Diabetes for Cardiologists: Practical Issues in Diagnosis and Management.
Diabetes mellitus (DM), a chronic metabolic disease characterized by hyperglycemia, is a profound cardiovascular (CV) risk factor. It compounds the effects of all other risk factors, leads to premature micro- and macrovascular disease, facilitates development of heart failure, worsens the clinical course of all CV diseases, and shortens life expectancy. Established DM, unrecognized DM, and dysglycemia that may progress to DM are all commonly present at the time of presentation of overt CV disease. Thus, CV specialists and trainees frequently treat patients with dysglycemia. The traditional and proven role of cardiologists in reducing the risk of macrovascular events in this population is through aggressive lipid and blood pressure treatment. However, a more proactive role in the detection and management of DM is likely to become increasingly important as the prevalence continues to increase and therapies continue to improve. The latter include antihyperglycemic therapies with proven cardiovascular safety profiles and CV event reduction properties not yet fully elucidated and not necessarily related to glycemic control. Accordingly, the purpose of this article is to (1) expand the interest of cardiologists in earlier stages of the natural history of DM, when prevention or early detection might help achieve greatest benefit; (2) highlight principles of optimal glycemic management, with an emphasis on add-on choices showing promising reduction of CV events and lacking CV adverse effects; and (3) encourage cardiologists to become proactive partners in the multidisciplinary care needed to ensure optimal lifelong vascular health in patients with, or who are at risk of, DM.


Experimental evolution of the genetic load and its implications for the genetic basis of inbreeding depression.
The degree to which, and rapidity with which, inbreeding depression can be purged from a population has important implications for conservation biology, captive breeding practices, and invasive species biology. The degree and rate of purging also informs us regarding the genetic mechanisms underlying inbreeding depression. We examine the evolution of mean survival and inbreeding depression in survival following serial inbreeding in a seed-feeding beetle, Stator limbatus, which shows substantial inbreeding depression at all stages of development. We created two replicate serially inbred populations perpetuated by full-sib matings and paired with outbred controls. The genetic load for the probability that an egg produces an adult was purged at approximately 0.45-0.50 lethal equivalents/generation, a reduction of more than half after only three generations of sib-mating. After serial inbreeding we outcrossed all beetles then measured (1) larval survival of outcrossed beetles and (2) inbreeding depression. Survival of outcrossed beetles evolved to be higher in the serially inbred populations for all periods of development. Inbreeding depression and the genetic load were significantly lower in the serially inbred than control populations. Inbreeding depression affecting larval survival of S. limbatus is largely due to recessive deleterious alleles of large effect that can be rapidly purged from a population by serial sib-mating. However, the effectiveness of purging varied among the periods of egg/larval survival and likely varies among other unstudied fitness components. This study presents novel results showing rapid and extensive purging of the genetic load, specifically a reduction of as much as 72% in only three generations of sib-mating. However, the high rate of extinction of inbred lines, despite the lines being reared in a benign laboratory environment, indicates that intentional purging of the genetic load of captive endangered species will not be practical due to high rates of subpopulation extinction.


Immunohistochemical study of vesicle monoamine transporter 2 in the hippocampal formation of PCP-treated mice.
The exact pathophysiology of schizophrenia is unknown despite intensive scientific studies using molecular biology, psychopharmacology, neuropathology, etc. It is thought that neurodevelopmental failures such as neuronal network incompetence and the inappropriate formation of neurons affect the neurotransmitters. Several animal models have been created to investigate the etiology of this disease. In this study, we investigated the expression of vesicle monoamine transporter 2 (VMAT2), which has a significant role in neurotransmission, in the hippocampal formation in 1-phenylcyclohexylpiperazine (PCP)-treated mice using immunohistochemical staining technique to clarify neuronal abnormalities. PCP-treated mice are thought to be one of novel animal models for schizophrenia. The expression of VMAT2 in the hippocampal formation was significantly reduced overall in the PCP-treated mice compared to that in control (saline-treated) mice, also these reductions were observed throughout the brain. These facts implied that the pathophysiology of this disease involves abnormal monoaminergic transmission through VMAT2, despite PCP was the N-methyl-d-aspartate (NMDA) receptor antagonist that might induce glutamatergic abnormality. Since insufficient or excess release of neurotransmitter might alter neurochemical function and neurotransmission, VMAT2 might be an important target for biological research in psychiatric disease including schizophrenia.


The clinical effect of lumbar puncture in normal pressure hydrocephalus.
Owing to all the difficulties involved in selecting patients with normal pressure hydrocephalus for shunt-operation, a cerebrospinal fluid-tap-test (CSF-TT) is introduced. Psychometric and motor capacities of the patients are measured before and after lumbar puncture and removal of 40-50 ml CSF. Patients fulfilling criteria for normal pressure hydrocephalus were compared to patients with dementia and atrophy shown by computed tomography. Normal pressure hydrocephalus patients showed temporary improvement after lumbar puncture. The extent of the temporary improvement appeared to be well correlated with the improvement after shunt operation. Accordingly, the CSF-TT seems to be of value when selecting those patients who will probably benefit from a shunt operation.


[Basic morphology and diagnosis of the prosencephaly malformation (author's transl)].
The basic morphology and neuroradiology of the prosencephalies are described. Differentiation of three groups is possible: 1. The dorsal sac category, 2. The intermediate category and 3. The pseudohemispheric category. Brains of the first group are entirely undivided into hemispheres, bowl-shaped and do have a dorsal sac. Those belonging to the intermediate category have lost the sac. Their posterior parts and the basal ganglia are increasingly cleft by incomplete interhemispheric fissure whereas the primitivity of the frontal region is fully preserved. Brains of the third category are pseudohemispheric i.e. there is a continuous, deep interhemispheric fissure the bottom of which is formed by an uninterrupted bridge for cingulate cortex instead of a corpus callosum. The fornices are lacking as well and the prosencephalic ventricles remain fused. The distribution of the cortical fields is similar to hemispheric brains but without ever achieving fully normality. The most important difference to lower category-brains is the complete separation of the motor cortex, and as regards gross morphology their superficial similarity to normal brains. The differential diagnosis from other monoventricular brains such as septum pellucidum defects and the callosal defects with interhemispheric cysts is discussed.


Sonographic evaluation of spinal cord birth trauma with pathologic correlation.
Birth trauma to the spinal cord is a serious potential complication of delivery. Determining the presence, severity, and extent of injury poses a difficult problem because of the often confusing clinical setting. Myelography has been recommended for assessing spinal cord birth trauma but is invasive and may not be helpful. The role of sonography in evaluating spinal cord birth trauma has not been previously described. We assessed the value of sonography in four patients, three of whom also had CT metrizamide myelography. Autopsy correlation was available in three patients. Sonography was able to easily demonstrate the cord configuration, allowing for multiple assessments over time. Internal cord echogenicity was helpful in a case of hematomyelia and in demonstrating the changes of myelomalacia. Sonography is useful in evaluating neonates with severe spinal cord injury; it obviates the need for myelography and also may allow less severely injured patients to be assessed more frequently.


Investigation of COVID-19 comorbidities reveals genes and pathways coincident with the SARS-CoV-2 viral disease.
The emergence of the SARS-CoV-2 virus and subsequent COVID-19 pandemic initiated intense research into the mechanisms of action for this virus. It was quickly noted that COVID-19 presents more seriously in conjunction with other human disease conditions such as hypertension, diabetes, and lung diseases. We conducted a bioinformatics analysis of COVID-19 comorbidity-associated gene sets, identifying genes and pathways shared among the comorbidities, and evaluated current knowledge about these genes and pathways as related to current information about SARS-CoV-2 infection. We performed our analysis using GeneWeaver (GW), Reactome, and several biomedical ontologies to represent and compare common COVID-19 comorbidities. Phenotypic analysis of shared genes revealed significant enrichment for immune system phenotypes and for cardiovascular-related phenotypes, which might point to alleles and phenotypes in mouse models that could be evaluated for clues to COVID-19 severity. Through pathway analysis, we identified enriched pathways shared by comorbidity datasets and datasets associated with SARS-CoV-2 infection.


Bayesian hierarchical structured variable selection methods with application to MIP studies in breast cancer.
The analysis of alterations that may occur in nature when segments of chromosomes are copied (known as copy number alterations) has been a focus of research to identify genetic markers of cancer. One high-throughput technique recently adopted is the use of molecular inversion probes (MIPs) to measure probe copy number changes. The resulting data consist of high-dimensional copy number profiles that can be used to ascertain probe-specific copy number alterations in correlative studies with patient outcomes to guide risk stratification and future treatment. We propose a novel Bayesian variable selection method, the hierarchical structured variable selection (HSVS) method, which accounts for the natural gene and probe-within-gene architecture to identify important genes and probes associated with clinically relevant outcomes. We propose the HSVS model for grouped variable selection, where simultaneous selection of both groups and within-group variables is of interest. The HSVS model utilizes a discrete mixture prior distribution for group selection and group-specific Bayesian lasso hierarchies for variable selection within groups. We provide methods for accounting for serial correlations within groups that incorporate Bayesian fused lasso methods for within-group selection. Through simulations we establish that our method results in lower model errors than other methods when a natural grouping structure exists. We apply our method to an MIP study of breast cancer and show that it identifies genes and probes that are significantly associated with clinically relevant subtypes of breast cancer.


Control of glycolysis in vertebrate skeletal muscle during exercise.
The gastrocnemius muscle of the frog (Rana temporaria) has a high capacity for anaerobic glycolysis from glycogen. Glycolytic metabolites and effectors of phosphofructokinase, particularly the hexose bisphosphates, were followed in muscle during exercise (swimming between 5 s and 5 min), recovery (rest for up to 2 h after 5 min of swimming), and repeated exercise (swimming for up to 60 s after 2 h of recovery). Glycogen phosphorylase and phosphofructokinase were swiftly activated with exercise. The hexose bisphosphates followed markedly different time courses. Fructose 1,6-bisphosphate was transiently increased in both exercise and repeated exercise. This appears to be an effect rather than a cause of phosphofructokinase activation. Glucose 1,6-biphosphate was accumulated only while phosphofructokinase was active and was unchanged at other times. Fructose 2,6-biphosphate showed a 10-fold transient increase on exercise in rested frogs, almost disappeared from the muscle during recovery, and did not change during repeated exercise. Fructose 2,6-biphosphate is a potent activator of phosphofructokinase in vitro under near physiological assay conditions, and it may serve this function also in vivo during exercise. Glucose 1,6-biphosphate could be an activator of phosphofructokinase in repeated exercise when fructose 2,6-biphosphate is not available.


Gastrointestinal tolerance of a pediatric fiber formula in developmentally disabled children.
We performed a masked, randomized, 2-month crossover study with developmentally disabled children to study the tolerance of a pediatric adapted enteral formula with added soy fiber. Twenty children and adolescents aged 1 to 17 years, requiring liquid nutrition, were fed Pediasure (PS) and Pediasure with approximately 10 g total dietary fiber/l, (PSF10) as their major source of energy and nutrient intake for 1 month each. During the two 4-week periods of the crossover study, intake, tolerance of the formula, and stool characteristics were monitored daily with diaries. Criteria for gastrointestinal tolerance were symptoms of emesis, gas, irritability or fussiness. Stool characteristics included frequency, consistency, and the need to use elimination aids to induce defecation. Following completion of the crossover study, the patients were fed PSF10 for an additional 2 months. Anthropometrics were obtained at study initiation and at each biweekly visit during the crossover phase and monthly during the follow-up phase. Bowel scintigraphy studies were conducted in patients with oral or nasogastric intake during the crossover periods. Biochemical assessments were conducted at entry, at the end of each crossover period, and at exit. There were no differences in any of the tolerance, stooling, growth, or biochemical measurements between the feeding regimens, in 11 children completing this phase of the study. However, there was a trend towards using less elimination aids to induce a bowel movement during the fiber supplemented formula phase. Pediasure with fiber is well tolerated in children with developmental disabilities.


Origins of human atherosclerotic plaques. The role of altered gene expression.
The dramatic rise and equally dramatic fall in the mortality from coronary heart disease in the 20th century is only partly explained. This article reviews the development of our ideas concerning possible pathways other than lipids that might play a role in the development of human atherosclerosis alone or in combination with one or more of the usually considered risk factors. In some instances, such as that of cigarette smoking, the proposed concept regarding genetic alterations in vascular smooth muscle suggests a mechanism for development of at least some of the lesions. Recent studies have shown that an aberration in platelet-derived growth factor gene expression is unlikely to be a factor in proliferation of smooth-muscle cells. Aberrant expression of other oncogenes or some as yet unknown virus remain as possible explanations of some of the incidence of atherosclerosis and its consequent coronary heart disease.


Fatal fat embolism syndrome: a case report.
Fat embolism syndrome is a dire complication of long bone trauma. It is usually associated with neurological, hematological and respiratory involvement, the latter being the major cause of death. We present a case of severe fat embolism syndrome occurring 3 hours after a long bone injury, leading to permanent vegetative state and death without any respiratory signs. The diagnosis was confirmed by cytology of the bronchoalveolar lavage fluid. Clinical presentation of the puzzling fat embolism syndrome and diagnostic tests in suspected fat embolism syndrome are reviewed.


The Central European diet as an alternative to the Mediterranean diet in atherosclerosis prevention in postmenopausal obese women with a high risk of metabolic syndrome - a randomized nutrition-al trial.
Metabolic syndrome (MS) is a powerful risk factor for atherosclerosis (AT). The crucial meth- od of minimizing the development of atherosclerosis and its clinical manifestations is lifestyle modifications, including following a healthy diet. The aim of the study was to check if the Central European Diet (CED) could be an alternative to the Mediterranean Diet (MED) in the prevention of AT in patients with a risk of MS. The randomized, single-blind nutritional trial involved 144 obese women with a risk of MS. The subjects were randomly assigned to two groups and followed MED (n = 72) or CED (n = 72) for 16 weeks. The concentrations of high-sensitivity C-reactive protein (hs-CRP) and asymmetrical dimethylarginine (ADMA) were measured before and after nutritional intervention. In both studied groups, the concentrations of hs-CRP decreased significantly after the nutritional in- tervention (CED: p = 0.0107; MED: p = 0.0002). The ADMA levels were significantly lower after nutritional intervention in the CED group (p = 0.0187) but not in the MED group (p = 0.8354). However, the observed changes of hs-CRP concentrations (Δhs-CRP) and ADMA levels (ΔADMA) were not different between the groups (p = 0.5307 and p = 0.0905, respectively). In the Central European post-menopausal obese population, a well-designed, energy-restricted diet with the use of food items traditional for the region (CED) could be a good alternative to MED in terms of AT prevention.


Effects of alpha lipoic acid on acrylamide-induced hepatotoxicity in rats.
Acrylamide (ACR) is a neurotoxicant, reproductive toxicant, and carcinogen in animal species. It is used in many industries and has been found to form naturally in foods cooked at high temperatures. Alpha-lipoic acid (ALA) is a naturally occurring antioxidant whose therapeutic effect has been related to its antioxidant activity. This study was carried out to study the protective effect of alpha lipoic acid on acrylamide induced perturbations in rat liver. Four groups of rats were studied viz., control rats, acrylamide treated rats, alpha lipoic acid treated rats, and alpha lipoic acid plus acrylamide treated rats. ACR and ALA treatment alone and together caused a signifi-cant increase in hepatic reduced glutathione content while a decrease in hepatic ascorbic content was observed when compared to control group. ALA pretreatment of acrylamide exposed rats caused no a signifi-cant alteration in superoxide dismutase activity but resulted in a tendency towards restoration of glutathione peroxidase and catalase activity to near normal levels. Gel electrophoresis showed fragmentation of DNA in the treated groups. The dose of ALA used in the present study afforded partial restoration of oxidative indices altered by ACR in rat liver.


Cytosolic carboxypeptidase 1 is involved in processing α- and β-tubulin.
The Purkinje cell degeneration (pcd) mouse has a disruption in the gene encoding cytosolic carboxypeptidase 1 (CCP1). This study tested two proposed functions of CCP1: degradation of intracellular peptides and processing of tubulin. Overexpression (2-3-fold) or knockdown (80-90%) of CCP1 in human embryonic kidney 293T cells (HEK293T) did not affect the levels of most intracellular peptides but altered the levels of α-tubulin lacking two C-terminal amino acids (delta2-tubulin) ≥ 5-fold, suggesting that tubulin processing is the primary function of CCP1, not peptide degradation. Purified CCP1 produced delta2-tubulin from purified porcine brain α-tubulin or polymerized HEK293T microtubules. In addition, CCP1 removed Glu residues from the polyglutamyl side chains of porcine brain α- and β-tubulin and also generated a form of α-tubulin with two C-terminal Glu residues removed (delta3-tubulin). Consistent with this, pcd mouse brain showed hyperglutamylation of both α- and β-tubulin. The hyperglutamylation of α- and β-tubulin and subsequent death of Purkinje cells in pcd mice was counteracted by the knock-out of the gene encoding tubulin tyrosine ligase-like-1, indicating that this enzyme hyperglutamylates α- and β-tubulin. Taken together, these results demonstrate a role for CCP1 in the processing of Glu residues from β- as well as α-tubulin in vitro and in vivo.


Selective protection by anguidine of normal versus transformed cells against 1-beta-D-arabinofuranosylcytosine and Adriamycin.
Anguidine, a protein synthesis inhibitor, has been shown previously to induce a reversible arrest of cell progression through all phases of the mitotic cycle without inducing appreciable cell kill. This "frozen" cell cycle state provided protection of Chinese hamster ovary cells against the lethal effects of 1-beta-D-arabinofuranosylcytosine, Adriamycin, hydroxyurea, 5-fluorouracil, and hyperthermia. We now report on the preferential induction of cytostasis by anguidine in normal WI-38 fibroblasts, occurring at one-tenth of the dosage required to inhibit the cycle progression of WI-38 VA13 cells, the SV40 transformant. Pretreatment with anguidine at a concentration producing effective inhibition of normal cell cycle traverse while permitting sustained proliferation of transformed cells resulted in almost complete protection of WI-38 normal cells against the growth-inhibitory effects of 1-beta-D-arabinofuranosylcytosine and Adriamycin, without reducing the antiproliferative effects of these two agents against WI-38 VA13 transformed cells. Thus, this cytokinetic concept of preferential normal tissue protection should be explored in vivo to increase the therapeutic index of cancer chemotherapy.


Conformational changes of contractile proteins accompanying modulation of skeletal muscle contraction. Polarized microfluorometry investigations.
Results of studies on the modulation of skeletal muscle contraction by phosphorylation of myosin regulatory light chains and by exchange of magnesium for calcium in myosin heads were reviewed. The polarized fluorescence method was used in these studies, and conformational changes of contractile proteins accompanying modulation of skeletal muscle contraction were investigated. It was found that both the exchange of bound magnesium for calcium on myosin heads and the phosphorylation of myosin regulatory light chains control the ability of myosin heads to induce, upon binding to actin, conformational changes of thin filament leading to decrease or increase of its flexibility. The changes in actin filament flexibility may be caused by alteration of both the inter- and the intramonomer structural organization.


Contribution of impactor misalignment to the neurofunctional variability in porcine spinal cord contusion models.
Traumatic spinal cord lesions studies are often carried out with animal models or numerical simulations. Unfortunately, animal models usually present a high variability in severity and type of neurofunctional impairments following impact surgery. We postulate that the variability of outcomes is strongly dependent on the positioning and alignment of the impactor during the contusion. A finite elements model of the spinal cord, predicting the action potential (AP) conduction alteration, was proposed and used to perform nine numerical simulations of a 50 g weight dropped from 200 mm on the exposed spinal cord in its spinal canal. Simulations followed a 32 factorial design with impactor eccentricity and spinal cord tilt angle as factors on two outcomes: injured spinal cord area (AP < 10 % of its baseline, 1h post-injury), and asymmetry of injury (ratio of right/left injured area of both half spinal cord). Eccentricity contributed highly and significantly on both outcomes, but not tilt angle. Damaged axons were found in conscious motor, sensory, and unconscious proprioception tracts. Variability in impactor alignment beyond ±6.2 % of the spinal canal width affects neurofunctional outcomes, and careful assessment of the impactor course is therefore key when producing spinal cord injury by contusion.Clinical Relevance- A precision value is proposed to mitigate the contribution of impactor misalignment to neurofunctional variability in animal models, allowing the reduction of animal used in research. The proposed method of action potential conduction assessment could easily be implanted in human numerical models for the cross-study of patient's cases.


Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones.
Heterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in labelling nucleophilic sidechains, especially cysteines. The vast number of tractable cysteines promotes a wide range of target proteins to examine; however, our focus was put on functional cysteines. We chose the main protease of SARS-CoV-2 harboring Cys145 at the active site that is a structurally characterized and clinically validated target of covalent inhibitors. We screened an in-house, cysteine-targeting covalent inhibitor library which resulted in several covalent fragment hits with benzoxazole, benzothiazole and benzimidazole cores. Thione derivatives and Michael acceptors were selected for further investigations with the objective of exploring the mechanism of inhibition of the thiones and using the thoroughly characterized Michael acceptors for benchmarking our studies. Classical and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were carried out that revealed a new mechanism of covalent cysteine labelling by thione derivatives, which was supported by QM and free energy calculations and by a wide range of experimental results. Our study shows that the molecular recognition step plays a crucial role in the overall binding of both sets of molecules.


Immunogenicity of leptospiral vaccines grown in protein-free medium.
Leptospira interrogans serovars pomona and hardjo were adapted to grow in a chemically-defined, protein-free (PF) medium. Formolised monovalent vaccines of serovars pomona and hardjo and a bivalent mixture of the two were prepared from PF cultures. Live PF cultures and the vaccine preparations retained their agglutinating antigens and their immunogenicity when tested in rabbits and guinea-pigs. The vaccines were not pyrogenic and dermal reactions were slight.


Moral Distress and Its Associated Factors Among Nurses in Northwest Amhara Regional State Referral Hospitals, Northwest Ethiopia.
Moral distress is the cognitive-emotional dissonance that arises when one feels compelled to act against one's moral requirements. The study aimed to assess the proportion of moral distress and associated factors among nurses working in Northwest Amhara Regional State referral hospitals in 2018. A cross-sectional study was conducted among nurses working at Northwest Amhara regional state referral hospitals from April 1-30/2018. A total of 423 study participants were enrolled in the study. A systematic random sampling technique was used to select the study participants. A pretested self-administered structured questionnaire was used to collect data. Moral Distress Scale-Revised (MDS-R) was used to assess the proportion of moral distress. Epi info version 7 for data entry and SPSS version 22 for data analysis were used. A binary logistic model was computed. Variables having p-value < 0.5 with 95% CI were used to declare the presence of significant associations. A total of 423 study participants were enrolled in the study with a response rate of 97.4%. The mean (SD) age of the respondents was 30.62 ± 5.7 years. The majority of nurses 350 (85%) were degree and above holders in nursing. The proportion of moral distress among nurses was found to be 83.7%. Work experience 11-20 years [adjusted odds ratio (AOR)=2, 95% CI: 1.01, 3.34], perceived poor team communication [AOR=4.5, 95% CI: 1.78, 11.62], perceived powerlessness in decision making [AOR=3.3, 95% CI: 1.38, 7.87], inadequate staffing [AOR=2.96, 95% CI: 1.26, 6.97], and inappropriate provision of care [AOR=4.12, 95% CI: 1.55, 10.9] were significantly associated with moral distress. Nurses frequently experienced moral distress in clinical settings. Perceived poor communication, perceived powerlessness in decision making, inadequate staffing, and inappropriate provision care were the factors associated with moral distress.


Complement reduction impairs the febrile response of guinea pigs to endotoxin.
Although it is generally believed that circulating exogenous pyrogens [e.g., lipopolysaccharides (LPS)] induce fever via the mediation of endogenous pyrogens (EP) such as cytokines, the first of these, tumor necrosis factor-alpha, is usually not detectable in blood until at least 30 min after intravenous administration of LPS, whereas the febrile rise begins within 15 min after its administration. Moreover, although abundant evidence indicates that circulating LPS is cleared primarily by liver macrophages [Kupffer cells (KC)], these do not secrete EP in immediate response. This would imply that other factors, presumably evoked earlier than EP, may mediate the onset of the febrile response to intravenous LPS. It is well known that blood-borne LPS very rapidly activates the intravascular complement (C) system, some components of which in turn stimulate the quick release into blood of various substances that have roles in the acute inflammatory reaction. KC contain receptors for C components and are in close contact with afferent vagal terminals in the liver; the involvement of hepatic vagal afferents in LPS-induced fever has recently been shown. In this study, we tested the hypothesis that the initiation of fever by intravenous LPS involves, sequentially, the C system and KC. To test this postulated mechanism, we measured directly the levels of prostaglandin E2 (PGE2) in the interstitial fluid of the preoptic anterior hypothalamus (POA), the presumptive site of the fever-producing controller, of conscious guinea pigs over their entire febrile course, before and after C depletion by cobra venom factor (CVF) and before and after elimination of KC by gadolinium chloride (GdCl3). CVF and GdCl3 pretreatment each individually attenuated the first of the biphasic core temperature (Tc) rises after intravenous LPS, inverted the second into a Tc fall, and greatly reduced the usual fever-associated increase in POA PGE2. We conclude, therefore, that C activation may indeed be pivotal in the induction of fever by intravenous LPS and that substance(s) generated presumably by KC in almost immediate reaction to the presence of LPS and/or C may transmit pyrogenic signals via hepatic vagal afferents to the POA, where they rapidly induce the production of PGE2 and, hence, fever.


The multiple RNA-binding domains of the mRNA poly(A)-binding protein have different RNA-binding activities.
The poly(A)-binding protein (PABP) is the major mRNA-binding protein in eukaryotes, and it is essential for viability of the yeast Saccharomyces cerevisiae. The amino acid sequence of the protein indicates that it consists of four ribonucleoprotein consensus sequence-containing RNA-binding domains (RBDs I, II, III, and IV) and a proline-rich auxiliary domain at the carboxyl terminus. We produced different parts of the S. cerevisiae PABP and studied their binding to poly(A) and other ribohomopolymers in vitro. We found that none of the individual RBDs of the protein bind poly(A) specifically or efficiently. Contiguous two-domain combinations were required for efficient RNA binding, and each pairwise combination (I/II, II/III, and III/IV) had a distinct RNA-binding activity. Specific poly(A)-binding activity was found only in the two amino-terminal RBDs (I/II) which, interestingly, are dispensable for viability of yeast cells, whereas the activity that is sufficient to rescue lethality of a PABP-deleted strain is in the carboxyl-terminal RBDs (III/IV). We conclude that the PABP is a multifunctional RNA-binding protein that has at least two distinct and separable activities: RBDs I/II, which most likely function in binding the PABP to mRNA through the poly(A) tail, and RBDs III/IV, which may function through binding either to a different part of the same mRNA molecule or to other RNA(s).


The impact of high-fat diet on metabolism and immune defense in small intestine mucosa.
Improved procedures for sample preparation and proteomic data analysis allowed us to identify 7700 different proteins in mouse small intestinal mucosa and calculate the concentrations of >5000 proteins. We compared protein concentrations of small intestinal mucosa from mice that were fed for two months with normal diet (ND) containing 34.4% carbohydrates, 19.6% protein, and 3.3% fat or high-fat diet (HFD) containing 25.3% carbohydrates, 24.1% protein, and 34.6% fat. Eleven percent of the quantified proteins were significantly different between ND and HFD. After HFD, we observed an elevation of proteins involved in protein synthesis, protein N-glycosylation, and vesicle trafficking. Proteins engaged in fatty acid absorption, fatty acid β-oxidation, and steroid metabolism were also increased. Enzymes of glycolysis and pentose phosphate cycle were decreased, whereas proteins of the respiratory chain and of ATP synthase were increased. The protein concentrations of various nutrient transporters located in the enterocyte plasma membrane including the Na(+)-d-glucose cotransporter SGLT1, the passive glucose transporter GLUT2, and the H(+)-peptide cotransporter PEPT1 were decreased. The concentration of the Na(+),K(+)-ATPase, which turned out to be the most strongly expressed enterocyte transporter, was also decreased. HFD also induced concentration changes of drug transporters and of enzymes involved in drug metabolism, which suggests effects of HFD on pharmacokinetics and toxicities. Finally, we observed down-regulation of antibody subunits and of components of the major histocompatibility complex II that may reflect impaired immune defense and immune tolerance in HFD. Our work shows dramatic changes in functional proteins of small intestine mucosa upon excessive fat consumption.


SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels.
Patients with coronavirus disease 2019 (COVID-19) present increased risk for ischemic cardiovascular complications up to 1 year after infection. Although the systemic inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques remains unknown. Here we report that SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases. SARS-CoV-2 targeted plaque macrophages and exhibited a stronger tropism for arterial lesions than adjacent perivascular fat, correlating with macrophage infiltration levels. SARS-CoV-2 entry was increased in cholesterol-loaded primary macrophages and dependent, in part, on neuropilin-1. SARS-CoV-2 induced a robust inflammatory response in cultured macrophages and human atherosclerotic vascular explants with secretion of cytokines known to trigger cardiovascular events. Our data establish that SARS-CoV-2 infects coronary vessels, inducing plaque inflammation that could trigger acute cardiovascular complications and increase the long-term cardiovascular risk.


Pollen-tube growth rates in Collinsia heterophylla (Plantaginaceae): one-donor crosses reveal heritability but no effect on sporophytic-offspring fitness.
Evolutionary change in response to natural selection will occur only if a trait confers a selective advantage and there is heritable variation. Positive connections between pollen traits and fitness have been found, but few studies of heritability have been conducted, and they have yielded conflicting results. To understand better the evolutionary significance of pollen competition and its potential role in sexual selection, the heritability of pollen tube-growth rate and the relationship between this trait and sporophytic offspring fitness were investigated in Collinsia heterophylla. Because the question being asked was if female function benefited from obtaining genetically superior fathers by enhancing pollen competition, one-donor (per flower) crosses were used in order to exclude confounding effects of post-fertilization competition/allocation caused by multiple paternity. Each recipient plant was crossed with an average of five pollen donors. Pollen-tube growth rate and sporophytic traits were measured in both generations. Pollen-tube growth rate in vitro differed among donors, and the differences were correlated with in vivo growth rate averaged over two to four maternal plants. Pollen-tube growth rate showed significant narrow-sense heritability and evolvability in a father-offspring regression. However, this pollen trait did not correlate significantly with sporophytic-offspring fitness. These results suggest that pollen-tube growth rate can respond to selection via male function. The data presented here do not provide any support for the hypothesis that intense pollen competition enhances maternal plant fitness through increased paternity by higher-quality sporophytic fathers, although this advantage cannot be ruled out. These data are, however, consistent with the hypothesis that pollen competition is itself selectively advantageous, through both male and female function, by reducing the genetic load among successful gametophytic fathers (pollen), and reducing inbreeding depression associated with self-pollination in plants with mix-mating systems.


The mechanism of inhibition of ribonucleic acid synthesis by 8-hydroxyquinoline and the antibiotic lomofungin.
RNA synthesis in yeast is rapidly inhibited by 8-hydroxyquinoline and the phenazine antibiotic lomofungin (5-formyl-1-methoxycarbonyl-4,6,8-trihydroxyphenazine). It is shown that lomofungin, like 8-hydroxyquinoline, is a chelating agent for bivalent cations. The mechanism of inhibition of RNA synthesis by lomofungin and 8-hydroxyquinoline was investigated in experiments with isolated Escherichia coli RNA polymerase. The results show that both inhibitors are capable of inhibiting polymerase activity solely by chelating the dissociable cations Mn2+ and Mg2+. Evidence is presented which shows that inhibition may occur in the absence of any direct contact between the RNA polymerase or DNA template and the inhibitor. The possibility that inhibition might also occur by chelation of the Zn2+, which is tightly bound to the polymerase, is discussed: it is concluded that lomofungin or 8-hydroxyquinoline is likely to inhibit the enzyme by removal of Mn2+ and Mg2+ before chelating the Zn2+. On the basis of inhibition by chelation of Mn2+ and Mg2+, explanations are proposed for why lomofungin and 8-hydroxyquinoline inhibit synthesis of ribosomal and polydisperse RNA more than that of 5S RNA and tRNA, and for why protein synthesis is not immediately inhibited in the intact yeast cell.


The immune response against hapten-autologous protein conjugates in the mouse.
Mice immunized with hapten-autologous serum albumin conjugates (DNP-mouse serum albumin) were shown to contain immune B and T cells with specificity for the conjugate. Fractionation on antigen-coated Sepharose beads showed that B cells could be subdivided in two major groups: those reacting against the haptenic group (DNP) and those reactive against the new antigenic determinants (NADs) introduced into the protein carrier by the hapten coupling. It was shown previously that humoral antibodies formed against hapten-mouse serum albumin conjugates also were directed against these two groups of antigenic determinants and that the immune response to the NADs does not follow the genetic rules of high or low response against the hapten used. All together these findings support the distinct nature of the NADs over the haptenic groups, as recognized both at the humoral and cellular level. Absorption of mouse cells immune to hapten-autologous serum albumin conjugates on antigen-coated Sepharose beads using a variety of incubation conditions resulted in no specific retention of T cells. Therefore we had to resort to specificity studies of T cells in relation to T cell function. Relatively pure immune T cell suspensions were obtained using fractionation on anti-immunoglobulin-coated columns. DNP-MSA-specific T cells were shown to be very specific for the DNP-MSA conjugate with only one exception: they cross-reacted with antigenic determinants on DNP-rat serum albumin. As DNP-specific help was excluded in the present transfer system (as shown by the inability of cells from DNP-skin-painted mice and DNP-heterologous protein conjugate specific T cells [anti-immunoglobulin column purified] to help a DNP-MSA response), these results demonstrate the NAD specificity of the DNP-MSA-reactive T cells. The cross-reactivity pattern of DNP-MSA-specific T cells was similar to that found for humoral anti-NAD antibodies produced against the same immunogen. Whether B and T cells are activated by the same antigenic determinants is discussed.


Depressed blood neutrophil response to lithium stimulation in newborn rats.
The blood neutrophil response to lithium chloride challenge was determined in one-day-old and young adult rats to test the hypothesis that granulocytopoiesis is less efficient in neonates than in adults. Adult animals responded rapidly to lithium chloride treatment, showing a 134% increase in blood neutrophils on the second day of exposure and ultimately increasing by 260% by the tenth day. Newborn rats on the other hand, showed a 25% decrease in blood neutrophils after one day of treatment with lithium, then remained at that or at pretreatment levels throughout the subsequent 10 days. These observations suggest that hematopoietic tissue in the newborn is less responsive than is that of adults.


Noninvasive measurement of viable cell number in tissue-engineered constructs in vitro, using 1H nuclear magnetic resonance spectroscopy.
Noninvasive monitoring of tissue-engineered constructs is of critical importance for accurate characterization of constructs and their remodeling in vitro and in vivo. This study investigated the utility of (1)H NMR spectroscopy to noninvasively quantify viable cell number in tissue-engineered substitutes in vitro. Agarose disk-shaped constructs containing betaTC3 cells were employed as the model tissue-engineered system. Two construct prototypes containing different initial cell numbers were monitored by localized, water-suppressed 1H NMR spectroscopy over the course of 13 days. (1)H NMR measurements of the total choline resonance at 3.2 ppm were compared with results from the traditional cell viability assay MTT and with insulin secretion rates. Results show a strong linear correlation between total choline and MTT (R (2) = 0.86), and between total choline and insulin secretion rate (R (2) = 0.90). Overall, this study found noninvasive measurement of total choline to be an accurate and nondestructive assay for monitoring viable betaTC3 cell numbers in tissue-engineered constructs. The applicability of this method to in vivo monitoring is also discussed.


[Different aspects of magnetic resonance imaging of muscles between dermatomyositis and polymyositis].
Although dermatomyositis (DM) and polymyositis (PM) share many clinical features in common, they have distinct pathophysiological and histological features. It is possible that these distinctions reflect also macroscopically, for example, in muscle alterations seen in magnetic resonance images (MRI). To compare simultaneously the MRI of various muscle compartments of the thighs of adult DM and PM. The present study is a cross-sectional that included, between 2010 and 2013, 11 newly diagnosed DM and 11 PM patients (Bohan and Peter's criteria, 1975), with clinical and laboratory activity. They were valued at RM thighs, T1 and T2 with fat suppression, 1.5 T MRI scanner sequences. The mean age at the time of MRI, the time between onset of symptoms and the realization of the MRI distribution of sex and drug therapy were comparable between the two groups (p>0.050). Concerning the MRI, muscle edema was significantly found in DM, and mainly in the proximal region of the muscles. The area of fat replacement was found predominantly in PM. The partial fat replacement area occurred mainly in the medial and distal region, whereas the total fat replacement area occurred mainly in the distal muscles. There was no area of muscle fibrosis. DM and PM have different characteristics on MRI muscles, alike pathophysiological and histological distinctions.


Radioiodine studies, low serum thyrotropin, and the influence of statin drugs.
A low serum thyrotropin (TSH) concentration is an excellent predictor of hyperthyroidism, either overt or subclinical. Whether statin use influences the ability of a low serum TSH measurement to detect hyperthyroidism has not been evaluated. In a cohort of 307 patients with low or undetectable serum TSH concentrations suggestive of hyperthyroidism, we determined whether concurrent statin use influenced the results of radioiodine uptakes and scans. Participants included 29 patients taking a statin medication and 278 who were not taking a statin. Radioiodine uptakes and scans were interpreted by board-certified nuclear medicine physicians. Sixteen of the 29 patients who were taking a statin (55%) had normal radioiodine uptakes and scans despite their low serum TSH. The remaining 13 low-TSH patients who were taking a statin (45%) had abnormal uptakes and scans, most commonly showing diffuse thyroid hyperplasia with increased radioiodine uptake. In contrast, the vast majority of the 278 patients not taking a statin had abnormal uptakes and scans (84%), while only 16% of them had normal uptakes and scans (p < 0.001 vs. those on statins). The age- and sex-adjusted odds ratio of a statin user with a low serum TSH having normal radioiodine studies (as opposed to abnormal studies) was 3.6 (95% CI, 1.6-8.4). In patients with a low serum TSH concentration, normal thyroid function and morphology, as assessed by radioiodine studies, were much more common if the patient was taking a statin. Statins may falsely lower the serum TSH without altering thyroid function ("pseudohyperthyroidism") or, alternatively, statins may improve thyroid function in patients with hyperthyroidism.


Functional analysis of combinatorial mutants with changes in the C-terminus of the CD loop of the D2 protein in photosystem II of Synechocystis sp. PCC 6803.
Photosystem II properties were investigated in a set of combinatorial mutants containing changes in the C-terminal end of the CD lumenal loop (Gly187-Asn194) in the D2 protein of Synechocystis sp. PCC 6803. Initial screening of variable fluorescence (F(v)) induction and decay in the presence of DCMU showed that all but one of the combinatorial strains tested had an increased rate of Q(A)(-) reoxidation. Two strains showed an increase in the amplitude of constant fluorescence (F(o)). Examination of the primary sequence of the combinatorial strains combined with results obtained from analysis of site-directed mutants suggested that alterations in residue 191 of D2 increased the rate of charge recombination. Indeed, reintroduction of Trp191, the residue present in wild type, slowed the Q(A)(-) reoxidation rate in the presence of DCMU by 2-3-fold. However, the nature of other residues, in particular at codon 192, was also important in determining charge recombination rates. The increase in F(o) yield was due to an increased fluorescence lifetime of open reaction centers in intact cells and may reflect a decreased excitation trapping rate in the reaction center. This change was reversed by reintroduction of Trp191 even though a mutant lacking just Trp191 was normal in this respect. Trapping efficiency therefore was decreased only when multiple changes were present at the same time. We interpret Trp191 and neighboring residues to influence the midpoint redox potential of P680/P680(+) and in certain sequence contexts to affect the energy trapping efficiency by P680. The stability or environment of Y(D)(ox) was essentially unaffected in the mutants. Interestingly, many combinatorial mutants displayed an increased requirement for chloride for photoautotrophic growth, and two mutants, C8-10 and C8-23, also required more calcium. This indicates that this CD loop region of D2 not only affects properties of P680 but also affects properties of the oxygen-evolving complex.


Imidazolium trans-di-aqua-dioxalato-chromate(III) dihydrate.
In the title hydrated mol-ecular salt, (C3H5N2)[Cr(C2O4)2(H2O)2]·2H2O, the complete cation is generated by a crystallographic twofold rotation axis, with one C atom lying on the rotation axis. The complete anion is generated by crystallographic inversion symmetry (Cr(III) site symmetry -1), to generate a slightly distorted CrO6 octa-hedron with trans water mol-ecules and chelating oxalate dianions. The oxalate ion is almost planar (r.m.s. deviation = 0.017 Å) and the five-membered chelate ring is a shallow envelope with the metal ion displaced by 0.126 (1) Å from the ligand atoms. The crystal structure features O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds, which link the components into a three-dimensional network.


Infestation of mammals by Ixodes ricinus ticks (Acari: Ixodidae) in south-central Sweden.
Infestation by Ixodes ricinus ticks on rodents, hares and cervids was examined at Bogesund, 10 km north of Stockholm, in south-central Sweden during 1991-1994 and on varying hares (Lepus timidus) at Stora Karlsö and Gotska Sandön in the Baltic Sea during 1992-1993. At Bogesund, there were great differences between two consecutive years in the number of I. ricinus larvae infesting bank voles (Clethrionomys glareolus). The seasonal pattern of infestation by I. ricinus larvae and nymphs on bank voles was unimodal in 1991, with peaks in June-July and bimodal in 1992, with peaks in June and August. Male bank voles, compared to females and older voles, compared to young voles, harboured greater numbers of I. ricinus ticks. Apodemus mice, compared to bank voles, harboured greater numbers of I. ricinus ticks. Ixodes ricinus larvae engorged on Apodemus mice were heavier than larvae engorged on bank voles and resulted in larger nymphs. However, there was no difference in the proportions of viable nymphs resulting from larvae engorged on mice or voles. The ranges in the numbers of I. ricinus ticks infesting individual hosts were 1-451 for rodents, 16-2374 for hares and 428-2072 for roe deer (Capreolus capreolus). These ranges of tick numbers are estimated to represent potential blood losses from individual hosts of approximately 0.2-65% for rodents, 0.2-13% for hares and 0.3-9.0% for roe deer. Within the populations of all host species examined, the distributions of all stages of I. ricinus were clumped, with most host individuals harbouring few ticks and only a few individuals harbouring many ticks. The data suggest that, even though a small proportion of tick hosts may be severely affected, the direct effects of feeding by I. ricinus are unlikely to play an important role on mammal population dynamics.


Orbital Emphysema: A Case Report and Comprehensive Review of the Literature.
The objective of this study was to report a case of persistent and likely self-induced orbital emphysema (OE) following functional endoscopic sinus surgery with dislodgement of a previously placed orbital floor implant and to review the literature surrounding etiologies, pathophysiology, and management of OE. Case report and review of the literature. While blunt trauma resulting in disruption of the medial orbital wall is the most common cause of OE, there are an additional 25 underlying etiologies reported in the current literature. Pathophysiology of OE is somewhat dependent on underlying etiology but often involves a 1-way ball valve mechanism such that air may enter the orbit but not exit. When sufficient air enters the orbit, complications secondary to increased intraorbital pressure, including central retinal artery occlusion and compressive optic neuropathy, can occur. Mild cases of OE are typically observed, with most resolving within 7 to 10 days. Moderate cases are often managed by lateral canthotomy and cantholysis with possible needle decompression. Severe cases may require urgent surgical decompression. While the majority of cases of OE are benign and self-limited, there have been 4 reports in the literature documenting significant vision loss. Although there is often a history of trauma in patients presenting with OE, many other underlying etiologies have been reported with several cases occurring spontaneously. As such, OE should be included on the differential for a patient presenting with a sudden onset of orbital signs.


Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial.
In TEMPO 3:4, the vasopressin V2 receptor antagonist tolvaptan slowed total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline relative to placebo. TEMPO 4:4 was designed to provide an additional 2 years of data on the long-term safety and efficacy of tolvaptan in subjects completing TEMPO 3:4. The objective was to assess the disease-modifying effects of tolvaptan on TKV and eGFR end-points including change from baseline over the combined duration of TEMPO 3:4 and TEMPO 4:4, and non-inferiority of slopes during TEMPO 4:4. Of the 1445 subjects randomized to TEMPO 3:4, 871 (60.3%) enrolled in TEMPO 4:4. Percent changes in TKV from TEMPO 3:4 baseline to TEMPO 4:4 Month 24 were 29.9% and 31.6% (prior tolvaptan versus prior placebo, P = 0.38). Adjusting for baseline covariates improved the TKV treatment difference at Month 24 in TEMPO 4:4 from -1.70% to - 4.15% between the groups (P = 0.04). Slopes of TKV growth during TEMPO 4:4 were higher in early- versus delayed-treatment groups (6.16% versus 4.96% per year, P = 0.05). Analysis of secondary eGFR endpoints demonstrated a persistent effect on eGFR (3.15 mL/min/1.73 m2, P < 0.001), and non-inferiority in eGFR slopes. The safety profile on exposure to tolvaptan in TEMPO 4:4 was similar to that in TEMPO 3:4. The results of TEMPO 4:4 support a sustained disease-modifying effect of tolvaptan on eGFR. The lack of a sustained treatment difference on TKV may be accounted for by limitations of the trial design, including loss of randomization and baseline imbalances ensuing TEMPO 3:4. The safety profile was similar to that observed in TEMPO 3:4.


Merging porphyrins with organometallics: synthesis and applications.
The coordination chemistry of porphyrins has traditionally involved the ability of the porphyrin's tetrapyrrolic core to accommodate metal ions of varying charges and sizes, and on the organometallic chemistry of the resulting metalloporphyrins. However, the organometallic chemistry of porphyrins is not necessarily restricted to the metal bound in the porphyrin core, but can also be extended to the porphyrin periphery, be it through direct metalation of the porphyrin macrocycle at the meso or beta position, or by attachment to or merger of the porphyrin skeleton with ligands, followed by metalation. This Review focuses on the synthetic strategies used for porphyrins with peripheral metal-carbon bonds. The exciting results that have been produced underscore the importance and future potential of this field.


Modified Constraint-Induced Movement Therapy is a feasible and potentially useful addition to the Community Rehabilitation tool kit after stroke: A pilot randomised control trial.
The National Stroke Foundation recommends that Occupational Therapists use Constraint-Induced Movement Therapy (CIMT) with stroke survivors that experience an upper limb deficit. CIMT involves constraining the unaffected upper limb coupled with intensive therapy. The aim of this study was to evaluate the feasibility and effectiveness of a modified, low intensity version of CIMT (mCIMT) provided within usual resources of an Australian community rehabilitation setting. A pilot randomised control trial (n = 19) was conducted with stroke survivors referred for community rehabilitation. Participants were randomly assigned to either mCIMT or usual care. Both groups received six one-hour outpatient Occupational Therapy sessions (focussed on upper limb rehabilitation) over a two-week period. The intervention group (mCIMT) were asked to wear a constraint device on their unaffected hand for 90% of their waking hours and were provided with a home exercise program based on CIMT principles. Participants were included if they had some active upper limb movement, no significant cognitive deficits and sufficient balance. Outcome measures included upper limb function (WMFT) and participation (MAL) evaluated at baseline, immediately following the two-week intervention period and at four-week follow-up. Only a very small proportion of patients met the eligibility criteria. There were no differences between groups, with the exception of a small increase in reported upper extremity use in functional tasks at post-intervention assessment when compared to the usual care group. Modified CIMT can be applied to a typical Australian community rehabilitation setting, to treat upper limb deficits in stroke survivors. The resources used for mCIMT largely equalled usual care, with no differences in outcomes, suggesting that the intervention is feasible and potentially beneficial. However, there were very few stroke survivors who met participation criteria, indicating that demand for the intervention is limited.


Time, costs, and clinical utilization of screening for health literacy: a case study using the Newest Vital Sign (NVS) instrument.
Difficulties in identifying and caring for patients with limited health literacy have prompted interest in clinical screening to assess health literacy. Little agreement exists, however, on the utility of such screening. In this case study we explore the business and clinical cases for screening for health literacy using the Newest Vital Sign (NVS), a brief instrument specifically developed for use in primary care settings. Data were collected in 2008 in the Morehouse School of Medicine Department of Family Medicine Primary Care Clinic, where health literacy screening was implemented as part of routine intake procedures within an ongoing quality improvement effort to improve cardiovascular disease and diabetes outcomes. Specifically, we monitored time requirements, administrative and training costs, and clinician utilization associated with the NVS. Results identified only small time and cost constraints associated with implementing NVS screening. Clinical utility was more problematic, however, because refresher trainings were needed to ensure continued staff and clinician buy-in, use of the NVS data, and implementation of best practices to communicate with at-risk patients. Though the time and cost constraints associated with screening for health literacy were small, clinician utilization of this data in decision making and care processes may require further training and/or support.


[D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P acts as a biased agonist toward neuropeptide and chemokine receptors.
Substance P derivatives are potential therapeutic compounds for the treatment of small cell lung cancer and can cause apoptosis in small cell lung cancer cells in culture. These peptides act as broad spectrum neuropeptide antagonists, blocking calcium mobilization induced by gastrin-releasing peptide, bradykinin, cholecystokinin, and other neuropeptides. We show that [D-Arg1,D-Phe5,D-Trp7,9, Leu11]substance P has unique agonist activities in addition to this described antagonist function. At doses that block calcium mobilization by neuropeptides, this peptide causes activation of c-Jun N-terminal kinase and cytoskeletal changes in Swiss 3T3 fibroblasts and stimulates migration and calcium flux in human neutrophils. Activation of c-Jun N-terminal kinase is dependent on the expression of the gastrin-releasing peptide receptor in rat 1A fibroblasts, demonstrating that the responses to the peptide are receptor-mediated. We hypothesize that [D-Arg1,D-Phe5,D-Trp7,9, Leu11]substance P acts as a biased agonist on neuropeptide and related receptors, activating certain guanine nucleotide-binding proteins through the receptor, but not others.


Cortisol and its possible role in regulation of sodium and potassium in human milk.
Cortisol (F), Na, and K were measured in human milk samples taken every 4 h during 28 24-h cycles in 19 subjects. F in milk, measured by radioimmunoassay of unchromatographed extracts, demonstrated a circadian variation similar to that of plasma F and was dexamethasone-suppressible. Values ranged from 220 +/- 41 (SE) ng/dl at 2300 h to 1,214 +/- 210 at 0700 h. When milk extracts were chromatographed, a similar circadian variation was seen, and F ranged from 87 +/- 27 (SE) ng/dl at 2300 h to 784 +/- 164 at 700 h. The morning values of F exceeded previous estimates of corticosteroid binding capacity in milk, indicating the possibility of significant levels of unbound F. The subjects were divided into three groups according to time postpartum: I, 3.5-6 wk; II, 8-18 wk, and III, 20-32 wk. In milk, normalized values of F (unchromatographed) and electrolytes (x/means) were compared, with x the value at time t and means the mean value for a 24-h cycle. A significant circadian variation was seen in milk for (x/means)Na, (x/means)K, (x/means)Na/K, and x/means)F. Correlation of (x/means)F with (x/means)Na 4 h later was negative in all three groups (r = -0.36 to -0.56, P less than 0.10-0.001) as was (x/means)F vs. (x/means)Na/K (r = -0.33 to -0.61, P less than 0.10-0.001); (x/means)F vs. (x/means)K 4 h later was positive (r = 0.38 to 0.52, P less than 0.05-0.001). Dexamethasone administration caused a significant decrease in milk means Na and an increase in meansK in all five subjects (P less than 0.01). Thus, milk Na and K concentrations appeared regulated by adrenal corticosteroids.


Cell determinants of vasopressin-stimulated water flow.
I present a technique that permits evaluation of the permeability to water of the luminal membrane of the toad urinary bladder, independently of constraints to water flow imposed by the remainder of the tissue. This technique essentially depends on fixation of the luminal membrane with 1% glutaraldehyde for 5 min, and subsequent elimination of cytosolic constraints by decreasing the tonicity of the serosal bath to 1/2 normal strength. The increased hydraulic conductivity found with serosal hypotonicity is readily reversible, as the bladder returns to an isotonic serosal bath. By evaluating water flow in luminally fixed bladders during bathing in normal and hypotonic bath, one may identify the relative contribution of the luminal membrane and the "cytosol" on water flow. Using this technique, I found that the effect of the prostaglandin inhibitor Naproxen to increase vasopressin-stimulated water flow is due to increased luminal membrane permeability. The effect of histidine to increase vasopressin-stimulated water flow, however, depends on increased permeability of both the luminal membrane as well as the underlying structures. The action of serosal hypertonicity to induce water flow is due to an increased luminal permeability. However, serosal hypertonicity decreases "cytosolic" permeability, so that its overall function is a composite effect of its action at the luminal membrane and the "cytosolic" level.


"Neo-PIRO": Introducing a Novel Grading System for Surgical Infections of Neonates.
Quantification of surgical sepsis was never done beyond superficial, subfascial, and deep surgical site infection (SSI). Invasive surgical sepsis with systemic manifestation has not been tried to be quantified in general and pediatric surgery in particular. Hence, this attempts to develop a novel grading system to quantify neonatal surgical infections. Predisposing factors, infection, response, and organ failure (PIRO) is being used in critical care institutions for medical sepsis; it was modified with neonate-specific surgical parameters. Authors have developed a grading of these parameters into Grade I, II, and III. A blinded statistical test was performed and results were put to test. Extended Mantel-Haenszel Chi-square test validated linear relationship with grade and outcome, hospital stay, deep SSI, and organ dysfunction. Analysis of variance also showed the significant relationship of changing trends in grade and outcome. (1) Higher the grade indicated the probability of death. (2) Grade I patients had less duration of hospital stay compared to Grade II and III (P = 0.04). (3) The requirement of organ support and SSI were also more in Grade III. (4) Grade I patients had less increase in trends compared to Grade II and III (F = 4.86). Authors therefore feel Neo-PIRO seems to be the first scoring system that shows a linear relationship between scores and grade. Neo-PIRO is a novel grading system with surgical neonate-specific parameters. Future versions to include molecular parameters, as well as parameters selected by regression analysis.


Left anterior descending coronary artery: long-term angiographic results of CABG with endarterectomy.
The procedure of coronary bypass grafting (CABG) with coronary endarterectomy (CE) is controversial. However, in the setting of severely calcified coronary arteries CE may enable complete revascularization. Complete revascularization, especially of the left anterior descending artery (LAD), is important for long-term outcome. In this study we assessed long-term LAD graft patency and anterior wall function after CABG with CE of the LAD. Between 1984 and 1992, 283 patients underwent CABG with CE of the LAD. In 50 patients (47 men), aged 59+/-7.6 (40-77), clinical reassessment and surveillance angiography were performed. In all patients complete revascularization had been achieved with 3.5+/-1 (1-5) grafts/patient with 1-3 CE/patient. The LAD was grafted either with a saphenous vein segment (N=38) or with left intern thoracic artery (N=12). A graft obstructed less than 50% in diameter was defined as patent. At follow-up 39 patients (78%) were in CCS class I/II and had improved significantly (P<0.000). Control angiography after 7.6+/-2.5 (3.5-11.7) years after CABG revealed a patent LAD graft in 30/50 patients (60%). Actuarial graft patency was 100%, 96%, and 56% after 2, 5, and 10 years and was lower in patients with diabetes (P=0.001). Deterioration of anterior wall motion was observed in 17 patients (34%) and was more frequent if anterior wall motion was preoperatively normal (P=0.002), irrespective of LAD graft patency. Clinical status and long-term graft patency of grafts on endarterectomized LAD is considerable. However, patients with preoperatively normal anterior wall function are at increased risk for myocardial damage in the long-term.


Regulation of DC development and DC-mediated T-cell immunity via CISH.
Cytokine inducible SH2-containing protein (CISH) plays a crucial role in type 1 dendritic cell (DC) development as well as in the DC-mediated activation of cytotoxic T lymphocytes (CTLs). CISH expression at late DC developmental stages shuts down the proliferation of DC progenitors by negatively regulating signal transducer and activator of transcription 5 (STAT5) and facilitates the differentiation of DCs into potent stimulators of CTLs.


Efficiency enhancement of dye-sensitized solar cells by the addition of an oxidizing agent to the TiO(2) paste.
The addition of various amounts of a strong oxidizing agent (3,5-dinitrosalicyclic acid, DNSA) to TiO2 paste enhances the solar-to-electrical-energy conversion efficiency of the corresponding dye-sensitized solar cells (DSSCs). Maximum performance was obtained from a device that was fabricated by using a TiO2 paste with 2 wt % DNSA, which showed a short-circuit current density of 17.88 mA cm(-2) , an open-circuit voltage of 0.78 V, and an overall conversion efficiency of 9.62 %, which was an improvement in comparison to reference cells without DNSA. This improvement was rationalized in terms of the amount of residual carbon (formed due to the oxidation of binders) remaining on the TiO2 surface. Addition of a larger amount of oxidizing agent led to a smaller amount of residual carbon on the TiO2 surface. This smaller amount of residual carbon enhanced the adsorption of a larger number of dye molecules on the TiO2 surface. The addition of an oxidizing agent facilitated the removal of more residual organic species during the high-temperature calcination process while causing no change in the surface morphology and microstructure of the TiO2 film.


[Esophagitis in alcoholics].
Morphological examinations of esophaguses of 65 subjects who had suffered from alcoholism revealed a high rate of inflammatory lesions in the esophagus and epithelial leukoplakias and dysplasias developing against this background. It is suggested that the regular use of alcohol may be classified among the factors predisposing to the development of esophageal precancer and cancer.


Physiological basis of salt stress tolerance in rice expressing the antiapoptotic gene SfIAP.
Programmed cell death-associated genes, especially antiapoptosis-related genes have been reported to confer tolerance to a wide range of biotic and abiotic stresses in dicotyledonous plants such as tobacco (Nicotiana tabacum L.) and tomato (Solanum lycopersicum L.). This is the first time the antiapoptotic gene SfIAP was transformed into a monocotyledonous representative: rice (Oryza sativa L.). Transgenic rice strains expressing SfIAP were generated by the Agrobacterium-mediated transformation method and rice embryogenic calli, and assessed for their ability to confer tolerance to salt stress at both the seedling and reproductive stages using a combination of molecular, agronomical, physiological and biochemical techniques. The results show that plants expressing SfIAP have higher salt tolerance levels in comparison to the wild-type and vector controls. By preventing cell death at the onset of salt stress and maintaining the cell membrane's integrity, SfIAP transgenic rice plants can retain plant water status, ion homeostasis, photosynthetic efficiency and growth to combat salinity successfully.


Selective reminiscences of beta-lactam antibiotics: early research on penicillin and cephalosporins.
The discovery, made in Oxford, that crude penicillin could cure systemic and life-threatening bacterial infections was followed by attempts to purify penicillin, to determine its structure and then to produce it by total chemical synthesis. The beta-lactam structure of the molecule, first proposed in October 1943, was a source of controversy until 1945. However, no useful chemical synthesis was achieved and fermentation became the commercial source of the antibiotic. In 1953, one of the products of a Cephalosporium sp. from Sardinia was shown to be a new and hydrophilic penicillin (penicillin N). This was contaminated with a substance having the same side-chain but a characteristic absorption spectrum. The latter, cephalosporin C, showed antibacterial activity but was not inactivated by a penicillinase. The determination of its beta-lactam structure and isolation of its nucleus enabled pharmaceutical companies to produce many semisynthetic cephalosporins. A new tripeptide was later found to be an intermediate in the biosynthesis of both penicillin N and cephalosporin C, and this was followed by the complete elucidation of the biosynthetic pathways leading to these compounds and to benzylpenicillin.


Structure of the Hexadecane Rotator Phase: Combination of X-ray Spectra and Molecular Dynamics Simulation.
Rotator phases are rotationally disordered plastic crystals, some of which can form upon freezing of alkane at alkane-water interfaces. Existing X-ray diffraction studies show only partial unit cell information for rotator phases of some alkanes. This includes the rotator phase of n-hexadecane, which is a transient metastable phase in pure alkane systems, but shows remarkable stability at interfaces when mediated by a surfactant. Here, we combine synchrotron X-ray diffraction data and molecular dynamics (MD) simulations, reporting clear evidence of the face-centered orthorhombic RI rotator phase from spectra for two hexadecane emulsions, one stabilized by Brij C10 and another by Tween 40 surfactants. MD simulations of pure hexadecane use the recently developed Williams 7B force field, which is capable of reproducing crystal-to-rotator phase transitions, and it also predicts the crystal structure of the RI phase. Full unit cell information is obtained by combining unit cell dimensions from synchrotron data and molecular orientations from MD simulations. A unit cell model of the RI phase is produced in the crystallographic information file (CIF) format, with each molecule represented by a superposition of four rotational positions, each with 25% occupancy. Powder diffraction spectra computed using this model are in good agreement with the experimental spectra.


DNA fragmentation of spermatozoa and assisted reproduction technology.
Despite the ever-increasing knowledge of the fertilization process, there is still a need for better understanding of the causes of sperm DNA fragmentation and its impact on fertilization and pregnancy. For this reason, human sperm DNA fragmentation was investigated by means of the terminal deoxynucleotidyl transferase-mediated dUDP nick-end labelling (TUNEL) assay and the production of reactive oxygen species (ROS) in the ejaculate and in the spermatozoa themselves. These data were correlated with fertilization and pregnancy data from IVF and intracytoplasmic sperm injection (ICSI) patients. Sperm DNA fragmentation did not correlate with fertilization rate, but there was a significantly reduced pregnancy rate in IVF patients inseminated with TUNEL-positive spermatozoa. ICSI patients exhibited the same tendency. This implies that spermatozoa with damaged DNA are able to fertilize an oocyte, but at the time the paternal genome is switched on, further development stops. The determination of ROS in the ejaculate and the percentage of ROS-producing spermatozoa revealed markedly stronger correlations between sperm functions (i.e. motility) and the percentage of ROS-producing spermatozoa. The influence of seminal leukocytes, known to produce large amounts of oxidants, on sperm DNA fragmentation should not be neglected.


Metabolic Messengers: ketone bodies.
Prospective molecular targets and therapeutic applications for ketone body metabolism have increased exponentially in the past decade. Initially considered to be restricted in scope as liver-derived alternative fuel sources during periods of carbohydrate restriction or as toxic mediators during diabetic ketotic states, ketogenesis and ketone bodies modulate cellular homeostasis in multiple physiological states through a diversity of mechanisms. Selective signalling functions also complement the metabolic fates of the ketone bodies acetoacetate and D-β-hydroxybutyrate. Here we discuss recent discoveries revealing the pleiotropic roles of ketone bodies, their endogenous sourcing, signalling mechanisms and impact on target organs, and considerations for when they are either stimulated for endogenous production by diets or pharmacological agents or administered as exogenous wellness-promoting agents.


Long term outcomes of surgical revascularization for isolated left main coronary artery stenosis: a single-center surveillance study.
The objective of this study was to retrospectively analyze the clinical course and postoperative long-term survival of patients diagnosed with isolated left main coronary artery (LMCA) stenosis after surgical revascularization. A total of 38 patients (27 males, 11 females) who were diagnosed with isolated LMCA stenosis and underwent surgical revascularization were enrolled in the study. Isolated LMCA stenosis was classified into 2 groups: ostial stenosis and nonostial stenosis. Coronary events were defined as death of cardiac origin, the need for a new myocardial revascularization procedure, or the occurrence of myocardial infarction in the course of follow-up. The postoperative assessment period included short- and long-term follow-up. The study endpoint was defined as all-cause mortality. Among the 38 patients who participated in the study, 25 suffered from ostial LMCA stenosis. The early postoperative mortality rate before hospital discharge was 2.6%. Median duration of postoperative long-term follow-up was 73.43 months (range: 0.17-187.23). Median duration of long-term follow-up free from coronary events or percutaneous coronary interventions was 73.43 months. Postoperative 2-year survival rate was 97.4%, and 5-year survival rate was 92.1%. The postoperative survival period and period free of coronary events of patients with isolated ostial LMCA stenosis did not differ significantly from those of patients with nonostial stenosis (p=0.801, p=0.970, respectively). Postoperative short- and long-term prognosis of isolated LMCA stenosis appears good in terms of mortality and coronary event symptoms.


Soft-copy sonography: cost reduction sensitivity analysis in a pediatric hospital.
Our objective was to determine whether interpreting sonograms of pediatric patients using soft-copy (computer workstation) instead of laser-printed film could reduce costs for a pediatric radiology department. We used theoretic models of growth to analyze costs. The costs of a sonographic picture archiving and communication system (three interface devices, two workstations, a network server, maintenance expenses, and storage media costs) were compared with the potential savings of eliminating film and increasing technologist efficiency or reducing the number of technologists. The model was based on historic trends and future capitation estimates that will reduce fee-for-service reimbursement. The effects of varying the study volume and reducing technologists' work hours were analyzed. By converting to soft-copy interpretation, we saved 6 min 32 sec per examination by eliminating film processing waiting time, thus reducing examination time from 30 min to 24 min. During an average day of 27 examinations, 176 min were saved. However, 33 min a day were spent retrieving prior studies from long-term storage; thus, 143 extra minutes a day were available for scanning. This improved efficiency could result in five more sonograms a day obtained by converting to soft-copy interpretation, using existing staff and equipment. Alternatively, five examinations a day would equate to one half of a full-time equivalent technologists position. Our analysis of costs considered that the hospital's anticipated growth of sonography and the depreciation of equipment during 5 years resulted in a savings of more than $606,000. Increasing the examinations by just 200 sonograms in the first year and no further growth resulted in a savings of more than $96,000. If the number of sonograms stayed constant, elimination of film printing alone resulted in a loss of approximately $157,000; reduction of one half of a full-time equivalent technologist's position would recuperate approximately $134,000 of that loss. Soft-copy sonography can save money through improved technologist efficiency, thereby increasing the number of sonograms obtained and revenue generated. If the number of sonograms does not increase, elimination of printing costs and reduction of staff technologists will not result in a savings.


Benign smooth muscle tumours.
A series of 7748 leiomyomas of the whole body is presented. Ninety-five per cent of lesions occurrred in the female genital tract. Sixty-one of the remaining 371 were rejected because of inadequate histology or uncertainty as to exact site of origin. The 310 cases thus selected were analysed for histology, sex, race, site and age distributions. Comparisons are made between 230 skin lesions, 42 gastric lesions and 5 oral lesions. A further 43 cases of oral lesions were found in an extensive review of the world literature.


Fusion gene vectors allowing for simultaneous drug selection, cell labeling, and reporter assay in vitro and in vivo.
Vector systems allowing simultaneously for rapid drug selection, cell labeling, and reporter assay are highly desirable in biomedical research including stem cell biology. Here, we present such a vector system including pCVpf or pCVpr, plasmids that express pf or pr, a fusion protein between puromycin acetyltransferase and green or red fluorescent protein from CV, the human cytomegalovirus enhancer/promoter. Transfection with pCVpf or pCVpr produced a ∼10% efficiency of gene transfer. A 2-day pulse puromycin selection resulted in ∼13-fold enrichment for transgenic cells, and continuous puromycin selection produced stable transgenic stem cell clones with retained pluripotency. Furthermore, we developed a PAC assay protocol for quantification of transgene expression. To test the usefulness for cell labeling and PAC assay in vivo, we constructed pVASpf containing pf linked to the regulatory sequence of medaka germ gene vasa and generated transgenic fish with visible GFP expression in germ cells. PAC assay revealed the highest expression in the testis. Interestingly, PAC activity was also detectable in somatic organs including the eye, which was validated by fluorescence in situ hybridization. Therefore, the pf and pr vectors provide a useful system for simultaneous drug selection, live labeling, and reporter assay in vitro and in vivo.


Additive effect of epinephrine to timolol therapy in primary open angle glaucoma.
Previous studies have suggested that the effect on intraocular pressure resulting from the combined use of timolol and epinephrine might be different when they are administered hours rather than minutes apart. Fourteen patients were randomly assigned to one of two treatment sequences in which 1% epinephrine borate was added either five minutes or three hours after 0.5% timolol maleate. Combined therapy was continued for two weeks, after which epinephrine administration was stopped for a two-week washout period. The patient groups were then crossed over to the other dosage interval. There was an initial enhancement of pressure reduction when epinephrine was added to timolol in both sequences. After crossover, epinephrine was significantly additive to timolol in reducing pressure only when administered three hours after timolol. This additive effect was still present after three months of combined therapy.


Visual function, traumatic brain injury, and posttraumatic stress disorder.
Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are signature injuries of the Iraq and Afghanistan conflicts. The conditions can be comorbid and have overlapping signs and symptoms, making it difficult to diagnose and treat each. TBI is associated with numerous changes in vision function, but vision problems secondary to PTSD have not been documented. To address this shortcoming, we reviewed the medical records of 100 patients with a history of TBI, noting PTSD diagnoses, visual symptoms, vision function abnormalities, and medications with visual side effects. Forty-one patients had PTSD and 59 did not. High rates of binocular vision and oculomotor function deficits were measured in patients with a history of TBI, but no significant differences between patients with or without PTSD were evident. However, compared to patients without PTSD, patients with PTSD had more self-reported visual symptoms in all four assessments and the complaint rates were significantly higher for light sensitivity and reading problems. Together, these findings may be beneficial in understanding vision problems in patients with TBI and PTSD as comorbid conditions compared with those with TBI alone.


Connecting Smartphone and Wearable Fitness Tracker Data with a Nationally Used Electronic Health Record System for Diabetes Education to Facilitate Behavioral Goal Monitoring in Diabetes Care: Protocol for a Pragmatic Multi-Site Randomized Trial.
Mobile and wearable technology have been shown to be effective in improving diabetes self-management; however, integrating data from these technologies into clinical diabetes care to facilitate behavioral goal monitoring has not been explored. The objective of this paper is to report on a study protocol for a pragmatic multi-site trial along with the intervention components, including the detailed connected health interface. This interface was developed to integrate patient self-monitoring data collected from a wearable fitness tracker and its companion smartphone app to an electronic health record system for diabetes self-management education and support (DSMES) to facilitate behavioral goal monitoring. A 3-month multi-site pragmatic clinical trial was conducted with eligible patients with diabetes mellitus from DSMES programs. The Chronicle Diabetes system is currently freely available to diabetes educators through American Diabetes Association-recognized DSMES programs to set patient nutrition and physical activity goals. To integrate the goal-setting and self-monitoring intervention into the DSMES process, a connected interface in the Chronicle Diabetes system was developed. With the connected interface, patient self-monitoring information collected from smartphones and wearable fitness trackers can facilitate educators' monitoring of patients' adherence to their goals. Feasibility outcomes of the 3-month trial included hemoglobin A1c levels, weight, and the usability of the connected system. An interface designed to connect data from a wearable fitness tracker with a companion smartphone app for nutrition and physical activity self-monitoring into a diabetes education electronic health record system was successfully developed to enable diabetes educators to facilitate goal setting and monitoring. A total of 60 eligible patients with type 2 diabetes mellitus were randomized into either group 1) standard diabetes education or 2) standard education enhanced with the connected system. Data collection for the 3-month pragmatic trial is completed. Data analysis is in progress. If results of the pragmatic multi-site clinical trial show preliminary efficacy and usability of the connected system, a large-scale implementation trial will be conducted. ClinicalTrials.gov NCT02664233; https://clinicaltrials.gov/ct2/show/NCT02664233 (Archived by WebCite at http://www.webcitation.org/6yDEwXHo5).


Dexamethasone in children mechanically ventilated for lower respiratory tract infection caused by respiratory syncytial virus: a randomized controlled trial.
To determine the efficacy of dexamethasone in the treatment of mechanically ventilated children with respiratory syncytial virus-severe lower respiratory tract infection. International, multicenter, randomized, double-blind, placebo-controlled trial. Twelve pediatric intensive care units. Children (<2 yrs) mechanically ventilated for respiratory syncytial virus lower respiratory tract infection. Children were prestratified for severity of oxygen abnormalities on admission. Intravenous dexamethasone (0.6 mg/kg/day, 48 hrs) or placebo. A superiority approach was used in the subgroup of patients with mild oxygen abnormalities (arterial partial pressure of oxygen/fractional inspired oxygen concentration [PaO(2)/FIO(2)] >200 mm Hg and/or mean arterial pressure ≤10 cm H(2)O) and a noninferiority approach in those with severe oxygen abnormalities (PaO(2)/FIO(2) ≤200 mm Hg and mean arterial pressure >10 cm H(2)O). Primary outcome was the duration of mechanical ventilation. In the subgroup with mild oxygenation abnormalities, 45 of the 89 included patients received dexamethasone and 44 placebo; in the subgroup with severe oxygenation abnormalities, 28 of the 56 included patients received dexamethasone and 28 placebo. Baseline characteristics in both treatment arms were similar for both subgroups. After the third interim analysis, the trial was stopped early for futility taking the slow enrollment into account. At that time, the median duration (interquartile range) of mechanical ventilation was 137 (91-195) hrs in the dexamethasone- and 139 (117-188) hrs in the placebo-treated patients in the subgroup with mild oxygenation abnormalities (p = .6). In the subgroup with severe oxygenation abnormalities, it was 171 (136-212) hrs in the dexamethasone- and 170 (125-201) hrs in the placebo-treated patients (p = .6). In this prematurely ended trial in children mechanically ventilated for severe respiratory syncytial virus-lower respiratory tract infection, we found no evidence of a beneficial effect of dexamethasone in children with mild oxygenation abnormalities. Neither was evidence found that dexamethasone may prolong mechanical ventilation in those with severe oxygenation abnormalities.


[Content of mineral elements in the diet of students of physical education faculty].
Research of the diet of students of the Faculty of Physical Education found discrepancy of caloric content and correlation of macro- and micronutrients to physiological norms accompanied by a deficiency of some mineral elements. Thus, this research found discrepancy of a diet in caloric content and correlation of macro- and micronutrients to physiological norms. Calorie deficiency in both groups is caused for lack of all macro- and micronutrients, but mostly for lack of carbohydrates with an average glycemic index, fruit, and vegetables that have prebiotic properties and mineral-rich elements. Deficiency in the diet of young men 9.6% of the total protein and 23.5% of carbohydrates was accompanied for lack 15.5% of calcium. In the group of girls the results showed a decrease of the required amounts of calcium, magnesium and iron of 36.4; 7.5 and 1.5% respectively, which was displayed against a background of reducing the consumption of the total protein 25.1 and 36.0% of carbohydrates. As a result, basic nutrition of students practicing sports requires rationalization and adjustment. To improve the biological value of the diet it is advisable for students to use daily dairy products and other sources of animal protein in their diets. It is also necessary to introduce fruit and vegetables as a source of dietary fibers and mineral elements. Created in both groups deficiency of calcium and biologically high-grade proteins of animal origin can be eliminated by various dairy products in which calcium and phosphorus are in easily digestible form and in a balanced quantity. Despite the considerable amount of calcium in many foods (meat, bread, cereals, vegetables) calcium is assimilated with difficulty from these products. The exception is the calcium of milk, curd, cheese and other dairy products. The ration between calcium and phosphorus in milk is 1:1-1.4:1. For example, taking 0.5 liters of milk provides 600 mg of assimilable calcium intake.


Historical claims and current interpretations of replicative aging.
Replicative aging is the process by which most normal human cells "count" the number of times they have divided, eventually undergoing a growth arrest termed cellular senescence. This process is dependent on the shortening of telomeres, repeated sequences at the ends of the chromosomes. The loss of telomeric sequences with each cell division eventually induces a growth arrest that has a similar phenotype to that of cells stressed by inadequate culture or other conditions. Experiments over the past several years have identified species in which replicative aging does not occur and many examples in which a failure to proliferate has been misinterpreted as replicative senescence. Insights from these studies now permit a reevaluation of much of the seemingly contradictory data concerning replicative aging. There are good theoretical reasons for believing a limited proliferative capacity contributes to declining tissue homeostasis with increasing age. Although the presence of telomere shortening provides strong circumstantial evidence that replicative aging is occurring in vivo, thus far there is only very limited direct evidence for actual physiological effects of replicative aging.


[Gestagens and the brain].
Modern data on molecular mechanisms underlying intracerebral pleutropic action ofgestagens (progesterone, its metabolites, and synthetic gestagens) are reviewed. Properties of classical and membrane-bound progesterone receptors involved in regulation of gene expression, modulation of neurotransmitter systems, and activation of signal cascades in neurons are described along with data of regional distribution of progesterone receptor subtypes in brain, metabolism, functional activity, and mechanisms of action of progesterone metabolites. Special attention is given to analysis of progesterone and metabolite neuroprotective activity in CNS, such as anti-inflammatory and antiapoptotic effects, and participation in neurogenesis regulation. Clinical application of progesterone-based drugs is discussed with reference to the treatment of brain injuries and prospects for extension of indications for their use in neurologic practice.


Mussel-inspired adhesive protein-based electrospun nanofibers reinforced by Fe(iii)-DOPA complexation.
Marine mussels utilize multiple bidentate complexes formed by Fe(iii) and DOPA in a mussel adhesive protein (fp-1) to reinforce tough and elastic byssal fibers as a specialized underwater adhesive aid. In this study, mussel-inspired electrospun nanofibers were fabricated using a recombinant mussel adhesive protein (rfp-1), Fe(iii)-DOPA complexes, and polycaprolactone. The mechanical properties of the fabricated nanofibers were reinforced by the Fe(iii)-DOPA complex found in fp-1, which is a key component of the naturally occurring high-performance mussel fiber coating. Experimental results show that the stoichiometry of Fe(iii)-DOPA complexes in the nanofibers could be controlled by buffer pH conditions and the stiffness of the nanofiber mat increased linearly with the concentration of the Fe(iii)-DOPA complexes, as monitored by resonance Raman spectroscopy. This suggests the potential of Fe(iii)-DOPA complexation as an effective strategy for modulating the mechanical properties of nanofibrous biomedical materials by using pH variations.


Recombinant bovine somatotropin (rbST) administration to creep-fed beef calves increases muscle mass but does not affect satellite cell number or concentration of myosin light chain-1f mRNA.
Our objective in this study was to determine the effect of recombinant bovine somatotropin (rbST) on indices of muscle development in creep-fed beef calves. Crossbred steer calves were assigned to one of two treatment groups: control (sham-injected; n = 12) or rbST-treated (.09 mg x kg(-1) x d(-1); n = 12). Calves were injected every 14 d starting at d 28 of age and were weaned at 205 d of age. Supplemental creep feed was supplied free access to all calves to compensate for an expected increased protein and energy requirement in calves given rbST. Biopsy (d 100) and slaughter (d 206) samples of semitendinosus muscle were evaluated for satellite cell, myofiber nuclei numbers, and myosin light chain (MLC-1f) mRNA quantification. Myofiber nuclei and satellite cell numbers per 100 myofibers and MLC-1f mRNA:rRNA ratios at 100 and 206 d of age were not different (P > .10) between control and rbST-treated calves. Total gain, ADG, quality grade, femur length, percentage kidney, pelvic, and heart fat, dressing percentage, plasma IGF-I, and plasma urea nitrogen concentrations did not differ (P > .10) between control and rbST-treated calves. However, rbST-treated calves had larger longissimus muscle areas (P < .03), less marbling (P < .001), higher carcass conformation scores (P < .04), greater mass of separated muscle (P < .03), more ground meat (P < .01), and heavier carcass weights (P < .05) than control calves. Thus, rbST treatment increased muscle characteristics while nuclei number and MLC-1f mRNA concentrations remained the same, implying that the additional muscle growth was in a normal fashion.


Secondhand smoke exposure among women and children: evidence from 31 countries.
We sought to describe the range of exposure to secondhand smoke (SHS) among women and children living with smokers around the world and generate locally relevant data to motivate the development of tobacco control policies and interventions in developing countries. In 2006, we conducted a cross-sectional exposure survey to measure air nicotine concentrations in households and hair nicotine concentrations among nonsmoking women and children in convenience samples of 40 households in 31 countries. Median air nicotine concentration was 17 times higher in households with smokers (0.18 mug/m(3)) compared with households without smokers (0.01 mug/m(3)). Air nicotine and hair nicotine concentrations in women and children increased with the number of smokers in the household. The dose-response relationship was steeper among children. Air nicotine concentrations increased an estimated 12.9 times (95% confidence interval=9.4, 17.6) in households allowing smoking inside compared with those prohibiting smoking inside. Our results indicate that women and children living with smokers are at increased risk of premature death and disease from exposure to SHS. Interventions to protect women and children from household SHS need to be strengthened.