Potential Effects of Coronaviruses on the Cardiovascular System: A Review.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19) has reached a pandemic level. Coronaviruses are known to affect the cardiovascular system. We review the basics of coronaviruses, with a focus on COVID-19, along with their effects on the cardiovascular system. Coronavirus disease 2019 can cause a viral pneumonia with additional extrapulmonary manifestations and complications. A large proportion of patients have underlying cardiovascular disease and/or cardiac risk factors. Factors associated with mortality include male sex, advanced age, and presence of comorbidities including hypertension, diabetes mellitus, cardiovascular diseases, and cerebrovascular diseases. Acute cardiac injury determined by elevated high-sensitivity troponin levels is commonly observed in severe cases and is strongly associated with mortality. Acute respiratory distress syndrome is also strongly associated with mortality. Coronavirus disease 2019 is associated with a high inflammatory burden that can induce vascular inflammation, myocarditis, and cardiac arrhythmias. Extensive efforts are underway to find specific vaccines and antivirals against SARS-CoV-2. Meanwhile, cardiovascular risk factors and conditions should be judiciously controlled per evidence-based guidelines.


Ethics in public health research: minding the gaps: a reassessment of the challenges to safe motherhood.
Maternal and perinatal mortality reduction has remained a priority on the international health agenda for nearly 2 decades. During this time, strategies for achieving these goals have shifted in emphasis from prevention of pregnancies to provision of care. Robust evidence is limited, particularly regarding what works best in delivering care in specific health system settings and at the population level. We describe the limited evidence base using a framework that highlights the consequences of the major gaps in measurement, evidence, and action, and we discuss existing opportunities for bridging these gaps at the policy level. Capitalizing on current global policy interests and generating demand-driven evidence is a priority for enabling documentation of progress toward reaching the United Nations Millennium Development Goals for 2015.


Intravenous lipid emulsions in term infants: impact on laboratory and clinical outcomes and long-term consequences.
Parenteral nutrition (PN) in term newborns and older infants is often required for nutritional support for temporary or permanent intestinal failure from any reason. Lipid emulsions (LEs) are an essential source of high-density energy, essential fatty acids, and fat-soluble vitamins. Depending on the fatty acid type, LEs may also have significant immunomodulatory effects. All LEs, starting with soybean oil-based LE and subsequently with medium-chain triglycerides-, olive oil- and fish oil-based LEs, have been investigated in newborns and infants. Laboratory data (mainly liver enzymes, plasma lipid profiles and some metabolic markers) have been investigated for some LEs. The outcome of intestinal failure-associated liver disease after switching to new fish oil-based LEs has been sporadically reported. Long-term outcome data have only looked at the relationship between PN and mortality/morbidity, especially liver disease, and a few studies have looked at growth. There are no controlled studies in this age group that investigated the relationship between different types of LEs and long-term outcomes. In spite of their contribution to understanding the use and indications of various LEs as well as their advantages and adverse effects, most studies in newborns and infants have been observational or retrospective, and the investigated population has been heterogeneous, either in terms of the degree of maturation, age or diagnoses. High-quality studies, preferably randomized and controlled, in this particular population are needed, especially with the widespread use of PN and the emergence of new LEs.


Understanding and Modulating Metalloenzymes with Unnatural Amino Acids, Non-Native Metal Ions, and Non-Native Metallocofactors.
Metalloproteins set the gold standard for performing important functions, including catalyzing demanding reactions under mild conditions. Designing artificial metalloenzymes (ArMs) to catalyze abiological reactions has been a major endeavor for many years, but most ArM activities are far below those of native enzymes, making them unsuitable for most pratical applications. A critical step to advance the field is to fundamentally understand what it takes to not only confer but also fine-tune ArM activities so they match those of native enzymes. Indeed, only once we can freely modulate ArM activity to rival (or surpass!) natural enzymes can the potential of ArMs be fully realized. A key to unlocking ArM potential is the observation that one metal primary coordination sphere can display a range of functions and levels of activity, leading to the realization that secondary coordination sphere (SCS) interactions are critically important. However, SCS interactions are numerous, long-range, and weak, making them very difficult to reproduce in ArMs. Furthermore, natural enzymes are tied to a small set of biologically available functional moieties from canonical amino acids and physiologically available metal ions and metallocofactors, severely limiting the chemical space available to probe and tune ArMs. In this Account, we summarize the use of unnatural amino acids (UAAs) and non-native metal ions and metallocofactors by our group and our collaborators to probe and modulate ArM functions. We incorporated isostructural UAAs in a type 1 copper (T1Cu) protein azurin to provide conclusive evidence that axial ligand hydrophobicity is a major determinant of T1Cu redunction potential ( E°'). Closely related work from other groups are also discussed. We also probed the role of protein backbone interactions that cannot be altered by standard mutagenesis by replacing the peptide bond with an ester linkage. We used insight gained from these studies to tune the E°' of azurin across the entire physiological range, the broadest range ever achieved in a single metalloprotein. Introducing UAA analogues of Tyr into ArM models of heme-copper oxidase (HCO) revealed a linear relationship between p Ka, E°', and activity. We also substituted non-native hemes and non-native metal ions for their native equivalents in these models to resolve several issues that were intractable in native HCOs and the closely related nitric oxide reductases, such as their roles in modulating substrate affinity, electron transfer rate, and activity. We incorporated abiological cofactors such as ferrocene and Mn(salen) into azurin and myoglobin, respectively, to stabilize these inorganic and organometallic compounds in water, confer abiological functions, tune their E°' and activity through SCS interactions, and show that the approach to metallocofactor anchoring and orientation can tune enantioselectivity and alter function. Replacing Cu in azurin with non-native Fe or Ni can impart novel activities, such as superoxide reduction and C-C bond formation. While progress was made, we have identified only a small fraction of the interactions that can be generally applied to ArMs to fine-tune their functions. Because SCS interactions are subtle and heavily interconnected, it has been difficult to characterize their effects quantitatively. It is vital to develop spectroscopic and computational techniques to detect and quantify their effects in both resting states and catalytic intermediates.


Oligodendrocytes damage in Alzheimer's disease: beta amyloid toxicity and inflammation.
Research on Alzheimer's disease (AD) focuses mainly on neuronal death and synaptic impairment induced by beta-Amyloid peptide (Abeta), events at least partially mediated by astrocyte and microglia activation. However, substantial white matter damage and its consequences on brain function warrant the study of oligodendrocytes participation in the pathogenesis and progression of AD. Here, we analyze reports on oligodendrocytes' compromise in AD and discuss some experimental data indicative of Abeta toxicity in culture. We observed that 1 microM of fibrilogenic Abeta peptide damages oligodendrocytes in vitro: while pro-inflammatory molecules (1 microg/ ml LPS + 1 ng/ml IFNgamma) or the presence of astrocytes reduced the Abeta-induced damage. This agrees with our previous results showing an astrocyte-mediated protective effect over Abeta-induced damage on hippocampal cells and modulation of the activation of microglial cells in culture. Oligodendrocytes protection by astrocytes could be, either by reduction of Abeta fibrilogenesis/deposition or prevention of oxidative damage. Likewise, the decrease of Abeta-induced damage by proinflammatory molecules could reflect the production of trophic factors by activated oligodendrocytes and/or a metabolic activation as observed during myelination. Considering the association of inflammation with neurodegenerative diseases. oligodendrocytes impairment in AD patients could potentiate cell damage under pathological conditions.


Rate of caesarean section as a process indicator of safe-motherhood programmes: the case of Kenya.
The study assessed the value of currently-available data on the rates of caesarean section as an indicator of safe-motherhood programmes. Data, collected through the routine health information system of the Ministry of Health, Kenya, were used for analyzing the available process indicators. The methodology of this study illustrates both usefulness and limitations of readily-available healthcare information. The rate of hospital-based caesarean section was 6.3% of all births (range 0.3-37%), whereas the rate of population-based caesarean section was 0.95% (range 0.1%-4%). The rate of population-based caesarean section indicates a significant unmet need for obstetric care in the rural areas and may be a useful tool for monitoring progress on safe-motherhood initiatives in poor settings. Rates of population-based caesarean section are low in Kenya, especially in the rural areas. The rate of caesarean section may be a valuable process indicator for identifying the gaps in obstetric care and may be used for advocating improvements for healthcare to the relevant authorities.


Non-Invasive Targeted Hepatic Irradiation and SPECT/CT Functional Imaging to Study Radiation-Induced Liver Damage in Small Animal Models.
Radiation therapy (RT) has traditionally not been widely used in the management of hepatic malignancies for fear of toxicity in the form of radiation-induced liver disease (RILD). Pre-clinical hepatic irradiation models can provide clinicians with better understanding of the radiation tolerance of the liver, which in turn may lead to the development of more effective cancer treatments. Previous models of hepatic irradiation are limited by either invasive laparotomy procedures, or the need to irradiate the whole or large parts of the liver using external skin markers. In the setting of modern-day radiation oncology, a truly translational animal model would require the ability to deliver RT to specific parts of the liver, through non-invasive image guidance methods. To this end, we developed a targeted hepatic irradiation model on the Small Animal Radiation Research Platform (SARRP) using contrast-enhanced cone-beam computed tomography image guidance. Using this model, we showed evidence of the early development of region-specific RILD through functional single photon emission computed tomography (SPECT) imaging.


A PECTIN METHYLESTERASE gene at the maize Ga1 locus confers male function in unilateral cross-incompatibility.
Unilateral cross-incompatibility (UCI) is a unidirectional inter/intra-population reproductive barrier when both parents are self-compatible. Maize Gametophyte factor1 (Ga1) is an intraspecific UCI system and has been utilized in breeding. However, the mechanism underlying maize UCI specificity has remained mysterious for decades. Here, we report the cloning of ZmGa1P, a pollen-expressed PECTIN METHYLESTERASE (PME) gene at the Ga1 locus that can confer the male function in the maize UCI system. Homozygous transgenic plants expressing ZmGa1P in a ga1 background can fertilize Ga1-S plants and can be fertilized by pollen of ga1 plants. ZmGa1P protein is predominantly localized to the apex of growing pollen tubes and may interact with another pollen-specific PME protein, ZmPME10-1, to maintain the state of pectin methylesterification required for pollen tube growth in Ga1-S silks. Our study discloses a PME-mediated UCI mechanism and provides a tool to manipulate hybrid breeding.


Three distinct chromatin domains in telomere ends of polytene chromosomes in Drosophila melanogaster Tel mutants.
Drosophila melanogaster telomeric DNA is known to comprise two domains: the terminal tract of retrotransposons (HeT-A, TART and TAHRE) and telomere-associated sequences (TAS). Chromosome tips are capped by a protein complex, which is assembled on the chromosome ends independently of the underlying terminal DNA sequences. To investigate the properties of these domains in salivary gland polytene chromosomes, we made use of Tel mutants. Telomeres in this background are elongated owing to the amplification of a block of terminal retroelements. Supercompact heterochromatin is absent from the telomeres of polytene chromosomes: electron microscopy analysis identifies the telomeric cap and the tract of retroelements as a reticular material, having no discernible banding pattern, whereas TAS repeats appear as faint bands. According to the pattern of bound proteins, the cap, tract of retroelements and TAS constitute distinct and non-overlapping domains in telomeres. SUUR, HP2, SU(VAR)3-7 and H3Me3K27 localize to the cap region, as has been demonstrated for HP1. All these proteins are also found in pericentric heterochromatin. The tract of retroelements is associated with proteins characteristic for both heterochromatin (H3Me3K9) and euchromatin (H3Me3K4, JIL-1, Z4). The TAS region is enriched for H3Me3K27. PC and E(Z) are detected both in TAS and many intercalary heterochromatin regions. Telomeres complete replication earlier than heterochromatic regions. The frequency of telomeric associations in salivary gland polytene chromosomes does not depend on the SuUR gene dosage, rather it appears to be defined by the telomere length.


A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model.
Acute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention. Murine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles. We identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD. Based on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention.


Extant diversity of bryophytes emerged from successive post-Mesozoic diversification bursts.
Unraveling the macroevolutionary history of bryophytes, which arose soon after the origin of land plants but exhibit substantially lower species richness than the more recently derived angiosperms, has been challenged by the scarce fossil record. Here we demonstrate that overall estimates of net species diversification are approximately half those reported in ferns and ∼30% those described for angiosperms. Nevertheless, statistical rate analyses on time-calibrated large-scale phylogenies reveal that mosses and liverworts underwent bursts of diversification since the mid-Mesozoic. The diversification rates further increase in specific lineages towards the Cenozoic to reach, in the most recently derived lineages, values that are comparable to those reported in angiosperms. This suggests that low diversification rates do not fully account for current patterns of bryophyte species richness, and we hypothesize that, as in gymnosperms, the low extant bryophyte species richness also results from massive extinctions.


Mealybug beta-proteobacterial endosymbionts contain gamma-proteobacterial symbionts.
Some insects have cultivated intimate relationships with mutualistic bacteria since their early evolutionary history. Most ancient 'primary' endosymbionts live within the cytoplasm of large, polyploid host cells of a specialized organ (bacteriome). Within their large, ovoid bacteriomes, mealybugs (Pseudococcidae) package the intracellular endosymbionts into 'mucus-filled' spheres, which surround the host cell nucleus and occupy most of the cytoplasm. The genesis of symbiotic spheres has not been determined, and they are structurally unlike eukaryotic cell vesicles. Recent molecular phylogenetic and fluorescent in situ hybridization (FISH) studies suggested that two unrelated bacterial species may share individual host cells, and that bacteria within spheres comprise these two species. Here we show that mealybug host cells do indeed harbour both beta- and gamma-subdivision Proteobacteria, but they are not co-inhabitants of the spheres. Rather, we show that the symbiotic spheres themselves are beta-proteobacterial cells. Thus, gamma-Proteobacteria live symbiotically inside beta-Proteobacteria. This is the first report, to our knowledge, of an intracellular symbiosis involving two species of bacteria.


[Management and costs of chronic pulmonary obstructive disease in France in 2011].
To estimate the prevalence of treated chronic obstructive pulmonary disease (COPD) and its associated costs by stage of severity. The study was conducted on the 2011 data of the french general beneficiary sample database (EGB). EGB is a 1/97th sample of the whole population of the beneficiaries of the main compulsory national health insurances. COPD cases and the level of severity of the disease have been identified using new algorithms established from the available parameters in EGB. Costs were estimated using a collective perspective. The minimal prevalence of treated COPD was estimated at 3.8% in patients of 40 years and older and 1.9% regardless of the age of individuals. This population was predominantly male (58.2%) with a mean age of 68.8 years (±12.7). A total of 6.2% of patients had a health-care utilization suggestive of a very severe stage of COPD and 8.1%, 13.8% and 71.9% suggestive of severe, moderate and mild stages respectively. Over one year, 28.8% of patients visited a specialist respiratory physician, 5.0% were hospitalized (≥24h) for COPD and 6.7% died. Patients experienced an average of 1.7 (±1.5) exacerbations per year and only 61.4% received specific pharmacological treatment for COPD during the year. The average yearly health-care cost of a patient with COPD was estimated at €9382, with €5342 directly related to COPD. This study based on medico-administrative databases confirms the high epidemiological and economic burden of COPD in France.


Differential effects of ethanol in adolescent and adult rats.
Alcohol use in children and adolescents is widespread. However, very little is known about the effects of alcohol exposure during this period of postnatal development. The goal of the present study was to compare the relative sensitivity to the sedative effects of alcohol in periadolescent and adult rats. After treatment with either 4 or 5 g/kg ethanol, both 20- and 30-day-old rats regained their righting reflex significantly earlier than 60-day old rats. In 30-day-old rats, serum ethanol concentrations (SECs) were significantly greater at the time of the recovery of the righting reflex than 60-day-old rats. Developmental differences in the effects of ethanol on locomotor activity were also observed. In 60-day-old rats, 2.5 g/kg ethanol generally decreased locomotor activity. Ethanol did not significantly alter locomotor activity in 20- and 30-day-old rats. Finally there were significant developmental differences in the pharmacokinetics of ethanol with a significant delay in the time to peak SECs in 60-day-old rats relative to 20- and 30-day-old rats. These findings indicate that peri-adolescent rats are less sensitive to the sedative effects of ethanol as they recovered their righting reflex earlier and at significantly higher SECs than adult rats.


Paenibacillus contaminans sp. nov., isolated from a contaminated laboratory plate.
A bacterial strain, designated CKOBP-6T, isolated from a contaminated laboratory plate, was characterized by using a polyphasic taxonomic approach. Chemotaxonomic and morphological properties of the strain were consistent with its classification in the genus Paenibacillus. Cells were Gram-variable, aerobic, sporulating, motile rods. 16S rRNA gene sequence analysis demonstrated that this novel isolate was unique, showing 94.6 % sequence similarity to Paenibacillus chitinolyticus NBRC 15660T and lower levels of similarity to Paenibacillus gansuensis KCTC 3950T (93.8 %) and Paenibacillus terrigena A35T (93.8 %). The novel isolate could be distinguished from the type strains of all of these species based on a range of phenotypic data. The major cellular phospholipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and one unknown phosphoglycolipid. The predominant isoprenologue was an unsaturated menaquinone with seven isoprene units (MK-7). The major fatty acids of strain CKOBP-6T were C(16 : 0) (12.0 %), anteiso-C(15 : 0) (52.0 %) and iso-C(16 : 0) (16.4 %). The G+C content of the genomic DNA was 51.2 mol%. It is evident from the genotypic and phenotypic data that strain CKOBP-6T should be classified as a representative of a novel species of the genus Paenibacillus, for which the name Paenibacillus contaminans sp. nov. is proposed. The type strain is CKOBP-6T (=BCRC 17728T=LMG 24216T).


Novel trimethoprim resistance gene dfrA34 identified in Salmonella Heidelberg in the USA.
Trimethoprim/sulfamethoxazole is a synthetic antibiotic combination recommended for the treatment of complicated non-typhoidal Salmonella infections in humans. Resistance to trimethoprim/sulfamethoxazole is mediated by the acquisition of mobile genes, requiring both a dfr gene (trimethoprim resistance) and a sul gene (sulfamethoxazole resistance) for a clinical resistance phenotype (MIC ≥4/76 mg/L). In 2017, the CDC investigated a multistate outbreak caused by a Salmonella enterica serotype Heidelberg strain with trimethoprim/sulfamethoxazole resistance, in which sul genes but no known dfr genes were detected. To characterize and describe the molecular mechanism of trimethoprim resistance in a Salmonella Heidelberg outbreak isolate. Illumina sequencing data for one outbreak isolate revealed a 588 bp ORF encoding a putative dfr gene. This gene was cloned into Escherichia coli and resistance to trimethoprim was measured by broth dilution and Etest. Phylogenetic analysis of previously reported dfrA genes was performed using MEGA. Long-read sequencing was conducted to determine the context of the novel dfr gene. The novel dfr gene, named dfrA34, conferred trimethoprim resistance (MIC ≥32 mg/L) when cloned into E. coli. Based on predicted amino acid sequences, dfrA34 shares less than 50% identity with other known dfrA genes. The dfrA34 gene is located in a class 1 integron in a multiresistance region of an IncC plasmid, adjacent to a sul gene, thus conferring clinical trimethoprim/sulfamethoxazole resistance. Additionally, dfrA34 is associated with ISCR1, enabling easy transmission between other plasmids and bacterial strains.


Binding of amphiphilic and triphilic block copolymers to lipid model membranes: the role of perfluorinated moieties.
A novel class of symmetric amphi- and triphilic (hydrophilic, lipophilic, fluorophilic) block copolymers has been investigated with respect to their interactions with lipid membranes. The amphiphilic triblock copolymer has the structure PGMA(20)-PPO(34)-PGMA(20) (GP) and it becomes triphilic after attaching perfluoroalkyl moieties (F9) to either end which leads to F(9)-PGMA(20)-PPO(34)-PGMA(20)-F(9) (F-GP). The hydrophobic poly(propylene oxide) (PPO) block is sufficiently long to span a lipid bilayer. The poly(glycerol monomethacrylate) (PGMA) blocks have a high propensity for hydrogen bonding. The hydrophobic and lipophobic perfluoroalkyl moieties have the tendency to phase segregate in aqueous as well as in hydrocarbon environments. We performed differential scanning calorimetry (DSC) measurements on polymer bound lipid vesicles under systematic variation of the bilayer thickness, the nature of the lipid headgroup, and the polymer concentration. The vesicles were composed of phosphatidylcholines (DMPC, DPPC, DAPC, DSPC) or phosphatidylethanolamines (DMPE, DPPE, POPE). We showed that GP as well as F-GP binding have membrane stabilizing and destabilizing components. PPO and F9 blocks insert into the hydrophobic part of the membrane concomitantly with PGMA block adsorption to the lipid headgroup layer. The F9 chains act as additional membrane anchors. The insertion of the PPO blocks of both GP and F-GP could be proven by 2D-NOESY NMR spectroscopy. By fluorescence microscopy we show that F-GP binding increases the porosity of POPC giant unilamellar vesicles (GUVs), allowing the influx of water soluble dyes as well as the translocation of the complete triphilic polymer and its accumulation at the GUV surface. These results open a new route for the rational design of membrane systems with specific properties.


Azadipyrromethenes: from traditional dye chemistry to leading edge applications.
Azadipyrromethenes were first described over 70 years ago as blue pigments, but now are rapidly emerging as a compound class with highly desirable near infrared photophysical properties. Since the turn of the century several routes to azadipyrromethenes have been developed and numerous post-synthesis derivatizations have allowed for their exploitation in both biological and material sciences. The relative ease of access to specifically designed derivatives is now allowing their use in multiple technological formats from real-time fluorescence imaging, to solar energy materials, to optoelectronic devices and many more. In this review we have highlighted the synthetic component of this story as it is the ability to generate the designer azadipyrromethene that opens the door to exciting applications.


Regulation of airway contractility by plasminogen activators through N-methyl-D-aspartate receptor-1.
Reactive airway disease is mediated by smooth muscle contraction initiated through several agonist-dependent pathways. Activation of type 1 N-methyl-D-aspartate receptors (NMDA-R1s) by plasminogen activators (PAs) has been linked to control of vascular tone, but their effect on airway smooth muscle contractility has not previously been studied to our knowledge. We observed that NMDA-R1s are expressed by human airway smooth muscle cells and constitutively inhibit the contraction of isolated rat tracheal rings in response to acetylcholine (Ach). Both tissue-type PA (tPA) and urokinase-type PA (uPA) bind to NMDA-R1 and reverse this effect, thereby enhancing Ach-induced tracheal contractility. Tracheal contractility initiated by Ach is reduced in rings isolated from tPA(-/-) and uPA(-/-) mice compared with their wild-type counterparts. The procontractile effect of uPA or tPA was mimicked and augmented by the nitric oxide synthase inhibitor, l-NAME. uPA and tPA further enhanced the contractility of rings denuded of epithelium, an effect that was inhibited by the NMDA-R antagonist, MK-801. Binding of PAs to NMDA-R1 and the subsequent activation of the receptor were inhibited by PA inhibitor type 1, by a PA inhibitor type 1-derived hexapeptide that recognizes the tPA and uPA docking domains, as well as by specific mutations within the docking site of tPA. These studies identify involvement of PAs and NMDA-R1 in airway contractility, and define new loci that could lead to the development of novel interventions for reactive airway disease.


The inter-relationship of diversity principles for the enhanced participation of older people in their care: a qualitative study.
The health and aged care workforce must understand and support the diverse needs of older people to enhance their care experience. We previously identified five principles of diversity training for this workforce: awareness of unconscious bias and prejudice; promotion of inclusion; access and equity; appropriate engagement; and intersectionality. This study aims to explore how these principles are considered from the perspectives of older Australians. Older people (≥65 years) receiving home care and nursing services based in Victoria, Australia were invited to participate in a home-based semi-structured interview about their experience of, or with, diversity. Interviews were thematically analysed using a priori categories based on our previous work on principles of diversity training, and themes were interpreted and expanded upon based on the participants' experiences and understanding of diversity concepts and their care needs. Fifteen older people (seven female, eight male), mean age 76 years (range 71-85 years), were interviewed. Five themes were drawn from the data. It was found that human connection through building (1) trust and rapport was highly valued as an approach by older people, crucial as a first step to understanding what is important to the older person. Identifying with (2) intersectionality, that is, the different intersecting aspects of who they are and their experiences was understood by the participants as an important framework to meet their needs. The participants were aware of (3) unconscious bias and prejudice by health professionals and its impact on their care. Participants also noted that (4) promotion of inclusion through language was important to for a positive relationship with the healthcare worker. The participants understood that to facilitate human connection, these four principles of human interaction were critical, underpinned by (5) access and equity of the system. A model articulating these relationships was developed. Health and aged care training should incorporate the five diversity principles to support older people to participate in their own care.


An up-date on the prevalence of sickle cell trait in Eastern and Western Uganda.
The first survey on sickle cell disease (SCD) done in Uganda in 1949, reported the district of Bundibugyo in Western Uganda to have the highest sickle cell trait (SCT) prevalence (45%). This is believed to be the highest in the whole world. According to the same survey, the prevalence of SCT in the districts of Mbale and Sironko in the East was 20-28%, whilst the districts of Mbarara and Ntungamo in the West had 1-5%. No follow-up surveys have been conducted over the past 60 years. SCA accounts for approximately 16.2% of all pediatric deaths in Uganda. The pattern of SCT inheritance, however, predicts likely changes in the prevalence and distribution of the SCT. The objective of the study therefore was to establish the current prevalence of the SCT in Uganda. This study was a cross sectional survey which was carried out in the districts of Mbale and Sironko in the Eastern, Mbarara/Ntungamo and Bundibugyo in Western Uganda. The participants were children (6 months-5 yrs). Blood was collected from each subject and analyzed for hemoglobin S using cellulose acetate Hb electrophoresis. The established prevalence of the SCT (As) in Eastern Uganda was 17.5% compared to 13.4% and 3% in Bundibugyo and Mbarara/Ntungamo respectively. 1.7% of the children in Eastern Uganda tested positive for haemoglobin ss relative to 3% in Bundibugyo, giving gene frequencies of 0.105 and 0.097 for the recessive gene respectively. No ss was detected in Mbarara/Ntungamo. A shift in the prevalence of the SCT and ss in Uganda is notable and may be explained by several biological and social factors. This study offers some evidence for the possible outcome of intermarriages in reducing the incidence of the SCT.


Evolution of functionally conserved enhancers can be accelerated in large populations: a population-genetic model.
The evolution of cis-regulatory elements (or enhancers) appears to proceed at dramatically different rates in different taxa. Vertebrate enhancers are often very highly conserved in their sequences, and relative positions, across distantly related taxa. In contrast, functionally equivalent enhancers in closely related Drosophila species can differ greatly in their sequences and spatial organization. We present a population-genetic model to explain this difference. The model examines the dynamics of fixation of pairs of individually deleterious, but compensating, mutations. As expected, small populations are predicted to have a high rate of evolution, and the rate decreases with increasing population size. In contrast to previous models, however, this model predicts that the rate of evolution by pairs of compensatory mutations increases dramatically for population sizes above several thousand individuals, to the point of greatly exceeding the neutral rate. Application of this model predicts that species with moderate population sizes will have relatively conserved enhancers, whereas species with larger populations will be expected to evolve their enhancers at much higher rates. We propose that the different degree of conservation seen in vertebrate and Drosophila enhancers may be explained solely by differences in their population sizes and generation times.


Spillover of cytokines and reactive oxygen species in ventilator-induced lung injury associated with inflammation and apoptosis in distal organs.
The mechanism between ventilator-induced lung injury (VILI) and multiple organ injury is unclear. The aim of our study was to investigate the mechanisms of VILI-induced distal organ injury. VILI was induced in rat lungs with high tidal volume (V(T)) ventilation of 40 mL/kg for 6 h. Rats with low V(T) ventilation of 6 mL/kg served as controls. Inflammatory and apoptotic indices in lung and distal organs were assessed. VILI increased lung weight, airway pressure, inflammation, and apoptotic pathologic changes without hemodynamic changes. The white blood cell count and the levels of H2O2, interleukin-1β (IL-1β), tumor necrosis factor alpha, and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid were higher in the VILI group compared with the control group. H2O2, IL-1β, and tumor necrosis factor alpha in blood from the left ventricle were up-regulated. H2O2, IL-1β, tumor necrosis factor alpha, macrophage inflammatory protein-2, c-Jun N-terminal kinase, p38, nuclear factor kappa B, and caspase-3 in lung, heart, liver, and kidney tissues in the VILI group were up-regulated. Furthermore, the apoptotic score for the kidneys was higher than those for other distal organs in the VILI group. High V(T) ventilation induces VILI and is associated with inflammation and apoptosis in distal organs. Up-regulation of reactive oxygen species and cytokines in VILI is associated with systemic inflammatory responses. Kidney tissue appears to be more vulnerable than heart and liver tissues following VILI.


Pathological changes in the brains of mice infected with Toxoplasma gondii: a histological, immunocytochemical and ultrastructural study.
The pathological changes in the brains of mice infected with T. gondii were studied at various intervals between 7 days and 22 months post-infection using histology, immunocytochemistry and electron microscopy. Initially, a few single parasites were observed (day 7) but necrotic lesions and microglial and inflammatory nodules rapidly appeared (9-I4 days). The majority of the lesions between days 9 and I4 contained proliferating toxoplasma and early cyst formation but from 2I days onwards the vast majority of nodules contained neither parasites nor Toxoplasma antigen. Intact intracellular cysts persisted throughout the period of study eliciting no host response. A generalized meningoencephalitis developed by day II and persisted with varying degrees of severity throughout the 22 months studied. At first, the inflammatory cells consisted of lymphocytes and monocyte/macrophages but during the chronic phase plasma cells predominated. In chronic infections, the number of microglial/inflammatory nodules was relatively constant with only a few containing toxoplasmic material resulting from recent cyst rupture. A few brains contained small nodules of dystrophic calcification. This study shows that in these asymptomatic animals, the major feature is perivascular cuffing by mononuclear cells and localized microglial/inflammatory nodules. After the development of the chronic state, there is no obvious increase or decrease in the severity of the pathological changes with time.


Flemingins G-O, cytotoxic and antioxidant constituents of the leaves of Flemingia grahamiana.
The known flemingins A-C (1-3) and nine new chalcones, named flemingins G-O (4-12), along with deoxyhomoflemingin (13) and emodin (14) were isolated from a leaf extract of Flemingia grahamiana. The isolated chalcones were found to have a geranyl substituent modified into a chromene ring possessing a residual chain, as shown by spectroscopic methods. The leaf extract showed an IC50 value of 5.9 μg/mL in a DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay. The chalcones flemingins A, B, C, G, and H were active in the DPPH radical scavenging assay (ED50 4.4-8.9 μM), while flemingins A and C showed cytotoxicity against MCF-7 human breast cancer cells (IC50 8.9 and 7.6 μM, respectively).


Comparing the efficacy of cyclooxygenase 2-specific inhibitors in treating osteoarthritis: appropriate trial design considerations and results of a randomized, placebo-controlled trial.
To compare the efficacy of the cyclooxygenase 2 (COX-2)-specific inhibitors celecoxib and rofecoxib in treating the signs and symptoms of osteoarthritis (OA). In this randomized, placebo-controlled, double-blind, multicenter study, 475 patients with OA of the knee received either celecoxib 200 mg/day (n = 189), rofecoxib 25 mg/day (n = 190), or placebo (n = 96) for 6 weeks. Arthritis assessments were performed at baseline, week 3, and week 6 (or at the time of early termination). In primary measures of efficacy (OA pain score on a 100-mm visual analog scale [VAS] and total domain score on the Western Ontario and McMaster Universities Osteoarthritis Index), celecoxib 200 mg/day and rofecoxib 25 mg/day demonstrated similar efficacy. At week 6, celecoxib was associated with a 34-mm mean improvement on the VAS for OA pain, compared with 31.6 mm for rofecoxib and 21.2 mm for placebo. The difference between celecoxib and rofecoxib was -2.5 mm, with an upper limit of the 95% confidence interval of 2.7 mm and within the prespecified definition of noninferiority. Secondary measures of efficacy showed similar results. All differences in primary and secondary measures of efficacy between the 2 active treatments and placebo were statistically significant (P < 0.02), whereas all of the comparisons of efficacy between celecoxib and rofecoxib met the predefined criteria for noninferiority. All treatments were well tolerated throughout the study, with similar proportions of patients withdrawing due to adverse events. Celecoxib 200 mg/day and rofecoxib 25 mg/day are equally efficacious in treating the signs and symptoms of OA.


Short-term effects of yoghurt containing a novel fat emulsion on energy and macronutrient intakes in non-obese subjects.
The satiating properties of fat remain poorly understood, particularly with reference to its physicochemical characteristics. To investigate the short-term effects of consumption of yoghurt containing either a novel fat emulsion or normal milk fat, on the energy and macronutrient intakes of non-obese subjects. Two double-blind, placebo-controlled, within-subject crossover studies were conducted three months apart. Twenty-nine (15 F, 14 M) and thirty (16 F, 14 M) subjects participated in Study 1 and Study 2 respectively. In each study, subjects were given in random order, 7 days apart, either a 200g portion of a test (5g of a novel fat emulsion + 1 g milk fat) or control (6g milk fat) yoghurt at 1300 h. At 4h post-consumption subjects were given ad libitum access to a range of foods. Amounts of food consumed by individuals were determined by pre- and post-covert weighing of individual serving dishes. Mean energy intakes were significantly lower after the test yoghurt compared with the control yoghurt in Study 1 (6.4 vs 7.6 MJ; P< 0.001), Study 2 (6.9 vs 7.9 MJ; P<0.001), and for both studies combined (6.7 vs 7.7 MJ; P<0.001). The corresponding fat intakes in Study 1, Study 2 and in the combined studies were all significantly reduced (P< 0.001). Protein and carbohydrate intakes were also significantly reduced in Study 1 (P< 0.05), Study 2 (P< 0.01), and for the combined studies (P< 0.001). These results suggest that the physicochemical characteristics of small amounts of dietary fat affect short-term satiety.


Reduced anorexigenic efficacy of leptin, but not of the melanocortin receptor agonist melanotan-II, predicts diet-induced obesity in rats.
Leptin gains access to the central nervous system where it influences activity of neuronal networks involved in ingestive behavior, neuroendocrine activity, and metabolism. In particular, the brain melanocortin (MC) system is important in leptin signaling and maintenance of energy balance. Although leptin or MC receptor insensitivity has been proposed to be associated with obesity, the present study compared central leptin and MC receptor stimulation on some of the above-mentioned parameters and investigated whether these treatments predict proneness to diet-induced obesity (DIO) in outbred Wistar rats. Third-cerebroventricular administration of equi-anorexigenic doses of leptin and of the MC agonist melanotan-II caused comparable increases in plasma ACTH and corticosterone levels and c-Fos-labeling in approximately 70% of paraventricular hypothalamic (PVN) neuronal cell bodies containing CRH. This reinforces involvement of paraventricular CRH neurons in the short-term neuroendocrine and ingestive effects of leptin and melanocortins. In the DIO prediction study, anorexigenic efficacy of melanotan-II was not correlated with any parameter linked to DIO but was highly correlated with MC in situ binding (with labeled [Nle(4),D-Phe(7)]alpha-MSH) as well as CRH immunoreactivity in the PVN of DIO rats. This suggests intricate relationships among MC signaling, the CRH system, and ingestive behavior unrelated to DIO. In the same animals, leptin's anorexigenic efficacy was not correlated with PVN MC in situ binding or CRH immunoreactivity but correlated inversely to post-DIO plasma leptin, liver weight, and abdominal adiposity, the latter being correlated to insulin resistance. Thus, differences in leptin but not MC signaling might underlie DIO, visceral obesity, and insulin resistance.


Accelerating knowledge to action: the pan-Canadian cancer control strategy.
In 2006, the federal government committed funding of $250 million over 5 years for the Canadian Partnership Against Cancer Corporation to begin implementation of the Canadian Strategy for Cancer Control (CSCC). The Partnership was established as a not-for-profit corporation designed to work actively with a broad range of stakeholders and organizations that had been engaged in the development of the CSCC and with the public more broadly. A policy experiment unto itself, the Partnership was the first disease-based organization funded at the federal level outside of government. It was charged with a mandate to enable transfer of knowledge and to catalyze coordinated and accelerated action across the country to reduce the burden of cancer. Implementation has involved establishing shared goals, objectives, and plans with participating partners. Knowledge management-incorporating pan-Canadian approaches to the identification of content, processes, technology, and culture change-was used to enable that work across the federated health care delivery system. Evaluation of the organization through independent review, the ability to achieve initiative-level targets by 2012, and progress measured using indicators of system performance was used to examine the effectiveness of the strategy and approach overall. Evaluation findings support the conclusions that Canada has made progress in achieving immediate outcomes (achievable in <5 years) associated with advancing its cancer control goals and that there is evidence that, with sustained effort, those goals will translate into a long-term (>25 years) impact on cancer. The mechanism of funding the Partnership to develop collaboration among stakeholders in cancer control to achieve coordinated action has been possible and has been enabled through the Partnership's knowledge-to-action mandate. Opportunities are available to further engage and clarify the roles of stakeholders in action, to clearly define outcomes, and to further quantify the economic benefits that have resulted from a coordinated approach. With the ongoing funding commitment to support coordinated action within a federated environment of health care delivery, there is opportunity to reduce the impact that cancer may have in the long term in Canada.


Maternal outcomes among pregnant women receiving live attenuated influenza vaccine.
Although the live attenuated influenza vaccine (LAIV) prescribing information contains warnings/precautions against use during pregnancy, administration of LAIV to pregnant women does occur. Data regarding maternal outcomes after LAIV administration during pregnancy are limited. Maternal outcomes after LAIV vaccination during pregnancy were examined. Data from a health insurance claims database that covers approximately 50 million individuals were analyzed for the six influenza seasons from 2003-2004 through 2008-2009. Emergency department (ED) visits and hospitalizations occurring within 42 days of vaccination were analyzed by primary diagnosis; outcomes were categorized as cardiopulmonary, obstetric, and other. Cohort characteristics were analyzed using descriptive statistics. Of 834,999 pregnancies identified, 138 (0·017%) were among women who received LAIV vaccinations. Of the 138 pregnant women, 13% were ≤19 years, 67% were 20-34 years, and 20% were ≥35 years of age. Eight events occurred within 42 days of vaccination: one ED visit for bronchitis, two hospitalizations for hyperemesis gravidarum and premature labor, and five ED visits/hospitalizations for common medical conditions. All outcomes identified after LAIV exposure occurred at rates similar to rates in unvaccinated pregnant women reported in the medical literature. Administration of LAIV to pregnant women is rare; the rate has remained constant since 2004-2005. In this cohort, there was no evidence of significant maternal adverse outcomes after receipt of LAIV. These data may offer some reassurance to providers and pregnant women in the event of inadvertent LAIV administration, but do not support the routine use of LAIV in pregnant women.


Moving to Opportunity: does long-term exposure to 'low-poverty' neighborhoods make a difference for adolescents?
This study re-analyzed data on adolescent health outcomes (N = 1780; M age = 15.15, SD = 2.30) from a 5-year evaluation of the Moving to Opportunity (MTO) Program. The MTO program is a randomized experiment conducted in five cities in the United States (Baltimore, Boston, Chicago, Los Angeles and New York) in which low-income families living in public housing in 'high-poverty' neighborhoods were offered vouchers and assistance to move to 'low-poverty' neighborhoods. The objective was to reexamine program effects as a function of exposure to 'low-poverty' neighborhoods to determine whether beneficial effects reported for girls' mental health and behavior generalized to other outcomes for girls and to boys. As found in previous evaluations, girls in the MTO program group, whose families remained in 'low-poverty' neighborhoods for comparatively long periods (approximately 5 years), had better mental health and engaged in fewer risky behaviors than a matched control sample of girls, whose families stayed in 'high-poverty' neighborhoods. Further, additional benefits for girls were seen in the education domain. Adverse program effects on boys' behavior problems, reported in other MTO research using different methods, were not evident in our analysis. Findings suggest that programs relocating low-income families to 'low-poverty' neighborhoods should provide supports to families and to receiving communities to promote residential stability and social integration.


[Mortality from malignant melanoma: epidemiological trends in Switzerland].
The skin doesn't forget damage by sun exposure (sunburn, ultraviolet radiation). Indeed, melanoma mortality increases quite linearly with rising age. For Swiss nationals the sex ratio of mortality rates is 1.7, i.e. risks for male foreigners and Swiss females are of similar size. However, in younger Swiss men (35 to 44 years) mortality rates between 1979/83 and 1997/2001 diminished by 66% (p < 0.02). Analyses of mortality by occupational groups revealed that indoor working males like graduates and employees with commercial or technical education have an increased risk. The results support the association between melanoma risk and intermittent sun exposure, outdoor workers with chronic sunlight exposure being slightly protected. Further declines in mortality may be expected with skin cancer prevention campaigns improving sun exposure behaviour.


Pattern-Driven Navigation in 2D Multiscale Visualizations with Scalable Insets.
We present Scalable Insets, a technique for interactively exploring and navigating large numbers of annotated patterns in multiscale visualizations such as gigapixel images, matrices, or maps. Exploration of many but sparsely-distributed patterns in multiscale visualizations is challenging as visual representations change across zoom levels, context and navigational cues get lost upon zooming, and navigation is time consuming. Our technique visualizes annotated patterns too small to be identifiable at certain zoom levels using insets, i.e., magnified thumbnail views of the annotated patterns. Insets support users in searching, comparing, and contextualizing patterns while reducing the amount of navigation needed. They are dynamically placed either within the viewport or along the boundary of the viewport to offer a compromise between locality and context preservation. Annotated patterns are interactively clustered by location and type. They are visually represented as an aggregated inset to provide scalable exploration within a single viewport. In a controlled user study with 18 participants, we found that Scalable Insets can speed up visual search and improve the accuracy of pattern comparison at the cost of slower frequency estimation compared to a baseline technique. A second study with 6 experts in the field of genomics showed that Scalable Insets is easy to learn and provides first insights into how Scalable Insets can be applied in an open-ended data exploration scenario.


Current trends in supraventricular tachycardia management.
Supraventricular tachycardia (SVT) is a general term describing a group of arrhythmias whose mechanism involves or is above the atrioventricular node. The mechanisms of most forms of SVT have been elucidated, and pharmacologic and invasive therapies have evolved simultaneously. We provide a brief overview of the mechanisms, classifications, and electrocardiographic characteristics of different SVTs and describe current trends in noninvasive and invasive therapies. The term SVT encompasses a heterogeneous group of arrhythmias with different electrophysiologic characteristics. Knowledge of the mechanism of each SVT is important in determining management at the bedside and in the electrophysiology laboratory. In the acute setting, vagal maneuvers and pharmacologic therapy can be effective in arrhythmia termination. Catheter-based radiofrequency ablation has revolutionized therapy for many SVTs, and newer techniques have significantly improved ablation efficacy and reduced periprocedural complications and procedure times. Cryoablation is currently being investigated as an alternative form of energy delivery, although the long-term effectiveness of this procedure currently limits its use for many SVTs.


Perceptions of oral health by those living with mental illnesses in the Victorian Community - The consumer's perspective.
To understand the way people living with mental illness in an Australian community experience and define oral health. People living with serious mental illness in the Victorian Community. Qualitative methodologies were used in this study. Two focus groups and four semi-structured interviews were conducted. The data were transcribed and thematically analysed. Participants generally valued oral health and recognized that attending regular dental appointments played a key role in improving their oral health. Participants felt that their mental illness overwhelmed their ability to maintain good oral health. Coping, dental fear, stigma, financial barriers and communication were identified as issues around utilization and access to care. Experiences of oral health were both positive and negative. Barriers and enablers, extending beyond participant oral health literacy for oral health, were identified from the data, and recommendations around personal, environmental and clinical supports were made. This is a valuable study that provides new insight into a complicated issue. Recommendations to create a supportive dental environment and direction to improve the dental experience have been made to make oral health more accessible for people living with mental illness. Recommendations have also been made for community-based mental health organizations to aid the improvements in oral health with this group of people, thus building a collaborative approach to support oral health for this vulnerable group.


Efficient hybrid de novo assembly of human genomes with WENGAN.
Generating accurate genome assemblies of large, repeat-rich human genomes has proved difficult using only long, error-prone reads, and most human genomes assembled from long reads add accurate short reads to polish the consensus sequence. Here we report an algorithm for hybrid assembly, WENGAN, that provides very high quality at low computational cost. We demonstrate de novo assembly of four human genomes using a combination of sequencing data generated on ONT PromethION, PacBio Sequel, Illumina and MGI technology. WENGAN implements efficient algorithms to improve assembly contiguity as well as consensus quality. The resulting genome assemblies have high contiguity (contig NG50: 17.24-80.64 Mb), few assembly errors (contig NGA50: 11.8-59.59 Mb), good consensus quality (QV: 27.84-42.88) and high gene completeness (BUSCO complete: 94.6-95.2%), while consuming low computational resources (CPU hours: 187-1,200). In particular, the WENGAN assembly of the haploid CHM13 sample achieved a contig NG50 of 80.64 Mb (NGA50: 59.59 Mb), which surpasses the contiguity of the current human reference genome (GRCh38 contig NG50: 57.88 Mb).


Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered thalidomide.
The clinical use of irinotecan (CPT-11) is hindered by dose-limiting diarrhea and myelosuppression. Recent clinical studies indicate that thalidomide, a known tumor necrosis factor-alpha inhibitor, ameliorated the toxicities induced by CPT-11. However, the mechanisms for this are unknown. This study aimed to investigate whether combination of thalidomide modulated the toxicities of CPT-11 using a rat model and the possible role of the altered pharmacokinetic component in the toxicity modulation using in vitro models. The toxicity model was constructed by treatment of healthy rats with CPT-11 at 60 mg/kg per day by intravenous (i.v.) injection. Body weight, acute and delayed-onset diarrhea, blood cell counts, and macroscopic and microscopic intestinal damages were monitored in rats treated with CPT-11 alone or combined therapy with thalidomide at 100 mg/kg administered by intraperitoneal (i.p.) injection. Single dose and 5-day multiple-dose studies were conducted in rats to examine the effects of concomitant thalidomide on the plasma pharmacokinetics of CPT-11 and its major metabolites SN-38 and SN-38 glucuronide (SN-38G). The effect of CPT-11 on thalidomide's pharmacokinetics was also checked. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were used to study the in vitro metabolic interactions between these two drugs. H4-II-E cells were also used to investigate the effect of thalidomide and its hydrolytic products on the transport of CPT-11 and SN-38. In addition, the effect of thalidomide and its hydrolytic products on rat plasma protein binding of CPT-11 and SN-38 was examined. Administration of CPT-11 by i.v. for 4 consecutive days to rats induced significant body weight loss, decrease in neutrophil and lymphocyte counts, severe acute- and delayed-onset diarrhea, and intestinal damages. These toxicities were alleviated when CPT-11 was combined with thalidomide. In both single-dose and 5-day multiple-dose pharmacokinetic study, coadministered thalidomide significantly increased the area under the plasma concentration-time curve (AUC) of CPT-11, but the AUC and elimination half-life (t(1/2)) of SN-38 were significantly decreased. However, CPT-11 did not significantly alter the pharmacokinetics of thalidomide. Thalidomide at 25 and 250 microM and its hydrolytic products at a total concentration of 10 microM had no significant effect on the plasma protein binding of CPT-11 and SN-38, except for that thalidomide at 250 microM caused a significant increase in the unbound fraction (f(u)) of CPT-11 by 6.7% (P < 0.05). The hydrolytic products of thalidomide (total concentration of 10 microM), but not thalidomide, significantly decreased CPT-11 hydrolysis by 16% in rat liver microsomes (P < 0.01). The formation of both SN-38 and SN-38G from CPT-11, SN-38 glucuronidation, or intracellular accumulation of both CPT-11 and SN-38 in H4-II-E cells followed Michaelis-Menten kinetics with the one-binding site model being the best fit for the kinetic data. Coincubation or 2-hr preincubation of thalidomide at 25 microM and 250 microM and its hydrolytic products at 10 microM did not show any significant effects on CPT-11 hydrolysis and SN-38 glucuronidation. However, preincubation of H4-II-E cells with thalidomide (250 microM), its hydrolytic products (total concentration of 10 microM), or phthaloyl glutamic acid (one major thalidomide hydrolytic product, 10 microM) significantly increased the intracellular accumulation of SN-38, but not CPT-11 (P < 0.01). The dose-limiting toxicities of CPT-11 were alleviated by combination with thalidomide in rats and the pharmacokinetic modulation by thalidomide may partially explain its antagonizing effects on the toxicities of CPT-11. The hydrolytic products of thalidomide, instead of the parental drug, modulated the hepatic hydrolysis of CPT-11 and intracellular accumulation of SN-38, probably contributing to the altered plasma pharmacokinetics of CPT-11 and SN-38. Further studies are needed to explore the role of both pharmacokinetics and pharmacodynamic components in the protective effect of thalidomide against the toxicities of CPT-11.


Modification of Proteins Using Olefin Metathesis.
Olefin metathesis has revolutionized synthetic approaches to carbon-carbon bond formation. With a rich history beginning in industrial settings through its advancement in academic laboratories leading to new and highly active metathesis catalysts, olefin metathesis has found use in the generation of complex natural products, the cyclization of bioactive materials, and in the polymerization of new and unique polymer architectures. Throughout this review, we will trace the deployment of olefin metathesis-based strategies for the modification of proteins, a process which has been facilitated by the extensive development of stable, isolable, and highly active transition-metal-based metathesis catalysts. We first begin by summarizing early works which detail peptide modification strategies that played a vital role in identifying stable metathesis catalysts. We then delve into protein modification using cross metathesis and finish with recent work on the generation of protein-polymer conjugates through ring-opening metathesis polymerization.


[Assessment of psychometric properties of the academic involvement questionnaire, expectations version].
Academic Involvement Questionnaire, Expectations version (CIA-A), assesses the expectations of involvement in studies. It is a relevant predictor of student success. However, the evidence of its validity and reliability in Chile is low, and in the case of Medical students, there is no evidence at all. To evaluate the factorial structure and internal consistency of the CIA-A in Chilean Medical school freshmen. The survey was applied to 340 Medicine freshmen, chosen by non-probability quota sampling. They answered a back-translated version of CIA-A from Portuguese to Spanish, plus a sociodemographic questionnaire. For psychometric analysis of the CIA-A, an exploratory factor analysis was carried on, the reliability of the factors was calculated, a descriptive analysis was conducted and their correlation was assessed. Five factors were identified: vocational, institutional and social involvement, use of resources and student participation. Their reliabilities ranged between Cronbach's alpha values of 0.71 to 0.87. Factors also showed statistically significant correlations between each other. Identified factor structure is theoretically consistent with the structure of original version. It just disagrees in one factor. In addition, the factors' internal consistency were adequate for using them in research. This supports the construct validity and reliability of the CIA-A to assess involvement expectations in medical school freshmen.


Controlled Low-Pressure Blast-Wave Exposure Causes Distinct Behavioral and Morphological Responses Modelling Mild Traumatic Brain Injury, Post-Traumatic Stress Disorder, and Comorbid Mild Traumatic Brain Injury-Post-Traumatic Stress Disorder.
The intense focus in the clinical literature on the mental and neurocognitive sequelae of explosive blast-wave exposure, especially when comorbid with post-traumatic stress-related disorders (PTSD) is justified, and warrants the design of translationally valid animal studies to provide valid complementary basic data. We employed a controlled experimental blast-wave paradigm in which unanesthetized animals were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast-wave produced by exploding a thin copper wire. By combining cognitive-behavioral paradigms and ex vivo brain MRI to assess mild traumatic brain injury (mTBI) phenotype with a validated behavioral model for PTSD, complemented by morphological assessments, this study sought to examine our ability to evaluate the biobehavioral effects of low-intensity blast overpressure on rats, in a translationally valid manner. There were no significant differences between blast- and sham-exposed rats on motor coordination and strength, or sensory function. Whereas most male rats exposed to the blast-wave displayed normal behavioral and cognitive responses, 23.6% of the rats displayed a significant retardation of spatial learning acquisition, fulfilling criteria for mTBI-like responses. In addition, 5.4% of the blast-exposed animals displayed an extreme response in the behavioral tasks used to define PTSD-like criteria, whereas 10.9% of the rats developed both long-lasting and progressively worsening behavioral and cognitive "symptoms," suggesting comorbid PTSD-mTBI-like behavioral and cognitive response patterns. Neither group displayed changes on MRI. Exposure to experimental blast-wave elicited distinct behavioral and morphological responses modelling mTBI-like, PTSD-like, and comorbid mTBI-PTSD-like responses. This experimental animal model can be a useful tool for elucidating neurobiological mechanisms underlying the effects of blast-wave-induced mTBI and PTSD and comorbid mTBI-PTSD.


A death with dignity in Oregon.
To inform readers about the Oregon Death With Dignity Act and present a compilation and summary of major arguments in debates regarding physician assistance in dying for the terminally ill. Experience, medical records, the patient's physician and family, books, periodicals, legislative documents, and publications. The Oregon Death With Dignity Act became a legal option for terminally ill Oregon residents in October 1997. Persuasive psychological, theological, philosophical, and pragmatic arguments protest the Act as being irrational, immoral, contrary to medical ethics, and dangerous. Equally persuasive arguments advocate the Act as rational, moral, consistent with the practice of healing, and safe. Physician assistance in dying is a legal option for terminally ill patients in the State of Oregon. For such a practice to be "out of the closet," as well as legal, is novel. The debate about the appropriateness of this Act revolves around values and beliefs that are seasoned and cherished. As the practice of the terminally ill requesting physician assistance to die moves into the realm of a rational patient choice and legal physician action, nurses increasingly will be faced with having to deal with their own beliefs, attitudes, and emotions regarding this issue. Nurses cannot hide behind glib responses, quick referals, institutional policies, or organizational standards to cover their own discomfort or confusion. They must discuss and formulate an understanding of healing and caring in situations that may challenge their core values.


From concept to application: the impact of a community-wide intervention to improve the delivery of preventive services to children.
To improve health outcomes of children, the US Maternal and Child Health Bureau has recommended more effective organization of preventive services within primary care practices and more coordination between practices and community-based agencies. However, applying these recommendations in communities is challenging because they require both more complex systems of care delivery within organizations and more complex interactions between them. To improve the way that preventive health care services are organized and delivered in 1 community, we designed, implemented, and assessed the impact of a health care system-level approach, which involved addressing multiple care delivery processes, at multiple levels in the community, the practice, and the family. Our objective was to improve the processes of preventive services delivery to all children in a defined geographic community, with particular attention to health outcomes for low-income mothers and infants. Observational intervention study in 1 North Carolina county (population 182 000) involving low- income pregnant mothers and their infants, primary care practices, and departments of health and mental health. An interrupted time-series design was used to assess rates of preventive services in office practices before and after the intervention, and a historical cohort design was used to compare maternal and child health outcomes for women enrolled in an intensive home visiting program with women who sought prenatal care during the 9 months before the program's initiation. Outcomes were assessed when the infants reached 12 months of age. Our primary objective was to achieve changes in the process of care delivery at the level of the clinical interaction between care providers and patients that would lead to improved health and developmental outcomes for families. We selected interventions that were directed toward major risk factors (eg, poverty, ineffective care systems for preventive care in office practices) and for which there was existing evidence of efficacy. The interventions involved community-, practice-, and family-level strategies to improve processes of care delivery to families and children. The objectives of the community-level intervention were: 1) to achieve policy level changes that would result in changes in resources available at the level of clinical care, 2) to engage multiple practice organizations in the intervention to achieve an effect on most, if not all, families in the community, and 3) to enhance communication between, among, and within public and private practice organizations to improve coordination and avoid duplication of services. The objective of the practice-level interventions was to overcome specific barriers in the process of care delivery so that preventive services could be effectively delivered. To assist the health department in implementing the family-level intervention, we provided assistance in hiring and training staff and ongoing consultation on staff supervision, including the use of structured protocols for care delivery, and regular feedback data about implementation of the program. Interventions with primary care practices focused on the design of the delivery system within the office and the use of teamwork and data in an "office systems" approach to improving clinical preventive care. All practices (N = 8) that enrolled at least 5 infants/month received help in assessing performance and developing systems (eg, preventive services flow sheets) for preventive services delivery. Family-level interventions addressed the process of care delivery to high-risk pregnant women (<100% poverty) and their infants. Mothers were recruited for the home visiting intervention when they first sought prenatal care at the community health center, the county's largest provider of prenatal care to underserved women. The home visiting intervention involved teams of nurses and educators and involved 2 to 4 visits per month through the infant's first year of life to provide parental education on fetal and infant health and development, enhance parents' informal support systems, and link parents with needed health and human services. We included training in injury prevention and discipline, and home visitors assisted mothers in obtaining care from one of the primary care offices. There were high levels of participation, changes in the organization of the delivery system, and improvements in preventive health outcomes. Agencies cooperated in joint contracting, staff training, and defining program eligibility. All 8 eligible practices agreed to participate and 7/8 implemented at least 1 new office system element. Of eligible women, 89% agreed to participate, and outcome data were available on 80% (180/225). After adjusting for differences in baseline characteristics, intervention group women were significantly more likely than comparison group women to use contraceptives (69% vs 47%), not smoke tobacco (27% vs 54%) and have a safe and stimulating home environment for their children. Intervention group children were more likely to have had an appropriate number of well-child care visits (57% vs 37%) and less likely to be injured (2% vs 7%). Intervention mothers also received Aid to Families with Dependent Children for fewer months after the birth of their child (7.7 months vs 11.3 months). We observed a number of positive effects at all 3 levels of intervention. Policy-level changes at the state and community led to lasting changes in the organization and financing of care, which enabled changes in clinical services to take place. These changes have now been expanded beyond this community to other communities in the state. We were also able to engage multiple practice organizations, reduce duplication, and improve the coordination of care. Changes in the process of preventive services delivery were noted in participating practices. Finally, the outcomes of the family-level intervention were comparable in direction and magnitude to the outcomes of previous randomized trials of the intervention. All the changes were achieved over a relatively brief 3-year study period, and many have been sustained since the project was completed. Tiered, interrelated interventions directed at an entire population of mothers and children hold promise to improve the effectiveness and outcomes of health care for families and children.


Asymmetric synthesis of highly functionalized spirothiazolidinone tetrahydroquinolines via a squaramide-catalyzed cascade reaction.
A bifunctional squaramide-catalyzed asymmetric cascade aza-Michael/Michael addition reaction for the synthesis of chiral spirothiazolidinone tetrahydroquinolines with three contiguous stereocenters has been developed. This cascade reaction proceeded well under mild conditions, and afforded the desired products in high to excellent yields (up to >99% yield) with excellent diastereoselectivities (>25 : 1 dr) and high enantioselectivities (up to 96% ee). More importantly, both the amplification and the derivation experiments do not affect the stereoselectivity.


Imidacloprid slows the development of preference for rewarding food sources in bumblebees (Bombus impatiens).
Bee pollination is economically and ecologically vital and recent declines in bee populations are therefore a concern. One possible cause of bee declines is pesticide use. Bumblebees exposed to imidacloprid, a neonicotinoid pesticide, have been shown to be less efficient foragers and collect less pollen on foraging trips than unexposed bees. We investigated whether bumblebees (Bombus impatiens) chronically exposed to imidacloprid at field-realistic levels of 2.6 and 10 ppb showed learning deficits that could affect foraging. Bumblebees were tested for their ability to associate flower colour with reward value in a simulated foraging environment. Bumblebees completed 10 foraging trips in which they collected sucrose solution from artificial flowers that varied in sucrose concentration. The reward quality of each artificial flower was predicted by corolla colour. Unexposed bumblebees acquired a preference for feeding on the most rewarding flower colour on the second foraging trip, while bumblebees exposed at 2.6 and 10 ppb did not until their third and fifth trip, respectively. The delay in preference acquisition in exposed bumblebees may be due to reduced flower sampling and shorter foraging trips. These results show that bumblebees exposed to imidacloprid are slow to learn the reward value of flowers and this may explain previously observed foraging inefficiencies associated with pesticide exposure.


Efficacy and safety of pemetrexed plus cisplatin as first-line chemotherapy in advanced malignant peritoneal mesothelioma.
Malignant peritoneal mesothelioma (MPeM) is a rare cancer for which no standard systemic chemotherapy has been established. While cisplatin plus pemetrexed, the standard treatment for malignant pleural mesothelioma (MPlM), is usually used for MPeM, its efficacy remains unclear. We retrospectively reviewed the medical charts of MPeM patients who had received cisplatin plus pemetrexed as first-line chemotherapy between January 2001 and July 2016 at the National Cancer Center Hospital. Patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day1, repeated every 3 weeks until progressive disease, unacceptable toxicities or patient's refusal to continue. A total of 29 MPeM patients received cisplatin plus pemetrexed. Median progression-free survival and overall survival were 7.1 months (95% CI: 4.8-9.3) and 15.4 months (95% CI: 9.5-21.2), respectively. Among 16 patients with measurable lesions, the response rate was 38%. Incidences of grade 3/4 leukopenia, neutropenia, anemia and thrombocytopenia were 21%, 17%, 14% and 3%, respectively. Non-hematological toxicities were mild, and there were no treatment-related deaths. Cisplatin plus pemetrexed, showing consistent efficacy with MPlM, can be recommended as first-line treatment for unresectable MPeM patients.


Preparation of a Breadfruit Flour Bar.
Breadfruit is a nutritious, high energy food with a low quantity of protein but excellent protein quality. It has the potential to be developed into desired products which will help increase its utilization and add value to the crop. The overall purposes of this investigation were to develop a portable, nutritious, ready-to-eat breadfruit product (bar), test the sensory qualities of the product, and evaluate the nutritional properties of the product. Flour made from the Micronesian variety, Meinpadahk (Artocarpus altilis × Artocarpus mariannensis), was utilized for the development of the breadfruit bar. Breadfruit is a rich source of fiber, vitamins such as vitamin C, minerals such as potassium, and phytochemicals such as flavonoids. Nutritional labeling indicates that the breadfruit bar is high in carbohydrates and low in fat, and sensory evaluation indicates that 81% of the panelists found the bar acceptable while 19% disliked the bar. The breadfruit bar can provide an appealing and inexpensive gluten-free food source based on locally available breadfruit.


Decade-long trends in the timeliness of receipt of a primary percutaneous coronary intervention.
The purpose of this study was to examine decade-long trends (2001-2011) in, and factors associated with, door-to-balloon time within 90 minutes of hospital presentation among patients hospitalized with ST-segment elevation myocardial infarction (STEMI) who received a primary percutaneous coronary intervention (PCI). Residents of central Massachusetts hospitalized with STEMI who received a primary PCI at two major PCI-capable medical centers in central Massachusetts on a biennial basis between 2001 and 2011 comprised the study population (n=629). Multivariable regression analyses were used to examine factors associated with failing to receive a primary PCI within 90 minutes after emergency department (ED) arrival. The average age of this patient population was 61.9 years; 30.5% were women, and 91.7% were White. During the years under study, 50.9% of patients received a primary PCI within 90 minutes of ED arrival; this proportion increased from 2001/2003 (17.2%) to 2009/2011 (70.5%) (P<0.001). Having previously undergone coronary artery bypass graft surgery, arriving at the ED by car/walk-in and during off-hours were significantly associated with a higher risk of failing to receive a primary PCI within 90 minutes of ED arrival. The likelihood of receiving a timely primary PCI in residents of central Massachusetts hospitalized with STEMI at the major teaching/community medical centers increased dramatically during the years under study. Several groups were identified for purposes of heightened surveillance and intervention efforts to reduce the likelihood of failing to receive a timely primary PCI among patients acutely diagnosed with STEMI.


Genomic and transcriptomic characterization of Pseudomonas aeruginosa small colony variants derived from a chronic infection model.
Phenotypic change is a hallmark of bacterial adaptation during chronic infection. In the case of chronic Pseudomonas aeruginosa lung infection in patients with cystic fibrosis, well-characterized phenotypic variants include mucoid and small colony variants (SCVs). It has previously been shown that SCVs can be reproducibly isolated from the murine lung following the establishment of chronic infection with mucoid P. aeruginosa strain NH57388A. Using a combination of single-molecule real-time (PacBio) and Illumina sequencing we identify a large genomic inversion in the SCV through recombination between homologous regions of two rRNA operons and an associated truncation of one of the 16S rRNA genes and suggest this may be the genetic switch for conversion to the SCV phenotype. This phenotypic conversion is associated with large-scale transcriptional changes distributed throughout the genome. This global rewiring of the cellular transcriptomic output results in changes to normally differentially regulated genes that modulate resistance to oxidative stress, central metabolism and virulence. These changes are of clinical relevance because the appearance of SCVs during chronic infection is associated with declining lung function.


Sexually transmitted infections in polygamous mating systems.
Sexually transmitted infections (STIs) are often associated with chronic diseases and can have severe impacts on host reproductive success. For airborne or socially transmitted pathogens, patterns of contact by which the infection spreads tend to be dispersed and each contact may be of very short duration. By contrast, the transmission pathways for STIs are usually characterized by repeated contacts with a small subset of the population. Here we review how heterogeneity in sexual contact patterns can influence epidemiological dynamics, and present a simple model of polygyny/polyandry to illustrate the impact of biased mating systems on disease incidence and pathogen virulence.


Current concepts in the management of idiopathic sudden sensorineural hearing loss.
The purpose of this manuscript is to review the initial management strategies for idiopathic sudden sensorineural hearing loss, with an emphasis on the role that steroids play in treatment of this condition, and discuss options for auditory rehabilitation of persistent unilateral hearing loss. Recent data suggest that hearing improvement may be greater for patients initially treated with both systemic and intratympanic steroid when compared with those treated with systemic steroids alone. Salvage intratympanic steroids have been shown to confer hearing benefit if initial management fails. The ideal dosing regimen for intratympanic steroids has not been established, but evidence supports that higher dosing strategies are advantageous. Cochlear implantation has emerged as a strategy for auditory rehabilitation of persistent unilateral hearing loss. Recent studies have demonstrated high patient satisfaction, subjective improvement in tinnitus, and objective performance benefit after cochlear implantation for single-sided deafness. Patients can be offered steroid therapy in the initial management of idiopathic sudden sensorineural hearing loss, but should be counseled that the efficacy of steroids remains unclear. If patients fail to improve with initial management, salvage intratympanic steroid administration should be considered. If hearing loss persists long term, options for auditory rehabilitation should be discussed.


Accelerating efforts to prevent childhood obesity: spreading, scaling, and sustaining healthy eating and physical activity.
During the past decade, progress has been made in addressing childhood obesity through policy and practice changes that encourage increased physical activity and access to healthy food. With the implementation of these strategies, an understanding of what works to prevent childhood obesity is beginning to emerge. The task now is to consider how best to spread, scale, and sustain promising childhood obesity prevention strategies. In this article we examine a project led by Nemours, a children's health system, to address childhood obesity. We describe Nemours's conceptual approach to spreading, scaling, and sustaining a childhood obesity prevention intervention. We review a component of a Nemours initiative in Delaware that focused on early care and education settings and its expansion to other states through the National Early Care and Education Learning Collaborative to prevent childhood obesity. We also discuss lessons learned. Focusing on the spreading, scaling, and sustaining of promising strategies has the potential to increase the reach and impact of efforts in obesity prevention and help ensure their impact on population health.


Graded levels of Ptf1a differentially regulate endocrine and exocrine fates in the developing pancreas.
The mechanisms regulating pancreatic endocrine versus exocrine fate are not well defined. By analyzing the effects of Ptf1a partial loss of function, we uncovered novel roles for this transcription factor in determining pancreatic fates. In a newly identified hypomorphic ptf1a mutant, pancreatic cells that would normally express ptf1a and become exocrine cells, express the endocrine marker Isl1, indicating a cell fate switch. Surprisingly, a milder reduction of Ptf1a leads to an even greater increase of ectopic endocrine cells, suggesting that Ptf1a also plays a role in promoting endocrine development. We propose that low levels of Ptf1a promote endocrine fate, whereas high levels repress endocrine fate and promote exocrine fate.


Synaptic distributions of GluA2 and PKMζ in the monkey dentate gyrus and their relationships with aging and memory.
Rhesus monkeys provide a valuable model for studying the neurobiological basis of cognitive aging, because they are vulnerable to age-related memory decline in a manner similar to humans. In this study, young and aged monkeys were first tested on a well characterized recognition memory test (delayed nonmatching-to-sample; DNMS). Then, electron microscopic immunocytochemistry was performed to determine the subcellular localization of two proteins in the hippocampal dentate gyrus (DG): the GluA2 subunit of the glutamate AMPA receptor and the atypical protein kinase C ζ isoform (PKMζ). PKMζ promotes memory storage by regulating GluA2-containing AMPA receptor trafficking. Thus, we examined whether the distribution of GluA2 and PKMζ is altered with aging in DG axospinous synapses and whether it is coupled with memory deficits. Monkeys with faster DNMS task acquisition and more accurate recognition memory exhibited higher proportions of dendritic spines coexpressing GluA2 and PKMζ. These double-labeled spines had larger synapses, as measured by postsynaptic density area, than single-labeled and unlabeled spines. Within this population of double-labeled spines, aged monkeys compared with young expressed a lower density of synaptic GluA2 immunogold labeling, which correlated with lower recognition accuracy. Additionally, higher density of synaptic PKMζ labeling in double-labeled spines correlated with both faster task acquisition and better retention. Together, these findings suggest that age-related impairment in maintenance of GluA2 at the synapse in the primate hippocampus is coupled with memory deficits.


Book lung development in juveniles and adults of the cobweb spider, Parasteatoda tepidariorum C. L. Koch, 1841 (Araneomorphae, Theridiidae).
Light and transmission electron microscopy were used to study the development of new book lung lamellae in juvenile and adult spiders (Parasteatoda tepidariorum). As hypothesized earlier in a study of embryos, mesenchyme cells dispersed throughout the opisthosoma (EMT) are a likely source of precursor epithelial cells (MET) for the new lamellae. The precursor cells in juveniles and adults continue many of the complex activities observed in embryos, e.g., migration, alignment, lumen formation, thinning, elongation, and secretion of the cuticle of air channel walls and trabeculae. The apicobasal polarity of precursor cells for new channels is apparently induced by the polarity pattern of precursor cells of channels produced earlier. Thus, new air and hemolymph channels extend and continue the alternating pattern of older channels. At sites more distant from the spiracle and atrium, new channels are usually produced by the mode II process (intracellular alignment and merging of vesicles). These air channels have bridging trabeculae and are quite stable in size throughout their length. At sites closer to the spiracle and atrium, new channels may be produced by mode I (coalescence of merocrine vesicle secretion). This raises the hypothesis that structural and functional differences in mode I and II channels and differing oxygen and fluid conditions with distance from the spiracle and atrium determine the mode of formation of new channels. Observations herein support an earlier hypothesis that there is some intercellular apical/apical and basal/basal affinity among the opposed surfaces of aligned precursor cells. This results in the alternating pattern of air channels at the apical and hemolymph channels at the basal cell surfaces.


A Phylogeny of the Gulls (Aves: Larinae) Inferred from Osteological and Integumentary Characters.
- Gulls (Aves: Larinae) are among the best-studied of birds, yet prior attempts to reconstruct gull relationships have met with little success. In the present study I use 117 characters from the skeleton and 64 from the integument to test gull monophyly and estimate gull phylogeny. One shortest tree, requiring 9747 unweighted changes and having a CI of 0.267, wasLarusis polyphyletic. Although the tree is fully resolved, support for many of the inferred clades is poor. In a comparison of osteological and integumentary evidence, I found that incongruence between the osteological and integumentary character sets accounts for only a minority of the total incongruence observed, and suggest that low between-set incongruence may be a consequence of the low signal-to-noise ratio in each set of characters. I also found that osteological evidence is particularly important for determining higher-level structure, whereas integumentary evidence is important for resolving lower-level relationships within the gull group. Finally, I found that integumentary characters are not dramatically more homoplasious than osteological characters, and argue that casual dismissal of integumentary characters as "too labile" is unwarranted.


Torsional anomalous retinal correspondence effectively expands the visual field in hemianopia.
Exotropia in congenital homonymous hemianopia has been reported to provide field expansion that is more useful when accompanied with harmonious anomalous retinal correspondence (HARC). Torsional strabismus with HARC provides a similar functional advantage. In a subject with hemianopia demonstrating a field expansion consistent with torsion, we documented torsional strabismus and torsional HARC. Monocular visual fields under binocular fixation conditions were plotted using a custom dichoptic visual field perimeter. The dichoptic visual field was also modified to measure perceived visual directions under dissociated and associated conditions across the central 50° diameter field. The field expansion and retinal correspondence of a subject with torsional strabismus (along with exotropia and right hypertropia) with congenital homonymous hemianopia was compared with that of another exotropic subject with acquired homonymous hemianopia without torsion and to a control subject with minimal phoria. Torsional rotations of the eyes were calculated from fundus photographs and perimetry. Torsional anomalous retinal correspondence documented in the subject with congenital homonymous hemianopia provided a functional binocular field expansion up to 18°. Normal retinal correspondence was mapped for the full 50° visual field in the control subject and for the seeing field of the acquired homonymous hemianopia subject, limiting the functional field expansion benefit. Torsional strabismus with anomalous retinal correspondence, when occurring with homonymous hemianopia provides useful field expansion in the lower and upper fields. Dichoptic perimetry permits documentation of ocular alignment (lateral, vertical, and torsional) and perceived visual direction under binocular and monocular viewing conditions. Evaluating patients with congenital or early strabismus for HARC is useful when considering surgical correction, particularly in the presence of congenital homonymous hemianopia.


Foveal electroretinograms and choroidal perfusion characteristics in fellow eyes of patients with unilateral neovascular age-related macular degeneration.
A prolonged choroidal filling phase on fluorescein angiography has been reported to be a common finding and associated with visual function abnormalities in patients with age-related macular degeneration (AMD). This investigation was carried out to determine whether this perfusion defect was related to the slowing of foveal cone electroretinogram (ERG) implicit time seen in patients with AMD. Fluorescein angiograms and foveal cone ERGs were evaluated in the fellow eyes of 67 patients with unilateral neovascular AMD. Twenty eight (42%) of the eyes had a choroidal perfusion defect. ERG implicit times averaged 1 ms slower (p = 0.0167) and were more likely to be delayed (p = 0.0078) in eyes with abnormal choroidal perfusion than in eyes with normal choroidal filling; significant relations were found also after controlling for age. ERG implicit time was also inversely related to ETDRS visual acuity and positively related to the extent of macular drusen; and the latter showed a borderline significant tendency to be more prevalent in eyes with prolonged choroidal perfusion. However, an association of a delayed ERG implicit time with prolonged choroidal filling remained after controlling for age, acuity, and the extent of drusen. These findings further establish prolonged choroidal perfusion as a common finding in AMD and link it to retinal malfunction.


MicroRNAs and respiratory diseases.
MicroRNAs (miRNAs) are a family of endogenous, small, noncoding RNA molecules that modulate physiological and pathological processes by post-transcriptional inhibition of gene expression. They were first recognised as regulators of development in worms and fruitflies. In recent years extensive research has explored their pivotal role in the pathogenesis of human diseases. Over 1,000 human miRNAs have been discovered to date; however, the biological function and protein targets for the majority remain to be uncovered. Within the respiratory system, miRNAs are important in normal pulmonary development and maintaining lung homeostasis. Recent studies have also begun to reveal that altered miRNA expression profiles may be associated with pathological processes within the lung and lead to the development of various pulmonary diseases, ranging from inflammatory diseases to lung cancers. Advancing our understanding of the role of miRNAs in the respiratory system will help provide new perspectives on disease mechanisms and reveal intriguing therapeutic targets and diagnostic markers for respiratory disorders.


Time processing in children and adults with ADHD.
A time-processing deficit has been proposed as a neuropsychological candidate endophenotype for Attention Deficit Hyperactivity Disorder (ADHD), but its developmental trajectory still needs to be explored. In the present study, children (N = 33) and adults (N = 22) with ADHD were compared to normal controls on two time-processing tasks. For time reproduction, ADHD-related impairment was found in the full group, but not when adults were analyzed separately. For the discrimination of brief intervals, children and adults with ADHD showed different patterns of deficit. We conclude that in ADHD some time-processing deficits are still present in adults, but may take on age-related different forms.


Doppler interpretation of quasar red shifts.
The hypothesis that the quasistellar sources (quasars) are local objects moving with velocities close to the speed of light is examined. Provided there is no observational cutoff on apparent bolometric magnitude for the quasars, the transverse Doppler effect leads to the expectation of fewer blue shifts than red shifts for an isotropic distribution of velocities. Such a distribution also yields a function N(z), the number of objects with red shift less than z which is not inconsistent with the present data. On the basis of two extreme assumptions concerning the origin of such rapidly moving sources, we computed curves of red shift plotted against magnitude. In particular, the curve obtained on the assumption that the quasars originated from an explosion in or nearby our own galaxy is in as good agreement with the observations as the curve of cosmological red shift plotted against magnitude.