnosis (P < .01) and ursodeoxycholic acid use (P = .02). After adjusting for confounders, no predictors were associated with composite neonatal morbidity. TBA 40-99.9 μmol/L and TBA ≥100 μmol/L were associated with increased risk of meconium-stained amniotic fluid (adjusted odds ratio, 3.55; 95% confidence interval, 1.45-8.68 and adjusted odds ratio, 4.55; 95% confidence interval, 1.47-14.08, respectively). In women with ICP, TBA level ≥100 μmol/L was associated with increased risk of stillbirth. TBA ≥40 μmol/L was associated with increased risk of meconium-stained amniotic fluid.


Influence of cocaine on ruptured intracranial aneurysms: a case control study of poor prognostic indicators.
The purpose of this study was to determine whether cocaine use is a significant prognostic factor for outcome measures such as Hunt and Hess grade and Glasgow Outcome Scale (GOS) score among patients presenting with ruptured intracranial aneurysms (IAs). The authors performed a MEDLINE/PubMed search for cases of ruptured IAs associated with cocaine use. Fourteen cases from the authors' experience were combined with 50 from a literature review, for a total of 64 cases associated with cocaine use. These 64 cases were compared with 65 cases without cocaine use (controls), which had been obtained from an aneurysm database. Logistic regression analysis was performed to determine significant prognostic factors for a poor Hunt and Hess grade and a poor GOS score, and a general linear model was applied to identify significant factors for these measures among cocaine users. There were 40 women in each group. The mean age was 32.3 +/- 8.1 years in the cocaine group and 49.7 +/- 10.6 years in the control group; thus, patients in the cocaine group were significantly younger (p < 0.01). Cocaine was snorted in 21% of cases, smoked in 55%, and intravenously injected or taken in through a combination of routes in 24%. Fifty-one percent of cocaine users and 7.7% of nonusers presented with a poor GOS score (p < 0.01). Fifty-six percent had ictus during cocaine abuse. At the end of a 30-day follow-up, 51% of the patients in the cocaine group had a good GOS score compared with 92% in the control group (p < 0.01). Controlling for the effects of other significant factors, cocaine use had a significant effect on Hunt and Hess grade (p < 0.03) and GOS score (p < 0.01). The odds of having a poor Hunt and Hess grade among cocaine users were 4.2 times greater than those in nonusers, and the odds of having a poor GOS score among cocaine users were 38.8 times greater. Aneurysms were significantly smaller and ruptured at a younger age among cocaine users compared with nonusers. Although the poor clinical grade was not significantly different between the 2 groups, outcome was significantly worse in cocaine users.


Two alternative methods for the measurement of MZ distance on a hip radiograph.
The aim of this study was to assess the use of two alternative measurement methods for the MZ distance, the distance between the acetabular centre (M) and the femoral head centre (Z), on an anteroposterior hip radiograph. The MZ distance was measured in 900 normal and 34 dysplastic adult hips by using the classic method (MZ-c) and two alternative methods (MZ-m and MZ-x). MZ-m utilized the vectorial distance between points M and Z, like MZ-c, but was expressed as a positive or negative value according to the localization of the points with respect to each other. MZ-x was the projected distance between points M and Z on the x-axis, which was the line perpendicular to the two parallel lines passing through points M and Z, and was expressed as a positive or negative value according to the localization of the points with respect to each other. There was a significant correlation between the centre-edge angle and the three measurement methods in both normal and dysplastic hips. The lowest normal limits for MZ-m and MZ-x in adult hips were considered to be -3 mm and -2 mm, respectively (point Z is lateral to point M). Intraobserver and interobserver measurement variations of both methods were less than 2 mm. Both alternative methods were considered more useful than the classic one in the exact determination of the distance between the centres of the femoral head and the acetabulum.


Associations between self-reported diabetes and 78 circulating markers of inflammation, immunity, and metabolism among adults in the United States.
Inflammation is increasingly thought to be associated with diabetes; however, only a few inflammation markers have been assessed concurrently in relation to history of diabetes. In the most comprehensive evaluation of inflammation markers and diabetes to date using a Luminex bead-based assay, we measured 78 inflammation-, immune-, and metabolic-related markers detectable in at least 10% of serum samples collected from participants from the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) screening trial (n = 1,814). At baseline, 6.6% (n = 120) of PLCO participants self-reported a history of diabetes. Cross-sectional associations between these markers and self-reported diabetes were assessed using weighted logistic regression adjusting for sex, smoking status, blood draw age and year, body mass index, and cohort sub-study. Including chemokines [C-C motif ligand (CCL) 19, CCL20, CCL21, C-X-C motif ligand (CXCL) 6, CXCL10, and CXCL11] and soluble cytokine and chemokine receptors [soluble (s) interleukin (IL) 6 receptor (R), soluble tumor necrosis factor receptor (sTNFR) 1, sTNFR2, and sIL-R2], ten inflammation-related markers, were nominally associated with diabetes (P<0.05). In addition to these associations, higher levels of insulin, gastric inhibitory polypeptide, and pancreatic polypeptide remained significantly associated with self-reported diabetes with a false discovery rate <5%, indicating that the assay was able to detect markers associated with diabetes. In summary, self-reported diabetes was nominally associated with circulating cytokines, chemokines, and soluble cytokine and chemokine receptors in the most expansive examination of diabetes and inflammation- and immune-related markers to date. These results highlight the need to explore in future prospective studies the role of inflammation markers in diabetes.


Distinct functions and requirements for the Cys-His boxes of the human immunodeficiency virus type 1 nucleocapsid protein during RNA encapsidation and replication.
The process of retroviral RNA encapsidation involves interaction between trans-acting viral proteins and cis-acting RNA elements. The encapsidation signal on human immunodeficiency virus type 1 (HIV-1) RNA is a multipartite structure composed of functional stem-loop structures. The nucleocapsid (NC) domain of the Gag polyprotein precursor contains two copies of a Cys-His box motif that have been demonstrated to be important in RNA encapsidation. To further characterize the role of the Cys-His boxes of the HIV-1 NC protein in RNA encapsidation, the relative efficiency of RNA encapsidation for virus particles that contained mutations within the Cys-His boxes was measured. Mutations that disrupted the first Cys-His box of the NC protein resulted in virus particles that encapsidated genomic RNA less efficiently and subgenomic RNA more efficiently than did wild-type virus. Mutations within the second Cys-His box did not significantly affect RNA encapsidation. In addition, a full complement of wild-type NC protein in virus particles is not required for efficient RNA encapsidation or virus replication. Finally, both Cys-His boxes of the NC protein play additional roles in virus replication.


Alumina and zirconia ceramics in joint replacements.
Ceramic biomaterials have gained widespread use in arthroprostheses joints. Ceramic oxides including alumina as á -corundum Al2 O3 and zirconia, as yttria-stabilised zirconia polycrystals, were used in large number of patients, especially in the manufacture of ball heads for hip replacements. The experience and the feedbacks gathered in more than 30-year clinical use of alumina, and 15-year use of zirconia are reviewed. The results of in vitro and in vivo studies on the biocompatibility of alumina and zirconia ceramics are analyzed as well as the studies on carcinogenicity. (Journal of Applied Biomaterials & Biomechanics 2003; 1: 19-32).


Why did Swiss citizens refuse a comprehensive second-hand smoke ban?
The ill effects of second-hand smoke are now well documented. To protect the population from exposure to tobacco smoke, comprehensive smoking bans are necessary as expressed in the WHO Framework Convention on Tobacco Control and its guidelines. Switzerland has only a partial smoking ban full of exceptions which has been in effect since 2010, which reproduces the so-called Spanish model. In September 2012, the Swiss citizens refused a proposal for a more comprehensive ban. This case study examines the reasons behind this rejection and draws some lessons that can be learnt from it.


Mercury levels and trends (1993-2009) in bream (Abramis brama L.) and zebra mussels (Dreissena polymorpha) from German surface waters.
Mercury concentrations have been analysed in bream (Abramis brama L.) and zebra mussels (Dreissena polymorpha) collected at 17 freshwater sites in Germany from 1993-2009 and 1994-2009, respectively, within the German Environmental Specimen programme. Mercury concentrations in bream ranged from 21 to 881 ng g(-1) wet weight with lowest concentrations found at the reference site Lake Belau and highest in fish from the river Elbe and its tributaries. Statistical analysis revealed site-specific differences and significant decreasing temporal trends in mercury concentrations at most of the sampling sites. The decrease in mercury levels in bream was most pronounced in fish from the river Elbe and its tributary Mulde, while in fish from the river Saale mercury levels increased. Temporal trends seem to level off in recent years. Mercury concentrations in zebra mussels were much lower than those in bream according to their lower trophic position and varied by one order of magnitude from 4.1 to 42 ng g(-1) wet weight (33-336 ng g(-1) dry weight). For zebra mussels, trend analyses were performed for seven sampling sites at the rivers Saar and Elbe of which three showed significant downward trends. There was a significant correlation of the geometric mean concentrations in bream and zebra mussel over the entire study period at each sampling site (Pearson's correlation coefficient=0.892, p=0.00002). A comparison of the concentrations in bream with the environmental quality standard (EQS) of 20 ng g(-1) wet weight set for mercury in biota by the EU showed that not a single result was in compliance with this limit value, not even those from the reference site. Current mercury levels in bream from German rivers exceed the EQS by a factor 4.5-20. Thus, piscivorous top predators are still at risk of secondary poisoning by mercury exposure via the food chain. It was suggested focusing monitoring of mercury in forage fish (trophic level 3 or 4) for compliance checking with the EQS for biota and considering the age dependency of mercury concentrations in fish in the monitoring strategy.


[A modern example of anthropogenic mummification from Savoca].
The Savoca mummies are probably the best known Sicilian collection of mummified human remains after those from Palermo. The 18th century subterranean chamber located in the Chiesa dei Cappuccini holds several preserved bodies, contained in either wall niches or coffins. A recent detailed inspection allowed the authors to determine that such corpses underwent spontaneous desiccation after being placed in the wall niches situated in the crypt beneath the Cathedral of Savoca. However, one unidentified specimen, belonging to an adult male and tentatively dated to the second half of the 19th century, shows clear signs of an artificial intervention aimed at preventing the decay of the cadaver. In addition, two skulls, located in the columbaria above the wall niches, show craniotomy, indicating that some of the remains were anthropogenically mummified. The case described seems to suggest that the traditional embalming techniques were still in use in the late Modern Era, despite the development of innovative methods of intra-arterial injection.


Medical cannabis oil for benign essential blepharospasm: a prospective, randomized controlled pilot study.
To examine the efficacy and safety of medical cannabis in benign essential blepharospasm (BEB). This is a prospective, double-blind, placebo-controlled study. All consecutive adult BEB patients who had been treated with BTX-A injections without success between 3/2019 and 2/2020 were recruited. The study patients were randomly allocated into a treatment and a control (placebo) group in a 1:1 ratio. The treatment group used cannabis drops and the control group used cannabis oil drops during the first 6 weeks of the study, and both groups were treated with the medical cannabis drops during the second 6 weeks. The cannabis dose was gradually increased for each patient depending upon effect and tolerability. Three patients were included in each group (treatment and control groups). The mean duration of spasm attack during the first 6 weeks was 4.29 min in the treatment group and 73.9 min in the placebo group (P < 0.01). During the last 6 weeks, the treatment group used an average of 6.27 drops and the placebo group used an average of 5.36 drops (P = 0.478). There were 61 spasm events in the treatment group and 94 spasm events in the placebo group (P = 0.05). The mean duration of spasm attack was 1.77 and 8.96 min, respectively (P < 0.01). The side effects were mild, and they included general fatigue, dry mouth, and insomnia. Medical cannabis can be an effective and safe treatment for BEB as a second line after BTX-A injections when used for 3 months. No significant ocular or systemic side effects was associated with the treatment.


Implications of the gas compositional measurements of pioneer venus for the origin of planetary atmospheres.
Comparisons are made between the volatile inventories of the terrestrial planets, including Pioneer Venus data, and the predictions of three classes of theories for the origin of planetary atmospheres. Serious difficulties arise for the primary atmosphere and external source hypotheses. The grain accretion hypothesis can account for the trends in the volatile inventory from Venus to Earth to Mars, if volatiles were incorporated into planet-forming grains at nearly the same temperature for all of these planets, but at systematically lower pressures in the regions of planet formation farther from the center of the solar nebula.


FDA Approval Summary: Tucatinib with Trastuzumab for Advanced Unresectable or Metastatic, Chemotherapy Refractory, HER2-Positive RAS Wild-Type Colorectal Cancer.
On January 19, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Approval was based on the pooled analysis of patients receiving tucatinib in combination with trastuzumab in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. The primary endpoint was overall response rate (ORR) by RECIST 1.1 as per blinded central review committee (BIRC) assessment. The main secondary endpoint was duration of response (DOR) per BIRC assessment. Eighty-four eligible patients received the combination tucatinib and trastuzumab. With a median follow-up of 16 months, the ORR was 38% [95% confidence interval (CI): 28-49] and median DOR was 12.4 months (95% CI: 8.5-20.5); 81% of responders had a response lasting more than 6 months. The most common adverse reactions observed in at least 20% of patients receiving tucatinib in combination with trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and fever. FDA concluded that the magnitude of ORR and durable responses observed in patients treated with tucatinib in combination with trastuzumab in the MOUNTAINEER trial are clinically meaningful, particularly in the context of a disease with estimated survival of 6-7 months with available therapy. This is the first approval for the subset of patients with HER2-positive colorectal cancer. This article summarizes the FDA's thought process and review of the data supporting this accelerated approval.


Gene expression variation to predict 10-year survival in lymph-node-negative breast cancer.
It is of great significance to find better markers to correctly distinguish between high-risk and low-risk breast cancer patients since the majority of breast cancer cases are at present being overtreated. 46 tumours from node-negative breast cancer patients were studied with gene expression microarrays. A t-test was carried out in order to find a set of genes where the expression might predict clinical outcome. Two classifiers were used for evaluation of the gene lists, a correlation-based classifier and a Voting Features Interval (VFI) classifier. We then evaluated the predictive accuracy of this expression signature on tumour sets from two similar studies on lymph-node negative patients. They had both developed gene expression signatures superior to current methods in classifying node-negative breast tumours. These two signatures were also tested on our material. A list of 51 genes whose expression profiles could predict clinical outcome with high accuracy in our material (96% or 89% accuracy in cross-validation, depending on type of classifier) was developed. When tested on two independent data sets, the expression signature based on the 51 identified genes had good predictive qualities in one of the data sets (74% accuracy), whereas their predictive value on the other data set were poor, presumably due to the fact that only 23 of the 51 genes were found in that material. We also found that previously developed expression signatures could predict clinical outcome well to moderately well in our material (72% and 61%, respectively). The list of 51 genes derived in this study might have potential for clinical utility as a prognostic gene set, and may include candidate genes of potential relevance for clinical outcome in breast cancer. According to the predictions by this expression signature, 30 of the 46 patients may have benefited from different adjuvant treatment than they received.


Vitamin E as adjuvant treatment for urinary tract infection in girls with acute pyelonephritis.
Vitamin E is a fat-soluble vitamin that functions as an antioxidant. The aim of this study was to investigate the effects of vitamins E supplementation in combination with antibiotics for the treatment of girls with acute pyelonephritis. This double-blinded randomized controlled trial was conducted on 152 girls aged 5 to 12 years with a first acute pyelonephritis episode based on technetium Tc 99m dimercaptosuccinic acid (99mTc-DMSA). They were randomized to receive a 14-day treatment with only antibiotics (control group; n = 76) and 14-day treatment with supplements of vitamin E (intervention group; n = 76) in addition to the antibiotics. Patients' clinical symptoms were monitored for 14 days and urine culture was performed 3 to 4 days and 7 to 10 days after the start of the treatment and its completion, respectively. All of the girls once underwent DMSA scan 4 to 6 months after the treatment. During the follow-up days, the mean frequency of fever (P = .01), urinary frequency (P = .001), urgency (P = .003), dribbling (P = .001), and urinary incontinence (P = .006) were significantly lower in the intervention group compared to the control group. There was no significant difference in the results of urine culture 3 to 4 days after the start of treatment (P = .16) and 7 to 10 days after its termination (P = .37). There was also no significant difference between the results of DMSA scan 4 to 6 months after the start of treatment (P = .31). Vitamin E supplementation has a significant effect in ameliorating sign and symptoms of UTI. However, further studies are recommended to confirm these findings.


Seroepidemiologic study on Lyme borreliosis in the Lublin region.
The frequency of anti-Borrelia burgdorferi antibodies in human sera of various groups of people from the Lublin region was studied. In the indirect immunofluorescence test (IFT) sera from 836 forestry workers and 56 farmers occupationally exposed to ticks were examined. Fifty healthy blood donors from the city of Lublin were examined as a control group. Forestry workers showed positive response in 26%, whereas farmers in 11% and the control group in 6%. In ELISA test, sera from 44 forestry workers, 217 farmers, 458 patients from the dermatologic and neurologic clinics, and 50 blood donors (controls) were examined. A positive response was found in 38.6% of forestry workers, 28.1% of farmers, 12.2% of patients of the neurologic clinic, 27.1% of patients of the dermatologic clinic and in 6% of controls. During this study, in one of an forestry workers the diagnosis of Lyme borreliosis as the occupational disease was clinically confirmed. High percent of anti-Borrelia burgdorferi antibodies found in people exposed to ticks may suggest that Borrelia burgdorferi is widespread in the forest environment of eastern Poland and that infection often has an occupational character.


Electrochemical protection of thin film electrodes in solid state nanopores.
Solid state nanopores are a core element of next-generation single molecule tools in the field of nano-biotechnology. Thin film electrodes integrated into a pore can interact with charges and fields within the pore. In order to keep the nanopore open and thus functional electrochemically induced surface alteration of electrode surfaces and bubble formation inside the pore have to be eliminated. This paper provides electrochemical analyses of nanopores drilled into TiN membranes which in turn were employed as thin film electrodes. We studied physical pore integrity and the occurrence of water decomposition yielding bubble formation inside pores by applying voltages between -4.5 and +4.5 V to membranes in various protection stages continuously for up to 24 h. During potential application pores were exposed to selected electrolyte-solvent systems. We have investigated and successfully eliminated electrochemical pore oxidation and reduction as well as water decomposition inside nanopores of various diameters ranging from 3.5 to 25 nm in 50 nm thick TiN membranes by passivating the nanopores with a plasma-oxidized layer and using a 90% solution of glycerol in water as KCl solvent. Nanopore ionic conductances were measured before and after voltage application in order to test for changes in pore diameter due to electrochemical oxidation or reduction. TEM imaging was used to confirm these observations. While non-passivated pores were electrochemically oxidized, neither electrochemical oxidation nor reduction was observed for passivated pores. Bubble formation through water decomposition could be detected in non-passivated pores in KCl/water solutions but was not observed in 90% glycerol solutions. The use of a protective self-assembled monolayer of hexadecylphosphonic acid (HDPA) was also investigated.


Montmorency cherry juice reduces muscle damage caused by intensive strength exercise.
Montmorency cherries contain high levels of polyphenolic compounds including flavonoids and anthocyanins possessing antioxidant and anti-inflammatory effects. We investigated whether the effects of intensive unilateral leg exercise on oxidative damage and muscle function were attenuated by consumption of a Montmorency cherry juice concentrate using a crossover experimental design. Ten well-trained male overnight-fasted athletes completed two trials of 10 sets of 10 single-leg knee extensions at 80% one-repetition maximum. Trials were separated by 2 wk, and alternate legs were used in each trial. Participants consumed each supplement (CherryActive® (CA) or isoenergetic fruit concentrate (FC)) for 7 d before and 48 h after exercise. Knee extension maximum voluntary contractions (MVC) were performed before, immediately after, and 24 and 48 h after the damaging exercise. Venous blood samples were collected at each time point, and serum was analyzed for creatine kinase (CK) activity, nitrotyrosine, high-sensitivity C-reactive protein, total antioxidant capacity, and protein carbonyls (PC). Two-way repeated-measures ANOVA were used for statistical analysis of the data. MVC force recovery was significantly faster (24 h: CA 90.9% ± 4.2% of initial MVC vs FC 84.9% ± 3.4% of initial MVC; 48 h: CA 92.9% ± 3.3% of initial MVC vs FC 88.5% ± 2.9% of initial MVC (mean ± SEM); P < 0.05) after CA than FC consumption. Only serum CK and PC increased significantly from baseline, peaking 24 h after exercise (P < 0.001). The exercise-induced increase in CK activity was not different between trials. However, both the percentage (24 h after: CA 23.8% ± 2.9% vs FC 82.7% ± 11.7%; P = 0.013) and absolute (24 h after: CA 0.31 ± 0.03 nmol·mg(-1) protein vs FC 0.60 ± 0.08 nmol·mg(-1) protein; P = 0.079) increase in PC was lower in CA than FC trials. Montmorency cherry juice consumption improved the recovery of isometric muscle strength after intensive exercise perhaps owing to the attenuation of the oxidative damage induced by the damaging exercise.


"If I've got latent TB, I would like to get rid of it": Derivation of the CARD (Constraints, Actions, Risks, and Desires) Framework informed by South African healthcare worker perspectives on latent tuberculosis treatment.
Healthcare workers (HWs) have at least twice the risk of tuberculosis (TB) compared to the general population. There is growing emphasis on latent TB infection (LTBI) in high-risk populations. Yet we know little about HWs' perspectives of LTBI testing and treatment to inform implementation in high-incidence settings. We developed a qualitative networked approach to analyze HWs' perspectives on LTBI testing and treatment. We conducted 22 in-depth interviews with nurse and physician stakeholders, who had been recruited as part of a larger study evaluating TB transmission risk in HWs at Tygerberg Hospital, Cape Town, South Africa. We performed open coding to identify emergent themes and selective coding to identify relevant text citations. We used thematic analysis to inductively derive the CARD (Constraints, Actions, Risks, Desires) framework. All HWs desired to avoid developing TB but few felt this was actionable. Despite LTBI knowledge gaps, safety and cost concerns, most HWs reported hypothetical willingness to take LTBI treatment. The CARD framework showed that desire and action related to LTBI testing and treatment was clearly framed by the interactions between constraints, administrative action, and risk. The surprise HWs described on receiving a negative LTBI (Quantiferon-Plus) result suggests LTBI testing may recalibrate HWs' perceptions regarding the futility of actions to reduce their TB risk. LTBI testing and treatment are acceptable to HWs and could counteract the perceived inevitability of occupational TB infection that currently may limit risk reduction action. This should be coupled with administrative leadership and infrastructural support. The CARD analytic framework is a helpful tool for implementation scientists to understand current practices within complex health systems. Application of CARD could facilitate the development of contextually-relevant interventions to address important public health problems such as occupational TB.


Dynamics of cerebral tissue injury and perfusion after temporary hypoxia-ischemia in the rat: evidence for region-specific sensitivity and delayed damage.
Selective regional sensitivity and delayed damage in cerebral ischemia provide opportunities for directed and late therapy for stroke. Our aim was to characterize the spatial and temporal profile of ischemia-induced changes in cerebral perfusion and tissue status, with the use of noninvasive MRI techniques, to gain more insight in region-specific vulnerability and delayed damage. Rats underwent 20 minutes of unilateral cerebral hypoxia-ischemia (HI). We performed combined repetitive quantitative diffusion-weighted, T2-weighted, and dynamic susceptibility contrast-enhanced MRI from before HI to 5 hours after HI. Data were correlated with parallel blood oxygenation level-dependent MRI and laser-Doppler flowmetry. Finally, MRI and histology were done 24 and 72 hours after HI. Severe hypoperfusion during HI caused acute reductions of the apparent diffusion coefficient (ADC) of tissue water in the ipsilateral hemisphere. Reperfusion resulted in dynamic perfusion alterations that varied spatially. The ADC recovered completely within 1 hour in the hippocampus (from 0.68 +/- 0.07 to 0.83 +/- 0.09 x 10[-3] mm2/s), cortex (from 0.56 +/- 0.06 to 0.77 +/- 0.07 x 10[-3] mm2/s), and caudate putamen (from 0.58 +/- 0.06 to 0.75 +/- 0.06 x 10[-3] mm2/s) but only partially or not at all in the thalamus (from 0.65 +/- 0.07 to 0.68 +/- 0.12 x 10[-3] mm2/s) and substantia nigra (from 0.80 +/- 0.08 to 0.76 +/- 0.10 x 10[-3] mm2/s). Secondary ADC reductions, accompanied by significant T2 elevations and histological damage, were observed after 24 hours. Initial and secondary ADC decreases were observed invariably in the hippocampus, cortex, and caudate putamen and in approximately 70% of the animals in the thalamus and substantia nigra. Region-specific responses and delayed ischemic damage after transient HI were demonstrated by MRI. Acute reperfusion-induced normalization of ADCs appeared to poorly predict ultimate tissue recovery since secondary, irreversible damage developed eventually.


Biochar and activated carbon act as promising amendments for promoting the microbial debromination of tetrabromobisphenol A.
The increasing occurrence of tetrabromobisphenol A (TBBPA) in the environment is raising questions about its potential environmental health impacts as it has been shown to cause various deleterious effects in humans. The fact that the highest concentrations of TBBPA have been reported in wastewater sludge is concerning as effluent discharge and biosolids land application are likely a route by which TBBPA can be further disbursed to the environment. Our objectives in this study were to evaluate the effect of biochar (BC) and activated carbon (AC) in promoting the biodegradation of TBBPA, and characterize the response of anaerobic sludge microbial communities following amendments. Both carbonaceous amendments were found to promote the reductive debromination of TBBPA. Nearly complete transformation of TBBPA to BPA was observed in the amended reactors ∼20 days earlier than in the control reactors. In particular, the transformation of diBBPA to monoBBPA, which appears to be the rate-limiting step, was accelerated in the presence of either amendment. Overall, microbial taxa responding to the amendments, i.e., 'sensitive responders', represented a small proportion of the community (i.e., 7.2%), and responded positively. However, although both amendments had a similar effect on TBBPA degradation, the taxonomic profile of the sensitive responders differed greatly from one amendment to the other. BC had a taxonomically broader and slightly more pronounced effect than AC. This work suggests that BC and AC show great potential to promote the biodegradation of TBBPA in anaerobic sludge, and their integration into wastewater treatment processes may be helpful for removing TBBPA and possibly other emerging hydrophobic contaminants.


Ontogenetic development of postural control in man: adaptation to altered support and visual conditions during stance.
Normal young children ranging in age from 1 1/2 to 10 years were assessed in a number of experimental paradigms testing the ability to adapt quickly their strategy of control to altered support surface and visual conditions. The experimental protocols, using a movable platform and visual surround, and the analytic techniques, using EMGs and measures of reaction forces and body motions, were identical to those employed in a complementary study in this issue (Nashner, L. M., F. O. Black, and C. Wall, III (1982) J. Neurosci. 2: 536-544). The structure of automatic postural adjustments in young children was, with the exception of greater variability, similar to that of adult subjects studied previously. However, young children below the age of 7 1/2 years were unable to suppress systematically the influence of inputs derived from the support surface or from vision when these provided inappropriate orientation information due to the motion of these surfaces. The discussion emphasizes that the automatic postural adjustments and the context-dependent reweighting of support surface, vestibular, and visual inputs are organizationally separate processes and that the hierarchically lower level automatic process matures before the higher level adaptive processes.


Long-term evaluation of refractive status and optical components in eyes of children born prematurely.
To evaluate the refractive status and optical components in school age children born prematurely and to examine the risk factors associated with refractive errors. The participants were a cohort of children aged 7 to 9 years with gestational age less than 35 weeks or birth weight less than 1500 g. The participants' neonatal histories were reviewed; their refractive status and optical components were measured. The study results were compared with the results of age-matched children from a national survey. Of the 108 children studied, 48 (44%) had retinopathy of prematurity (ROP); 29 (27%) had ROP ≥ stage 3. Compared with the control subjects, the study cases showed higher prevalence of myopia (48% vs. 29%), hyperopia (23% vs. 15%), and astigmatism (73% vs. 41%). Common ocular features included shallow anterior chamber depth (ACD), thick lenses, and steep corneal curvature. The hyperopic cases had the shortest axial length (AL), whereas the myopia cases had significantly shallower ACD and greater LT. Those with a history of ROP had more prominent changes in the anterior segment. Generalized estimating equations showed that refractive errors could be predicted by a combination of optical components. In children born prematurely, the development of myopia is mainly influenced by anterior segment components, whereas hyperopia is mainly attributable to short AL. Astigmatism is primarily cornea-related. A combination of various optical components results in complicated refractive outcomes. The presence of ROP may be associated with significantly shorter ACD, thicker lens, and higher myopia and astigmatism. (ClinicalTrials.gov number, NCT01045616.).


Total body catecholamine kinetics before and after birth in spontaneously hypoxemic fetal lambs.
To study the effect of fetal hypoxemia on perinatal norepinephrine and epinephrine total body kinetics, 13 near-term fetal lambs were instrumented with vascular catheters under general anesthesia. One week later, norepinephrine and epinephrine kinetics were measured in normoxemic (n = 7) or spontaneously hypoxemic fetuses (n = 6) with isotope dilution methodology. Hypoxemic fetuses had lower body (P < 0.02) and placental (P = 0.01) weights and a threefold elevation in plasma norepinephrine (P < 0.005) and epinephrine (P < 0.025) associated with correspondingly higher total body norepinephrine (P < 0.005) and epinephrine (P < 0.05) spillovers. After birth, total body norepinephrine and epinephrine spillover increased 45% and 3.2-fold, respectively, in normoxemic animals (both P < 0.001). However, in the hypoxemic group, norepinephrine total body spillover was unchanged between fetal and 1-h lambs and then fell in 4-h lambs (P < 0.005). In addition, total body epinephrine release rose postnatally (P < 0.05) but less than in the normoxemic group (P < 0.02). No differences in norepinephrine or epinephrine total body clearance occurred between normoxemic and hypoxemic groups in either fetal or newborn lambs. These findings indicate that in hypoxemic and growth-restricted fetuses 1) elevated circulating norepinephrine and epinephrine levels are related to increased sympathoadrenal activity and 2) birth is associated with an initial maintenance and subsequent decline in global sympathetic activity but a blunting of adrenal medullary activation.


The analysis of essential oils and extracts (oleoresins) from seasonings--a critical review.
A critical review of the analytical methods employed for the determination of the relevant components of seasonings is presented. Where the available methods were inadequate, new ones have been devised. Particular emphasis has been placed on those methods of analysis that provide a rapid and sufficiently accurate appraisal of seasoning extracts and essential oils from seasonings under routine control laboratory conditions. At the same time, the margin of error of these methods has been determined. The individual seasoning extracts were assessed according to the following criteria: (1) essential oil--cardamom, laurel leaves, cloves, origanum (marjoram), sage, and thyme; (2) essential oil and nonvolatile lipids--dillseed, coriander, caraway, mace, nutmeg, pimento (allspice), and celery seed; (3) essential oil and/or pungent ingredients--capsicum, ginger, and pepper; (4) essential oil and/or coloring matter--turmeric (curcuma) and paprika; (5) essential oil and other components--garlic, onion, and cinnamon.


Improving pilot response to in-flight strokes: a randomized controlled trial.
When a passenger suffers an in-flight stroke (IFS), the pilot decides when to expedite access to ground care. Pilot pro-activeness towards IFS could improve outcome and should be promoted. Unfortunately, little is known about a pilot's stroke pro-activeness or limiting factors. Randomized controlled trial of an educational intervention (American Stroke Association, 30-slide stroke awareness lecture) through an internet-based computer system using pilot students and instructors as subjects. Pilots completed pre-intervention and post-intervention tests of 25 simulated in-flight scenarios that describe strokes and other neurological and medical symptoms. Outcomes chosen were the percentage of pilots that would use a medical radio service, declare an emergency on board, or divert to the nearest airport for each scenario. Participant pilots (n = 104) were less likely to respond to IFS than to myocardial infarction (p < 0.001). Fear of retaliation by an employer was the most important modifiable limitation. The educational program increased the simulated rate of emergency declarations for in-flight vertebrobasilar strokes (p < 0.001) and subarachnoid hemorrhage (p < 0.001). Pilot-simulated response to certain IFS improves immediately after this educational intervention, which should be disseminated in schools and airlines. Further studies are needed to determine the long-term benefits of this intervention and the impact on actual diversion rates. Companies should also review their policies to shield pilots from retaliation when altering the flight plan for patients.


Epidemiology of major congenital heart defects in Sweden, 1981-1986.
The aim was to make an epidemiological study of major congenital heart defects and to make comparisons between groups of heart defects regarding different epidemiological variables. The cases with congenital heart defects were identified from two Swedish registries: the Registry of Congenital Malformations and the Child Cardiology Registry. A classification with nine groups of heart defects is proposed. This was a national survey in Sweden during the period 1981-1986. The total number of cases reported during the six years was 1605. Cases that presented a patent ductus arteriosus only and a birthweight below 2500 g were excluded. The prevalence at birth was 2.8 per 1000. When cases with a chromosomal anomaly were excluded, no maternal age effect was observed except a possible under-risk for women above 40 years. The risk for a heart defect seems to increase with increasing parity independent of age. A higher risk was also observed among twin infants compared with singletons although no specificity in cardiac malformation type appeared. Sex ratio, the tendency for having an associated extracardiac malformation, and the proportion of isolated v non-isolated cardiac defects differed between the different groups of heart malformations. The differences observed between groups of defects indicate different aetiologies and show that this classification may be suitable for further analyses of congenital heart defects.


Scientific Reporting: Raising the Standards.
This article is based on a presentation that was made at the 2014 annual meeting of the editorial board of Health Education & Behavior. The article addresses critical issues related to standards of scientific reporting in journals, including concerns about external and internal validity and reporting bias. It reviews current reporting guidelines, effects of adopting guidelines, and offers suggestions for improving reporting. The evidence about the effects of guideline adoption and implementation is briefly reviewed. Recommendations for adoption and implementation of appropriate guidelines, including considerations for journals, are provided.


Push and pull factors in international nurse migration.
To describe the push and pull factors of migration in relation to international recruitment and migration of nurses. Review of literature on nurse migration, examination of effects of donor and receiving countries, and discussion of ethical concerns related to foreign nurse recruitment. The primary donor countries are Australia, Canada, the Philippines, South Africa, and the United Kingdom (UK); the primary receiving countries are Australia, Canada, Ireland, the UK, and the United States (US). The effects of migration on donor countries include the loss of skilled personnel and economic investment; receiving countries receive skilled nurses to fill critical shortages with less economic investment. Ethical concerns include the potential for exploitation of foreign nurses. Nurses migrate to seek better wages and working conditions than they have in their native countries. Given the current conditions, developed countries continue to actively recruit foreign nurses to fill critical shortages. Migration is predicted to continue until developed countries address the underlying causes of nurse shortages and until developing countries address conditions that cause nurses to leave.


Altitude exposure as a training & iron overload management strategy post leukemia.
To examine iron stores, hemoglobin mass, and performance before, during and after intermittent altitude exposure in a professional male rugby player experiencing iron overload following blood transfusions for treatment for acute myeloid leukemia. Longitudinal, repeated measures, single case-study. The player was followed prior to (control), and during (study), an in-season block of altitude training. During the control period two venesections were performed for a total of 750mL of blood removal. Internal and external training load, match statistics, blood volume, plasma volume, haemoglobin mass, serum ferritin and reticulocyte count were monitored throughout. During the control period serum ferritin declined following the two venesections (∼51%) as did haemoglobin mass (∼2%), reticulocyte count remained stable. During the study period serum ferritin further declined (∼30%), however haemoglobin mass and reticulocyte count increased (∼4% and ∼14% respectively). Internal training load for the control and study period was similar, however external training load was lower in the study period. Match statistics were not favourable for the player during the control period, however they improved during the study period. This case supports the theory that individuals with elevated iron availability are well placed to achieve increases in haemoglobin mass. Furthermore, although therapeutic venesections may still be required to manage iron overload, the addition of altitude exposure may be a method to assist in reducing total body iron by means of mobilising available (excessive) iron to incorporate into haemoglobin. Altitude exposure did not hinder the players' performance. Further research is encouraged.


Responsibility for evidence-based policy in cardiovascular disease in rural communities: implications for persistent rural health inequalities.
Objective The aim of this study was to understand, from the perspective of policy makers, who holds the responsibility for driving evidence-based policy to reduce the high burden of cardiovascular disease (CVD) in rural Australia. Methods Qualitative interviews were conducted with policy makers at the local, state and federal government levels in Australia (n=21). Analysis was conducted using the Conceptual Framework for Understanding Rural and Remote Health to understand perceptions of policy makers around who holds the key responsibility in driving evidence-based policy. Results At all levels of government, there were multiple examples of disconnect in the understanding of who is responsible for driving the generation of evidence-based policy to reduce CVD in rural areas. Policy makers suggested that the rural communities themselves, health services, health professionals, researchers and the health sector as a whole hold large responsibilities in driving evidence-based policy to address CVD in rural areas. Within government, there was also a noticeable disconnect, with local participants feeling it was the federal government that held this responsibility; however, federal government participants suggested this was largely a local government issue. Overall, there seemed to be a lack of responsibility for CVD policy, which is reflected in a lack of action in rural areas. Conclusion There was a lack of clarity about who is responsible for driving evidence-based policy generation to address the high burden of CVD in Australia, providing one possible explanation for the lack of policy action. Clarity among policy makers over shared roles and leadership for policy making must be addressed to overcome the current burden of CVD in rural communities. What is known about the topic? Rural health inequalities, such as the increased burden of CVD in rural Australia are persistent. Such health inequalities are unjust, with global theory suggesting political processes have facilitated, in part, the inequalities. With similar examples observed internationally in rural areas, little is known about the influence of the perspectives of policy makers regarding who is responsible for addressing health issues in rural areas, in the government context. What does this paper add? This paper provides empirical evidence, for all levels of government in Australia, that there is a lack of clarity in policy roles and responsibilities to address the unequal burden of CVD in rural Australia, at all levels of government. The paper provides evidence to support the urgent need for clarity within government around policy stakeholder roles. Without such clarity, it is unlikely that national-level progress in addressing rural health inequalities will be achieved in the near future. What are the implications for practitioners? Addressing ambiguity around who is responsible for the development of evidence-based policy to address the high burden of CVD in rural areas must be a high priority to ensure health disparities do not persist for future Australian generations. The results reported here are highly relevant to the Australian context, but also reflect similar findings internationally, namely that a lack of clarity among policy stakeholders appears to contribute to reduced action in addressing preventable health inequalities in disadvantaged populations. This paper provides evidence for policy makers and public health professionals to advocate for clear policy roles and direction in rural Australia.


Assessment of skin blood flow following spinal manual therapy: a systematic review.
Skin blood flow (SBF) indexes have been used to describe physiological mechanisms associated with spinal manual therapy (SMT). The aims of the current review were to assess methods for data collection, assess how investigators interpreted SBF changes, and formulate recommendations to advance manual medicine research. A database search was performed in PubMed, Cochrane Library, the Physiotherapy Evidence Database, and the Cumulative Index to Nursing and Allied Health Literature through April 2014. Articles were included if at least 1 outcome measure was changes in 1 SBF index following SMT. The database search yielded 344 records. Two independent authors applied the inclusion criteria. Twenty studies met the inclusion criteria. Selected studies used heterogeneous methods to assess short-term post-SMT changes in SBF, usually vasoconstriction, which was interpreted as a general sympathoexcitatory effect through central mechanisms. However, this conclusion might be challenged by the current understanding of skin sympathetic nervous activity over local endothelial mechanisms that are specifically controlling SBF. Evaluation of SBF measurements in peripheral tissues following SMT may document physiological responses that are beyond peripheral sympathetic function. Based on the current use of SBF indexes in clinical and physiological research, 14 recommendations for advancing manual medicine research using laser Doppler flowmetry are presented.


Lambert-eaton myasthenic syndrome: diagnosis and treatment.
A high index of suspicion is essential in arriving at the correct diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). LEMS should be considered in the differential in any patient who has proximal weakness, reduced or absent muscle stretch reflexes, and dry mouth. Weakness predominates in hip and shoulder muscles, but may also affect ocular and oropharyngeal muscles to a lesser extent. The diagnosis is confirmed by demonstrating characteristic electromyographic findings-low-amplitude muscle responses that increase dramatically after activation. Most patients also have circulating antibodies to the voltage-gated calcium channel. Half the patients with LEMS have a malignancy, usually small-cell lung cancer. The diagnosis should trigger an intensive search for malignancy, especially in older patients with a history of smoking. Younger, nonsmoking patients are likely to have LEMS as part of a more general autoimmune state. Successful treatment of the underlying cancer leads to improvement in many patients. More than 85% of patients have clinically significant benefit from 3,4-diaminopyridine (DAP). In over half of these, the improvement is marked. If severe weakness persists despite DAP, immunotherapy should be considered. Plasma exchange and high-dose immunoglobulin induce transient improvement in many patients, but function rarely becomes normal. Combinations of prednisone, azathioprine, or cyclosporine have been used with variable success. Improvement, if any, occurs only after many months and requires chronic administration of immunosuppressive medications at significant doses. The long-term prognosis in LEMS is determined by the presence of cancer or other autoimmune disease.


Novel Two-Component System MacRS Is a Pleiotropic Regulator That Controls Multiple Morphogenic Membrane Protein Genes in Streptomyces coelicolor.
As with most annotated two-component systems (TCSs) of Streptomyces coelicolor, the function of TCS SCO2120/2121 was unknown. Based on our findings, we have designated this TCS MacRS, for morphogenesis and actinorhodin regulator/sensor. Our study indicated that either single or double mutation of MacRS largely blocked production of actinorhodin but enhanced formation of aerial mycelium. Chromatin immunoprecipitation (ChIP) sequencing, using an S. coelicolor strain expressing MacR-Flag fusion protein, identified in vivo targets of MacR, and DNase I footprinting of these targets revealed a consensus sequence for MacR binding, TGAGTACnnGTACTCA, containing two 7-bp inverted repeats. A genome-wide search revealed sites identical or highly similar to this consensus sequence upstream of six genes encoding putative membrane proteins or lipoproteins. These predicted sites were confirmed as MacR binding sites by DNase I footprinting and electrophoretic mobility shift assays in vitro and by ChIP-quantitative PCR in vivo, and transcriptional analyses demonstrated that MacR significantly impacts expression of these target genes. Disruption of three of these genes, sco6728, sco4924, and sco4011, markedly accelerated aerial mycelium formation, indicating that their gene products are novel morphogenic factors. Two-hybrid assays indicated that these three proteins, which we have named morphogenic membrane protein A (MmpA; SCO6728), MmpB (SCO4924), and MmpC (SCO4011), interact with one another and with the putative membrane protein and MacR target SCO4225. Notably, SAV6081/82 and SVEN1780/81, homologs of MacRS TCS from S. avermitilis and S. venezuelae, respectively, can substitute for MacRS, indicating functional conservation. Our findings reveal a role for MacRS in cellular morphogenesis and secondary metabolism in StreptomycesIMPORTANCE TCSs help bacteria adapt to environmental stresses by altering gene expression. However, the roles and corresponding regulatory mechanisms of most TCSs in the Streptomyces model strain S. coelicolor are unknown. We investigated the previously uncharacterized MacRS TCS and identified the core DNA recognition sequence, two seven-nucleotide inverted repeats, for the DNA-binding protein MacR. We further found that MacR directly controls a group of membrane proteins, including MmpA-C, which are novel morphogenic factors that delay formation of aerial mycelium. We also discovered that these membrane proteins interact with one another and that other Streptomyces species have conserved MacRS homologs. Our findings suggest a conserved role for MacRS in morphogenesis and/or other membrane-associated activities. Additionally, our study showed that MacRS impacts, albeit indirectly, the production of the signature metabolite actinorhodin, further suggesting that MacRS and its homologs function as novel pleiotropic regulatory systems in Streptomyces.


Evaluation of the humoral response to the third dose of SARS-COV-2 vaccines in liver transplant recipients.
Solid organ transplant recipients (SOTR) commonly develop an unsatisfactory humoral response to vaccines compared to immunocompetent individuals (IC). We have previously evaluated the humoral response in liver transplant recipients (LTR) who received two-dose vaccines against SARS-CoV-2 and reported that 38 % of LTR did not produce anti-Spike antibodies. Thus, we set out to evaluate the humoral response after the third dose of SARS-CoV-2 vaccines. For this purpose, samples from a cohort of 81 LTR and 27 IC were extracted between 21 and 90 days after the third dose. Serology for anti-Spike IgG antibodies and neutralizing antibodies against Wuhan, Delta and Omicron variants were evaluated. We found that 73.5 % of LTR were responders for anti-Spike IgG, while all the IC mounted a measurable response. LTR who responded to the third dose showed significantly lower anti-Spike IgG levels and neutralizing antibodies than IC. We found that there is less neutralization in LTR compared to IC across all variants. Specifically, the neutralization titers in both groups decrease when encountering the Delta variant, and this decline is even more pronounced with the Omicron variant, compared to the Wuhan variant. Furthermore, we identified that the use of high doses of mycophenolate and advanced age were factors that negatively affected the development of anti-Spike IgG antibodies. Regarding vaccine regimes, the regime viral vector/mRNA/mRNA elicited significantly higher responses in LTR compared to other vaccine schemes. In addition to the recommended and necessary booster doses in this population, strategies that achieve adequate immunization should be evaluated.


A peripheral "cold" fiber population responsive to innocuous and noxious thermal stimuli applied to monkey's face.
The activity of 134 cold fibers innervating the hairy skin of the face was recorded from fine dissected strands of the infraorbital nerve in rhesus monkeys anesthetized with sodium pentobarbital. A precisely controlled contact thermode was used to produce rapid temperature shifts of approximately 10 degrees C/s in the cooling and warming directions with a 20-60 degrees C range. Cold fiber receptive fields usually were single spots less than 300 mum in diameter. The mean conduction velocity of 94 cold fibers determined by electrical stimulation of the receptive field was 9.0 m/s, with a range indicating an almost exclusive A-delta population. Rapid cooling shifts of 1-10 degrees C produced an initial transient period of high-frequency discharges, which decayed rapidly and was followed by a period of slow adaptation. Intensity functions were linear for cooling shifts up to 6-8 degrees C, and the slope of the intensity function was independent on the base-line temperature over a 30-40 degree C range. Rapid warming shifts produced a transient suppression of cold fiber activity. Previous cooling stimuli also influenced cold fiber responses, and these effects were dependent on the intensity of the previous stimulus as well as the stimulus interval. The average maximum discharge frequency of cold fibers to constant or steady-strate temperatures occurred at 30 degrees C, but varied over a 20-35 degrees C range for individual fibers. Periodic burst discharges separated by silent periods were present at steady-state temperatures of 20-35 degrees C.


Identification of Two Novel Mutations of ABCD1 Gene in Pedigrees with X-Linked Adrenoleukodystrophy and Review of the Literature.
X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal metabolism disorder, resulting from the loss-of-function mutation of ATP-binding cassette protein subfamily D1 (ABCD1) gene. The dysfunction of ALD protein, a peroxisomal ATP-binding cassette transporter, results in the excessive saturated very long-chain fatty acids (VLCFAs) accumulation in organs including the brain, spine, and adrenal cortex. X-ALD is characterized as the childhood, adolescent, adult cerebral ALD, adrenomyeloneuropathy (AMN), adrenal insufficiency, and asymptomatic phenotypes, exhibiting a high variety of clinical neurological manifestations with or without adrenocortical insufficiency. In this study, we reported two cases of X-ALD, which were first diagnosed as adrenal insufficiency (Addison's disease) and treated with adrenocortical supplement. However, both of the cases progressed as neurological symptoms and signs after decades. Elevated VLCFAs level, brain MRI scan, and genetic analysis confirmed final diagnosis. In addition, we identified two novel mutations of ABCD1 gene, NM_000033.3 (ABCD1): c.874_876delGAG (p.Glu292del) and NM_000033.3 (ABCD1): c.96_97delCT (p.Tyr33Profs∗161), in exon 1 of ABCD1 gene. Sanger sequencing confirmed that the proband's mother of the first case was heterozygous carrying the same variant. Adrenal insufficiency-only type is very rare; however, it may be the starting performance of X-ALD. In addition, we summarized reported mutation sites and clinical manifestations to investigate the correlationship of phenotype-genotype of X-ALD. The early warning manifestations should be noticed, and the probability of X-ALD should be considered. This report could be beneficial for the early diagnosis and genetic counseling for patients with X-ALD.


Risk factors for amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. It is typically fatal within 2-5 years of symptom onset. The incidence of ALS is largely uniform across most parts of the world, but an increasing ALS incidence during the last decades has been suggested. Although recent genetic studies have substantially improved our understanding of the causes of ALS, especially familial ALS, an important role of non-genetic factors in ALS is recognized and needs further study. In this review, we briefly discuss several major genetic contributors to ALS identified to date, followed by a more focused discussion on the most commonly examined non-genetic risk factors for ALS. We first review factors related to lifestyle choices, including smoking, intake of antioxidants, physical fitness, body mass index, and physical exercise, followed by factors related to occupational and environmental exposures, including electromagnetic fields, metals, pesticides, β-methylamino-L-alanine, and viral infection. Potential links between ALS and other medical conditions, including head trauma, metabolic diseases, cancer, and inflammatory diseases, are also discussed. Finally, we outline several future directions aiming to more efficiently examine the role of non-genetic risk factors in ALS.


NIH. Imaging institute picks up momentum.
Last week a House panel approved the creation of the National Institute of Biomedical Imaging and Bioengineering (NIBIE) despite pleas from top National Institutes of Health officials that such a move will balkanize research. The bipartisan proposal, which is also backed by Democratic presidential candidate Al Gore, may have enough momentum to sail through Congress by the time it adjourns early next month. Even if it falls short, NIBIE reflects the growing desire of segments of the biomedical community to have their own address on the Bethesda campus.


Determination of the underlying cause of death in three multicenter international HIV clinical trials.
Describe processes and challenges for an Endpoint Review Committee (ERC) in determining and adjudicating underlying causes of death in HIV clinical trials. Three randomized HIV trials (two evaluating interleukin-2 and one treatment interruption) enrolled 11,593 persons from 36 countries during 1999-2008. Three ERC members independently reviewed each death report and supporting source documentation to assign underlying cause of death; differences of opinion were adjudicated. Of 453 deaths reported through January 14, 2008, underlying causes were as follows: 10% AIDS-defining diseases, 21% non-AIDS malignancies, 9% cardiac diseases, 9% liver disease, 8% non-AIDS-defining infections, 5% suicides, 5% other traumatic events/accidents, 4% drug overdoses/acute intoxications, 11% other causes, and 18% unknown. Major reasons for unknown classification were inadequate clinical information or supporting documentation to determine cause of death. Half (51%) of deaths reviewed by the ERC required follow-up adjudication; consensus was eventually always reached. ERCs can successfully provide blinded, independent, and systematic determinations of underlying cause of death in HIV clinical trials. Committees should include those familiar with AIDS and non-AIDS-defining diseases and have processes for adjudicating differences of opinion. Training for local investigators and procedure manuals should emphasize obtaining maximum possible documentation and follow-up information on all trial deaths.


Is calcium sensitization the best strategy to improve myocardial contractility in acute heart failure?
The finely-tuned increases and decreases in the intracellular calcium levels in myocytes ultimately regulate the contraction and relaxation of the heart. Therapeutic agents can improve or interfere with this delicate balance. Calcium sensitizers enhance cardiac contraction by improving the use of calcium that is available, rather than by inundating the cell with excessive calcium, as is the case with traditional inotropes. With the sensitizing mechanism, the energy cost of contraction is maintained at a near-normal level, and the threat of arrhythmias and sudden death is low. Levosimendan is the first calcium sensitizer to become available for the treatment of patients with acute heart failure. In recent clinical studies, levosimendan increased cardiac output and stroke volume without significantly increasing oxygen demand. By its additional action as a vasodilator (via potassium channel opening), levosimendan also corrects the hemodynamic decompensation, thus lowering the pulmonary capillary wedge pressure and systemic vascular resistance. Furthermore, levosimendan increases the coronary circulation thus leading to an improved function of the stunned myocardium and lessened ischemia. Taken together, levosimendan's primary calcium-sensitizing action, along with its complementary vasodilator properties, make this new drug a highly promising agent for the treatment of patients with acute heart failure.


Total myrosinase activity estimates in brassica vegetable produce.
Isothiocyanates, generated from the hydrolysis of glucosinolates in plants of the Brassicaceae family, promote health, including anticancer bioactivity. Hydrolysis requires the plant enzyme myrosinase, giving myrosinase a key role in health promotion by brassica vegetables. Myrosinase measurement typically involves isolating crude protein, potentially underestimating activity in whole foods. Myrosinase activity was estimated using unextracted fresh tissues of five broccoli and three kale cultivars, measuring the formation of allyl isothiocyanate (AITC) and/or glucose from exogenous sinigrin. A correlation between AITC and glucose formation was found, although activity was substantially lower measured as glucose release. Using exogenous sinigrin or endogenous glucoraphanin, concentrations of the hydrolysis products AITC and sulforaphane correlated (r = 0.859; p = 0.006), suggesting that broccoli shows no myrosinase selectivity among sinigrin and glucoraphanin. Measurement of AITC formation provides a novel, reliable estimation of myrosinase-dependent isothiocyanate formation suitable for use with whole vegetable food samples.


Monocyte chemotactic protein-1 and -2 messenger ribonucleic acids in the ovine uterus: regulation by pregnancy, progesterone, and interferon-tau.
Endometrial leukocytes may play important roles during pregnancy. Because chemokines are regulators of immune cell activity and trafficking, this study determined if mRNAs for monocyte chemotactic proteins (MCP) were present in the ovine uterus and regulated by progesterone (P) and/or recombinant ovine interferon tau (roIFN-tau). Uteri of normal cycling and pregnant ewes (experiment 1) and uteri of ovariectomized ewes receiving intrauterine infusions of IFN-tau and/or i.m. injections of P (experiment 2) were used to detect MCP-1 and MCP-2 mRNA. In experiment 1, slot-blot hybridization analysis of endometrial total RNA revealed that MCP-1 and MCP-2 mRNA levels did not change during the estrous cycle but increased between Days 13 and 19 of pregnancy. Using in situ hybridization, MCP-1 and MCP-2 mRNA were localized to immune cells in the subepithelial compact stroma. Histomorphological studies and in situ hybridization for major basic protein (MBP) indicated that MCP-positive immune cells were eosinophils. In experiment 2, treatment with P and roIFN-tau increased (P < 0.05) the number of MCP-1- and MCP-2-expressing eosinophils in the endometrium compared to ewes treated with P alone. Injection of the P receptor antagonist (ZK 137,316) inhibited effects of P and/or roIFN-tau to recruit eosinophils expressing MCP-1 and MCP-2 mRNAs. Endometrial production of MCPs by eosinophils during early pregnancy may play a role(s) in central implantation and/or placentation in ewes that is crucial for successful establishment of pregnancy.


Serotonergic and dopaminergic modulation of gambling behavior as assessed using a novel rat gambling task.
Pathological gambling (PG) is characterized by persistent, maladaptive gambling behavior, which disrupts personal and professional life. Animal models of gambling behavior could make a significant contribution to improving our understanding of the neural and neurochemical basis of gambling, and the treatment of PG. When gambling, failing to win critically results in the loss of resources wagered as well as the absence of additional gain. Here, we have incorporated these concepts into a novel rat gambling task (rGT), based, in part, on the 'Iowa' gambling task (IGT) commonly used clinically to measure gambling-like behavior. Rats choose among four different options to earn as many sugar pellets as possible within 30 min. Each option is associated with the delivery of a different amount of reward, but also with a different probability and duration of punishing time-out periods during which reward cannot be earned. The schedules are designed such that persistent choice of options linked with larger rewards result in fewer pellets earned per unit time. Rats learn to avoid these risky options to maximize their earnings, comparable with the optimal strategy in the IGT. Both d-amphetamine and the 5-HT(1A) receptor agonist, 8-OH-DPAT, impaired task performance. In contrast, the dopamine D(2) receptor antagonist, eticlopride, improved performance, whereas the D(1) receptor antagonist, SCH23390, had no effect. These data suggest that both serotonergic and dopaminergic agents can impair and improve gambling performance, and indicate that the rGT will be a useful tool to study the biological basis of gambling.


Reducing respiratory motion artifacts in positron emission tomography through retrospective stacking.
Respiratory motion artifacts in positron emission tomography (PET) imaging can alter lesion intensity profiles, and result in substantially reduced activity and contrast-to-noise ratios (CNRs). We propose a corrective algorithm, coined "retrospective stacking" (RS), to restore image quality without requiring additional scan time. Retrospective stacking uses b-spline deformable image registration to combine amplitude-binned PET data along the entire respiratory cycle into a single respiratory end point. We applied the method to a phantom model consisting of a small, hot vial oscillating within a warm background, as well as to 18FDG-PET images of a pancreatic and a liver patient. Comparisons were made using cross-section visualizations, activity profiles, and CNRs within the region of interest. Retrospective stacking was found to properly restore the lesion location and intensity profile in all cases. In addition, RS provided CNR improvements up to three-fold over gated images, and up to five-fold over ungated data. These phantom and patient studies demonstrate that RS can correct for lesion motion and deformation, while substantially improving tumor visibility and background noise.