Longitudinal follow-up of oxidative stress and DNA damage parameters in detergent workers.
The aim of this study was the follow-up of work place enzyme and detergent dust exposure effects and smoking habit on DNA damage parameters of workers and the evaluation of their antioxidant enzyme activities and lipid peroxidation with regard to bag-filter installation in the work place. All investigated parameters were studied in a group of 153 workers of enzyme-free detergent production plant (E-free) and a group of 138 workers of enzyme-plus detergent plant (E-plus) and compared with 45 controls 7.2 years before and 3.1 years after filter system installation. The following methods were used: antioxidant enzymes by an ultraviolet-visibles spectrophotometer, malondialdehyde (MDA), 8-hydroxy-2'deoxyguanosine (8OH-2'dG) by high-performance liquid chromatography, trace elements by atomic absorption spectroscopy, and comet assay by single cell gel electrophoresis. Compared with controls, significant increases were observed in both detergent-exposed groups with respect to the levels of MDA, antioxidant enzyme activities, and DNA damage parameters, including 8OH-2'dG, endonuclease III-sensitive sites, and DNA strand breaks, with enhancement effect of smoking before filter system installation. After filter installation, besides significant decrease in the detergent and enzyme dust of airborne and oxidative stress indicators, there was improvement in all DNA damage investigated parameters at the end of this study. The levels of cumulative exposure index of detergent dusts decreased significantly after airborne improvement and showed positive correlation with internal biochemical parameters. We concluded that high levels of enzyme and detergent contents of work place dusts had a cumulative effect and smoking had a synergistic effect on the imbalance of antioxidant status and lipid peroxidation, suggesting that oxidation stress is important in the occurrence and progression of DNA damage over this study. Detergent and enzyme contents in respirable and total dust had the main role and sufficient potential in their genotoxicity.


Tools in the Design of Therapeutic Drugs for CNS Disorders: An up-to-date Review.
The brain is a vital part of the central nervous system (CNS), characterized by the presence of soft tissue in its internal structure which protects itself. Research on design of drugs for CNS disorders is in progress and up to date information is required for further investigation. The present paper is written with the objective to compile all the available data and information on CNS disorders and CNS acting drugs. CNS acting drugs are important to consider because some drugs get ineffective owing to incapability to efficiently deliver and sustain them within the brain for effective treatment. The current trend to design therapeutic drugs for CNS disorders focuses on neurotransmitters release and their reuptake, including Parkinson's, Alzheimer's, and other CNS disorders. The disorders associated with CNS are characterized by the progressive loss of gray matter and/or white matter structures. CNS stimulants are the class of drugs, producing response to alleviate a particular medical condition. CNS stimulants improve the brain function in patients with schizophrenia and related diseases. CNS stimulants are a class of therapeutic drugs used to treat CNS disorder including the conditions like lack of adrenergic stimulation, symptoms of narcolepsy and neonatal apnea, etc. Apart from drugs, a number of smart tools including Multi-Target Designed Ligands (MTDL) and "predictor" models are contemporarily used to design therapeutic agents for CNS disorders. The majority of CNS stimulants causes stimulation of the traditional "fight or flight" syndrome which is concerned with activation of sympathetic nervous system. These neurotransmitters associated receptors are concerned in drug abuse and addiction withdrawal related phenomenon. The present review embarks on detail up-to-date information on CNS stimulant drugs, their mechanism of action, in vivo models for biological evaluations with major emphasis on tools in design of therapeutic drugs for CNS disorders.


Instabilities in the Early Solar System due to a Self-gravitating Disk.
Modern studies of the early solar system routinely invoke the possibility of an orbital instability among the giant planets triggered by gravitational interactions between the planets and a massive exterior disk of planetesimals. Previous works have suggested that this instability can be substantially delayed (~100s Myr) after the formation of the giant planets. Bodies in the disk are typically treated in a semi-active manner, wherein their gravitational force on the planets is included, but interactions between the planetesimals are ignored. We perform N-body numerical simulations using GENGA, which makes use of GPUs to allow for the inclusion of all gravitational interactions between bodies. Although our simulated Kuiper belt particles are more massive than the probable masses of real primordial Kuiper belt objects, our simulations indicate that the self-stirring of the primordial Kuiper belt is very important to the dynamics of the giant planet instability. We find that interactions between planetesimals dynamically heat the disk and typically prevent the outer solar system instability from being delayed by more than a few tens of million years after giant planet formation. Longer delays occur in a small fraction of systems that have at least 3.5 AU gaps between the planets and planetesimal disk. Our final planetary configurations match the solar system at a rate consistent with other previous works in most regards. Pre-instability heating of the disk typically yields final Jovian eccentricities comparable to the modern solar system value, which has been a difficult constraint to match in past works.


Crystallization of methyl ammonium lead halide perovskites: implications for photovoltaic applications.
Hybrid organic/lead halide perovskites are promising materials for solar cell fabrication, resulting in efficiencies up to 18%. The most commonly studied perovskites are CH3NH3PbI3 and CH3NH3PbI3-xClx where x is small. Importantly, in the latter system, the presence of chloride ion source in the starting solutions used for the perovskite deposition results in a strong increase in the overall charge diffusion length. In this work we investigate the crystallization parameters relevant to fabrication of perovskite materials based on CH3NH3PbI3 and CH3NH3PbBr3. We find that the addition of PbCl2 to the solutions used in the perovskite synthesis has a remarkable effect on the end product, because PbCl2 nanocrystals are present during the fabrication process, acting as heterogeneous nucleation sites for the formation of perovskite crystals in solution. We base this conclusion on SEM studies, synthesis of perovskite single crystals, and on cryo-TEM imaging of the frozen mother liquid. Our studies also included the effect of different substrates and substrate temperatures on the perovskite nucleation efficiency. In view of our findings, we optimized the procedures for solar cells based on lead bromide perovskite, resulting in 5.4% efficiency and Voc of 1.24 V, improving the performance in this class of devices. Insights gained from understanding the hybrid perovskite crystallization process can aid in rational design of the polycrystalline absorber films, leading to their enhanced performance.


Evidence that genomic and antigenomic RNA self-cleaving elements from hepatitis delta virus have similar secondary structures.
The two sequences that define the self-cleaving elements from the genomic and antigenomic RNA of hepatitis delta virus were folded into secondary structures with similar features. Evidence in support of the two models was obtained from limited ribonuclease digestion of genomic and antigenomic RNA fragments containing the sequence 3' of the cleavage site. Under conditions where the rates of self-cleavage are enhanced by addition of 5 M urea (2-10 mM Mg2+ at 37 degrees C), ribonucleases T1, U2, A and V1 generated digestion patterns consistent with the proposed RNA structures. The evidence for a relatively stable structure in urea when Mg2+ is present suggests that denaturant-enhanced rates of self-cleavage could result from destabilization of competing inactive structures.


Dual versus triple therapy in patients on oral anticoagulants and undergoing coronary stent implantation: A systematic review and meta-analysis.
There is contrasting evidence regarding the optimal antithrombotic regimen after percutaneous coronary stent implantation in patients on oral anticoagulants. A systematic review and meta-analysis was performed to explore the comparative efficacy and safety of dual (an antiplatelet plus an oral anticoagulant) versus triple therapy (dual antiplatelet therapy plus an oral anticoagulant). We searched the literature for randomized controlled trials (RCTs) or observational studies (OSs) addressing this issue. The efficacy outcomes were all-cause mortality, cardiovascular mortality, myocardial infarction and stent thrombosis. The safety outcomes were major bleeding events and all bleeding events. The analyses were stratified by type of anticoagulant and of antiplatelet used in dual therapy. Four RCTs and ten OSs met our inclusion criteria including a total of 10,126 patients. 5671 patients received triple therapy whereas 4455 received dual therapy. Median follow up was 12 months. There was no difference between dual therapy and triple therapy regarding efficacy outcomes. Dual therapy significantly reduced the risk of major bleeding (RR 0.66; CI 95% 0.52-0.83; P = 0.0005) and of all bleeding events (RR 0.67, CI 95% 0.55-0.80; P < 0.0001). The effect was consistent regardless of the type of antiplatelet and anticoagulant used in dual therapy. Dual antithrombotic therapy after coronary stenting in anticoagulated patients significantly reduces bleeding events compared with triple therapy. Dual therapy might be considered in this setting especially when bleeding risk outweighs ischemic risk, although our study was not sufficiently powered to detect a difference in ischemic endpoints.


Fiber/Yarn-Based Triboelectric Nanogenerators (TENGs): Fabrication Strategy, Structure, and Application.
With the demand of a sustainable, wearable, environmentally friendly energy source, triboelectric nanogenerators (TENGs) were developed. TENG is a promising method to convert mechanical energy from motion into electrical energy. The combination of textile and TENG successfully enables wearable, self-driving electronics and sensor systems. As the primary unit of textiles, fiber and yarn become the focus of research in designing of textile-TENGs. In this review, we introduced the preparation, structure, and design strategy of fiber/yarn TENGs in recent research. We discussed the structure design and material selection of fiber/yarn TENGs according to the different functions it realizes. The fabrication strategy of fiber/yarn TENGs into textile-TENG are provided. Finally, we summarize the main applications of existing textile TENGs and give forward prospects for their subsequent development.


Functional profiling of the G protein-coupled receptor C3aR1 reveals ligand-mediated biased agonism.
G protein-coupled receptors (GPCRs) are leading druggable targets for several medicines, but many GPCRs are still untapped for their therapeutic potential due to poor understanding of specific signaling properties. The complement C3a receptor 1 (C3aR1) has been extensively studied for its physiological role in C3a-mediated anaphylaxis/inflammation, and in TLQP-21-mediated lipolysis, but direct evidence for the functional relevance of the C3a and TLQP-21 ligands and signal transduction mechanisms are still limited. In addition, C3aR1 G protein coupling specificity is still unclear, and whether endogenous ligands, or drug-like compounds, show ligand-mediated biased agonism is unknown. Here, we demonstrate that C3aR1 couples preferentially to Gi/o/z proteins and can recruit β-arrestins to cause internalization. Furthermore, we showed that in comparison to C3a63-77, TLQP-21 exhibits a preference toward Gi/o-mediated signaling compared to β-arrestin recruitment and internalization. We also show that the purported antagonist SB290157 is a very potent C3aR1 agonist, where antagonism of ligand-stimulated C3aR1 calcium flux is caused by potent β-arrestin-mediated internalization. Finally, ligand-mediated signaling bias impacted cell function as demonstrated by the regulation of calcium influx, lipolysis in adipocytes, phagocytosis in microglia, and degranulation in mast cells. Overall, we characterize C3aR1 as a Gi/o/z-coupled receptor, and demonstrate functional relevance of ligand-mediated signaling bias in key cellular models. Due to C3aR1 and its endogenous ligands being implicated in inflammatory and metabolic diseases, these results are of relevance toward future C3aR1 drug discovery.


Intra-Articular Cellular Therapy for Osteoarthritis and Focal Cartilage Defects of the Knee: A Systematic Review of the Literature and Study Quality Analysis.
Intra-articular cellular therapy injections constitute an appealing strategy that may modify the intra-articular milieu or regenerate cartilage in the settings of osteoarthritis and focal cartilage defects. However, little consensus exists regarding the indications for cellular therapies, optimal cell sources, methods of preparation and delivery, or means by which outcomes should be reported. We present a systematic review of the current literature regarding the safety and efficacy of cellular therapy delivered by intra-articular injection in the knee that provided a Level of Evidence of III or higher. A total of 420 papers were screened. Methodological quality was assessed using a modified Coleman methodology score. Only 6 studies (4 Level II and 2 Level III) met the criteria to be included in this review; 3 studies were on treatment of osteoarthritis and 3 were on treatment of focal cartilage defects. These included 4 randomized controlled studies without blinding, 1 prospective cohort study, and 1 retrospective therapeutic case-control study. The studies varied widely with respect to cell sources, cell characterization, adjuvant therapies, and assessment of outcomes. Outcome was reported in a total of 300 knees (124 in the osteoarthritis studies and 176 in the cartilage defect studies). Mean follow-up was 21.0 months (range, 12 to 36 months). All studies reported improved outcomes with intra-articular cellular therapy and no major adverse events. The mean modified Coleman methodology score was 59.1 ± 16 (range, 32 to 82). The studies of intra-articular cellular therapy injections for osteoarthritis and focal cartilage defects in the human knee suggested positive results with respect to clinical improvement and safety. However, the improvement was modest and a placebo effect cannot be disregarded. The overall quality of the literature was poor, and the methodological quality was fair, even among Level-II and III studies. Effective clinical assessment and optimization of injection therapies will demand greater attention to study methodology, including blinding; standardized quantitative methods for cell harvesting, processing, characterization, and delivery; and standardized reporting of clinical and structural outcomes. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Discussing adjuvant cancer therapy.
To document the adequacy of patient information in oncology consultations concerning adjuvant therapy and explore predictors of physician communication patterns, treatment decisions, patient information recall, and satisfaction. Retrospective analysis of audiotapes and verbatim transcripts of 101 initial adjuvant therapy consultations with medical and radiation oncologists was undertaken. Content analysis, data on communication patterns, treatment decisions, patient anxiety, satisfaction, and information recall were collected. Predictors of physician communication, treatment decisions, recall, and satisfaction with the consultation were identified. The majority of patients were well informed of their prognosis, benefits and risks of therapy, and alternative management options. Only half were asked about preferences for information or decision-making involvement. Predictors of information detail given include patient sex, age, occupation, and education. Radiation and medical oncologists express prognosis and treatment benefit using similar phrases. When offered the chance to delay decision-making, most patients do so (P <.01). Final treatment decisions appear to be influenced by the presentation of choice in treatment options by the oncologist and whether the treatment decision was made during the initial consultation (P <.01). Information recall was not influenced by communication factors. Patients receiving less detailed information had slightly higher satisfaction with the consultation (P =.03). More anxious patients tended to be less satisfied (P =.07). The optimal way to discuss adjuvant therapy is undefined. More emphasis can be placed on soliciting patient preferences for information and decision-making involvement and tailoring both to the needs of the individual patient. Providing choice in treatment and delaying decision-making may affect the patient's treatment decision.


Polymerase chain reaction in diagnosis of Borrelia burgdorferi infections and studies on taxonomic classification.
Lyme borreliosis caused by the spirochete Borrelia burgdorferi is now the most common vectorborne disease in North America, Europe and Asia. It is a multisystemic infection which may cause skin, neurological, cardiac or rheumatologic disorders. The aims of the present thesis were: (i) to develop a PCR assay for direct detection of B. burgdorferi DNA and to evaluate the diagnostic utility of PCR in clinical specimens from patients with Lyme borreliosis and (ii) to study the taxonomic classification of B. burgdorferi isolates and its implications for epidemiology and clinical presentation. Laboratory diagnosis of Lyme borreliosis by direct demonstration of B. burgdorferi in clinical specimens would compared to current serology allow (i) optimal specificity, (ii) increased sensitivity during the first weeks of infection, when the antibody response is not yet detectable and (iii) discrimination between ongoing and past infection. Due to the extreme paucity of spirochetes in clinical specimens neither in vitro culture nor antigen detection had yielded a sufficient diagnostic sensitivity. Thus the recently introduced highly sensitive PCR methodology could be a solution and was thus studied. Assays for PCR amplification and subsequent identification of B. burgdorferi specific sequences were established and used. For all assays the analytical sensitivity was a few genome copies using purified DNA as template. The efficacy of PCR was initially evaluated using tissue samples from experimentally infected gerbils in order to start with biological samples a priori known to contain B. burgdorferi. B. burgdorferi DNA was detectable in 88% of the specimens. Thus the diagnostic sensitivity of PCR was comparable to and even higher than in vitro culture. PCR was significantly more sensitive than a histological B. burgdorferi specific immunophosphatase-staining method. The utility of the PCR was then tested for identification of B. burgdorferi DNA in skin biopsies from 31 patients with erythema migrans. The sensitivity of PCR was 71%, which was superior to culture and serology. Based on own and otherwise published results there is clear evidence for PCR being the most sensitive and specific test for detection of B. burgdorferi in skin biopsies from patients with both early and late dermatoborreliosis. However, since the clinical diagnosis of dermatoborreliosis in most instances is easy, an invasive procedure as a skin biopsy, will only be justified in patients with an atypical clinical presentation. The most frequent and serious manifestation of disseminated Lyme borreliosis is neuroborreliosis. PCR was applied to 190 patients with untreated and confirmed neuroborreliosis. B. burgdorferi DNA was detectable in 17-21% of CSF samples from patients with neuroborreliosis. In patients with very early neuroborreliosis (< 2 weeks), still being negative for specific intrathecal antibody synthesis, a positive PCR was more frequent than in patients with longer disease duration. PCR can be used as a diagnostic aid in these patients. However, in general the measurement of specific intrathecal antibody production in patients with neuroborreliosis was superior to PCR. In urine samples from patients with Lyme borreliosis the diagnostic sensitivity varied, generally showing a low reproducibility. Urine is thus not regarded as a suitable sample source for B. burgdorferi PCR. The reason may be the variable presence of Taq polymerase inhibitors. Based on a semi-quantitative detection system for amplicons, reflecting the input amount of specific DNA and thus the density of spirochetes in the clinical samples high amounts of DNA were found in skin biopsies whereas especially in urine the amount of DNA was low. When the present study was initiated there was no accepted classification of B. burgdorferi. A heterogeneity among B. burgdorferi strains might have important implications for understanding the epidemiology and different clinical presentations (dermatoborreliosis versus neuroborreliosis) and courses (self-limiting versus chronic disease). Furthermore, strain differences were of importance for selection of suitable antigens for diagnostic assays and for vaccine development. Since then, B. burgdorferi isolates have been studied by phenotypic and genotypic traits and have been shown to be highly heterogeneous. Our first approach was to genotype a panel of human B. burgdorferi isolates by restriction fragment length polymorphism (RFLP) of three genes. Thereafter, sequencing and dideoxy fingerprinting of ospA was applied. By RFLP the strains could be differentiated into two to five groups. The RFLP classification was compared with four different phenotypic and genotypic methods including the rRNA typing. Results obtained with the different methods correlated highly and confirmed the meanwhile accepted taxonomic classification by Baranton et al., According to this the term B. burgdorferi sensu lato comprises three different human pathogenic genospecies B. burgdorferi sensu stricto, B. garinii and B. afzelii. All three genospecies have been isolated among Danish patients with Lyme borreliosis and are thus prevalent in Denmark. Since isolation of B. burgdorferi from patients with Lyme borreliosis is laborious and often unsuccessful molecular typing methods based on PCR are recommended obviating the need for isolation by prior culture. Of special interest was to study a possible association of neuroborreliosis to certain B. burgdorferi genospecies, indicating species depended organotropism. By RFLP all six CSF isolates tested belonged to B. garinii and that 6 out of 7 isolates from patients with acrodermatitis chronica atrophicans belonged to B. afzelii. Due to the low culture yield of B. burgdorferi from CSF, the association of B. garinii and neuroborreliosis was further studied by sequence analysis and dideoxyfingerprinting analysis of ospA PCR amplicons obtained from CSF samples from patients with neuroborreliosis. Phylogenetic analysis showed that in 11 out of 13 patients B. garinii DNA was found in CSF. These data strongly supports the hypothesis that B. garinii is the principal agent of Lyme neuroborreliosis in Europe. Similarly it was shown that B. afzelii is associated with acrodermatitis chronica atrophicans and thus dermatoborreliosis. Due to a strain dependent different selection pressure in culture only PCR based methods can be used to answer whether mixed infection in patients specimens occur. Our data indicate that mixed infections in humans if ever are rare.


Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti-parkinsonian drug receptor signaling.
Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through beta-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human beta-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying beta-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating beta-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced beta-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most anti-psychotics are incapable of stimulating beta-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling.


A millennial myosin census.
The past decade has seen a remarkable explosion in our knowledge of the size and diversity of the myosin superfamily. Since these actin-based motors are candidates to provide the molecular basis for many cellular movements, it is essential that motility researchers be aware of the complete set of myosins in a given organism. The availability of cDNA and/or draft genomic sequences from humans, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Dictyostelium discoideum has allowed us to tentatively define and compare the sets of myosin genes in these organisms. This analysis has also led to the identification of several putative myosin genes that may be of general interest. In humans, for example, we find a total of 40 known or predicted myosin genes including two new myosins-I, three new class II (conventional) myosins, a second member of the class III/ninaC myosins, a gene similar to the class XV deafness myosin, and a novel myosin sharing at most 33% identity with other members of the superfamily. These myosins are in addition to the recently discovered class XVI myosin with N-terminal ankyrin repeats and two human genes with similarity to the class XVIII PDZ-myosin from mouse. We briefly describe these newly recognized myosins and extend our previous phylogenetic analysis of the myosin superfamily to include a comparison of the complete or nearly complete inventories of myosin genes from several experimentally important organisms.


Structure and expression of myelin basic protein gene sequences in the mld mutant mouse: reiteration and rearrangement of the MBP gene.
The mld mutation on chromosome 18 in the mouse is a putative allele of the shiverer (shi) mutation. We have analyzed the structure of myelin basic protein (MBP) gene sequences in mld DNA by restriction mapping of genomic DNA. The results indicate that the mld chromosome carries two copies of the MBP structural gene, one of which is intact and one of which is interrupted. Genetic analysis indicates that the interrupted gene is close to the intact MBP structural gene and cosegregates with the mld mutation. We have also analyzed the levels of MBP polypeptides and MBP-specific mRNA in wild-type, homozygous and heterozygous shiverer and mld mice and in mice carrying both mutations. The results indicate that both shi and mld are cis-acting codominant mutations that cause severely reduced steady state levels of MBP-specific mRNA and MBP polypeptides in the brain. We have analyzed the total number of oligodendrocytes and the number of MBP-positive oligodendrocytes in mld and shi brain primary cultures. In shi cultures, none of the oligodendrocytes expresses MBP. However, in mld cultures, approximately 5% of the oligodendrocytes express MBP. The nature of the "revertant" mld oligodendrocytes is not known.


Decreased number and impaired functionality of endothelial progenitor cells in subjects with metabolic syndrome: implications for increased cardiovascular risk.
Metabolic syndrome (MetS) is characterized by low-grade inflammation and confers an increased risk for cardiovascular disease. Endothelial progenitor cells (EPCs) are a measure of vascular health and are decreased in patients with various risk factors for cardiovascular disease (CVD). There is a paucity of data examining the EPC status especially in terms of their functionality in MetS subjects without diabetes or cardiovascular disease. We aimed to enumerate and functionally characterize EPCs in subjects with MetS in comparison to healthy controls. The study was performed at the University of California Davis Medical Center. Healthy controls (n=31) and MetS (n=46) subjects were included in the study. EPCs were enumerated in fasting blood by KDR/CD34 dual positivity. Functionality was assessed by the colony forming units (CFU) assay, migration and tubule formation. Subjects with MetS had significantly decreased number of EPCs compared to control subjects. Furthermore, EPCs from MetS subjects depicted significantly impaired clonogenic capacity, i.e., decreased colony forming units, and impaired capacity to incorporate into tubular structures suggesting functional impairment of EPCs from MetS subjects. We make the novel observation that MetS subjects without diabetes or CVD have decreased EPC number and impaired functionality as compared to control subjects. These findings could contribute to the increased CV risk in this population.


The permeability of rat transitional epithelium. Kertinization and the barrier to water.
Permeability barriers must exist in transitional epithelium to prevent the free flow of water from underlying blood capillaries through the epithelium into the hypertonic urine, and such a barrier has now been demonstrated in isolated bladders. This barrier is passive in function and can be destroyed by damaging the luminal surface of the transitional epithelium with sodium hydroxide and 8 M urea solutions, by digesting it with trypsin, lecithinase C, and lecithinase D, or by treating it with lipid solvents such as Triton x 100 and saponin. From this it is concluded that the barrier depends on the integrity of lipoprotein cell membranes. The barrier function is also destroyed by sodium thioglycollate solutions, and electron microscope investigations show that sodium thioglycollate damages the thick asymmetric membrane which limits the luminal face of the superficial squamous cell. Cytochemical staining shows the epithelium to contain disulfide and thiol groups and to have a concentration of these groups at the luminal margin of the superficial cells. It thus appears that the permeability barrier also depends on the presence of disulfide bridges in the epithelium, and it is presumed that these links are located in keratin. Because of the effect of thioglycollates, both on the barrier function and on the morphology of the membrane, it is suggested that keratin may be incorporated in the thick barrier membrane. It is proposed that the cells lining the urinary bladder and ureters should be regarded as a keratinizing epitheluim.


ICU incident reporting systems.
Intensive care is one of the largest and most expensive components of American health care. Studies suggest that errors and resulting adverse events are common in intensive care units (ICUs). The incidence may be as high as 2 errors per patient per day; 1 in 5 ICU patients may sustain a serious adverse event, and virtually all are exposed to serious risk for harm. Theories of error developed in aviation and other high-risk industries suggest that errors are likely to occur in all complex systems. Reporting of incidents, including both adverse events and near misses, is an essential component for improving safety. Voluntary, confidential reporting is likely to be more important than mandatory reporting. There have been a few efforts to apply such systems in medicine. In intensive care, the Australian Incident Monitoring System (AIMS)-ICU has been the most prominent. We have designed a Web-based ICU Safety Reporting System (ICUSRS). The goal is to identify high-risk situations and working conditions, to help change systems, and reduce the risk for error. The analysis and feedback of reports will inform the design of interventions to improve patient safety. The effort is aided substantially by collaboration with the 30 participating ICUs and important stakeholders including the Society of Critical Care Medicine, the American Society for Health-care Risk Management, the Food and Drug Administration Center for Devices and Radiological Health, the Foundation for Accountability, and the Leapfrog Group. A demonstration and evaluation of the system is underway, funded by the Agency for Healthcare Re-search and Quality.


Wistar Kyoto rats exhibit decreased serotonin neuronal firing and increased norepinephrine burst activity but dampened hippocampal α2-adrenoceptor sensitivity.
Wistar Kyoto (WKY) rats manifest abnormalities in the function of monoamine receptors and transporters, as well as levels of these neurotransmitters in the brain. The present study assessed alterations in the firing activity of serotonin (5-hydroxytryptamine [5-HT]), norepinephrine (NE), and dopamine (DA) neurons, as well as the activity of 5-HT and NE receptors and transporters in the hippocampus. In vivo electrophysiological recordings were conducted in male WKY and Wistar rats. Extracellular single-unit recordings of 5-HT, NE, and DA neurons were performed. Recordings of pyramidal neurons were conducted in the medial prefrontal cortex (mPFC) and the hippocampus, where direct application of 5-HT and NE by iontophoresis was also carried out. The mean firing rate of 5-HT neurons was significantly decreased in WKY compared to Wistar rats. The burst activity of NE neurons was significantly increased in WKY, while their mean firing activity was not changed. There was no alteration in the firing, burst, and population activity of DA neurons in WKY animals. In the hippocampus, a decrease in sensitivity of α2-adrenoceptors, but not 5-HT receptors, was observed. There was, however, no change in the activity of 5-HT and NE transporters. The firing activity of mPFC pyramidal neurons was similar in WKY versus Wistar rats. In WKY rats, there was a decrease in the firing activity of 5-HT neurons. There was also an enhanced burst activity of NE neurons, accompanied by a reduction in sensitivity of the α2-adrenoceptor in the hippocampus, inferring a decrease in NE transmission.


Quantitative Analysis of UDP-Glucuronosyltransferase Ugt1a and Ugt2b mRNA Expression in the Rat Liver and Small Intestine: Sex and Strain Differences.
UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation of numerous endogenous and exogenous compounds to facilitate their excretion from the body. Because rats are commonly used in nonclinical studies, information regarding UGT species differences between rats and humans would be helpful for understanding human pharmacokinetics. In this study, we determined the absolute mRNA expressions of Ugt isoforms in the liver and small intestine of male and female Sprague-Dawley, Fischer 344, and Wistar rats. The sum of the mRNA levels of Ugt isoforms expressed in the liver was significantly (P < 0.005) higher than that in the small intestine regardless of the strain and sex. Ugt2b mRNA levels represented approximately 80% of total Ugt mRNA levels in the liver, whereas Ugt1a mRNA levels accounted for almost 90% in the small intestine. Ugt2b2 mRNA was specifically expressed in Wistar rat liver, resulting in 2-fold higher expression of total hepatic Ugt mRNA in Wistar rats than that in the other strains. Wistar rats showed prominently higher Ugt2b3 and Ugt2b8 mRNA levels in the small intestine than the other strains. The difference between sexes was remarkable with regard to hepatic Ugt1a10 in any of the strains, although slight differences between sexes were also observed in multiple Ugt isoforms. Taken together, this study revealed sex and strain differences in mRNA levels of rat Ugts. The data shown here would be useful for the selection of rat strains in nonclinical studies.


New ischemic brain lesions on diffusion-weighted MRI after carotid artery stenting with filter protection: frequency and relationship with plaque morphology.
CAS carries an inherent risk of distal cerebral embolization, precipitating new brain ischemic lesions and neurologic symptoms. Our purpose was to evaluate the frequency of new ischemic lesions found on DWI after protected CAS placement and to determine its association with plaque morphology. Fifty patients (mean age 65.13 ± 7.08 years) with moderate and severe internal carotid artery stenosis underwent CAS with distal filter protection. Fibrolipid and fibrocalcified plaque morphology was determined by sonography according to the relative contribution of echogenic and echolucent material, and by multisection CT using plaque attenuation. There were 46.81% of patients with fibrolipid and 53.19% with fibrocalcified plaques. DWI was performed before and 24 hours after CAS. Seven (14.89%) patients showed new lesions. Four (8.51%) had 6 new lesions inside the treated vascular territory. Three had a single lesion and 1 patient had 3 lesions (mean: 1.5 ± 1). Most lesions (66.66%) were subcortical, with a mean diameter of 9 mm (range 5-15 mm). All lesions occurred in the area supplied by the middle cerebral artery and were clinically silent. A significant relationship was found between plaque morphology and the appearance of new lesions. Patients with fibrolipid plaques had a significantly higher number of new lesions compared with patients with fibrocalcified plaques (P = .041). The absolute risk of new lesions in the fibrolipid group was 18.18%. New ischemic lesions were observed in the treated vascular territory in 8.51% of patients. The appearance of new ischemic lesions was significantly related to the plaque morphology. Fibrolipid plaques were associated with higher numbers of new lesions.


Growth of the ICRC bacilli in the foot-pad of mice.
The ICRC bacilli are acid-fast bacilli cultivated from M. leprae isolates of lepromatous tissue. The ICRC bacilli from C-44 in the conditioned medium were subjected to foot-pad test, in both normal and T/900r mice. The bacilli exhibits a limited multiplication in normal mice while a continuous growth in T/900r mice. The maximum yield for normal and T/900r mice was 10(7) and 10(9)/foot-pad, respectively. The infiltration of voluntary muscle tissue as the main localization site was common for both normal and T/900r mice with evidence of dissemination in the latter. The spread of AFB to sciatic nerve, induction of liver granuloma and the foot-drop was observed only in T/900r mice. These experiments show that the growth of ICRC bacilli in mouse foot-pad is very similar to that of M. leprae confirming a test for identification.


Bacillus velezensis YC7010 Enhances Plant Defenses Against Brown Planthopper Through Transcriptomic and Metabolic Changes in Rice.
Brown planthopper (BPH; Nilaparvata lugens Stål) is one of the most serious insect pests, which reduce rice yield remarkably in many rice-growing areas. A few plant growth-promoting rhizobacteria induce systemic resistance against herbivorous insects. Here we show that root drenching of rice seedlings with an endophytic strain Bacillus velezensis YC7010 enhanced defenses against BPH. Based on high-throughput transcriptome analysis, systemic resistance against BPH was induced by B. velezensis YC7010 via salicylic acid (SA)- and jasmonic acid (JA)-dependent pathways. Increased leaf contents of secondary metabolites, tricin and C-glycosyl flavone and cell-wall contents of lignin and cellulose were the key defense mechanisms inducing resistance against BPH during the three-way interaction. This study shows for the first time that chemical changes and strengthening of physical barriers play important roles simultaneously in plant defense against BPH in rice by the endophytic bacteria. This defense was induced by lipopeptides including a novel bacillopeptin X.


Amino-acid pool composition of Saccharomyces cerevisiae as a function of growth rate and amino-acid nitrogen source.
The composition of the amino-acid pool of Saccharomyces cerevisiae is markedly influenced by the amino-acid nitrogen source. The yeast tends to accumulate the amino acid supplied and those closely related to it metabolically. A relatively high concentration of glutamic acid is maintained in the pools of all cultures irrespective of the nitrogen source, reflecting the central role of glutamic acid in nitrogen metabolism. The total amino-acid pool concentration increases as a function of growth rate, although differences exist in the behaviour of individual amino acids.


Predicting clone genotypes from tumor bulk sequencing of multiple samples.
Analyses of data generated from bulk sequencing of tumors have revealed extensive genomic heterogeneity within patients. Many computational methods have been developed to enable the inference of genotypes of tumor cell populations (clones) from bulk sequencing data. However, the relative and absolute accuracy of available computational methods in estimating clone counts and clone genotypes is not yet known. We have assessed the performance of nine methods, including eight previously-published and one new method (CloneFinder), by analyzing computer simulated datasets. CloneFinder, LICHeE, CITUP and cloneHD inferred clone genotypes with low error (<5% per clone) for a majority of datasets in which the tumor samples contained evolutionarily-related clones. Computational methods did not perform well for datasets in which tumor samples contained mixtures of clones from different clonal lineages. Generally, the number of clones was underestimated by cloneHD and overestimated by PhyloWGS, and BayClone2, Canopy and Clomial required prior information regarding the number of clones. AncesTree and Canopy did not produce results for a large number of datasets. Overall, the deconvolution of clone genotypes from single nucleotide variant (SNV) frequency differences among tumor samples remains challenging, so there is a need to develop more accurate computational methods and robust software for clone genotype inference. CloneFinder is implemented in Python and is available from https://github.com/gstecher/CloneFinderAPI. Supplementary data are available at Bioinformatics online.


Pseudomonas aeruginosa virulence analyzed in a Dictyostelium discoideum host system.
Pseudomonas aeruginosa is an important opportunistic pathogen that produces a variety of cell-associated and secreted virulence factors. P. aeruginosa infections are difficult to treat effectively because of the rapid emergence of antibiotic-resistant strains. In this study, we analyzed whether the amoeba Dictyostelium discoideum can be used as a simple model system to analyze the virulence of P. aeruginosa strains. The virulent wild-type strain PAO1 was shown to inhibit growth of D. discoideum. Isogenic mutants deficient in the las quorum-sensing system were almost as inhibitory as the wild type, while rhl quorum-sensing mutants permitted growth of Dictyostelium cells. Therefore, in this model system, factors controlled by the rhl quorum-sensing system were found to play a central role. Among these, rhamnolipids secreted by the wild-type strain PAO1 could induce fast lysis of D. discoideum cells. By using this simple model system, we predicted that certain antibiotic-resistant mutants of P. aeruginosa should show reduced virulence. This result was confirmed in a rat model of acute pneumonia. Thus, D. discoideum could be used as a simple nonmammalian host system to assess pathogenicity of P. aeruginosa.


A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis.
Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC <40 mg/L) or better. Median time to hematological response was 1 week. Patients with no response after 4 doses were unlikely to respond further. Renal and cardiac responses occurred in 8 and 7 patients, respectively. Daratumumab was well tolerated, with no unexpected adverse events. With a median follow-up of 26 months, the 2-year overall survival rate was 74% (95% confidence interval, 62-81). Daratumumab monotherapy is associated with deep and rapid hematological responses in previously treated AL patients, with a good safety profile. Further studies of daratumumab in combination regimens are warranted.


Recruitment maneuvers modulate epithelial and endothelial cell response according to acute lung injury etiology.
To investigate the effects of the rate of increase in airway pressure and duration of lung recruitment maneuvers in experimental pulmonary and extrapulmonary acute lung injury. Prospective, randomized, controlled experimental study. University research laboratory. Fifty adult male Wistar rats. Acute lung injury was induced by Escherichia coli lipopolysaccharide either intratracheally (pulmonary acute lung injury) or intraperitoneally (extrapulmonary acute lung injury). After 24 hours, animals were assigned to one of three different recruitment maneuvers, targeted to maximal airway pressure of 30 cm H2O: 1) continuous positive airway pressure for 30 seconds (CPAP-30); 2) stepwise airway pressure increase (5 cm H2O/step, 8.5 s at each step) over 51 seconds (STEP-51) to achieve a pressure-time product similar to that of CPAP-30; and 3) stepwise airway pressure increase (5 cm H2O/step, 5 s at each step) over 30 seconds with maximum pressure sustained for a further 30 seconds (STEP-30/30). All recruitment maneuvers reduced static lung elastance independent of acute lung injury etiology. In pulmonary acute lung injury, CPAP-30 yielded lower surfactant protein-B and higher type III procollagen expressions compared with STEP-30/30. In extrapulmonary acute lung injury, CPAP-30 and STEP-30/30 increased vascular cell adhesion molecule-1 expression, but the type of recruitment maneuver did not influence messenger ribonucleic acid expression of receptor for advanced glycation end products, surfactant protein-B, type III procollagen, and pro-caspase 3. CPAP-30 worsened markers of potential epithelial cell damage in pulmonary acute lung injury, whereas both CPAP-30 and STEP-30/30 yielded endothelial injury in extrapulmonary acute lung injury. In both acute lung injury groups, recruitment maneuvers improved respiratory mechanics, but stepwise recruitment maneuver without sustained airway pressure appeared to associate with less biological impact on lungs.


Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin.
Iron chelators are pluripotent neuronal antiapoptotic agents that have been shown to enhance metabolic recovery in cerebral ischemia models. The precise mechanism(s) by which these agents exert their effects remains unclear. Recent studies have demonstrated that iron chelators activate a hypoxia signal transduction pathway in non-neuronal cells that culminates in the stabilization of the transcriptional activator hypoxia-inducible factor-1 (HIF-1) and increased expression of gene products that mediate hypoxic adaptation. We examined the hypothesis that iron chelators prevent oxidative stress-induced death in cortical neuronal cultures by inducing expression of HIF-1 and its target genes. We report that the structurally distinct iron chelators deferoxamine mesylate and mimosine prevent apoptosis induced by glutathione depletion and oxidative stress in embryonic cortical neuronal cultures. The protective effects of iron chelators are correlated with their ability to enhance DNA binding of HIF-1 and activating transcription factor 1(ATF-1)/cAMP response element-binding protein (CREB) to the hypoxia response element in cortical cultures and the H19-7 hippocampal neuronal cell line. We show that mRNA, protein, and/or activity levels for genes whose expression is known to be regulated by HIF-1, including glycolytic enzymes, p21(waf1/cip1), and erythropoietin, are increased in cortical neuronal cultures in response to iron chelator treatment. Finally, we demonstrate that cobalt chloride, which also activates HIF-1 and ATF-1/CREB in cortical cultures, also prevents oxidative stress-induced death in these cells. Altogether, these results suggest that iron chelators exert their neuroprotective effects, in part, by activating a signal transduction pathway leading to increased expression of genes known to compensate for hypoxic or oxidative stress.


Whole transcriptome characterization of the effects of dehydration and rehydration on Cladonia rangiferina, the grey reindeer lichen.
Lichens are symbiotic organisms with a fungal and an algal or a cyanobacterial partner. Lichens inhabit some of the harshest climates on earth and most lichen species are desiccation-tolerant. Lichen desiccation-tolerance has been studied at the biochemical level and through proteomics, but the underlying molecular genetic mechanisms remain largely unexplored. The objective of our study was to examine the effects of dehydration and rehydration on the gene expression of Cladonia rangiferina. Samples of C. rangiferina were collected at several time points during both the dehydration and rehydration process and the gene expression intensities were measured using a custom DNA microarray. Several genes, which were differentially expressed in one or more time points, were identified. The microarray results were validated using qRT-PCR analysis. Enrichment analysis of differentially expressed transcripts was also performed to identify the Gene Ontology terms most associated with the rehydration and dehydration process. Our data identify differential expression patterns for hundreds of genes that are modulated during dehydration and rehydration in Cladonia rangiferina. These dehydration and rehydration events clearly differ from each other at the molecular level and the largest changes to gene expression are observed within minutes following rehydration. Distinct changes are observed during the earliest stage of rehydration and the mechanisms not appear to be shared with the later stages of wetting or with drying. Several of the most differentially expressed genes are similar to genes identified in previous studies that have investigated the molecular mechanisms of other desiccation-tolerant organisms. We present here the first microarray experiment for any lichen species and have for the first time studied the genetic mechanisms behind lichen desiccation-tolerance at the whole transcriptome level.


Multimode simulation of dimer absorption spectra from first principles calculations: application to the 3,4,9,10-perylenetetracarboxylic diimide dimer.
First principles calculations based on density functional theory (DFT) have been combined with the multimode vibronic theory of coupled identical monomers to simulate the absorption spectra of dimers. In comparison to our previous study [J. Guthmuller et al., J. Chem. Theory Comput. 4, 2094 (2008)], where the vibrational excitations strictly accompany the electronic excitations, the vibronic model has been generalized so that the vibronic basis set contains vibrational excitations for both the ground and the excited electronic states. As a matter of illustration, this approach has been applied to a perylenetetracarboxylic diimide dimer employing a fixed dimer geometry. The exciton coupling energy is evaluated with time dependent DFT and random phase approximation calculations and by describing the effects of the solvent with the polarizable continuum model. First, the simulated monomer absorption spectrum is found to be in excellent agreement with experiment. Then, the simulated dimer absorption spectrum presents a strong dependency on the exciton coupling energy and on the inclusion of ground state vibrational excitations in the basis set. It is further shown that considering only fundamental vibrational excitations for the ground electronic state provides almost converged spectra and can therefore be used as a good first approximation. Moreover, the comparison with experiment demonstrates that the dimer absorption spectrum can be successfully reproduced by employing the exciton coupling energy determined at the time dependent DFT level provided that the effects of the solvent are included.


A bibliometric analysis of global research trends of inflammation in cervical cancer: A review.
Cervical cancer is a common malignant tumor and a leading cause of death in women worldwide. It plays a crucial role in tumorigenesis and progression of cervical cancer. A total of 1606 references on inflammation in cervical cancer were retrieved from the Web of Science Core Collection and visual analysis was performed using VOSviewer. Inflammation in cervical cancer has attracted the attention of researchers. Even though China is the country that publishes the most papers, with the most of the top-ranking institutions, there is no extensive collaboration and exchange of papers by Chinese scholars. PLOS One is a popular journal on inflammation in cervical cancer. Instead, authors from other countries perform better, for example, the Sjoerd H. Van Der Burg is the most widely cited author and "M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4 + Th1 cells" (Moniek Heusinkveld, Leiden University Medical Center) is the most cited article of inflammation in cervical cancer. Keywords associated with "apoptosis," "HPV," "NF-κB," and "oxidative stress have been used in many studies, and keywords associated with "apoptosis," "human papillomavirus (HPV)," "NF-κB," and "oxidative stress" are involved in many studies, and there may be more research ideas in the future. From the perspective of precision medicine, more substantive research articles can promote scientific value, strengthen communication and cooperation, produce more extensive research results, and greatly promote the clinical diagnosis and treatment of cervical cancer. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.


Towards sustained silencing of HER2/neu in cancer by epigenetic editing.
The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neugene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu- overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression. Epigenetic editing provides a novel (synergistic) approach to modulate expression of oncogenes.


[Current life expectancy in Chile].
An increased life expectancy is associated to a nation's progress. Life expectancy at birth is 78 years in developed countries, 72 in Latin America, 70 in China, 63 in Eastern Europe and 51 in Africa. Chile is the Latin American country with the higher increment in life expectancy, reaching 75 years at birth, during the period 1990-95. A higher life expectancy is not always an advantage. People over 60 years old may survive with a burden of chronic diseases or physical and mental disability. The higher health care needs of the increasing population of elderly people is raising the costs of health care in modern nations.


Benoxaprofen administered once a day: determination of optimum dosage schedule.
Six centers participated in a double-blind crossover study in patients with rheumatoid arthritis (RA) and osteoarthritis to evaluate the most advantageous timing of the daily dose of benoxaprofen. The study results revealed no significant difference between the morning and evening dose administered at a daily dose of 600 mg; however, more patients with RA preferred the evening dose.


Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design.
Heart failure (HF) affects >5 million patients in the United States, and its prevalence is increasing every year. Despite the compelling scientific evidence that angiotensin-converting enzyme inhibitors and beta-blockers reduce hospitalizations and mortality rates in patients with HF, these lifesaving therapies continue to be underused. Several studies in a variety of clinical settings have documented that a significant proportion of eligible patients with HF are not receiving treatment with these guideline-recommended, evidence-based therapies. In patients hospitalized with HF, who are at particularly high risk for re-hospitalization and death, the initiation of beta-blockers is often delayed because of concern that early initiation of these agents may exacerbate HF. Recent studies suggest that beta-blockers can be safely and effectively initiated in patients with HF before hospital discharge and that clinical outcomes are improved. The Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial demonstrated that pre-discharge initiation of carvedilol was associated with a higher rate of beta-blocker use after hospital discharge, with no increase in hospital length of stay. In addition, there was no increase in the risk of worsening of HF. Studies of hospital-based management systems that rely on early (pre-discharge) initiation of evidence-based therapies for patients with cardiovascular disease have also found increases in post-discharge use of therapy and a reduction in the rates of mortality and hospitalization. On the basis of these pivotal studies, the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) program is designed to improve medical care and education of hospitalized patients with HF and accelerate the initiation of evidence-based HF guideline recommended therapies by administering them before hospital discharge. A registry component, planned as the most comprehensive database of the hospitalized HF population focusing on admission to discharge and 60- to 90-day follow-up, is designed to evaluate the demographic, pathophysiologic, clinical, treatment, and outcome characteristics of patients hospitalized with HF. The ultimate aim of this program is to improve the standard of HF care in the hospital and outpatient settings and increase the use of evidence-based therapeutic strategies to save lives.


The variable anticoagulant response to unfractionated heparin in vivo reflects binding to plasma proteins rather than clearance.
The anticoagulant response to fixed doses of unfractionated heparin is variable in patients with acute illness, and some patients with venous thromboembolism require high doses of heparin to achieve a therapeutic anticoagulant response. To investigate the mechanism responsible for the variable anticoagulant response to heparin in acute illness, heparin clearance and nonspecific protein binding were compared in control and endotoxin-treated rabbits. The plasma half-life (t 1/2) of radiolabeled heparin increased in a dose-dependent fashion. At all doses of heparin studied, the t 1/2 of radiolabeled heparin was unaffected by experimental endotoxemia when compared with control animals. In contrast, the amount of heparin recovered was lower in the plasma of endotoxemic animals because of increased binding to plasma proteins. A chemically modified heparin with low affinity for antithrombin III was added ex vivo or in vivo to displace heparin bound nonspecifically to plasma proteins. The proportion of heparin bound to plasma proteins was significantly greater in the plasma of endotoxemic animals than in controls. These findings indicate that acute inflammation alters heparin recovery but does not affect heparin clearance. The variability of the anticoagulant response to heparin seen in patients with thromboembolism may, in part, be due to this effect of the underlying disease process.


Genital ulcer disease in women in Durban, South Africa.
To study the microbial aetiology of genital ulcer disease (GUD) in women. Microbial and clinical assessment of genital ulcers in women. City Health sexually transmitted diseases clinic, King Edward VIII Hospital, Durban, South Africa. 100 Zulu women with genital ulceration who had not received antibiotics in the previous two weeks. Syphilis was diagnosed in 40%, genital herpes in 18%, donovanosis (granuloma inguinale) in 16%, chancroid in 14%, lymphogranuloma venereum in 7% and scabies in 2%. No recognised cause was detected in 18%. Secondary syphilis was diagnosed in 21%, primary syphilis in 16% and mixed primary and secondary syphilis in 3%. Multiple infections were detected in 13 women, of whom 12 had syphilis. Bleeding was observed from the ulcers of 59 during swab collection. Three women had HIV-1 antibodies. Neisseria gonorrhoeae was isolated from the ulcers and endocervix of two women and from the endocervix alone in nine. Generalised scabies was diagnosed in 14. All the major causes of GUD are prevalent in Zulu women in Durban: secondary syphilis was the commonest diagnosis. Donovanosis, which often presents late with large ulcers, and genital herpes are now significant problems. Mixed infections with coexisting syphilis are common. All women in this population with GUD should be treated for syphilis and receive oral antibiotics effective for chancroid and donovanosis.


NMR identifies atherogenic lipoprotein abnormalities in early diabetic nephropathy that are unrecognized by conventional analysis.
Lipoprotein abnormalities are likely contributors to the high risk of cardiovascular disease in the chronic kidney disease (CKD) population, although information is limited. Specifically, little is known about lipoprotein abnormalities during the early stages of diabetic kidney disease. The aim of this study was to investigate the relationship between lipoproteins and early manifestations of CKD in the 517 Type 2 diabetes mellitus (T2DM) patients who participated in the Insulin Resistance Atherosclerosis Study (IRAS). Lipoprotein abnormalities were measured by conventional lipid analysis, nuclear magnetic resonance (NMR) spectroscopy, gel gradient electrophoresis (GE), immunoprecipitation (IP), and ELISA. We grouped the cases into albumin to creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) quartiles. In the conventional lipid analysis, triglycerides (TG) correlated directly with ACR and inversely with eGFR quartiles (p = 0.01), while LDL, HDL cholesterol did not correlate with change in ACR or eGFR. ACR was directly associated with apoB, total VLDL, medium VLDL, IDL and small LDL particle concentrations (p < or = 0.03), and inversely with large LDL particles (p = 0.01) and LDL size (p = 0.008). Estimated GFR quartiles were inversely associated with total VLDL, small VLDL, IDL, and medium HDL particles (p < or = 0.01). In subjects with T2DM, mild albuminuria and reduction in eGFR were associated with numerous atherogenic lipoprotein abnormalities that were detected by the combination of NMR spectroscopy, gel gradient electrophoresis, immunoprecipitation and ELISA but not by the standard clinical lipid analysis.


[Morbidity among job applicants in the Metropolitan Region of Salvador, Bahia, Brazil].
This cross-sectional study evaluates the pre-employment health status of job applicants, based on prevalence estimates of abnormal laboratory test results, clinical diagnosis, and a physician-signed fit-for-work assessment, which is mandatory in Brazil. The study population was a random sample of 1,237 male workers selected from medical records (1988-1996) from an Occupational Medical Center located in Salvador, the capital of Bahia State, Brazil. The data were from a single pre-employment medical assessment for each individual. The most common diseases were intestinal parasites (51.7%), anemia (12.8%), and hypertension (12.7%). Drivers showed a high prevalence of overweight (38.2%) and hypertension (16.2%). In addition to work-related risks and diseases, occupational hygiene and safety programs need to address prevailing illnesses and risk factors, which in this population are typical of poor living conditions. Special attention should to be given to drivers, who are at increased risk of cardiovascular disease.


Living with a chronic disease: insights from patients with a low socioeconomic status.
Little is known about how patients with low socioeconomic status (SES) experience their chronic disease, and how it impacts health-related quality of life (HRQoL). Compared to their more affluent counterparts, worse outcomes have been reported. A better understanding of the domains of HRQoL that are relevant to these specific populations is therefore needed. We explored the experiences of living with a chronic disease in low SES persons. A qualitative interview study was performed in Flanders, Belgium. Semi-structured interviews were conducted in chronically ill patients, selected through purposive sampling. Interviews were audio-recorded and transcribed verbatim. Analysis followed an inductive and iterative approach. Fifteen patients were interviewed. Six major themes were identified: a heavy bag to carry, loss of autonomous life, inner and outer loneliness, emotional imbalance, unmet need for support, and coping strategies. Patients experienced their illness as an additional problem on top of all other problems (i.e. financial/social problems, traumatic life events). In general, the disease burden and non-disease burden were mutually reinforcing, resulting in greater dependency, greater risk of social isolation, greater psychological distress, and greater risk of impaired HRQoL. This study is the first to provide detailed insight into the experiences of living with a chronic disease in low SES persons. A conceptual model is proposed that can be used in daily clinical practice to raise awareness among clinicians and health care providers that the patient's needs go beyond the disease itself. Future research is needed to validate and test the model.


Medication adherence: WHO cares?
The treatment of chronic illnesses commonly includes the long-term use of pharmacotherapy. Although these medications are effective in combating disease, their full benefits are often not realized because approximately 50% of patients do not take their medications as prescribed. Factors contributing to poor medication adherence are myriad and include those that are related to patients (eg, suboptimal health literacy and lack of involvement in the treatment decision-making process), those that are related to physicians (eg, prescription of complex drug regimens, communication barriers, ineffective communication of information about adverse effects, and provision of care by multiple physicians), and those that are related to health care systems (eg, office visit time limitations, limited access to care, and lack of health information technology). Because barriers to medication adherence are complex and varied, solutions to improve adherence must be multifactorial. To assess general aspects of medication adherence using cardiovascular disease as an example, a MEDLINE-based literature search (January 1, 1990, through March 31, 2010) was conducted using the following search terms: cardiovascular disease, health literacy, medication adherence, and pharmacotherapy. Manual sorting of the 405 retrieved articles to exclude those that did not address cardiovascular disease, medication adherence, or health literacy in the abstract yielded 127 articles for review. Additional references were obtained from citations within the retrieved articles. This review surveys the findings of the identified articles and presents various strategies and resources for improving medication adherence.


Hereditary hypophosphatemic rickets with hypercalciuria: case report.
We report a case of a male aged 50 years who consulted for renal disease recurrent lithiasis and nephrocalcinosis. The clinical examination showed external signs of rickets/osteomalacia and biochemical data as well as a severe loss of renal phosphate with hypophosphatemia, normal 25 OH vitamin D, high 1,25 OH vitamin D and hypercalciuria. Parathyroid hormone was low and renal ultrasound confirmed the existence of severe bilateral medullary nephrocalcinosis. They also found incipient chronic renal failure and incomplete renal tubular acidosis, both secondary to nephrocalcinosis and unrelated to the underlying disease. The molecular study found a change in homozygosity in intron 5 of gene SLC34A3 (NM_080877.2:c[ 448 +5G>A] + [ 448 +5G>A] ). His three children were carriers of the same variant in heterozygosis and although they were clinically asymptomatic two of them had hypercalciuria. All these data suggest that the patient had hereditary hypophosphataemic rickets with hypercalciuria (HHRH) secondary to an alteration in the sodium dependent phosphate cotransporter located in proximal tubule (NaPi-IIc). The HHRH is transmitted by autosomal recessive inheritance and is an extremely rare form of hypophosphatemic rickets. The diagnosis and treatment are essential to prevent bone sequelae of rickets and nephrocalcinosis. A correct differential diagnosis with other forms of hypophosphatemic rickets has implications on the treatment, as the management based only on phosphorus supplementation usually corrects all clinical and biochemical abnormalities, except for the loss of phosphorus in the urine. The exogenous supply of calcitriol, as advised in other hypophosphatemic rickets, may induce renal calcium deposits and nephrocalcinosis and worsens the prognosis.


Fusion of intelligence information: a Bayesian approach.
The attack that occurred on September 11, 2001 was, in the end, the result of a failure to detect and prevent the terrorist operations that hit the United States. The U.S. government thus faces at this time the daunting tasks of first, drastically increasing its ability to obtain and interpret different types of signals of impending terrorist attacks with sufficient lead time and accuracy, and second, improving its ability to react effectively. One of the main challenges is the fusion of information, from different sources (U.S. or foreign), and of different types (electronic signals, human intelligence. etc.). Fusion thus involves two very distinct and separate issues: communications, i.e., ensuring that the different U.S. and foreign intelligence agencies communicate all relevant and accurate information in a timely fashion and, perhaps more difficult, merging the content of signals, some "sharp" and some "fuzzy," some dependent and some independent into useful information. The focus of this article is on the latter issue, and on the use of the results. In this article, I present a classic probabilistic Bayesian model sometimes used in engineering risk analysis, which can be helpful in the fusion of information because it allows computation of the posterior probability of an event given its prior probability (before the signal is observed) and the quality of the signal characterized by the probabilities of false positive and false negative. Experience suggests that the nature of these errors has been sometimes misunderstood; therefore, I discuss the validity of several possible definitions.


Examination of extraintestinal tissue cysts of Isospora belli.
Relapse is common in immunocompetent and immunosuppressed humans infected with Isospora belli and is believed to be associated with the presence of extraintestinal stages. In the present study, we examined this important stage in an AIDS patient using histological, immunohistological, histochemical, and ultrastructural methods to better understand the development and structure of this stage and to develop better means of detecting infections. Antisera made in rabbits to Isospora suis, Toxoplasma gondii, Hammondia hammondi, Sarcocystis neurona, Neospora caninum, and Caryospora bigenetica were tested against I. belli tissue cysts in the avidin-biotin peroxidase complex (ABC) immunohistological test. Most antisera reacted positively in the ABC test at dilutions of 1:100 but not at dilutions of 1:250. Some antisera to N. caninum and H. hammondi reacted positively at dilutions of 1:1,000 in the ABC test. Most reactive antisera stained the tissue cyst wall and not the enclosed zoite. Eight histochemical tests were examined and most were nonreactive with I. belli zoites or tissue cysts. Transmission electron microscopy revealed that the tissue cyst wall was composed of granular material and was directly beneath the parasitophorous vacuole membrane. Zoites were in the center of the tissue cysts and were surrounded by fibrillar material that appeared to originate from the zoite surface. Tubulelike structures were present in the granular tissue cyst wall and in the fibrillar material that surrounded the zoite. Zoites contained a crystalloid body. New findings in the present study consisted of identifying what are probably early tissue cysts that lack a developed tissue cyst wall, demonstrating that more than 1 tissue cyst can occupy a host cell, describing the distribution of micronemes and the shedding of zoite membranes, and identifying tubular structures in the inner tissue cyst wall and inner compartment.


Implantable SDF-1α-loaded silk fibroin hyaluronic acid aerogel sponges as an instructive component of the glioblastoma ecosystem: Between chemoattraction and tumor shaping into resection cavities.
In view of inevitable recurrences despite resection, glioblastoma (GB) is still an unmet clinical need. Dealing with the stromal-cell derived factor 1-alpha (SDF-1α)/CXCR4 axis as a hallmark of infiltrative GB tumors and with the resection cavity situation, the present study described the effects and relevance of a new engineered micro-nanostructured SF-HA-Hep aerogel sponges, made of silk fibroin (SF), hyaluronic acid (HA) and heparin (Hep) and loaded with SDF-1α, to interfere with the GB ecosystem and residual GB cells, attracting and confining them in a controlled area before elimination. 70 µm-pore sponges were designed as an implantable scaffold to trap GB cells. They presented shape memory and fit brain cavities. Histological results after implantation in brain immunocompetent Fischer rats revealed that SF-HA-Hep sponges are well tolerated for more than 3 months while moderately and reversibly colonized by immuno-inflammatory cells. The use of human U87MG GB cells overexpressing the CXCR4 receptor (U87MG-CXCR4+) and responding to SDF-1α allowed demonstrating directional GB cell attraction and colonization of the device in vitro and in vivo in orthotopic resection cavities in Nude rats. Not modifying global survival, aerogel sponge implantation strongly shaped U87MG-CXCR4+ tumors in cavities in contrast to random infiltrative growth in controls. Overall, those results support the interest of SF-HA-Hep sponges as modifiers of the GB ecosystem dynamics acting as "cell meeting rooms" and biocompatible niches whose properties deserve to be considered toward the development of new clinical procedures. STATEMENT OF SIGNIFICANCE: Brain tumor glioblastoma (GB) is one of the worst unmet clinical needs. To prevent the relapse in the resection cavity situation, new implantable biopolymer aerogel sponges loaded with a chemoattractant molecule were designed and preclinically tested as a prototype targeting the interaction between the initial tumor location and its attraction by the peritumoral environment. While not modifying global survival, biocompatible SDF1-loaded hyaluronic acid and silk fibroin sponges induce directional GB cell attraction and colonization in vitro and in rats in vivo. Interestingly, they strongly shaped GB tumors in contrast to random infiltrative growth in controls. These results provide original findings on application of exogenous engineered niches that shape tumors and serve as cell meeting rooms for further clinical developments.


Risk factors for not reaching minimal clinically important difference at 90 days and 1 year after elective lumbar spine surgery: a cohort study.
Patient-perceived functional improvement is a core metric in lumbar surgery for degenerative disease. It is important to identify both modifiable and nonmodifiable risk factors that can be evaluated and possibly optimized prior to elective surgery. This case-control study was designed to study risk factors for not achieving the minimal clinically important difference (MCID) in Patient-Reported Outcomes Measurement Information System Function 4-item Short Form (PROMIS PF) score. The authors queried the Michigan Spine Surgery Improvement Collaborative database to identify patients who underwent elective lumbar surgical procedures with PROMIS PF scores. Cases were divided into two cohorts based on whether patients achieved MCID at 90 days and 1 year after surgery. Patient characteristics and operative details were analyzed as potential risk factors. The authors captured 10,922 patients for 90-day follow-up and 4453 patients (40.8%) did not reach MCID. At the 1-year follow-up period, 7780 patients were identified and 2941 patients (37.8%) did not achieve MCID. The significant demographic characteristic-adjusted relative risks (RRs) for both groups (RR 90 day, RR 1 year) included the following: symptom duration > 1 year (1.34, 1.41); previous spine surgery (1.25, 1.30); African American descent (1.25, 1.20); chronic opiate use (1.23, 1.25); and less than high school education (1.20, 1.34). Independent ambulatory status (0.83, 0.88) and private insurance (0.91, 0.85) were associated with higher likelihood of reaching MCID at 90 days and 1 year, respectively. Several key unique demographic risk factors were identified in this cohort study that precluded optimal postoperative functional outcomes after elective lumbar spine surgery. With this information, appropriate preoperative counseling can be administered to assist in shaping patient expectations.


Predictive Impact of Contextual Objects during Action Observation: Evidence from Functional Magnetic Resonance Imaging.
The processing of congruent stimuli, such as an object or action in its typical location, is usually associated with reduced neural activity, probably due to facilitated recognition. However, in some situations, congruency increases neural activity-for example, when objects next to observed actions are likely versus unlikely to be involved in forthcoming action steps. Here, we investigated using fMRI whether the processing of contextual cues during action perception is driven by their (in)congruency and, thus, informative value to make sense of an observed scene. Specifically, we tested whether both highly congruent contextual objects (COs), which strongly indicate a future action step, and highly incongruent COs, which require updating predictions about possible forthcoming action steps, provide more anticipatory information about the action course than moderately congruent COs. In line with our hypothesis that especially the inferior frontal gyrus (IFG) subserves the integration of the additional information into the predictive model of the action, we found highly congruent and incongruent COs to increase bilateral activity in action observation nodes, that is, the IFG, the occipitotemporal cortex, and the intraparietal sulcus. Intriguingly, BA 47 was significantly stronger engaged for incongruent COs reflecting the updating of prediction in response to conflicting information. Our findings imply that the IFG reflects the informative impact of COs on observed actions by using contextual information to supply and update the currently operating predictive model. In the case of an incongruent CO, this model has to be reconsidered and extended toward a new overarching action goal.


Antibodies to single glycolipids and glycolipid complexes in Guillain-Barré syndrome subtypes.
To comprehensively investigate the relationship between antibodies to single glycolipids and their complexes and Guillain-Barré syndrome subtypes and clinical features. In acute sera from 199 patients with Guillain-Barré syndrome, immunoglobulin G (IgG) antibodies to glycolipids and ganglioside complexes were tested using ELISA against individual antigens from single glycolipids including gangliosides (LM1, GM1, GM1b, GD1a, GalNAc-GD1a, GD1b, GT1a, GT1b, GQ1b) and a neutral glycolipid, asialo-GM1 (GA1), and antigens from the combination of 2 different glycolipids. Based on serial nerve conduction studies, the electrodiagnoses were as follows: 69 demyelinating subtype, 85 axonal subtypes, and 45 unclassified. Significant associations were detected between acute motor axonal neuropathy subtype and IgG antibodies to GM1, GalNAc-GD1a, GA1, or LM1/GA1 complex. Reversible conduction failure was significantly associated with IgG antibodies to GM1, GalNAc-GD1a, GD1b, or complex of LM1/GA1. No significant association was demonstrated between acute inflammatory demyelinating polyneuropathy and any of the glycolipids or ganglioside complexes. Anti-ganglioside complex antibodies alone were detected in 7 patients (5 axonal subtype). The current study demonstrates that antibodies to single glycolipids and ganglioside complexes are associated with acute motor axonal neuropathy or acute motor conduction block neuropathy but not acute inflammatory demyelinating polyneuropathy. This study provides Class II evidence that antibodies to glycolipids are increased in patients with acute motor axonal neuropathy and acute motor conduction block neuropathy but not acute inflammatory demyelinating polyneuropathy.


Endovascular stent implantation in congenital heart defects.
We report the immediate and short-term results of endovascular stent implantations from our center. We performed stent implantations in four patients (3, 12, 18 and 20 years old) with different stenoses or obstructions: right ventricular outflow conduit obstruction, left Blalock-Taussig obstruction, post-operative recoarctation and cavopulmonary anastomosis obstruction. Stent were implanted successfully. The mean diameters of stenoses were expanded from 4.5 +/- 3.5 (2-7) mm to 9 +/- 1. 2 (8-10) mm, and the complaints of patients were improved significantly by stent implantation. There was no complication related to the procedures. All patients are living except one who died from cerebrovascular event unrelated to the stent implantation. The mean follow-up period of three living patients is 6.3 +/- 5.5 (1-2) months. As of the last control, all have remained at the caliber achieved at original placement. In light of our limited experience and previous reported studies, we conclude that intravascular stents are safe and can be used effectively in selected patients with congenital heart defects.


Integrative molecular profiling of routine clinical prostate cancer specimens.
Comprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging. We developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing. We identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations. Our results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications.


E-cadherin is under constitutive actomyosin-generated tension that is increased at cell-cell contacts upon externally applied stretch.
Classical cadherins are transmembrane proteins at the core of intercellular adhesion complexes in cohesive metazoan tissues. The extracellular domain of classical cadherins forms intercellular bonds with cadherins on neighboring cells, whereas the cytoplasmic domain recruits catenins, which in turn associate with additional cytoskeleton binding and regulatory proteins. Cadherin/catenin complexes are hypothesized to play a role in the transduction of mechanical forces that shape cells and tissues during development, regeneration, and disease. Whether mechanical forces are transduced directly through cadherins is unknown. To address this question, we used a Förster resonance energy transfer (FRET)-based molecular tension sensor to test the origin and magnitude of tensile forces transmitted through the cytoplasmic domain of E-cadherin in epithelial cells. We show that the actomyosin cytoskeleton exerts pN-tensile force on E-cadherin, and that this tension requires the catenin-binding domain of E-cadherin and αE-catenin. Surprisingly, the actomyosin cytoskeleton constitutively exerts tension on E-cadherin at the plasma membrane regardless of whether or not E-cadherin is recruited to cell-cell contacts, although tension is further increased at cell-cell contacts when adhering cells are stretched. Our findings thus point to a constitutive role of E-cadherin in transducing mechanical forces between the actomyosin cytoskeleton and the plasma membrane, not only at cell-cell junctions but throughout the cell surface.


Relationship between time-resolved and non-time-resolved Beer-Lambert law in turbid media.
The time-resolved Beer-Lambert law proposed for oxygen monitoring using pulsed light was extended to the non-time-resolved case in a scattered medium such as living tissues with continuous illumination. The time-resolved Beer-Lambert law was valid for the phantom model and living tissues in the visible and near-infrared regions. The absolute concentration and oxygen saturation of haemoglobin in rat brain and thigh muscle could be determined. The temporal profile of rat brain was reproduced by Monte Carlo simulation. When the temporal profiles of rat brain under different oxygenation states were integrated with time, the absorbance difference was linearly related to changes in the absorption coefficient. When the simulated profiles were integrated, there was a linear relationship within the absorption coefficient which was predicted for fractional inspiratory oxygen concentration from 10 to 100% and, in the case beyond the range of the absorption coefficient, the deviation from linearity was slight. We concluded that an optical pathlength which is independent of changes in the absorption coefficient is a good approximation for near-infrared oxygen monitoring.


George Lyman Duff Memorial Lecture. Multifactorial etiology of hypercholesterolemia. Implications for prevention of coronary heart disease.
This review underlines the concept that multiple factors are responsible for hypercholesterolemia in the American public. Dietary factors (cholesterol, saturated fatty acids, and obesity) clearly raise the cholesterol level, and they are important causes of borderline-high cholesterol. Still, the unexplained decline of LDL receptor activity with aging contributes importantly to borderline-high levels and cannot be ignored. The loss of estrogen-stimulated LDL receptor synthesis after menopause is an important contributor to elevated cholesterol in postmenopausal women. In addition, several genetic defects inherited singly appear to be responsible for moderate hypercholesterolemia. Some of these defects may represent genetic hypersensitivity to diet, and dietary therapy alone may provide adequate cholesterol lowering. Other defects impart resistance to dietary control, and use of a single cholesterol-lowering drug may be required. With the exception of heterozygous FH, most cases of severe hypercholesterolemia appear to be the result of the coexistence of at least two defects in LDL metabolism, and as a rule, they can be treated successfully only by using cholesterol-lowering drugs in combination.


Formulary streamlining through therapeutic class review.
The authors describe their methods for streamlining the formulary at a small teaching hospital. The therapeutic drug review process comparatively examined pharmacology, pharmacokinetics, indications, side-effects, interactions, usage patterns, and costs within classes of medications. The information was presented in a table format which aided in the dissemination of large volumes of material and served as an educational tool for the medical and pharmacy staff. The goals of this program were avoidance of therapeutic duplication, assurance of efficacy, and cost containment without compromised patient outcome. The authors discuss methods for assuring intra-pharmacy and hospital wide cohesion in achieving the goals of formulary streamlining.


Uptake of Proactively Offered Online and Telephone Support Services Targeting Multiple Health Risk Behaviors Among Vocational Education Students: Process Evaluation of a Cluster Randomized Controlled Trial.
A high proportion of vocational education students smoke tobacco, have inadequate nutrition (ie, low fruit and vegetable intake), drink alcohol at risky levels, or are physically inactive. The extent to which vocational education students will sign up for proactively offered online and telephone support services for multiple health risk behaviors is unknown. The aim of this study is to examine the uptake of proactively offered online and telephone support services for smoking, nutrition, alcohol consumption, and physical activity risk behaviors, individually and in combination, among vocational education students in the Technical and Further Education (TAFE) setting. The characteristics associated with the uptake of online or telephone services for smoking, nutrition, alcohol consumption, and physical activity risk behaviors were also examined. Vocational education students enrolled in a TAFE class in New South Wales, Australia, which ran for 6 months or more, were recruited to participate in a cluster randomized controlled trial from May 2018 to May 2019. In the intervention arm, participants who did not meet the Australian health guidelines for each of the smoking, nutrition, alcohol consumption, and physical activity risk behaviors were provided electronic feedback and proactively offered online and telephone support services. Uptake of support was measured by whether participants signed up for the online and telephone services they were offered. Vocational education students (N=551; mean age 25.7 years, SD 11.1; 310/551, 56.3% male) were recruited into the intervention arm. Uptake of the proactive offer of either online or telephone services was 14.5% (59/406) for fruit and vegetables, 12.7% (29/228) for physical activity, 6.8% (13/191) for smoking, and 5.5% (18/327) for alcohol use. Uptake of any online or telephone service for at least two health behaviors was 5.8% (22/377). Participants who were employed (odds ratio [OR] 0.10, 95% CI 0.01-0.72) and reported not being anxious (OR 0.11, 95% CI 0.02-0.71) had smaller odds of signing up for online or telephone services for smoking, whereas participants who reported not being depressed had greater odds (OR 10.25, 95% CI 1.30-80.67). Participants who intended to change their physical activity in the next 30 days had greater odds (OR 4.01, 95% CI 1.33-12.07) of signing up for online or telephone services for physical activity. Employed participants had smaller odds (OR 0.18, 95% CI 0.06-0.56) of signing up for support services for at least two behaviors. Although the uptake of proactively offered online and telephone support services is low, these rates appear to be higher than the self-initiated use of some of these services in the general population. Scaling up the proactive offer of online and telephone services may produce beneficial health outcomes. Australian New Zealand Clinical Trials Registry: ACTRN12618000723280; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375001.


[Outcomes and complications of open versus closed reduction and internal fixation for Delbet type Ⅱ and Ⅲ hip fractures in children and adolescents].
To compare the outcomes and complications of open versus closed reduction and internal fixation for Delbet type Ⅱ and Ⅲ hip fractures in children and adolescents. We retrospectively analyzed the data of 42 patients with Delbet type Ⅱ (22 cases) and Ⅲ (20 cases) hip fractures (including 24 male and 18 female patients with a mean age of 8.19± 3.23 years, range 2-15 years) admitted in the Fifth and Third Affiliated Hospital of Southern Medical University from January, 2013 to January, 2022. Nineteen of the patients received closed and 23 underwent open reduction and internal fixation. The operation time, postoperative healing time, and Ratliff standard hip function results were compared between the two groups, and the incidences of such complications as premature epiphyseal closure and femoral head necrosis were analyzed. All the patients were followed up for 13-84 months (mean 36.04±8.23 months). The operation time of closed reduction and internal fixation was significantly shorter than that of open surgery (68.23±24.68 vs 119.71±32.75 min, P < 0.05). All the patients showed good fracture healing after the operations with similar healing time between the two groups (3.32±0.31 vs 3.18±0.20 months, P > 0.05). The rate of excellent and good hip joint function was 90.48% in the overall patients and showed no significant difference between the two groups (17/19 vs 21/23, P > 0.05). The incidences of premature epiphyseal closure (3/19 in closed vs 4/23 in open reduction group, P > 0.05) and femoral head necrosis (2/19 vs 1/23, P > 0.05) were comparable between the two groups. In children and adolescents, open reduction can achieve definite surgical effect for Delbet type Ⅱ and Ⅲ hip fractures, but closed reduction and internal fixation are recommended when anatomic reduction can be achieved. Premature epiphyseal closure and femoral head necrosis are common and serious complications of these fractures.