Contribution of cervical cord MRI and brain magnetization transfer imaging to the assessment of individual patients with multiple sclerosis: a preliminary study.
This study was performed to assess how established diagnostic criteria for brain magnetic resonance imaging (MRI) interpretation in cases of suspected multiple sclerosis (MS) (Barkhofs criteria) would perform in the distinction of MS from other diseases and whether other MR techniques (cervical cord imaging and brain magnetization transfer imaging [MTI]), might help in the diagnostic work-up of these patients. We retrospectively identified 64 MS and 59 non-MS patients. The latter group included patients with systemic immune-mediated disorders (SID; n=44) and migraine (n=15). All patients had undergone MRI scans of the brain (dual echo and MTI) and of the cervical cord (fast short-tau inversion recovery). The number and location of brain T2-hyperintense lesions and the number and size of cervical cord lesions were assessed. Brain images were also postprocessed to quantify the total lesion volumes (TLV) and to create histograms of magnetization transfer ratio (MTR) values from the whole of the brain tissue. Barkhofs criteria correctly classified 108/123 patients, thus showing an accuracy of 87.8%. "False negative" MS patients were 13, while 2 patients with systemic lupus erythematosus (SLE) were considered as "false positives". Using brain T2 TLV, nine of the "false negative" patients were correctly classified. Correct classification of 10 MS patients and both the SLE patients was possible based upon the presence or absence of one cervical cord lesion. Two MS patients with negative Barkhofs criteria and no cervical cord lesions were correctly classified based on their brain MTR values. Overall, only one MS patient could not be correctly classified by any of the assessed MR quantities. These preliminary data support a more extensive use of cervical cord MRI and brain MTI to differentiate between MS and other disorders in case of incondusive findings on T2-weighted MRI scans of the brain.


The serotonin transporter is required for stress-evoked increases in adrenal catecholamine synthesis and angiotensin II AT(2) receptor expression.
High numbers of serotonin transporter (SERT) binding sites and high serotonin (5-HT) content are expressed in the adrenal medulla of wild-type (SERT+/+) mice. Acute restraint stress increases adrenomedullary 5-HT, norepinephrine (NE) and epinephrine (E) release, adrenomedullary tyrosine hydroxylase (TH) mRNA, and angiotensin II AT(2) receptor expression. There are no alterations in adrenal catecholamine content during restraint. In littermate SERT-/- mice, which do not express SERT binding sites, the basal adrenomedullary 5-HT content is significantly reduced and does not increase after stress. The stress-induced increase in plasma E is higher in SERT-/- than in SERT+/+ animals. In SERT-/- mice, the stress-induced increase in expression of TH mRNA does not occur, and as a consequence, adrenal E content decreases, and adrenal E and NE content are lower than that of SERT+/+ mice during restraint. In addition, instead of increased expression, stress induces a profound decrease in the number of adrenomedullary AT(2) receptors in SERT-/- mice. Our results indicate that SERT is necessary for the stress-induced increase in adrenomedullary catecholamine synthesis and AT(2) receptor expression. These data further indicate a close relationship between the adrenomedullary 5-HT and angiotensin II systems, and an important role of adrenomedullary AT(2) receptors in catecholamine synthesis and release during stress.


Spatial heterogeneity analysis of brain activation in fMRI.
In many brain diseases it can be qualitatively observed that spatial patterns in blood oxygenation level dependent (BOLD) activation maps appear more (diffusively) distributed than in healthy controls. However, measures that can quantitatively characterize this spatial distributiveness in individual subjects are lacking. In this study, we propose a number of spatial heterogeneity measures to characterize brain activation maps. The proposed methods focus on different aspects of heterogeneity, including the shape (compactness), complexity in the distribution of activated regions (fractal dimension and co-occurrence matrix), and gappiness between activated regions (lacunarity). To this end, functional MRI derived activation maps of a language and a motor task were obtained in language impaired children with (Rolandic) epilepsy and compared to age-matched healthy controls. Group analysis of the activation maps revealed no significant differences between patients and controls for both tasks. However, for the language task the activation maps in patients appeared more heterogeneous than in controls. Lacunarity was the best measure to discriminate activation patterns of patients from controls (sensitivity 74%, specificity 70%) and illustrates the increased irregularity of gaps between activated regions in patients. The combination of heterogeneity measures and a support vector machine approach yielded further increase in sensitivity and specificity to 78% and 80%, respectively. This illustrates that activation distributions in impaired brains can be complex and more heterogeneous than in normal brains and cannot be captured fully by a single quantity. In conclusion, heterogeneity analysis has potential to robustly characterize the increased distributiveness of brain activation in individual patients.


Trends in Maternal Mortality by Sociodemographic Characteristics and Cause of Death in 27 States and the District of Columbia.
To analyze recent trends in maternal mortality by sociodemographic characteristics and cause of death and to evaluate data quality. This observational study compared data from 2008-2009 with 2013-2014 for 27 states and the District of Columbia that had comparable reporting of maternal mortality throughout the period. Maternal mortality rates were computed per 100,000 live births. Statistical significance of trends and differentials was evaluated using a two-proportion z-test. The study population included 1,687 maternal deaths and 7,369,966 live births. The maternal mortality rate increased by 23% from 20.6 maternal deaths per 100,000 live births in 2008-2009 to 25.4 in 2013-2014. However, most of the increase was among women aged 40 years or older and for nonspecific causes of death. From 2008-2009 to 2013-2014, maternal mortality rates increased by 90% for women 40 years of age or older but did not increase significantly for women younger than 40 years. The maternal mortality rate for nonspecific causes of death increased by 48%; however, the rate for specific causes of death did not increase significantly between 2008-2009 (13.5) and 2013-2014 (15.0). Despite the United Nations Millennium Development Goal and a 44% decline in maternal mortality worldwide from 1990 to 2015, maternal mortality has not improved in the United States and appears to be increasing. Maternal mortality rates for women 40 years or older and for nonspecific causes of death were implausibly high and increased rapidly, suggesting possible overreporting of maternal deaths, which may be increasing over time. Efforts to improve reporting for the pregnancy checkbox and to modify coding procedures to place less reliance on the checkbox are essential to improving vital statistics maternal mortality data, the official data source for maternal mortality statistics used to monitor trends, identify at-risk populations, and evaluate the success of prevention efforts.


Evaluation of Nanopore sequencing for Mycobacterium tuberculosis drug susceptibility testing and outbreak investigation: a genomic analysis.
Mycobacterium tuberculosis whole-genome sequencing (WGS) has been widely used for genotypic drug susceptibility testing (DST) and outbreak investigation. For both applications, Illumina technology is used by most public health laboratories; however, Nanopore technology developed by Oxford Nanopore Technologies has not been thoroughly evaluated. The aim of this study was to determine whether Nanopore sequencing data can provide equivalent information to Illumina for transmission clustering and genotypic DST for M tuberculosis. In this genomic analysis, we analysed 151 M tuberculosis isolates from Madagascar, South Africa, and England, which were collected between 2011 and 2018, using phenotypic DST and matched Illumina and Nanopore data. Illumina sequencing was done with the MiSeq, HiSeq 2500, or NextSeq500 platforms and Nanopore sequencing was done on the MinION or GridION platforms. Using highly reliable PacBio sequencing assemblies and pairwise distance correlation between Nanopore and Illumina data, we optimise Nanopore variant filters for detecting single-nucleotide polymorphisms (SNPs; using BCFtools software). We then used those SNPs to compare transmission clusters identified by Nanopore with the currently used UK Health Security Agency Illumina pipeline (COMPASS). We compared Illumina and Nanopore WGS-based DST predictions using the Mykrobe software and mutation catalogue. The Nanopore BCFtools pipeline identified SNPs with a median precision of 99·3% (IQR 99·1-99·6) and recall of 90·2% (88·1-94·2) compared with a precision of 99·6% (99·4-99·7) and recall of 91·9% (87·6-98·6) using the Illumina COMPASS pipeline. Using a threshold of 12 SNPs for putative transmission clusters, Illumina identified 98 isolates as unrelated and 53 as belonging to 19 distinct clusters (size range 2-7). Nanopore reproduced 15 out of 19 clusters perfectly; two clusters were merged into one cluster, one cluster had a single sample missing, and one cluster had an additional sample adjoined. Illumina-based clusters were also closely replicated using a five SNP threshold and clustering accuracy was maintained using mixed Illumina and Nanopore datasets. Genotyping resistance variants with Nanopore was highly concordant with Illumina, having zero discordant SNPs across more than 3000 SNPs and four insertions or deletions (indels), across 60 000 indels. Illumina and Nanopore technologies can be used independently or together by public health laboratories performing M tuberculosis genotypic DST and outbreak investigations. As a result, clinical and public health institutions making decisions on which sequencing technology to adopt for tuberculosis can base the choice on cost (which varies by country), batching, and turnaround time. Academy for Medical Sciences, Oxford Wellcome Institutional Strategic Support Fund, and the Swiss South Africa Joint Research Award (Swiss National Science Foundation and South African National Research Foundation).


Tumoricidal activities of pterostilbene depend upon destabilizing the MTA1-NuRD complex and enhancing P53 acetylation in hepatocellular carcinoma.
The present study aimed to assess the tumoricidal effect of metastasis-associated protein 1 (MTA1) induced by pterostilbene (PTER) in hepatocellular carcinoma (HCC). The SMMC-7721 hepatoma cell line was treated with PTER. Following treatment, the mRNA transcript abundance of MTA1 was measured using quantitative polymerase chain reaction. Additionally, cell viability was determined using an MTT assay, and protein expression was measured through western blotting. Cell invasion, motility and apoptosis, as well as the cell cycle, were also investigated. Following PTER treatment, MTA1, histone deacetylase (HDAC) 1 and HDAC2 were downregulated, whereas the ratio of acetyl-p53 to total p53 was increased in HCC cells. Cell viability decreased as the PTER dose increased. MTA1 may be associated with proliferation, motility, invasion and metastasis in HCC cells. PTER appeared to repress cell proliferation, trigger apoptosis, induce cell cycle arrest, and inhibit motility and invasion via MTA1 in human liver cancer cells. The results of the present study demonstrated that PTER can downregulate the MTA1-nucleosome remodeling and deacetylase complex, and enhance p53 acetylation to inhibit the growth of tumor cells in HCC.


Proline and hydroxyproline metabolism: implications for animal and human nutrition.
Proline plays important roles in protein synthesis and structure, metabolism (particularly the synthesis of arginine, polyamines, and glutamate via pyrroline-5-carboxylate), and nutrition, as well as wound healing, antioxidative reactions, and immune responses. On a per-gram basis, proline plus hydroxyproline are most abundant in collagen and milk proteins, and requirements of proline for whole-body protein synthesis are the greatest among all amino acids. Therefore, physiological needs for proline are particularly high during the life cycle. While most mammals (including humans and pigs) can synthesize proline from arginine and glutamine/glutamate, rates of endogenous synthesis are inadequate for neonates, birds, and fish. Thus, work with young pigs (a widely used animal model for studying infant nutrition) has shown that supplementing 0.0, 0.35, 0.7, 1.05, 1.4, and 2.1% proline to a proline-free chemically defined diet containing 0.48% arginine and 2% glutamate dose dependently improved daily growth rate and feed efficiency while reducing concentrations of urea in plasma. Additionally, maximal growth performance of chickens depended on at least 0.8% proline in the diet. Likewise, dietary supplementation with 0.07, 0.14, and 0.28% hydroxyproline (a metabolite of proline) to a plant protein-based diet enhanced weight gains of salmon. Based on its regulatory roles in cellular biochemistry, proline can be considered as a functional amino acid for mammalian, avian, and aquatic species. Further research is warranted to develop effective strategies of dietary supplementation with proline or hydroxyproline to benefit health, growth, and development of animals and humans.


Wartime research on malaria chemotherapy.
Malaria was a major problem for the opposing forces in World War II. During the first year of operations in the South West Pacific the casualties caused by this disease greatly exceeded the numbers of battle casualties. In response to this situation comprehensive research and development programs to discover new antimalarial drugs were undertaken in the United States and Britain. In both countries compounds synthesised by co-operating chemical laboratories were screened against bird malaria and those with high activity and low toxicity were tested in man. The wartime program in America was funded by the Office of Scientific Research and Development and co-ordinated through a specially designated body under the Committee on Medical Research of the National Research Council. It was an enormous undertaking involving a massive co-operative effort between pharmacologists, chemists, and clinical research scientists from American universities, the US Public Health Service, and the laboratories of commercial pharmaceutical companies. The British program, on a much smaller scale, was based on a co-operative arrangement between the research laboratories of Imperial Chemical Industries at Manchester, the Liverpool School of Tropical Medicine and the British Medical Research Council. The wartime programs in both countries identified a number of promising leads but lacked the resources to permit their rapid clinical evaluation against field strains of human malaria. This deficiency was overcome by experiments conducted by the Land Headquarters Medical Research Unit of the Australian Army in Cairns, Queensland with the use of army volunteers. Large scale clinical trials of the most promising compounds which emerged from the American and British programs were carried out in Australia. This co-operative endeavour among allied scientists resulted in a range of new drugs which have had an enduring influence on malaria chemotherapy.


PEPFAR, health system strengthening, and promoting sustainability and country ownership.
Evidence demonstrates that scale-up of HIV services has produced stronger health systems and, conversely, that stronger health systems were critical to the success of the HIV scale-up. Increased access to and effectiveness of HIV treatment and care programs, attention to long-term sustainability, and recognition of the importance of national governance, and country ownership of HIV programs have resulted in an increased focus on structures that compromise the broader health system. Based on a review published literature and expert opinion, the article proposes 4 key health systems strengthening issues as a means to promote sustainability and country ownership of President's Emergency Plan for AIDS Relief and other global health initiatives. First, development partners need provide capacity building support and to recognize and align resources with national government health strategies and operational plans. Second, investments in human capital, particularly human resources for health, need to be guided by national institutions and supported to ensure the training and retention of skilled, qualified, and relevant health care providers. Third, a range of financing strategies, both new resources and improved efficiencies, need to be pursued as a means to create more fiscal space to ensure sustainable and self-reliant systems. Finally, service delivery models must adjust to recent advancements in areas of HIV prevention and treatment and aim to establish evidence-based delivery models to reduce HIV transmission rates and the overall burden of disease. The article concludes that there needs to be ongoing efforts to identify and implement strategic health systems strengthening interventions and address the inherent tension and debate over investments in health systems.


Hypercoagulability in hereditary hemorrhagic telangiectasia with epilepsy.
Recent data indicate that in patients with hereditary hemorrhagic teleangiectasia (HHT), low iron levels due to inadequate replacement after hemorrhagic iron losses are associated with elevated factor-VIII plasma levels and consecutively increased risk of venous thrombo-embolism. Here, we report a patient with HHT, low iron levels, elevated factor-VIII, and recurrent venous thrombo-embolism. A 64-year-old multimorbid Serbian gipsy was diagnosed with HHT at age 62 years. He had a history of recurrent epistaxis, teleangiectasias on the lips, renal and pulmonary arterio-venous malformations, and a family history positive for HHT. He had experienced recurrent venous thrombosis (mesenteric vein thrombosis, portal venous thrombosis, deep venous thrombosis), insufficiently treated with phenprocoumon during 16 months and gastro-intestinal bleeding. Blood tests revealed sideropenia and elevated plasma levels of coagulation factor-VIII. His history was positive for diabetes, arterial hypertension, hyperlipidemia, smoking, cerebral abscess, recurrent ischemic stroke, recurrent ileus, peripheral arterial occluding disease, polyneuropathy, mild renal insufficiency, and epilepsy. Following recent findings, hypercoagulability was attributed to the sideropenia-induced elevation of coagulation factor-VIII. In conclusion, HHT may be associated with hypercoagulability due to elevated factor-VIII associated with low serum iron levels from recurrent bleeding. Iron substitution may prevent HHT patients from hypercoagulability.


Effect of volcanic aerosols on stratospheric radiance at wavelengths between 8 and 13 microm.
A set of stratospheric aerosol optical models is employed in a radiative-transfer computation to study the effects of postvolcanic particle size distributions and compositions on the spectral radiance in the 8-13-microm window region. The models are based on direct measurements of post El Chichon aerosol size distributions and vertical profiles. They represent various maturity states of aerosols composed of sulfuric acid aqueous solutions, formed and evolved in the stratosphere following a massive volcanic eruption. Comparisons are made with concurrent radiance observations obtained on balloon flights 6 months after the eruption and 1 yr later. Most of the calculations are done using the LOWTRAN-6 code (either alone or combined with a multiple scattering calculation), revised so as to include the appropriate aerosol optical models. A better quantitative agreement is found between the calculated and observed spectral radiances when the aerosol loading is relatively high, indicating that additional minor radiance sources of a yet unresolved nature should be incorporated in the present version of the calculation.


Surface interaction parameter measurement of solvated polymers via model end-tethered chains.
We present a method for the direct measurement of the relative energy of interaction between a solvated polymer and a solid interface. By tethering linear chains covalently to the surface, we ensured the idealized and constant configuration of polymer molecules for measurement, modeling, and parameter estimation. For the case of amine-terminated polystyrene bound to a glycidoxypropyl silane film submerged in cyclohexane-d12, we estimated the χ parameter for the temperature range 10.7 °C to 52.0 °C, and found a downward sloping trend that crosses the χ = 0.5 threshold at 37 °C to 40 °C, in agreement with solution estimates for the same system. We simultaneously estimated the surface interaction parameter χs at each temperature, finding a decreasing affinity of the chains for the surface with increasing temperature, consistent with empirical observations. The theoretical model shows some limitations in a stronger solvent (toluene-d8) that prevent rigorous parameter estimation, but we demonstrate a qualitative change in χ and χs towards stronger solvency and weaker surface interaction with increasing temperature.


Phospholipid Scrambling by G Protein-Coupled Receptors.
Rapid flip-flop of phospholipids across the two leaflets of biological membranes is crucial for many aspects of cellular life. The transport proteins that facilitate this process are classified as pump-like flippases and floppases and channel-like scramblases. Unexpectedly, Class A G protein-coupled receptors (GPCRs), a large class of signaling proteins exemplified by the visual receptor rhodopsin and its apoprotein opsin, are constitutively active as scramblases in vitro. In liposomes, opsin scrambles lipids at a unitary rate of >100,000 per second. Atomistic molecular dynamics simulations of opsin in a lipid membrane reveal conformational transitions that expose a polar groove between transmembrane helices 6 and 7. This groove enables transbilayer lipid movement, conceptualized as the swiping of a credit card (lipid) through a card reader (GPCR). Conformational changes that facilitate scrambling are distinct from those associated with GPCR signaling. In this review, we discuss the physiological significance of GPCR scramblase activity and the modes of its regulation in cells.


Cognitive and psychomotor performance, mood, and pressor effects of caffeine after 4, 6 and 8 h caffeine abstinence.
Many studies have found that caffeine consumed after overnight caffeine abstinence improves cognitive performance and mood. Much less is known, however, about the effects of caffeine after shorter periods of caffeine abstinence. The aim of this study was to measure the effects on psychomotor and cognitive performance, mood, hand steadiness, blood pressure and heart rate of caffeine administration after periods of 4, 6, and 8 h of caffeine abstinence. Participants (n = 49, 27 female) were moderate to moderate-high caffeine consumers (mean daily intake 370 mg/day). Following overnight caffeine abstinence, a 'pre-dose' of caffeine (1.2 mg/kg) was administered at 9 A.M, 11 A.M or 1 P.M. The participants started a baseline battery of measurements at 4 P.M.: before receiving caffeine (1.2 mg/kg) or placebo at 5 P.M.: They then performed the battery of tests again, starting at 5:30 P.M. This was a double-blind, placebo-controlled, randomised study. Performance and mood measurements confirmed a psychostimulant action of caffeine (versus placebo), but only after 8 h of caffeine abstinence. Caffeine also increased blood pressure after 8-h abstinence, whereas hand steadiness was decreased and perception of task demand was increased by caffeine after 4 h, but not after 6- and 8-h abstinence. A second cup-of-coffee equivalent dose of caffeine only reliably affected cognitive performance and mood after an 8-h interval between doses, but not after shorter intervals (when caffeine had some adverse effects). These results show that, apart from caffeine consumption soon after waking, the daily pattern of caffeine intake of many typical caffeine consumers is not well explained by the short-term psychostimulant effects of caffeine.


Comparable Nutrient Uptake across Diel Cycles by Three Distinct Phototrophic Communities.
The capacity of microalgae to advance the limit of technology of nutrient recovery and accumulate storage carbon make them promising candidates for wastewater treatment. However, the extent to which these capabilities are influenced by microbial community composition remains poorly understood. To address this knowledge gap, 3 mixed phototrophic communities sourced from distinct latitudes within the continental United States (28° N, Tampa, FL; 36° N, Durham, NC; and 40° N, Urbana, IL) were operated in sequencing batch reactors (8 day solids residence time, SRT) subjected to identical diel light cycles with media addition at the start of the nighttime period. Despite persistent differences in community structure as determined via 18S rRNA (V4 and V8-V9 hypervariable regions) and 16S rRNA (V1-V3) gene amplicon sequencing, reactors achieved similar and stable nutrient recovery after 2 months (8 SRTs) of operation. Intrinsic carbohydrate and lipid storage capacity and maximum specific carbon storage rates differed significantly across communities despite consistent levels of observed carbon storage across reactors. This work supports the assertion that distinct algal communities cultivated under a common selective environment can achieve consistent performance while maintaining independent community structures and intrinsic carbon storage capabilities, providing further motivation for the development of engineered phototrophic processes for wastewater management.


Assessment of bowel function in the peripartum period.
Obstetric patients frequently experience changes in bowel function, throughout pregnancy and into the postpartum period. Little is known regarding the timing and consistency of bowel movements immediately postpartum. The primary aim of this study was to characterize the timing and consistency of the first bowel movement after obstetric delivery in a racially diverse population at an academic medical center. Patients were approached on the day of delivery. Patients received a data collection survey to record the date and consistency of their first bowel movement. Consistency was assessed using the Bristol Stool Form Scale. One hundred and sixty-nine patients were enrolled and 101 completed surveys were returned, for a response rate of 59%. The average number of days to first bowel movement was 1.55 versus 3.38 (p < 0.01), for vaginal delivery and cesarean section, respectively. Univariate analysis revealed cesarean delivery (+1.79 days, p < 0.01) and breastfeeding (-0.64 days, p = 0.01) as independent factors affecting the timing of the first bowel movement. Both route of delivery and breastfeeding status may affect timing and consistency of the first bowel movement after obstetric delivery.


Land tenure drives Brazil's deforestation rates across socio-environmental contexts.
Many tropical forestlands are experiencing changes in land-tenure regimes, but how these changes may affect deforestation rates remains ambiguous. Here, we use Brazil's land-tenure and deforestation data and quasi-experimental methods to analyze how six land-tenure regimes (undesignated/untitled, private, strictly-protected and sustainable-use protected areas, indigenous, and quilombola lands) affect deforestation across 49 spatiotemporal scales. We find that undesignated/untitled public regimes with poorly defined tenure rights increase deforestation relative to any alternative regime in most contexts. The privatization of these undesignated/untitled lands often reduces this deforestation, particularly when private regimes are subject to strict environmental regulations such as the Forest Code in Amazonia. However, private regimes decrease deforestation less effectively and less reliably than alternative well-defined regimes, and directly privatizing either conservation regimes or indigenous lands would most likely increase deforestation. This study informs the ongoing political debate around land privatization/protection in tropical landscapes and can be used to envisage policy aligned with sustainable development goals.


[Effect of acetylcholine on gastric secretory function and its vascular tonus].
Depending on doses, acetylcholine can produce the same effects in respect to activation of the stomach gland secretion either in hypodermic or intramuscular administration or acting from the surface of the stomach mucosa. Combination of acetylcholine and histamine produces the same secretory effect as food irritation. In acute experiments on dogs i.v. administration of acetylcholine causes a temporary contraction of vessels and a decrease of partial oxygen pressure, whereas in chronic experiments the same combination of the agents increases partial oxygen pressure which is suggestive of a decrease in the tone of stomach mucosa vessels.


[The spectrum of infections caused by the Epstein-Barr virus].
The observation by Epstein and Barr (EB) of virus particles in Burkitt lymphoma cells in 1964 led 4 years later to the discovery that this virus was the long sought agent responsible for infectious mononucleosis. Pathophysiologically the EB virus specifically infects B lymphocytes of the immune system and induces perpetual multiplication of these cells if infection remains uncontrolled. The T lymphocytes, once sensitized against these virus infected cells, either kill them or suppress their continuous growth. During acute infectious mononucleosis, these stimulated T cells appear in the bloodstream as "atypical lymphocytes". If cell-mediated immunity is hampered by either congenital or acquired immunodeficiency the proliferative potential of EBV infected B lymphocytes may become uncontrolled and lead either to fulminant and lethal infectious mononucleosis or to polyclonal or monoclonal B cell proliferation. This later phenomenon appears to be the source of most of the lymphoma observed in transplant patients who are chronically immunosuppressed. Much remains to be understood of the mechanisms of EBV infections, which in some geographic areas lead to inapparent infections and in others to Burkitt lymphoma or nasopharyngeal carcinoma, while in temperate regions the clinical manifestations are those of infectious mononucleosis.


Functional B7.2 and B7-H2 molecules on myeloma cells are associated with a growth advantage.
B7 family molecules expressed on antigen-presenting cells stimulate or inhibit normal immune responses. The aim of this study was to investigate whether functional B7.2 and B7-H2 molecules are expressed on myeloma cells and, if so, whether they are associated with pathophysiology in myeloma. The expression of B7.2 and B7-H2 molecules on normal plasma and neoplastic (myeloma) plasma cells was analyzed. The cell proliferation and immunomodulatory function of myeloma cells related to B7.2 and B7-H2 expression were examined. Human myeloma cell lines commonly expressed B7.2 and B7-H2 molecules. B7.2 expression on plasma cells was more common in myeloma patients (n = 35) compared with that in patients with monoclonal gammopathy of unknown significance (n = 12) or hematologically normal individuals (n = 10). Plasma cells expressing B7-H2 were observed in myeloma patients alone, although rarely. Patients whose myeloma cells showed high B7.2 expression were more anemic and thrombocytopenic than other myeloma patients. The expression of these molecules was induced or augmented by cultivating myeloma cells with autologous stroma cells or tumor necrosis factor-alpha, a key cytokine in myeloma biology. Cell proliferation was more rapid in the B7.2+ and B7-H2+ populations compared with the B7.2(-) and B7-H2(-) populations, respectively, in the human myeloma cell lines examined. B7.2 and B7-H2 molecules on myeloma cells induced normal CD4+ T cells to proliferate and produce soluble factors, including interleukin-10 that stimulate myeloma cell proliferation. Functional B7.2 and B7-H2 molecules detected on myeloma cells may be involved in the pathophysiology of myeloma.


Antibiotics for preventing respiratory tract infections in adults receiving intensive care.
Pneumonia is an important cause of mortality in intensive care units. The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care. We searched MEDLINE, proceedings of scientific meetings and reference lists of articles from January 1984 to September 1997. We also contacted investigators in the field. Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients. Trials were assessed for quality and investigators contacted for additional information. Overall 33 trials involving 5727 people were included. There was variation in the antibiotics used, patient characteristics and the risk of respiratory tract infections and mortality in the control groups. In 16 trials (involving 3493 patients) of a topical and systemic antibiotic combination, the average rates of respiratory tract infections and deaths in the control group were 33% and 28% respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.36, 95% confidence interval 0.30 to 0. 43) and total mortality (odds ratio 0.80, 95% confidence interval 0. 68 to 0.93). On average five patients needed to be treated to prevent one infection and 23 treated to prevent one death. In 17 trials (involving 2366 patients) of topical antimicrobials the rates of respiratory tract infections and deaths in the control groups were 30% and 24% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.57, 95% confidence interval 0.46 to 0.69) but not in total mortality (odds ratio 1.01, 95% confidence interval 0.84 to 1.22). A combination of topical and systemic prophylactic antibiotics can reduce respiratory tract infections and overall mortality in adult patients receiving intensive care. [This abstract has been prepared centrally.]


Saponins as adipokines modulator: A possible therapeutic intervention for type 2 diabetes.
Development of type 2 diabetes has been linked to β-cell failure coupled with insulin resistance and obesity. Adipose tissue, known as the fat store, secretes a number of hormones and proteins collectively termed adipokines some of which regulate insulin sensitivity. Dysregulation in the secretion of adipokines has been linked to insulin resistance and type 2 diabetes. In this review, we summarized evidence of the role of adipokines with focus on leptin, adiponectin, adipsin, visfatin and apelin in the pathogenesis of type 2 diabetes and discussed the potential of saponins to modify the ill-regulated adipokines secretions, which could promote the use of this class of phytochemicals as potential antidiabetics agents.


Clinical case of acute myeloblastic leukemia with t(8;21)(q22;q22) in a patient with Klinefelter's syndrome.
Klinefelter's syndrome is characterized by abnormal karyotype 47, XXY and a phenotype associated with hypogonadism and gynecomastia. Often the disease can be diagnosed accidentally, when carrying out cytogenetic analysis in cases of a malignant blood disease. We present the clinical case of a patient diagnosed with acute myelomonoblastic leukemia-M4 Eo (AML- M4), where by means of classic cytogenetics a karyotype was found corresponding to Klinefelter's syndrome. Three induction courses of polychemotherapy wermade, which led to remission of the disease, documented both flowcytometrically and cytogenetically.


Evaluation of biosecurity measures to prevent indirect transmission of porcine epidemic diarrhea virus.
The effectiveness of biosecurity methods to mitigate the transmission of porcine epidemic diarrhea virus (PEDV) via farm personnel or contaminated fomites is poorly understood. This study was undertaken to evaluate the effectiveness of biosecurity procedures directed at minimizing transmission via personnel following different biosecurity protocols using a controlled experimental setting. PEDV RNA was detected from rectal swabs of experimentally infected (INF) and sentinel pigs by real-time reverse transcription polymerase chain reaction (rRT-PCR). Virus shedding in INF pigs peaked at 1 day post infection (dpi) and viral RNA levels remained elevated through 19 dpi. Sentinel pigs in the low biosecurity group (LB) became PEDV positive after the first movement of study personnel from the INF group. However, rectal swabs from pigs in the medium biosecurity (MB) and high biosecurity (HB) groups were negative during the 10 consecutive days of movements and remained negative through 24 days post movement (dpm) when the first trial was terminated. Viral RNA was detected at 1 dpm through 3 dpm from the personal protective equipment (PPE) of LB personnel. In addition, at 1 dpm, 2 hair/face swabs from MB personnel were positive; however, transmission of virus was not detected. All swabs of fomite from the HB study personnel were negative. These results indicate that indirect PEDV transmission through contaminated PPE occurs rapidly (within 24 h) under modeled conditions. Biosecurity procedures such as changing PPE, washing exposed skin areas, or taking a shower are recommended for pig production systems and appear to be an effective option for lowering the risk of PEDV transmission between groups of pigs.


[Anti-CD 10 maternal-fetal allo-immunisation].
Maternal-fetal alloimmunisation with antenatal glomerulopathies (FMAIG) is a recently described allo-immune disorder that results from the production of maternal antibodies which cross the placenta, bind to fetal glomerular podocytes and thereby cause renal dysfunction. The pathogenic antibodies are directed against CD10/neutral endopeptidase (NEP). The infant's mother is apparently healthy but is genetically NEP-deficient, and thus becomes immunized against CD10/NEP expressed by placental cells during her first pregnancy. This disease, that we have now diagnosed in five families, is the first described organ-specific disorder due to maternal-fetal allo-immunisation. Because future pregnancies in CD10/NEP-immunized mothers are at high risk for the fetus, antigen-driven therapies aimed at eliminating pathogenic antibodies are urgently needed. This will require identification of the pathogenic epitopes born by the antigen.


Transient elastic support for vein grafts using a constricting microfibrillar polymer wrap.
Arterial vein grafts (AVGs) often fail due to intimal hyperplasia, thrombosis, or accelerated atherosclerosis. Various approaches have been proposed to address AVG failure, including delivery of temporary mechanical support, many of which could be facilitated by perivascular placement of a biodegradable polymer wrap. The purpose of this work was to demonstrate that a polymer wrap can be applied to vein segments without compromising viability/function, and to demonstrate one potential application, i.e., gradually imposing the mid-wall circumferential wall stress (CWS) in wrapped veins exposed to arterial levels of pressure. Poly(ester urethane)urea, collagen, and elastin were combined in solution, and then electrospun onto freshly-excised porcine internal jugular vein segments. Tissue viability was assessed via Live/Dead staining for necrosis, and vasomotor challenge with epinephrine and sodium nitroprusside for functionality. Wrapped vein segments were also perfused for 24h within an ex vivo vascular perfusion system under arterial conditions (pressure = 120/80 mmHg; flow = 100 mL/min), and CWS was calculated every hour. Our results showed that the electrospinning process had no deleterious effects on tissue viability, and that the mid-wall CWS vs. time profile could be dictated through the composition and degradation of the electrospun wrap. This may have important clinical applications by enabling the engineering of an improved AVG.


Rapid diagnosis of cholera by coagglutination test using 4-h fecal enrichment cultures.
A simple, rapid, and reliable method to detect Vibrio cholerae in fecal specimens would assist in the management of cases of severe diarrhea, especially since most such cases occur in areas with minimal laboratory facilities. A coagglutination test was used to detect V. cholerae antigen in bile-peptone broth incubated with feces. In the technique, Staphylococcus aureus Cowan 1 coated with anti-V. cholerae O1 antiserum was tested with cultures incubated for 4 h. When 165 specimens were tested, the sensitivity, specificity, and accuracy of the test, compared with standard culture methods, were 97, 99, and 98%, respectively. These promising results were better than those of dark-field microscopy using the same specimens, and the test was logistically easy to perform. The coagglutination test using enrichment broth culture of feces is a simple and rapid method which may be used to confirm a diagnosis of cholera.


Patients at high risk for ischemic stroke: identification and actions.
Atherosclerosis is a disease of chronic inflammation. It is diffuse, multisystemic and affects the vascular, metabolic and immune systems. The traditional evaluation of risk is based on methods of clinical and biological assessments, and conventional imaging. The existence of symptomatic disease and the number of symptomatic sites of atherothrombosis are critical factors in predicting the recurrence of major vascular events. However, these methods are insufficient to predict near-future episodes, above all in the individual standard clinical practice. Active treatment of modifiable risk factors such as hypertension, dyslipidemia and atrial fibrillation can reduce the number of patients who develop a stroke. There is considerable evidence suggesting that a substantial proportion of the population with high blood pressure receives insufficient treatment. More active treatment of this condition is probably the most efficient single measure. Lifestyle factors such as smoking, diet, physical inactivity and obesity contribute to the relatively high incidence of stroke. There is a need to incorporate new systemic markers and new investigation techniques in the future so as to identify the individuals at risk in the population and to administer more individualized intervention therapies.


Evolutionary models of the emergence of methicillin-resistant Staphylococcus aureus.
Five major lineages of methicillin-resistant Staphylococcus aureus (MRSA) have evolved since the introduction of methicillin for the treatment of infections caused by penicillin-resistant S. aureus in 1959. The clones of these lineages are responsible for the vast majority of hospital-acquired MRSA disease globally. We have constructed high-resolution evolutionary models for each lineage using a parsimony approach with 15 partial gene sequences from 147 geographically diverse isolates. On the basis of these models, we infer that MRSA has emerged at least 20 times upon acquisition of the methicillin resistance determinant, which is carried on a mobile genetic element called the staphylococcal cassette chromosome mec (SCCmec). The acquisition of SCCmec by sensitive clones was four times more common than the replacement of one SCCmec with another. Notably, SCCmec type IV was found in twice as many clones as any other SCCmec type, and it is this SCCmec type which is commonly found in clones from patients with community-acquired MRSA disease. Our findings suggest that most clones of MRSA arise by the acquisition of SCCmec type IV by methicillin-sensitive isolates.


Common Polymorphisms in the Age of Research Domain Criteria (RDoC): Integration and Translation.
The value of common polymorphisms in guiding clinical psychiatry is limited by the complex polygenic architecture of psychiatric disorders. Common polymorphisms have too small an effect on risk for psychiatric disorders as defined by clinical phenomenology to guide clinical practice. To identify polymorphic effects that are large and reliable enough to serve as biomarkers requires detailed analysis of a polymorphism's biology across levels of complexity from molecule to cell to circuit and behavior. Emphasis on behavioral domains rather than clinical diagnosis, as proposed in the Research Domain Criteria framework, facilitates the use of mouse models that recapitulate human polymorphisms because effects on equivalent phenotypes can be translated across species and integrated across levels of analysis. A knockin mouse model of a common polymorphism in the brain-derived neurotrophic factor gene (BDNF) provides examples of how such a vertically integrated translational approach can identify robust genotype-phenotype relationships that have relevance to psychiatric practice.


A comparison of the analgesic effect of intramuscular nalbuphine and morphine in patients with postoperative pain.
In a double-study, using patients' subjective reports as indices of analgesia, the relative analgesic potency of intramuscular nalbuphine and morphine was determined in 56 postoperative patients. A total of 28 crossover comparisons (utilizing the twin passover, balanced four-point incomplete block design) were performed in two sequentially related experiments, each assay comparing 4 and 8 mg of morphine with either 3 and 6 or 6 and 12 mg of nalbuphine. When both intensity and duration of analgesia are considered (i.e., total analgesic effect), nalbuphine was 0.8 to 0.9 times as potent as morphine. In terms of peak analgesic effect, nalbuphine was 0.7 to 0.8 times as potent. Both the time-effect curves and the relative potency estimates suggest that nalbuphine has a slightly longer duration of action than morphine at doses that are equianalgesic in terms of peak effect. Side effects of the type usually noted after the administration of potent injectable analgesics to postoperative patients were observed after both morphine and nalbuphine. Although nalbuphine is a potent narcotic antagonist, no psychotomimetic reactions were observed.


Effect of monosaccharide composition and proportion on the bioactivity of polysaccharides: A review.
Polysaccharides have been widely used in pharmaceutical and food industries due to their diverse bioactivity, high safety, and few or no side effects. However, inability to quickly produce, screen, and synthesize bioactive polysaccharides is the limiting factor for their development and application. Structural features determine and influence the bioactivity of polysaccharides. Among them, monosaccharide is the basic unit of polysaccharide, which not only affects electrification, functional group, and bioactivity of polysaccharide but also is one of the simplest polysaccharide indexes to be detected. At present, effects of monosaccharide composition and proportion on anti-inflammatory, antioxidant, antitumor, immunomodulatory, antibacterial, and prebiotic activities of polysaccharides are reviewed. Further problems need to be considered during regulation and analysis of monosaccharide composition and proportion of polysaccharides. Overall, present work will provide help and reference for production, development, and structure-function investigation of polysaccharides based on their monosaccharide.


The interrelationship of polycyclic hydrocarbon metabolism and steroidogenesis in primary cultures of bovine adrenal cortical cells.
The interrelationship between adrenal steroidogenesis and polycyclic aromatic hydrocarbon metabolism has been examined in cultured bovine adrenal cortical (BAC) cells. Adrenocorticotropin (ACTH) selectively induced steroidogenic cytochrome P-450-dependent enzyme activities from BAC cell cultures. In the presence of 10(-7) M ACTH, steroid production requiring 17 alpha-hydroxylation (cortisol + androgens) was increased 5-fold over the formation of 17- deoxysteroids (corticosterone). The effect of 10 microns benz[a]anthracene on steroidogenesis was characterized by suppression of both steroid 17 alpha-hydroxylation (90%) and total steroidogenesis (50%), with a concomitant rise in 17- deoxysteroid formation. The order of stimulation of steroidogenic enzyme activities by ACTH (17 alpha-hydroxylase greater than side chain cleavage greater than 21-hydroxylase) paralleled the order of suppression by benz[a]anthracene. BAC cell cultures incubated with Su-10603, a specific 17 alpha-hydroxylase inhibitor, exhibited similar changes in the pattern of steroidogenesis, as did benz[a]anthracene-treated cells, suggesting that benz[a] anthracene also inhibits steroidogenesis as an inhibitor of 17 alpha-hydroxylase. In addition, benz[a]anthracene induced benzo[a]pyrene metabolism 4- to 6-fold over control levels in these cells. The profile of benzo[a]pyrene metabolites revealed predominantly water-soluble products (nonhydrolyzable greater than sulfates greater than glucuronides), 9,10- monooxygenation products, and 3-phenol. ACTH (10(-7) M) and 0.5 mM cyclic AMP each decreased benzo[a]pyrene metabolism by more than 50%. Both benz[a]anthracene-induced and uninduced benzo[a]- pyrene metabolism were equally reduced in response to ACTH and cyclic AMP. In the presence of 0.2 mM aminoglutethimide, which completely inhibited steroidogenesis, ACTH decreased benz[a]anthracene induction of benzo[a]pyrene metabolism to the same extent as ACTH treatment alone. It is concluded that the suppression of benzo[a]pyrene metabolism by ACTH is mediated by cyclic AMP and does not involve steroids generated in response to ACTH. These studies demonstrate that cytochrome P-450 isozymes involved in steroidogenesis and polycyclic aromatic hydrocarbon metabolism are regulated, in opposing directions, by ACTH.


Inflammatory Responses Regulating Alveolar Ion Transport during Pulmonary Infections.
The respiratory epithelium is lined by a tightly balanced fluid layer that allows normal O2 and CO2 exchange and maintains surface tension and host defense. To maintain alveolar fluid homeostasis, both the integrity of the alveolar-capillary barrier and the expression of epithelial ion channels and pumps are necessary to establish a vectorial ion gradient. However, during pulmonary infection, auto- and/or paracrine-acting mediators induce pathophysiological changes of the alveolar-capillary barrier, altered expression of epithelial Na,K-ATPase and of epithelial ion channels including epithelial sodium channel and cystic fibrosis membrane conductance regulator, leading to the accumulation of edema and impaired alveolar fluid clearance. These mediators include classical pro-inflammatory cytokines such as TGF-β, TNF-α, interferons, or IL-1β that are released upon bacterial challenge with Streptococcus pneumoniae, Klebsiella pneumoniae, or Mycoplasma pneumoniae as well as in viral infection with influenza A virus, pathogenic coronaviruses, or respiratory syncytial virus. Moreover, the pro-apoptotic mediator TNF-related apoptosis-inducing ligand, extracellular nucleotides, or reactive oxygen species impair epithelial ion channel expression and function. Interestingly, during bacterial infection, alterations of ion transport function may serve as an additional feedback loop on the respiratory inflammatory profile, further aggravating disease progression. These changes lead to edema formation and impair edema clearance which results in suboptimal gas exchange causing hypoxemia and hypercapnia. Recent preclinical studies suggest that modulation of the alveolar-capillary fluid homeostasis could represent novel therapeutic approaches to improve outcomes in infection-induced lung injury.


Sodium channels in membrane vesicles from cultured toad bladder cells.
Electrical potential-driven 22Na+ fluxes were measured in membrane vesicles prepared from TBM-18(c123) cells (a clone of the established cell line TB-M). Fifty to seventy percent of the tracer uptake in vesicles derived from cells that were cultivated on a porous support were blocked by the diuretic amiloride. The amiloride inhibition constant was less than 0.1 microM, indicating that this flux is mediated by the apical Na+-specific channels. Vesicles prepared from cells that were not grown on a porous support exhibited much smaller amiloride-sensitive fluxes. Two Ca2+-dependent processes that down-regulate the channel conductance and were previously identified in native epithelia were found in the cultured cells as well. Vesicles isolated from cells that were preincubated with 5 X 10(-7) M aldosterone for 16-20 h exhibited higher amiloride-sensitive conductance than vesicles derived from control, steroid-depleted cells. Thus membrane derived from TBM-18(c123) cells can be used to characterize the epithelial Na+ channel and its hormonal regulation.


Retinoids as critical modulators of immune functions: new therapeutic perspectives for old compounds.
Retinoids are vitamin A derivatives that critically regulate several physiological and pathological processes, including immune functions and cancer development. These biological response modifiers exert their pleiotropic effects through the interaction with nuclear receptors, defined as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). These ligand-activated nuclear receptors induce the transcription of target genes by binding to responsive elements in the promoter regions. RARs and RXRs are also capable to interact with other nuclear receptors, thus expanding their spectrum of action on gene expression. Evidence has been accumulated indicating that retinoids may exert beneficial effects in both immune-mediated disorders and tumors. With regard to cancer, retinoids directly target neoplastic cells by inducing differentiation, inhibiting cell growth or promoting survival. However, the efficacy of these compounds in cancer treatment probably resides in their ability to modulate also the function of immune effectors. Vitamin A derivatives are currently used in the therapy of acute promyelocytic leukemia and of cutaneous T cell lymphomas, but they could be effective also on B-cell malignancies. Clinical trials are ongoing to test their efficacy in solid tumors. In this review, we give a broad depiction of how retinoids influence the function of immune effectors and affect growth and survival of hematological malignancies. This with the aim to better understand the clinical effects of retinoid-based therapies and provide the rationale to combine retinoids with other active compounds in new synergistic treatment strategies.


Tyramine receptor (SER-2) isoforms are involved in the regulation of pharyngeal pumping and foraging behavior in Caenorhabditis elegans.
Octopamine regulates essential processes in nematodes; however, little is known about the physiological role of its precursor, tyramine. In the present study, we have characterized alternatively spliced Caenorhabditis elegans tyramine receptor isoforms (SER-2 and SER-2A) that differ by 23 amino acids within the mid-region of the third intracellular loop. Membranes prepared from cells expressing either SER-2 or SER-2A bind [3H]lysergic acid diethylamide (LSD) in the low nanomolar range and exhibit highest affinity for tyramine. Similarly, both isoforms exhibit nearly identical Ki values for a number of antagonists. In contrast, SER-2A exhibits a significantly lower affinity than SER-2 for other physiologically relevant biogenic amines, including octopamine. Pertussis toxin treatment reduces affinity for both tyramine and octopamine, especially for octopamine in membranes from cells expressing SER-2, suggesting that the conformation of the mid-region of the third intracellular loop is dictated by G-protein interactions and is responsible for the differential tyramine/octopamine affinities of the two isoforms. Tyramine reduces forskolin-stimulated cAMP levels in HEK293 cells expressing either isoform with nearly identical IC50 values. Tyramine, but not octopamine, also elevates Ca2+ levels in cells expressing SER-2 and to a lesser extent SER-2A. Most importantly, ser-2 null mutants (pk1357) fail to suppress head movements while reversing in response to nose-touch, suggesting a role for SER-2 in the regulation of foraging behavior, and fail to respond to tyramine in assays measuring serotonin-dependent pharyngeal pumping. These are the first reported functions for SER-2. These results suggest that C. elegans contains tyramine receptors, that individual SER-2 isoforms may differ significantly in their sensitivity to other physiologically relevant biogenic amines, such as octopamine (OA), and that tyraminergic signaling may be important in the regulation of key processes in nematodes.


Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. "Alive, with good vision and no comorbidity".
Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a "state of metastatic grace" never to be violated. Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy. Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the "state of metastatic grace", with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.


Chlamydia trachomatis, Chlamydial Heat Shock Protein 60 and Anti-Chlamydial Antibodies in Women with Epithelial Ovarian Tumors.
Chlamydia trachomatis (C. trachomatis) infection has been suggested to promote epithelial ovarian cancer (EOC) development. This study sought to explore the presence of C. trachomatis DNA and chlamydial heat shock protein 60 (chsp60) in ovarian tissue, as well as anti-chlamydial IgG antibodies in plasma, in relation to subtypes of EOC. This cross-sectional cohort consisted of 69 women who underwent surgery due to suspected ovarian pathology. Ovarian tissue and corresponding blood samples were collected at the time of diagnosis. In ovarian tumor tissue, p53, p16, Ki67 and chsp60 were analyzed immunohistochemically, and PCR was used to detect C. trachomatis DNA. Plasma C. trachomatis IgG and cHSP60 IgG were analyzed with a commercial MIF-test and ELISA, respectively. Eight out of 69 women had C. trachomatis DNA in their ovarian tissue, all were invasive ovarian cancer cases (16.7% of invasive EOC). The prevalence of the chsp60 protein, C. trachomatis IgG and cHSP60 IgG in HGSC, compared to other ovarian tumors, was 56.0% vs. 37.2% P = .13, 15.4% vs. 9.3% P = .46 and 63.6% vs. 45.5% P = .33 respectively. None of the markers of C. trachomatis infection were associated with p53, p16 or Ki67. C. trachomatis was detected in invasive ovarian cancer, supporting a possible role in carcinogenesis of EOC. However, there were no statistically significant associations of chsp60 in ovarian tissue, or plasma anti-chlamydial IgG antibodies, with any of the subtypes of ovarian tumors.


Use of combined microautoradiography and fluorescence in situ hybridization to determine carbon metabolism in mixed natural communities of uncultured bacteria from the genus Achromatium.
Combined microautoradiography and fluorescence in situ hybridization (FISH) was used to investigate carbon metabolism in uncultured bacteria from the genus Achromatium. All of the Achromatium species identified in a freshwater sediment from Rydal Water, Cumbria, United Kingdom, which were distinguishable only by FISH, assimilated both [(14)C]bicarbonate and [(14)C]acetate. This extends previous findings that Achromatium spp. present at another location could only utilize organic carbon sources. Achromatium spp., therefore, probably exhibit a range of physiologies, i.e., facultative chemolithoautotrophy, mixotrophy, and chemoorganoheterotrophy, similar to other large sulfur bacteria (e.g., Beggiatoa spp.).


Dynamic experimentation on the confocal laser scanning microscope: application to soft-solid, composite food materials.
Confocal laser scanning microscopy (CLSM) is used to follow the dynamic structural evolution of several phase-separated mixed biopolymer gel composites. Two protein/polysaccharide mixed gel systems were examined: gelatin/maltodextrin and gelatin/agarose. These materials exhibit 'emulsion-like' structures, with included spherical particles of one phase (i.e. polymer A) within a continuous matrix of the second (i.e. polymer B). Compositional control of these materials allows the phase order to be inverted (i.e. polymer B included and polymer A continuous), giving four basic variants for the present composites. Tension and compression mechanical tests were conducted dynamically on the CLSM, with crack/microstructure interactions investigated using a notched compact tension geometry. Gelatin/maltodextrin composites exhibit a 'pseudo-yielding' stress/strain response in both tension and compression, when the gelatin-rich phase is continuous, which was attributed to debonding of the particle/matrix interface. This behaviour is significantly less apparent for both the gelatin/agarose composites, and the maltodextrin continuous gelatin/maltodextrin composites, with these materials responding in a nominally linear elastic manner. Values of the interfacial fracture energy for selected compositions of the two biopolymer systems were determined by 90 degrees peel testing, where a gelatin layer was peeled from either a maltodextrin or agarose substrate. For biopolymer layers 'cast' together, a value of 0.2 +/- 0.2 J m-2 was obtained for the fracture energy of a gelatin/maltodextrin interface, while a significantly higher value of 6.5 +/- 0.2 J m-2 was determined for a gelatin/agarose interface. The interfacial fracture energy of the two mixed systems was also determined following an indirect elastomer composite debonding model. An interfacial fracture energy of approximately 0.25 J m-2 was determined using this approach for the gelatin continuous gelatin/maltodextrin composite, which compares favourably with the value calculated directly by peel testing (i.e. approximately 0.2 J m-2). A somewhat higher value was estimated for the gelatin continuous gelatin/agarose system (1.0-2.0 J m-2), using this model, although there are severe limitations to this approach for this mixed gel system. In the present case, it is believed that the differing mechanical response of the two mixed biopolymer systems, when the gelatin phase is continuous, arises from the order of magnitude difference in interfacial fracture energy. It is postulated that polymer interdiffusion may occur across the interface for the gelatin/agarose system, to a significantly greater extent than for interfaces between gelatin and maltodextrin, resulting in a higher interfacial fracture energy.


Case Report: Clostridium neonatale Bacteremia in a Preterm Neonate With Necrotizing Enterocolitis.
Necrotizing enterocolitis is a life-threatening acquired gastrointestinal disorder among preterm neonates and is associated with a high mortality rate and long-term neurodevelopmental morbidity. No etiologic agent has been definitively established; nonetheless, the most implicated bacteria include members of the Clostridium genus. We reported here on a case of Clostridium neonatale bacteremia in a preterm neonate with necrotizing enterocolitis, providing more information regarding the potential role of this bacterium in pathogenesis of necrotizing enterocolitis. We emphasized the sporulating form of C. neonatale that confers resistance to disinfectants usually applied for the hospital environmental cleaning. Further works are needed to establish the causal relationship between the occurrence of NEC and the isolation of C. neonatale, with promising perspectives in terms of diagnostic and therapeutic management.


Antibody response to bacteriophage hyaluronidase in acute glomerulonephritis after group A streptococcal infection.
In a test of the hypothesis that lysogeny of group A streptococci by a temperate bacteriophage might confer nephritogenicity, 283 sera from 69 patients were examined for IgG and IgM antibodies to M 49 streptococcal bacteriophage hyaluronidase. The IgG and IgM response to bacteriophage hyaluronidase was greatest in M 49 streptococci-infected individuals with nephritis, but M 49 streptococci-infected subjects without nephritis also had a greater immune response than did subjects infected with serotypes other than M 49. Although antibody to bacterial hyaluronidase was detected in all Streptococcus-infected groups, antibody to M 49 streptococcal bacteriophage hyaluronidase usually was found in only M 49 streptococci-infected patients. Although the greatest IgG and IgM antibody response to bacteriophage hyaluronidase can be demonstrated in individuals with glomerulonephritis, the antibody response does not indicate a direct relation of lysogeny and nephritis because subjects with and without nephritis after M 49 streptococcal infection all had a significant rise in antibody titer.


Inactivation of NADPH oxidases NOX4 and NOX5 protects human primary fibroblasts from ionizing radiation-induced DNA damage.
Human exposure to ionizing radiation from medical procedures has increased sharply in the last three decades. Recent epidemiological studies suggest a direct relationship between exposure to ionizing radiation and health problems, including cancer incidence. Therefore, minimizing the impact of radiation exposure in patients has become a priority in the development of future clinical practices. Crucial players in radiation-induced DNA damage include reactive oxygen species (ROS), but the sources of these have remained elusive. To the best of our knowledge, we show here for the first time that two members of the ROS-generating NADPH oxidase family (NOXs), NOX4 and NOX5, are involved in radiation-induced DNA damage. Depleting these two NOXs in human primary fibroblasts resulted in reduced levels of DNA damage as measured by levels of radiation-induced foci, a marker of DNA double-strand breaks (DSBs) and the comet assay coupled with increased cell survival. NOX involvement was substantiated with fulvene-5, a NOXs-specific inhibitor. Moreover, fulvene-5 mitigated radiation-induced DNA damage in human peripheral blood mononuclear cells ex vivo. Our results provide evidence that the inactivation of NOXs protects cells from radiation-induced DNA damage and cell death. These findings suggest that NOXs inhibition may be considered as a future pharmacological target to help minimize the negative effects of radiation exposure for millions of patients each year.


Memory failure predicts belief regression after the correction of misinformation.
After misinformation has been corrected, people initially update their belief extremely well. However, this change is rarely sustained over time, with belief returning towards pre-correction levels. This is called belief regression. The current study aimed to examine the association between memory for the correction and belief regression, and whether corrected misinformation suffers from belief regression more than affirmed facts. Participants from Prolific Academic (N = 612) rated the veracity of 16 misinformation and 16 factual items and were randomly assigned to a correction condition or test-retest control. Immediately after misinformation was corrected and facts affirmed, participants re-rated their belief and were asked whether they could remember the items' presented veracity. Participants repeated this post-test one month later. We found that belief and memory were highly associated, both immediately (⍴ = 0.51), and after one month (⍴ = 0.82), and that memory explained 66% of the variance in belief regression after correcting for measurement reliability. We found the rate of dissenting (accurately remembering that misinformation was presented as false but still believing it) remained stable between the immediate and delayed post-test, while the rate of forgetting quadrupled. After one month, 57% of participants who believed in the misinformation thought that the items were presented to them as true. Belief regression was more pronounced for misinformation than facts, but this was greatly attenuated once pre-test belief was equated. Together, these results clearly indicate that memory plays a fundamental role in belief regression, and that repeated corrections could be an effective method to counteract this phenomenon.


Large current modulation and spin-dependent tunneling of vertical graphene/MoS2 heterostructures.
Vertical graphene heterostructures have been introduced as an alternative architecture for electronic devices by using quantum tunneling. Here, we present that the current on/off ratio of vertical graphene field-effect transistors is enhanced by using an armchair graphene nanoribbon as an electrode. Moreover, we report spin-dependent tunneling current of the graphene/MoS2 heterostructures. When an atomically thin MoS2 layer sandwiched between graphene electrodes becomes magnetic, Dirac fermions with different spins feel different heights of the tunnel barrier, leading to spin-dependent tunneling. Our finding will develop the present graphene heterostructures for electronic devices by improving the device performance and by adding the possibility of spintronics based on graphene.


Healing of fresh frozen bone allograft with or without platelet-rich plasma: a histologic and histometric study in rats.
This study histomorphometrically analyzed the effect of autogenous platelet-rich plasma (PRP) on healing of fresh frozen bone allograft (FFBA) in bony defects in rat calvaria. A 5mm-diameter defect was created in the calvarium of 30 rats. Animals were divided into three groups: C (defect was filled by blood clot only), FFBA (defect was filled with 0.01mL of FFBA), and FFBA/PRP (defect was filled with 0.01mL of FFBA combined with 100µL of PRP). All animals were euthanized at 30 days postoperatively. Histomorphometry and histology analyses were performed. Data were statistically analyzed (analysis of variance, Tukey, p<.05). FFBA had a statistically smaller new bone area than groups FFBA/PRP and C. No statistically significant differences were observed between groups FFBA and FFBA/PRP with regard to remaining bone graft particle area. It can be concluded that (1) PRP improved the incorporation of FFBA, increasing the amount of new bone formed; (2) PRP has not influenced the resorption of nonviable particles of the FFBA; and (3) presence of remaining FFBA particles might have accounted for the smaller amount of new bone observed in group FFBA when compared with control group.


Retirement patterns and the macroeconomy, 1992-2010: the prevalence and determinants of bridge jobs, phased retirement, and reentry among three recent cohorts of older americans.
Older Americans contemplating retirement today face a very different economic environment than prior cohorts did. This article examines whether the retirement patterns of older Americans have changed as a result. Using data from 10 waves of the Health and Retirement Study (HRS), we examine the prevalence of bridge jobs, phased retirement, and labor market reentry among 3 recent cohorts of older Americans, from 1992 through 2010. Determinants of retirement transitions are examined using bivariate comparisons and multivariate logistic and multinomial logistic regression models. We find that traditional one-time, permanent exits from the labor force continue to be the exception rather than the rule and that the retirement patterns of the Early Boomers, those on the cusp of retirement during the recent Great Recession, appear to be diverging from those of earlier cohorts. The Early Boomer women, in particular, were more likely than those in previous cohorts, the HRS Core and the HRS War Babies, to move to a bridge job prior to exiting the labor force completely and both Early Boomer men and women were more likely to leave their career jobs involuntarily, with layoffs being a key factor. The "do-it-yourself" approach to retirement planning-with individuals managing a large portion of their retirement finances-is now common among older Americans. This change in the retirement environment, combined with a significant and persistent cyclical downturn, may have long-lasting effects and suggests that the concept of retirement in the United States will continue to evolve.


Relationship between body composition and dyslipidemia in children and adolescentes.
We studied the relationship between different anthropometric indexes and plasma lipids. Data were collected from 2014 to 2016 in 854 schoolchildren (6-18 years). Waist circumference (WC), body fat percentage (BFP) by bioimpedance, body mass index (BMI), and waist-to-height ratio (WHtR) were measured. Total cholesterol (TC), HDLc, and triglycerides were measured in fasting blood samples and Non-HDL cholesterol (Non-HDLc) was calculated. Data are presented as mean ± standard deviation, with percentages. Means were compared using the t test or ANOVA followed by Tukey's test. The association between variables was tested by linear regression. The study was approved by the Research Ethics Committee of the Universidade Federal do Espírito Santo. Obese boys had higher TC, non-HDLc, and LDLc than eutrophic boys (p < 0.05). In girls this difference was found only for non-HDLc (p < 0.05). Children with inappropriate BFP and WHtR presented higher LDLc and non-HDLc concentrations (p < 0.001), which showed positive association (p<0.001) with lipid fractions (TC and non-HDLc). Excess body fat increased the probability of cholesterol above the reference value (170 mg/dL) by 21%. Excess body fat was associated with an atherogenic lipid profile (higher non-HDLc), especially in boys.


[The formation of absorbed doses of 137Cs in the body of the female and her progeny during suckling].
The transfer of 137Cs with maternal milk to progeny was studied in rats. The rats were administered with 25 kBq/g of 137Cs nitrate (pH = 6) in a single oral dose immediately after delivery. Nonpregnant females served as control. Absorbed doses per activity unit to lactating rats were 23% lover than to nonlactating ones. Over the suckling period, absorbed doses to young rats amounted to about 35% of the absorbed dose to the nursing female. For nonlactating females, the internal dose approximately equalled the sum of doses to the nursing female and young rats.


Bismuth tungstate Bi2WO6: a review on structural, photophysical and photocatalytic properties.
This review paper provides a comprehensive overview of the recent trends in bismuth tungstate (Bi2WO6) research, covering its structural, electrical, photoluminescent, and photocatalytic properties. The structural characteristics of bismuth tungstate are explored in detail, including its different allotropic crystal structures with respect to its isotypic materials. The electrical properties of bismuth tungstate, such as its conductivity and electron mobility, are also discussed, along with its photoluminescent properties. The photocatalytic activity of bismuth tungstate is a particular focus, with recent advances in doping and co-doping strategies with metals, rare earth and other elements summarized. The limitations and challenges of using bismuth tungstate as a photocatalyst are also examined, such as its low quantum efficiency and susceptibility to photodegradation. Finally, recommendations for future research directions are provided, including the need for further studies on the underlying mechanisms of photocatalytic activity, the development of more efficient and stable bismuth tungstate-based photocatalysts, and the exploration of new applications in fields such as water treatment and energy conversion.


Heme oxygenase-1 regulates mitochondrial quality control in the heart.
The cardioprotective inducible enzyme heme oxygenase-1 (HO-1) degrades prooxidant heme into equimolar quantities of carbon monoxide, biliverdin, and iron. We hypothesized that HO-1 mediates cardiac protection, at least in part, by regulating mitochondrial quality control. We treated WT and HO-1 transgenic mice with the known mitochondrial toxin, doxorubicin (DOX). Relative to WT mice, mice globally overexpressing human HO-1 were protected from DOX-induced dilated cardiomyopathy, cardiac cytoarchitectural derangement, and infiltration of CD11b+ mononuclear phagocytes. Cardiac-specific overexpression of HO-1 ameliorated DOX-mediated dilation of the sarcoplasmic reticulum as well as mitochondrial disorganization in the form of mitochondrial fragmentation and increased numbers of damaged mitochondria in autophagic vacuoles. HO-1 overexpression promotes mitochondrial biogenesis by upregulating protein expression of NRF1, PGC1α, and TFAM, which was inhibited in WT animals treated with DOX. Concomitantly, HO-1 overexpression inhibited the upregulation of the mitochondrial fission mediator Fis1 and resulted in increased expression of the fusion mediators, Mfn1 and Mfn2. It also prevented dynamic changes in the levels of key mediators of the mitophagy pathway, PINK1 and parkin. Therefore, these findings suggest that HO-1 has a novel role in protecting the heart from oxidative injury by regulating mitochondrial quality control.


Patterns of dermal exposure to hazardous substances in European union workplaces.
Workplace dermal exposure assessment is a complex task that aims to understand the dynamic interaction between the skin and the hazardous substances present in the surrounding environment. A European project known as RISKOFDERM gathered dermal exposure data in 85 workplaces (industrial and other types) in five countries in Europe. In order to optimize data collection and to develop a representative picture of dermal exposure, scenarios (tasks made up of a series of activities) were grouped together into dermal exposure operation units (DEOs). The allocation of scenarios to relevant DEOs was achieved on the basis of similarities of exposure routes, tasks and professional judgement. Sampling and quantification procedures were based on the approaches recommended by the OECD protocol. The laboratories involved in the analysis of the samples participated in quality assurance programmes. This exercise resulted in 419 body measurements and 437 measurements on hands expressed in terms of formulation (product) in use. Exposures for a given scenario varied by several orders of magnitude. The extent and patterns of exposure were found to be dependent on various exposure determinants, including inter- and intra-scenario variations. Hands were found to be the most contaminated parts of the body. Exposure patterns for liquid and solid contaminants were different. On the basis of the analysis of the data presented here, the averaged results (median and 95th percentile) for a given DEO unit should not be used as a representative measure of dermal exposure for all scenarios within that DEO without taking the exposure determinants into account. However, the data could be used to develop an exposure matrix (indicative exposure distributions) for different types of scenario and workplace, using determinants of exposure and a Bayesian approach to integrating expert opinion.


[Derangement of the mind in the Paracelsus tract "Liber de lunaticis Theophrasti"].
In a treatise "Liber de lunaticis Theophrasti" Paracelsus describes his view of "lunatici". These are men, inflicted by a psychopathological process, that gradually destroys their minds. He develops his argumentation on the base of iatroastrological, new-neoplatonistical and Christian thoughts. In his view man is a microcosm in macrocosm and a trichotomically organized being. Man is influenced by three lights. These lights are representing three levels of vitalisation, knowledge and cognition. According to this, man consists of the body (corresponding to the level of visible material light), the soul (corresponding to the invisible astral-sidereal light of the firmamental macrocosm) and the spirit (corresponding to the light of Christ and the divine-Christian sphere of spiritual light). The origin of lunatic confusion of the mind is caused by the intrinsically motivated intention of man (representing the microcosm) to shift his spiritual focus from the protective sphere of spiritual light to the sphere of astral-sidereal macrocosmic emanations. The latter have a deteriorative influence on man's mind, due to the lack of guidance of man's consciousness by the spiritual light. Paracelsus describes the individual and sociological effects of lunatic confusion. These effects may range from personal confusion up to the aggregation of lunatics in ideologically coordinated groups of fanatics, displaying wrong teachings, dissensions and even warfare and homicide. Concerning the therapy of "lunatici" Paracelsus develops ideas, which show a resemblance towards integrative and holistic tendencies of our days discussed in the field of Psychoanalysis, Behavioral Medicine and "Holistic Health Medicine". In general the Paracelsian concept of lunatic deterioration can be regarded as an historic example that deals with an integrative approach towards the description of psychiatric disorders.


A high-molecular-mass neutral endopeptidase-24.5 from human lung.
A high-Mr neutral endopeptidase-24.5 (NE) that cleaved bradykinin at the Phe5-Ser6 bond was purified to apparent homogeneity from human lung by (NH4)2SO4 fractionation, ion-exchange chromatography and gel filtration. The final enzyme preparation produced a single enzymically active protein band after electrophoresis on a 5% polyacrylamide gel. Human lung NE had an Mr of 650,000 under non-denaturing conditions, but after denaturation and electrophoresis on an SDS/polyacrylamide gel NE dissociated into several lower-Mr components (Mr 21,000-32,000) and into two minor components (Mr approx. 66,000). The enzyme activity was routinely assayed with the artificial substrate Z-Gly-Gly-Leu-Nan (where Z- and -Nan represent benzyloxycarbonyl- and p-nitroanilide respectively). NE activity was enhanced slightly by reducing agents, greatly diminished by thiol-group inhibitors and unchanged by serine-proteinase inhibitors. Human lung NE was inhibited by the univalent cations Na+ and K+. No metal ions were essential for activity, but the heavy-metal ions Cu2+, Hg2+ and Zn2+ were potent inhibitors. With the substrate Z-Gly-Gly-Leu-Nan a broad pH optimum from pH 7.0 to pH 7.6 was observed, and a Michaelis constant value of 1.0 mM was obtained. When Z-Gly-Gly-Leu-Nap (where -Nap represents 2-naphthylamide) was substituted for the above substrate, no NE-catalysed hydrolysis occurred, but Z-Leu-Leu-Glu-Nap was readily hydrolysed by NE. In addition, NE hydrolysed Z-Gly-Gly-Arg-Nap rapidly, but at pH 9.8 rather than in the neutral range. Although human lung NE was stimulated by SDS, the extent of stimulation was not appreciable as compared with the extent of SDS stimulation of NE from other sources.


Ground-state cooling of a single atom at the center of an optical cavity.
A single neutral atom is trapped in a three-dimensional optical lattice at the center of a high-finesse optical resonator. Using fluorescence imaging and a shiftable standing-wave trap, the atom is deterministically loaded into the maximum of the intracavity field where the atom-cavity coupling is strong. After 5 ms of Raman sideband cooling, the three-dimensional motional ground state is populated with a probability of (89±2)%. Our system is the first to simultaneously achieve quantum control over all degrees of freedom of a single atom: its position and momentum, its internal state, and its coupling to light.


The hospitalization experience and single-parent families. A time of special vulnerability.
Hospitalization of a child is always stressful to families. For families without two parents to share the responsibilities and support one another, the stress is not easily borne. Furthermore, such families are likely to already have additional stresses related to the reason for the family breakup (divorce or death of a parent) and have the limited resources of single-parenthood: financial, social, time, and energy. If nurses and other health care personnel will evaluate the strengths and weaknesses of these vulnerable families and offer support and workable solutions to relieve specific pressures, these families may cope with the stresses more competently and, indeed, may discover new resources within themselves, with their families, and with their nonfamily support systems that can be used again in times of crisis. Ultimately the competent family will be able to nurture the child optimally, no matter what the specific health problems. Therefore pediatric nurses supporting the family also support the hospitalized child.


Inhibition of cell proliferation by interferons. Relative contributions of changes in protein synthesis and breakdown to growth control of human lymphoblastoid cells.
Treatment of the Daudi line of human lymphoblastoid cells with concentrations of human interferons within the physiological range progressively inhibits cell proliferation over 1-4 days. Rigorous measurement of the overall rate of protein synthesis during this period, using a concentration of [3H]phenylalanine sufficient to equalize the specific radioactivity of intracellular and extracellular precursor pools, shows that protein synthesis becomes progressively inhibited as the growth inhibition develops. There is a strong correlation between inhibition of amino acid incorporation and inhibition of cell proliferation. In contrast, we find no evidence for any increase in protein degradation rate under these conditions. These results suggest that interferon treatment of susceptible cells can inhibit protein synthesis even in the absence of virus infection and that this inhibition is of a sufficient magnitude to account for the anti-proliferative effect.


Acne is not associated with yet-uncultured bacteria.
Current clinical and microbiological information on acne fails to demonstrate a clear association between particular species, including Propionibacterium acnes, and disease, and the disease continues to be a considerable problem. To test if acne is associated with hitherto uncultured bacteria residing in diseased skin follicles, sequencing and phylogenetic analysis of approximately 5,700 amplified and cloned 16S rRNA genes were used to determine the microbial diversity in follicles from acne patients and healthy individuals and from the superficial skin of acne patients. Follicles from healthy skin were exclusively colonized by P. acnes, whereas the follicular microbiota of acne patients included, in addition, Staphylococcus epidermidis and minor proportions of other species. In comparison, samples from superficial skin showed a complex microbiota represented by 12 to 16 bacterial species. The findings of the study exclude the possibility that acne is associated with yet-uncultured bacteria and shows that healthy skin follicles constitute a remarkably exclusive habitat allowing colonization only by P. acnes.


Zn-responsive proteome profiling and time-dependent expression of proteins regulated by MTF-1 in A549 cells.
Zinc plays a critical role in many biological processes. However, it is toxic at high concentrations and its homeostasis is strictly regulated by metal-responsive transcription factor 1 (MTF-1) together with many other proteins to protect cells against metal toxicity and oxidative stresses. In this paper, we used high-resolution two-dimensional gel electrophoresis (2DE) to profile global changes of the whole soluble proteome in human lung adenocarcinoma (A549) cells in response to exogenous zinc treatment for 24 h. Eighteen differentially expressed proteins were identified by MALDI TOF/TOF and MASCOT search. In addition, we used Western blotting and RT-PCR to examine the time-dependent changes in expression of proteins regulated by MTF-1 in response to Zn treatment, including the metal binding protein MT-1, the zinc efflux protein ZnT-1, and the zinc influx regulator ZIP-1. The results indicated that variations in their mRNA and protein levels were consistent with their functions in maintaining the homeostasis of zinc. However, the accumulation of ZIP-1 transcripts was down-regulated while the protein level was up-regulated during the same time period. This may be due to the complex regulatory mechanism of ZIP-1, which is involved in multiple signaling pathways. Maximal changes in protein abundance were observed at 10 h following Zn treatment, but only slight changes in protein or mRNA levels were observed at 24 h, which was the time-point frequently used for 2DE analyses. Therefore, further study of the time-dependent Zn-response of A549 cells would help to understand the dynamic nature of the cellular response to Zn stress. Our findings provide the basis for further study into zinc-regulated cellular signaling pathways.


Five-Year Assessment of Multiple Gene Variants Associated with Bone Marrow Hypocellularity, Reduced Bone Density, and Ovarian Insufficiency in Adolescence.
This study covers the 5-year interval prior to COVID-19 admission for an otherwise healthy 46,XX adolescent expanding the developmental characterization of an unusual convergence of amenorrhea and genetic mutations. The patient experienced rapid collapse of endogenous estradiol output followed by secondary amenorrhea at 13 years of age. Euploid, diffusely hypocellular bone marrow was present on biopsy, although anemia or reduced total immunoglobulin production was not identified. Bone density was 1.5 years below mean; multiple dental anomalies were also documented. While alterations in "master regulator" genes RUNX2, SALL1, and SAMD9 are usually diagnosed in early childhood when missed milestones, dysmorphic features, or chronic infection/immune impairment warrant cross-disciplinary evaluation, this study is the first known report to associate ovarian failure with adolescence with such variants. Immunoglobulin patterns, osseous histomorphology, dentition, hematology/renal screening, pelvic anatomy, ovarian reserve data, and thyroid findings are also correlated. Although severe pathology is typically encountered when any of these genes are disrupted alone, this longitudinal survey reveals that a mild phenotype can prevail if these 3 variants occur simultaneously. Periodic monitoring is planned given the unclassified status of this unique mutation set.


[The effect of smoking on environmental exposure to carbon of inhabitants in highly and little industrially developed areas].
The aim of the work was an estimation of the effect of smoking on environmental exposure to CO people living in industrial area of Sosnowiec (a city situated in Upper Silesia) and Tomaszów Lubelski (not much industrially town situated at the border of Roztocze National Park). The investigated material was vein blood of 102 blood donors from Sosnowiec and 103 blood donors from Tomaszów Lubelski both smokers and non-smokers. The level of CO exposure was estimated by determination of carbon monoxide haemoglobin (HbCO) concentration in blood by Wolf's method in Antczak's adaptation. It was stated that average HbCO concentration at non-smokers from Sosnowiec (2.09%) was about 0.9% higher than the one at non-smokers from Tomaszów Lubelski (1.17%). An increase of HbCO concentration in blood of non-smokers from Sosnowiec as compared with non-smokers from Tomaszów Lubelski included also 50 and 90 percentile. In relation to 50 percentile it was 2.05 and 1.0% and in relation to 90 percentile 2.4 and 3.7% respectively. The influence of external environment on CO exposure at smokers was estimated on the base of HbCO determination in blood before starting smoking. It was 2.77 at smokers from Sosnowiec and 1.41% at smokers from Tomaszów Lubelski. Analysing the effect of smoking on smokers exposure to CO it was stated that HbCO concentration in blood in both groups increased linearly with the increase of the number of smoked cigarettes, and average increase per one cigarette was 0.43% for smokers from Sosnowiec and 0.57% for smokers from Tomaszów Lubelski. On the base of the obtained results the following conclusions were drawn: 1. industrial and communal environment contamination with carbon monoxide influences considerably the exposure of both smokers and non-smokers. 2. smoking effects significantly more the exposure of people (smokers) to carbon monoxide than environmental pollution in the investigated industrial area. 3. the exposure to carbon monoxide at smokers up with the environmental exposure.


Mechanism of the formation of DNA-protein cross-links by antitumor cisplatin.
DNA-protein cross-links are formed by various DNA-damaging agents including antitumor platinum drugs. The natures of these ternary DNA-Pt-protein complexes (DPCLs) can be inferred, yet much remains to be learned about their structures and mechanisms of formation. We investigated the origin of these DPCLs and their cellular processing on molecular level using gel electrophoresis shift assay. We show that in cell-free media cisplatin [cis-diamminedichloridoplatinum(II)] forms DPCLs more effectively than ineffective transplatin [trans-diamminedichloridoplatinum(II)]. Mechanisms of transformation of individual types of plain DNA adducts of the platinum complexes into the DPCLs in the presence of several DNA-binding proteins have been also investigated. The DPCLs are formed by the transformation of DNA monofunctional and intrastrand cross-links of cisplatin. In contrast, interstrand cross-links of cisplatin and monofunctional adducts of transplatin are stable in presence of the proteins. The DPCLs formed by cisplatin inhibit DNA polymerization or removal of these ternary lesions from DNA by nucleotide excision repair system more effectively than plain DNA intrastrand or monofunctional adducts. Thus, the bulky DNA-protein cross-links formed by cisplatin represent a more distinct and persisting structural motif recognized by the components of downstream cellular systems processing DNA damage considerably differently than the plain DNA adducts of this metallodrug.


In Situ Investigation of the Phase Transition at the Surface of Thermoelectric PbTe with van der Waals Control.
The structure of thermoelectric materials largely determines the thermoelectric characteristics. Hence, a better understanding of the details of the structural transformation process/conditions can open doors for new applications. In this study, the structural transformation of PbTe (a typical thermoelectric material) is studied at the atomic scale, and both nucleation and growth are analyzed. We found that the phase transition mainly occurs at the surface of the material, and it is mainly determined by the surface energy and the degree of freedom the atoms have. After exposure to an electron beam and high temperature, high-density crystal-nuclei appear on the surface, which continue to grow into large particles. The particle formation is consistent with the known oriented-attachment growth mode. In addition, the geometric structure changes during the transformation process. The growth of nanoparticles is largely determined by the van der Waals force, due to which adjacent particles gradually move closer. During this movement, as the relative position of the particles changes, the direction of the interaction force changes too, which causes the particles to rotate by a certain angle.


Comparative analysis of human ex vivo-generated platelets vs megakaryocyte-generated platelets in mice: a cautionary tale.
Thrombopoiesis is the process by which megakaryocytes release platelets that circulate as uniform small, disc-shaped anucleate cytoplasmic fragments with critical roles in hemostasis and related biology. The exact mechanism of thrombopoiesis and the maturation pathways of platelets released into the circulation remain incompletely understood. We showed that ex vivo-generated murine megakaryocytes infused into mice release platelets within the pulmonary vasculature. Here we now show that infused human megakaryocytes also release platelets within the lungs of recipient mice. In addition, we observed a population of platelet-like particles (PLPs) in the infusate, which include platelets released during ex vivo growth conditions. By comparing these 2 platelet populations to human donor platelets, we found marked differences: platelets derived from infused megakaryocytes closely resembled infused donor platelets in morphology, size, and function. On the other hand, the PLP was a mixture of nonplatelet cellular fragments and nonuniform-sized, preactivated platelets mostly lacking surface CD42b that were rapidly cleared by macrophages. These data raise a cautionary note for the clinical use of human platelets released under standard ex vivo conditions. In contrast, human platelets released by intrapulmonary-entrapped megakaryocytes appear more physiologic in nature and nearly comparable to donor platelets for clinical application.