Utility of the first few100 approach during the 2009 influenza A(H1N1) pandemic in the Netherlands.
To guide policy and control measures, decent scientific data are needed for a comprehensive assessment of epidemiological, clinical and virological characteristics of the First Few hundred (FF100) cases. We discuss the feasibility of the FF100 approach during the 2009 pandemic and the added value compared with alternative data sources available. The pandemic preparedness plan enabled us to perform a case-control study, assessing patient characteristics and risk factors for experiencing symptomatic influenza A(H1N1)2009 infection and providing insight into transmission. We assessed to what extent timely and novel data were generated compared to other available data sources. In May-December 2009, a total of 68 cases and 48 controls were included in the study. Underlying non-respiratory diseases were significantly more common among cases compared to controls, while a protective effect was found for frequent hand washing. Seroconversion was found for 7/30 controls (23%), and persisting high titers for 4/30 controls (13%). The labour-intensive study design resulted in slow and restricted recruitment. The findings of our case-control study gave new insights in transmission risks and possible interventions for improved control. Nevertheless, the FF100 approach lacked timeliness and power due to limited recruitment. For future pandemics we suggest pooling data from several countries, to enable collecting sufficient data in a relatively short period.


Effect of subcutaneous infusion of pituitary-derived chicken growth hormone on growth performance of broiler pullets.
The effect of subcutaneous infusion of pituitary-derived chicken growth hormone (p-cGH) on plasma hormone/metabolite status and growth performance of young broiler pullets was investigated. Two-week-old pullets were surgically prepared and maintained via a fluid swivel/spring tether/harness system. Birds were subcutaneously infused 24 h a day for 21 days with 1.0 mL/day of either a p-cGH or vehicle (control) solution (20 micrograms/kg BW/day). Subcutaneous infusion of p-cGH had no significant effect on growth performance parameters in comparison with controls. Differences between levels of overall feed intake, net BW gain, feed efficiency, and carcass composition were not significant for treatments. However, dressing percentage was lower in p-cGH treated birds than in vehicle infused birds (P less than .04). Growth hormone treatment resulted in a modest degree of enlargement of the liver (P less than .06). However treatment had no effect upon wet weights of other measured organs or upon parameters of longitudinal bone growth, including length and mass of the tibiotarsus and width of the epiphyseal growth plate. Differences between treatment groups in preinfusion plasma concentration of GH, insulin, and glucose were not significant. Postinfusion plasma concentrations of GH were elevated over three-fold by p-cGH treatment (P less than .0001), with no treatment differences in plasma insulin or glucose concentrations. This study indicated that a sustained, 24-h elevation in plasma GH concentration in response to a physiological dosage of exogenous p-cGH is ineffective in altering growth performance of young, rapidly growing meat type chickens.


Adhesion to porcine squamous epithelium of saccharide and protein moieties of Lactobacillus fermentum strain 104-S.
The mechanism by which Lactobacillus fermentum strain 104-S adheres to porcine squamous epithelium was investigated by studying the adsorption to epithelial cells, and control surfaces, of radioactively labelled material released from the bacterial cells by water extraction. The released material was fractionated by gel filtration and the adsorption of pronase-sensitive and -resistant material in the various fractions to porcine gastric tissue and the control surfaces of polystyrene and immobilized bovine serum albumin (BSA) was determined. The fraction with affinity for the epithelium was characterized by enzymic degradation, periodate oxidation, lipid extraction, and protein and carbohydrate analyses. The adsorption pattern of radioactively labelled crude released material mimicked the adhesion of whole labelled cells to polystyrene and to gastric squamous tissue pieces. On fractionation, the pattern of adsorption to polystyrene and BSA was different from that obtained for the tissue pieces. Considerably less labelled pronase-stable material bound to surfaces of polystyrene and BSA, as compared with the tissue, suggesting that the pronase-resistant component has a tissue-specific affinity. After pronase treatment of the fraction of M(r) about 20,000 (20 K) containing labelled components with affinity for the epithelium, only saccharides were detected. Radioactivity was lost after hydrolysis with HCl, and therefore this pronase-resistant labelled component must be a saccharide. It is concluded that protein moieties in the extract have an affinity for several surfaces, including polystyrene, and that saccharide moieties have a specific affinity for the gastric squamous epithelium.


The role of autologous and allogeneic stem cell transplantation in the management of indolent B-cell lymphoma.
Despite improvements over the past decade in the overall survival of patients with indolent non-Hodgkin lymphomas, these lymphomas remain largely incurable with standard therapies. Immunochemotherapy with rituximab-based regimens has become a well-established standard of care in the primary and relapsed disease settings. The role of hematopoietic stem cell transplantation in indolent lymphoma has been defined by the adoption of this therapy largely in the relapse setting because randomized trials in the first-line setting have not shown survival advantages. Allogeneic stem cell transplantation has the possibility for cure because of the potential for immunologic graft-versus-lymphoma effect, but there are significant concerns regarding nonrelapse mortality. Autologous stem cell transplantation offers a safe treatment platform, but relapse remains a significant issue. The role of transplantation in the current treatment landscape of immunochemotherapy has not been conclusively proven, and randomized trials are lacking. This review summarizes the current relevant data regarding transplantation in indolent non-Hodgkin lymphoma and highlights the issues relevant to clinicians in the field.


Accumulation of different shapes of microplastics initiates intestinal injury and gut microbiota dysbiosis in the gut of zebrafish.
Different shapes of microplastics are widely detected in the environment and organisms and most of them remain in the gut. However, the influences of shapes on the bioaccumulation and toxicity of microplastics in the gut are largely unknown. Three shapes (bead, fragment, and fiber) of microplastics of comparable size in one dimension were prepared to exposure to zebrafish. The accumulation and toxicities of microplastics in the gut were detected. Shape-dependent accumulation in the gut was observed with the order of fibers (8.0 μg/mg) > fragments (1.7 μg/mg) > beads (0.5 μg/mg). The accumulation of microplastics caused multiple toxic effects in fish intestine, including mucosal damage, and increased permeability, inflammation and metabolism disruption. Based on these toxic effects, microplastic fibers resulted in more severe intestinal toxicity than microplastic fragments and beads did. Furthermore, microplastics also induced gut microbiota dysbiosis and specific bacteria alterations, which will provide novel insights into the potential mechanism of microplastics causing intestinal toxicities in fish. Our results also suggested that shape-depended effects should not be ignored in the health risk assessment of microplastics.


[Protein phosphorylation in the causative agent of plague].
The phenomenon of the reversible phosphorylation of proteins has been discovered in Y. pestis cells. Eight proteins with a molecular weight of 30-80 kilodaltons have been found capable of phosphorylation. The intensity of phosphorylation has been found to be influenced by the temperature of cultivation and the composition of the incubation medium. This newly found phenomenon of the chemical modification of proteins is supposed to play a certain role in the organization of rapid responses of the cell to changes in the environment.


Tamm-Horsfall Protein Regulates Granulopoiesis and Systemic Neutrophil Homeostasis.
Tamm-Horsfall protein (THP) is a glycoprotein uniquely expressed in the kidney. We recently showed an important role for THP in mediating tubular cross-talk in the outer medulla and in suppressing neutrophil infiltration after kidney injury. However, it remains unclear whether THP has a broader role in neutrophil homeostasis. In this study, we show that THP deficiency in mice increases the number of neutrophils, not only in the kidney but also in the circulation and in the liver, through enhanced granulopoiesis in the bone marrow. Using multiplex ELISA, we identified IL-17 as a key granulopoietic cytokine specifically upregulated in the kidneys but not in the liver of THP(-/-) mice. Indeed, neutralization of IL-17 in THP(-/-) mice completely reversed the systemic neutrophilia. Furthermore, IL-23 was also elevated in THP(-/-) kidneys. We performed real-time PCR on laser microdissected tubular segments and FACS-sorted renal immune cells and identified the S3 proximal segments, but not renal macrophages, as a major source of increased IL-23 synthesis. In conclusion, we show that THP deficiency stimulates proximal epithelial activation of the IL-23/IL-17 axis and systemic neutrophilia. Our findings provide evidence that the kidney epithelium in the outer medulla can regulate granulopoiesis. When this novel function is added to its known role in erythropoiesis, the kidney emerges as an important regulator of the hematopoietic system.


Mechanism of Cobalt-Catalyzed CO Hydrogenation: 2. Fischer-Tropsch Synthesis.
Fischer-Tropsch (FT) synthesis is one of the most complex catalyzed chemical reactions in which the chain-growth mechanism that leads to formation of long-chain hydrocarbons is not well understood yet. The present work provides deeper insight into the relation between the kinetics of the FT reaction on a silica-supported cobalt catalyst and the composition of the surface adsorbed layer. Cofeeding experiments of 12C3H6 with 13CO/H2 evidence that CH x surface intermediates are involved in chain growth and that chain growth is highly reversible. We present a model-based approach of steady-state isotopic transient kinetic analysis measurements at FT conditions involving hydrocarbon products containing up to five carbon atoms. Our data show that the rates of chain growth and chain decoupling are much higher than the rates of monomer formation and chain termination. An important corollary of the microkinetic model is that the fraction of free sites, which is mainly determined by CO pressure, has opposing effects on CO consumption rate and chain-growth probability. Lower CO pressure and more free sites leads to increased CO consumption rate but decreased chain-growth probability because of an increasing ratio of chain decoupling over chain growth. The preferred FT condition involves high CO pressure in which chain-growth probability is increased at the expense of the CO consumption rate.


Osteoprotegerin ligand induces beta-casein gene expression through the transcription factor CCAAT/enhancer-binding protein beta.
Osteoprotegerin ligand (OPGL, also known as RANKL), a member of the tumor necrosis factor superfamily, is essential for mammary gland development during pregnancy in addition to key roles in the immune system and bone development. Here we show that OPGL induces beta-casein transcription through the CCAAT/enhancer-binding protein beta (C/EBPbeta). In both HC11 cell lines and primary mammary epithelial cells, OPGL stimulation triggers rapid nuclear translocation of C/EBPbeta, which is critical for the expression of the beta-casein gene. Mutation of C/EBbeta binding sites in the beta-casein gene promoter completely abrogated OPGL-induced beta-casein promoter activity. By contrast, OPGL stimulation did not result in STAT5 phosphorylation. In vivo immunohistochemistry studies further demonstrated defective nuclear translocation of C/EBPbeta, but normal STAT5 activation, in OPGL-deficient mice. These data show that OPGL is a critical activator of beta-casein gene expression via the transcription factor C/EBPbeta. Our data provide new insights into the understanding of the molecular events involved in milk protein gene expression.


An Opportunity to Understand Concerns about COVID-19 Vaccination: Perspectives from EMS Professionals.
Some healthcare professionals, including emergency medical service (EMS) professionals, remain hesitant about receiving COVID-19 vaccines. This study sought to understand EMS professionals' perspectives regarding COVID-19 vaccination. Using open-ended comments from a national survey deployed electronically to over 19,000 EMS professionals in April of 2021, we examined perspectives about acceptance of and hesitancy toward COVID-19 vaccines. Survey comments revealed differences in perspectives between vaccinated and unvaccinated EMS professionals regarding their personal role in improving public health through COVID-19 vaccination as well as vaccine benefits and the protection conferred by vaccination. Unvaccinated individuals also expressed concerns over the research and development of the COVID-19 vaccines that led to their decision not to get vaccinated. Individuals who were vaccinated suggested ways to increase uptake of the vaccine including having healthcare professionals serve as leaders for vaccination and educating individuals about COVID-19 vaccination through credible resources. Vaccine hesitancy remains a challenge to achieving herd immunity to COVID-19 through vaccination, even among healthcare professionals. Understanding the perspectives of those who have chosen not to be vaccinated can help direct strategies to reduce confusion and concerns. The perspectives of vaccinated individuals may also be valuable in identifying opportunities to promote vaccination in the professional setting.


Xwnt-8, a Xenopus Wnt-1/int-1-related gene responsive to mesoderm-inducing growth factors, may play a role in ventral mesodermal patterning during embryogenesis.
In amphibian embryos, formation of the basic body plan depends on positional differences in the mesoderm. Although peptide growth factors involved in mesoderm induction have tentatively been identified, additional signals are required to generate pattern in this tissue. We have isolated a Xenopus cDNA for a Wnt-1 related gene, designated Xwnt-8, which is activated in response to mesoderm-inducing growth factors. Xwnt-8 transcripts are transiently expressed, being most abundant during gastrulation at which time expression is confined primarily to ventral mesodermal cells. Embryos dorsoanteriorized by exposure to lithium exhibit greatly reduced levels of Xwnt-8 mRNA, supporting a correlation between Xwnt-8 expression and a ventral mesodermal cell fate. Surprisingly, ectopic expression of Xwnt-8 in embryos causes a dorsoanterior-enhanced phenotype. These findings suggest that Xwnt-8 may be a secondary signalling agent which is produced in response to mesoderm-inducing factors and is involved in the early steps of mesodermal patterning.


Nonmagnetic spin-singlet dimer formation and coupling to the lattice in the 6H perovskite Ba3CaRu2O9.
Non-conservation of magnetic neutron scattering from the six-layer hexagonal perovskite Ba3CaRu2O9 on cooling reveals that (Ru(5+))2 dimers form nonmagnetic spin-singlet ground states. This is in contrast to Ba3BRu2O9 (B=Co or Ni) analogues which display long range spin ordered ground states containing antiferromagnetic (Ru(5+))2 dimers (Lightfoot and Battle 1990 J. Solid State Chem. 89 174). Dimer formation is weakly coupled to the lattice, resulting in an excess [101] microstrain broadening of diffraction peaks at low temperatures. Non-conservation of magnetic neutron scattering is also observed around the charge ordering transition in Ba3NaRu2O9 showing that the ground state structure is coupled to spin-singlet formation in charge ordered Ru2O9 dimers.


A scleroderma-like cutaneous syndrome associated with a marked Th2-type immune response occurring after a prosthetic joint implant.
A scleroderma-like cutaneous syndrome, occurring after implantation of a prosthetic knee joint in an elderly woman, is reported. This case did not seem to typically fit into any of the known scleroderma-like disorders of the skin described to date. The patient was shown to be sensitized to metals contained in the prosthesis and to mount a Th2-type immune response concomitantly with development of skin fibrosis. In particular, eosinophilia, markedly elevated serum IgE levels, in vitro spontaneous production of interleukin (IL)-4 by T lymphocytes, and elevated serum levels of Th2 cytokines (namely, IL-4, IL-5, and IL-13) were observed during the acute phase of illness. Since eosinophils and such Th2 cytokines as IL-13 also have recognized fibrogenic properties, it is speculated that the pathogenesis of skin fibrosis in this case could have been the direct and/or indirect consequence of the coexisting Th2-type immune response.


Cumulative effects of the Gulf oil spill and other disasters on mental health among reproductive-aged women: The Gulf Resilience on Women's Health study.
To test whether effects of multiple (up to 5) disasters on mental health responses were cumulative (additive effects), or whether an earlier disaster produced sensitization (higher) or habituation (lower) responses to a later one. The Gulf Resilience on Women's Health study interviewed 1,366 southern Louisiana women regarding their exposure to Hurricanes Katrina, Rita, Gustav, and Ike and the Gulf oil spill (measured several ways), and administered validated measures of symptoms of depression and posttraumatic stress disorder (PTSD). Multiple linear and logistic regression with disaster exposures entered singly, combined, and as an interaction were used to model mental health. Both exposure to the oil spill and hurricane disaster were associated with likely depression and PTSD, consistent with a cumulative model, but we did not find statistical interactions that would suggest sensitization or habituation. When results were examined with continuous symptom measures of depression and PTSD, they were similar, with the exception that exposure to the oil spill and experiencing illness or injury because of the hurricane disaster showed a significant interaction (p < .05) in a manner consistent with a sensitization effect when predicting PTSD symptoms. The results of this study point mainly to a cumulative risk for the mental health effects of multiple disasters, although some indication of sensitization occurred among those with particularly severe experiences. There was no evidence for habituation. These findings may guide efforts to assist those in regions experiencing multiple disasters that occur in close sequence. (PsycINFO Database Record


A comparison of selected hockey skating starts.
The purpose of this study was to determine the effectiveness of three different methods of initiating forward movement (IFM). Six S's from four levels of Ice Hockey competition were instructed in the methods then were timed for 20 feet of forward skating from a standing start. Selected S's within each group were also analyzed biomechanically, via the cinema-computer process. Both statistical and biomechanical analysis showed a superiority of the rarely taught thrust and glide or "t" start over the two conventional techniques, the cross-over and normal standing start facing the direction of movement. Results indicate a need to include the thrust and glide in Ice Hockey instructional programs.


Familial Duplication/Deletion of 1q42.13q43 as Meiotic Consequence of an Intrachromosomal Insertion in Chromosome 1.
Rearrangements of the region 1q42.13q43 are rare, with only 7 cases reported to date. The imbalances described are usually the result of inherited translocations with other chromosomes. Moreover, few cases of both inter- and intrachromosomal deletions/duplications detected cytogenetically have been described. We report the molecular cytogenetic characterization of an inverted insertion involving the region 1q42.13q43 and segregating in 2 generations of a family. The deletion and the duplication of the same segment were detected in 2 affected family members. SNP array analysis showed the familial origin of the deletion/duplication due to the occurrence of a crossing-over during meiosis. Our report underlines the importance of determining the correct origin of chromosomal aberrations using different molecular cytogenetic tests in order to provide a good estimation of the reproductive risk for the members of the family.


Plasmid-mediated histamine biosynthesis in the bacterial fish pathogen Vibrio anguillarum.
Histamine production in bacteria-contaminated fish is the result of the presence of bacterial histidine decarboxylase activity, which converts histidine present in muscle proteins to histamine. The fish pathogen Vibrio anguillarum harbors a plasmid-encoded histidine decarboxylase gene (angH) that is essential for biosynthesis of the siderophore anguibactin. However, the role of angH in histamine biosynthesis by this pathogen has not been fully determined. Thus, the objectives of this study were to monitor the production and release of histamine by the wild-type as well as by a plasmidless strain and angH isogenic mutants generated by allelic exchange. Reverse transcription polymerase chain reaction showed that only the wild-type strain expressed angH, while no angH message was detected in the mutants and the plasmidless derivative. The iron uptake-deficient phenotype of one of the angH mutants confirmed the location of the mutation and the unique role of this gene in iron acquisition. Thin-layer chromatography, gas chromatography, and mass spectrometry showed that histamine was released by the strain harboring a wild-type angH gene when grown in excess histidine. This biogenic amine was not detected in the culture supernatants of the plasmidless derivative and the angH mutant when cultured under the same experimental conditions. These results indicate that angH is essential for histamine biosynthesis in V. anguillarum, a compound responsible for food poisoning and potentially involved in bacterial virulence. Thin-layer chromatography of wild-type culture supernatants and beta-galactosidase assays using the isogenic angH mutant demonstrated that the expression of this gene is independent of the histidine concentration of the medium under both iron-rich and iron-limiting conditions.


The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia.
Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age (P = .022) and dyslipidemia (P = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.


Quality-of-life implications of immediate surgery and watchful waiting in asymptomatic aortic stenosis: a decision-analytic model.
BACKGROUND- Traditional management of severe aortic stenosis (AS) is based on delay in aortic valve replacement (AVR) until the development of symptoms. Surgery for asymptomatic AS has been proposed to reduce the small risk of sudden death before AVR and avoid heart failure (HF) after AVR. Because a trial to compare these options is unlikely, we developed a Markov model to inform the choice between immediate surgery and watchful waiting in asymptomatic AS. METHODS AND RESULTS- We defined health states as preoperative, postoperative, postcomplication, and death. We calculated the implications of watchful waiting, tissue and mechanical AVR-based on risks, transitions, utilities, and cost derived from literature review. Further analyses evaluated situations thought to favor immediate surgery and watchful waiting. Sensitivity analyses were based on the likelihood of preoperative death and HF in follow-up. In the reference case (age, 65 years; post-AVR utility, 0.9; annualized pre-AVR mortality, 1%; and post-AVR HF, 11.3%), the utility of watchful waiting was superior to that of immediate mechanical or tissue AVR (quality-adjusted life-years, 7.4 versus 5.3 versus 5.3, respectively), and the cost was less than immediate surgery. Sensitivity analyses showed immediate surgery was not likely to be more effective regardless of the yearly probability of post-AVR HF in the watchful waiting group (range, 0% to 80%). Immediate surgery was likely to be effective when pre-AVR annual mortality reached 13%. CONCLUSIONS- Immediate surgery in asymptomatic severe AS does not improve outcomes unless risk of sudden death pre-AVR and HF after AVR are higher than currently reported.


Ebstein's anomaly with coarctation of the aorta. An unusual association.
Ebstein's anomaly with coarctation of the aorta is an extremely unusual condition. In this report, the clinical and surgical features of 3 male patients, aged 7 months, 4 years and 14 years, are discussed. All patients were in situs solitus. The first 2 patients had atrioventricular and ventriculoarterial discordance and progressed to heart failure in the neonatal period. The third had atrioventricular and ventriculoarterial concordance, as well as Wolf-Parkinson-White syndrome, with frequent episodes of paroxysmal tachycardia. The 3 patients underwent surgery for correction of the coarctation of the aorta. The patient with atrioventricular and ventriculoarterial concordance underwent tricuspid valvuloplasty using a DeVega-like technique. In addition, ablation of 2 anomalous pathways (Kent bundle), which were detected by the electrophysiologic study, was also subsequently performed. The 3 patients showed a good postoperative outcome for 2 years, although, in those with discordance, the surgical procedure did not influence the dysplasia of the tricuspid valve, because this valve showed light to moderate dysfunction.


Perception of Discrete Emotions in Others: Evidence for Distinct Facial Mimicry Patterns.
Covert facial mimicry involves subtle facial muscle activation in observers when they perceive the facial emotional expressions of others. It remains uncertain whether prototypical facial features in emotional expressions are being covertly mimicked and also whether covert facial mimicry involves distinct facial muscle activation patterns across muscles per emotion category, or simply distinguishes positive versus negative valence in observed facial emotions. To test whether covert facial mimicry is emotion-specific, we measured facial electromyography (EMG) from five muscle sites (corrugator supercilii, levator labii, frontalis lateralis, depressor anguli oris, zygomaticus major) whilst participants watched videos of people expressing 9 different basic and complex emotions and a neutral expression. This study builds upon previous research by including a greater number of facial muscle measures and emotional expressions. It is the first study to investigate activation patterns across muscles during facial mimicry and to provide evidence for distinct patterns of facial muscle activation when viewing individual emotion categories, suggesting that facial mimicry is emotion-specific, rather than just valence-based.


Identification of antigenic sites mediating antibody-dependent enhancement of feline infectious peritonitis virus infectivity.
We have previously demonstrated antibody-dependent enhancement of feline infectious peritonitis virus (FIPV) infection of macrophages using both virus-specific antisera and monoclonal antibodies (MAbs) to the spike (S) protein of FIPV. To increase our understanding of this phenomenon, six representative MAbs from a previously documented group of 12 enhancing MAbs were used to identify epitopes that mediate antibody-dependent enhancement of FIPV infectivity. Analysis of the results of kinetics-based competitive ELISA (K-cELISA) among these six enhancing MAbs grouped the epitopes into two clusters. Because transmissible gastroenteritis virus (TGEV) and FIPV are so closely related antigenically, we also conducted K-cELISA experiments between the FIPV MAbs and TGEV S protein-specific MAbs for which the epitopes had previously been mapped to specific sites on the TGEV S protein. Results of these assays indicated that the two FIPV epitope clusters are homologues of the previously defined TGEV S protein sites A and E/F. In addition, two TGEV S protein-specific MAbs also induced antibody-dependent enhancement of FIPV infection of macrophages. This functional cross-reactivity provides further support for the close antigenic relationship between FIPV and TGEV. Our results provide a preliminary localization of several enhancing epitopes within the amino acid sequence of the FIPV S protein.


[Effect of prodigiozan and pyrogenal on the neural regulation of the frog heart].
The action of bacterial lipopolysaccharides (pyrogenal and prodigiosan) on nervous regulation of the frog heart was studied. Both the substances provoked a considerable increase in the arrest of spontaneous contractility of the atria during stimulation of the extracardial nerves. This effect did not occur after atropine administration, but became manifest during the benzohexonium-induced blockade of conduction in the intracardiac ganglia. The bacterial lipopolysaccharides did not alter acetylcholinesterase activity or myocardial sensitivity to acetylcholine. It is assumed that variation of the nervous regulation of the heart under the effect of prodigiosan and pyrogenal is determined by the effect of these substances on the transmitter release from the presynaptic endings of the extracardial ganglia.


Ephedrine-induced cardiac ischemia: exposure confirmed with a serum level.
The temporal association of symptoms consistent with ephedrine toxicity after ingestion of ephedrine-containing dietary supplements is heavily relied upon to confirm exposure. Few reports in the literature attempt to associate toxicity with serum levels of these drugs. We report a case of ephedrine-induced cardiac ischemia confirmed by a plasma level. A 22-year-old woman ingesting an ephedrine- and caffeine-containing product for 2 days presented with multiple symptoms, including palpitations, nausea, tremulousness, abdominal pain, and vomiting. The initial electrocardiogram (ECG) revealed a normal sinus rhythm with 1 mm of ST segment depression in leads V3 and V4, along with inverted T waves in leads V1-V4. Her symptoms and ST segment depression resolved over several hours with medical management. The amplitude of her T wave inversions notably diminished with therapy; however, they did not completely resolve. Troponins at presentation and the following morning were negative, and an echocardiogram showed only trace tricuspid regurgitation. A serum ephedrine level, drawn approximately 6 to 7 hr after ingestion, was 150 ng/mL. She was discharged from the hospital after being instructed to avoid ephedrine-containing products.


Lightning on jupiter: rate, energetics, and effects.
Voyager data on the optical and radio-frequency detection of lightning discharges in the atmosphere of Jupiter suggest a stroke rate significantly lower than on the earth. The efficiency of conversion of atmospheric convective energy flux into lightning is almost certainly less than on the earth, probably near 10(-7) rather than the terrestrial value of 10(-4). At this level the rate of production of complex organic molecules by lightning and by thunder shock waves is negligible compared to the rates of known photochemical processes for forming colored inorganic solids.


Isolation of a novel cell-attachment and spreading-promoting protein from human serum.
A protein with potent cell-attachment and spreading-promoting activity was isolated from fibronectin-free human serum. The purification steps included affinity chromatography on heparin-agarose and preparative isoelectric focusing. The purified protein was homogeneous as judged from dodecyl sulphate/polyacrylamide-gel electrophoresis. It had an isoelectric point of 5.0 and an Mr of 52 000. The protein promoted the spreading of Chinese-hamster ovary cells to plastic in a manner similar to that observed with fibronectin.


Organotypic brain slices: a model to study the neurovascular unit micro-environment in epilepsies.
It is now recognized that the neuro-vascular unit (NVU) plays a key role in several neurological diseases including epilepsy, stroke, Alzheimer's disease, multiple sclerosis and the development of gliomas. Most of these disorders are associated with NVU dysfunction, due to overexpression of inflammatory factors such as vascular endothelial growth factor (VEGF). Various in vitro models have been developed previously to study the micro-environment of the blood-brain barrier (BBB). However none of these in vitro models contained a complete complement of NVU cells, nor maintained their interactions, thus minimizing the influence of the surrounding tissue on the BBB development and function. The organotypic hippocampal culture (OHC) is an integrative in vitro model that allows repeated manipulations over time to further understand the development of cell circuits or the mechanisms of brain diseases. OHCs were cultured from hippocampi of 6-7 day-old Sprague Dawley rats. After 2 weeks in culture, seizures were induced by application of kainate or bicuculline into culture medium. The regulation of BBB integrity under physiological and pathological conditions was evaluated by immunostaining of the main tight junction (TJ) proteins and of the basal membrane of microvessels. To mimic or prevent BBB disassembly, we used diverse pro- or anti-angiogenic treatments. This study demonstrates that NVU regulation can be investigated using OHCs. We observed in this model system an increase in vascularization and a down-regulation of TJ proteins, similar to the vascular changes described in a chronic focus of epileptic patients, and in rodent models of epilepsy or inflammation. We observed that Zonula occludens-1 (ZO-1) protein disappeared after seizures associated with neuronal damage. In these conditions, the angiopoeitin-1 system was down-regulated, and the application of r-angiopoeitin-1 allowed TJ re-assembly. This article demonstrates that organotypic culture is a useful model to decipher the links between epileptic activity and vascular damage, and also to investigate NVU regulation in diverse neurological disorders.


Clonally Focused Public and Private T Cells in Resected Brain Tissue From Surgeries to Treat Children With Intractable Seizures.
Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.


Invasion of human tissue ex vivo by Borrelia burgdorferi.
Borrelia burgdorferi sensu stricto is an etiological agent of Lyme disease. The lack of an adequate ex vivo system for human tissue infection is an obstacle to fully understanding the molecular mechanisms of invasion of tissue by B. burgdorferi and its adaptation within the human host. Here, we report on the development of such a system. We inoculated blocks of human tonsillar tissue with B. burgdorferi spirochetes, cultured them in a low-shear rotating wall vessel (RWV) bioreactor, and analyzed them using light and electron microscopy, nested polymerase chain reaction (PCR), and quantitative real-time PCR. Also, we evaluated the expression of the outer surface proteins (Osps) OspA and OspC by use of quantitative Western blotting. Light and electron microscopic analysis revealed multiple spirochetes localized extracellularly within the tissue, and their identity was confirmed by PCR. Quantification of spirochetes inside the RWV-cultured tonsillar tissue demonstrated that the number of B. burgdorferi exceeded the initial inoculum by an order of magnitude, indicating that spirochetes replicated in the tissue. Electron microscopic analysis showed that some spirochetes were arranged in cystic structures and that invading spirochetes differentially expressed surface proteins; both of these features have been described for infected tissues in vivo. The system we have developed can be used to study B. burgdorferi pathogenesis under controlled conditions ex vivo, in particular to explore the gene activation responsible for the adaptation of B. burgdorferi to human tissue that leads to Lyme disease.


Succession of embryonic and the intestinal bacterial communities of Atlantic salmon (Salmo salar) reveals stage-specific microbial signatures.
Host-associated microbiota undergoes a continuous transition, from the birth to adulthood of the host. These developmental stage-related transitions could lead to specific microbial signatures that could impact the host biological processes. In this study, the succession of early-life and intestinal bacterial communities of Atlantic salmon (starting from embryonic stages to 80-week post hatch; wph) was studied using amplicon sequencing of 16S rRNA. Stage-specific bacterial community compositions and the progressive transitions of the communities were evident in both the early life and the intestine. The embryonic communities showed lower richness and diversity (Shannon and PD whole tree) compared to the hatchlings. A marked transition of the intestinal communities also occurred during the development; Proteobacteria were dominant in the early stages (both embryonic and intestinal), though the abundant genera under this phylum were stage-specific. Firmicutes were the most abundant group in the intestine of late freshwater; Weissella being the dominant genus at 20 wph and Anaerofilum at 62 wph. Proteobacteria regained its dominance after the fish entered seawater. Furthermore, LEfSe analysis identified genera under the above - mentioned phyla that are significant features of specific stages. The environmental (water) bacterial community was significantly different from that of the fish, indicating that the host is a determinant of microbial assemblage. Overall the study demonstrated the community dynamics during the development of Atlantic salmon.


Modulation of Kv1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex.
The cAMP/PKA signaling system constitutes an inhibitory pathway in T cells and, although its biochemistry has been thoroughly investigated, its possible effects on ion channels are still not fully understood. K(V)1.3 channels play an important role in T-cell activation, and their inhibition suppresses T-cell function. It has been reported that PKA modulates K(V)1.3 activity. Two PKA isoforms are expressed in human T cells: PKAI and PKAII. PKAI has been shown to inhibit T-cell activation via suppression of the tyrosine kinase Lck. The aim of this study was to determine the PKA isoform modulating K(V)1.3 and the signaling pathway underneath. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP), a nonselective activator of PKA, inhibited K(V)1.3 currents both in primary human T and in Jurkat cells. This inhibition was prevented by the PKA blocker PKI(6-22). Selective knockdown of PKAI, but not PKAII, with siRNAs abolished the response to 8-BrcAMP. Additional studies were performed to determine the signaling pathway mediating PKAI effect on K(V)1.3. Overexpression of a constitutively active mutant of Lck reduced the response of K(V)1.3 to 8-Br-cAMP. Moreover, knockdown of the scaffolding protein disc large 1 (Dlg1), which binds K(V)1.3 to Lck, abolished PKA modulation of K(V)1.3 channels. Immunohistochemistry studies showed that PKAI, but not PKAII, colocalizes with K(V)1.3 and Dlg1 indicating a close proximity between these proteins. These results indicate that PKAI selectively regulates K(V)1.3 channels in human T lymphocytes. This effect is mediated by Lck and Dlg1. We thus propose that the K(V)1.3/Dlg1/Lck complex is part of the membrane pathway that cAMP utilizes to regulate T-cell function.


[Short- and intermediate-term angular results of Cüppers retro-equatorial myopexy, with or without additional simultaneous recession].
79 variable esotropias underwent bilateral "Fadenoperations". In the first group, the posterior fixation has been performed alone. In the second series, conventional symmetrical recessions of the medial recti have been performed during the same procedure. Two further additional weakening techniques are compared in the last group: anterior medial tenotomies and the so-called "stretch effect". Concomittant recessions considerably enforced the amount of angle reduction for distance and near without affecting precision, predictibility and stability of the results. Tenotomies and stretching procedures were followed by inconstant results.


Outcome of children prenatally exposed to cocaine and other drugs: a path analysis of three-year data.
Cocaine and other drug use during pregnancy continues to be a major health concern. With increasing use of cocaine by women of childbearing age, large numbers of children have been exposed to this and other substances in utero. Currently, very little information regarding the long-term developmental implications of cocaine/polydrug exposure exists. The purpose of this study is to present 3-year cognitive and behavioral data on infants exposed to cocaine and other drugs during gestation. The subjects and controls in this study are currently enrolled in a longitudinal, prospective evaluation. At 3 years of age, 92 children exposed to cocaine and other drugs, 25 children exposed to multiple drugs but no cocaine, and 45 drug-free controls were evaluated using the Stanford-Binet Intelligence Scale (fourth edition), the Child Behavioral Checklist, the Home Screening Questionnaire, and a Summative Perseverance Scale. The data were analyzed using an a priori model and path analytic procedures. The results indicate that prenatal drug exposure has significant direct and indirect effects on 3-year cognitive functioning as measured on the Stanford-Binet scale. The fit indices indicated that overall, the hypothesized model accurately reflected the actual data. The findings of the study provide specific evidence elucidating the nature of long-term developmental risk associated with intrauterine drug exposure. Drug exposure was found to have a direct effect on cognitive ability at 3 years of age. However, the effects of drug exposure are also mediated indirectly through head circumference, home environment, and level of perseverance at a task. Future explorations should continue to utilize path analysis techniques to further clarify the ramifications of drug exposure on the development of the growing child.


Replicase-mediated resistance to potato virus Y in transgenic tobacco plants.
Nicotiana tabacum 'Turkish Samsun NN' plants were transformed with nuclear inclusion b (NIb) gene sequences of potato virus Y, O strain (PVYO). The full-length construct included an additional in-frame initiation codon contiguous to the putative N-terminal amino acid codon and a stop codon replacing the C-terminal amino acid codon. Of 13 independently transformed lines, four yielded 37 (out of 100) plants in the R1 generation that were resistant to PVYO infection. Progeny of 13 out of 15 of R1 plants tested expressed resistance in the R2 generation. Conversely, 30 independently transformed tobacco lines expressing essentially the same sequence but deleted for the Gly-Asp-Asp (GDD) motif were not resistant. Two other constructs encoding either the 5'-deleted or 3'-truncated NIb gene, but harboring the GDD motif, conferred resistance to PVYO in some tobacco plants. Despite the high level of nucleotide and amino acid identity shared by strains PVYO and PVYN for the NIb gene, PVYN replication was found in all PVYO-resistant plants. However, plants of one R2 line showed reduced PVYN replication.


Offenders: characteristics and treatment.
People who sexually abuse children are diverse in terms of age, occupation, income level, marital status, and ethnic group. At one time it was believed that sex offenders could be easily categorized along three dimensions: offending against either adults or children; offending against either members of their families or against acquaintances and strangers; offending in noncontact ways (for example, exhibitionism) or through bodily contact. There is growing evidence that a number of offenders offend across these categories. Many child sexual abusers are themselves adolescents, and many adult offenders first offended when they were adolescents. A review of the literature reveals a paucity of controlled therapy outcome studies on the effectiveness of treatment, and existing uncontrolled studies are marked by methodological problems. This has led some to conclude that there is insufficient evidence to prove the effectiveness of treatment for child molesters. However, there have been major changes in treatment programs over the years, and some more recent studies provide reason for optimism about the effectiveness of current treatment methods for some offenders.


Urethral infection of chimpanzees by Ureaplasma urealyticum.
Two strains of Ureaplasma urealyticum serotype V that had produced urethritis in human volunteers were, after a number of subcultures in artificial media, introduced intra-urethrally into three chimpanzees. One strain given to two chimpanzees rapidly multiplied 1000-fold whereas there was less evidence that organisms of another strain multiplied in a third animal. Over a 14-day period the ureaplasmas persisted in all animals, did not spread to the throat and did not produce an inflammatory response. After this time they were eliminated by tetracycline therapy.


Synovial Cell Count Poorly Predicts Septic Arthritis in the Presence of Crystalline Arthropathy.
Introduction: A synovial cell count greater than 50,000/mm3 is the threshold most commonly used to diagnose septic arthritis. This lab value may be nonspecific in the setting of crystalline arthropathy. The purpose of this study was to evaluate the accuracy of diagnosing septic arthritis using a synovial cell count cut-off of 50,000/mm3 in the setting of crystalline arthropathy. Methods: This was a retrospective review of joint aspirations performed between July 1st, 2013 and June 30th, 2016. Synovial fluid samples were evaluated for cell count, crystals, Gram stain, and culture. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the synovial markers were calculated. Results: During the study period, 738 joint aspirations were sent for testing, of which 358 aspirations in 348 patients met inclusion criteria. There were 49 (13.7%) cases of culture-positive septic arthritis, and 47 patients underwent surgical irrigation and debridement. Gout and pseudogout crystals were present in 163 aspirates (45.5%). Three joints (0.8% overall rate) had concomitant crystalline arthropathy and septic arthritis, each of which had a synovial WBC ≥85,000/mm3. Increasing the WBC count cutoff to 85,000/mm3 demonstrated a specificity of 100%, but a PPV of 12.0%. Conclusions: A cut-off of 85,000/mm3 may be more appropriate to diagnose concomitant septic arthritis and crystalline arthropathy. We recommend medical management and observation in patients with crystal-positive joint aspirations unless the synovial cell count is elevated above 85,000/mm3. Prospective studies using this treatment guideline are needed to evaluate its validity and accuracy.


TGF-beta induces expression of monocyte chemoattractant JE/monocyte chemoattractant protein 1 via transcriptional factor AP-1 induced by protein kinase in osteoblastic cells.
In this work, we demonstrate the signal-transducing mechanism of TGF-beta 1 for gene expression of monocyte chemoattractant JE/monocyte chemoattractant protein 1 (MCP-1) in clonal osteoblastic MC3T3-E1 cells. TGF-beta 1-induced JE/MCP-1 gene expression in the cells was inhibited markedly by H-7 (1-(5-isoguinolinesulfonyl)-2-O-methylpiperazine-dihydrochloride) and staurosporine, potent inhibitors of protein kinase. TGF-beta 1-induced expression of both early proto-oncogenes c-fos and c-jun in the cells was also inhibited by H-7 and staurosporine. Antisense oligonucleotides to c-fos and c-jun genes inhibited significantly the cytokine-induced JE/MCP-1 gene expression. Curcumin, a specific inhibitor of c-jun/AP-1, inhibited the cytokine-induced c-jun gene expression in a dose-dependent manner, though the c-fos gene expression was not affected. TGF-beta 1 stimulated transcriptionally the JE/MCP-1 gene expression, and this stimulation was inhibited significantly by curcumin. Curcumin-induced inhibition of the JE/MCP-1 gene product was also evidenced by both an assay involving immunoprecipitation with antiserum specific for JE/MCP-1 and an assay for monocyte chemotaxis. Curcumin markedly inhibited AP-1 binding activity to 12-tetradecanoyl phorbol-13-acetate-responsive element (TRE) in the cytokine-treated cells. Furthermore, H-7 and staurosporine also inhibited the binding activity to TRE in the cells treated by the cytokine. These results demonstrate that TGF-beta 1 induces expression of monocyte chemoattractant JE/MCP-1 via the transcriptional factor AP-1 induced by protein kinase in the osteoblastic cells.


Effect of management on prevention of Salmonella Dublin exposure of calves during a one-year control programme in 84 Danish dairy herds.
Studies reporting on how to control Salmonella in cattle herds have mainly been theoretical simulation models or case reports describing control of clinical salmonellosis outbreaks. The objective of this observational study was to investigate which management routines were associated with successful control of Salmonella Dublin in calves in dairy herds with previous signs of endemic infection. A total of 86 bulk-tank milk Salmonella Dublin antibody-positive bovine dairy herds were enrolled in the study in September 2008 and were all encouraged to control spread of the infection. One year later it was assessed if they were successful. The criterion for successful control was defined as the 10 youngest calves above three months of age testing Salmonella Dublin antibody-negative, indicating that exposure to Salmonella of these calves from birth until close to the day of testing had been successfully prevented. Management routines were registered through telephone interviews based on a questionnaire resulting in 45 variables for analysis. By the end of the study, a total of 84 herds had completed the interviews and had serum samples collected from calves. Data were analysed using two statistical methods: logistic regression analysis and discriminant analysis. Both analyses identified that increased probability of successful control was strongly associated with avoiding purchase of cattle from test-positive herds. Additionally, ensuring good calving area management, separating calf pens by solid walls rather than bars and not introducing biosecurity routines between the barn sections (e.g. boot wash, change of clothing) were associated with increased probability of successful control in the logistic analysis. The latter may seem illogical, but may be explained by successful herds already having good hygienic routines in place and therefore not having introduced new routines between barn sections in the study period. The discriminant analysis furthermore identified successful control to be associated with preventing cows from calving before being moved to the designated calving pen, by only letting one person be responsible for colostrum management and by not feeding poorer quality colostrum to bull calves than to heifer calves. The results are useful for dairy cattle producers and veterinary authorities to substantiate advice on management practices that are likely to lead to successful control of Salmonella Dublin.


High-resolution mapping and digital atlas of subcortical regions in the macaque monkey based on matched MAP-MRI and histology.
Subcortical nuclei and other deep brain structures are known to play an important role in the regulation of the central and peripheral nervous systems. It can be difficult to identify and delineate many of these nuclei and their finer subdivisions in conventional MRI due to their small size, buried location, and often subtle contrast compared to neighboring tissue. To address this problem, we applied a multi-modal approach in ex vivo non-human primate (NHP) brain that includes high-resolution mean apparent propagator (MAP)-MRI and five different histological stains imaged with high-resolution microscopy in the brain of the same subject. By registering these high-dimensional MRI data to high-resolution histology data, we can map the location, boundaries, subdivisions, and micro-architectural features of subcortical gray matter regions in the macaque monkey brain. At high spatial resolution, diffusion MRI in general, and MAP-MRI in particular, can distinguish a large number of deep brain structures, including the larger and smaller white matter fiber tracts as well as architectonic features within various nuclei. Correlation with histology from the same brain enables a thorough validation of the structures identified with MAP-MRI. Moreover, anatomical details that are evident in images of MAP-MRI parameters are not visible in conventional T1-weighted images. We also derived subcortical template "SC21" from segmented MRI slices in three-dimensions and registered this volume to a previously published anatomical template with cortical parcellation (Reveley et al., 2017; Saleem and Logothetis, 2012), thereby integrating the 3D segmentation of both cortical and subcortical regions into the same volume. This newly updated three-dimensional D99 digital brain atlas (V2.0) is intended for use as a reference standard for macaque neuroanatomical, functional, and connectional imaging studies, involving both cortical and subcortical targets. The SC21 and D99 digital templates are available as volumes and surfaces in standard NIFTI and GIFTI formats.


Microtensile properties and failure mechanisms of cortical bone at the lamellar level.
Bone features a remarkable combination of toughness and strength which originates from its complex hierarchical structure and motivates its investigation on multiple length scales. Here, in situ microtensile experiments were performed on dry ovine osteonal bone for the first time at the length scale of a single lamella. The micromechanical response was brittle and revealed larger ultimate tensile strength compared to the macroscale (factor of 2.3). Ultimate tensile strength for axial and transverse specimens was 0.35 ± 0.05 GPa and 0.13 ± 0.02 GPa, respectively. A significantly greater strength anisotropy relative to compression was observed (axial to transverse strength ratio of 2.7:1 for tension, 1.3:1 for compression). Fracture surface and transmission electron microscopic analysis suggested that this may be rationalized by a change in failure mode from fibril-matrix interfacial shearing for axial specimens to fibril-matrix debonding in the transverse direction. An improved version of the classic Hashin's composite failure model was applied to describe lamellar bone strength as a function of fibril orientation. Together with our experimental observations, the model suggests that cortical bone strength at the lamellar level is remarkably tolerant to variations of fibrils orientation of about ±30°. This study highlights the importance of investigating bone's hierarchical organization at several length scales for gaining a deeper understanding of its macroscopic fracture behavior. STATEMENT OF SIGNIFICANCE: Understanding bone deformation and failure behavior at different length scales of its hierarchical structure is fundamental for the improvement of bone fracture prevention, as well as for the development of multifunctional bio-inspired materials combining toughness and strength. The experiments reported in this study shed light on the microtensile properties of dry primary osteonal bone and establish a baseline from which to start further investigations in more physiological conditions. Microtensile specimens were stronger than their macroscopic counterparts by a factor of 2.3. Lamellar bone strength seems remarkably tolerant to variations of the sub-lamellar fibril orientation with respect to the loading direction (±30°). This study underlines the importance of studying bone on all length scales for improving our understanding of bone's macroscopic mechanical response.


Alcohol consumption and the risk of nasopharyngeal carcinoma: a systematic review.
The evidence concerning the influence of alcohol drinking on the risk of nasopharyngeal carcinoma (NPC) has yielded intriguing findings but has lacked a clear-cut interpretation due to inconsistencies. To unify this body of evidence, we performed a systematic review. With funding and using a protocol developed by the World Cancer Research Fund (WCRF), 15 bibliographic databases were searched for epidemiological studies that reported a measure of association between alcoholic beverage consumption and NPC. Pooled odds ratios (ORs) for highest-vs.-lowest categories of total alcohol intake was obtained by using an inverse-variance weighted random-effects model. A dose-response trend was examined in models using generalized least square estimation. The search identified 14 case-control studies from 5 countries. For total alcohol intake, the pooled ORs in a comparison of the highest to the lowest category was 1.33 (95% CI: = 1.09-1.62) in 11 studies. Data from 6 studies indicated a J-shape dose-response trend, with NPC risk decreasing with up to 15 drinks/wk and increasing with higher intake. Fewer data were available to assess the associations between NPC and intake of beer, wine, and spirits. The potential J-shaped dose-response trend suggests a reduced risk of NPC related to the light alcohol drinking, an observation that warrants further study. Considered in total, the quantitative summaries of the case-control evidence suggest that heavy alcohol consumption is associated with an increased risk of NPC.


BioPortal as a Dataset of Linked Biomedical Ontologies and Terminologies in RDF.
BioPortal is a repository of biomedical ontologies-the largest such repository, with more than 300 ontologies to date. This set includes ontologies that were developed in OWL, OBO and other formats, as well as a large number of medical terminologies that the US National Library of Medicine distributes in its own proprietary format. We have published the RDF version of all these ontologies at http://sparql.bioontology.org. This dataset contains 190M triples, representing both metadata and content for the 300 ontologies. We use the metadata that the ontology authors provide and simple RDFS reasoning in order to provide dataset users with uniform access to key properties of the ontologies, such as lexical properties for the class names and provenance data. The dataset also contains 9.8M cross-ontology mappings of different types, generated both manually and automatically, which come with their own metadata.


Ocular coloboma: a reassessment in the age of molecular neuroscience.
Congenital colobomata of the eye are important causes of childhood visual impairment and blindness. Ocular coloboma can be seen in isolation and in an impressive number of multisystem syndromes, where the eye phenotype is often seen in association with severe neurological or craniofacial anomalies or other systemic developmental defects. Several studies have shown that, in addition to inheritance, environmental influences may be causative factors. Through work to identify genes underlying inherited coloboma, significant inroads are being made into understanding the molecular events controlling closure of the optic fissure. In general, severity of disease can be linked to the temporal expression of the gene, but this is modified by factors such as tissue specificity of gene expression and genetic redundancy.


Purinergic and cholinergic agonists induce exocytosis from the same granule pool in HT29-Cl.16E monolayers.
Several secretagogues induce mucin secretion in epithelial monolayers, as determined by measuring released granule contents. To assess whether different agonists act on the same granule pool, capacitance changes in intact monolayers of the goblet cell line HT29-Cl.16E were measured by a novel impedance method. Apical ATP (purinergic agonist) and basolateral carbachol (cholinergic agonist) induce rapid exocytosis with maximal capacitance changes within 3 min. The maximal levels of exocytosis that can be induced by optimal concentrations of either agonist are the same and produce a 30-40% increase in total monolayer capacitance. When ATP and carbachol are applied simultaneously, the magnitude of exocytosis is unchanged from the single-secretagogue level. The recovery of capacitance to baseline (endocytosis) is significantly faster after ATP stimulation than after carbachol stimulation. When ATP and carbachol are applied sequentially at doses that give maximal exocytosis, the magnitude of the capacitance increase produced by the second secretagogue is less than or equal to that of the capacitance decrease during the recovery period. Together, these data suggest that purinergic and cholinergic agonists act on the same granule pool.


[Instability of a three-dimnsional linear vortex in a simple model of a heterogenous excitable medium].
We studied the dynamics of three-dimensional linear vortex in a heterogeneous excitable medium. Using the Aliev-Panfilov model we showed that even a small heterogeneity in excitation threshold can lead to drastic deformations of the vortex filament and an instability in its behavior.


Uniform-density Bose-Einstein condensates of the Gross-Pitaevskii equation found by solving the inverse problem for the confining potential.
In this work, we study the existence and stability of constant density (flat-top) solutions to the Gross-Pitaevskii equation (GPE) in confining potentials. These are constructed by using the "inverse problem" approach which corresponds to the identification of confining potentials that make flat-top waveforms exact solutions to the GPE. In the one-dimensional case, the exact solution is the sum of stationary kink and antikink solutions, and in the overlapping region, the density is constant. In higher spatial dimensions, the exact solutions are generalizations of this wave function. In the absence of self-interactions, the confining potential is similar to a smoothed-out finite square well with minima also at the edges. When self-interactions are added, terms proportional to ±gψ^{*}ψ and ±gM with M representing the mass or number of particles in Bose-Einstein condensates get added to the confining potential and total energy, respectively. In the realm of stability analysis, we find (linearly) stable solutions in the case with repulsive self-interactions which also are stable to self-similar deformations. For attractive interactions, however, the minima at the edges of the potential get deeper and a barrier in the center forms as we increase the norm. This leads to instabilities at a critical value of M. Comparing the stability criteria from Derrick's theorem with Bogoliubov-de Gennes (BdG) analysis stability results, we find that both predict stability for repulsive self-interactions and instability at a critical mass M for attractive interactions. However, the numerical analysis gives a much lower critical mass. This is due to the emergence of symmetry-breaking instabilities that were detected by the BdG analysis and violate the symmetry x→-x assumed by Derrick's theorem.


A single mild episode of subacute ruminal acidosis does not affect ruminal barrier function in the short term.
Twenty-four German Merino sheep (72.3±10.1 kg of body weight) were fed an all-hay diet and assigned to either the subacute ruminal acidosis (SARA) treatment (n=17) or sham treatment (n=7). The SARA sheep were orally dosed with a 2.2 M glucose solution to supply 5 g of glucose/kg of body weight, whereas sham sheep received an equal volume of water. Ruminal pH was measured for 48 h before and 3 h after the oral dose. Sheep were then killed and ruminal epithelia from the ventral sac were mounted in Ussing chambers. The serosal-to-mucosal flux rate of partially (3)H-labeled mannitol (J(mannitol-SM)), an indicator of barrier function, was measured while epithelia were exposed to 3 sequential in vitro measurement periods lasting 1 h each. The measurement periods consisted of baseline, challenge, and recovery periods and were interspersed by 30-min periods for treatment equilibration. Baseline conditions were pH 6.1 (mucosal solution) and pH 7.4 (serosal solution) with a bilateral osmolarity of 293 mOsm/L. During the challenge period, the mucosal side of the epithelia was exposed to either an acidotic challenge (pH 5.2, osmolarity 293 mOsm/L) or an osmotic challenge (pH 6.1, osmolarity 450 mOsm/L); a third group served as control (pH 6.1, osmolarity 293 mOsm/L). The mucosal buffer solution was replaced for the recovery period. In vivo, sheep on the SARA treatment had lower mean (5.77 vs. 6.67) and nadir (5.48 vs. 6.47) ruminal pH for the 3h following the oral drench compared with sham sheep, indicating the successful induction of SARA with the oral glucose dose. Despite the marked reduction in pH in vivo, induction of SARA had no detectable effects on the baseline measurements of J(mannitol-SM), tissue conductance (G(t)), and short-circuit current (I(sc)) in vitro. However, reducing mucosal pH to 5.2 in vitro had negative effects on epithelial barrier function in the recovery period, including increased J(mannitol-SM), increased G(t), and decreased I(sc). The osmotic challenge increased J(mannitol-SM) and G(t) and decreased I(sc) during the challenge period, which was reversible in the recovery period except for slight reduction in I(sc). Interactions between the in vitro treatment and measurement period were detected for J(mannitol-SM), G(t), and I(sc). These data indicate that a mild episode of SARA (nadir pH, 5.48; duration ruminal pH <5.8, 111 min relative to the 180-min measurement period) does not affect ruminal epithelial barrier function immediately after the episode but that a rapid and more severe acidification (pH 5.2) in vitro increases epithelial permeability following the insult.


Regional Systems of Care to Optimize Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement.
This study sought to describe the development of a multicenter, transcatheter aortic valve replacement program and regional systems of care intended to optimize coordinated, efficient, and appropriate delivery of this new therapy. Transcatheter aortic valve replacement (TAVR) has become an accepted treatment option for patients with severe aortic stenosis who are at high surgical risk. Regional systems of care have led to improvements in outcomes for patients undergoing intervention for myocardial infarction, cardiac arrest, and stroke. We implemented a regional system of care for patients undergoing TAVR in British Columbia, Canada. We describe a prospective observational cohort of 583 patients who underwent TAVR in British Columbia between 2012 and 2014. Regionalization of TAVR care in British Columbia refers to a centrally coordinated, funded, and evaluated program led by a medical director and a multidisciplinary advisory group that oversees planning, access to care, and quality of outcomes at the 4 provincial sites. Risk-stratified case selection for transfemoral TAVR is performed by heart teams at each site on the basis of consensus provincial indications. Referrals for lower volume and more complicated TAVR, including nontransfemoral access and valve-in-valve procedures, are concentrated at a single site. In-hospital and 30-day outcomes are reported. The median age was 83 years (interquartile range [IQR]: 78 to 87 years) and median STS score was 6% (IQR: 4% to 8%). Transfemoral access was performed in 499 (85.6%) cases and nontransfemoral in 84 (14.4%). Transcatheter valve-in-valve procedures in for failed bioprosthetic valves were performed in 43 patients (7.4%). A balloon-expandable valve was inserted in 386 (66.2%) and a self-expanding valve in 189 (32.4%). All-cause 30-day mortality was 3.5%. All-cause in-hospital mortality and disabling stroke occurred in 3.1% and 1.9%, respectively. Median length of stay was 3 days (IQR: 3 to 6 days), with 92.8% of patients discharged directly home. This experience demonstrates the potential benefits of a regional system of care for TAVR. Excellent outcomes were demonstrated: most patients had short in-hospital stays and were discharged directly home.


Metal-nonmetal transition in the boron group elements.
Structural competition in boron group elements has been studied by means of ab initio calculations. For boron we predict a structural change alpha-B-->alpha-Ga accompanied by a nonmetal-metal transition at a pressure of about 74 GPa. For Al and Ga we find an icosahedron based elemental modification (alpha-B) 0.22 and 0.05 eV/atom, respectively, higher in energy than the corresponding metallic ground state structures. In particular, the low energy difference for Ga raises expectations into the experimental feasibility of new modifications for these elements, especially in nanosized systems.


Dose Number as a Tool to Guide Lead Optimization for Orally Bioavailable Compounds in Drug Discovery.
Small molecule developability challenges have been well documented over the last two decades. One of these critical developability parameters is aqueous solubility. In general, more soluble compounds have improved oral absorption. While enabling formulation technologies exist to improve bioperformance for low solubility compounds, these are often more complex, expensive, and challenging to scale up. Therefore, to avoid these development issues, medicinal chemists need tools to rapidly profile and improve the physicochemical properties of molecules during discovery. Dose number (Do) is a simple metric to predict whether a compound will be reasonably absorbed based on solubility at an expected clinical dose and represents a valuable parameter to the medicinal chemist defining a clinical candidate. The goal of this mini-Perspective is to present the background of the Do equation and how it can be effectively used to rapidly predict oral absorption potential for molecules in the discovery space.


Alterations in energy metabolism in cardiomyopathies.
Despite the fact that the heart requires huge amounts of energy to sustain contractile function, it has limited energy reserves and must therefore continually produce large amounts of adenosine triphosphate (ATP) to sustain function. Fatty acids are the primary energy substrate of the adult heart, with more than 60% of the energy normally obtained from the oxidation of fatty acids, the remainder coming from the metabolism of carbohydrates. Alterations in both the rates of ATP production and the type of energy substrate used by the heart can have consequences on contractile function, as well as on its ability to respond to energetic stresses. Switches in myocardial substrate utilization and energy production rates have been shown to occur in various cardiomyopathies, as well as in any subsequent heart failure. Heart failure is characterized by an inefficient pumping of the heart, which fails to meet the energy requirements of the body. A number of cardiomyopathies can lead to heart failure. This paper will review the alterations in energy metabolism that occur in a number cardiomyopathies, including ischemic and diabetic cardiomyopathies, as well as hypertrophic cardiomyopathies resulting from mutations in enzymes involved in energy metabolism, such as 5' adenosine monophosphate-activated protein kinase (AMPK).


Photochemistry of Fe:H2O Adducts in Argon Matrixes: A Combined Experimental and Theoretical Study in the Mid-IR and UV-Visible Regions.
The photochemistry of Fe:H2O adducts is of interest in fields as diverse as catalysis and astrochemistry. Industrially, iron can be used as a catalyst to convert H2O to H2, whereas in the interstellar medium it may be an important component of dust grains, influencing the chemistry on their icy surfaces. This study consisted of the deposition and spectral characterization of binary systems of atomic iron with H2O in cryogenic argon matrixes. In this way, we were able to obtain information about the interaction of the two species; we observed the formation of adducts of iron monomers and dimers with water molecules in the mid-IR and UV-visible spectral domains. Upon irradiation with a UV radiation source, the iron species were inserted into the water molecules to form HFeOH and HFe2OH, leading in some cases to the formation of FeO possibly accompanied by the production of H2. DFT and correlated multireference wave function calculations confirmed our attributions. This combination of IR and UV-visible spectroscopy with theoretical calculations allowed us to determine, for the first time, the spectral characteristics of iron adducts and their photoproducts in the UV-visible and in the OH stretching region of the mid-IR domain.


Steroid regulation of the synthesis and secretion of retinol-binding protein by the uterus of the pig.
The endometrium of the pig secretes retinol-binding protein (RBP) under the influence of progesterone (P4). The objective of this study was to determine how conceptus-derived estrogen might modulate this production of RBP around days 11-13 of pregnancy when conceptuses elongate from spheres to long thread-like forms. Concentrations of retinol and RBP were low (35 +/- 7 ng/ml) in uterine flushings obtained on days 10-12 of the estrous cycle or from pregnant gilts in which conceptuses had not elongated. Concentrations of retinol and RBP increased 7- to 8-fold (P less than 0.01) in flushings where filamentous conceptuses were present. Size exclusion and ion exchange chromatography demonstrated that virtually all retinol assayed in uterine flushings was associated with RBP. Northern blot analysis with a cDNA representing uterine RBP revealed a single endometrial mRNA 1.1 kilobases in length. Expression of RBP mRNA in uterine endometrium was measured in ovariectomized prepubertal gilts after the administration of steroids according to the following regimens: I, corn oil (days 0-16; n = 10); II, estradiol benzoate (EB; days 13-14; n = 11); III, EB (days 1-2; n = 12); IV, EB (days 1-2) plus P4 (days 3-16; n = 12); and V, EB (days 1-2) plus P4 (days 3-16) plus EB (days 13-14; n = 12). EB (200 micrograms) and P4 (100 mg) were administered twice daily. Treatment IV was designed to stimulate the estrous cycle, and treatment V simulated early pregnancy. All gilts were hysterectomized on day 16, and total uterine mRNA (3 micrograms) was analyzed by Northern blotting. No RBP mRNA was detected in groups I, II, or III. In group IV, 5 of 12 gilts had detectable RBP mRNA, as measured by densitometric scanning (OD = 0.35 +/- 0.14). RNA isolated from all gilts in group V (12 of 12) gave a strong hybridization signal (OD = 1.58 +/- 0.22) for RBP. Finally, RBP mRNA was examined in the uterine endometrium of mature gilts on day 13 of the estrous cycle (n = 4), day 13 of pseudopregnancy (2.5 mg EB given on days 11-12; n = 4), or day 13 of pregnancy after conceptuses had elongated (n = 4). RBP mRNA was present in all groups, but was enhanced approximately 12-fold (P less than 0.01) in pregnant and pseudopregnant gilts compared to that in control gilts.(ABSTRACT TRUNCATED AT 400 WORDS)


Exploring an Artificial Intelligence-Based, Gamified Phone App Prototype to Track and Improve Food Choices of Adolescent Girls in Vietnam: Acceptability, Usability, and Likeability Study.
Adolescents' consumption of healthy foods is suboptimal in low- and middle-income countries. Adolescents' fondness for games and social media and the increasing access to smartphones make apps suitable for collecting dietary data and influencing their food choices. Little is known about how adolescents use phones to track and shape their food choices. This study aimed to examine the acceptability, usability, and likability of a mobile phone app prototype developed to collect dietary data using artificial intelligence-based image recognition of foods, provide feedback, and motivate users to make healthier food choices. The findings were used to improve the design of the app. A total of 4 focus group discussions (n=32 girls, aged 15-17 years) were conducted in Vietnam. Qualitative data were collected and analyzed by grouping ideas into common themes based on content analysis and ground theory. Adolescents accepted most of the individual- and team-based dietary goals presented in the app prototype to help them make healthier food choices. They deemed the overall app wireframes, interface, and graphic design as acceptable, likable, and usable but suggested the following modifications: tailored feedback based on users' medical history, anthropometric characteristics, and fitness goals; new language on dietary goals; provision of information about each of the food group dietary goals; wider camera frame to fit the whole family food tray, as meals are shared in Vietnam; possibility of digitally separating food consumption on shared meals; and more appealing graphic design, including unique badge designs for each food group. Participants also liked the app's feedback on food choices in the form of badges, notifications, and statistics. A new version of the app was designed incorporating adolescent's feedback to improve its acceptability, usability, and likability. A phone app prototype designed to track food choice and help adolescent girls from low- and middle-income countries make healthier food choices was found to be acceptable, likable, and usable. Further research is needed to examine the feasibility of using this technology at scale.


Liver cirrhosis.
Liver fibrosis and its related complications continue to represent a significant worldwide healthcare burden. Over the past decade there has been considerable improvement in our understanding of the cellular mechanisms and pathophysiology underlying hepatic fibrosis. This greater insight into the relevant basic sciences may lead to the development of novel treatment strategies designed to block the fibrogenic cascade or even enhance matrix degradation. In addition, there have been significant advances in the management of the complications of cirrhosis, with specific treatments now available for some conditions. Perhaps most notably, liver transplantation is now a highly successful treatment for end-stage liver disease and should be considered in all patients with chronic liver disease.


[The effect of drugs that correct regional blood circulation on the function of the parotid salivary glands in the combined treatment of patients with Sjögren's disease].
A study was made of the effect of some drugs that correct microcirculatory disorders (dimethylsulfoxide (DMSO), heparin, novocaine) on the function of the auricular salivary glands (ASG) in combined treatment of 20 patients suffering from Sjögren's disease (SD). It has been established that the use of the indicated remedies is conducive to a more rapid counteracting of the inflammatory process in the ASG, making it possible to stabilize their function for a long time in persons with the initial and marked stages of chronic parotitis (CP) but not preventing repeated exacerbations of CP. In order to maintain the therapeutic level of the response of the vascular bed of the ASG to DMSO, it is desirable that compresses with DMSO in a "pure" form be applied in 6 hours, using a 1% hydrocortisone ointment "laying" 1 to 2 times a day.


Exploring protein domain structure.
The protein databank contains coordinates of over 10,000 protein structures, which constitute more than 25,000 structural domains in total. The investigation of protein structural, functional and evolutionary relationships is fundamental to many important fields in bioinformatics research, and will be crucial in determining the function of the human and other genomes. This review describes the SCOP and CATH databases of protein structure classification, which define, classify and annotate each domain in the protein databank. The hierarchical structure, use and annotation of the databases are explained. Other tools for exploring protein structure relationships are also described.


Healthcare workers' views on mandatory SARS-CoV-2 vaccination in the UK: A cross-sectional, mixed-methods analysis from the UK-REACH study.
Several countries now have mandatory SARS-CoV-2 vaccination for healthcare workers (HCWs) or the general population. HCWs' views on this are largely unknown. Using data from the nationwide UK-REACH study we aimed to understand UK HCW's views on improving SARS-CoV-2 vaccination coverage, including mandatory vaccination. Between 21st April and 26th June 2021, we administered an online questionnaire via email to 17 891 UK HCWs recruited as part of a longitudinal cohort from across the UK who had previously responded to a baseline questionnaire (primarily recruited through email) as part of the United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH) nationwide prospective cohort study. We categorised responses to a free-text question "What should society do if people do not get vaccinated against COVID-19?" using qualitative content analysis. We collapsed categories into a binary variable: favours mandatory vaccination or not, using logistic regression to calculate its demographic predictors, and its occupational, health, and attitudinal predictors adjusted for demographics. Of 5633 questionnaire respondents, 3235 answered the free text question. Median age of free text responders was 47 years (IQR 36-56) and 2705 (74.3%) were female. 18% (n = 578) favoured mandatory vaccination (201 [6%] participants for HCWs and others working with vulnerable populations; 377 [12%] for the general population), but the most frequent suggestion was education (32%, n = 1047). Older HCWs (OR 1.84; 95% CI 1.44-2.34 [≥55 years vs 16 years to <40 years]), HCWs vaccinated against influenza (OR 1.49; 95% CI 1.11-2.01 [2 vaccines vs none]), and with more positive vaccination attitudes generally (OR 1.10; 95% CI 1.06-1.15) were more likely to favour mandatory vaccination, whereas female HCWs (OR= 0.79, 95% CI 0.63-0.96, vs male HCWs) and Black HCWs (OR=0.46, 95% CI 0.25-0.85, vs white HCWs) were less likely to. Only one in six of the HCWs in this large, diverse, UK-wide sample favoured mandatory vaccination. Building trust, educating, and supporting HCWs who are hesitant about vaccination may be more acceptable, effective, and equitable. MRC-UK Research and Innovation grant (MR/V027549/1) and the Department of Health and Social Care (DHSC) via the National Institute for Health Research (NIHR). Core funding was also provided by NIHR Biomedical Research Centres.


Validity Testing and Cultural Adaptation of the eHealth Literacy Questionnaire (eHLQ) Among People With Chronic Diseases in Taiwan: Mixed Methods Study.
Advancements in digital technologies seek to promote health and access to services. However, people lacking abilities and confidence to use technology are likely to be left behind, leading to health disparities. In providing digital health services, health care providers need to be aware of users' diverse electronic health (eHealth) literacy to address their particular needs and ensure equitable uptake and use of digital services. To understand such needs, an instrument that captures users' knowledge, skills, trust, motivation, and experiences in relation to technology is required. The eHealth Literacy Questionnaire (eHLQ) is a multidimensional tool with 7 scales covering diverse dimensions of eHealth literacy. The tool was simultaneously developed in English and Danish using a grounded and validity-driven approach and has been shown to have strong psychometric properties. This study aims to translate and culturally adapt the eHLQ for application among Mandarin-speaking people with chronic diseases in Taiwan and then undertake a rigorous set of validity-testing procedures. The cross-cultural adaptation of the eHLQ included translation and evaluation of the translations. The measurement properties were assessed using classical test theory and item response theory (IRT) approaches. Content validity, known-group validity, and internal consistency were explored, as well as item characteristic curves (ICCs), item discrimination, and item location/difficulty. The adapted version was reviewed, and a recommended forward translation was confirmed through consensus. The tool exhibited good content validity. A total of 420 people with 1 or more chronic diseases participated in a validity-testing survey. The eHLQ showed good internal consistency (Cronbach α=.75-.95). For known-group validity, all 7 eHLQ scales showed strong associations with education. Unidimensionality and local independence assumptions were met except for scale 2. IRT analysis showed that all items demonstrated good discrimination (range 0.27-12.15) and a good range of difficulty (range 0.59-1.67) except for 2 items in scale 7. Using a rigorous process, the eHLQ was translated from English into a culturally appropriate tool for use in the Mandarin language. Validity testing provided evidence of satisfactory-to-strong psychometric properties of the eHLQ. The 7 scales are likely to be useful research tools for evaluating digital health interventions and for informing the development of health technology products and interventions that equitably suit diverse users' needs.


Aberrant signaling pathways of the lung mesenchyme and their contributions to the pathogenesis of bronchopulmonary dysplasia.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease in infants born extremely preterm, typically before 28 weeks' gestation, characterized by a prolonged need for supplemental oxygen or positive pressure ventilation beyond 36 weeks postmenstrual age. The limited number of autopsy samples available from infants with BPD in the postsurfactant era has revealed a reduced capacity for gas exchange resulting from simplification of the distal lung structure with fewer, larger alveoli because of a failure of normal lung alveolar septation and pulmonary microvascular development. The mechanisms responsible for alveolar simplification in BPD have not been fully elucidated, but mounting evidence suggests that aberrations in the cross-talk between growth factors of the lung mesenchyme and distal airspace epithelium have a key role. Animal models that recapitulate the human condition have expanded our knowledge of the pathology of BPD and have identified candidate matrix components and growth factors in the developing lung that are disrupted by conditions that predispose infants to BPD and interfere with normal vascular and alveolar morphogenesis. This review focuses on the deviations from normal lung development that define the pathophysiology of BPD and summarizes the various candidate mesenchyme-associated proteins and growth factors that have been identified as being disrupted in animal models of BPD. Finally, future areas of research to identify novel targets affected in arrested lung development and recovery are discussed.


Two-year evaluation of Intermittent Preventive Treatment for Children (IPTc) combined with timely home treatment for malaria control in Ghana.
Intermittent preventive treatment (IPT) has recently been accepted as an important component of the malaria control strategy. Intermittent preventive treatment for children (IPTc) combined with timely treatment of malaria related febrile illness at home to reduce parasite prevalence and malaria morbidity in children aged between six and 60 months in a coastal community in Ghana. This paper reports persistence of reduced parasitaemia two years into the intervention. The baseline and year-one-evaluation findings were published earlier. The main objective in the second year was to demonstrate whether the two interventions would further reduce parasite prevalence and malaria-related febrile illness in the study population. This was an intervention study designed to compare baseline and evaluation findings without a control group. The study combined home-based delivery of intermittent preventive treatment for children (IPTc) aged 6 - 60 months and home treatment of suspected febrile malaria-related illness within 24 hours. All children aged 6-60 months received home-based delivery of intermittent preventive treatment using amodiaquine + artesunate, delivered at home by community assistants every four months (6 times in 24 months). Malaria parasite prevalence surveys were conducted before the first and after the third and sixth IPTc to the children. The evaluation surveys were done four months after the third and sixth IPTc was given. Parasite prevalence which reduced from 25% to 3.0% at year-one evaluation had reduced further from 3% to 1% at year-two-evaluation. At baseline, 13.8% of the children were febrile (axilary temperature of ≥ 37.5 °C) compared to 2.2% at year-one-evaluation while 2.1% were febrile at year-two-evaluation. The year-two-evaluation result indicates that IPTc given three times in a year (every four months) combined with timely treatment of febrile malaria illness, is effective to reduce malaria parasite prevalence in children aged 6 to 60 months in the study community. This must give hope to malaria control programme managers in sub-Saharan Africa where the burden of the disease is most debilitating.


Keeping chromatin quiet: how nucleosome remodeling restores heterochromatin after replication.
Disruption of chromatin organization during replication poses a major challenge to the maintenance and integrity of genome organization. It creates the need to accurately reconstruct the chromatin landscape following DNA duplication but there is little mechanistic understanding of how chromatin based modifications are restored on newly synthesized DNA. ATP-dependent chromatin remodeling activities serve multiple roles during replication and recent work underscores their requirement in the maintenance of proper chromatin organization. A new component of chromatin replication, the SWI/SNF-like chromatin remodeler SMARCAD1, acts at replication sites to facilitate deacetylation of newly assembled histones. Deacetylation is a pre-requisite for the restoration of epigenetic signatures in heterochromatin regions following replication. In this way, SMARCAD1, in concert with histone modifying activities and transcriptional repressors, reinforces epigenetic instructions to ensure that silenced loci are correctly perpetuated in each replication cycle. The emerging concept is that remodeling of nucleosomes is an early event imperative to promote the re-establishment of histone modifications following DNA replication.


Anticancer activity of beta-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration.
Naturally occurring nucleosides and all anticancer nucleoside analogue drugs are in the beta-D configuration. L-(-)-dioxolane-cytidine [(-)-OddC] is the first L-nucleoside analogue ever shown to have anticancer activity. This compound was converted within cells to its mono-, di-, and triphosphate metabolites and was incorporated into DNA. As with cytosine arabinoside, conversion to the monophosphate was catalyzed by cellular deoxycytidine kinase, which was essential for cytotoxicity. However, unlike cytosine arabinoside, (-)-OddC was not susceptible to degradation by deoxycytidine deaminase. Because (-)-OddC inhibited the growth of hepatocellular and prostate tumors that are generally difficult to treat, it is a promising candidate for additional testing. Our results indicate that there is a great deal of variability in the chiral specificities of cellular enzymes and demonstrate how these differences can be exploited in the design of better anti-viral and anticancer drugs.


Imaging of the diaphragm: anatomy and function.
The diaphragm is the primary muscle of ventilation. Dysfunction of the diaphragm is an underappreciated cause of respiratory difficulties and may be due to a wide variety of entities, including surgery, trauma, tumor, and infection. Diaphragmatic disease usually manifests as elevation at chest radiography. Functional imaging with fluoroscopy (or ultrasonography or magnetic resonance imaging) is a simple and effective method of diagnosing diaphragmatic dysfunction, which can be classified as paralysis, weakness, or eventration. Diaphragmatic paralysis is indicated by absence of orthograde excursion on quiet and deep breathing, with paradoxical motion on sniffing. Diaphragmatic weakness is indicated by reduced or delayed orthograde excursion on deep breathing, with or without paradoxical motion on sniffing. Eventration is congenital thinning of a segment of diaphragmatic muscle and manifests as focal weakness. Treatment of diaphragmatic paralysis depends on the cause of the dysfunction and the severity of the symptoms. Treatment options include plication and phrenic nerve stimulation. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.322115127/-/DC1.


Pharmaceutical product development: A quality by design approach.
The application of quality by design (QbD) in pharmaceutical product development is now a thrust area for the regulatory authorities and the pharmaceutical industry. International Conference on Harmonization and United States Food and Drug Administration (USFDA) emphasized the principles and applications of QbD in pharmaceutical development in their guidance for the industry. QbD attributes are addressed in question-based review, developed by USFDA for chemistry, manufacturing, and controls section of abbreviated new drug applications. QbD principles, when implemented, lead to a successful product development, subsequent prompt regulatory approval, reduce exhaustive validation burden, and significantly reduce post-approval changes. The key elements of QbD viz., target product quality profile, critical quality attributes, risk assessments, design space, control strategy, product lifecycle management, and continual improvement are discussed to understand the performance of dosage forms within design space. Design of experiments, risk assessment tools, and process analytical technology are also discussed for their role in QbD. This review underlines the importance of QbD in inculcating science-based approach in pharmaceutical product development.