Blood Eosinophil Levels and Prognosis of Hospitalized Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.
Studies about the clinical significance of high eosinophil levels in chronic obstructive pulmonary disease (COPD) are conflicting, and it has been less studied in hospitalized patients with acute exacerbation of COPD (AECOPD).This study was to examine blood eosinophil levels in relation to the prognosis of hospitalized patients with AECOPD. This was a retrospective cohort study of patients with AECOPD as their primary diagnosis and admitted to Beijing Shijitan Hospital, Capital Medical University, from January 2010 to December 2016. The patients were assigned according to the count of eosinophil in peripheral blood at their first hospitalization. Patients were grouped as ≤100, 100-300, and ≥300 eosinophils/µL of peripheral blood. The use of glucocorticoids, duration of hospitalization, in-hospital mortality, and re-hospitalization were examined. Compared with the 100-300 eosinophils/µL group, the ≤100 eosinophils/µL group showed higher frequencies of fever, respiratory failure, and the use of systemic glucocorticoids. Eosinophil counts were not associated with in-hospital mortality and duration of hospitalization. The multivariable analysis showed that GOLD3/4 (odds ratio (OR)=2.04, 95%CI: 1.20-3.44, P = 0.008), systemic glucocorticoids (OR=1.84, 95%CI: 1.41-2.98, P = 0.012), mechanical ventilation (OR=2.66, 95%CI: 1.36-5.18, P = 0.004), and acute exacerbation in the past year before hospitalization (OR=2.03, 95%CI: 1.27-3.23, P = 0.003) were independently associated with acute exacerbation within 1 year after discharge. Eosinophil count was not associated with acute exacerbation within 1 year after discharge. Peripheral blood eosinophil counts are not associated with the 1-year AECOPD prognosis.


Cephalometric Norms for Mewari Children using Steiner's Analysis.
A thorough background in craniofacial growth and development is necessary for every dentist. An important concept in the study of growth and development is variability. Cephalometrics is an important part of morphological diagnostic procedures to assess craniofacial growth and development. The aim of this study was to obtain cephalometric norms for Mewari children of Rajasthan by Steiner analysis and compare with Caucasian norms. The method involved clinical examination, collection and analysis of 100 lateral cephalometric radiographs of Mewari children (50 males and 50 females, between 11 and 13 years of age). All cephalometric landmarks were located and determined and subsequently tracing was done according to Steiner analysis. The mean value and standard deviation of each measurement were calculated. Statistical comparison was done using Student t-test. The result of this study showed that the Mewari children had retrusion of mandible relative to cranial base, proclined maxillary and mandibular teeth, with greater convexity of face. They also showed anteriorly placed occlusal plane to cranium and Less prominent chin. In conclusion, these ethnic differences should be considered during orthodontic treatment. How to cite this article: Rathore AS, Dhar V, Arora R, Diwanji A. Cephalometric Norms for Mewari Children using Steiner's Analysis. Int J Clin Pediatr Dent 2012;5(3):173-177.


Loop-mediated isothermal amplification (LAMP) assays for detection of the New Guinea fruit fly Bactrocera trivialis (Drew) (Diptera: Tephritidae).
The cue-lure-responding New Guinea fruit fly, Bactrocera trivialis, poses a biosecurity risk to neighbouring countries, e.g., Australia. In trapping programs, lure caught flies are usually morphologically discriminated from non-target species; however, DNA barcoding can be used to confirm similar species where morphology is inconclusive, e.g., Bactrocera breviaculeus and B. rufofuscula. This can take days-and a laboratory-to resolve. A quicker, simpler, molecular diagnostic assay would facilitate a more rapid detection and potential incursion response. We developed LAMP assays targeting cytochrome c oxidase subunit I (COI) and Eukaryotic Translation Initiation Factor 3 Subunit L (EIF3L); both assays detected B. trivialis within 25 min. The BtrivCOI and BtrivEIF3L assay anneal derivatives were 82.7 ± 0.8 °C and 83.3 ± 1.3 °C, respectively, detecting down to 1 × 101 copies/µL and 1 × 103 copies/µL, respectively. Each assay amplified some non-targets from our test panel; however notably, BtrivCOI eliminated all morphologically similar non-targets, and combined, the assays eliminated all non-targets. Double-stranded DNA gBlocks were developed as positive controls; anneal derivatives for the COI and EIF3L gBlocks were 84.1 ± 0.7 °C and 85.8 ± 0.2 °C, respectively. We recommend the BtrivCOI assay for confirmation of suspect cue-lure-trapped B. trivialis, with BtrivEIF3L used for secondary confirmation when required.


Isotropic 3D fast FLAIR imaging of the brain in multiple sclerosis patients: initial experience.
The application of image registration and subtraction to detect change in multiple sclerosis (MS) disease burden on serial MR scans benefits from the use of isotropic voxels. An optimised 3D fast fluid-attenuated inversion recovery (FLAIR) sequence with 1.2- and 1.8-mm cubic voxels was compared with a 2D T2 SE sequence using standard 3-mm slices. Three-dimensional fast FLAIR and T2 SE series were obtained in 20 MS patients and 15 controls. Whole brain acquisition times for the 1.2- and 1.8-mm FLAIR were 21 and 10.5 min, respectively, for the interleaved T2 SE 16 min. Brain lesions were marked in consensus by two radiologists and the CNR was calculated in ten lesions. The mean number of lesions detected with the 1.2-mm FLAIR sequence was 115 +/- 76, compared with 85 +/- 59 for the T2 SE series ( p<0.001). The 1.8-mm FLAIR detected only 73 +/- 46 lesions. The CNR of the 1.2-mm FLAIR was significantly better than the T2 SE ( p<0.01), but not as good as the 1.8-mm FLAIR. In conclusion, isotropic 3D fast FLAIR using 1.2-mm cubic voxels is superior to the 2D T2 SE in the detection of brain lesions in MS patients. The isotropic 1.8-mm FLAIR is faster and has better contrast characteristics but lacks sensitivity.


The asymmetric syntheses of cryptocaryols A and B.
The recent total syntheses of cryptocaryols A and B are reviewed. These efforts include the correction of the initially assigned absolute and relative stereochemistry of this class of natural products. In addition to enabling the initial structure activity relationships for this class of natural products, these syntheses demonstrated the practical utility of several novel synthetic approaches.


Factors influencing detection and enumeration of Pseudomonas aeruginosa by most-probable-number and membrane filtration techniques.
Most-probable-number (MPN) and membrane filtration (mF) techniques were evaluated with respect to selectivity, sensitivity, and efficiency in recovering Pseudomonas aeruginosa strains in hospital fluids and extramural water environments. Known numbers of cells of a naturally occurring strain of P. aeruginosa maintained in distilled water or cells subcultured on Standard Methods agar were added to test samples containing various types and levels of background microbial contamiants. Environmental samples containing unknown numbers of P. aeruginosa strains also were tested. Asparagine and acetamide broths were employed as presumptive media in MPN tests, and mPA and Pseudosel agars were used in mF assays. Statistical analyses of data showed the superiority and comparability of the asparagine-MPN and mPA-mF systems. Greater precision and accuracy were consistently obtained in either assay technique by the use of naturally occurring cells as test organisms. The type of filter and nature of diluents employed, as well as pH of assay media, were found to greatly influence both recovery and developemnt of characteristic colonial morphology in the mPA-mF system.


Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif.
The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants.


Relationship between plasma ghrelin, insulin, leptin, interleukin 6, adiponectin, testosterone and longevity in the Baltimore Longitudinal Study of Aging.
Caloric restriction (CR) is the most robust and reproducible intervention for slowing aging, and maintaining health and vitality in animals. Previous studies found that CR is associated with changes in specific biomarkers in monkeys that were also associated with reduced risk of mortality in healthy men. In this study we examine the association between other potential biomarkers related to CR and extended lifespan in healthy humans. Based on the Baltimore Longitudinal Study of Aging, "long-lived" participants who survived to at least 90 years of age (n=41, cases) were compared with "short-lived" participants who died between 72-76 years of age (n=31, controls) in the nested case control study. Circulating levels of ghrelin, insulin, leptin, interleukin 6, adiponectin and testosterone were measured from samples collected between the ages 58 to 70 years. Baseline differences between groups were examined with t-test or Wilcoxon test, and mixed effects general linear model was used for a logistic model to differentiate the two groups with multiple measurements on some subjects. At the time of biomarkers evaluation (58-70 yrs), none of the single biomarker levels was significantly different between the two groups. However, after combining information from multiple biomarkers by adding the z-transformed values, the global score differentiated the long- and short-lived participants (p=0.05). In their sixties, long-lived and short-lived individuals do not differ in biomarkers that have been associated with CR in animals. However, difference between the groups was only obtained when multiple biomarker dysregulation was considered.


Anaemias and other haematological changes due to disease of the alimentary tract.
Often anaemia and other haematological changes are unrelated to primary diseases of the erythron but are secondary to gastrointestinal alterations, such as occult or overt blood loss or defective absorption of essential haemopoietic factors. This overview emphasizes, through the description of different pathological conditions, the fundamental role of the gastrointestinal tract in maintaining a normal haematological balance. This role is jeopardized in diseases related to the liver and to the various sections of the alimentary tract from the oesophagus to the rectum. Of primary importance in inducing haematological changes which may be modified by curing the primary condition are essentially the diseases of the small intestine, following malabsorption of iron, folic acid and vitamin B12, such as conditions associated with small intestine bacterial overgrowth, tropical sprue, gluten sensitive enteropathy whipple's disease and various infections with intestinal parasites. Moreover, the Authors briefly survey the other pathological conditions of the alimentary tract often associated with chronic bleeding. In this context of particular relevance are the screening procedures which may reveal the presence of occult bleeding caused by neoplastic diseases. It is important that the clinician be aware of this possibility and of the underlying physiopathological mechanism of the diseases of the alimentary tract, so that appropriate and timely therapeutic measures may be undertaken.


A mechanism for tunable autoinhibition in the structure of a human Ca2+/calmodulin- dependent kinase II holoenzyme.
Calcium/calmodulin-dependent kinase II (CaMKII) forms a highly conserved dodecameric assembly that is sensitive to the frequency of calcium pulse trains. Neither the structure of the dodecameric assembly nor how it regulates CaMKII are known. We present the crystal structure of an autoinhibited full-length human CaMKII holoenzyme, revealing an unexpected compact arrangement of kinase domains docked against a central hub, with the calmodulin-binding sites completely inaccessible. We show that this compact docking is important for the autoinhibition of the kinase domains and for setting the calcium response of the holoenzyme. Comparison of CaMKII isoforms, which differ in the length of the linker between the kinase domain and the hub, demonstrates that these interactions can be strengthened or weakened by changes in linker length. This equilibrium between autoinhibited states provides a simple mechanism for tuning the calcium response without changes in either the hub or the kinase domains.


A Preliminary Comparative Assessment of the Role of CD8+ T Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis.
Background. CD8+ T cells have putative roles in the regulation of adaptive immune responses during infection. The purpose of this paper is to compare the status of CD8+ T cells in Multiple Sclerosis (MS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Methods. This preliminary investigation comprised 23 CFS/ME patients, 11 untreated MS patients, and 30 nonfatigued controls. Whole blood samples were collected from participants, stained with monoclonal antibodies, and analysed on the flow cytometer. Using the following CD markers, CD27 and CD45RA (CD45 exon isoform 4), CD8+ T cells were divided into naïve, central memory (CM), effector memory CD45RA- (EM), and effector memory CD45RA+ (EMRA) cells. Results. Surface expressions of BTLA, CD127, and CD49/CD29 were increased on subsets of CD8+ T cells from MS patients. In the CFS/ME patients CD127 was significantly decreased on all subsets of CD8+ T cells in comparison to the nonfatigued controls. PSGL-1 was significantly reduced in the CFS/ME patients in comparison to the nonfatigued controls. Conclusions. The results suggest significant deficits in the expression of receptors and adhesion molecules on subsets of CD8+ T cells in both MS and CFS/ME patients. These deficits reported may contribute to the pathogenesis of these diseases. However, larger sample size is warranted to confirm and support these encouraging preliminary findings.


Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis.
Ovarian carcinomas comprise a heterogeneous group of neoplasms, the four most common subtypes being serous, endometrioid, clear cell and mucinous. In recent years, our understanding of the underlying pathogenesis and initiating molecular events in the different tumour subtypes has greatly increased, and although ovarian carcinoma is often considered clinically as one disease, there is now a much greater realisation that the various subtypes have a different natural behaviour and prognosis. At present, adjuvant therapy is mainly dependent upon tumour stage and grade rather than type; however, this is likely to change in the future with the development of new chemotherapeutic agents and targeted therapies and clinical trials are necessary to evaluate the efficacy of different agents in clear cell, mucinous and low grade serous carcinomas, neoplasms which are considered relatively resistant to traditional chemotherapeutic regimes. In this review, the major subtypes of ovarian carcinoma are discussed. It is now firmly established that there are two distinct types of ovarian serous carcinoma, low grade and high grade, the former being much less common and arising in many cases from a serous borderline tumour. Low grade and high grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis rather than low grade and high grade variants of the same neoplasm. Both are usually advanced stage (stage III or IV) at diagnosis. B-raf and k-ras mutations are important molecular events in low grade serous carcinomas while high grade serous carcinomas are almost always associated with TP53 mutation. There is now emerging and compelling evidence that many high grade serous carcinomas (by far the most common subtype of ovarian carcinoma) actually arise from the epithelium of the distal fallopian tube. Future studies regarding the initiating molecular events in the development of this aggressive neoplasm should concentrate on this site. Primary ovarian mucinous carcinomas are uncommon, almost always unilateral and stage I, and largely of so-called intestinal or enteric type. Most arise in a stepwise manner from a pre-existing mucinous cystadenoma and mucinous borderline tumour. Endometrioid and clear cell carcinomas typically present as low stage neoplasms and in many, or most, cases arise from endometriosis; the former are usually well differentiated and there is now evidence that the majority of neoplasms reported in the past as high grade endometrioid carcinoma are of serous type. WT1 is useful in this regard since it is a relatively specific marker of a serous phenotype. It is recommended that different subtypes of ovarian carcinoma are graded using different systems rather than employing a universal grading system.


Developing an operational definition of housing instability and homelessness in Veterans Health Administration's medical records.
The main objective of this study was to examine how homelessness and housing instability is captured across data sources in the Veterans Health Administration (VHA). Data from 2021 were extracted from three data repositories, including the Corporate Data Warehouse (CDW), the Homeless Operations Management System (HOMES), and the Homeless Management Information System (HMIS). Using these three data sources, we identified the number of homeless and unstably housed veterans across a variety of indicators. The results showed that the use of diagnostic codes and clinic stop codes identified a large number of homeless and unstably housed veterans, but the use of HOMES and HMIS data identified additional homeless and unstably housed veterans to provide a complete count. A total of 290,431 unique veterans were identified as experiencing homelessness or housing instability in 2021 and there was regional variability in how homelessness and housing stability were captured across data sources, supporting the need for more uniform ways to operationalize these conditions. Together, these findings highlight the and encourage use of all available indicators and data sources to identify homelessness and housing instability in VHA. These methodologies applied to the largest healthcare system in the U.S. demonstrate their utility and possibilities for other healthcare systems. Transparent practices about data sources and indicators used to capture homelessness and housing instability should be shared to increase uniform use.


Neuroprotective effect of Mayan medicinal plant extracts against glutamate-induced toxicity.
Neurological disorders are a public health problem worldwide for which there is currently no direct treatment of the cause of the disorder. The goal of this study was to investigate the potential in vitro neuroprotective property of plants used in Mayan traditional medicine. Plant ethanolic extracts were prepared and tested on models in which neuronal damage was induced by glutamate, i.e., a human neuroblastoma cell line (SH-SY5Y) and rat cortical neurons. HPLC profiles from active extracts were also obtained. A total of 51 plant species were identified in the literature as plant species used in Mayan traditional medicine for the treatment of symptoms suggestive of neurological disorders, and we studied 34 of these in our analysis. Six extracts had a neuroprotective effect on SH-SY5Y cells, with the most active extract being that from Schwenckia americana roots (half maximal effective concentration [EC50] 11.3 ± 2.9 μg/mL), and three extracts exhibited a neuroprotective effect in the rat neuron cortical model, with the most active extract being that from Elytraria imbricata aerial parts (EC50 6.8 ± 3.1 μg/mL). These results suggest that the active extracts from such plants have the potential to be a great resource. Future studies should be performed that are more extensive and which isolate the active constituents.


Interactions between different corneal proteoglycans.
Proteoglycans were extracted from bovine cornea with 4M-guanidinium chloride and purified by CsCl-density-gradient centrifugation. Under associative conditions two fractions were found: one capable of forming assemblies of high molecular weight and another lacking this property. The heavier fraction (density 1.59 g/ml) was eluted as a single retarded peak from Sepharose 2B, but on DEAE-Sephadex chromatography, gave two peaks: the first (eluted with 0.75 M-NaCl) contained mainly proteochondroitin sulphate and the second (eluted with 1.25 M-NaCl) mainly proteokeratan sulphate. Each of these proteoglycans was more retarded on Sepharose 2B than was the original sample from density-gradient centrifugation. Re-aggregation was obtained by recombination of the two fractions. The lighter fraction (density 1.44 g/ml), containing predominantly keratan sulphate chains, was eluted from DEAE-Sephadex as a single peak with 1.25 M-NaCl and was retarded on Sepharose 2B: this fraction was not able to form aggregates with proteochondroitin sulphate. Chemical analyses of the carbohydrate and protein moieties of the proteoglycans from DEAE-Sephadex confirmed that, in the cornea, different subunits are present with characteristic aggregation properties and hydrodynamic volumes.


Free-energy functionals of the electrostatic potential for Poisson-Boltzmann theory.
In simulating charged systems, it is often useful to treat some ionic components of the system at the mean-field level and solve the Poisson-Boltzmann (PB) equation to get their respective density profiles. The numerically intensive task of solving the PB equation at each step of the simulation can be bypassed using variational methods that treat the electrostatic potential as a dynamic variable. But such approaches require the access to a true free-energy functional: a functional that not only provides the correct solution of the PB equation upon extremization, but also evaluates to the true free energy of the system at its minimum. Moreover, the numerical efficiency of such procedures is further enhanced if the free-energy functional is local and is expressed in terms of the electrostatic potential. Existing PB functionals of the electrostatic potential, while possessing the local structure, are not free-energy functionals. We present a variational formulation with a local free-energy functional of the potential. In addition, we also construct a nonlocal free-energy functional of the electrostatic potential. These functionals are suited for employment in simulation schemes based on the ideas of dynamical optimization.


The Novelty in Fabrication of Poly Vinyl Alcohol/κ-Carrageenan Hydrogel with Lactobacillus bulgaricus Extract as Anti-inflammatory Wound Dressing Agent.
Material barrier properties to microbes are an important issue in many pharmaceutical applications like wound dressings. A wide range of biomaterials has been used to manage the chronic inflamed wounds. Eight hydrogel membranes of poly vinyl alcohol (PVA) with κ-carrageenan (KC) and Lactobacillus bulgaricus extract (LAB) have been prepared by using freeze-thawing technique. To evaluate the membranes efficiency as wound dressing agents, various tests have been done like gel fraction, swelling behavior, mechanical properties, etc. The antibacterial activities of the prepared membranes were tested against the antibiotic-resistant bacterial isolates. In addition, the safety usage of the prepared hydrogel was checked on human dermal fibroblast cells. The anti-inflammatory properties of the prepared hydrogel on LPS-PBMC cell inflammatory model were quantified using enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-qPCR). The analysis data of TGA, SEM, gel fraction, and swelling behavior showed changes in properties of prepared PVA\KC\LAB hydrogel membrane than pure PVA hydrogel membrane. The antibacterial activities of the prepared membranes augmented in LAB extract-prepared membranes. Out of the eight used hydrogel membranes, the PVAKC4 hydrogel membrane is the safest one on fibroblast cellular proliferation with a maximum proliferation percentage 97.3%. Also, all the used hydrogel membrane showed abilities to reduce the concentration of IL-2 and IL-8 compared with both negative and positive control. In addition, almost all the prepared hydrogel membrane showed variable abilities to downregulate the expression of TNF-α gene with superior effect of hydrogel membrane KC1. PVA/KC/LAB extract hydrogel membrane may be a promising material for wound dressing application and could accelerate the healing process of the chronic wound because of its antimicrobial and anti-inflammatory properties.


Dual Delivery of Gemcitabine and Paclitaxel by Wet-Spun Coaxial Fibers Induces Pancreatic Ductal Adenocarcinoma Cell Death, Reduces Tumor Volume, and Sensitizes Cells to Radiation.
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with surgical resection of the tumor in conjunction with systemic chemotherapy the only potential curative therapy. Up to 80% of diagnosed cases are deemed unresectable, prompting the need for alternative treatment approaches. Herein, coaxial polymeric fibers loaded with two chemotherapeutic agents, gemcitabine (Gem) and paclitaxel (Ptx), are fabricated to investigate the effect of local drug delivery on PDAC cell growth in vitro and in vivo. A wet-spinning fabrication method to form a coaxial fiber with a polycaprolactone shell and alginate core loaded with Ptx and Gem, respectively, is used. In vitro, Gem+Ptx fibers display significant cytotoxicity as well as radiosensitizing properties toward PDAC cell lines greater than the equivalent free drugs, which may be attributed to a radiosensitizing effect of the polymers. In vivo studies assessing Gem+Ptx fiber efficacy found that Gem+Ptx fibers reduce tumor volume in a xenograft mouse model of PDAC. Importantly, no difference in mouse weight, circulating cytokines, or liver function is observed in mice treated with Gem+Ptx fibers compared to the empty fiber controls confirming the safety of the implant approach. With further development, Gem+Ptx fibers can improve the treatment of unresectable PDAC in the future.


[Endogenic activation of prorenin in hypertension].
Two forms of renin (active-APR and inactive-IPR) and its total production were studied in relation to the daily excretion of kallikrein in patients with essential hypertension of the labile and the stable stage at rest and following the stimulation by an hour's walk and the intravenous infusion of prostaglandin E (PGE). The results showed inverse correlations of APR and IPR in the total production of renin in hypertensive patients in different "renin" subgroups, and an inverse correlation between the level of IPR and the 24-hour excretion of kallikrein in the basal conditions and following an hour's walk. PGE infusion elevated APR and decreased IPR levels, leaving the total production of renin unchanged. The level of kidney kallikrein was inversely correlated with IPR and directly correlated with APR. The findings suggested the involvement of kidney kallikrein in the endogenic activation of prorenin.


Objective Versus Self-Reported Physical Activity in Overweight and Obese Young Adults.
To compare moderate-to-vigorous intensity physical activity (MVPA) assessed via questionnaires to an objective measure of MVPA in overweight or obese young adults. MVPA was assessed in 448 [median BMI = 31.2 (Interquartile Range: 28.5-34.3) kg/m2] young adults [median age: 30.9 (Interquartile Range: 27.8-33.7) years]. Measures included the SenseWear Armband (MVPAOBJ), the Paffenbarger Questionnaire (MVPAPAFF), and the Global Physical Activity Questionnaire (GPAQ). The GPAQ was used to compute total MVPA (MVPAGPAQ-TOTAL) and MVPA from transportation and recreation (MVPAGPAQ-REC). The association between MVPAOBJ and MVPAPAFF was rs = 0.40 (P < .0001). Associations between MVPAOBJ and MVPAGPAQ-TOTAL and MVPAGPAQ-REC were rs = 0.19 and rs = 0.32, respectively (P < .0001). MVPAGPAQ-TOTAL was significantly greater than MVPAOBJ (P < .0001). Median differences in MET-min/week between MVPAOBJ and MVPAPAFF or MVPAGPAQ-REC were not significantly different from zero. There was proportional bias between each self-reported measure of MVPA and MVPAOBJ. There were significant associations between all measures of MVPA and fitness. MVPAOBJ was significantly associated with BMI and percent body fat. Objective and self-reported measures of MVPA are weakly to moderately correlated, with substantial differences between measures. MVPAOBJ provided predictive validity with fitness, BMI, and percent body fat. Thus, an objective measure of MVPA may be preferred to self-report in young adults.


An in vitro experimental pipeline to characterize the binding specificity of SARS-CoV-2 neutralizing antibodies.
The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to over 760 million cases and >6.8 million deaths worldwide. We developed a panel of human neutralizing monoclonal antibodies (mAbs) targeting the SARS-CoV-2 Spike protein using Harbour H2L2 transgenic mice immunized with Spike receptor binding domain (RBD) (1). Representative antibodies from genetically-distinct families were evaluated for inhibition of replication-competent VSV expressing SARS-CoV-2 Spike (rcVSV-S) in place of VSV-G. One mAb (denoted FG-10A3) inhibited infection of all rcVSV-S variants; its therapeutically-modified version, STI-9167, inhibited infection of all tested SARS-CoV-2 variants, including Omicron BA.1 and BA.2, and limited virus proliferation in vivo (1). To characterize the binding specificity and epitope of FG-10A3, we generated mAb-resistant rcVSV-S virions and performed structural analysis of the antibody/antigen complex using cryo-EM. FG-10A3/STI-9167 is a Class 1 antibody that prevents Spike-ACE2 binding by engaging a region within the Spike receptor binding motif (RBM). Sequencing of mAb-resistant rcVSV-S virions identified F486 as a critical residue for mAb neutralization, with structural analysis revealing that both the variable heavy and light chains of STI-9167 bound the disulfide-stabilized 470-490 loop at the Spike RBD tip. Interestingly, substitutions at position 486 were later observed in emerging variants of concern BA.2.75.2 and XBB. This work provides a predictive modeling strategy to define the neutralizing capacity and limitations of mAb therapeutics against emerging SARS-CoV-2 variants. The COVID-19 pandemic remains a significant public health concern for the global population; development and characterization of therapeutics, especially ones that are broadly effective, will continue to be essential as SARS-CoV-2 variants emerge. Neutralizing monoclonal antibodies remain an effective therapeutic strategy to prevent virus infection and spread with the caveat that they interact with the circulating variants. The epitope and binding specificity of a broadly neutralizing anti-SARS-CoV-2 Spike RBD antibody clone against many SARS-CoV-2 VOC was characterized by generating antibody-resistant virions coupled with cryo-EM structural analysis. This workflow can serve to predict the efficacy of antibody therapeutics against emerging variants and inform the design of therapeutics and vaccines.


Electronic Health Physical Activity Behavior Change Intervention to Self-Manage Cardiovascular Disease: Qualitative Exploration of Patient and Health Professional Requirements.
Cardiovascular diseases are a leading cause of premature death worldwide. International guidelines recommend routine delivery of all phases of cardiac rehabilitation. Uptake of traditional cardiac rehabilitation remains suboptimal, as attendance at formal hospital-based cardiac rehabilitation programs is low, with community-based cardiac rehabilitation rates and individual long-term exercise maintenance even lower. Home-based cardiac rehabilitation programs have been shown to be equally effective in clinical and health-related quality of life outcomes and yet are not readily available. Given the potential that home-based cardiac rehabilitation programs have, it is important to explore how to appropriately design any such intervention in conjunction with key stakeholders. The aim of this study was to engage with individuals with cardiovascular disease and other professionals within the health ecosystem to (1) understand the personal, social, and physical factors that inhibit or promote their capacity to engage with physical activity and (2) explore their technology competencies, needs, and wants in relation to an eHealth intervention. Fifty-four semistructured interviews were conducted across two countries. Interviews were audiotaped, transcribed verbatim, and analyzed using thematic analysis. Barriers to the implementation of PATHway were also explored specifically in relation to physical capability and safety as well as technology readiness and further mapped onto the COM-B model for future intervention design. Key recommendations included collection of patient data and use of measurements, harnessing hospital based social connections, and advice to utilize a patient-centered approach with personalization and tailoring to facilitate optimal engagement. In summary, a multifaceted, personalizable intervention with an inclusively designed interface was deemed desirable for use among cardiovascular disease patients both by end users and key stakeholders. In-depth understanding of core needs of the population can aid intervention development and acceptability.


Within-subject, double-blinded, randomized, and placebo-controlled evaluation of the combined effects of the cannabinoid dronabinol and the opioid hydromorphone in a human laboratory pain model.
This Phase II study evaluated analgesia, abuse liability, and cognitive performance of hydromorphone and oral delta-9-tetrahydrocannabinol (THC; dronabinol) using a within-subject, double-blind, randomized, placebo-controlled, human laboratory trial. Healthy adults (N = 29) with no history of drug use disorder received combinations of placebo, hydromorphone (4 mg; oral), and dronabinol (2.5 mg, 5.0 mg, 10 mg; oral). Primary outcomes were quantitative sensory testing (QST) measures of acute (thermal, pressure pain; thermal, punctate probe temporal summation; cold pressor; conditioned pain modulation) and chronic pain (capsaicin 10% topical cream with thermal rekindling), measures of drug abuse liability, cognitive functioning, and adverse events. Subgroup analyses were conducted within opioid-responders (endorsed >20 on a Drug Effect visual analog scale during the hydromorphone-only condition) and nonresponders. A consistent dose-effect relationship of dronabinol on hydromorphone across all measures was not observed. Analgesia only improved in the hydromorphone + dronabinol 2.5 mg condition. Hydromorphone + dronabinol 2.5 mg showed the lowest and hydromorphone+dronabinol 5 mg showed the highest risk for abuse. Hydromorphone+dronabinol 10 mg produced a high rate of dysphoric effects, and hydromorphone+dronabinol 5 mg and hydromorphone + dronabinol 10 mg produced AEs. Subgroup analyses showed subjective effects and abuse risk was increased among opioid responders and largely absent among nonresponders. Overall, only hydromorphone+dronabinol 2.5 mg modestly enhanced hydromorphone-based analgesia and hydromorphone + dronabinol 5 mg and 10 mg increased risk for abuse and AEs. These data can help inform opioid-sparing efforts in clinical pain populations. Demonstration that potential opioid effects varied as a function of participant opioid sensitivity (e.g., responder status) is a novel finding that warrants additional research.


Free muscle flap reconstructions using interpositional vein grafts vs. local anastomosis: a 5-year experience at a rural tertiary care center.
The use of free muscle or myocutaneous flaps is well established as a means for reconstructing tissue defects over nearly any part of the body. This free tissue transfer is based on the availability of a robust blood supply in the recipient wound. The reliability of native blood supplies within the zone of injury is suspect even in the best of conditions. There are several causes of flap failure however; one of the most common is vascular compromise. Though refinements in the technique of vascular anastomosis have lessened the risk, it is still significant, especially when dealing with an area of injury at the recipient site. The mechanisms of scar formation and healing that occur within the zone of injury often limit the potential for viable anastomotic targets. This often leads to delay in wound coverage and exposes the patient to all of the risks associated with having an open wound. Free flap failure can be devastating for patients, even leading to the loss of limbs. Therefore, it is vital that all measures possible to ensure the survival of the transferred tissue be employed. We will examine interpositional vein grafts versus local anastomoses in the context of free tissue transfer for wound coverage in the traumatized and reconstructed patient. We will retrospectively review the case histories of free tissue transfers preformed at West Virginia University Hospital over a 5-year period (2001-2006). We will examine data including the demographics of our patient population, type and locations of the free flaps, length of stay in the hospital, time interval between injury and repair, and the Success and failure rate. The overall success rate was 38 out of 45 or 84%. Success was defined as a healthy flap and preservation of the limb and/or successful wound coverage at time of discharge. Flap success was present in 18 of 23 (78%) of the vein interposition grafts, and flap failure occurred in 5 (22%). In patients with local anastomoses, 20 out of 22 flaps survived (91%) with 2 failures (9%). We will demonstrate that the use of interpositional vein grafts for free tissue transfer is a viable option in the wound coverage. We will demonstrate that this is especially 'true in the patient population that exists in rural America.


Response to rituximab and prednisolone for opsoclonus-myoclonus-ataxia syndrome in a child with ganglioneuroblastoma.
Opsoclonus-myoclonus-ataxia (OMA) syndrome is a rare neurobehavioral paraneoplastic disorder in children with neuroblastic tumors. The neurologic symptoms are generally treated with a number of immunosupressive and immunomodulating agents. A 4-year-old previously healthy male patient was admitted to the authors' center with progressive ataxia, gait disturbance, difficulty of speech, and opsoclonus. He had a diagnosis of ganglionueroblastoma at the thoracal paraspinal region. Following surgery, the patient received IVIG and prednisolone but his cerebellar symptoms progressed. Rituximab therapy was started and continued for total 8 weeks without any side effect. The authors observed excellent neurologic response in the patient at the 4th week of treatment. Rituximab is a new, promising, and safe therapy for OMA syndrome in children with neuroblastoma.


Impact of smart pump-electronic health record interoperability on patient safety and finances at a community hospital.
In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Integrating smart pumps with an electronic health record (EHR) reduces medication errors by automating pump programming and EHR documentation. This study describes the patient safety and financial impact of pump-EHR interoperability at a community hospital. A 316-bed community hospital in Sugar Land, TX, went live with pump-EHR interoperability in October 2019. Data were collected from April 1, 2019, to June 30, 2019 (before implementation) and from April 1, 2020, to June 30, 2020 (after implementation). Rates of drug library compliance, alert firing, alert override, override within 2 seconds, high-risk alert override, and alert resulting in pump reprogramming were measured. Financial impact was measured by Current Procedural Terminology code capture per kept appointment in the infusion center. Drug library compliance increased from 73.8% to 82.9% with pump-EHR interoperability (P < 0.001). Infusions generating alerts among all infusions programmed with the drug library decreased from 3.5% to 2.6% (P < 0.001), overridden alerts increased from 64.8% to 68.9% (P < 0.001), alerts overridden within 2 seconds decreased from 17.3% to 13.8% (P < 0.001), and reprogrammed alerts decreased from 20.7% to 18.3% (P = 0.002). Pump-EHR interoperability leads to safer administration of intravenous medications based on improved drug library compliance and more accurate smart pump programming.


The development of chiral drugs.
For many years, scientists in drug development have been blind to the 3-dimensional consequences of stereochemistry, mainly due to the problem of synthesis and analytical methodology. Now that new techniques are available for the resolution of racemic mixtures, there is an increasing pressure to only synthesise single enantiomers, and although guidelines on stereoisomers from the all regulatory agencies are awaited, there is already sufficient information to suggest that developmental studies on racemates will be greatly increased. There is often stereospecificity in pharmacology and toxicology, but this is frequently not the case for pharmacokinetics where enantiomeric differences may only play a relatively small contribution to overall drug activity, except for some exceptions (NSAI). Other chiral developments are discussed, for example, dextro fenfluramine from rac-fenfluramine, together with the ideas of what may be required for their registration.


Siderotic cerebral macrophages in the acquired immunodeficiency syndrome.
Excessive hemosiderin-laden perivascular macrophages have been described in the brains of patients with the acquired immunodeficiency syndrome (AIDS) who underwent autopsy; its meaning remains unclear. In the brains of 53 patients with AIDS who consecutively underwent autopsy, we quantified the abnormality, elucidated its relationship to the pathologic features of AIDS, and asked if there was some relationship to endogenous iron storage and transport proteins in brain macrophages and microglia. The number of perivascular siderotic macrophages was significantly increased in patients with AIDS compared with age-matched control subjects. Macrophage siderosis was strongly correlated with the presence of disseminated mycobacterial infection and vacuolar myelopathy at autopsy; a generalized wasting (cachexia) also was related significantly. Many other pathologic abnormalities were not related, including putative human immunodeficiency virus-specific neuropathologic changes such as multinucleated cells and myelin pallor. Activated macrophages and microglial cells in the central nervous system had dense intracytoplasmic accumulation of ferritin (iron storage protein) in AIDS and non-AIDS patients. These results suggest that siderosis of cerebral macrophages is related to an ill-defined nonspecific systemic imbalance associated with the breakdown of abundant stores of endogenous intracellular ferritin. Understanding chronic "secondary" effects of human immunodeficiency virus type 1 infection will become increasingly important as improved survival in patients with AIDS is realized.


[Use of immunomodulator polyoxydony in treatment and prevention of septic conditions in surgical patients].
52 patients (group 1) with a high risk of postoperative infective and septic complications and 58 surgical patients (group 2) with the developed infective septic complications are analysed. In 32 patients of group 1 and in 37 patients of group 2 immunomodulator Polyoxydony was used. The use of Polyoxydony in patients of both groups contributed to favourable dynamics of immune status, decrease of the rate of complications and postoperative mortality. Polyoxydony is effective medicine in prevention and treatment of postoperative infective and septic complications.


WASh multicentre randomised controlled trial: water-assisted sigmoidoscopy in English NHS bowel scope screening.
The English Bowel Cancer Screening Programme invites 55 year olds for a sigmoidoscopy (Bowel Scope Screening (BSS)), aiming to resect premalignant polyps, thus reducing cancer incidence. A national patient survey indicated higher procedural pain than anticipated, potentially impacting on screening compliance and effectiveness. We aimed to assess whether water-assisted sigmoidoscopy (WAS), as opposed to standard CO2 technique, improved procedural pain and detection of adenomatous polyps. The WASh (Water-Assisted Sigmoidoscopy) trial was a multicentre, single-blind, randomised control trial for people undergoing BSS. Participants were randomised to either receive WAS or CO2 from five sites across England. The primary outcome measure was patient-reported moderate/severe pain, as assessed by patients on a standard Likert scale post procedure prior to discharge. The key secondary outcome was adenoma detection rate (ADR). The costs of each technique were also measured. 1123 participants (50% women, mean age 55) were randomised (561 WAS, 562 CO2). We found no difference in patient-reported moderate/severe pain between WAS and CO2 (14% in WAS, 15% in CO2; p=0.47). ADR was 15% in the CO2 arm and 11% in the WAS arm (p=0.03); however, it remained above the minimum national performance standard in both arms. There was no statistical difference in mean number of adenomas nor overall polyp detection rate. There was negligible cost difference between the two techniques. In the context of enema-prepared unsedated screening sigmoidoscopies performed by screening-accredited endoscopists, no difference in patient-reported pain was seen when using either a CO2 or WAS intubation technique. ISRCTN81466870.


Nanopore Targeted Sequencing for the Accurate and Comprehensive Detection of SARS-CoV-2 and Other Respiratory Viruses.
The ongoing global novel coronavirus pneumonia COVID-19 outbreak has engendered numerous cases of infection and death. COVID-19 diagnosis relies upon nucleic acid detection; however, currently recommended methods exhibit high false-negative rates and are unable to identify other respiratory virus infections, thereby resulting in patient misdiagnosis and impeding epidemic containment. Combining the advantages of targeted amplification and long-read, real-time nanopore sequencing, herein, nanopore targeted sequencing (NTS) is developed to detect SARS-CoV-2 and other respiratory viruses simultaneously within 6-10 h, with a limit of detection of ten standard plasmid copies per reaction. Compared with its specificity for five common respiratory viruses, the specificity of NTS for SARS-CoV-2 reaches 100%. Parallel testing with approved real-time reverse transcription-polymerase chain reaction kits for SARS-CoV-2 and NTS using 61 nucleic acid samples from suspected COVID-19 cases show that NTS identifies more infected patients (22/61) as positive, while also effectively monitoring for mutated nucleic acid sequences, categorizing types of SARS-CoV-2, and detecting other respiratory viruses in the test sample. NTS is thus suitable for COVID-19 diagnosis; moreover, this platform can be further extended for diagnosing other viruses and pathogens.


Streptococcus anginosus group disseminated infection: case report and review of literature.
Streptococcus anginosus group is widely known for its ability to cause invasive pyogenic infections. There are very few reports of disseminated infections sustained by members of this streptococcal group. We report a case of a highly disseminated infection and analyse previous literature reports. Disseminated pyogenic infection has been defined as an infection affecting two or more of the following organs/systems: central nervous system, lung, liver and spleen. We performed a PubMed search using the terms: S. milleri, S. anginosus, brain abscess, pulmonary abscess, hepatic abscess, spleen abscess. We reviewed 12 case reports including the one presented in this paper. Underlying conditions such as dental infections, malignancy, gastrointestinal and respiratory tract disease accounted for 42% of cases. No definite endocarditis was encountered, even though positive blood cultures were found in 67% of patients. Concomitant brain-liver, brain-lung and brain-spleen involvement occurred in 50%, 42% and 8% of cases respectively. Ninety-one percent (91%) of patients were treated with β-lactams, and surgical procedures were performed in 67% of patients. Infections caused by S. anginosus group members are satisfactorily treated with penicillin G and cephalosporins. It is very important to associate surgery to antimicrobial chemotherapy in order to achieve a full or nearly full clinical recovery.


The structure of HasB reveals a new class of TonB protein fold.
TonB is a key protein in active transport of essential nutrients like vitamin B12 and metal sources through the outer membrane transporters of Gram-negative bacteria. This inner membrane protein spans the periplasm, contacts the outer membrane receptor by its periplasmic domain and transduces energy from the cytoplasmic membrane pmf to the receptor allowing nutrient internalization. Whereas generally a single TonB protein allows the acquisition of several nutrients through their cognate receptor, in some species one particular TonB is dedicated to a specific system. Despite a considerable amount of data available, the molecular mechanism of TonB-dependent active transport is still poorly understood. In this work, we present a structural study of a TonB-like protein, HasB dedicated to the HasR receptor. HasR acquires heme either free or via an extracellular heme transporter, the hemophore HasA. Heme is used as an iron source by bacteria. We have solved the structure of the HasB periplasmic domain of Serratia marcescens and describe its interaction with a critical region of HasR. Some important differences are observed between HasB and TonB structures. The HasB fold reveals a new structural class of TonB-like proteins. Furthermore, we have identified the structural features that explain the functional specificity of HasB. These results give a new insight into the molecular mechanism of nutrient active transport through the bacterial outer membrane and present the first detailed structural study of a specific TonB-like protein and its interaction with the receptor.


Hypertension and the brain. The National High Blood Pressure Education Program.
Neurogenic mechanisms are important in the maintenance of most forms of hypertension, yet the brain is highly vulnerable to the deleterious effects of elevated blood pressure. Hypertensive encephalopathy results from a sudden, sustained rise in blood pressure sufficient to exceed the upper limit of cerebral blood flow autoregulation. The cerebral circulation adapts to chronic less severe hypertension but at the expense of changes that predispose to stroke due to arterial occlusion or rupture. Stroke is a generic term for a clinical syndrome that includes focal infarction or hemorrhage in the brain, or subarachnoid hemorrhage. Atherothromboembolism and thrombotic occlusion of lipohyalinotic small-diameter end arteries are the principal causes of cerebral infarction. Microaneurysm rupture is the usual cause of hypertension-associated intracerebral hemorrhage. Rupture of aneurysms on the circle of Willis is the most common cause of nontraumatic subarachnoid hemorrhage. Stroke is a major cause of morbidity and mortality, particularly among persons aged 65 years or older. Treatment of diastolic hypertension reduces the incidence of stroke by about 40%. Treatment of isolated systolic hypertension in persons aged 60 years and older reduces the incidence of stroke by more than one third. Blood pressure management in the setting of acute stroke and the role of antihypertensive therapy in the prevention of multi-infarct dementia require further study.


The Potential of Surveillance Data for Dengue Risk Mapping: An Evaluation of Different Approaches in Cuba.
To better guide dengue prevention and control efforts, the use of routinely collected data to develop risk maps is proposed. For this purpose, dengue experts identified indicators representative of entomological, epidemiological and demographic risks, hereafter called components, by using surveillance data aggregated at the level of Consejos Populares (CPs) in two municipalities of Cuba (Santiago de Cuba and Cienfuegos) in the period of 2010-2015. Two vulnerability models (one with equally weighted components and one with data-derived weights using Principal Component Analysis), and three incidence-based risk models were built to construct risk maps. The correlation between the two vulnerability models was high (tau > 0.89). The single-component and multicomponent incidence-based models were also highly correlated (tau ≥ 0.9). However, the agreement between the vulnerability- and the incidence-based risk maps was below 0.6 in the setting with a prolonged history of dengue transmission. This may suggest that an incidence-based approach does not fully reflect the complexity of vulnerability for future transmission. The small difference between single- and multicomponent incidence maps indicates that in a setting with a narrow availability of data, simpler models can be used. Nevertheless, the generalized linear mixed multicomponent model provides information of covariate-adjusted and spatially smoothed relative risks of disease transmission, which can be important for the prospective evaluation of an intervention strategy. In conclusion, caution is needed when interpreting risk maps, as the results vary depending on the importance given to the components involved in disease transmission. The multicomponent vulnerability mapping needs to be prospectively validated based on an intervention trial targeting high-risk areas.


Hypokalemia after resuscitation from out-of-hospital ventricular fibrillation.
We studied serum electrolyte levels, blood gas values, and diuretic history in 115 patients immediately after resuscitation from out-of-hospital ventricular fibrillation. Comparisons were made with 84 patients admitted for acute myocardial infarction and with 88 ambulatory patients with coronary heart disease. Admission serum potassium values of 3.60 mEq/L or lower were found in 56 (49%) of the resuscitated patients, compared with 16 (19%) and eight (9%) of the comparison groups, respectively. In the resuscitated patients, the mean serum potassium level was 3.70 +/- 0.72 (SD) mEq/L, compared with 4.09 +/- 0.66 and 4.17 +/- 0.35 mEq/L in the respective comparison groups. Reduced serum potassium concentration was not related to simple extracellular alkalosis. However, the absence of a causative relationship to diuretic use suggested that it occurred during cardiac arrest and resuscitation. Rapid correction of extracellular acidosis by bicarbonate therapy and ventilation may have produced a shift of extracellular potassium into the intracellular compartment even in the absence of extracellular alkalosis.


Bisphenol AF promotes estrogen receptor-positive breast cancer cell proliferation through amphiregulin-mediated crosstalk with receptor tyrosine kinase signaling.
Exposure to bisphenol A (BPA), an endocrine-disrupting compound, is associated with increased risk of estrogen-related diseases, including estrogen receptor-positive (ER+) breast cancer. Although bisphenol analogs, i.e. bisphenol AF (BPAF), have replaced BPA in industrial settings, increasing data indicate that these alternatives may have similar or even more potent estrogenic effects. As such, BPAF exhibits increased ER binding affinities than BPA in biochemical assays. However, preclinical studies exploring the effects of BPAF on ER+ breast cancer are missing mechanistic data. Thus, we aimed to characterize the effects of BPAF on MCF-7 and T47D ER+ breast cancer cells with mechanistic insight. We found that BPAF promoted cell growth and cell cycle progression concurrently with BPAF-induced ERα transcriptional activity and ER-RTK signaling activation. ER signaling blockage revealed that BPAF-induced cell proliferation and ER-RTK crosstalk were ER-dependent. Gene expression data demonstrated that AREG is a sensitive target of BPAF in our in vitro models. Importantly, we determined that AREG upregulation is necessary for BPAF-induced cellular responses. Ultimately, our novel finding that AREG mediates BPAF-induced ER-RTK crosstalk in ER+ breast cancer cells supports future studies to characterize the impact of BPAF on human ER+ breast cancer risk and to assess the safety profile of BPAF.


Vesicoureteric reflux and renal scars in asymptomatic siblings of children with reflux.
The purpose of the study was to determine the incidence of vesicoureteric reflux (VUR), renal scars and hypertension in asymptomatic siblings of children with VUR. The study comprised 105 siblings of patients with VUR. Their age ranged from 4 months to 6.3 years. All had a direct radionuclide voiding cystography (DRVC) performed, and VUR was detected in 47 of 105 (45%). High grade VUR in the first year of life had an incidence of 50% compared with a 9% incidence in siblings older than 2 years, while only one of the 27 siblings with a low VUR grade was younger than 1 year. In 43 of 47 siblings with VUR, a technetium-99m dimercaptosuccinic acid (99mTc-DMSA) scan was performed and renal scars were found in 10, which presents 23% of siblings with VUR who were scanned and 10% of all siblings studied. One child had hypertension. Identifying VUR among asymptomatic siblings could possibly prevent renal damage and its consequences. Thus, the predictive value of positive family history alone in identifying VUR was 45% while 23% of siblings had renal scars. This incidence justifies the routine investigation of asymptomatic siblings, by using DRVC at an early stage.


A NOTE ON THE RESPIRATION OF ARBACIA EGGS.
Methods used in preparing Arbacia eggs for respiration studies, in carrying through the manometric determinations, and in estimating egg quantities have been reexamined. Discrepancies in previous results are almost entirely due to a steady error in measuring egg volume by centrifuging. Volumes so obtained averaged 80 per cent too high. The respiration of unfertilized eggs of Arbacia punctulata at 21 degrees C. is 0.9 c.mm. O(2) per hour per 10 c.mm. of eggs.


New Experiments and a Model-Driven Approach for Interpreting Middle Stone Age Lithic Point Function Using the Edge Damage Distribution Method.
The Middle Stone Age (MSA) is associated with early evidence for symbolic material culture and complex technological innovations. However, one of the most visible aspects of MSA technologies are unretouched triangular stone points that appear in the archaeological record as early as 500,000 years ago in Africa and persist throughout the MSA. How these tools were being used and discarded across a changing Pleistocene landscape can provide insight into how MSA populations prioritized technological and foraging decisions. Creating inferential links between experimental and archaeological tool use helps to establish prehistoric tool function, but is complicated by the overlaying of post-depositional damage onto behaviorally worn tools. Taphonomic damage patterning can provide insight into site formation history, but may preclude behavioral interpretations of tool function. Here, multiple experimental processes that form edge damage on unretouched lithic points from taphonomic and behavioral processes are presented. These provide experimental distributions of wear on tool edges from known processes that are then quantitatively compared to the archaeological patterning of stone point edge damage from three MSA lithic assemblages-Kathu Pan 1, Pinnacle Point Cave 13B, and Die Kelders Cave 1. By using a model-fitting approach, the results presented here provide evidence for variable MSA behavioral strategies of stone point utilization on the landscape consistent with armature tips at KP1, and cutting tools at PP13B and DK1, as well as damage contributions from post-depositional sources across assemblages. This study provides a method with which landscape-scale questions of early modern human tool-use and site-use can be addressed.


Plasma, adrenal, and heart catecholamines in physically trained normal and diabetic rats.
This study was designed to evaluate the possibility that the enhanced insulin sensitivity of physically trained normal and diabetic rats is due to adaptive changes in the adrenergic system. Mild diabetes mellitus was induced in male Wistar rats with streptozocin (STZ, 45 mg/kg i.v.) and a 10-wk conditioning program was conducted by having the animals run on a treadmill. Rats were cannulated 16 h after the last period of exercise and blood sampling was obtained 48 h later for basal plasma glucose, insulin, epinephrine, and norepinephrine determination. Catecholamine measurements were also made in adrenals, atria, and ventricles from sedentary control, trained control, sedentary diabetic, and trained diabetic rats. The previously reported beneficial effect of physical training on diabetes mellitus was reproduced. While diabetes mellitus did not modify the catecholamine levels, the training program provoked an increase in plasma epinephrine concentrations, with a concomitant significant rise in adrenal epinephrine content. In heart tissue, the epinephrine values also tended to be increased by training although statistical significance was not reached. These data suggest that basal secretion of epinephrine is somewhat increased in trained rats. Whether this may trigger adaptive changes that could be involved in the beneficial effect of physical training on experimental diabetes mellitus remains to be elucidated.


Mechanisms of myocardial hypercarbic acidosis during cardiac arrest.
During the global myocardial ischemia of cardiac arrest and during regional myocardial ischemia due to local impairment of coronary blood flow, intramyocardial carbon dioxide tensions (Pmco2) of ischemic myocardium increase to levels exceeding 400 Torr. The mechanism of such myocardial hypercarbic acidosis is as yet incompletely understood, specifically whether these increases in Pmco2 are due to increased oxidative metabolism, decreased CO2 removal, or buffering of metabolic acids. We therefore measured Pmco2 and the total CO2 content of rat hearts harvested before, during, and after resuscitation from cardiac arrest. Pmco2 significantly increased from an average of 63 to 209 Torr during a 4-min interval of untreated ventricular fibrillation. This was associated with concurrent decreases in intracellular pH from an average of 7.03 to 6.02 units. The total CO2 content of the myocardium simultaneously decreased from 17.0 to 16.5 mmol/kg. Accordingly, increases in Pmco2 and [H+] were observed in the absence of increases in the total CO2 content and therefore the calculated myocardial bicarbonate. These observations in the rat model implicate buffering of metabolic acids by bicarbonate rather than increases in CO2 production or decreases in CO2 removal as the predominant mechanism accounting for myocardial hypercarbia.


Socioeconomic and food-related physical characteristics of the neighbourhood environment are associated with body mass index.
To determine whether socioeconomic and food-related physical characteristics of the neighbourhood are associated with body mass index (BMI; kg/m(2)) independently of individual-level sociodemographic and behavioural characteristics. Observational study using (1) individual-level data previously gathered in five cross-sectional surveys conducted by the Stanford Heart Disease Prevention Program between 1979 and 1990 and (2) neighbourhood-level data from (a) the census to describe socioeconomic characteristics and (b) data obtained from government and commercial sources to describe exposure to different types of retail food stores as measured by store proximity, and count of stores per square mile. Data were analysed using multilevel modelling procedures. The setting was 82 neighbourhoods in agricultural regions of California. 7595 adults, aged 25-74 years. After adjusting for age, gender, ethnicity, individual-level socioeconomic status, smoking, physical activity and nutrition knowledge, it was found that (1) adults who lived in low socioeconomic neighbourhoods had a higher mean BMI than adults who lived in high socioeconomic neighbourhoods; (2) higher neighbourhood density of small grocery stores was associated with higher BMI among women; and (3) closer proximity to chain supermarkets was associated with higher BMI among women. Living in low socioeconomic neighbourhoods, and in environments where healthy food is not readily available, is found to be associated with increased obesity risk. Unlike other studies which examined populations in other parts of the US, a positive association between living close to supermarkets and reduced obesity risk was not found in this study. A better understanding of the mechanisms by which neighbourhood physical characteristics influence obesity risk is needed.


[Complications after cesarean section in untreated Addison disease].
We report on a case of a patient with unknown Addison's disease who showed a variety of complications after caesarean section (preterm labour, breech presentation, 32 wks.). The main complications were endomyometritis, altered serum electrolytes, severe hypotension and weakness. Based on clinical observations and cortisol provocation test, the patient was diagnosed with Addison's disease on day 10 after caesarean section. Substitution with corticoids was started immediately. With this medication, rapid restitution and normalisation of the pathological parameters could be achieved.


A surface-plasmon-resonance analysis of polylysine interactions with a peptide substrate of protein kinase CK2 and with the enzyme.
The mechanism of protein kinase CK2 (CK2) activity stimulation by polylysine has been studied by surface plasmon resonance (SPR). The kinetics of the polylysine interaction with a peptide substrate of the enzyme, and with the enzyme itself, have been investigated. A peptide containing a threonine (T) residue surrounded by a cluster of negatively charged acidic [arginine (R) and glutamic acid (E)] residues, RRREEETEEE, and specifically phosphorylated by CK2, was selected. Polylysine interacts with both the enzyme and the peptide substrate. The rate constant, the stoichiometry of the polylysine-peptide substrate interaction and the kinetic parameters of the stimulated enzyme were used to calculate the polylysine-dependent stimulation of CK2. The results are in agreement with experimentally determined polylysine-dependent stimulation. The polylysine-enzyme interaction is too slow to account for enzyme stimulation. The behaviour of polylysine is not reproduced by the polyamine spermine. The results are consistent with a substrate-mediated mechanism of CK2 stimulation by polylysine, and they suggest that the CK2 stimulation by polyamines occurs by a different mechanism.


An open-source code for Mie extinction extended multiplicative signal correction for infrared microscopy spectra of cells and tissues.
Infrared spectroscopy of single cells and tissue is affected by Mie scattering. During recent years, several methods have been proposed for retrieving pure absorbance spectra from such measurements, while currently no user-friendly version of the state-of-the-art algorithm is available. In this work, an open-source code for correcting highly scatter-distorted absorbance spectra of cells and tissues is presented, as well as several improvements of the latest version of the Mie correction algorithm based on extended multiplicative signal correction (EMSC) published by Konevskikh et al. In order to test the stability of the code, a set of apparent absorbance spectra was simulated. To this purpose, pure absorbance spectra based on a Matrigel spectrum are simulated. Scattering contributions where obtained by mimicking the scattering features observed in a set of experimentally obtained spectra . It can be concluded that the algorithm is not depending strongly on the reference spectrum used for initializing the algorithm and retrieves well the underlying pure absorbance spectrum. The calculation time of the algorithm is considerably improved with respect to the resonant Mie scattering EMSC algorithm used by the community today.


PGE2-EP2/EP4 signaling elicits mesoCAR T cell immunosuppression in pancreatic cancer.
For many years, surgery, adjuvant and combination chemotherapy have been the cornerstone of pancreatic cancer treatment. Although these approaches have improved patient survival, relapse remains a common occurrence, necessitating the exploration of novel therapeutic strategies. CAR T cell therapies are now showing tremendous success in hematological cancers. However, the clinical efficacy of CAR T cells in solid tumors remained low, notably due to presence of an immunosuppressive tumor microenvironment (TME). Prostaglandin E2, a bioactive lipid metabolite found within the TME, plays a significant role in promoting cancer progression by increasing tumor proliferation, improving angiogenesis, and impairing immune cell's function. Despite the well-established impact of PGE2 signaling on cancer, its specific effects on CAR T cell therapy remain under investigation. To address this gap in knowledge the role of PGE2-related genes in cancer tissue and T cells of pancreatic cancer patients were evaluated in-silico. Through our in vitro study, we manufactured fully human functional mesoCAR T cells specific for pancreatic cancer and investigated the influence of PGE2-EP2/EP4 signaling on proliferation, cytotoxicity, and cytokine production of mesoCAR T cells against pancreatic cancer cells. In-silico investigations uncovered a significant negative correlation between PGE2 expression and gene signature of memory T cells. Furthermore, in vitro experiments demonstrated that the activation of PGE2 signaling through EP2 and EP4 receptors suppressed the proliferation and major antitumor functions of mesoCAR T cells. Interestingly, the dual blockade of EP2 and EP4 receptors effectively reversed PGE2-mediated suppression of mesoCAR T cells, while individual receptor antagonists failed to mitigate the PGE2-induced suppression. In summary, our findings suggest that mitigating PGE2-EP2/EP4 signaling may be a viable strategy for enhancing CAR T cell activity within the challenging TME, thereby improving the efficacy of CAR T cell therapy in clinical settings.


Stretching before sleep reduces the frequency and severity of nocturnal leg cramps in older adults: a randomised trial.
In adults who experience nocturnal leg cramps, does stretching of the calf and hamstring muscles each day just before sleep reduce the frequency and severity of the cramps? A randomised trial with concealed allocation and intention-to-treat analysis. Eighty adults aged over 55 years with nocturnal leg cramps who were not being treated with quinine. The experimental group performed stretches of the calf and hamstring muscles nightly, immediately before going to sleep, for six weeks. The control group performed no specific stretching exercises. Both groups continued other usual activities. Participants recorded the frequency of nocturnal leg cramps in a daily diary. Participants also recorded the severity of the pain associated with nocturnal leg cramps on a 10-cm visual analogue scale. Adverse events were also recorded. All participants completed the study. At six weeks, the frequency of nocturnal leg cramps decreased significantly more in the experimental group, mean difference 1.2 cramps per night (95% CI 0.6 to 1.8). The severity of the nocturnal leg cramps had also decreased significantly more in the experimental group than in the control group, mean difference 1.3 cm (95% CI 0.9 to 1.7) on the 10-cm visual analogue scale. Nightly stretching before going to sleep reduces the frequency and severity of nocturnal leg cramps in older adults. NCT01421628.


Automated localization of breast cancer in DCE-MRI.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is increasingly being used for the detection and diagnosis of breast cancer. Compared to mammography, DCE-MRI provides higher sensitivity, however its specificity is variable. Moreover, DCE-MRI data analysis is time consuming and depends on reader expertise. The aim of this work is to propose a novel automated breast cancer localization system for DCE-MRI. Such a system can be used to support radiologists in DCE-MRI analysis by marking suspicious areas. The proposed method initially corrects for motion artifacts and segments the breast. Subsequently, blob and relative enhancement voxel features are used to locate lesion candidates. Finally, a malignancy score for each lesion candidate is obtained using region-based morphological and kinetic features computed on the segmented lesion candidate. We performed experiments to compare the use of different classifiers in the region classification stage and to study the effect of motion correction in the presented system. The performance of the algorithm was assessed using free-response operating characteristic (FROC) analysis. For this purpose, a dataset of 209 DCE-MRI studies was collected. It is composed of 95 DCE-MRI studies with 105 breast cancers (55 mass-like and 50 non-mass-like malignant lesions) and 114 DCE-MRI studies from women participating in a screening program which were diagnosed to be normal. At 4 false positives per normal case, 89% of the breast cancers (91% and 86% for mass-like and non-mass-like malignant lesions, respectively) were correctly detected.


New graduate burnout: the impact of professional practice environment, workplace civility, and empowerment.
The future of professional nursing depends on finding ways to create high-quality work environments that retain newcomers to the profession. The purpose of this study was to examine the combined effect of supportive professional practice environments, civil working relationships, and empowerment on new graduates' experiences of burnout at work. The results support previous evidence of the importance of working environments that enable new graduates to practice according to professional standards learned in their educational programs. Further, the results provide a more comprehensive understanding of the impact of workplace conditions on new graduate burnout by demonstrating the additive value of working in collegial work settings in which nurses respected others and refrain from incivility behaviors in their day to day work. Given the current nursing shortage, every effort must be made to ensure that new graduates are exposed to high-quality work environments that engage them with their work.


How effective is adjuvant cancer chemotherapy? Lucy Wortham James Clinical Research Award.
Some of the breast cancer chemotherapy trials conducted during the past 25 years were reviewed. In general, most authors noted a significantly improved disease-free survival and overall survival in premenopausal patients but not in postmenopausal patients. Considering all patients, most authors found a significant increase in the disease-free survival but not in overall survival. In one study, the relapse rate increased with time. In the first three years, the relapse rate in the control group greatly exceeded that in the treatment group, but as the years went on, this trend reversed, and an increasing percentage of the treated group had relapse. More time is required to draw firm conclusions.


Microbial lipids and stable foam formation in the activated sludge process.
The presence of fats and oils in sewage has been related to the formation of stable foams in activated sludge treatment systems. Foam forming microbes can utilise and, in some cases, store lipid substrates. Since surface lipids would confer the hydrophobicity necessary for flotation on the sludge biomass, the extractable lipids in foaming and non-foaming biomass samples were examined. Both pure mono-cultures and sludge samples were used. The results showed that, whilst there were some differences in the lipid profiles of the mono-cultures, the different sludge types did not show any significant pattern or variation which could be used as a lipid-based explanation for foam formation.


A longitudinal study of the moderating effects of romantic relationships on the associations between alcohol use and trauma in college students.
College students report high levels of alcohol use, which can be exacerbated by interpersonal trauma exposure (IPT). Romantic relationships may represent salient contexts for moderating associations between IPT and alcohol use. We examined whether relationship status, partner alcohol use and relationship satisfaction moderated associations between IPT and alcohol use, and whether these associations varied in a sex-specific manner. University-wide longitudinal survey of college students. Large, urban public university in mid-Atlantic United States. We used two subsets of participants (n = 5673 and 3195) from the Spit for Science project, a longitudinal study of college students. Participants completed baseline assessments during the autumn of their freshman year and were invited to complete follow-up assessments every spring thereafter. Participants were included in the present study if they completed surveys at baseline and at least one follow-up assessment (meanfollow-ups = 1.70, range = 1-4). Predictors included precollege and college-onset IPT, relationship status, partner alcohol use, relationship satisfaction and sex. Alcohol consumption was the primary outcome of interest. Pre-college IPT was measured at baseline and all other measures were assessed at each follow-up. Individuals with pre-college IPT consumed more alcohol than those without IPT, but this was mitigated for those in relationships (β = -0.15, P = 0.046, 95% confidence interval (CI) = -0.29, 0.00). Individuals with college-onset IPT consumed more alcohol than those without IPT, and this was more pronounced for those with higher partner alcohol use (β = -0.18, P = 0.001, 95% CI = -0.29, -0.07). Relationship satisfaction was not a significant moderator of the associations between IPT and alcohol use (Ps > 0.05 and 95% CIs include 0). Involvement in relationships, but not relationship satisfaction, appears to reduce the effects of interpersonal trauma exposure (IPT) on alcohol use among US college students, while high partner alcohol use appears to exacerbate it. The moderating effects of relationship characteristics depend on the developmental timing of IPT.


IL-1 alpha and TNF alpha act synergistically to stimulate production of myeloid colony-stimulating factors by cultured human bone marrow stromal cells and cloned stromal cell strains.
Human bone marrow stromal cells respond to stimulation by the monokines IL-1 and TNF by producing colony-stimulating factors such as GM-CSF and G-CSF. In this study we show that IL-1 alpha and TNF alpha act synergistically to stimulate GM-CSF and G-CSF production by cultured marrow stromal cells. We further show that IL-1 alpha and TNF alpha synergistically stimulate production of GM-CSF and G-CSF by a clonal stroma-derived cell strain. Although IL-1 and TNF share many of the same biological activities, we show that IL-1 alpha and TNF alpha have an unequal ability to induce myeloid-CSF production by both cultures, with IL-1 alpha being the more potent inducer. We found that induction by IL-1 alpha and TNF alpha was independent of cell proliferation. The effect of IL-1 alpha and TNF alpha on production of the two myeloid-CSFs by the clonal cells was significantly greater than the unfractionated passaged stromal cultures, having the greater effect on G-CSF production. The clonally derived stromal cells constitutively produced colony-stimulating activity, in particular GM-CSF, at levels easily detected by ELISA. These findings show that, in addition to the overlapping and additive activities of IL-1 alpha and TNF alpha, they can interact synergistically. Our findings further suggest that a small subpopulation of stroma cells may be the major producer of G-CSF in the marrow microenvironment during immune response.


Molecular-Level Control over Surface Order in Self-Assembled Monolayer Films of Thiols on Gold.
Long-chain omegahydroxyalkanethiols [HS(CH(2))nOH] coordinate to gold surfaces through the sulfur atom and produce ordered, hydrophilic monolayers in which the hydroxyl groups are exposed at the outer surface. Coadsorption of two omega-hydroxyalkanethiols of different chain lengths n resulted in the formation of a monolayer having a disordered surface region that was markedly less hydrophilic than the homogeneous, hydroxylic surface formed from either pure compound. By controlling the composition of the monolayer, it was also possible to control simultaneously the degree of order in the surface and its hydrophilicity. In the monolayers containing a mixture of alkanethiol components, these components apparently did not phase-segregate into macroscopic islands, but were dispersed on a molecular scale. assistance and many useful discussions.


An isoenergetic high-protein, moderate-fat diet does not compromise strength and fatigue during resistance exercise in women.
Resistance exercise is recommended to individuals following high-protein diets in order to augment changes in body composition. However, alterations in macronutrient composition may compromise physical performance. The present study investigated the effects of an isoenergetic high-protein diet on upper and lower limb strength and fatigue during high-intensity resistance exercise. Ten recreationally active women, aged 25-40 years, followed a control diet (55, 15 and 30 % of energy from carbohydrate, protein and fat, respectively) and a high-protein diet (respective values, 30, 40 and 30) for 7 d each in a random counterbalanced design. Each participant underwent strength testing of upper limb (isometric handgrip strength and endurance) and lower limb (four sets of sixteen maximal knee flexions and extensions on an isokinetic dynamometer) before and after applying each diet. Body weight, body fat and RER were significantly reduced following the high-protein diet (P < 0.05). No differences were found between diets in any of the strength performance parameters (handgrip strength, handgrip endurance, peak torque, total work and fatigue) or the responses of heart rate, systolic and diastolic arterial pressure, blood lactate and blood glucose to exercise. Women on a short-term isoenergetic high-protein, moderate-fat diet maintained muscular strength and endurance of upper and lower limbs during high-intensity resistance exercise without experiencing fatigue earlier compared with a control diet.


Web-based exercise interventions for patients with depressive and anxiety disorders: a systematic review of randomized controlled trials.
The number of people suffering from depression and/or anxiety has increased steadily due to the coronavirus disease 2019 (COVID-19) pandemic. In this context, web-based exercise interventions have emerged as a potential treatment strategy. The objective of this study was to synthetize evidence from randomized controlled trials regarding the effects of web-based exercise interventions on patients with depressive and/or anxiety disorders. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Six databases were searched (Cochrane Library, EBSCO, PubMed, SciELO, Scopus, and Web of Science), and eligible articles were identified according to a PICOS inclusion-exclusion approach (participants with depressive or anxiety disorders; web-based exercise interventions; active or passive control group; assessment of changes in depressive or anxiety disorders; randomized design). Primary outcomes were depressive and/or anxiety symptoms. The quality of evidence was assessed with Grading of Recommendations Assessment, Development, and Evaluation. Of 7,846 search results, three studies met the inclusion criteria (172 participants between 18 and 65 years of age, 95.9% women). The web-based exercise interventions lasted 8-12 weeks and involved endurance training, yoga, or combined endurance and strength training. The comparators involved non-exercise controls or active controls. Compliance rates were low. Web-based exercise interventions were not superior to controls regarding anxiety symptoms, and only one study found benefits for depressive symptoms (p ≤ 0.05). The quality of the cumulative evidence was low. The available data regarding the effects of web-based exercise interventions on depression and/or anxiety symptoms is scarce, the risk of bias is high, and the quality of the cumulative results is low. Currently, no clear recommendations can be provided. PROSPERO CRD42021225938.


In-depth genomic data analyses revealed complex transcriptional and epigenetic dysregulations of BRAFV600E in melanoma.
The recurrent BRAF driver mutation V600E (BRAF (V600E)) is currently one of the most clinically relevant mutations in melanoma. However, the genome-wide transcriptional and epigenetic dysregulations induced by BRAF (V600E) are still unclear. The investigation of this driver mutation's functional consequences is critical to the understanding of tumorigenesis and the development of therapeutic strategies. We performed an integrative analysis of transcriptomic and epigenomic changes disturbed by BRAF (V600E) by comparing the gene expression and methylation profiles of 34 primary cutaneous melanoma tumors harboring BRAF (V600E) with those of 27 BRAF (WT) samples available from The Cancer Genome Atlas (TCGA). A total of 711 significantly differentially expressed genes were identified as putative BRAF (V600E) target genes. Functional enrichment analyses revealed the transcription factor MITF (p < 3.6 × 10(-16)) and growth factor TGFB1 (p < 3.1 × 10(-9)) were the most significantly enriched up-regulators, with MITF being significantly up-regulated, whereas TGFB1 was significantly down-regulated in BRAF (V600E), suggesting that they may mediate tumorigenesis driven by BRAF (V600E). Further investigation using the MITF ChIP-Seq data confirmed that BRAF (V600E) led to an overall increased level of gene expression for the MITF targets. Furthermore, DNA methylation analysis revealed a global DNA methylation loss in BRAF (V600E) relative to BRAF (WT). This might be due to BRAF dysregulation of DNMT3A, which was identified as a potential target with significant down-regulation in BRAF (V600E). Finally, we demonstrated that BRAF (V600E) targets may play essential functional roles in cell growth and proliferation, measured by their effects on melanoma tumor growth using a short hairpin RNA silencing experimental dataset. Our integrative analysis identified a set of BRAF (V600E) target genes. Further analyses suggested a complex mechanism driven by mutation BRAF (V600E) on melanoma tumorigenesis that disturbs specific cancer-related genes, pathways, and methylation modifications.


A modular system of DNA enhancer elements mediates tissue-specific activation of transcription by high dietary zinc in C. elegans.
Zinc is essential for biological systems, and aberrant zinc metabolism is implicated in a broad range of human diseases. To maintain homeostasis in response to fluctuating levels of dietary zinc, animals regulate gene expression; however, mechanisms that mediate the transcriptional response to fluctuating levels of zinc have not been fully defined. Here, we identified DNA enhancer elements that mediate intestine-specific transcriptional activation in response to high levels of dietary zinc in C. elegans. Using bioinformatics, we characterized an evolutionarily conserved enhancer element present in multiple zinc-inducible genes, the high zinc activation (HZA) element. The HZA was consistently adjacent to a GATA element that mediates expression in intestinal cells. Functional studies using transgenic animals demonstrated that this modular system of DNA enhancers mediates tissue-specific transcriptional activation in response to high levels of dietary zinc. We used this information to search the genome and successfully identified novel zinc-inducible genes. To characterize the mechanism of enhancer function, we demonstrated that the GATA transcription factor ELT-2 and the mediator subunit MDT-15 are necessary for zinc-responsive transcriptional activation. These findings define new mechanisms of zinc homeostasis and tissue-specific regulation of transcription.


The Selective Advantage of the lac Operon for Escherichia coli Is Conditional on Diet and Microbiota Composition.
The lac operon is one of the best known gene regulatory circuits and constitutes a landmark example of how bacteria tune their metabolism to nutritional conditions. It is nearly ubiquitous in Escherichia coli strains justifying the use of its phenotype, the ability to consume lactose, for species identification. Lactose is the primary sugar found in milk, which is abundant in mammals during the first weeks of life. However, lactose is virtually non-existent after the weaning period, with humans being an exception as many consume dairy products throughout their lives. The absence of lactose during adulthood in most mammals and the rarity of lactose in the environment, means that the selective pressure for maintaining the lac operon could be weak for long periods of time. Despite the ability to metabolize lactose being a hallmark of E. coli's success when colonizing its primary habitat, the mammalian intestine, the selective value of this trait remains unknown in this ecosystem during adulthood. Here we determine the competitive advantage conferred by the lac operon to a commensal strain of E. coli when colonizing the mouse gut. We find that its benefit, which can be as high as 11%, is contingent on the presence of lactose in the diet and on the presence of other microbiota members in the gut, but the operon is never deleterious. These results help explaining the pervasiveness of the lac operon in E. coli, but also its polymorphism, as lac-negative E. coli strains albeit rare can naturally occur in the gut.


Double aromaticity in a BBe6H6+ cluster with a planar hexacoordinate boron structure.
Aromaticity is one of the central concepts in chemistry and stabilizes many clusters that have interesting structural motifs. Herein, a cationic BBe6H6 cluster featuring a planar hexacoordinate boron structure stabilized by 2π/6σ double aromaticity was predicted theoretically. The cluster was predicted to be dynamically stable well above room temperature.


Hematopoietic progenitor cells of lymphocytes and dendritic cells.
Lymphocytes and dendritic cells (DCs) are critical for immune responses, yet how they develop from pluripotent hematopoietic stem cells is poorly defined. In humans and mice, it is possible to isolate phenotypically defined subsets of bone marrow (BM) cells that represent intermediate progenitors without long-term repopulating characteristics but with specific lineage differentiation properties. For instance, murine BM CD34+ CD45RA+ cells are progenitors for B and T lymphocytes with no in vivo repopulation activity. In human BM, a small subset (5%) of cells having the phenotype CD34+ Lin- CD10+ CD45RA+ CD38+ Thy-1- c-kit- represents a new class of hematopoietic progenitor cells that gives rise to lymphocytes [T, B, and natural killer (NK) cells] and to DCs but does not produce myeloid or erythroid cells. The identification of such progenitor cells provides the opportunity to define the differentiation and growth requirements for the production of lymphocytes and DCs. Genes involved in lineage specification can also be studied. Altogether, these studies have fundamental implications for understanding the biology of pivotal lineages of immune cells. This understanding could be used to treat a variety of immunodeficiencies and to design novel immunotherapies particularly in the context of hematopoietic cell transplantation.


Developments in interventional management of hepatic metastases from neuroendocrine tumours.
Neuroendocrine tumours commonly metastasise to the liver, particularly those arising from the intestinal tract and pancreas. Whilst surgery offers the only approach with intent to cure, the vast majority of patients with neuroendocrine liver metastases are ineligible. Liver-directed interventional therapies seek to exploit the patho-anatomy of the blood supply of hepatic metastases to deliver therapy to liver deposits. This may involve percutaneous ablation, bland embolization, or the selective infusion of chemotherapeutics, targeted agents or radiolabelled embolic material. Retrospective case series evidence has characterised objective response rates, disease control rates, and longer-term outcomes associated with each approach. Recent advances in this field include ongoing comparative trials of different techniques, but more importantly, combinations of interventional liver-directed therapies and other systemic therapy in multimodal treatment concepts.


Substantial chest-wall deformity following tissue expansion after radiotherapy.
We present the case of a 54-year-old woman who underwent a two-stage breast reconstruction with a tissue expander after sustaining a lumpectomy and local radiotherapy for breast cancer. During expansion, the woman developed an abnormal concave deformity of the chest wall. Although respiratory or aesthetic consequences were expected, our patient reported only pain and was satisfied with the end result. Osteoporosis or local recurrence was excluded as predisposing factors, and radiotherapy was considered to be the causal factor in our patient. On the basis of this finding, we advise surgeons to take the risk of chest-wall deformity into consideration when planning a reconstruction with tissue expanders, especially in patients with a history of radiotherapy, and we recommend an alternative reconstructive method in this group of patients.


Cognitive and Emotional Impairment after Minor Stroke and Non-ST-Elevation Myocardial Infarction (NSTEMI): A Prevalence Study.
To study the prevalence of cognitive and emotional impairment following a minor ischemic stroke compared to an age-matched group with non-ST-elevation myocardial infarction (NSTEMI). We included patients aged 18-70 years with a minor ischemic stroke defined as modified Rankin Scale (mRS) 0-2 at day 7 or at discharge if before and age-matched NSTEMI patients with the same functional mRS. We applied a selection of cognitive tests and the patients completed a questionnaire comprising of Hospital Anxiety and Depression scale (HADS) and Fatigue Severity Scale (FSS) at follow-up 12 months after the vascular event. Results of cognitive tests were also compared to normative data. 325 ischemic stroke and 144 NSTEMI patients were included. There was no significant difference in cognitive functioning between ischemic stroke and NSTEMI patients. Minor stroke patients and to a lesser extent NSTEMI patients scored worse on more complex cognitive functions including planning and implementation of activities compared to validated normative data. For the minor stroke patients the location of the ischemic lesion had no influence on the result. The prevalence of anxiety, depression, and fatigue was significantly higher in the stroke group compared to the NSTEMI group. Depression was independently associated with reduced cognitive function. Minor ischemic stroke patients, and to lesser degree NSTEMI patients, had reduced cognitive function compared to normative data, especially executive functioning, on 12-month follow-up. The difference in cognitive function between stroke and NSTEMI patients was not significant. Depression was associated with low scores on cognitive tests highlighting the need to adequately address emotional sequelae when considering treatment options for cognitive disabilities.


Patient education for endoscopy.
An increasing number of physicians are considering laparoscopy to be a viable alternative to conventional procedures. To meet the complex educational needs of the patient, health care providers must continually update their assessment and communication skills. This article discusses methods are tools to be used in providing procedure-specific patient education for endoscopic procedures.