Risk assessment of leukaemia and occupational exposure to benzene.
Experimental toxicological studies have offered clear evidence that benzene induces haematopoietic neoplasms, and it is generally accepted that exposure to benzene is a risk factor for leukaemia, in particular for acute non-lymphatic leukaemia. Quantitative aspects of benzene risk assessment are still a matter of controversy, however. In several risk assessments an estimated 50 deaths from leukaemia per 1000 deaths would arise from exposures to benzene of 10 ppm during a working life of 30 years. The assessment presented in this paper leads to lower estimates, which are more in agreement with the weak toxicological data. Furthermore, an approach is presented to incorporate the results of low exposure epidemiological studies into the process of quantitative risk assessment.


Dupuytren's contracture and alcohol.
Reported alcohol consumption was quantified and scored by a validated questionnaire administered by an interviewer to 64 patients (10 female) with Dupuytren's contracture (DC) before hand surgery and to 89 controls (44 female) admitted for other hand or foot surgery. Serum urate (SUA), gamma-glutamyl transferase (GGT), and mean red cell volume (MCV) were measured on admission. Thirteen of 54 men with DC reported current daily alcohol intake of 40 g or more compared with one of 45 male controls (p = 0.0001). Two of 10 women with DC (but none of 44 controls) admitted consuming at least 40 g alcohol daily (p = 0.03). MCV was higher in men (but not women) with DC than in controls (p less than 0.0005). Current alcohol consumption score of patients with DC correlated with SUA (r = 0.308, p less than 0.05), MCV (r = 0.44, p less than 0.01), and GGT (r = 0.54, p much less than 0.001) on admission. DC among men is strongly associated with heavy drinking, reflected both in self reporting and haematological data.


Micro simulated moving bed chromatography-mass spectrometry as a continuous on-line process analytical tool.
Continuous manufacturing is becoming increasingly important in the (bio-)pharmaceutical industry, as more product can be produced in less time and at lower costs. In this context, there is a need for powerful continuous analytical tools. Many established off-line analytical methods, such as mass spectrometry (MS), are hardly considered for process analytical technology (PAT) applications in biopharmaceutical processes, as they are limited to at-line analysis due to the required sample preparation and the associated complexity, although they would provide a suitable technique for the assessment of a wide range of quality attributes. In this study, we investigated the applicability of a recently developed micro simulated moving bed chromatography system (µSMB) for continuous on-line sample preparation for MS. As a test case, we demonstrate the continuous on-line MS measurement of a protein solution (myoglobin) containing Tris buffer, which interferes with ESI-MS measurements, by continuously exchanging this buffer with a volatile ammonium acetate buffer suitable for MS measurements. The integration of the µSMB significantly increases MS sensitivity by removing over 98% of the buffer substances. Thus, this study demonstrates the feasibility of on-line µSMB-MS, providing a versatile PAT tool by combining the detection power of MS for various product attributes with all the advantages of continuous on-line analytics.


Optical and thermal properties of edible coatings for application in solar drying.
Solar drying is a sustainable process that may impact the quality of dried food. This is because, pigments contained in food are sensitive to sunlight, and exposure to ultraviolet radiation can affect them. We applied biopolymer-based coatings on strawberry, from hydro-colloidal solutions of Opuntia ficus indica-mucilage, fenugreek, xanthan gum, gum Arabic, and guar gum to evaluate their potential use as UV filters for solar drying of food. Thermal properties and the optical transmittance, absorbance and reflectance of the coatings were measured to assess their influence on food-sunlight interaction. During the drying experiments, the moisture content, total anthocyanins (TA), and total phenolic compounds (TPC) were measured. Optical and thermal properties are influenced by the biopolymer-based coatings. Also, the optical properties are influenced by the coating thickness. The differences in optical and thermal properties influence the drying process. Differences exist in the drying rate for strawberry slices with coating, compared with those without the coatings. In general, the TA and TPC content in the product are better preserved under solar drying than in control experiments done in a drying oven. A partial transmittance of solar UV radiation is recommended to obtain increased TA and TPC contents in the dried product.


Epidemiological Analysis of Salmonella enterica subsp. enterica Serovar Dublin in German Cattle Herds Using Whole-Genome Sequencing.
Salmonella enterica subsp. enterica serovar Dublin is a cattle-adapted serovar that causes enteritis and systemic diseases in animals. In Germany, S. Dublin is not detected or is very rarely detected in some federal states but is endemic in certain regions. Information on detailed genetic characteristics of S. Dublin is not available. An understanding of the paths and spreading of S. Dublin within and between regions and over time is essential to establish effective control strategies. Whole-genome sequencing (WGS) and bioinformatic analysis were used to explore the genetic traits of S. Dublin and to determine their epidemiological context. Seventy-four S. Dublin strains collected in 2005 to 2018 from 10 federal states were studied. The phylogeny was analyzed using core-genome single-nucleotide polymorphisms (cgSNPs) and core-genome multilocus sequence typing. Genomic clusters at 100 cgSNPs, 40 cgSNPs, and 15 cgSNPs were selected for molecular epidemiology. WGS-based genoserotyping confirmed serotyping. Important specific virulence determinants were detected in all strains, but multidrug resistance in German S. Dublin organisms is uncommon. Use of different thresholds for cgSNP analysis enabled a broad view and also a detailed view of the occurrence of S. Dublin in Germany. Genomic clusters could be allocated nationwide, to a limited number of federal states, or to special regions only. Results indicate both persistence and spread of S. Dublin within and between federal states in short and longer time periods. However, to detect possible routes of infection or persistence of S. Dublin indicated by genomic analysis, information on the management of the cattle farms and contacts with corresponding farms are essential. IMPORTANCE Salmonella enterica subsp. enterica serovar Dublin is a bovine host-adapted serovar that causes up to 50% of all registered outbreaks of salmonellosis in cattle in Germany. S. Dublin is not detected or is only rarely detected in some federal states but has been endemic in certain regions of the country for a long time. Information on genetic traits of the causative strains is essential to determine routes of infection. WGS and bioinformatic analysis should be used to explore the genetic characteristics of S. Dublin. Combining the genomic features of S. Dublin strains with information on the management of the cattle farms concerned should enable the detection of possible routes of infection or persistence of S. Dublin. This approach is regarded as a prerequisite to developing effective intervention strategies.


Calibrating duckweeds: light, clocks, metabolism, flowering.
The roles of photoperiodism and related light-dependent and hormonal processes in plants are not well understood. Rapid growth, aquatic habit, and adaptability to axenic culture make the Lemnaceae, or duckweeds, excellent material for investigating these topics and others in which highly defined conditions or the presence of organic substances are crucial. As a major example among several that are described, recent work with one species suggests a relation between some features of carbon dioxide flux and the photoperiodic timing mechanism, thus providing a system in which the biochemical basis of the latter may be explored.


Simulated accuracy assessment of small footprint body-mounted probe alignment device for MRI-guided cryotherapy of abdominal lesions.
Magnetic resonance imaging (MRI)-guided percutaneous cryotherapy of abdominal lesions, an established procedure, uses MRI to guide and monitor the cryoablation of lesions. Methods to precisely guide cryotherapy probes with a minimum amount of trial-and-error are yet to be established. To aid physicians in attaining precise probe alignment without trial-and-error, a body-mounted motorized cryotherapy-probe alignment device (BMCPAD) with motion compensation was clinically tested in this study. The study also compared the contribution of body motion and organ motion compensation to the guidance accuracy of a body-mounted probe alignment device. The accuracy of guidance using the BMCPAD was prospectively measured during MRI-guided percutaneous cryotherapies before insertion of the probes. Clinical parameters including patient age, types of anesthesia, depths of the target, and organ sites of target were collected. By using MR images of the target organs and fiducial markers embedded in the BMCPAD, we retrospectively simulated the guidance accuracy with body motion compensation, organ motion compensation, and no compensation. The collected data were analyzed to test the impact of motion compensation on the guidance accuracy. Thirty-seven physical guidance of probes were prospectively recorded for sixteen completed cases. The accuracy of physical guidance using the BMCPAD was 13.4 ± 11.1 mm. The simulated accuracy of guidance with body motion compensation, organ motion compensation, and no compensation was 2.4 ± 2.9 mm, 2.2 ± 1.6 mm, and 3.5 ± 2.9 mm, respectively. Data analysis revealed that the body motion compensation and organ motion compensation individually impacted the improvement in the accuracy of simulated guidance. Moreover, the difference in the accuracy of guidance either by body motion compensation or organ motion compensation was not statistically significant. The major clinical parameters impacting the accuracy of guidance were the body and organ motions. Patient age, types of anesthesia, depths of the target, and organ sites of target did not influence the accuracy of guidance using BMCPAD. The magnitude of body surface movement and organ movement exhibited mutual statistical correlation. The BMCPAD demonstrated guidance accuracy comparable to that of previously reported devices for CT-guided procedures. The analysis using simulated motion compensation revealed that body motion compensation and organ motion compensation individually impact the improvement in the accuracy of device-guided cryotherapy probe alignment. Considering the correlation between body and organ movements, we also determined that body motion compensation using the ring fiducial markers in the BMCPAD can be solely used to address both body and organ motions in MRI-guided cryotherapy.


[Mathematical modeling of ampicillin pharmacokinetics in patients with altered excretory function of the kidneys].
A physiological model of ampicillin pharmacokinetics in man is proposed. Its design stems from the data characterizing the antibiotic distribution in rats. The model is useful in describing the pharmacokinetics of ampicillin after its intravenous and intramuscular administration. An adequate description of the antibiotic distribution in blood suggested an agreement with the real values of the estimated antibiotic concentrations in the tissues. The concentrations of ampicillin and sulbactam in the tissues after their intramuscular combined administration in doses of 1 and 0.5 g, respectively, were compared. The physiological model of the pharmacokinetics was applied to evaluation of a possible interval in changing of the antibiotic half-life. There was analytical relationship between the ampicillin half-life and efficiency of the renal function.


Functional diversification of duplicated CYC2 clade genes in regulation of inflorescence development in Gerbera hybrida (Asteraceae).
The complex inflorescences (capitula) of Asteraceae consist of different types of flowers. In Gerbera hybrida (gerbera), the peripheral ray flowers are bilaterally symmetrical and lack functional stamens while the central disc flowers are more radially symmetrical and hermaphroditic. Proteins of the CYC2 subclade of the CYC/TB1-like TCP domain transcription factors have been recruited several times independently for parallel evolution of bilaterally symmetrical flowers in various angiosperm plant lineages, and have also been shown to regulate flower-type identity in Asteraceae. The CYC2 subclade genes in gerbera show largely overlapping gene expression patterns. At the level of single flowers, their expression domain in petals shows a spatial shift from the dorsal pattern known so far in species with bilaterally symmetrical flowers, suggesting that this change in expression may have evolved after the origin of Asteraceae. Functional analysis indicates that GhCYC2, GhCYC3 and GhCYC4 mediate positional information at the proximal-distal axis of the inflorescence, leading to differentiation of ray flowers, but that they also regulate ray flower petal growth by affecting cell proliferation until the final size and shape of the petals is reached. Moreover, our data show functional diversification for the GhCYC5 gene. Ectopic activation of GhCYC5 increases flower density in the inflorescence, suggesting that GhCYC5 may promote the flower initiation rate during expansion of the capitulum. Our data thus indicate that modification of the ancestral network of TCP factors has, through gene duplications, led to the establishment of new expression domains and to functional diversification.


Chronic restraint stress increases the protein expression of VEGF and its receptor VEGFR-2 in the prefrontal cortex.
In the present study the central and peripheral regulation of VEGF, its cognate receptors, and regulators were examined after acute and chronic restraint stress in rats. After chronic restraint stress (6 h per day for 21 days) the protein levels of VEGF (175 ± 24%) and its receptor VEGFR-2 (169 ± 17%) increased significantly in the prefrontal cortex (A and B). mRNA levels of VEGFR-2 (132 ± 11%) were also significantly increased (D). In the hippocampus no significant changes were observed at the mRNA or protein levels. In serum there was a tendency towards increased VEGF protein expression after both acute and chronic restraint stress (C).


Mold species in dust from the International Space Station identified and quantified by mold-specific quantitative PCR.
Dust was collected over a period of several weeks in 2007 from HEPA filters in the U.S. Laboratory Module of the International Space Station (ISS). The dust was returned on the Space Shuttle Atlantis, mixed, sieved and the DNA was extracted. Using a DNA-based method called mold-specific quantitative PCR (MSQPCR), 39 molds were measured in the dust. Potential opportunistic pathogens Aspergillus flavus and Aspergillus niger and potential moderate toxin producers Penicillium chrysogenum and Penicillium brevicompactum were noteworthy. No cells of the potential opportunistic pathogens Aspergillus fumigatus, Aspergillus terreus, Fusarium solani or Candida albicans were detected.


Are mimics monophyletic? The necessity of phylogenetic hypothesis tests in character evolution.
The processes governing the origin and maintenance of mimetic phenotypes can only be understood in a phylogenetic framework. Phylogenetic estimates of evolutionary relationships can provide a context for analyses of character evolution; however, when phylogenetic estimates conflict, rigorous analyses of alternative evolutionary histories are necessary to determine the likelihood of a specific history giving rise to the observed pattern of diversity. The polyphenic butterfly Limenitis arthemis provides a case in point. This species is comprised of three lineages, two of which are mimetic and one of which is non-mimetic. Conflicting estimates of the relationships among these three lineages requires direct evaluation of the alternative hypotheses of mimicry evolution. Using a coalescent framework, we found support for a sister-taxon relationship between the non-mimetic L. a. arthemis and the mimetic L. a. astyanax, congruent with the previous hypothesis that the non-mimetic form of L. a. arthemis was derived from a mimetic ancestor. We found no support for a mimetic clade (L. a. astyanax + L. a. arizonensis) despite analyzing numerous models of population structure. These results provide the foundation for future studies of mimicry, which should integrate phylogenetic and developmental analyses of wing pattern formation. We propose future analyses of character evolution accommodate conflicting phylogenetic estimates by explicitly testing alternative evolutionary hypotheses.


The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb.
Gene deletion studies in mice and in Drosophila have shown that the 40S ribosomal protein S6 Kinases, dS6K in Drosophila and S6K1 and S6K2 in mice are important regulators of cell growth in response to insulin stimulation and nutrition availability. Here we chiefly focus on dS6k and S6K1, whose activities are regulated by an upstream kinase termed the mammalian target of rapamycin (mTOR, or dTOR in Drosophila). Our understanding of the mechanisms regulating the mTOR/S6K1-signalling pathway will be fundamental in determining the mechanisms which control cell growth in response to insulin signalling. Recent findings from this laboratory and others suggests that the tumour suppressor complex made of two proteins TSC1/hamartin and TSC2/tuberin, acts as a negative regulator of mTOR/S6K1 signalling. Mutations in either TSC1 or TSC2 are genetically linked to tuberous sclerosis complex (TSC) syndrome, which can lead to severe pathological consequences, including mental retardation, epilepsy and autism, as well as cardiac, pulmonary and renal failure. Despite a large number of initial reports on the TSC1/TSC2 complex, and the finding that its activity is regulated by protein kinase B (PKB), the direct target of the TSC1/TSC2 inhibitory complex was unknown until recently. Since TSC2 has a GTPase-activating domain, or GAP-like sequence, others and we searched for a small GTP binding protein, which may serve as the target of TSC1/TSC2 inhibitory complex. In our case we took advantage of a genome wide screen in Drosophila for effectors of cell growth and in parallel searched for a small GTPase whose activity is up-regulated in TSC2-deficient cells. The identified gene was a member of the Ras family of GTPases termed Ras homologue enriched in brain or Rheb. Here we review recent findings demonstrating that the TSC1/TSC2 inhibitory complex normally acts on Rheb to mediate mTOR/S6K1-signalling.


Vector analysis of postcardiotomy behavioral phenomena.
The classification of postcardiotomy behavioral phenomena in Figure 1 is proposed for use as a clinical instrument to analyze etiological determinants. The utilization of a vector analysis analogy inherently denies absolutism. Classifications A-P are presented as prototypes of certain ratio imbalances of the metabolic, hemodynamic, environmental, and psychic vectors. Such a system allows for change from one type to another according to the individuality of the patient and the highly specific changes in his clinical presentation. A vector analysis also allows for infinite intermediary ratio imbalances between classification types as a function of time. Thus, postcardiotomy behavioral phenomena could be viewed as the vector summation of hemodynamic, metabolic, environmental, and psychic processes at a given point in time. Elaboration of unknown determinants in this complex syndrome appears to be task for the future.


A short history of microbial biofilms and biofilm infections.
The observation of aggregated microbes surrounded by a self-produced matrix adhering to surfaces or located in tissues or secretions is old since both Leeuwenhoek and Pasteur have described the phenomenon. In environmental and technical microbiology, biofilms, 80-90 years ago, were already shown to be important for biofouling on submerged surfaces, for example, ships. The concept of biofilm infections and their importance in medicine was, however, initiated in the early 1970s by the observation of heaps of Pseudomonas aeruginosa cells in sputum and lung tissue from chronically infected cystic fibrosis patients. The term biofilm was introduced into medicine in 1985 by J. W. Costerton. During the following decades, the number of published biofilm articles and methods for studying biofilms increased rapidly and it was shown that adhering and nonadhering biofilm infections are widespread in medicine. The medical importance of biofilm infections is now generally accepted and guidelines for prophylaxis, diagnosis, and treatment have been published.


MD-1 is a critical part of the mechanism causing Th1-cytokine-triggered murine fetal loss syndrome.
Fetal loss syndrome (abortion/resorption) occurring on or after gestation day (gd) 9.5 in CBA/JxDBA/2 matings is dependent upon presence of TNF-alpha + IFN-gamma, which act by increasing expression of fg12 prothrombinase at the feto-maternal interface. The magnitude by which the abortion rate can be boosted by an injection of these cytokines on gd 7.5 depends on endogenous rate of loss, and appears to depend on microbial flora. Is cytokine-triggered abortion dependent upon a third signaling pathway that senses 'danger'? Female CBA/J were mated to DBA/2 males and, C57B1/6 and C57B1/6 TNFalphaR1-/-Mak were mated to C57B1/6 control or TNFalphaR1-/-Mak males. LPS from Escherichia coli and Salmonella enteritidis, or the combination of TNF-alpha + IFN-gamma, was injected to stimulate abortions. The effect of anti-MD-1, which interferes with expression of CD14 and, hence, with signaling by LPS via the CD14-tlr4 complex, on TNF-alpha + IFN-gamma was tested. The presence of MD-1 in the uterus was evaluated by in situ hybridization, and effect of lipopolysaccharide (LPS) on mice lacking TNF-alphaR1 was tested. Anti-MD-1 completely abrogated TNF-alpha + IFN-gamma-induced abortions. MD-1 was expressed on trophoblast and in deciduas on gd 8.5 but LPS could not abort mice that lacked the type 1 receptor for TNF-alpha. Pregnant CBA/J females had classical resorptions (abortions) countable on gd 13.5-14.5 in response to LPS from E. coli or S. enteritidis, but C57B1/6 strain mice resorbed only in response to the latter, and E. coli LPS appeared to induce 'occult' losses. 'Occult' loss did not require TNF-alphaR1. TNF-alpha + IFN-gamma could not induce murine abortions without co-presence of a 'danger' signal such as LPS acting via CD14 on toll receptors, and LPS could not act without co-signaling by TNF-alpha. Classical resorptions/abortions and 'occult' losses have a different mechanism in these models as reflected in type of endotoxin and requirement for TNF-alphaR1 signaling.


Immunologic functions as prognostic indicators in melanoma.
Outcome in melanoma patients with advanced disease is poor and systemic treatment seems to benefit only a subset of patients. Predictive markers identifying these patients are currently not available. Early studies showed an association of immune-related side effects such as vitiligo and autoimmune thyroiditis with response to IL-2 or IFNα treatment. However, conflicting data have been reported as well, mentioning the effect of a higher rate of immune-related toxicities during prolonged administration of the drug in responders. The review discusses the prognostic significance of autoimmunity during various forms of immunotherapy and stresses the importance of correcting for guarantee-time bias. In addition, other immune-related factors which have been associated with melanoma prognosis such as, CRP, white blood cell count, absolute lymphocyte count and human leukocyte antigen will be reviewed as well. A better understanding of the immune system and the host-tumor interactions should ultimately lead to more effective treatment. A major challenge expected to be addressed in future is proving ways to uncouple tumor immunity from autoimmunity.


Endoscopic endonasal nasopharyngectomy in selected cancers.
To describe the different surgical techniques for nasopharyngeal endoscopic resection (NER) and to support the efficacy of the endoscopic endonasal approach in the management of selected primary and locally recurrent nasopharyngeal tumors (NPTs). Case series with chart review. Patients affected by NPTs who underwent NER from 1997 to 2011 at two Italian referral centers. NER was tailored to the NPT extension and classified as follows: type 1 NER, resection of the posterior nasopharyngeal wall; type 2 NER, resection superiorly extended to the sphenoid; type 3 NER, trans-pterygoid approach to the postero-lateral nasopharynx with removal of pterygoid plates and Eustachian tube, under control of parapharyngeal-petrous-cavernous segments of the internal carotid artery. Thirty-six consecutive patients with primary (9 cases) or locally recurrent (27 cases) NPTs were enrolled. The lesions were staged as follows: stage I, 16 (44.4%); stage II, 3 (8.4%); stage III, 15 (41.6%); and stage IVA, 2 (5.6%). Type 1 NER was performed in 6 cases, type 2 NER in 12, type 3 NER in 16, and bilateral-extended type 3 NER in 2. No perioperative mortality or major complications were observed. Postoperatively, 11 patients received intensity-modulated radiotherapy, with or without chemotherapy. Follow-up ranged from 2 to 173 months (mean: 38 months). Five years overall, disease-specific, and disease-free survivals were 75.1% ± 9.13%, 80.9% ± 7.79%, and 58.1% ± 14.8%, respectively. NER is a feasible and minimally invasive surgical approach for the management of selected primary and locally recurrent NPTs. Our preliminary outcomes are promising, with local control rates comparable to those of conventional procedures. Larger case series and longer follow-up are needed to validate the reproducibility and efficacy of the technique.


Nonheme Oxoiron(IV) Complexes of Pentadentate N5 Ligands: Spectroscopy, Electrochemistry, and Oxidative Reactivity.
Oxoiron(IV) species have been found to act as the oxidants in the catalytic cycles of several mononuclear nonheme iron enzymes that activate dioxygen. To gain insight into the factors that govern the oxidative reactivity of such complexes, a series of five synthetic S = 1 [Fe(IV)(O)(L(N5))](2+) complexes has been characterized with respect to their spectroscopic and electrochemical properties as well as their relative abilities to carry out oxo transfer and hydrogen atom abstraction. The Fe=O units in these five complexes are supported by neutral pentadentate ligands having a combination of pyridine and tertiary amine donors but with different ligand frameworks. Characterization of the five complexes by X-ray absorption spectroscopy reveals Fe=O bonds of ca. 1.65 Å in length that give rise to the intense 1s→3d pre-edge features indicative of iron centers with substantial deviation from centrosymmetry. Resonance Raman studies show that the five complexes exhibit ν(Fe=O) modes at 825-841 cm(-1). Spectropotentiometric experiments in acetonitrile with 0.1 M water reveal that the supporting pentadentate ligands modulate the E(1/2)(IV/III) redox potentials with values ranging from 0.83 to 1.23 V vs. Fc, providing the first electrochemical determination of the E(1/2)(IV/III) redox potentials for a series of oxoiron(IV) complexes. The 0.4-V difference in potential may arise from differences in the relative number of pyridine and tertiary amine donors on the L(N5) ligand and in the orientations of the pyridine donors relative to the Fe=O bond that are enforced by the ligand architecture. The rates of oxo-atom transfer (OAT) to thioanisole correlate linearly with the increase in the redox potentials, reflecting the relative electrophilicities of the oxoiron(IV) units. However this linear relationship does not extend to the rates of hydrogen-atom transfer (HAT) from 1,3-cyclohexadiene (CHD), 9,10-dihydroanthracene (DHA), and benzyl alcohol, suggesting that the HAT reactions are not governed by thermodynamics alone. This study represents the first investigation to compare the electrochemical and oxidative properties of a series of S = 1 Fe(IV)=O complexes with different ligand frameworks and sheds some light on the complexities of the reactivity of the oxoiron(IV) unit.


Myeloproliferative disorders--neurological complications.
Primary myeloproliferative disorders (MPD) are often associated with hemostasis abnormalities, which may cause many thrombotic or hemorrhagic complications during the course of the disease. Clinical consequences following abnormal hemostatic conditions include various neurological manifestations. It is extremely difficult to predict and evaluate the risk and chance, that MPD patients will develop neurological symptoms. The up-to-date background of pathological thrombocytosis, as well as the neurological aspects of abnormal hemostasis during the course of myeloproliferative disorders have been reviewed in this study.


The Silver Surfer: Trends of Internet Usage in the Over 65 and the Potential Health Benefits.
The Internet provides medical information and interventions with promising benefits. This cross-sectional study explores trends in Internet use among the elderly in Ireland from 2002 to 2010 and considers possible implications for health benefit. Data were analysed on 1606 Irish individuals. Internet use in Ireland is increasing at similar rates to the rest of Europe; the percentage of over-65s using the Internet in Ireland nearly trebled from 2002 to 2010, from 26(8.3%) to 92 (24. 1%) (p < 0.001). Subgroups of this population displayed significantly higher rates of Internet usage; namely those with a better education, living with a partner, males and urban dwellers. Of those with good subjective general health, 230 (21%) had internet access, versus 36 (7.1%) with poor health. Web-based interventions targeting the elderly should become more available. These could be particularly useful in populations with limited access to transport and mobility.


Nuclear transcription factor-kappa beta-dependent ultrastructural alterations within the placenta and systemic inflammatory activation in pregnant patients with hemolysis, elevated liver functions and low thrombocyte count (HELLP) syndrome: a case-control study.
Preeclampsia appears to be associated with a higher extent of inflammation than in uncomplicated pregnancies. We aimed to test whether this was the case in patients with hemolysis, elevated liver functions and low platelet count (HELLP) syndrome and to clarify the contribution of placental and systemic inflammatory variables in the development of this syndrome. Thirty healthy pregnant women (control group) and 20 patients with HELLP syndrome (study group) were included in the study. Placental inflammatory activity was evaluated by quantifying immunohistochemically the levels of p65/RelA expression of nuclear transcription factor-kappa beta (NF-kB) in paraffin-embedded tissue samples. In addition, ultrastructural changes in placental morphology in HELLP patients were evaluated by transmission electron microscopy (TEM). The serum concentrations of myeloperoxidase (MPO) and C-reactive protein (CRP) were also measured and compared. p65/RelA immunoexpression and serum MPO and CRP levels were significantly higher in patients with HELLP syndrome (p < 0.05). TEM of placenta in the study group revealed severely vacuolized syncytiotrophoblasts, irregular basal lamina and damaged capillary endothelium when compared with the placenta of control subjects. Our results suggest that over-expression of placental NF-kB is correlated with elevation of serum inflammatory markers and placental ultrastructural changes, which may point to an important role of local and systemic inflammatory activation in the pathogenesis of HELLP syndrome.


Histories of childhood maltreatment in schizophrenia: relationships with premorbid functioning, symptomatology, and cognitive deficits.
A number of studies have demonstrated an increased rate of histories of childhood maltreatment among adults with serious mental illness. The present investigation documented the presence of childhood maltreatment in a sample of 40 psychiatric inpatients with schizophrenia spectrum disorders. The type (neglect, physical abuse, sexual abuse), duration, and severity of childhood maltreatment was examined along with measures of premorbid functioning, current symptomatology, and cognitive functioning. Participants with histories of maltreatment were significantly more likely to have poorer peer relationships in childhood, more difficulty in school, an earlier age at first hospitalization, more previous hospitalizations, elevated symptoms of anxiety, depression, and suicidality on the Brief Psychiatric Rating Scale (BPRS), and more impaired performance on a task of visual-perceptual organization. Severity and frequency of childhood maltreatment were both positively correlated with hallucinations and delusions on the BPRS. Linear trend analysis indicated a pattern of more severe impairment as the number of types of maltreatment increased. No relationships were found between maltreatment and measures of executive functioning, verbal fluency, or verbal processing speed. A history of childhood maltreatment appears to be a significant determinant of premorbid functioning, illness-related symptom expression, and specific forms of cognitive dysfunction.


Infection with Aleutian disease virus-like virus in a captive striped skunk.
A 5-month-old captive female striped skunk (Mephitis mephitis) was evaluated because of lethargy, signs of depression, azotemia, and erythema of the skin around the eyes. Antemortem diagnostic tests revealed renal disease but failed to identify an etiologic agent. A diagnosis of severe nonsuppurative interstitial nephritis was made on the basis of results of histologic examination of renal biopsy specimens. The skunk was administered isotonic fluids SC daily and later every other day because of the handling-related stress. Because of the skunk's deteriorating condition, it was euthanized after 24 days of supportive care. Aleutian disease was diagnosed on the basis of positive results of a PCR assay that targeted the DNA from Aleutian disease virus (ADV); positive results for ADV were also obtained by use of plasma counterimmunoelectrophoresis and an ELISA. Genetic sequencing of the 365-base pair PCR product revealed 90% sequence identity with mink ADV. In the skunk of this report, infection with a skunk-specific parvovirus resulted in clinical signs and pathologic changes similar to those associated with ADV infection in mink. For skunks with signs of renal failure, differential diagnoses should include parvovirus infection. In confirmed cases of infection with this ADV-like virus, appropriate quarantine and biosecurity measures should be in place to prevent spread to other susceptible animals within a zoological collection.


Shaping the mouse heart tube from the second heart field epithelium.
As other tubular organs, the embryonic heart develops from an epithelial sheet of cells, referred to as the heart field. The second heart field, which lies in the dorsal pericardial wall, constitutes a transient cell reservoir, integrating patterning and polarity cues. Conditional mutants have shown that impairment of the epithelial architecture of the second heart field is associated with congenital heart defects. Here, taking the mouse as a model, we review the epithelial properties of the second heart field and how they are modulated upon cardiomyocyte differentiation. Compared to other cases of tubulogenesis, the cellular dynamics in the second heart field are only beginning to be revealed. A challenge for the future will be to unravel key physical forces driving heart tube morphogenesis.


HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition.
Epithelial-mesenchymal transition (EMT) is important during embryonic cell layer movement and tumor cell invasiveness. EMT converts adherent epithelial cells to motile mesenchymal cells, favoring metastasis in the context of cancer progression. Transforming growth factor-beta (TGF-beta) triggers EMT via intracellular Smad transducers and other signaling proteins. We previously reported that the high mobility group A2 (HMGA2) gene is required for TGF-beta to elicit EMT in mammary epithelial cells. In the present study we investigated the molecular mechanisms by which HMGA2 induces EMT. We found that HMGA2 regulates expression of many important repressors of E-cadherin. Among these, we analyzed in detail the zinc-finger transcription factor SNAIL1, which plays key roles in tumor progression and EMT. We demonstrate that HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. Furthermore, we observed that HMGA2 cooperates with the TGF-beta/Smad pathway in regulating SNAIL1 gene expression. The mechanism behind this cooperation involves physical interaction between these factors, leading to an increased binding of Smads to the SNAIL1 promoter. SNAIL1 seems to play the role of a master effector downstream of HMGA2 for induction of EMT, as SNAIL1 knock-down partially reverts HMGA2-induced loss of epithelial differentiation. The data propose that HMGA2 acts in a gene-specific manner to orchestrate the transcriptional network necessary for the EMT program.


Major lung complications of systemic sclerosis.
Systemic sclerosis (SSc) is associated with high mortality owing to internal organ complications, and lung disease is the leading cause of SSc-associated death. The most notable lung complications in SSc are fibrosis and pulmonary arterial hypertension (PAH). A major challenge for the management of lung disease in SSc is detecting those patients with severe pathology and those patients who are likely to benefit from available treatments. In the past few years, strategies for managing lung fibrosis and pulmonary hypertension, including PAH, have greatly progressed. For lung fibrosis, the tools to assess risk of progression and severity of the disease have been refined. Clinical trial results support the use of immunosuppression, including high-intensity regimens with autologous stem cell transplantation. New trials are underway to test other potential therapies including treatments that are approved for use in idiopathic lung fibrosis. For PAH, identifying individuals at high risk of disease development is critical. In addition, individuals who have borderline elevation of pulmonary arterial pressure need to be appropriately managed and followed up. Many approved drugs targeting PAH are now available, and results from large-scale clinical trials provide robust evidence that various treatments for SSc-associated PAH are associated with good long-term outcomes.


The spatial layout of doorways and environmental boundaries shape the content of event memories.
Physical boundaries in our environment have been observed to define separate events in episodic memory. To date, however, there is little evidence that the spatial properties of boundaries exert any control over event memories. To examine this possibility, we conducted four experiments that took manipulations involving boundaries that have been demonstrated to influence spatial representations, and adapted them for use in an episodic object memory paradigm. Here, participants were given 15 min to freely explore an environment that contained 36 objects, equally dispersed among six discriminable buildings. In a subsequent test of object-location binding, participants were required to indicate where they remembered encountering the objects. In Experiment 1 the spatial properties of the building boundaries were identical; however, in Experiment 2 the boundaries were differentiated by their geometric shape and the location of the doorways in the buildings. In the test phases of these experiments, we observed a shift from a bias towards remembering the positions of objects within a building but not the building itself (Experiment 1), to a bias towards remembering which building an object was in but not the location within the building (Experiment 2). In Experiment 3, the buildings shared the same geometry but were differentiated by the locations of doorways, and we observed no significant differences between response types. Finally, in Experiment 4, the buildings were uniquely shaped but shared the same doorway location, and we observed a bias towards remembering the positions of objects within a building. In addition, exploratory analyses of non-spatial interference revealed more correct recall for objects housed in the first building a participant visited during exploration, compared to all other buildings. Together, our data indicates that the location of doorways in boundaries and, to a lesser extent, boundary geometries influence event models, and that a primacy effect can be observed in the recall of multiple object-location bindings.


Resource and appointment scheduling: closing the information loop.
Hospital-wide preparation is currently underway for a new patient care information system at Baystate Medical Center in Springfield, Massachusetts. Integral to this new system are two new products recently developed by the TDS Healthcare Systems Corporation: a permanent patient record system and a resource and appointment scheduling application. The new patient care information system can maintain up to 16 million records on-line and can be used throughout the medical center. This article will focus on the resource and appointment scheduling application and how it can be used to track resource utilization and close the information loop related to patient appointment activities.


Clinical significance of respiratory isolates for Mycobacterium abscessus complex from pediatric patients.
Mycobacterium abscessus complex is the most virulent of rapidly growing mycobacteria causing invasive lung disease. To better delineate clinical pediatric experience and outcomes with M. abscessus complex, we retrospectively gathered 5-year data on M. abscessus complex infection and outcomes in a large, hospital-based pediatric pulmonary center. Patients were selected from the database of the microbiology department at Miller Children's Hospital in Long Beach, CA. Patients had at least one positive pulmonary isolate for M. abscessus complex from February 2006 to May 2011. Treatment modality data were collected and successful therapy of disease was determined as clearance of M. abscessus complex infection after antibiotics proven by culture negative respiratory isolate within at least 12 months of therapy initiation. Two cystic fibrosis patients with M. abscessus complex were identified, one with failed therapy and the other with stable pulmonary status despite persistent isolation. One primary ciliary dyskinesia patient had successful clearance of M. abscessus complex, however is now growing M. avium intracellulare. A patient with no prior medical history was successfully treated with antimycobacterial therapy. Eleven patients with neuromuscular disorders had tracheal aspirates positive for M. abscessus complex. None were treated due to stable lung status and all but two had spontaneous clearance of the mycobacteria. The two remaining persist with sporadic isolation of M. abscessus complex without clinical significance. We concluded that patients with tracheostomy associated M. abscessus complex infections do not appear to require treatment and often have spontaneous resolution. Cystic fibrosis or primary ciliary dyskinesia patients may have clinical disease warranting treatment, but current antimycobacterial therapy has not proven to be completely successful. As M. abscessus complex gains prevalence, standardized guidelines for diagnosis and therapy are needed in the pediatric population. Multicenter cohort analysis is necessary to achieve such guidelines.


Conformational transition of SARS-CoV-2 spike glycoprotein between its closed and open states.
In 2020, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide and caused the coronavirus disease 2019 (COVID-19). Spike (S) glycoproteins on the viral membrane bind to ACE2 receptors on the host cell membrane and initiate fusion, and S protein is currently among the primary drug target to inhibit viral entry. The S protein can be in a receptor inaccessible (closed) or accessible (open) state based on down and up positions of its receptor-binding domain (RBD), respectively. However, conformational dynamics and the transition pathway between closed to open states remain unexplored. Here, we performed all-atom molecular dynamics (MD) simulations starting from closed and open states of the S protein trimer in the presence of explicit water and ions. MD simulations showed that RBD forms a higher number of interdomain interactions and exhibits lower mobility in its down position than its up position. MD simulations starting from intermediate conformations between the open and closed states indicated that RBD switches to the up position through a semi-open intermediate that potentially reduces the free energy barrier between the closed and open states. Free energy landscapes were constructed, and a minimum energy pathway connecting the closed and open states was proposed. Because RBD-ACE2 binding is compatible with the semi-open state, but not with the closed state of the S protein, we propose that the formation of the intermediate state is a prerequisite for the host cell recognition.


Mechanisms of antiinflammatory action of alpha-MSH peptides. In vivo and in vitro evidence.
alpha-Melanocyte stimulating hormone (alpha-MSH) modulates all forms of inflammation by acting on peripheral inflammatory cells, glial inflammatory cells, and on CNS receptors that activate descending antiinflammatory neural pathways. The multiple actions of this ancient peptide suggest that there is no singular biochemical mechanism through which it exerts its antiinflammatory activity. However, research on IL-10 deficient and Agouti protein hypersecreting mice provide new insights into the actions of the peptide in living animals. Studies of cultured human astrocytes, whole murine brain, and human monocyte/macrophages indicate that a primary effect of the peptide is modulation of activation of the nuclear transcription factor kappa B. The latter influence may underlie the established reduction of gene expression and production of proinflammatory peptides and inducible nitric oxide by alpha-MSH peptides.


Strain of Supramolecular Interactions in Single-Stacking Junctions.
Supramolecular electronics provide opportunities to integrate molecular building blocks into electronic circuits, and investigations of the mechanical properties of the non-covalent interactions are necessary to understand the role of the assembly configuration in the electronic coupling among different assembly blocks. However, the mechanical characterization of supramolecular interactions remains experimentally challenging. We investigated the strain distribution of the supramolecular interactions through a series of single-stacking junctions. The alpha values exhibit a clear odd-even effect versus the numbers of thiophene rings. The theoretical calculations demonstrated that a larger rotational barrier of the single-stacking junctions with an even number of thiophene rings leads to limited torsional freedom and thus a smaller strain distribution. These results provide new insights into the control of supramolecular interactions by the design of the basic molecular building blocks.


Correlations of antioxidant activity against phenolic content revisited: a new approach in data analysis for food and medicinal plants.
This study presents a new approach to analyze data correlating total antioxidant activity and total phenolic compounds in foods. The correlation of both variables is a common practice found in the literature. The purpose of these correlations is to determine the contribution of phenolics to the total antioxidant activity of foods. When low R(2) values are obtained, the general conclusion is that other compounds have a higher relevance than phenolics in the total antioxidant activity of the samples. However, these correlations do not consider differences in the phenolic profiles that can be qualitatively (type of phenolics present) and quantitatively (the relative amounts or proportions of phenolics present) among the samples under investigation. The new approach to analyze these simple correlations presented herein takes into consideration the phenolic profiles and provides information on the effectiveness of phenolics present in the samples to neutralize free radicals. Data obtained from carrots stored under conditions of air and hyperoxia (superatmospheric oxygen) are used to exemplify how to apply this new approach.


Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation.
X-linked hereditary demyelinating neuropathies (Charcot-Marie-Tooth Disease [CMTX]) caused by mutations in the connexin 32 (Cx32) gene account for approximately 10% to 20% of all hereditary demyelinating neuropathies. Mild subclinical central nervous system (CNS) involvement has been previously described, and CMTX patients with transient white matter lesions allied to CNS symptoms have very recently been described. This is of potential interest, as Cx32 is widely expressed in both peripheral nerve and the brain. We describe a family with hereditary demyelinating neuropathy and transient CNS symptoms. For this study, family members underwent genotyping and detailed clinical, electrophysiological, and magnetic resonance imaging examination. We present a CMTX family with a novel mutation in the Cx32 gene. Affected family members show, in addition to the classic polyneuropathy, transient and reversible white matter lesions on magnetic resonance imaging scans, correlating similarly transient CNS symptoms. Patients with CMTX can present with transient CNS symptoms and marked white matter lesions on magnetic resonance imaging scans.


Preschool-age wheezing phenotypes and asthma persistence in adolescents.
Predicting long-term outcomes in individuals with childhood wheezing is of major clinical relevance. To identify and characterize childhood wheezing phenotypes related to asthma persistence in adolescence with a multidimensional statistical model, independent of predefined hypotheses. This prospective cohort study included 308 children, ages < 7 years, with recurrent wheezing. We systematically evaluated asthma prevalence in children at 3, 8, and 13 years of follow-ups. Risk factors associated with asthma persistence in adolescence were analyzed with multivariable logistic regression. Early childhood wheezing phenotypes were identified with k-means cluster analysis of variables selected with the logistic regression analysis, which were based on questionnaires and skin-prick tests. These phenotypes were compared for predicting asthma prevalence, use of control treatments, and lung function in childhood and adolescence. Asthma prevalence was 58.3% (n = 249) and 53.5% (n = 170) at the 8- and 13-year follow-ups, respectively. Preschool-age diagnoses of atopy (odds ratio 11.8 [95% confidence interval, 4.0-34.6]) and rhinitis (odds ratio 10.4 [95% confidence interval, 3.7-29.1]) were independent risk factors for asthma persistence in adolescence. We identified three early childhood wheezing phenotypes: transient, persistent atopic, and persistent nonatopic. The latter two were characterized by rhinitis during preschool age. These phenotypes could predict the following outcomes: asthma symptom persistence, use of control treatments, and lung function during childhood and adolescence (p < 0.03). Asthma persistence through adolescence reflected different wheezing phenotypes based on preschool-age comorbidities, particularly rhinitis, with or without atopy. Our results supported that wheezing phenotypes, identified at early ages from simple measurements, could predict asthma and lung function outcomes.


Red knots (Calidris canutus islandica) manage body mass with dieting and activity.
Mass regulation in birds is well documented. For example, birds can increase body mass in response to lower availability and/or predictability of food and decrease body mass in response to increased predation danger. Birds also demonstrate an ability to maintain body mass across a range of food qualities. Although the adaptive significance of mass regulation has received a great deal of theoretical and empirical attention, the mechanisms by which birds achieve this have not. Several non-exclusive mechanisms could facilitate mass regulation in birds. Birds could regulate body mass by adjusting food intake (dieting), activity, baseline energetic requirements (basal metabolic rate), mitochondrial efficiency or assimilation efficiency. Here, we present the results of two experiments in captive red knots (Calidris canutus islandica) that assess three of these proposed mechanisms: dieting, activity and up- and down-regulation of metabolic rate. In the first experiment, knots were exposed to cues of predation risk that led them to exhibit presumably adaptive mass loss. In the second experiment, knots maintained constant body mass despite being fed alternating high- and low-quality diets. In both experiments, regulation of body mass was achieved through a combination of changes in food intake and activity. Both experiments also provide some evidence for a role of metabolic adjustments. Taken together, these two experiments demonstrate that fine-scale management of body mass in knots is achieved through multiple mechanisms acting simultaneously.


Detection of cortisol at a gold nanoparticle|Protein G-DTBP-scaffold modified electrochemical immunosensor.
An ultrasensitive electrochemical immmunosensor was demonstrated to be capable of detecting the hormone cortisol down to concentrations as low as 16 pg mL(-1). In addition, the immunosensor displayed a sensitivity of 1.6 μA pg(-1) mL(-1) and a linear range up to ∼2500 pg mL(-1) of cortisol. This immunosensor was constructed based on a Au nanoparticle|dimethyl 3,3'-dithiobispropionimidate·2HCl (DTBP)-Protein G scaffold-modified Au electrode. In this work, the Au nanoparticles were used to increase the electrochemically active surface area by 28% (with a standard deviation of 3%) to enhance the quantity of the Protein G scaffold on the electrode. Thiolation of Protein G by DTBP aided in avoiding the confirmation change of Protein G, while this Protein G-DTBP component offered an orientation-controlled immobilisation of the capture antibody on the Au electrode. In this immunosensor, a monoclonal anti-cortisol capture antibody was optimally aligned by the scaffold before a competitive immunoassay between sample cortisol and a horseradish peroxidase-labelled cortisol conjugate was conducted. For quantitative analysis, square wave voltammetry was used to monitor the reduction current of benzoquinone produced from a horseradish peroxidase catalysed reaction. The improved analytical performance of our immunosensor was attributed to the synergetic effect of Au nanoparticles and the Protein G-DTBP scaffold.


Weak opiate analgesics: modest practical merits.
(1) The first-line drugs for mild to moderate pain are non opiate analgesics, namely paracetamol and nonsteroidal antiinflammatory drugs (NSAIDs). (2) Codeine, dextropropoxyphene and tramadol are weak opiates; they are often used with paracetamol in fixed-dose combinations, in order to reinforce the analgesic effect of paracetamol. (3) These analgesic combinations have only been evaluated in a few situations associated with chronic and acute pain. And the endpoints used in clinical trials are designed more to show statistically significant differences than clear clinical differences. (4) In acute pain, available meta-analyses confirm that the first-line drug is paracetamol, or, if necessary, ibuprofen, a NSAID. (5) The paracetamol + codeine combination slightly increases the analgesic effect of paracetamol, but causes more adverse effects. Combinations of paracetamol + dextropropoxyphene and paracetamol + tramadol are even less useful. (6) The few available clinical trials fail to demonstrate that combining paracetamol with a NSAID is any more effective than either drug given alone, while adverse effects are increased. (7) Paracetamol is also the first-line treatment for chronic non cancer pain, such as low back pain or pain due to osteoarthritis of the hip. NSAIDs have no advantages over paracetamol in these settings. We found no trials of paracetamol + NSAID combinations. Combinations of paracetamol and weak opiates have been inadequately studied in this situation, and are only second-line options.


Evolutionary adaptation revealed by comparative genome analysis of woolly mammoths and elephants.
Comparative genomics studies typically limit their focus to single nucleotide variants (SNVs) and that was the case for previous comparisons of woolly mammoth genomes. We extended the analysis to systematically identify not only SNVs but also larger structural variants (SVs) and indels and found multiple mammoth-specific deletions and duplications affecting exons or even complete genes. The most prominent SV found was an amplification of RNase L (with different copy numbers in different mammoth genomes, up to 9-fold), involved in antiviral defense and inflammasome function. This amplification was accompanied by mutations affecting several domains of the protein including the active site and produced different sets of RNase L paralogs in four mammoth genomes likely contributing to adaptations to environmental threats. In addition to immunity and defense, we found many other unique genetic changes in woolly mammoths that suggest adaptations to life in harsh Arctic conditions, including variants involving lipid metabolism, circadian rhythms, and skeletal and body features. Together, these variants paint a complex picture of evolution of the mammoth species and may be relevant in the studies of their population history and extinction.


Design of a MUC1-based tricomponent vaccine adjuvanted with FSL-1 for cancer immunotherapy.
MUC1 is an attractive target for cancer vaccines as a result of its over-expression and aberrant glycosylation pattern on many tumor cells. However, the low immunogenicity of MUC1 and immune tolerance have limited its application. Herein, we designed MUC1-based tricomponent antitumor vaccines adjuvanted with fibroblast stimulating lipopeptide 1 (FSL-1). Immunological results indicate that the glycosylated tricomponent vaccine candidate has elicited both humoral and cellular immune responses. The induced antibodies could effectively bind to MCF-7. Furthermore, the vaccine exhibited an obvious reduction in tumour burden.


Prolonged streptokinase infusion in patients with unstable angina: results of a randomized, placebo-controlled clinical trial.
The purpose of this study was to assess the efficacy both of prolonged (48 h) and of short-duration (1 h) administrations of streptokinase in patients with unstable angina. In unstable angina, thrombosis is a dynamic process that waxes and wanes for hours and even days. The majority of previous studies have investigated the efficacy of short-duration thrombolytic regimens. One hundred patients with acute unstable angina were randomly allocated to receive placebo, 1,500,000 U streptokinase during 1 h or 250,000 U streptokinase during 1 h and then a prolonged infusion of 100,000 U for the next 48 h. All of the treatments included intravenous heparin administration for 72 h. No death occurred in the study population. One of 34 patients treated with placebo (2.9%), three of 33 treated with streptokinase during 1 h (9.0%) and three of 33 treated with streptokinase during 48 h (9.0%) had a myocardial infarction. Refractory angina occurred in nine, three and seven patients receiving placebo, streptokinase during 1 h and streptokinase during 48 h, respectively. Kaplan-Meier analysis showed that the total probability for a patient to be free of cumulative events did not differ among the three groups of patients (NS). Fourteen patients (41%) receiving placebo, 15 patients (45%) receiving streptokinase during 1 h and 14 patients (42%) receiving streptokinase during 48 h had ischaemic episodes detected by Holter monitoring during the first 72 h after hospital admission (NS). Two patients receiving streptokinase during 48 h required blood transfusion, and a greater incidence of minor bleeding (P < 0.05) and adverse events (P < 0.02) was observed in patients receiving prolonged streptokinase administration than in those receiving streptokinase during 1 h or placebo. In patients with acute unstable angina, the administration of two different regimens of streptokinase significantly reduces the probability neither of developing cardiac events during hospitalization nor of ischaemia detected by Holter monitoring in the early phase after hospital admission. Although the sample size of the study provided sufficient power to exclude only a large difference in effect size, it did allow us to detect a significantly higher incidence of bleeding in the group of patients treated with prolonged streptokinase infusion.


[The clinical laboratory comparison in the assessment of treatment prognosis in patients with infiltrative tuberculosis of lungs].
The comprehensive prospective examination of 66 patients with first established non-treated infiltrative tuberculosis of lungs was used to analyze the possibility of optimization of assessment of course of specific inflammatory process on the basis of levels of proteins-reactants of acute phase. The characteristics of dynamics of clinical roentgenologic data and terms of coming of abacillarization as a result of three months anti-tuberculosis therapy has been used as grouping factors. It is established that the constellation of 3 out of 12 basic (before treatment) analyzed level indicators are the most prognostic informative--haptoglobin, ceruloplasmin and blood albumin. Their combined application according the proposed decisive rule provides 90.6% of effectiveness of prognosis of the results of treatment in the discussed category of patients.


Increased frequency of acute reactions to iodinated contrast media in cancer patients treated with anti-CTLA-4 immunomodulatory antibodies.
Contrast-enhanced computed tomography (CECT) is an indispensable tool in the management of cancer patients. However, this procedure can be complicated by the development of acute adverse reactions (ARs) to iodinated contrast media (ICM). On the basis of the hypothesis that cancer immunotherapy, in particular with immune checkpoint inhibitors, increases the incidence of allergic-like immediate ARs to ICM with respect to "standard" cancer chemotherapy/targeted therapy (CHT) we retrospectively evaluated the incidence of CECT-related immediate ARs in cancer patients undergoing cancer treatments. All patients who underwent at least one CECT scan after starting any cancer treatment between 2006 and 2014 were included in a mono-institutional radiological database. The staff of the Radiology Unit recorded any ARs that occurred within 30 min of the ICM injection and classified them as "allergic-like" or "physiologic" and graded as mild, moderate, or severe according to the American College of Radiology (ACR) Manual on Contrast Media, version 10.1. Fifty-nine of the 3,521 patients included in the database received ipilimumab (Ipi), 75 received cytokines (Cys), and the remaining 3,387 received non-immunologic agents (CHT). Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in Ipi- and Cy-treated patients than in those who received CHT (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering CECT-related immediate ARs with respect to non-immunologic agents. Although these findings need to be validated in larger prospective studies, they serve as a "wake-up call" for radiologists to closely monitor patients who have previously received cancer immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies when using ICM in order to reduce the risk of potentially severe immediate ARs.


A retrospective study of the profile of ESN children seen at the Child Psychiatric Clinic.
A retrospective study of 50 cases of educationally subnormal children seen at the Child Psychiatric Clinic was done. Almost half of the referrals were initiated by schools, the majority being picked up at Primary 1. Forty-six percent of fathers and sixty percent of mothers had no more than primary education. Eighty-two percent of fathers had unskilled or semi-skilled jobs. Besides being below average in academic performance in school, these children also showed some behavioural problems like restlessness, disobedience, bullying, quarrelling or fighting with other children. They tended to be solitary, unresponsive, inert or apathetic, and were not much liked by others. Although all the children were referred and registered for special education, only half the number of parents accepted the offer for their children.


Functional Outcomes of 24-Hour Thumb Immobilization in Healthy Volunteers: Prospective Comparative Study.
Background Immobilization is often needed for the treatment of wrist and hand injuries. The current best method of immobilization for several types of injuries has yet to be elucidated with little being reported on the functional differences of each type of immobilization. Purpose The purpose of this study is to compare the functional outcome between healthy young volunteers with a 24-hour short arm cast (SAC) versus thumb spica cast (TSC) immobilization. Methods A total of 50 healthy volunteers completed a baseline typing assessment and a Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity functional scoring assessment. Participants in group 1 were randomly initially assigned to a TSC of their dominant hand followed by an SAC, whereas participants in group 2 were randomly initially assigned to a TSC of their nondominant hand followed by an SAC. The volunteers completed the typing assessment and PROMIS assessment at the end of the 24-hour casting period. Results A total of 50 participants were enrolled in the study with 25 in group 1 and 25 in group 2. There was a 24.3-point difference between the average PROMIS score for participants with SAC compared with participants with TSC (93 vs. 68.7; p = 0.0001). There was a significant difference between the typing speed and accuracy of participants with SAC compared with participants with TSC ( p = 0.0001). Conclusion There is a significant difference in functionality of a TSC immobilization versus an SAC immobilization according to the PROMIS functional outcome score and typing speed in a 24-hour casting period. SAC immobilization should be considered to have a possible similar effect in pathologic conditions instead of TSC immobilization given these findings even though a 24-hour period is not enough to provide adequate long-term conclusions. Level of Evidence I, prospective comparative study.


Drug treatment of bipolar depression and mania.
Bipolar manic-depressive disorder may present as mania, depression, or mixed states, and there is increasing knowledge of its responsiveness to drugs as therapeutic agents. In addition a number of drugs may act as aggravating factors for the disorder.


Cerebral Air Embolism: The Importance of Computed Tomography Evaluation.
Cerebral air embolism (CAE) is a serious disease, often underdiagnosed due to nonspecific neurological findings and clinical and imaging unawareness. Early diagnosis is crucial for a prompt specific treatment, which differs from other types of brain infarcts. Immediate computed tomography (CT) scan is the imaging technique of choice, allowing to depict acute intracranial air, most commonly seen in the high convexity along cortical grooves, in a sulcal subarachnoid gyriform pattern. The use of thin-slice (thickness of 5 mm or smaller) and the measurement of air attenuation coefficient can reduce false-negative studies. Hyperbaric oxygen therapy (HBOT) is the first-line treatment for CAE and may affect the outcome. We report four cases of iatrogenic CAE and review the literature.


Genetic Imbalance in Patients with Cervical Artery Dissection.
Genetic and environmental risk factors are assumed to contribute to the susceptibility to cervical artery dissection (CeAD). To explore the role of genetic imbalance in the etiology of CeAD, copy number variants (CNVs) were identified in high-density microarrays samples from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study and from control subjects from the CADISP study and the German PopGen biobank. Microarray data from 833 CeAD patients and 2040 control subjects (565 subjects with ischemic stroke due to causes different from CeAD and 1475 disease-free individuals) were analyzed. Rare genic CNVs were equally frequent in CeAD-patients (16.4%; n=137) and in control subjects (17.0%; n=346) but differed with respect to their genetic content. Compared to control subjects, CNVs from CeAD patients were enriched for genes associated with muscle organ development and cell differentiation, which suggests a possible association with arterial development. CNVs affecting cardiovascular system development were more common in CeAD patients than in control subjects (p=0.003; odds ratio (OR) =2.5; 95% confidence interval (95% CI) =1.4-4.5) and more common in patients with a familial history of CeAD than in those with sporadic CeAD (p=0.036; OR=11.2; 95% CI=1.2-107). The findings suggest that rare genetic imbalance affecting cardiovascular system development may contribute to the risk of CeAD. Validation of these findings in independent study populations is warranted.


Sports anaemia and anthropometric evaluation of footballers at Kwame Nkrumah University of Science and Technology (KNUST).
Sports anaemia is a physiological activity that occurs amongst footballers and may be due to poor diet, over-training, as well as an increase in plasma volume in endurance training activities. High plasma volume leads to changes in haematological parameters that may impact on endurance of footballers. The objective of the study was to determine the correlation between haematological and an-thropometric indices and their role in sports anaemia in a tropical setting. Venous blood was taken into EDTA for 12 soccer players of KNUST soccer team before training and after training for the first (W1) and fifth (W5) weeks of training sessions. Complete blood count analysis was done for each blood sample and anthropometric parameters such as height, weight, body mass index, body fat percent and lean body mass were also measured. Cross-tabulations with mean and standard deviation or median and range were computed. Paired t-test & and Mann-Whitney test for parametric and non-parametric data computations were carried out and a p-value ≤ 0.05 was taken to rep-resent significant difference between data groups. There was significant reduction in haemoglobin (p = 0.003), haematocrit (p = 0.002), mean cell volume (MCV) (p = 0.034) and red blood cell (RBC) count (p = 0.011) as a result of a significant expansion of plasma volume (p= 0.006). Neutrophil, lymphocyte and eosinophil counts were reduced significantly (p= 0.043, 0.001 and 0.007, respectively) after the training at W5. Lean body mass (LBM) inversely correlated with haemoglobin (r = -0.787, p = 0.002) and haematocrit (r = -0.588, p = 0.044). Body fat percentage (BFP) also negatively correlated with lymphocyte count (r = -0.700, p = 0.011). Furthermore, there was a positive correlation between body mass index (BMI) and plasma volume change after the training programme (r = 0.689, p = 0.013). The results suggest that sports anaemia was induced by an increase in plasma volume that resulted in changes in haematological parameters.


Numerical investigation of heat transfer enhancement in a rectangular heated pipe for turbulent nanofluid.
Thermal characteristics of turbulent nanofluid flow in a rectangular pipe have been investigated numerically. The continuity, momentum, and energy equations were solved by means of a finite volume method (FVM). The symmetrical rectangular channel is heated at the top and bottom at a constant heat flux while the sides walls are insulated. Four different types of nanoparticles Al2O3, ZnO, CuO, and SiO2 at different volume fractions of nanofluids in the range of 1% to 5% are considered in the present investigation. In this paper, effect of different Reynolds numbers in the range of 5000 < Re < 25000 on heat transfer characteristics of nanofluids flowing through the channel is investigated. The numerical results indicate that SiO2-water has the highest Nusselt number compared to other nanofluids while it has the lowest heat transfer coefficient due to low thermal conductivity. The Nusselt number increases with the increase of the Reynolds number and the volume fraction of nanoparticles. The results of simulation show a good agreement with the existing experimental correlations.


Delayed-onset bleb-associated endophthalmitis: clinical features and visual acuity outcomes.
To investigate clinical factors, causative organisms, treatments, and visual acuity and intraocular pressure outcomes associated with delayed-onset, bleb-associated endophthalmitis. Retrospective, noncomparative, consecutive case series. All patients treated for bleb-associated endophthalmitis at Bascom Palmer Eye Institute between January 1, 1996, and July 1, 2001. All patients had prior glaucoma filtering surgery. Patients with inadvertent functioning blebs after cataract extraction were excluded. Visual acuity outcomes and intraocular pressure control after endophthalmitis. An antifibrotic agent was used in 40 (82%) of the 49 eyes identified, including mitomycin-C in 33 (67%) and 5-fluorouracil (5-FU) in 7 (14%). The mean interval between the initial filtering surgery and endophthalmitis diagnosis was 5.0 years (range, 0.7-12.2 years). The mean follow-up time after treatment for endophthalmitis was 6.9 months (range, 1-60 months). As recorded in the medical record, potential risk factors and clinical features among the study population included history of bleb leak in 13 (27%) eyes, bleb manipulations in 15 (31%) (needling in 3 [6%], compression sutures in 2 [4%], laser suture lysis in 6 [12%], bleb revision in 5 [10%], and autologous blood injection in 2 [4%]), bleb defects in 6 (12%), inferior bleb location 6 (12%), and nasolacrimal duct obstruction in 1 (2%). The most common causative organisms were Streptococcus species in 15 eyes (31%) and Staphylococcus species in 11 eyes (22%). Final visual acuities in the vitrectomy group (n = 22) versus the initial tap group (n = 26) were as follows: > or = 20/40 (5% versus 15%), 20/50 to 20/400 (32% versus 54%), and < 5/200 (64% versus 31%). Eleven (22%) patients eventually underwent enucleation or evisceration secondary to pain and/or poor vision (light perception to no light perception). In 4 (11%) of the 38 eyes not enucleated, intraocular pressures were poorly controlled at last follow-up (>21 mmHg) after treatment of endophthalmitis. Streptococcus species and Staphylococcus species were the most common causative organisms in the current series of patients with delayed-onset bleb-associated endophthalmitis. Despite successful treatment of the infection, visual outcomes are generally poor.


Pathological examination of 12 regional lymph nodes and long-term survival in stages I-III colon cancer patients: an analysis of 2,056 consecutive patients in two branches of same institution.
Pathologic examination of at least 12 lymph nodes (LNs) is widely accepted as a standard for colon cancer surgery. We sought to address its association with patient source, other clinicopathological factors, and survival by comparing information from two branches in a large single institution. Patients with stages I-III adenocarcinoma of the colon between 1998 and 2003 were identified from the Chang Gung Colorectal Tumor Registry in two branches (Linkou and Kaohsiung branches) of same institution. We used multivariate analysis to adjust for variables with P < 0.1 in univariate analyses. A minimum of 12 examined nodes were observed in 80% of patients in Linkou branch versus 25% in Kaohsiung branch (P < 0.0001). Younger age, right hemicolectomy, larger tumor, higher tumor stage, higher caseload of surgeons, and patients at Linkou branch with an odds ratio (OR) as high as 23 (95% CI, 17-31) were independently associated with a higher frequency of ≥12 examined nodes. Patients with examined node number of <12 had a greater risk of recurrence within stages II and III (stage II: adjusted OR 1.88, 95% CI 1.27-2.79; stage III: adjusted OR 1.58, 95% CI 1.15-2.17) but not within stage I (OR 0.73, 95% CI 0.23-2.24). The results confirm that factors influencing nodal harvest are multifactorial and the examined LN number of 12 or more is associated with an increased long-term survival in stages II-III colon cancer. It is possible to adequately sample and examine a sufficient number of nodes in the majority of colon cancer specimens by standardized conventional methods.


Mechanism of paracetamol-induced hypotension in critically ill patients: a prospective observational cross-over study.
To elucidate the mechanism of hypotension following intravenous administration of paracetamol (acetaminophen) to patients on the Intensive Care Unit. Prospective observational cross-over study. Intensive Care Unit, University Hospital Královské Vinohrady, Prague, Czech Republic. Ventilated critically ill patients monitored by PiCCO and administered intravenous paracetamol at the same time were eligible for the study. We recorded haemodynamic indices, as well as core and peripheral temperatures, continuously for 3 h after the dose of paracetamol. Ranitidine was then used as a control drug known not to influence haemodynamics. We included 6 subjects, and recorded 48 cycles of observations after administration of paracetamol, and 35 cycles after administration of the control drug. Haemodynamic parameters were not different at the baseline and administration of control drug did not result in any change in haemodynamics. After intravenous paracetamol, mean arterial pressure (MAP) dropped by 7% (p<0.001) with a nadir at the 19th minute. In 22 measurement cycles (45%) we noted >15% reduction in MAP with paracetamol. Analysis of these cycles suggests that hypotension with paracetamol can be caused by reduction of both cardiac index and systemic vascular resistance. In febrile cycles paracetamol caused narrowing of the gradient between central and peripheral temperatures suggesting skin vasodilation. These changes were not correlated to a change of systemic vascular resistance at any time point. Hypotension with intravenous paracetamol in critically ill patients is caused by a reduction of both cardiac output and systemic vascular resistance. We did not demonstrate any relation between haemodynamic changes and antipyretic action of paracetamol. A possibility that cardiac output is reduced with paracetamol might be clinically important.


Graves' disease with only unilateral involvement; a case report.
Graves' disease characteristically presents with a diffuse goiter secondary to the autoantibodies that target the thyrotropin receptors of the thyroid gland. Few cases have been reported of only one of the two lobes being affected. The cause of this phenomenon is still uncertain. Here we report on another case of unilateral Graves' disease. A 43-year-old female patient presented with a history of weight loss, palpitations and right sided neck swelling for 4 months. Clinical examination showed an enlarged right thyroid lobe. Laboratory investigations yielded evidence of thyrotoxicosis with suppressed thyroid stimulating hormone. In addition, anti-TSH receptor and anti-thyroperoxidase antibodies were positive. Neck Ultrasound showed an enlarged right thyroid lobe with increased vascularization. The isthmus and left lobe were both normal in size. A Tc99m pertechnetate thyroid scan demonstrated enlargement of the right thyroid lobe with diffuse intense uptake, whereas the left lobe was suppressed. A diagnosis of unilateral Graves' disease was made. The thyrotoxicosis was treated and maintained with methimazole. Unilateral Graves' disease is a rare manifestation of Graves' disease, sharing the same autoimmune background and the symptoms of thyrotoxicosis. Enlargement of only one lobe was evident on clinical examination. The distinctive feature was unilateral uptake during thyroid scintigraphy. The exact pathophysiology of this condition has yet to be elucidated. Management options and responses are similar to those of classical Graves' disease. Unilateral uptake during thyroid scintigraphy and/or unilateral lobar goiter in the setting of hyperthyroidism can be the presentation of unilateral Graves' disease.


Characterisation of a Pseudomonas aeruginosa twitching motility gene and evidence for a specialised protein export system widespread in eubacteria.
Type-4 fimbriae (pili) are associated with a phenomenon known as twitching motility, which appears to be involved with bacterial translocation across solid surfaces. Pseudomonas aeruginosa mutants which produce fimbriae, but which have lost the twitching motility function, display altered colony morphology and resistance to fimbrial-specific bacteriophage. We have used phenotypic complementation of such mutants to isolate a region of DNA involved in twitching motility. This region was physically mapped to a SpeI fragment around 20 min on the P. aeruginosa PAO chromosome, remote from the major fimbrial locus (around 75 min) where the structural subunit-encoding gene (fimA/pilA) and ancillary genes required for fimbrial assembly (pilB, C and D) are found. A gene, pilT, within the twitching motility region is predicted to encode a 344-amino acid protein which has strong homology to a variety of other bacterial proteins. These include the P. aeruginosa PilB protein, the ComG ORF-1 protein from the Bacillus subtilis comG operon (necessary for competence), the PulE protein from the Klebsiella oxytoca (formerly K. pneumoniae) pulC-O operon (involved in pullulanase export), and the VirB-11 protein from the virB operon (involved in virulence) which is located on the Agrobacterium tumefaciens Ti plasmid. We have also identified other sets of homologies between P. aeruginosa fimbrial assembly (Pil) proteins and B. subtilis Com and K. oxytoca Pul proteins, which suggest that these are all related members of a specialised protein export pathway which is widespread in the eubacteria.


Pancreatic pseudocyst: heparin-induced haemorrhage through the ampulla of Vater.
Bleeding from a pancreatic pseudocyst through the ampulla of Vater is a rare cause of overt gastrointestinal haemorrhage. Previously described mechanisms of such haemorrhage are reviewed. We report a case of a 74-year-old female with a pancreatic pseudocyst that bled into the gastrointestinal tract following the administration of heparin. We believe that this is the first reported case of its kind.


Awareness and Attitudes Toward HIV Self-Testing in Northern Thailand.
Human Immunodeficiency Virus self-testing (HIVST) was recently introduced in Thailand, but little is known about receptivity among its residents. Because Human Immunodeficiency Virus (HIV) testing is a critical component of HIV prevention, it is important to understand how HIVST is perceived among potential users. The purpose of this study was to examine awareness and attitudes toward HIVST among adults in Northern Thailand. A convenience sample of 403 adult residents of the Sanpatong district, Chiang Mai Province, was interviewed using a structured questionnaire in 2019. Awareness of HIVST was low (14%), as was the overall HIVST negative attitude score (6.44; possible range of 0-14). The odds of being aware of HIVST were more than twice as high for those with more education compared to those with less (AOR = 2.29, 95% CI: 1.22-4.30), and roughly half as high for those who expressed HIV stigma compared to those who did not (AOR = 0.49, 95% CI: 0.26-0.91). Holding negative attitudes towards HIVST also was associated with lower education and expressing HIV stigma, but these relationships disappeared in multivariate analysis. Findings may be used by local health organizations to tailor HIVST education efforts.


Alpha-synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells by antagonizing ER/Golgi SNAREs.
Toxicity of human alpha-synuclein when expressed in simple organisms can be suppressed by overexpression of endoplasmic reticulum (ER)-to-Golgi transport machinery, suggesting that inhibition of constitutive secretion represents a fundamental cause of the toxicity. Whether similar inhibition in mammals represents a cause of familial Parkinson's disease has not been established. We tested elements of this hypothesis by expressing human alpha-synuclein in mammalian kidney and neuroendocrine cells and assessing ER-to-Golgi transport. Overexpression of wild type or the familial disease-associated A53T mutant alpha-synuclein delayed transport by up to 50%; however, A53T inhibited more potently. The secretory delay occurred at low expression levels and was not accompanied by insoluble alpha-synuclein aggregates or mistargeting of transport machinery, suggesting a direct action of soluble alpha-synuclein on trafficking proteins. Co-overexpression of ER/Golgi arginine soluble N-ethylmaleimide-sensitive factor attachment protein receptors (R-SNAREs) specifically rescued transport, indicating that alpha-synuclein antagonizes SNARE function. Ykt6 reversed alpha-synuclein inhibition much more effectively than sec22b, suggesting a possible neuroprotective role for the enigmatic high expression of ykt6 in neurons. In in vitro reconstitutions, purified alpha-synuclein A53T protein specifically inhibited COPII vesicle docking and fusion at a pre-Golgi step. Finally, soluble alpha-synuclein A53T directly bound ER/Golgi SNAREs and inhibited SNARE complex assembly, providing a potential mechanism for toxic effects in the early secretory pathway.


Childhood maltreatment and post-deployment psychological distress: The indirect role of emotional numbing.
Childhood maltreatment is an increasingly established predictor of psychological problems. However, limited research addresses pathways though which childhood maltreatment influences the mental health of military personnel following deployment. The current study investigated the direct, and indirect through emotional numbing, relations between childhood maltreatment and psychological distress of recently deployed veterans. For a sample of 131 predominantly White, male Operation Iraqi Freedom/Operation Enduring Freedom members of U.S. Army National Guard and Reserve units, a path model was used to test the direct and indirect (through numbing) roles of childhood maltreatment on distress. Results showed that childhood maltreatment was not significantly directly associated with psychological distress one-year post-deployment but was indirectly related to distress by way of emotional numbing symptoms. Our findings suggest that childhood maltreatment may serve to influence returning veterans' experiences of psychological distress indirectly through increased emotional numbing following deployment. The importance of attending to emotional numbing symptoms among veterans with experiences of childhood maltreatment after deployment is highlighted. (PsycINFO Database Record


Venous lactate improves the prediction of in-hospital adverse outcomes in normotensive pulmonary embolism.
Arterial lactate is an established risk marker in patients with pulmonary embolism (PE). However, its clinical applicability is limited by the need of an arterial puncture. In contrast, venous lactate can easily be measured from blood samples obtained via routine peripheral venepuncture. We investigated the prognostic value of venous lactate with regard to in-hospital adverse outcomes and mortality in 419 consecutive PE patients enrolled in a single-center registry between 09/2008 and 09/2017. An optimised venous lactate cut-off value of 3.3 mmol/l predicted both, in-hospital adverse outcome (OR 11.0 [95% CI 4.6-26.3]) and all-cause mortality (OR 3.8 [95%CI 1.3-11.3]). The established cut-off value for arterial lactate (2.0 mmol/l) and the upper limit of normal for venous lactate (2.3 mmol/l) had lower prognostic value for adverse outcomes (OR 3.6 [95% CI 1.5-8.7] and 5.7 [95% CI 2.4-13.6], respectively) and did not predict mortality. If added to the 2019 European Society of Cardiology (ESC) algorithm, venous lactate <2.3 mmol/l was associated with a high negative predictive value (0.99 [95% CI 0.97-1.00]) for adverse outcomes in intermediate-low-risk patients, whereas levels ≥3.3 mmol/l predicted adverse outcomes in the intermediate-high-risk group (OR 5.2 [95% CI 1.8-15.0]). Venous lactate above the upper limit of normal was associated with increased risk for adverse outcomes and an optimised cut-off value of 3.3 mmol/l predicted adverse outcome and mortality. Adding venous lactate to the 2019 ESC algorithm may improve risk stratification. Importantly, the established cut-off value for arterial lactate has limited specificity in venous samples and should not be used.


Assessing the relationship between perfluoroalkyl substances, thyroid hormones and binding proteins in pregnant women; a longitudinal mixed effects approach.
The mechanisms involved in thyroid homeostasis are complex, and perfluoroalkyl substances (PFASs) have been indicated to interfere at several levels in this endocrine system. Disruption of the maternal thyroid homeostasis during early pregnancy is of particular concern, where subclinical changes in maternal thyroid hormones (THs) may affect embryonic and foetal development. The present study investigated associations between THs, thyroid binding proteins (TH-BPs) and PFAS concentrations in pregnant women from Northern Norway. Women participating in The Northern Norway Mother-and-Child contaminant Cohort Study (MISA) donated a blood sample at three visits related to their pregnancy and postpartum period (during the second trimester, 3 days and 6 weeks after delivery) in the period 2007-2009. Participants were assigned to quartiles according to PFAS concentrations during the second trimester and mixed effects linear models were used to investigate potential associations between PFASs and repeated measurements of THs, TH-BPs, thyroxin binding capacity and thyroid peroxidase antibodies (anti-TPOs). Women within the highest perfluorooctane sulfonate (PFOS) quartile had 24% higher mean concentrations of thyroid stimulating hormone (TSH) compared to the first quartile at all sampling points. Women within the highest quartiles of perfluorodecanoate (PFDA) had 4% lower mean concentrations of triiodothyronine (T3) and women within the highest quartile of perfluoroundecanoate (PFUnDA) had 3% lower mean concentrations of free triiodothyronine (FT3). Further, the difference in concentrations and the changes between three time points were the same for the PFAS quartiles. Thyroxin binding capacity was associated with all the THs and TH-BPs, and was selected as a holistic adjustment for individual changes in TH homeostasis during pregnancy. Finally, adjusting for maternal iodine status did not influence the model predictions. Findings in the present study suggest modifications of TH homeostasis by PFASs in a background exposed maternal population. The variation in levels of THs between PFAS quartiles was within normal reference ranges and may not be of clinical significance in the pregnant woman. However, subtle individual changes in maternal THs may have significant consequences for foetal health.


A Paradoxical Vasodilatory Nutraceutical Intervention for Prevention and Attenuation of Migraine-A Hypothetical Review.
Studies suggest that migraine pain has a vascular component. The prevailing dogma is that peripheral vasoconstriction activates baroreceptors in central, large arteries. Dilatation of central vessels stimulates nociceptors and induces cortical spreading depression. Studies investigating nitric oxide (NO) donors support the indicated hypothesis that pain is amplified when acutely administered. In this review, we provide an alternate hypothesis which, if substantiated, may provide therapeutic opportunities for attenuating migraine frequency and severity. We suggest that in migraines, heightened sympathetic tone results in progressive central microvascular constriction. Suboptimal parenchymal blood flow, we suggest, activates nociceptors and triggers headache pain onset. Administration of NO donors could paradoxically promote constriction of the microvasculature as a consequence of larger upstream central artery vasodilatation. Inhibitors of NO production are reported to alleviate migraine pain. We describe how constriction of larger upstream arteries, induced by NO synthesis inhibitors, may result in a compensatory dilatory response of the microvasculature. The restoration of central capillary blood flow may be the primary mechanism for pain relief. Attenuating the propensity for central capillary constriction and promoting a more dilatory phenotype may reduce frequency and severity of migraines. Here, we propose consideration of two dietary nutraceuticals for reducing migraine risk: L-arginine and aged garlic extracts.


Sequence characteristics required for cooperative binding and efficient in vivo titration of the replication initiator protein DnaA in E. coli.
Plasmids carrying the mioC promoter region, which contains two DnaA boxes, R5 and R6 with one misfit to the consensus TT(A)/(T)TNCACA, are as efficient in in vivo titration of the DnaA protein as plasmids carrying a replication-inactivated oriC region with its eight DnaA boxes. Three additional DnaA boxes around the promoter proximal R5 DnaA box were identified and shown by mutational analysis to be necessary for the cooperative binding of DnaA required for titration. These four DnaA boxes are located in the same orientation and with a spacing of two or three base-pairs. The cooperative binding was eliminated by insertion of half a helical turn between any of the DnaA boxes. Titration strongly depends on the presence and orientation of the promoter distal R6 DnaA box located 104 bp upstream of the R5 box as well as neighbouring sequences downstream of R6. Titration depends on the integrity of a 43 bp region containing the R5 DnaA box, while repression of mioC transcription by DnaA, which is dependent on the R5 DnaA box, was independent of the two DnaA boxes downstream of R5. Repression was also independent of the spacing between the two upstream DnaA boxes and the promoter as long as a DnaA box was located less than 20 bp upstream of the -35 sequence. Thus, the architectural requirements for titration and for repression of transcription are different. A new set of rules for identifying efficiently titrating DnaA box regions was formulated and used to analyse sequences for which good titration data are available.


Finding the Genomic Basis of Local Adaptation: Pitfalls, Practical Solutions, and Future Directions.
Uncovering the genetic and evolutionary basis of local adaptation is a major focus of evolutionary biology. The recent development of cost-effective methods for obtaining high-quality genome-scale data makes it possible to identify some of the loci responsible for adaptive differences among populations. Two basic approaches for identifying putatively locally adaptive loci have been developed and are broadly used: one that identifies loci with unusually high genetic differentiation among populations (differentiation outlier methods) and one that searches for correlations between local population allele frequencies and local environments (genetic-environment association methods). Here, we review the promises and challenges of these genome scan methods, including correcting for the confounding influence of a species' demographic history, biases caused by missing aspects of the genome, matching scales of environmental data with population structure, and other statistical considerations. In each case, we make suggestions for best practices for maximizing the accuracy and efficiency of genome scans to detect the underlying genetic basis of local adaptation. With attention to their current limitations, genome scan methods can be an important tool in finding the genetic basis of adaptive evolutionary change.