The leucine-responsive regulatory protein, Lrp, activates transcription of the fim operon in Salmonella enterica serovar typhimurium via the fimZ regulatory gene.
The fim operon of Salmonella enterica serovar Typhimurium encodes type 1 fimbriae. The expression of fim is controlled in response to environmental signals through a complex regulatory cascade involving the proteins FimW, FimY, and FimZ and a genetic locus, fimU, that encodes a rare arginine tRNA. We discovered that a knockout mutation in lrp, the gene that codes for the leucine-responsive regulatory protein (Lrp), inhibited fim transcription. The loss of fim gene expression was accompanied by a corresponding loss of the mannose-sensitive hemagglutination that is a characteristic of type 1 fimbriae. Normal type 1 fimbrial expression was restored following the introduction into the knockout mutant of a plasmid carrying a functional copy of the lrp gene. Electrophoretic mobility shift analysis revealed no interactions between purified Lrp protein and the regulatory region of the fimA, fimU, or fimW gene. Instead, Lrp produced protein-DNA complexes with the regulatory region of the fimZ gene, and the nature of these complexes was leucine sensitive. DNase I footprinting showed that Lrp binds within a region between -65 and -170 with respect to the fimZ transcription start site, consistent with the binding and wrapping of the DNA in this upstream region. Ectopic expression of the fimZ gene from an inducible promoter caused Lrp-independent type 1 fimbriation in serovar Typhimurium. These data show that Lrp makes a positive contribution to fim gene expression through direct interaction with the fimZ promoter region, possibly by antagonizing the binding of the H-NS global repressor protein.


Dystonia in an adolescent on risperidone following the discontinuation of methylphenidate: a case report.
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with common comorbidities that include oppositional defiant disorder, conduct disorder, anxiety disorder, and affective disorders. Because of these comorbidities, drug combination treatments and drug-drug interactions are becoming increasingly more frequent. The present case report describes an acute dystonic reaction following the abrupt discontinuation of methylphenidate from a drug regimen with risperidone. The patient experienced acute dystonic reactions on three separate occasions when he forgot to take his methylphenidate medication. The present report informs clinicians about the possible side effects, such as dystonia, when psychostimulant and antipsychotic drug combinations are altered and suggests that the abrupt cessation of stimulants may lead to the development of movement disorders. Therefore, appropriate care is necessary when changing the dose of a drug or abruptly discontinuing a drug from a combination of psychostimulants and antipsychotics.


[Phospholipid composition of E. coli cells and membranes under repression and derepression of alkaline phosphatase biosynthesis].
Lipid composition of E. coli membranes and cells in conditions of repression, derepression and constitutive synthesis of alkaline phosphatase is studied. The identity of qualitative composition of phospholipids and neutral lipids in these conditions is demonstrated. Derepressed and constitutive enzyme syntheses are correlating, a certain increase of phosphatidylglycerol in the total phospholipid pool being more pronounced in cells, than in membranes. The enzyme synthesis correlates also with the increase of 14C-label incorporation into lipids.


The crucial role of the MyD88 adaptor protein in the inflammatory response induced by Bothrops atrox venom.
Most snake accidents in North Brazil are attributed to Bothrops atrox, a snake species of the Viperidae family whose venom simultaneously induces local and systemic effects in the victims. The former are clinically more important than the latter, as they cause severe tissue lesions associated with strong inflammatory responses. Although several studies have shown that inflammatory mediators are produced in response to B. atrox venom (BaV), there is little information concerning the molecular pathways involved in innate immune system signaling. Myeloid differentiation factor 88 (MyD88) is an adaptor molecule responsible for transmitting intracellular signals from most toll-like receptors (TLRs) after they interact with pathogen-associated molecular patterns (PAMPs) or other stimuli such as endogenous damage-associated molecular patterns (DAMPs). The MyD88-dependent pathway leads to activation of transcription factors, which in turn induce synthesis of inflammatory mediators such as eicosanoids, cytokines and chemokines. The aim of this study was to investigate the involvement of MyD88 on the acute inflammatory response induced by BaV. Wild-type (WT) C57BL/6 mice and MyD88 knockout (MyD88(-/-)) mice were intraperitoneally injected with BaV. Compared to WT mice, MyD88(-/-) animals showed an impaired inflammatory response to BaV, with lower influx of polymorphonuclear and mononuclear cells to the peritoneal cavity. Furthermore, peritoneal leukocytes from BaV-injected MyD88(-/-) mice did not induce COX-2 or LTB4 protein expression and released low concentrations of PGE2. These mice also failed to produce Th1 and Th17 cytokines and CCL-2, but IL-10 levels were similar to those of BaV-injected WT mice. Our results indicate that MyD88 signaling is required for activation of the inflammatory response elicited by BaV, raising the possibility of developing new therapeutic targets to treat Bothrops sp. poisoning.


Functional and topological analysis of PSENEN, the fourth subunit of the γ-secretase complex.
The γ-secretase complexes are intramembrane cleaving proteases involved in the generation of the Aβ peptides in Alzheimer's Disease. The complex consists of four subunits, with Presenilin, harboring the catalytic site. Here, we study the role of the smallest subunit, PSENEN or Presenilin enhancer 2 (PEN-2), encoded by the gene Psenen, in vivo and in vitro. We find a profound Notch-deficiency phenotype in Psenen-/- embryos confirming the essential role of PSENEN in the γ-secretase complex. We used Psenen-/- fibroblasts to explore the structure-function of PSENEN by the Scanning Cysteine Accessibility Method. Glycine22 and Proline27 which border the membrane domains 1 and 2 of PSENEN are involved in complex formation and stabilization of γ-secretase. The hairpin structured hydrophobic membrane domains 1 and 2 are exposed to a water-containing cavity in the complex, while transmembrane domain 3 is not water exposed. We finally demonstrate the essential role of PSENEN for the cleavage activity of the complex. PSENEN is more than a structural component of the γ-secretase complex and might contribute to the catalytic mechanism of the enzyme.


Experiences of exercise during pregnancy among women who perform regular resistance training: a qualitative study.
Women who are pregnant and healthy are recommended to do 30 minutes or more of light to moderate exercise a day on most, if not all, days of the week. However, only 1 of 6 pregnant women in the United States and northern Europe follows these recommendations. Little attention has been given to the experience of exercise in pregnancy. The aim of the study was to describe experiences of exercise during pregnancy among women who performed regular resistance training. This was a qualitative, inductive content analysis study. Seventeen pregnant women who exercised on a regular basis participated in individual semistructured, face-to-face interviews that were recorded, transcribed, coded, and condensed into subcategories and categories. Four categories emerged (subcategories within parentheses): (1) positive impact on body and mind (reduced pregnancy-related problems, increased self-confidence and sense of control, immediate positive feedback, and effects on lifestyle and quality of life); (2) expected benefits and facilitators (knowledge of health benefits, part of one's lifestyle, preventing pregnancy-related problems, social support, staying in good shape, and healthy living with regard to the fetus); (3) new exercise barriers (physical limitations, taking care not to harm oneself or the fetus, uncertainty or lack of knowledge, sense of exclusion at the fitness center, lack of understanding on the part of others, and the pregnancy itself provided an easy excuse); and (4) overcoming exercise barriers (lowering the intensity of exercise, modifying the type of exercise, changing exercise goals, and being extra attentive during exercise). Pregnant women strived to exercise if the exercise facilitators outweighed the barriers. As the study described facilitators, barriers, and strategies for how to overcome exercise barriers, the results can be useful in exercise promotion in healthy pregnancy.


Improved bacterial clearance and decreased mortality can be induced by LPS tolerance and is not dependent upon IFN-gamma.
Endotoxin (LPS) tolerance is induced by exposure to sublethal doses of LPS, resulting in a suppressed proinflammatory response and an improved survival rate after challenge with a normally lethal dose of LPS. We studied the effects of tolerance induced by either Escherichia coli-derived LPS or Pseudomonas aeruginosa-derived LPS on the innate immune response to a subsequent P. aeruginosa bacterial challenge and determined if the induction of tolerance was dependent on interferon gamma (IFN-gamma) activity. LPS tolerance was induced in wild-type (WT) and IFN-gamma knockout mice by i.p. injection of 1 microg of LPS on 2 consecutive days. Mice were challenged with an i.p. injection of live P. aeruginosa (1 x 10(8) colony-forming units) 2 days after the second LPS dose. LPS tolerance in WT mice was associated with diminished serum IFN-gamma and IL-12 and increased serum IL-10 responses to the Pseudomonas challenge. Both clearance of the bacterial challenge and survival were improved in WT animals pretreated with either E. coli LPS or P. aeruginosa LPS compared with saline-pretreated control mice. Similarly, IFN-gamma knockout mice exposed to LPS before the Pseudomonas challenge also had improved bacterial clearance of the challenge and an improved survival rate. In separate experiments, priming with IFN-gamma at a dose that approximated the serum concentration induced by LPS priming did not alter cytokine production or bacterial clearance after a Pseudomonas challenge. Finally, administration of IFN-gamma at the time of Pseudomonas challenge amplified cytokine production in LPS-tolerant animals but did not affect bacterial clearance. These results suggest that IFN-gamma is not necessary for the induction of LPS tolerance. Furthermore, IFN-gamma seems to play a role in propagating the inflammatory cytokine response to Pseudomonas challenge, but it did not seem to have any role in bacterial clearance.


Introduction of microsystems in a level 3 neonatal intensive care unit-an interprofessional approach.
Growth of neonatal intensive care units in number and size has raised questions towards ability to maintain continuity and quality of care. Structural organization of intensive care units is known as a key element for maintaining the quality of care of these fragile patients. The reconstruction of megaunits of intensive care to smaller care units within a single operational service might help with provision of safe and effective care. The clinical team and patient distribution lay out, admission and discharge criteria and interdisciplinary round model was reorganized to follow the microstructure philosophy. A working group met weekly to formulate the implementation planning, to review the adaptation and adjustment process and to ascertain the quality of implementation following the initiation of the microsystem model. In depth examination of microsystem model of care in this study, provides systematic evaluation of this model on variable aspects of health care. The individual projects of this trial can be source of solid evidence for guidance of future decisions on optimized model of care for the critically ill newborns. ClinicalTrial.gov, NCT02912780 . Retrospectively registered on 22 September 2016.


Differentially methylated regions in maternal and paternal uniparental disomy for chromosome 7.
DNA methylation is a hallmark of genomic imprinting and differentially methylated regions (DMRs) are found near and in imprinted genes. Imprinted genes are expressed only from the maternal or paternal allele and their normal balance can be disrupted by uniparental disomy (UPD), the inheritance of both chromosomes of a chromosome pair exclusively from only either the mother or the father. Maternal UPD for chromosome 7 (matUPD7) results in Silver-Russell syndrome (SRS) with typical features and growth retardation, but no gene has been conclusively implicated in SRS. In order to identify novel DMRs and putative imprinted genes on chromosome 7, we analyzed eight matUPD7 patients, a segmental matUPD7q31-qter, a rare patUPD7 case and ten controls on the Infinium HumanMethylation450K BeadChip with 30 017 CpG methylation probes for chromosome 7. Genome-scale analysis showed highly significant clustering of DMRs only on chromosome 7, including the known imprinted loci GRB10, SGCE/PEG10, and PEG/MEST. We found ten novel DMRs on chromosome 7, two DMRs for the predicted imprinted genes HOXA4 and GLI3 and one for the disputed imprinted gene PON1. Quantitative RT-PCR on blood RNA samples comparing matUPD7, patUPD7, and controls showed differential expression for three genes with novel DMRs, HOXA4, GLI3, and SVOPL. Allele specific expression analysis confirmed maternal only expression of SVOPL and imprinting of HOXA4 was supported by monoallelic expression. These results present the first comprehensive map of parent-of-origin specific DMRs on human chromosome 7, suggesting many new imprinted sites.


Vasculitis Following Influenza Vaccination: A Review of the Literature.
Influenza vaccine is safe and effective for the general population as well as for patients with autoimmune diseases. However, although rare, vasculitis has been reported as an adverse event following influenza vaccination. The aims of this literature review were to identify patients who developed vasculitis following influenza vaccination and to clarify the clinical manifestations of vasculitis in these patients. Using the PubMed database and search engine, we performed a search of the Englishlanguage literature by combining the term influenza vaccination with each term for a specific form of vasculitis from January 1966 through April 2016. A total of 65 patients who developed vasculitis after influenza vaccination were identified from 45 published reports. The majority of patients were elderly, and the patients were predominantly female. The vasculitides included large vessel vasculitis (13 patients), medium vessel vasculitis (2), small vessel vasculitis (42), single organ vasculitis (5), vasculitis associated with systemic disease (1), and vasculitis associated with probable etiology (1). Although the majority of patients achieved complete recovery or remission, there were 3 deaths in patients with ANCA-associated vasculitis and severe long-term sequelae developed in 3 patients (1 with granulomatosis with polyangiitis, 1 with IgA vasculitis and 1 with unclassified small vessel vasculitis). Since vasculitis following influenza vaccination has been only rarely reported, routine influenza vaccination should not be restricted. However, caution should be required when patients with small vessel vasculitis, especially with ANCA-associated vasculitis following influenza vaccination or with post-influenza vaccination-reactivated IgA vasculitis, receive influenza vaccination again.


Update on the management of severe hypertriglyceridemia--focus on free fatty acid forms of omega-3.
High levels of plasma triglycerides (TG) are a risk factor for cardiovascular diseases, often associated with anomalies in other lipids or lipoproteins. Hypertriglyceridemia (HTG), particularly at very high levels, significantly increases also the risk of acute pancreatitis. Thus, interventions to lower TG levels are required to reduce the risk of pancreatitis and cardiovascular disease. Several strategies may be adopted for TG reduction, including lifestyle changes and pharmacological interventions. Among the available drugs, the most commonly used for HTG are fibrates, nicotinic acid, and omega-3 polyunsaturated fatty acids (usually a mixture of eicosapentaenoic acid, or EPA, and docosahexaenoic acid, or DHA). These last are available under different concentrated formulations containing high amounts of omega-3 fatty acids, including a mixture of EPA and DHA or pure EPA. The most recent formulation contains a free fatty acid (FFA) form of EPA and DHA, and exhibits a significantly higher bioavailability compared with the ethyl ester forms contained in the other formulations. This is due to the fact that the ethyl ester forms, to be absorbed, need to be hydrolyzed by the pancreatic enzymes that are secreted in response to fat intake, while the FFA do not. This higher bioavailability translates into a higher TG-lowering efficacy compared with the ethyl ester forms at equivalent doses. Omega-3 FFA are effective in reducing TG levels and other lipids in hypertriglyceridemic patients as well as in high cardiovascular risk patients treated with statins and residual HTG. Currently, omega-3 FFA formulation is under evaluation to establish whether, in high cardiovascular risk subjects, the addition of omega-3 to statin therapy may prevent or reduce major cardiovascular events.


Enhanced VEGF/VEGF-R and RUNX2 Expression in Human Periodontal Ligament Stem Cells Cultured on Sandblasted/Etched Titanium Disk.
Bone formation, in skeletal development or in osseointegration processes, is the result of interaction between angiogenesis and osteogenesis. To establish osseointegration, cells must attach to the implant in a direct way without any deposition of soft tissue. Structural design and surface topography of dental implants enhance the cell attachment and can affect the biological response. The aim of the study was to evaluate the cytocompatibility, osteogenic and angiogenic markers involved in bone differentiation of human periodontal ligament stem cells (hPDLSCs) on different titanium disks surfaces. The hPDLSCs were cultured on pure titanium surfaces modified with two different procedures, sandblasted (Control-CTRL) and sandblasted/etched (Test-TEST) as experimental titanium surfaces. After 1 and 8 weeks of culture VEGF, VEGF-R, and RUNX2 expression was evaluated under confocal laser scanning microscopy. To confirm the obtained data, RT-PCR and WB analyses were performed in order to evaluate the best implant surface performance. TEST surfaces compared to CTRL titanium surfaces enhanced cell adhesion and increased VEGF and RUNX2 expression. Moreover, titanium TEST surfaces showed a different topographic morphology that promoted cell adhesion, proliferation, and osteogenic/angiogenic commitment. To conclude, TEST surfaces performed more efficiently than CTRL surfaces; furthermore, TEST surface results showed them to be more biocompatible, better tolerated, and appropriate for allowing hPDLSC growth and proliferation. This fact could also lead to more rapid bone-titanium integration.


[Notes on ancient Islamic medicine].
Arab medicine arose as a consequence of the assimilation and breeding of Hellenistic medicine, particularly of Galenic medicine. It reached its high point between the X and XII centuries and, after the XIII century, lost all creative capabilities. Nevertheless, it achieved the status of being an incentive for European medieval medicine. Some aspects of the medical teaching and publications of the most distinguished Moslem physicians, such as Rhazes (865-932), Avicenna (980-1037), and Averroës (1126-1198) are described. The main characteristics of Moslem medical institutions such as guilds, hospitals, and organizations of professional practice also are discussed. Although Arab medicine essentially constituted a transmission vehicle of master ideas of ancient medical thought, this medicine awoke the interest and initiative of the medieval physicians of western Europe, for example, those at the medical school of Salerno.


Egg and cholesterol consumption and mortality from cardiovascular and different causes in the United States: A population-based cohort study.
Whether consumption of egg and cholesterol is detrimental to cardiovascular health and longevity is highly debated. Data from large-scale cohort studies are scarce. This study aimed to examine the associations of egg and cholesterol intakes with mortality from all causes, cardiovascular disease (CVD), and other causes in a US population. Overall, 521,120 participants (aged 50-71 years, mean age = 62.2 years, 41.2% women, and 91.8% non-Hispanic white) were recruited from 6 states and 2 additional cities in the US between 1995 and 1996 and prospectively followed up until the end of 2011. Intakes of whole eggs, egg whites/substitutes, and cholesterol were assessed by a validated food frequency questionnaire. Cause-specific hazard models considering competing risks were used, with the lowest quintile of energy-adjusted intake (per 2,000 kcal per day) as the reference. There were 129,328 deaths including 38,747 deaths from CVD during a median follow-up of 16 years. Whole egg and cholesterol intakes were both positively associated with all-cause, CVD, and cancer mortality. In multivariable-adjusted models, the hazard ratios (95% confidence intervals) associated with each intake of an additional half of a whole egg per day were 1.07 (1.06-1.08) for all-cause mortality, 1.07 (1.06-1.09) for CVD mortality, and 1.07 (1.06-1.09) for cancer mortality. Each intake of an additional 300 mg of dietary cholesterol per day was associated with 19%, 16%, and 24% higher all-cause, CVD, and cancer mortality, respectively. Mediation models estimated that cholesterol intake contributed to 63.2% (95% CI 49.6%-75.0%), 62.3% (95% CI 39.5%-80.7%), and 49.6% (95% CI 31.9%-67.4%) of all-cause, CVD, and cancer mortality associated with whole egg consumption, respectively. Egg white/substitute consumers had lower all-cause mortality and mortality from stroke, cancer, respiratory disease, and Alzheimer disease compared with non-consumers. Hypothetically, replacing half a whole egg with equivalent amounts of egg whites/substitutes, poultry, fish, dairy products, or nuts/legumes was related to lower all-cause, CVD, cancer, and respiratory disease mortality. Study limitations include its observational nature, reliance on participant self-report, and residual confounding despite extensive adjustment for acknowledged dietary and lifestyle risk factors. In this study, intakes of eggs and cholesterol were associated with higher all-cause, CVD, and cancer mortality. The increased mortality associated with egg consumption was largely influenced by cholesterol intake. Our findings suggest limiting cholesterol intake and replacing whole eggs with egg whites/substitutes or other alternative protein sources for facilitating cardiovascular health and long-term survival. ClinicalTrials.gov NCT00340015.


Extraction of cellulose nanocrystalline from Camellia oleifera Abel waste shell: Study of critical processes, properties and enhanced emulsion performance.
Cellulose nanocrystals (CNCs) extracted from the waste shell of Camellia oleifera Abel (C. oleifera) are gaining attention as valuable materials. In this study, CNCs were extracted from the agricultural waste shell of C. oleifera through phosphoric acid and sulfuric acid hydrolysis, respectively. Firstly, we optimized the alkaline treatment process for cellulose isolation by using response surface methodology. Furthermore, the properties of CNCs were investigated by neutralizing them with NaOH and NH3·H2O, and by dialysis in water. In addition, the characterization methods including FT-IR, TGA, AFM and TEM were used to analysis the properties of the synthesized CNCs. Finally, CNCs were studied for their application in essential oil-based Pickering emulsions. CNCs obtained from sulfuric acid showed the smallest particle size and good dispersibility. Moreover, the release profiles of essential oils in the emulsions were followed by Peppa's kinetic release model. The antibacterial activity of the emulsions against E. coli and S. aureus showed that CNCs-stabilized emulsions enhanced the antibacterial activity of essential oils. Therefore, neutralization treatments may enhance the properties of CNCs, and CNCs stabilized Pickering emulsions can enhance antibacterial activity of essential oil. This study provides insight into the potential application of CNCs derived from C. oleifera waste shells.


Association between urinary glyphosate exposure and bone mineral density in adults.
There is very limited evidence linking glyphosate exposure to bone mineral density in adults aged 20 to 59 years in the National Health and Nutrition Examination Survey database. Hence, this study aimed to investigate the correlation between urinary glyphosate concentrations and total bone mineral density (BMD) in adults aged 20 to 59 years. A cross-sectional study was conducted using data from the 2013 to 2016 National Health and Nutrition Examination Survey, which included 594 men (mean age 39.1 years) and 610 women (mean age 40.0 years). In our study, we utilized a weighted multiple regression equation model to investigate the potential correlation between urinary glyphosate concentration and total BMD. Additionally, we conducted a stratified analysis to differentiate between various special populations. Our findings revealed a significant negative association between urinary glyphosate concentration and total BMD across 3 different regression models (Model 1, β [95% CI]: -0.0160 [-0.0200, -0.0120]; Model 2, β [95% CI]: -0.0135 [-0.0172, -0.0098]; Model 3, β [95% CI]: -0.0141 [-0.0178, -0.0104]). However, after stratifying by gender, age, and race, we observed varying conclusions. This study found that urinary glyphosate concentration was negatively associated with total BMD in both men and women when stratified by sex. Additionally, when stratified by age, the negative association was more significant in the 20 to 29 and 50 to 59 year age groups. When stratified by race, a significant negative association was found in races other than Hispanic. Therefore, the impact of glyphosate exposure on BMD should attract more people's attention.


Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits.
Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer's disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed. Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition. A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores. In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance. Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions.


Effects of D-beta-hydroxybutyrate and long- and medium-chain triglycerides on leucine metabolism in humans.
Ketone bodies and/or fatty acids might play a protein-sparing role during prolonged fasting or parenteral nutrition. To assess this problem, we studied whole body leucine metabolism, using L-[1-13C]leucine in normal postabsorptive volunteers who received either long-chain triglycerides (LCT, 0.15 g.kg-1.h-1, 6 subjects), a 50-50 mixture of medium-chain triglycerides (MCT) and LCT (0.15 g.kg-1.h-1, 6 subjects), D-beta-hydroxybutyrate (540 mumol.kg-1.h-1, 6 subjects), or saline (4 subjects). Leucine concentration decreased only with MCT-LCT. Leucine flux decreased by 10-20% from basal in all groups. Leucine oxidation, which was corrected for the contribution to 13CO2 of the 13C natural abundance of the infused substrates, decreased during LCT infusion (0.31 +/- 0.02 to 0.24 +/- 0.01 mumol.kg-1.min-1, P less than 0.01), but was unaffected by MCT-LCT (despite plasma free fatty acid levels similar to those obtained with LCT), D-beta-hydroxybutyrate, or saline infusion. Therefore, 1) the effect of fatty acids on amino acid oxidation is not mediated by ketone bodies, 2) it depends on the fatty acid chain length, 3) long-chain fatty acids but not medium-chain fatty acids could play a protein-sparing role during parenteral nutrition.


The translationally controlled tumor protein is a novel calcium binding protein of the human placenta and regulates calcium handling in trophoblast cells.
The translationally controlled tumor protein (TPT1, also known as TCTP) is a highly conserved, abundantly expressed protein found in mammals as well as in a wide range of other organisms of both the animal and plant kingdom. Initially considered as a growth-related protein, later studies showed TPT1 is endowed with multiple biological activities, including calcium binding. The present study aimed to evaluate the expression of TPT1 in the human placenta and to examine the functional role of the protein in the calcium binding and homeostasis of trophoblast cells. Samples were analyzed by Western blot, reverse transcription-polymerase chain reaction and immunohistochemistry. The effect of TPT1 knockdown by small interfering RNA (siRNA) on calcium uptake and buffering was assessed in the HTR-8/SVneo cell line. TPT1 protein and mRNA were detected in first-trimester and term placenta. In the tissue, TPT1 was localized in the villous trophoblast. TPT1 expression significantly increased during gestation, with the higher protein and mRNA levels reached at term. Recombinant placental TPT1 bound calcium in vitro, while downregulation of the protein levels by siRNA in HTR-8/SVneo cells was associated with a reduced cellular calcium-uptake activity and buffering capacity. These data demonstrate, for the first time, the expression of TPT1 in the human placenta and support a direct role of the protein in placental calcium transport.


Analysis of the microvasculature and tissue type ratios in normal vs. benign and malignant breast tissue.
To analyze the microvasculature and tissue type ratios in normal vs. benign and malignant breast tissue to establish a baseline for expected values against which future imaging studies can be benchmarked. Using computer-assisted techniques on immunostained breast tissue (normal [n = 28], fibrocystic [n = 37], fibroadenomas [n = 19], invasive carcinomas [n = 19]), values were obtained for microvessel density (MVD), mean vessel area (MVA), vessel orientation (shape) and epithelial:stromal ratio (E:S). Measurement reproducibility and the effects of fibroadenoma stromal hyalinization and fibrocystic disease severity were also tested. Value ranges for the 4 diagnostic groups were significantly different (P < .001). For invasive breast carcinomas, E:S and MVD were significantly higher (P < .001) but MVA was smaller as compared to that in fibroadenomas. Peripherally vs. centrally there was no significant difference in MVD, MVA or vessel shape in the neoplasms. Decreases in E:S and MVD correlated with fibroadenoma stromal hyalinization. Increases in E:S and MVA correlated with more severe fibrocystic disease. Correlation coefficients for measurement reproducibility were high across the diagnostic categories. This study established a specific, reproducible, computer-assisted technique and baseline of expected values for morphologic criteria in normal, benign and malignant breast tissue that may be used in the future to correlate new breast imaging responses with these underlying biologic properties.


Foot posture influences the electromyographic activity of selected lower limb muscles during gait.
Some studies have found that flat-arched foot posture is related to altered lower limb muscle function compared to normal- or high-arched feet. However, the results from these studies were based on highly selected populations such as those with rheumatoid arthritis. Therefore, the objective of this study was to compare lower limb muscle function of normal and flat-arched feet in people without pain or disease. Sixty adults aged 18 to 47 years were recruited to this study. Of these, 30 had normal-arched feet (15 male and 15 female) and 30 had flat-arched feet (15 male and 15 female). Foot posture was classified using two clinical measurements (the arch index and navicular height) and four skeletal alignment measurements from weightbearing foot x-rays. Intramuscular fine-wire electrodes were inserted into tibialis posterior and peroneus longus under ultrasound guidance, and surface EMG activity was recorded from tibialis anterior and medial gastrocnemius while participants walked barefoot at their self-selected comfortable walking speed. Time of peak amplitude, peak and root mean square (RMS) amplitude were assessed from stance phase EMG data. Independent samples t-tests were performed to assess for significant differences between the normal- and flat-arched foot posture groups. During contact phase, the flat-arched group exhibited increased activity of tibialis anterior (peak amplitude; 65 versus 46% of maximum voluntary isometric contraction) and decreased activity of peroneus longus (peak amplitude; 24 versus 37% of maximum voluntary isometric contraction). During midstance/propulsion, the flat-arched group exhibited increased activity of tibialis posterior (peak amplitude; 86 versus 60% of maximum voluntary isometric contraction) and decreased activity of peroneus longus (RMS amplitude; 25 versus 39% of maximum voluntary isometric contraction). Effect sizes for these significant findings ranged from 0.48 to 1.3, representing moderate to large differences in muscle activity between normal-arched and flat-arched feet. Differences in muscle activity in people with flat-arched feet may reflect neuromuscular compensation to reduce overload of the medial longitudinal arch. Further research is required to determine whether these differences in muscle function are associated with injury.


Hyperemia prior to acute brain swelling during rewarming of patients who have been treated with moderate hypothermia for severe head injuries.
The goal of this study was to elucidate the optimal time for rewarming of patients who have been treated with hypothermia for severe head injury. Eleven patients with severe head injuries who had been treated by hypothermia underwent transcranial Doppler (TCD) ultrasonography examinations. The patients were divided into two groups: Group A consisted of three patients in whom acute brain swelling occurred during the rewarming period and Group B was composed of eight patients who displayed no significant intracranial hypertension during or after hypothermia therapy. In all patients, the mean flow velocity of the middle cerebral artery (FV(MCA)) recorded transcranially and the mean flow velocity of the internal carotid artery (FV(ICA)), recorded high in the neck, were monitored at 24-hour intervals after the patient was admitted to the hospital. In Group A, the FV(MCA) was normal at 48 hours (maintenance state of hypothermia) in each patient, and abnormal increases and peak values (> 100 cm/second) occurred from 96 to 144 hours postinjury (rewarming period). The FV(ICA), which was monitored concurrently also varied as the FV(MCA) increased. The pulsatility indices in the arteries decreased at the time of the peak FV(MCZ). The enhanced FV(MCA) was consistent with hyperemia because of the low FV(MCA)/FV(ICA) ratios (< 3). Two patients in whom jugular venous oxygen saturation was monitored were found to have high values (> 80%), representing hyperemia. All intracranial pressures (ICPs) that lay within the normal range at 48 hours postinjury elevated acutely after the peak FV(MCA). In Group B, both FV(MCA) and FV(ICA) values were normal at 48 hours postinjury and remained stable throughout the rewarming period. Values of ICP were also maintained within the normal range until the patients were weaned from hypothermia therapy. Hyperemia, detectable by TCD ultrasonography, may serve as an index in the prediction of acute brain swelling, and rewarming should be terminated when such a hemodynamic phenomenon is observed.


Facilitators and barriers to implementing quality measurement in primary mental health care: Systematic review.
OBJECTIVE To identify facilitators and barriers to implementing quality measurement in primary mental healthcare as part of a large Canadian study (Continuous Enhancement of Quality Measurement) to identify and select key performances measures for quality improvement in primary mental health care.DATA SOURCES CINAHL, EMBASE, MEDLINE, and PsycINFO were searched, using various terms that represented the main concepts, for articles published in English between 1996 and 2005.STUDY SELECTION In consultation with a health sciences research librarian, the initial list of identified references was reduced to 702 abstracts, which were assessed for relevance by 2 coders using predetermined selection criteria. Following a consensus process, 34 articles were selected for inclusion in the analysis. An additional 106 citations were identified in the references of these articles, 14 of which were deemed relevant to this study, for a total of 57 empirical articles identified for review. Most articles described implementation of health care innovations and clinical practice guidelines, 5 focused on quality indicators, and 1 examined mental health indicators.SYNTHESIS Content analysis of the 57 articles identified 7 common categories of facilitators and barriers for implementing innovations, guidelines, and quality indicators: indicator characteristics, promotional strategies,implementation strategies, resources, individual-level factors, organizational-level factors, and external factors.Implementation studies in which these factors were addressed were more likely to achieve successful outcomes.CONCLUSION The overlap in facilitators and barriers across implementation of mental health indicators, healthcare innovations, and practice guidelines is not surprising, as they are often related. The overlap strengthens the findings of the limited number of studies of quality indicators. The Continuous Enhancement of Quality Measurement process for identification and selection of indicators has attended to some of these issues by using a rigorous scientific approach and by engaging a range of stakeholders in selecting and prioritizing the indicators.


The route to best science in implementation of the Endangered Species Act's consultation mandate: the benefits of structured effects analysis.
The Endangered Species Act is intended to conserve at-risk species and the ecosystems upon which they depend, and it is premised on the notion that if the wildlife agencies that are charged with implementing the statute use the best available scientific information, they can successfully carry out this intention. We assess effects analysis as a tool for using best science to guide agency decisions under the Act. After introducing effects analysis, we propose a framework that facilitates identification and use of the best available information in the development of agency determinations. The framework includes three essential steps--the collection of reliable scientific information, the critical assessment and synthesis of available data and analyses derived from those data, and the analysis of the effects of actions on listed species and their habitats. We warn of likely obstacles to rigorous, structured effect analyses and describe the extent to which independent scientific review may assist in overcoming these obstacles. We conclude by describing eight essential elements that are required for a successful effects analysis.


Retroviral technology--applications for expressed peptide libraries.
The cell is an extremely complex network of interactions between large numbers of molecules. Understanding this entire network and the information arising from it is an overwhelming and challenging task. Reverse genetics has given us the possibility to discover unknown interactions and their related pathways. With the help of peptide libraries, interactions between biomolecules can be disrupted or distorted and the signaling pathways where these proteins are involved, altered. Consequently, novel biological pathways can be discerned. The peptide libraries become a pool of shapes, some of them might behave as dominant effectors. With the use of retroviral transfer vectors those libraries can be expressed in a stable manner in the mammalian cell. A strong selection and screening process can finally lead to specific peptides. Novel high-throughput approaches might allow for the rapid creation of small-molecule switches in protein-protein interactions. Reverse genetics and as such the expression of small molecules that will have a specific biological outcome, can become an answer to our queries.


Derived more-less relational mands in children diagnosed with autism.
In Experiment 1, more and less relations were trained for arbitrary Stimuli A1 and A2 with 3 children with autism. The following conditional discriminations were then trained: A1-B1, A2-B2, B1-C1, B2-C2. In subsequent tests, participants showed derived more-less mands (mand with C1 for more and mand with C2 for less). A training procedure reversed the B-C conditional discriminations, and participants then showed derived reversed more-less mands (mand with C1 for less, C2 for more). Baseline B-C relations were retrained, and participants subsequently demonstrated a return to the original derived manding. A second experiment with 1 prior participant and 1 naive participant removed a possible confounding effect. Establishing derived manding may be an advantageous component when teaching a mand repertoire in applied settings.


Normalization of Naxos plakoglobin levels restores cardiac function in mice.
Arrhythmogenic cardiomyopathy (AC) is associated with mutations in genes encoding intercalated disc proteins and ultimately results in sudden cardiac death. A subset of patients with AC have the autosomal recessive cardiocutaneous disorder Naxos disease, which is caused by a 2-base pair deletion in the plakoglobin-encoding gene JUP that results in a truncated protein with reduced expression. In mice, cardiomyocyte-specific plakoglobin deficiency recapitulates many aspects of human AC, and overexpression of the truncated Naxos-associated plakoglobin also results in an AC-like phenotype; therefore, it is unclear whether Naxos disease results from loss or gain of function consequent to the plakoglobin mutation. Here, we generated 2 knockin mouse models in which endogenous Jup was engineered to express the Naxos-associated form of plakoglobin. In one model, Naxos plakoglobin bypassed the nonsense-mediated mRNA decay pathway, resulting in normal levels of the truncated plakoglobin. Moreover, restoration of Naxos plakoglobin to WT levels resulted in normal heart function. Together, these data indicate that a gain of function in the truncated form of the protein does not underlie the clinical phenotype of patients with Naxos disease and instead suggest that insufficiency of the truncated Naxos plakoglobin accounts for disease manifestation. Moreover, these results suggest that increasing levels of truncated or WT plakoglobin has potential as a therapeutic approach to Naxos disease.


Biogeography of American Northwest Hot Spring A/B'-Lineage Synechococcus Populations.
Previous analyses have shown how diversity among unicellular cyanobacteria inhabiting island-like hot springs is structured relative to physical separation and physiochemical differences among springs, especially at local to regional scales. However, these studies have been limited by the low resolution provided by the molecular markers surveyed. We analyzed large datasets obtained by high-throughput sequencing of a segment of the photosynthesis gene psaA from samples collected in hot springs from geothermal basins in Yellowstone National Park, Montana, and Oregon, all known from previous studies to contain populations of A/B'-lineage Synechococcus. The fraction of identical sequences was greater among springs separated by <50 km than among springs separated by >50 km, and springs separated by >800 km shared sequence variants only rarely. Phylogenetic analyses provided evidence for endemic lineages that could be related to geographic isolation and/or geochemical differences on regional scales. Ecotype Simulation 2 was used to predict putative ecotypes (ecologically distinct populations), and their membership, and canonical correspondence analysis was used to examine the geographical and geochemical bases for variation in their distribution. Across the range of Oregon and Yellowstone, geographical separation explained the largest percentage of the differences in distribution of ecotypes (9.5% correlated to longitude; 9.4% to latitude), with geochemical differences explaining the largest percentage of the remaining differences in distribution (7.4-9.3% correlated to magnesium, sulfate, and sulfide). Among samples within the Greater Yellowstone Ecosystem, geochemical differences significantly explained the distribution of ecotypes (6.5-9.3% correlated to magnesium, boron, sulfate, silicon dioxide, chloride, and pH). Nevertheless, differences in the abundance and membership of ecotypes in Yellowstone springs with similar chemistry suggested that allopatry may be involved even at local scales. Synechococcus populations have diverged both by physical isolation and physiochemical differences, and populations on surprisingly local scales have been evolving independently.


Sensitivity of some nitrogen fixers and the target pest Fusarium oxysporum to fungicide thiram.
This study was carried out to investigate the toxic effects of the fungicide thiram (TMTD) against five nitrogen fixers and the thiram target pest Fusarium oxysporum under laboratory conditions. Nitrogen fixing bacteria Falvobacterium showed the highest values of LD(50) and proved to be the most resistant to the fungicide followed by Fusarium oxysporum, while Pseudomonas aurentiaca was the most affected microorganism. LD(50) values for these microorganisms were in 2-5 orders of magnitude lower in comparison with LD(50) value for Fusarium oxysporum. Thiram was most toxic to Pseudomonas aurentiaca followed by Azospirillum. The lowest toxicity index was recorded for Fusarium oxysporum and Flavobacterium. The slope of the curve for Azomonas, Fusarium oxysporum and Flavobacterium is more steep than that of the other curves, suggesting that even a slight increase of the dose of the fungicide can cause a very strong negative effect. Thiram was more selective to Pseudomonas aurentiaca followed by Azospirillum, Rhizobium meliloti and Azomonas. The lowest selectivity index of the fungicide was recorded for Falvobacterium followed by Fusarium oxysporum. The highest safety coefficient of the fungicide was assigned for Flavobacterium, while Pseudomonas aurentiaca showed the lowest value.


[Activation of T cells in experimental autoimmune encephalomyelitis and multiple sclerosis].
In this study we describe the main findings from research into the autoreactive process triggered by activated T lymphocytes, which are generated in the peripheral compartment and then migrate towards the central nervous system (CNS) in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) its animal model. The different strategies that have been developed to date for the immunological treatment of MS have been designed to intervene in the pathogenic process of the disease by blocking the activation of T cells and B cells with specific antigens, interfering with immunological effector mechanisms and inhibiting the migration of lymphocytes towards the CNS. The cause of the inflammatory response in MS has still not been defined, but the findings from EAE studies and in patients with MS suggest that the disease has an autoimmune aetiology involving autoreactive T cells which are specific for antigens in the myelin membrane. To activate these cells at least two cues are needed during antigen recognition and later the T CD4+ lymphocytes are differentiated in two subpopulations, Th1 and Th2, which differ in the pattern of secretion of cytosines depending on the stage of the disease process. The progressions of EAE and MS give rise to changes in the primary and secondary self reactive responses of the T cells during the progression of the disease. The pathological immune mechanisms mediated by activated myelin specific T lymphocytes play a key role in the progression and recuperation, as well as the mediation, of tissue damage during the course of MS and EAE.


Porokeratosis ptychotropica: a rare manifestation with typical histological exam.
Porokeratosis is a disorder of epidermal keratinization characterized clinically by a distinctive ridge-like border, and histologically by cornoid lamellae. The known clinical variants of porokeratosis are: classic porokeratosis of Mibelli, disseminated superficial (actinic) porokeratosis (DSAP), porokeratosis palmaris et plantaris disseminata, linear porokeratosis and punctate porokeratosis. In 1995, a seventh form was described as porokeratosis ptychotropica: a verrucous form resembling psoriasis involving the gluteal cleft presenting on the histological exam multiple cornoid lamellae. There are very few reports in the literature of this clinical variant. The present study describes the case of a healthy male presenting gluteal hyperkeratotic plaques for 22 years. He had been to several dermatologists, none of them had achieved a definitive diagnosis. We present a typical clinical presentation and its dermoscopy findings, in addition to histological examination that confirmed the diagnosis.


SEM2: Introducing mechanics in cell and tissue modeling using coarse-grained homogeneous particle dynamics.
Modeling multiscale mechanics in shape-shifting engineered tissues, such as organoids and organs-on-chip, is both important and challenging. In fact, it is difficult to model relevant tissue-level large non-linear deformations mediated by discrete cell-level behaviors, such as migration and proliferation. One approach to solve this problem is subcellular element modeling (SEM), where ensembles of coarse-grained particles interacting via empirically defined potentials are used to model individual cells while preserving cell rheology. However, an explicit treatment of multiscale mechanics in SEM was missing. Here, we incorporated analyses and visualizations of particle level stress and strain in the open-source software SEM++ to create a new framework that we call subcellular element modeling and mechanics or SEM2. To demonstrate SEM2, we provide a detailed mechanics treatment of classical SEM simulations including single-cell creep, migration, and proliferation. We also introduce an additional force to control nuclear positioning during migration and proliferation. Finally, we show how SEM2 can be used to model proliferation in engineered cell culture platforms such as organoids and organs-on-chip. For every scenario, we present the analysis of cell emergent behaviors as offered by SEM++ and examples of stress or strain distributions that are possible with SEM2. Throughout the study, we only used first-principles literature values or parametric studies, so we left to the Discussion a qualitative comparison of our insights with recently published results. The code for SEM2 is available on GitHub at https://github.com/Synthetic-Physiology-Lab/sem2.


ERS statement on paediatric long-term noninvasive respiratory support.
Long-term noninvasive respiratory support, comprising continuous positive airway pressure (CPAP) and noninvasive ventilation (NIV), in children is expanding worldwide, with increasing complexities of children being considered for this type of ventilator support and expanding indications such as palliative care. There have been improvements in equipment and interfaces. Despite growing experience, there are still gaps in a significant number of areas: there is a lack of validated criteria for CPAP/NIV initiation, optimal follow-up and monitoring; weaning and long-term benefits have not been evaluated. Therapeutic education of the caregivers and the patient is of paramount importance, as well as continuous support and assistance, in order to achieve optimal adherence. The preservation or improvement of the quality of life of the patient and caregivers should be a concern for all children treated with long-term CPAP/NIV. As NIV is a highly specialised treatment, patients are usually managed by an experienced paediatric multidisciplinary team. This statement written by experts in the field of paediatric long-term CPAP/NIV aims to emphasise the most recent scientific input and should open up new perspectives and research areas.


Case 297.
History A 70-year-old man was referred to our institution with chronic obstructive urinary symptoms and constipation for 2 years before admission. His medical history was unremarkable. Outside laboratory tests revealed an elevated serum prostate-specific antigen level (21.7 ng/mL [normal range, 0.00-4.00 ng/mL]), and urinalysis results were negative. He was admitted for evaluation of possible prostate cancer. The patient reported no specific symptoms of infection and denied fever, dysuria, hematuria, and abdominal pain. He had no family history of prostate cancer. On physical examination, he was afebrile, and the digital rectal examination was not painful. These findings were evidence of an enlarged prostate and a hard multilobulated mass, which was palpable bilaterally. The urologic team performed MRI of the prostate (Figs 1-4).


Interferon-specific effects on protein synthesis in P3HR-1 cells.
The effect of interferon (IFN) on protein synthesis was studied in the Burkitt's lymphoma cell line P3HR-1 by [35S]methionine labelling of the cells, followed by two-dimensional gel electrophoresis of cell extracts. De novo synthesis of three proteins (mol. wts. 33 000, 62 000, and 98 000, respectively) and alterations in the rate of synthesis for a small number of additional proteins were observed during the first 12 h of treatment, while the rate of overall protein synthesis was unaffected. Treatment of P3HR-1 cells with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or hydrocortisone (HC), which induce similar changes in cell cycle distribution as does IFN, did not induce comparable changes in the rates of protein synthesis. Thus, the effects were specific for IFN and not induced by the change in cell cycle distribution per se, i.e., accumulation in G0. Treatment of cells with 2'-5' pA core did not mimic the effect of IFN at the translational level. A substrain of P3HR-1 cells, selected for resistance to the anti-proliferative effect of IFN, lacked six proteins found in the wild-type. The 62 000 mol. wt. protein was induced in this substrain as well as in native P3HR-1 cells on addition of IFN. The resistant substrain still developed an anti-viral effect in response to IFN. Thus, it seems as if the anti-proliferative and anti-viral effects of IFN, at least in some cells are mediated by different intracellular molecular mechanisms.


Genetic structure and environmental heterogeneity in the European hake (Merluccius merluccius).
This study aimed at assessing the genetic structure and the state of the stocks of the European hake (Merluccius merluccius). To this end, 15 samples were taken from the whole range of the species and analysed using allozymes. Since 11 samples were taken from the poorly studied Mediterranean Sea, the results obtained provided a complete picture of the hake's genetic structure and an initial insight into its relationships with environmental features. Atlantic and Mediterranean hake populations are separated by the Almeria-Oran front. This area has been proved to be the boundary between Atlantic and Mediterranean stocks of many marine organisms, but some doubt exists concerning the efficaciousness of the local gyres as barriers to the gene flow. Our data have evidenced a latitudinal cline at loci Gapdh and Gpi-2 within the Mediterranean Sea, with a further steep change across the Almeria-Oran front. The genetic pattern showed a strong correlation with the values of the salinity both at the surface and at -320 m and of the salinity + temperature at the surface, suggesting a role for these parameters in maintaining the genetic differentiation among the two population groups through selective processes. Finally, the levels of genetic variability were found to be slightly lower in the depleted Atlantic stock than in the Mediterranean one.


Pharmacology and mechanisms of action of calcium-channel blockers.
The calcium-channel blockers represent a group of organic chemical structures that share the ability to inhibit Ca2+ entry into excitable cells. In coronary and peripheral arterial smooth muscle and the heart, inhibition of Ca2+ entry blunts the ability of Ca2+ to serve as an intracellular messenger. Thus, calcium-channel blockers are smooth-muscle dilators and have a negative inotropic effect on the working myocardial cells of the atria and ventricles. Calcium-channel blockers also have effects on impulse formation and conduction in some regions of the heart. A fast, Na+-dependent ionic current is responsible for the upstroke of the action potential in the working cells of the atria and ventricles and in the rapidly conducting cells of the His-Purkinje system, so that the calcium-channel blockers do not inhibit conduction in these cells. In the sinoatrial and atrioventricular nodes, where depolarization is due primarily to a Ca2+-dependent slow inward current, the calcium-channel blockers slow the sinus pacemaker and inhibit atrioventricular conduction. The actions of different calcium-channel blockers are not always similar; for example, nifedipine is much more potent as an inhibitor of calcium channels in smooth muscle than in the heart, whereas verapamil and diltiazem are approximately equipotent in heart and vascular smooth muscle. It is likely that the calcium-channel blockers reach their specific binding sites in membranes by first dissolving in the phospholipid bilayer, after which they may interact with hydrophobic regions of proteins that make up, or regulate, these channels. Further knowledge of these molecular properties should facilitate the development of new calcium-channel blockers with improved specificity.


The function of IGF-IR in NNK-mediated lung tumorigenesis.
The type I insulin-like growth factor receptor (IGF-IR) is associated with many different types of cancer and it has been found to be involved in many aspects of the malignant phenotype, such as mitogenesis, survival, transformation and metastasis. This receptor has been observed to be overexpressed in the majority of lung cancer cell lines and human lung tumor biopsies. Two doxycycline-inducible transgenic mouse models in which the human IGF-IR was overexpressed in either the Clara cells or the type II alveolar cells of the lung were used in this study to examine the interaction between the nicotine derivative, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the IGF-IR. NNK was injected into both of the transgenic mouse models that overexpress human IGF-IR in the lung tissue in order to determine whether IGF-IR overexpression would affect NNK-induced tumorigenesis. No significant differences in the overall tumor burden were found between mice overexpressing the IGF-IR transgene that were treated with NNK and those that were not, however NNK-treated mice expressing high levels of IGF-IR transgene developed larger tumors than mice expressing high levels of IGF-IR transgene that did not receive NNK injections. In addition, endogenous murine IGF-IR was found to be expressed at high levels in the tumors that developed in the wild type, NNK injected mice suggesting that NNK induces lung tumors through inducing endogenous IGF-IR expression.


Yohimbine impairs extinction of cocaine-conditioned place preference in an alpha2-adrenergic receptor independent process.
Extinction, a form of learning that has the ability to reshape learned behavior based on new experiences, has been heavily studied utilizing fear learning paradigms. Mechanisms underlying extinction of positive-valence associations, such as drug self-administration and place preference, are poorly understood yet may have important relevance to addiction treatment. Data suggest a major role for the noradrenergic system in extinction of fear-based learning. Employing both pharmacological and genetic approaches, we investigated the role of the alpha(2)-adrenergic receptor (alpha(2)-AR) in extinction of cocaine-conditioned place preference (CPP) and glutamatergic transmission in the bed nucleus of the stria terminalis (BNST). We found that pre-extinction systemic treatment with the alpha(2)-AR antagonist yohimbine impaired cocaine CPP extinction in C57BL/6J mice, an effect that was not mimicked by the more selective alpha(2)-AR antagonist, atipamezole. Moreover, alpha(2A)-AR knockout mice exhibited similar cocaine CPP extinction and exacerbated extinction impairing effects of yohimbine. Using acute brain slices and electrophysiological approaches, we found that yohimbine produces a slowly evolving depression of glutamatergic transmission in the BNST that was not mimicked by atipamezole. Further, this action was extant in slices from alpha(2A)-AR knockout mice. Our data strongly suggest that extinction-modifying effects of yohimbine are unlikely to be due to actions at alpha(2A)-ARs.


A meta-ethnography and theory of parental ethical decision making in the neonatal intensive care unit.
To synthesize the existing qualitative literature about parent ethical decision making in the neonatal intensive care unit (NICU) and to investigate the potential impact of culture on parents' decision making experiences. PubMed, CINAHL plus, and PsychInfo using the search terms parental decision making, culture, race, decision making, and parental decisions. Qualitative research studies investigating decision making for infants in the NICU from the parents' perspective were included. Studies involving older pediatric populations were excluded. Ten primary qualitative research articles were included. The primary author read all manuscripts and tabulated themes related to parents' ethical decision making. Study findings were synthesized using meta-ethnography involving translating concepts of separate studies into one another, exploring contradictions, and organizing these concepts into new theories. Key themes included parent involvement in decision making, parental role, necessity of good information, need for communication, desire for hope and compassion conveyed by providers, decision making satisfaction, and trust in caregiving team. A preliminary theoretical framework of ethical parent decision making was modeled based on the proposed relationships between the themes. Parent preferences for their involvement in decision making, their perceptions of communication with providers, and their relationships with providers are all important factors in the experience of making decisions for their infants. Needs of parents were the same regardless the ethnic or racial diversity of study participants.


Hyperbaric oxygen therapy and its role in the treatment of chronic osteomyelitis: a preliminary report involving refractory osteomyelitis in the foot.
Osteomyelitis, both acute and chronic, is difficult to treat and often does not respond to conventional methods of therapy. Hyperbaric oxygen can be used as an adjunctive treatment in chronic refractory osteomyelitis after all other types of therapy have proved unsuccessful or response is slow. Risk factors and cost must be considered when deciding whether to use hyperbaric oxygen in conjunction with other methods of therapy.


Ethnicity and body dissatisfaction: are Hispanic and Asian girls at increased risk for eating disorders?
To compare prevalences and correlates of body dissatisfaction among white, Hispanic, and Asian girls. A total of 939 6th and 7th grade girls (mean age 12.4 years) attending four middle schools in northern California completed self-administered assessments of age, ethnicity, desired body shape, parent education levels, mother's and father's body shapes, pubertal stage, and body dissatisfaction. Body dissatisfaction was assessed with the Body Dissatisfaction scale of the Eating Disorder Inventory. Height, weight, triceps skinfold thickness, and waist and hip circumferences were measured by trained examiners. Hispanic girls reported significantly greater body dissatisfaction than white girls, with Asian girls in-between. After adjustment for body mass index (weight/height), normal and overweight white, Hispanic, and Asian girls reported similar levels of body dissatisfaction. However, among the leanest 25% of girls, Hispanics and Asians reported significantly more body dissatisfaction than white girls. Body mass index was the strongest independent predictor of increased body dissatisfaction in all three ethnic groups. Shorter height among white girls and taller height among Asian girls also made significant independent contributions. Parent education level, a measure of socioeconomic status, was not significantly associated with body dissatisfaction. Body dissatisfaction is not limited to white girls in middle and upper socioeconomic strata. These findings suggest Hispanic and Asian girls may be at greater risk for adopting eating disorder behaviors than previously recognized.


"No distinction of Black or Fair": The Natural History of Race in Adam Ferguson's Lectures on Moral Philosophy.
Recent scholarship on the Scottish Enlightenment has emphasized the increasing importance, in the last decades of the eighteenth century, of the concept of race. Yet race was a conceptual, moral, and taxonomic puzzle for Scots intellectuals such as Adam Ferguson (1723-1816). While the influence of Ferguson's published works has received wide scholarly attention, the content of his teaching has not. His surviving moral philosophy lecture notes offer us a window into the development of thought on race at the disciplinary intersections of moral philosophy and natural history, and the crossroads of Edinburgh's curricula and Britain's Empire.


Endogenous Metabolites and Genome Instability in Aging and Disease.
Proper maintenance of genomic DNA is upheld by tight control of cellular metabolism and DNA processing. Herein, we review recent advances in examining the role of endogenous metabolites and genomic instability in aging and disease as presented at the Fall 2023 American Chemical Society Meeting.


A novel Dmrt gene is specifically expressed in the testis of Chinese mitten crab, Eriocheir sinensis.
Dmrt is a family of genes related to the sexual regulators Doublesex of Drosophila melanogaster and Mab-3 of Caenorhabditis elegans. Dmrt genes are widely conserved and known for their involvement in sex determination and differentiation across phyla. In this study, we report here the identification of a novel Dmrt gene, named EsDmrt-like, from Chinese mitten crab Eriocheir sinensis. EsDmrt-like encodes a protein of 236 amino acids without intron. The protein contains a conserved DNA-binding DM domain that is characteristic of Dmrt genes. The DM domain shares 98% identity with that of Drosophila Dmrt99B and vertebrate Dmrt5, but outside the DM domain, there is little homology in sequence and no other conserved domain such as DMA specific to the Dmrt99B and Dmrt3-5. Interestingly, the expression pattern of EsDmrt-like is quite similar with that of vertebrate Dmrt1. Reverse transcription-polymerase chain reaction showed that EsDmrt-like transcripts were detectable only in testis with much higher expression at immature stage. In situ hybridization to gonad sections indicated that the EsDmrt-like mRNA was exclusively localized in Sertoli cells around the periphery of seminiferous tubules and developing germ cells including spermatogonium, spermatocyte, and spermatid, but absent in spermatozoa. This finding strongly suggests an essential role for EsDmrt-like in the male testicular development/differentiation of the crab.


Cystoid macular edema.
Cystoid macular edema (CME) may develop in association with a wide variety of ocular conditions. It is the result of cystic accumulation of extracellular intraretinal fluid in the outer plexiform and inner nuclear layers of the retina, as a result of breakdown of the blood-retinal barrier. It is most common following intraocular surgery, and in patients with venous occlusive disease, diabetic retinopathy, and posterior segment inflammatory conditions. A variety of approaches to the treatment of CME have been attempted, with a variable degree of success. These options have included topical and oral steroids, nonsteroidal anti-inflammatory agents, and laser photocoagulation treatment. The exact cause of CME and the effective treatment of this condition have remained elusive.


Evaluation of the effectiveness of Er:YAG laser and conventional periodontal treatment in a patient with acute streptococcal gingivitis: a 2-year follow-up.
The aim of this study was to evaluate the effectiveness of Er:YAG laser and conventional periodontal therapy in the treatment of acute streptococcal gingivitis both clinically and microbiologically. This case report describes a 2-year follow-up of a 30-year-old, female, chronic periodontitis patient, presenting severe gingival inflammation, sensitivity, pain, and acute gingival lesions that were treated with Er:YAG laser and conventional hand and ultrasonic instruments. Before the initial periodontal treatment, microbiological samples were taken from the lesion sites with sterile paper points from the sulcuses bilaterally, and excisional biopsies were obtained from the lesions. Following diagnostic tests, the lesions were identified as acute streptococcal gingivitis. Following the measurement of clinical indices, initial periodontal therapy was performed with Er:YAG laser on the right side and conventional hand and ultrasonic instruments on the left side, which were performed as two sessions at weekly intervals. As an adjunct to mechanical periodontal therapy, 500 mg amoxicillin was prescribed t.i.d. for a week. Microbiological samples grew mostly Streptococcus sp. and black pigmented obligate anaerobic bacteria. The histopathological examination revealed acanthosis, papillomatosis, and spongiotic lesions in the keratinized stratified squamous epithelium; infiltration of polymorphonuclear neutrophils, lymphocytes, and macrophages and plasma cells in the connective tissue; infiltration and accumulation of polymorphonuclear neutrophils in the epithelium, especially in the spongiotic lesions; and formation of microabscess-like clusters. After the initial periodontal treatment, clinical and microbiological measurements were repeated and reductions in clinical indices and the number of microorganisms were observed. both treatment modalities gave similar results, and no recurrences were observed during the 2-year follow-up. Er:YAG laser seems to be promising and as effective as conventional periodontal therapy in the treatment of acute streptococcal gingivitis.


The unique aromatic catabolic genes in sphingomonads degrading polycyclic aromatic hydrocarbons (PAHs).
Many members of the sphingomonad genus isolated from different geological areas can degrade a wide variety of polycyclic aromatic hydrocarbons (PAHs) and related compounds. These sphingomonads such as Sphingobium yanoikuyae strain B1, Novosphingobium aromaticivorans strain F199, and Sphingobium sp. strain P2 have been found to possess a unique group of genes for aromatic degradation, which are distantly related with those in pseudomonads and other genera reported so far both in sequence homology and gene organization. Genes for aromatics degradation in these sphingomonads are complexly arranged; the genes necessary for one degradation pathway are scattered through several clusters. These aromatic catabolic gene clusters seem to be conserved among many other sphingomonads such as Sphingobium yanoikuyae strain Q1, Sphingomonas paucimobilis strain TNE12, S. paucimobilis strain EPA505, Sphingobium agrestis strain HV3, and Sphingomonas chungbukensis strain DJ77. Furthermore, some genes for naphthalenesulfonate degradation found in Sphingomonas xenophaga strain BN6 also share a high sequence homology with their homologues found in these sphingomonads. On the other hand, protocatechuic catabolic gene clusters found in fluorene-degrading Sphingomonas sp. strain LB126 appear to be more closely related with those previously found in lignin-degrading S. paucimobilis SYK-6 than the genes in this group of sphingomonads. This review summarizes the information on the distribution of these strains and relationships among their aromatic catabolic genes.


Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure.
Many large genome-wide association studies (GWAS) have identified common blood pressure (BP) variants. However, most of the identified BP variants do not overlap with the linkage evidence observed from family studies. We thus hypothesize that multiple rare variants contribute to the observed linkage evidence. We performed linkage analysis using 517 individuals in 130 European families from the Cleveland Family Study (CFS) who have been genotyped on the Illumina OmniExpress Exome array. The largest linkage peak was observed on chromosome 16p13 (MLOD = 2.81) for systolic blood pressure (SBP). Follow-up conditional linkage and association analyses in the linkage region identified multiple rare, coding variants in RBFOX1 associated with reduced SBP. In a 17-member CFS family, carriers of the missense variant rs149974858 are normotensive despite being obese (average BMI = 60 kg/m2). Gene-based association test of rare variants using SKAT-O showed significant association with SBP (p-value = 0.00403) and DBP (p-value = 0.0258) in the CFS participants and the association was replicated in large independent replication studies (N = 57,234, p-value = 0.013 for SBP, 0.0023 for PP). RBFOX1 is expressed in brain tissues, the atrial appendage and left ventricle in the heart, and in skeletal muscle tissues, organs/tissues which are potentially related to blood pressure. Our study showed that associations of rare variants could be efficiently detected using family information.


Hypertension control improved through patient education. Chinese PEP Investigators.
To evaluate the effects of patient education for hypertension on hypertension control. Of 169 eligible patients (systolic blood pressure > or = 160 mmHg and/or diastolic blood pressure > or = 95 mmHg), 60 were assigned to educational group (group E, antihypertensive drug treatment with an addition of patient education) and 109 to routine group (group R, antihypertensive drug treatment alone). The average follow-up approximated to 3 years. The blood pressure was reduced from at baseline and sustained in the three-year follow-up by 20/13 mmHg in group E and by 22/13 mmHg in group R. For this similar blood pressure reduction, about 10 mg less of metoprolol and 6 mg less of nitrendipine were used in group E than in group R. The percentage of the patients in whom goal blood pressure (under 160/90 mmHg) was achieved during follow-up was higher and progressively increased in group E (1st year: 65%, 2nd year: 72%) in comparison with in group R (1st year: 45%; 2nd year: 55%). Body weight was significantly reduced by 1.36 and 1.81 kg from at baseline to at the 1st and 2nd year repeated measurements in group E. The significant reduction from at baseline to at the 2nd year was significantly different from that in group R (P = 0.02). For 24-hour urinary sodium excretion, it was decreased in the group E, whereas it was increased in the group R. The cumulative rates of hypertension-related complications were 4.43% in group E and 7.02% in group R (absolute difference = 2.59%, P = 0.48). The rate of missed appointments was somewhat higher in group R (10%) than in group E (7%) during the first year but lower in the 2nd and 3rd year (R vs E: 10% vs 2% in the 2nd year; 8% vs 2% in the 3rd year). Four patients lost to follow-up in group R (6.87%) and 1 patient in group E (1.74%, P = 0.08). The findings of this study suggest that patient education is of some benefits to the hypertension control.


Opposite orientations of an inverted duplication and allelic variation at the mouse agouti locus.
The mouse agouti protein is a paracrine signaling molecule that causes yellow pigment synthesis. A pale ventral coloration distinguishes the light-bellied agouti (AW) from the agouti (A) allele, and is caused by expression of ventral-specific mRNA isoforms with a unique 5' untranslated exon. Molecular cloning demonstrates this ventral-specific exon lies within a 3.1-kb element that is duplicated in the opposite orientation 15-kb upstream to produce an interrupted palindrome and that similarity between the duplicated elements has been maintained by gene conversion. Orientation of the palindrome is reversed in A compared to AW, which suggests that mutation from one allele to the other is caused by intrachromosomal homologous recombination mediated by sequences within the duplicated elements. Analysis of 15 inbred strains of laboratory and wild-derived mice with Southern hybridization probes and closely linked microsatellite markers suggests six haplotype groups: one typical for most strains that carry AW (129/SvJ, LP/J, CE/J, CAST/Ei), one typical for most strains that carry A (Balb/cJ, CBA/J, FVB/N, PERA/Rk, RBB/Dn); and four that are atypical (MOLC/Rk, MOLG/Dn, PERA/Ei, PERC/Ei, SPRET/Ei, RBA/Dn). Our results suggest a model for molecular evolution of the agouti locus in which homologous recombination can produce a reversible switch in allelic identity.


Factors controlling plasticity of leaf morphology in Robinia pseudoacacia: III. biophysical constraints on leaf expansion under long-term water stress.
In this article, we measured the relative growth rate (RGR) of leaves of Robinia pseudoacacia seedlings under well-watered and water-stressed conditions (mid-day Ψ(w) = leaf water potential estimated with a pressure bomb of -0.48 and -0.98 MPa, respectively). Pressure-volume (PV) curves were done on growing leaves at 25, 50 and 95% of the mature size (growth stage) in order to compute solute potential (Ψ) and turgor pressure (Ψ(P) ) as a function of Ψ(w) . The PV curves and diurnal measurements of Ψ(w) and RGR allowed us to evaluate the parameters (cell wall extensibility m and growth turgor threshold Y) of the Lockhart equation, RGR = m(Ψ(P)-Y), at each growth stage. Our data showed that m and Y did change with leaf age, but the changes were slow enough to evaluate m and Y on any given day. We believe this is the first study to provide evidence that the Lockhart equation adequately quantifies leaf growth of trees over a range of time domains. The value of m linearly declined and Y linearly increased with growth stage. Also, mild drought stress caused a decline in m and increase in Y relative to controls. Although water stress caused an osmotic adjustment which, in turn, increased Ψ(P) in stressed plants relative to controls, the RGR and final leaf sizes were reduced in water-stressed plants because of the impact of water stress on decreased m and increased Y.


Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.
Mutations in the connexin 31 (GJB3) gene have been found in subjects with dominant and recessive deafness and in patients with erythrokeratodermia variabilis. We report here a dominant mutation in the GJB3 gene (D66del) in a family affected with peripheral neuropathy and sensorineural hearing impairment. A wide range of disease severity for peripheral neuropathy, from asymptomatic cases to subjects with chronic skin ulcers in their feet and osteomyelitis leading to amputations, was detected in D66del patients. Mild, often asymmetrical, hearing impairment was found in all but one patient with mutation D66del of this family and the same mutation was present in an independent family ascertained because of hearing impairment. We have found mouse connexin 31 (Gjb3) gene expression in the cochlea and in the auditory and sciatic nerves, showing a pattern similar to that of Gjb1 (connexin 32), of which the human ortholog (GJB1) is involved in X-linked peripheral neuropathy. This expression pattern, together with auditory-evoked brainstem anomalous response in D66del patients, indicates that hearing impairment due to GJB3 mutations involves alterations in both the cochlea and the auditory nerve. Peripheral neuropathy is the third phenotypic alteration linked to GJB3 mutations, which enlarges the list of genes that cause this group of heterogeneous disorders.


Characterization and mutational analysis of a cluster of three genes expressed preferentially during sporulation of Saccharomyces cerevisiae.
A differential hybridization screen of a genomic yeast DNA library previously identified 14 genes of Saccharomyces cerevisiae that are expressed preferentially during sporulation. Three of these sporulation-specific genes, SPS1, SPS2, and SPS3, have been shown to be closely linked. A mutational analysis has demonstrated that expression of the SPS1 gene, but not the SPS2 gene, is essential for the completion of sporulation. A diploid MATa/MAT alpha strain homozygous for a disruption of the SPS1 gene failed to form asci when subjected to sporulation conditions. The 3' end of the transcript encoded by the SPS1 gene was found to map only 185 base pairs from the 5' end of the SPS2 gene. The SPS1-SPS2 intergenic region was shown to contain all of the regulatory sequences necessary for the sporulation-specific activation of the SPS2 gene as assessed by expression of a translational SPS2-lacZ fusion gene present on a replicating, centromere-containing plasmid. The fusion gene was found to be expressed at the same time during sporulation as the chromosomal wild-type SPS2 gene.


Complex System Approaches for Animal Health Surveillance.
Many new and highly variable data are currently being produced by the many participants in farmed animal productions systems. These data hold the promise of new information with potential value for animal health surveillance. The current analytical paradigm for dealing with these new data is to implement syndromic surveillance systems, which focus mainly on univariate event detection methods applied to individual time series, with the goal of identifying epidemics in the population. This approach is relatively limited in the scope and not well-suited for extracting much of the additional information that is contained within these data. These approaches have value and should not be abandoned. However, an additional, new analytical paradigm will be needed if surveillance and disease control agencies wish to extract additional information from these data. We propose a more holistic analytical approach borrowed from complex system science that considers animal disease to be a product of the complex interactions between the many individuals, organizations and other factors that are involved in, or influence food production systems. We will discuss the characteristics of farmed animal food production systems that make them complex adaptive systems and propose practical applications of methods borrowed from complex system science to help animal health surveillance practitioners extract additional information from these new data.


Outcomes of Bebtelovimab Therapy in Patients With Solid Organ Transplantation With Mild and Moderate COVID-19.
Solid organ transplant recipients (SOTRs) are at greater risk of poorer outcomes from coronavirus disease 2019 (COVID-19) as compared to the general population. Because of significant drug-drug interactions between nirmatrelvir-ritonavir and immunosuppressive agents as well as logistical challenges of outpatient administration of remdesivir, anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) monoclonal antibodies (mAbs) had been the mainstay of outpatient treatment of COVID-19 among SOTRs, with bamlanivimab, casirivimab-imdevimab, and sotrovimab having been previously granted emergency use authorization by the Food and Drug Administration (FDA). The challenge with the ongoing use of these monoclonal antibodies is the loss of efficacy against emerging variants of SARS-CoV-2. Bebtelovimab, which retained efficacy against early subvariants of Omicron, was granted emergency use authorization by the Food and Drug Administration when Omicron BA.4 and BA.5 became the predominant variants in the United States. However, the study based on which bebtelovimab was authorized by the FDA did not include SOTRs. The only available safety and efficacy data on these patients are from retrospective studies. In our retrospective analysis of 62 SOTRs who received bebtelovimab infusion between May 11, 2022, and October 11, 2022, 28 had a kidney transplant, 18 had a liver transplant, 10 had a heart transplant, and six had multi-organ transplants (liver/kidney: 4, heart/kidney: 2). None of the patients reported infusion-associated adverse reaction. Only one (1.6%) patient developed progression of COVID-19, requiring subsequent treatment with remdesivir, steroids, and oxygen supplementation. The rate of need for intensive care and death from COVID-19 during the 30-day follow-up period was 0%.


Adverse events with sacubitril/valsartan in the real world: emerging signals to target preventive strategies from the FDA adverse event reporting system.
The aim of this study was to characterise clinical priority of adverse events with sacubitril/valsartan for targeting preventive measures. We used the US Food and Drug Administration adverse event reporting system (worldwide pharmacovigilance database) to compare adverse events recording sacubitril/valsartan as suspect with other cardiovascular drugs. Disproportionality analyses were performed by calculating the reporting odds ratios, deemed significant when the lower limit of the 95% confidence interval was greater than 1. Clinical priority was assigned to adverse events with significant disproportionality by scoring (range 0-10 points) five features (number of events, magnitude of the lower limit of the 95% confidence interval, mortality frequency, important/designated medical event, biological plausibility). Sacubitril/valsartan was recorded in 20,021 reports, with 178 adverse events associated with significant disproportionality: 71.9%, 25.9% and 2.2% were classified as weak, moderate and strong clinical priorities, respectively. Increased reporting emerged for several cardiovascular adverse events, including 'renal failure' (N = 388; lower limit of the 95% confidence interval 2.26), 'hyperkalaemia' (314; 2.42) and 'angioedema' (309; 1.56). Sudden cardiac death (priority score 9 points) was the only designated medical event with strong clinical priority. Notably, sudden cardiac death occurred early after sacubitril/valsartan administration (average onset 124 days), with concomitant drugs known for pro-arrhythmic potential (e.g. amiodarone, escitalopram, mirtazapine, loop diuretics) in 26.2% of records. The increased cardiovascular reporting of sacubitril/valsartan in the real world was largely predictable from pre-approval evidence, underlying disease and likely patients' comorbidities. The unexpected reporting of sudden cardiac death occurred well before the complete development of positive electrical remodelling induced by sacubitril/valsartan, and calls for stringent clinical monitoring (to reduce the pro-arrhythmic burden related to co-medications), and further investigation on appropriate combination with other preventive measures.


Mapping an Extended Neurochemical Profile at 3 and 7 T Using Accelerated High-Resolution Proton Magnetic Resonance Spectroscopic Imaging.
The aim of this study was to compare high-resolution free induction decay magnetic resonance spectroscopic imaging (FID-MRSI) at 3 T and 7 T in the brain of healthy subjects and to showcase the clinical potential of accelerated FID-MRSI at 7 T in 2 brain tumor cases. In this institutional review board-approved study, 10 healthy volunteers (8 men/2 women; age: 31 ± 6 years) were measured at 3 T and 7 T (Trio and 7T-Magnetom; Siemens Healthcare, Germany) and 2 patients (a 38-year-old man and a 37-year-old man), 1 with an anaplastic oligoastrocytoma (grade III) and 1 with a low-grade glioma (oligodendroglioma), were measured at 7 T.Free induction decay MR spectroscopic imaging with 3.4 × 3.4 mm in-plane resolution was acquired in 30 minutes/6 minutes (nonaccelerated/accelerated) at both field strengths. In addition, single-slice or multi-slice FID-MRSI at 7 T was measured in the 2 tumor patients at 7 T within 6 minutes/13.3 minutes. Signal-to-noise ratio, Cramer-Rao lower bounds, and parallel imaging efficiency were assessed. High-resolution maps were created for 9 different brain metabolites. At 7 T, 7 of 9 metabolites were reliably mapped over the whole slice but only 3 at 3 T. Parallel imaging efficiency was significantly improved at 7 T. Signal-to-noise ratios were +75%/+66% (P < 0.05) for N-acetylaspartate and +97%/+74%(P < 0.05) for glutamine + glutamate [Glx], and full-widths at half maximum were +112%/+109%(P < 0.05) higher at 7 T than at 3 T (nonaccelerated/accelerated) for N-acetylaspartate. Cramer-Rao lower bounds were more than double at 3 T (P < 0.05). At 7 T, FID-MRSI allowed the assessment of an extended neurochemical profile and yielded better metabolic maps in only approximately 6 minutes at 7 T than in approximately 30 minutes at 3 T. We found several potentially therapy-relevant neurochemical alterations in brain tumors that highlighted the potential of fast clinical FID-MRSI at 7 T.


Neutrophil-Related Oxidants Drive Heart and Brain Remodeling After Ischemia/Reperfusion Injury.
The inflammatory response associated with myocardial and brain ischemia/reperfusion injury (IRI) is a critical determinant of tissue necrosis, functional organ recovery, and long-term clinical outcomes. In the post-ischemic period, reactive oxygen species (ROS) are involved in tissue repair through the clearance of dead cells and cellular debris. Neutrophils play a critical role in redox signaling due to their early recruitment and the large variety of released ROS. Noteworthy, ROS generated during IRI have a relevant role in both myocardial healing and activation of neuroprotective pathways. Anatomical and functional differences contribute to the responses in the myocardial and brain tissue despite a significant gene overlap. The exaggerated activation of this signaling system can result in adverse consequences, such as cell apoptosis and extracellular matrix degradation. In light of that, blocking the ROS cascade might have a therapeutic implication for cardiomyocyte and neuronal loss after acute ischemic events. The translation of these findings from preclinical models to clinical trials has so far failed because of differences between humans and animals, difficulty of agents to penetrate into specific cellular organs, and specifically unravel oxidant and antioxidant pathways. Here, we update knowledge on ROS cascade in IRI, focusing on the role of neutrophils. We discuss evidence of ROS blockade as a therapeutic approach for myocardial infarction and ischemic stroke.


Establishing a community network for recruitment of African Americans into a clinical trial. The African-American antiplatelet stroke Prevention Study (AAASPS) experience.
A major aspect of a clinical trial is the ability to successfully recruit patients. There is a paucity of information concerning the nuances of recruiting study patients, especially those from minority communities. As minorities generally have been underrepresented in the health-care system, they may be less likely to participate in clinical trials or other studies. Thus, a strategy is needed to overcome this potential shortfall. One of our solutions has been the development of a community network to help disseminate information about our program. We believe that a key aspect has been the involvement of community members during pre-trial planning, community awareness programs, and our Community Advisory Panel. We also believe that it may be a major error to bring a health-care initiative unannounced into a targeted community without extensive pre-program planning in cooperation with that community. As our community awareness scheme suggests (Figure), there are many possible avenues to heighten awareness about a health-care program. While the church remains an important institution for religious and cultural activities in the African-American community, we have found that the news, television, and radio media also can be a powerful source for spreading awareness. Thus, we recommend creating awareness about an initiative through a "grassroots" approach of church and community organizations, along with a global approach through news, television, and radio media. As part of the awareness promotion campaign, it must be emphasized that the study is safe and provides benefits to enrollees. The success of health programs is largely dependent on community acceptance, which must be established in the pre-program planning stages of the initiative. This concept of obtaining community approval and acceptance prior to program initiation is not a new one, nor does it exclusively apply to the African-American community. Community leaders and members need to have a vested interest in such a program and a sense of empowerment. Through this type of communication, patient enrollment and community satisfaction can be substantial. Such success can serve as a springboard for other targeted health-care studies or programs in high-risk communities.


Hereditary polyposis coli I: the diagnostic value of colonoscopy, barium enema, and fecal occult blood.
In families with one of the Mendelian hereditary polyposes, one can predict the proportion of patients at risk and thus obtain a denominator against which colonoscopy, barium enema, and fecal occult blood can be validated. Colonoscopy is more sensitive than barium enema. There were 42 positive colonoscopies, 12 positive barium enemas, both being positive in 10 of these. There were 141 negative enemas, 133 negative colonscopies, and 118 negative for both. Occult blood was positive in 30% of patients with polyposis, five to seven times more frequently than in those without evident polyposis. Colonoscopy detected polyposis in 30% of the progeny of affected people. The shortfall, compared with the 50% expected under the Mendelian hypothesis, is readily explained by removal of affected cases from the study by surgery or death from cancer.


Trends in the population-based incidence of squamous cell carcinoma of the skin first diagnosed between 1984 and 1992.
To examine the incidence of first diagnosis of invasive squamous cell carcinoma (SCC) of the skin over time. Retrospective, population-based incidence study. Enumerated, geographically isolated, semiurban population served by the Mayo Clinic and its affiliated hospitals and the Olmsted Medical Center, including its affiliated hospital in Rochester, Minn. Using the Rochester Epidemiology Project databases that capture virtually all medical care provided to the residents of Rochester, we identified and reviewed records of all documented residents in whom histologically proven, invasive SCC of the skin was first diagnosed between 1984 and 1992. Age and sex stratum-specific rates were calculated, and age-adjusted rates observed over time for individuals aged 35 years or older were analyzed using Poisson regression. Adjusted rates were compared with the results of other studies. Review of 1630 records identified 511 incidence cases of SCC. Tumors located on the head and neck accounted for 66.4% of tumors in females and 72.9% in males. The annual age- and sex-specific incidence rates per 100,000 increased from 0 cases among males aged 0 to 14 years to 1286.0 cases among males aged 85 years or older. Over time, the annual age-adjusted incidence rates per 100,000 females rose from 46.5 (95% confidence interval [CI], 32.4-60.6) for the 1984 to 1986 period to 99.6 (95% CI, 80.4-118.7) for the 1990 to 1992 period and were 71.2 (95% CI, 61.7-80.8) overall. The corresponding rates for males were 125.9 (95% CI, 95.3-156.4), 191.0 (95% CI, 156.9-225.0), and 155.5 (95% CI, 137.0-174.0). The age- and sex-adjusted SCC incidence rates for the period from 1987 to 1989 and 1990 to 1992 exceeded those for the period from 1984 to 1986 (P = .03 and P < .001, respectively). Our age-adjusted rates for SCC were within the ranges seen in other white populations from temperate climates. The frequencies of first diagnosis of SCC are increasing at rates beyond those explainable by demographic shifts alone.