Severe accidental overdose of 4-aminopyridine due to a compounding pharmacy error.
4-Aminopyridine (4-AP) is a potassium channel-blocking drug used to ameliorate symptoms of multiple sclerosis and spinal cord injury by facilitating neural impulse conduction. It is not Food and Drug Administration (FDA) approved, but information about it is disseminated via the Internet, and it is currently available from compounding pharmacies with a physician's prescription. Dose-related toxicity is frequent and includes dizziness, insomnia, paresthesia, asthenia, headache, tremor, delirium, choreoathetosis, and seizures. To report a case of life-threatening accidental overdose of 4-AP resulting from a pharmacy error. A 42-year-old man with a history of C3 spinal cord injury with residual left-sided weakness and anesthesia, taking 4-AP, presented to the Emergency Department with the sudden onset of abdominal pain, vertigo, anxiety, profuse diaphoresis, hypersalivation, hypertension, bradycardia, agitation, and choreoathetosis, followed by status epilepticus. Toxicity due to 4-AP was suspected and the patient was treated symptomatically. He recovered with permanent short-term memory loss after a prolonged and complicated hospital course. Analysis of the pills, which had been prescribed for him by a physician and specially compounded by a pharmacist, showed that they contained approximately 10 times the dose indicated on the label, a dose that reliably produces severe toxicity. Emergency physicians should be familiar with the signs of 4-AP toxicity. Additionally, they should be aware that 4-AP and other non-FDA-approved medications may be available to patients from compounding pharmacies, and that quality control of made-to-order drug compounding may not be up to the standard that is expected with mass-produced pharmaceuticals.


Puerperal mental illness, clinical features and classification: a study of 142 mother-and-baby admissions.
The case notes were studied of 142 mothers admitted to psychiatric hospitals in the south-east Thames region within 12 months of childbirth during the years 1979 and 1980. Only 6% of the sample were categorised as schizophrenics by RDC criteria, whereas affective disorders were found to predominate in 80%. Manic and schizo-affective illnesses almost always began within two weeks of parturition, as did psychotic depressions. A third of the patient sample had suffered relatively minor disorders, and given adequate resources, some might have been better managed in the community. A parallel investigation of diagnostic returns to the Department of Health revealed considerable uncertainty about how to classify puerperal mental illnesses in accordance with ICD-9. There is an urgent need to improve the system for categorising and registering mental illnesses related to childbirth. Until this is achieved, research into aetiology, outcome, and the provision of services will continue to be impeded.


MolTarPred: A web tool for comprehensive target prediction with reliability estimation.
Molecular target prediction can provide a starting point to understand the efficacy and side effects of phenotypic screening hits. Unfortunately, the vast majority of in silico target prediction methods are not available as web tools. Furthermore, these are limited in the number of targets that can be predicted, do not estimate which target predictions are more reliable and/or lack comprehensive retrospective validations. We present MolTarPred ( http://moltarpred.marseille.inserm.fr/), a user-friendly web tool for predicting protein targets of small organic compounds. It is powered by a large knowledge base comprising 607,659 compounds and 4,553 macromolecular targets collected from the ChEMBL database. In about 1 min, the predicted targets for the supplied molecule will be listed in a table. The chemical structures of the query molecule and the most similar compounds annotated with the predicted target will also be shown to permit visual inspection and comparison. Practical examples of the use of MolTarPred are showcased. MolTarPred is a new resource for scientists that require a more complete knowledge of the polypharmacology of a molecule. The introduction of a reliability score constitutes an attractive functionality of MolTarPred, as it permits focusing experimental confirmatory tests on the most reliable predictions, which leads to higher prospective hit rates.


Architecture and inherent robustness of a bacterial cell-cycle control system.
A closed-loop control system drives progression of the coupled stalked and swarmer cell cycles of the bacterium Caulobacter crescentus in a near-mechanical step-like fashion. The cell-cycle control has a cyclical genetic circuit composed of four regulatory proteins with tight coupling to processive chromosome replication and cell division subsystems. We report a hybrid simulation of the coupled cell-cycle control system, including asymmetric cell division and responses to external starvation signals, that replicates mRNA and protein concentration patterns and is consistent with observed mutant phenotypes. An asynchronous sequential digital circuit model equivalent to the validated simulation model was created. Formal model-checking analysis of the digital circuit showed that the cell-cycle control is robust to intrinsic stochastic variations in reaction rates and nutrient supply, and that it reliably stops and restarts to accommodate nutrient starvation. Model checking also showed that mechanisms involving methylation-state changes in regulatory promoter regions during DNA replication increase the robustness of the cell-cycle control. The hybrid cell-cycle simulation implementation is inherently extensible and provides a promising approach for development of whole-cell behavioral models that can replicate the observed functionality of the cell and its responses to changing environmental conditions.


Characterization of light transport in scattering media at sub-diffusion length scales with Low-coherence Enhanced Backscattering.
Low-coherence enhanced backscattering (LEBS) is a technique that has recently shown promise for tissue characterization and the detection of early pre-cancer. Although several Monte Carlo models of LEBS have been described, these models have not been accurate enough to predict all of the experimentally observed LEBS features. We present an appropriate Monte Carlo model to simulate LEBS peak properties from polystyrene microsphere suspensions in water. Results show that the choice of the phase function greatly impacts the accuracy of the simulation when the transport mean free path (ls*) is much greater than the spatial coherence length (L(SC)). When ls* < L(SC), a diffusion approximation based model of LEBS is sufficiently accurate. We also use the Monte Carlo model to validate that LEBS can be used to measure the radial scattering probability distribution (radial point spread function), p(r), at small length scales and demonstrate LEBS measurements of p(r) from biological tissue. In particular, we show that pre-cancerous and benign mucosal tissues have different small length scale light transport properties.


Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1.
Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.


Identification of proteins absorbed to hemodialyser membranes from heparinized plasma.
The protein layers formed during contact of plasma with hemodialysis membranes were studied. Dialysers having membranes of cellulose acetate (CA), saponified cellulose ester (SCE), cuprophane (CUP), polymethylmethacrylate (PMMA), and polyacrylonitrile (PAN) were used. Heparinized human plasma was recirculated through the dialysers for four hours. They were then rinsed and the proteins adsorbed to the membranes were eluted with 2% SDS. The yields of protein from the different membranes increased in the order: PMMA < CA < SCE < CUP < PAN. This is the probable order of increasing hydrophilicity. SDS-PAGE and Western blots were performed on the dialyser eluates. The blots were positive for most of the twenty proteins tested for. There were some interesting differences in adsorption patterns among the different membrane materials, notably for high molecular weight kininogen (HMWK), plasminogen and the C3 component of complement. HMWK was intact in the eluates from CA, CUP and SCE, whereas on PMMA and PAN there was evidence of cleavage, suggesting that activation of the contact phase of coagulation was more extensive on the latter two materials. Intact plasminogen was visible on all the blots. However, low molecular weight fragments were visible in the PAN eluates, suggesting activation of the fibrinolytic pathway. Low molecular weight fibrinogen fragments eluted from PAN membranes support this conclusion. C3 was visible in the blots obtained for all membrane materials, and the data suggest that complement is activated by all the membranes. A C3 fragment at about 30 kD (possibly C3d) was seen in the blots for the cellulosic membranes but not for PMMA or PAN.


Glutamate receptor 1 phosphorylation at serine 831 and 845 modulates seizure susceptibility and hippocampal hyperexcitability after early life seizures.
Neonatal seizures can lead to later life epilepsy and neurobehavioral deficits, and there are no treatments to prevent these sequelae. We showed previously that hypoxia-induced seizures in a neonatal rat model induce rapid phosphorylation of serine-831 (S831) and Serine 845 (S845) sites of the AMPA receptor GluR1 subunit and later neuronal hyperexcitability and epilepsy, suggesting that seizure-induced posttranslational modifications may represent a novel therapeutic target. To unambiguously assess the contribution of these sites, we examined seizure susceptibility in wild-type mice versus transgenic knock-in mice with deficits in GluR1 S831 and S845 phosphorylation [GluR1 double-phosphomutant (GluR1 DPM) mice]. Phosphorylation of the GluR1 S831 and S845 sites was significantly increased in the hippocampus and cortex after a single episode of pentyleneterazol-induced seizures in postnatal day 7 (P7) wild-type mouse pups and that transgenic knock-in mice have a higher threshold and longer latencies to seizures. Like the rat, hypoxic seizures in P9 C57BL/6N wild-type mice resulted in transient increases in GluR1 S831 and GluR1 S845 phosphorylation in cortex and were associated with enhanced seizure susceptibility to later-life kainic-acid-induced seizures. In contrast, later-life seizure susceptibility after hypoxia-induced seizures was attenuated in GluR1 DPM mice, supporting a role for posttranslational modifications in seizure-induced network excitability. Finally, human hippocampal samples from neonatal seizure autopsy cases also showed an increase in GluR1 S831 and S845, supporting the validation of this potential therapeutic target in human tissue.


High thermal stability of block copolymer-capped Au and Cu nanoparticles.
Producing solution-based metal nanoparticles that do not agglomerate at elevated temperatures remains challenging. We show that thermally stable Au and Cu nanoparticles can be prepared using polystyrene-poly(4-vinylpyridine) diblock copolymers as capping agents. These materials remain stable when their solutions are subjected to prolonged heating up to 160 °C for more than 48 h. These conditions are sufficient for applications in most wet chemical processes and reactions.


Measuring behavioral responses of sea turtles, saltwater crocodiles, and crested terns to drone disturbance to define ethical operating thresholds.
Drones are being increasingly used in innovative ways to enhance environmental research and conservation. Despite their widespread use for wildlife studies, there are few scientifically justified guidelines that provide minimum distances at which wildlife can be approached to minimize visual and auditory disturbance. These distances are essential to ensure that behavioral and survey data have no observer bias and form the basis of requirements for animal ethics and scientific permit approvals. In the present study, we documented the behaviors of three species of sea turtle (green turtles, Chelonia mydas, flatback turtles, Natator depressus, hawksbill turtles, Eretmochelys imbricata), saltwater crocodiles (Crocodylus porosus), and crested terns (Thalasseus bergii) in response to a small commercially available (1.4 kg) multirotor drone flown in Northern Territory and Western Australia. Sea turtles in nearshore waters off nesting beaches or in foraging habitats exhibited no evasive behaviors (e.g. rapid diving) in response to the drone at or above 20-30 m altitude, and at or above 10 m altitude for juvenile green and hawksbill turtles foraging on shallow, algae-covered reefs. Adult female flatback sea turtles were not deterred by drones flying forward or stationary at 10 m altitude when crawling up the beach to nest or digging a body pit or egg chamber. In contrast, flyovers elicited a range of behaviors from crocodiles, including minor, lateral head movements, fleeing, or complete submergence when a drone was present below 50 m altitude. Similarly, a colony of crested terns resting on a sand-bank displayed disturbance behaviors (e.g. flight response) when a drone was flown below 60 m altitude. The current study demonstrates a variety of behavioral disturbance thresholds for diverse species and should be considered when establishing operating conditions for drones in behavioral and conservation studies.


Impact of anabolic androgenic steroids on sexual function.
To describe the impact of supra-physiologic anabolic-androgenic steroid (AAS) use, including agent, dosage, and duration of therapy, on sexual function. We reviewed data from an online survey of AAS users to evaluate their sexual function on and off AAS. The online survey consisted of questions addressing demographics, anabolic steroid use and patterns, ancillary medications, testosterone (T)-related symptoms while on and off of therapy, as well as sexual function which was assessed using the 5-item, International Index of Erectile Function (IIEF-5). A total of 321 men responded to the survey, of which 90 failed to meet inclusion criteria, for a final cohort of 231 AAS users. The majority of men were Caucasian (85%), employed (62%), and younger than 35 years (58%), while an equal mix were single (47%) or married (46%). The mean IIEF-5 was 22.5, with higher scores associated with increased T dosages (>600 mg/week), use of 17-alpha alkylated hormones and anti-estrogens, and absence of concurrent medical conditions. Lower mean IIEF scores were associated with current and pre-AAS low T symptoms, self-reported angry or violent tendencies, self-reported erectile dysfunction (ED), decreased libido, decreased energy, and depression. After controlling for age, low T symptoms and decreased energy remained significantly associated with lower IIEF scores. Among 127 men reporting de novo decreased libido when not taking AAS, several factors were significantly associated including frequency and duration of T and use of adjunctive therapies, while post-cycle therapies were protective. Men who reported any other de novo symptom (decreased energy, libido, muscle mass or depression) after discontinuing T were also more likely to report de novo ED, as well as those using >10 years or for >40 weeks per year. The long-term impact of high dose AAS use on sexual function remains poorly defined. Although high T dosages appeared to be protective of erectile function during use, de novo symptoms such as decreased libido and ED occurred more frequently after discontinuing T, particularly among those using more frequently and for longer durations. Given the importance of these findings, long-term studies evaluating the impacts of discontinuing T on sexual dysfunction are indicated.


A Review of HIV and Surgery in Africa.
HIV has a significant impact on surgery in Africa. Its' influence has spanned a period of about 30 years. In the 1980s' Africa experienced a rise in the national prevalence of HIV spreading across East Africa through Southern Africa, and reaching peak prevalence in the Southern African region. These prevalence levels have affected four key areas of surgical practice; namely patient care, practice of surgery, surgical pathologies, the practitioner and more recently prevention. The surgical patient is more likely to be HIV positive in Africa, than elsewhere in the world. The patients are also more likely to have co infection with Hepatitis C or B and are unlikely to be aware of his or her HIV status. Surgical patients are also more likely to have impaired liver and renal function at the time of presentation. Therefore, HIV has affected the pattern of surgical pathologies, by influencing disease presentation, diagnosis, management and outcomes. It has also influenced the surgeon by increasing occupational risk and management of that risk. Recently in an ironic change of roles, surgery has impacted HIV prevention through the role of male circumcision as a significant tool in HIV prevention, which has traditionally focused on behavioural interventions. The story of surgery and HIV continues to unfold on the continent. Ultimately presenting a challenge which requires innovation, dedication and hard work in the already resource limited environments of Africa.


Unresolved maternal attachment representations, disrupted maternal behavior and disorganized attachment in infancy: links to toddler behavior problems.
Attachment theory's original formulation was substantially driven by Bowlby's (1969/1982) quest for a meaningful model of the development of psychopathology. Bowlby posited that aberrant experiences of parenting increase the child's risk of psychopathological outcomes, and that these risks are mediated by the quality of the attachment relationship. To empirically examine this hypothesis, the current study explores the associations between the development of toddler behavior problems and a) maternal unresolved attachment representations, b) maternal interactive behavior, and c) infant attachment relationships. Second, we test the mediating role of disorganized attachment in the association between disruptive behavior and toddler behavior problems, as well as unresolved attachment and behavior problems. Sixty-four adolescent mother-infant dyads participated in this longitudinal study. The Adult Attachment Interview was administered at 6 months, the Strange Situation procedure was conducted at 12 months, disrupted behavior was assessed during play interactions at 12 months using the AMBIANCE measure, and the Child Behavior Checklist (CBCL) was used to assess behavior problems at 24 months of age. Maternal reports of externalizing problems were significantly associated with unresolved representations of attachment, disrupted maternal behavior, and disorganized attachment. Inclusion of these variables in a path analytic model suggested that disorganized attachment mediated the associations between disrupted maternal behavior and externalizing problems. Although the association between unresolved attachment representations and externalizing problems was no longer significant when mediation by disrupted behavior and disorganized attachment was taken into account, this indirect pathway was not significant. The results are consistent with Bowlby's (1969/1982) original conceptualization of the explanatory role of the attachment relationship in the development and manifestation of behavioral maladaptation. Effects of unresolved attachment on externalizing problems await further explanation.


Adaptive evolution of an sRNA that controls Myxococcus development.
Small RNA (sRNA) molecules regulate a vast array of processes in biology, but evidence for adaptive evolution of sRNA sequences has been indirect. Here, we identify an sRNA, Pxr, that negatively regulates fruiting body development in Myxococcus xanthus. We further show that a spontaneous evolutionary mutation in Pxr abolished its regulatory function and thereby adaptively restored developmental proficiency to a socially defective M. xanthus cheater. In wild-type M. xanthus, development is initiated only upon starvation, but deletion of pxr allows development to proceed even while nutrients remain abundant. Thus, Pxr serves as a major checkpoint controlling the transition from growth to development in the myxobacteria. These findings show that an sRNA molecule governs a complex form of multicellular development in prokaryotes and directly demonstrate the ability of sRNA regulators to facilitate evolutionary adaptations of major phenotypic effect.


A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos.
We have generated the first mouse model of fibro-blast growth factor receptor 3 (Fgfr3) with the K644E mutation, which accurately reflects the embryonic onset of a neonatal lethal dwarfism, thanatophoric dysplasia type II (TDII). Long-bone abnormalities were identified as early as embryonic day 14, during initiation of endochondral ossification. Increased expression of PATCHED: (PTC:) was observed, independent of unaltered expression of parathyroid hormone-related peptide (PTHrP) receptor and Indian Hedgehog (IHH:), suggesting a new regulatory role for Fgfr3 in embryos. We demonstrate that the mutation enhances chondrocyte proliferation during the early embryonic skeletal development, in contrast to previous reports that showed decreased proliferation in postnatal-onset dwarf mice with activating Fgfr3 mutations. This suggests that signaling through Fgfr3 both promotes and inhibits chondrocyte proliferation, depending on the time during development. In contrast, suppressed chondrocyte differentiation was observed throughout the embryonic stages, defining decreased differentiation as the primary cause of retarded longitudinal bone growth in TDII. This model was successfully crossed with a cartilage-specific CRE: transgenic strain, excluding the lung as the primary cause of lethality.


Acetylation of the transcriptional repressor Ume6p allows efficient promoter release and timely induction of the meiotic transient transcription program in yeast.
Differentiation programs require strict spatial and temporal control of gene transcription. Genes expressed during meiotic development in Saccharomyces cerevisiae display transient induction and repression. Early meiotic gene (EMG) repression during mitosis is achieved by recruiting both histone deacetylase and chromatin remodeling complexes to their promoters by the zinc cluster DNA binding protein Ume6p. Ume6p repression is relieved by ubiquitin-mediated destruction that is stimulated by Gcn5p-induced acetylation. In this report, we demonstrate that Gcn5p acetylation of separate lysines within the zinc cluster domain negatively impacts Ume6p DNA binding. Mimicking lysine acetylation using glutamine substitution mutations decreased Ume6p binding efficiency and resulted in partial derepression of Ume6p-regulated genes. Consistent with this result, molecular modeling predicted that these lysine side chains are adjacent to the DNA phosphate backbone, suggesting that acetylation inhibits Ume6p binding by electrostatic repulsion. Preventing acetylation did not impact final EMG induction levels during meiosis. However, a delay in EMG induction was observed, which became more severe in later expression classes, ultimately resulting in delayed and reduced execution of the meiotic nuclear divisions. These results indicate that Ume6p acetylation ensures the proper timing of the transient transcription program during meiotic development.


A Spatial Analysis of Physician Assistant Programs.
The Accreditation Review Commission on Education for the Physician Assistant projects a total of 273 accredited programs by the summer of 2020. Over the past 10 years, the number of Central Application Service for Physician Assistants (CASPA) applicants per seat has increased by 53%. However, no studies have addressed the current geographic relationship of applicants to programs and program growth. The purpose of this study was to describe the geospatial patterns and relationships of physician assistant (PA) programs and CASPA applicants. Program directory information for established (n = 159), satellite (n = 18), and new PA programs (n = 95) was mapped using ArcGIS software. Permanent US ZIP codes for PA applicants (n = 22,603) from the 2014 to 2015 CASPA admissions cycle were also mapped. Point data were used to calculate the nearest neighbor by program type. Correlation was used to measure the association between PA applicants, program class size, and state population metrics. Most of the 95 new PA programs were geographically close to established programs. The median distance of new programs to the nearest neighboring established program was 25.6 miles (mean 39, standard deviation 38). Both established and new PA programs were found to be highly clustered (Moran's I z score < 2.58, p = .01). The geographic distribution of the CASPA applicant pool was related to distribution of the US population, certified PAs, and practicing physicians. PA program growth has exceeded projections. The close proximity of new programs to established programs will likely result in continued competition for quality applicants, PA faculty members, and clinical training sites.


Large Thermal Conductivity Drops in the Diamondoid Lattice of CuFeS2 by Discordant Atom Doping.
Doping in a lattice refers to the introduction of very small quantities of foreign atoms and has a generally small effect on decreasing the lattice thermal conductivity, unlike alloying which involves large fractions of other elements and strongly enhances point defect phonon scattering. Here, we report that, by alloying only 3% of In on the Cu sites of the diamond-like lattice of CuFeS2 chalcopyrite compound (Cu1-xInxFeS2, x = 0.03) has a disproportionally large effect in reducing the lattice thermal conductivity of the compound from 2.32 to 1.36 Wm-1K-1 at 630 K. We find that In is not fully ionized to +3 when on the Cu sublattice and exists mainly in the +1 oxidation state. The 5s2 lone pair of electrons of In+ makes this atom incompatible (referred to as discordant) with the tetrahedral geometry of the crystallographic site. This causes strong local bond distortions thereby softening the In-S and Cu-S chemical bonds and introducing localized low frequency vibrations. The latter couple with the base phonon frequencies of the CuFeS2 matrix enhancing the anharmonicity and decreasing the phonon velocity, and consequently the lattice thermal conductivity. The control material in which the In doping is on the Fe3+ site of the structure at the same doping level (and found in the site-compatible In3+ state), has a far smaller effect on the phonon scattering.


The molecular basis of myelodysplastic syndromes.
The myelodysplastic syndromes comprise a heterogeneous group of neoplastic disorders characterized by ineffective hematopoiesis with an increased tendency to evolve to acute leukemia. Clinically, the common manifestations include peripheral blood cytopenias of one or more lineages and a normal to hyperplastic marrow. MDS has been defined on the basis of morphological criteria, namely the percentage of blast cells in the bone marrow, by the French-American-British study group. Scoring systems have been developed to include such factors as hemoglobin, leukocyte count and age in the evaluation of MDS prognosis. Although useful in the prediction of clinical course and design of therapy regimens, our understanding of the basis of MDS has come from recent advances in molecular analysis of these disorders. This review describes some of the established and recent contributions to our understanding of the molecular basis of the myelodysplastic syndromes. The authors of the present review have been working in the field of myelodysplastic syndromes for several years and have contributed original papers on the molecular pathogenesis of these disorders. In addition, in the present review they have critically examined articles and abstracts published in journals covered by the Science Citation Index and Medline. Cytogenetic anomalies and proto-oncogene abnormalities point to new understanding of the pathogenesis of MDS as a sequence of DNA lesions leading to the evolution of the pre-malignant clone. The prognostic significance of these factors in predicting leukemic transformation and survival remains controversial. Characterization of MDS cells in vitro in response to combinations of exogenous growth factors have not only provided valuable information regarding ineffective hematopoiesis in MDS but have provided a new insight into treatment of MDS. One major development in our understanding of MDS is the possible explanation for the apparent paradox of a cellular marrow in combination with peripheral cytopenias. Extensive premature programmed cell death or apoptosis has been reported to be at least partly responsible. It will remain to be seen whether this fundamental characteristic of myelodysplastic hematopoiesis will play a central role in the drug or genetic based therapy in the myelodysplastic syndromes.


Osteoporosis: impact on health and economics.
Osteoporosis is a major public health problem through associated fragility fractures. The most common sites of fracture are the hip, spine and wrist, and these have an enormous health and economic impact. All fractures result in some degree of morbidity, but fractures at the hip are associated with the worst outcomes. The worldwide direct and indirect annual costs of hip fracture in 1990 were estimated at US$34.8 billion, and are expected to increase substantially over the next 50 years. Fracture incidence varies between populations, and is set to increase over coming decades as the global population becomes more elderly. This effect will be particularly marked in the developing world, which is additionally assuming more-westernized lifestyles that predispose to increased fracture risk. Strategies to target those at high risk of fracture have been developed, but preventative measures at the public health level are also urgently needed to reduce the burden of this devastating disease.


AFOMP Policy Statement No. 3: recommendations for the education and training of medical physicists in AFOMP countries.
AFOMP recognizes that clinical medical physicists should demonstrate that they are competent to practice their profession by obtaining appropriate education, training and supervised experience in the specialties of medical physics in which they practice, as well as having a basic knowledge of other specialties. To help its member countries to achieve this, AFOMP has developed this policy to provide guidance when developing medical physicist education and training programs. The policy is compatible with the standards being promoted by the International Organization for Medical Physics and the International Medical Physics Certification Board.


Plasma LDL and HDL cholesterol and oxidized LDL concentrations are altered in normo- and hypercholesterolemic humans after intake of different levels of cocoa powder.
Cocoa powder is rich in polyphenols, such as catechins and procyanidins, and has been shown in a variety of subject models to inhibit oxidized LDL and atherogenesis. Our study evaluated plasma LDL cholesterol and oxidized LDL concentrations following the intake of different levels of cocoa powder (13, 19.5, and 26 g/d) in normocholesterolemic and mildly hypercholesterolemic humans. In this comparative, double-blind study, we examined 160 subjects who ingested either cocoa powder containing low-polyphenolic compounds (placebo-cocoa group) or 3 levels of cocoa powder containing high-polyphenolic compounds (13, 19.5, and 26 g/d for low-, middle-, and high-cocoa groups, respectively) for 4 wk. The test powders were consumed as a beverage after the addition of hot water, twice each day. Blood samples were collected at baseline and 4 wk after intake of the test beverages for the measurement of plasma lipids. Plasma oxidized LDL concentrations decreased in the low-, middle-, and high-cocoa groups compared with baseline. A stratified analysis was performed on 131 subjects who had a LDL cholesterol concentrations of > or =3.23 mmol/L at baseline. In these subjects, plasma LDL cholesterol, oxidized LDL, and apo B concentrations decreased, and the plasma HDL cholesterol concentration increased, relative to baseline in the low-, middle-, and high-cocoa groups. The results suggest that polyphenolic substances derived from cocoa powder may contribute to a reduction in LDL cholesterol, an elevation in HDL cholesterol, and the suppression of oxidized LDL.


Electrical and mechanical activity in the human lower esophageal sphincter during diaphragmatic contraction.
To determine the effect of contraction of the diaphragm on the lower esophageal sphincter (LES) pressure, we studied eight healthy volunteers during spontaneous breathing, maximal inspiration, and graded inspiratory efforts against a closed airway (Muller's maneuver). Electrical activity of the crural diaphragm (DEMG) was recorded from bipolar esophageal electrodes, transdiaphragmatic pressure (Pdi) was calculated as the difference between gastric and esophageal pressures, and LES pressure was recorded using a sleeve device. During spontaneous breathing, phasic inspiratory DEMG was accompanied by phasic increases in Pdi and LES pressure. With maximal inspiration, DEMG increased 15-20-fold compared with spontaneous inspiration, and LES pressure rose from an end-expiratory pressure of 21 to 90 mmHg. Similar values were obtained during maximal Muller's maneuvers. LES pressure fell promptly when the diaphragm relaxed. Graded Muller's maneuver resulted in proportional increases in the Pdi, LES pressure, and DEMG. The LES pressure was always greater than Pdi and correlated with it in a linear fashion (P less than 0.001). We conclude that the contraction of the diaphragm exerts a sphincteric action at the LES, and that this effect is an important component of the antireflux barrier.


A preliminary study of the short circuit current (Isc) responses of sweat gland cells from normal and anhidrotic horses to purinergic and adrenergic agonists.
The causal factors of equine anhidrosis have not yet been elucidated but defective electrolyte transport mechanisms in the gland are likely to be involved. To investigate this possibility, experiments were performed on cultured equine sweat gland epithelia from five free-sweating UK horses (3 intact males, 2 mares, aged 2-4 years) and from three free-sweating Singapore horses (1 intact male, 2 mares, aged 3-5 years) and three anhidrotic (Singapore) horses (1 intact male, 1 gelding, 1 mare, aged 3-6 years). Cultured cells from each animal were grown on permeable supports and loaded into Ussing chambers to quantify transepithelial resistance and agonist-induced electrolyte transport by the short circuit current (Isc) technique. Transepithelial resistances across the layers of cultured cells were not significantly different between cells from UK and Singapore free-sweating horses, but were significantly reduced in anhidrotic animals. Purinergic agonists added to the apical and basolateral aspects of the cultured cells caused similar increases in Isc between the two populations of unaffected cells, but Isc increases were significantly reduced in anhidrotic animals. Beta-adrenergic agonist stimulation of the anhidrotic cell layers failed to elicit any change in Isc. These pilot results not only confirm earlier conclusions from anatomical findings that failure in the secretory process occurs in anhidrosis but also indicate that both of the known ion transport mechanisms are involved. The trigger for these failures warrants further investigation.


Red meat and colorectal cancer: a critical summary of prospective epidemiologic studies.
Meat consumption and cancer has been evaluated in hundreds of epidemiologic studies over the past three decades; however, the possible role of this food group on carcinogenesis is equivocal. In this comprehensive review, the currently available epidemiologic prospective studies of red meat intake and colorectal cancer are summarized to provide a greater understanding of any potential relationships. Specifically, salient demographic, methodological and analytical information is synthesized across 35 prospective studies. Collectively, associations between red meat consumption and colorectal cancer are generally weak in magnitude, with most relative risks below 1.50 and not statistically significant, and there is a lack of a clear dose-response trend. Results are variable by anatomic tumour site (colon vs. rectum) and by gender, as the epidemiologic data are not indicative of a positive association among women while most associations are weakly elevated among men. Colinearity between red meat intake and other dietary factors (e.g. Western lifestyle, high intake of refined sugars and alcohol, low intake of fruits, vegetables and fibre) and behavioural factors (e.g. low physical activity, high smoking prevalence, high body mass index) limit the ability to analytically isolate the independent effects of red meat consumption. Because of these factors, the currently available epidemiologic evidence is not sufficient to support an independent positive association between red meat consumption and colorectal cancer.


Neural injury alters proliferation and integration of adult-generated neurons in the dentate gyrus.
Neural plasticity following brain injury illustrates the potential for regeneration in the central nervous system. Lesioning of the perforant path, which innervates the outer two-thirds of the molecular layer of the dentate gyrus, was one of the first models to demonstrate structural plasticity of mature granule cells (Parnavelas et al., 1974; Caceres and Steward, 1983; Diekmann et al., 1996). The dentate gyrus also harbors a continuously proliferating population of neuronal precursors that can integrate into functional circuits and show enhanced short-term plasticity (Schmidt-Hieber et al., 2004; Abrous et al., 2005). To examine the response of adult-generated granule cells to unilateral complete transection of the perforant path in vivo, we tracked these cells using transgenic POMC-EGFP mice or by retroviral expression of GFP. Lesioning triggered a marked proliferation of newborn neurons. Subsequently, the dendrites of newborn neurons showed reduced complexity within the denervated zone, but dendritic spines still formed in the absence of glutamatergic nerve terminals. Electron micrographs confirmed the lack of intact presynaptic terminals apposing spines on mature cells and on newborn neurons. Newborn neurons, but not mature granule cells, had a higher density of dendritic spines in the inner molecular layer postlesion accompanied by an increase in miniature EPSC amplitudes and rise times. Our results indicate that injury causes an increase in newborn neurons and lamina-specific synaptic reorganization indicative of enhanced plasticity. The presence of de novo dendritic spines in the denervated zone suggests that the postlesion environment provides the necessary signals for spine formation.


The performance of MLEM for dynamic imaging from simulated few-view, multi-pinhole SPECT.
Stationary small-animal SPECT systems are being developed for rapid dynamic imaging from limited angular views. This paper quantified, through simulations, the performance of Maximum Likelihood Expectation Maximization (MLEM) for reconstructing a time-activity curve (TAC) with uptake duration of a few seconds from a stationary, three-camera multi-pinhole SPECT system. The study also quantified the benefits of a heuristic method of initializing the reconstruction with a prior image reconstructed from a conventional number of views, for example from data acquired during the late-study portion of the dynamic TAC. We refer to MLEM reconstruction initialized by a prior-image initial guess (IG) as MLEM ig . The effect of the prior-image initial guess on the depiction of contrast between two regions of a static phantom was quantified over a range of angular sampling schemes. A TAC was modeled from the experimentally measured uptake of 99m Tc-hexamethylpropyleneamine oxime (HMPAO) in the rat lung. The resulting time series of simulated images was quantitatively analyzed with respect to the accuracy of the estimated exponential washin and washout parameters. In both static and dynamic phantom studies, the prior-image initial guess improved the spatial depiction of the phantom, for example improved definition of the cylinder boundaries and more accurate quantification of relative contrast between cylinders. For example in the dynamic study, there was ~50% error in relative contrast for MLEM reconstructions compared to ~25-30% error for MLEM ig . In the static phantom study, the benefits of the initial guess decreased as the number of views increased. The prior-image initial guess introduced an additive offset in the reconstructed dynamic images, likely due to biases introduced by the prior image. MLEM initialized with a uniform initial guess yielded images that faithfully reproduced the time dependence of the simulated TAC; there were no statistically significant differences in the mean exponential washin/washout parameters estimated from MLEM reconstructions compared to the true values. Washout parameters estimated from MLEM ig reconstructions did not differ significantly from the true values, however the estimated washin parameter differed significantly from the true value in some cases. Overall, MLEM reconstruction from few views and a uniform initial guess accurately quantified the time dependance of the TAC while introducing errors in the spatial depiction of the object. Initializing the reconstruction with a late-study initial guess improved spatial accuracy while decreasing temporal accuracy in some cases.


Solution-state polymer assemblies influence BCS class II drug dissolution and supersaturation maintenance.
Spray dried dispersions (SDDs), solid dispersions of polymer excipients and active pharmaceuticals, are important to the field of oral drug delivery for improving active stability, bioavailability, and efficacy. Herein, we examine the influence of solution-state polymer assemblies on amorphous spray-dried dispersion (SDD) performance with two BCS II model drugs, phenytoin and probucol. These drugs were spray dried with 4 model polymer excipients consisting of poly(ethylene-alt-propylene) (PEP), N,N,-dimethylacrylamide (DMA), or 2-methacrylamido glucopyranose (MAG): amphiphilic diblock ter- and copolymers, PEP-P(DMA-grad-MAG) and PEP-PDMA, and their respective hydrophilic analogues, P(DMA-grad-MAG) and PDMA. Selective and nonselective solvents for the hydrophilic block of the diblock ter- and copolymers were used to induce or repress solution-state assemblies prior to spray drying. Prespray dried solution-state assemblies of these four polymers were probed with dynamic light scattering (DLS) and showed differences in solution assembly size and structure (free polymer versus aggregates versus micelles). Solid-state structures of spray dried dispersions (SDDs) showed a single glass transition event implying a homogeneous mixture of drug/polymer. Crystallization temperatures and enthalpies indicated that the drugs interact mostly with the DMA-containing portions of the polymers. Scanning electron microscopy was used to determine SDD particle size and morphology for the various polymer-drug pairings. In vitro dissolution tests showed excellent performance for one system, spray-dried PEP-PDMA micelles with probucol. Dissolution structures were investigated through DLS to determine drug-polymer aggregates that lead to enhanced SDD performance. Forced aggregation of the polymer into regular micelle structures was found to be a critical factor to increase the dissolution rate and supersaturation maintenance of SDDs, and may be an attractive platform to exploit in excipient design for oral drug delivery.


Establishment of the Asia Oncology Nursing Society (AONS).
Over the past several years, whenever an informal group of Asian oncology nurses gathered, they talked about their mutual desire to create an organization closer to their homes that would be similar to the European Oncology Nursing Society (EONS). They saw this as a means for more of their colleagues to learn about the latest in cancer nursing and to have a time and place to network among themselves. This message continued to gain strength whenever these nurses met at other international meetings such as the International Conference on Cancer Nursing (ICCN), the Multinational Association of Supportive Care in Cancer (MASCC) and the Oncology Nursing Society in US. A definite and planned step toward forming an Asian organization as the first meeting was taken on June 24 2011 when several Asian nurses were attending a MASCC meeting in Greece. The second meeting was held in Prague, Czech Republic, in conjunction with the 17th ICCN meeting on September 10 2012, where the participants of the meeting included 21 oncology nurses from Asian countries. Finally, the first official meeting of the board directors from nine countries was held on November 21 2013 in Bangkok, Thailand. Now, and in the future, sharing and collaborating in the practice, education and research for oncology nursing in Asia is needed.


Photoprotection in the antenna complexes of photosystem II: role of individual xanthophylls in chlorophyll triplet quenching.
In this work the photoprotective role of all xanthophylls in LHCII, Lhcb4, and Lhcb5 is investigated by laser-induced Triplet-minus-Singlet (TmS) spectroscopy. The comparison of native LHCII trimeric complexes with different carotenoid composition shows that the xanthophylls in sites V1 and N1 do not directly contribute to the chlorophyll triplet quenching. The largest part of the triplets is quenched by the lutein bound in site L1, which is located in close proximity to the chlorophylls responsible for the low energy state of the complex. The lutein in the L2 site is also active in triplet quenching, and it shows a longer triplet lifetime than the lutein in the L1 site. This lifetime difference depends on the occupancy of the N1 binding site, where neoxanthin acts as an oxygen barrier, limiting the access of O(2) to the inner domain of the Lhc complex, thereby strongly contributing to the photostability. The carotenoid triplet decay of monomeric Lhcb1, Lhcb4, and Lhcb5 is mono-exponential, with shorter lifetimes than observed for trimeric LHCII, suggesting that their inner domains are more accessible for O(2). As for trimeric LHCII, only the xanthophylls in sites L1 and L2 are active in triplet quenching. Although the chlorophyll to carotenoid triplet transfer is efficient (95%) in all complexes, it is not perfect, leaving 5% of the chlorophyll triplets unquenched. This effect appears to be intrinsically related to the molecular organization of the Lhcb proteins.


A bioinformatics workflow to decipher transcriptomic data from vitamin D studies.
The link between the experimental laboratory studies and bioinformatic approaches aims to find procedures to connect tools from both branches producing workflows that bring together different techniques that are capable of exploiting data at many levels. Thanks to the open access sources and the numerous tools available, it is possible to create various pipelines capable of solving specific problems. Nevertheless the lack of connectivity between them that interconnect different approaches complicates the exploitation of these workflows. Here, we present a detailed description of a workflow composed of different bioinformatics tools that exploits data from large-scale gene expression experiments, contextualizing them at many biological levels. To illustrate the relevance of our workflow for the vitamin D community we applied it to data from myeloid cell models treated with the hormonally active form of vitamin. From raw files of functional genomic studies it is possible to utilize the whole information to obtain a biological insight. Different software and algorithms are included to analyse at pathway, metabolic, ontology and molecular biology level the effects on gene expression. The usage of different databases to analyse gene expression data allows to perform a complete interpretation of functional genomic studies and the implementation of analysis and visualization software tools gives a better understanding of the biological meaning of the results. This review is an example of how to select and bring together several software modules to create one pipeline that processes and analyses genomic data at many biological levels making it open, reproducible and user friendly. Finally, the application of our bioinformatic pipeline revealed that vitamin D modulates crucial metabolic pathways in different myeloid cells that may play an important role in their immune function.


Non-pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy.
Acute kidney injury (AKI) is a common complication amongst people who are critically ill, and it is associated with an increased risk of death. For people with severe AKI, continuous kidney replacement therapy (CKRT), which is delivered over 24 hours, is needed when they become haemodynamically unstable. When CKRT is interrupted due to clotting of the extracorporeal circuit, the delivered dose is decreased and thus leading to undertreatment. This review assessed the efficacy of non-pharmacological measures to maintain circuit patency in CKRT. We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 which includes records identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. We included all randomised controlled trials (RCTs) (parallel-group and cross-over studies), cluster RCTs and quasi-RCTs that examined non-pharmacological interventions to prevent clotting of extracorporeal circuits during CKRT. DATA COLLECTION AND ANALYSIS: Three pairs of review authors independently extracted information including participants, interventions/comparators, outcomes, study methods, and risk of bias. The primary outcomes were circuit lifespan and death due to any cause at day 28. We used a random-effects model to perform quantitative synthesis (meta-analysis). We assessed risk of bias in included studies using the Cochrane Collaboration's tool for assessing risk of bias. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A total of 20 studies involving 1143 randomised participants were included in the review. The methodological quality of the included studies was low, mainly due to the unclear randomisation process and blinding of the intervention. We found evidence on the following 11 comparisons: (i) continuous venovenous haemodialysis (CVVHD) versus continuous venovenous haemofiltration (CVVH) or continuous venovenous haemodiafiltration (CVVHDF); (ii) CVVHDF versus CVVH; (iii) higher blood flow (≥ 250 mL/minute) versus standard blood flow (< 250 mL/minute); (iv) AN69 membrane (AN69ST) versus other membranes; (v) pre-dilution versus post-dilution; (vi) a longer catheter (> 20 cm) placing the tip targeting the right atrium versus a shorter catheter (≤ 20 cm) placing the tip in the superior vena cava; (vii) surface-modified double-lumen catheter versus standard double-lumen catheter with identical geometry and flow design; (viii) single-site infusion anticoagulation versus double-site infusion anticoagulation; (ix) flat plate filter versus hollow fibre filter of the same membrane type; (x) a filter with a larger membrane surface area versus a smaller one; and (xi) a filter with more and shorter hollow fibre versus a standard filter of the same membrane type. Circuit lifespan was reported in 9 comparisons. Low certainty evidence indicated that CVVHDF (versus CVVH: MD 10.15 hours, 95% CI 5.15 to 15.15; 1 study, 62 circuits), pre-dilution haemofiltration (versus post-dilution haemofiltration: MD 9.34 hours, 95% CI -2.60 to 21.29; 2 studies, 47 circuits; I² = 13%), placing the tip of a longer catheter targeting the right atrium (versus placing a shorter catheter targeting the tip in the superior vena cava: MD 6.50 hours, 95% CI 1.48 to 11.52; 1 study, 420 circuits), and surface-modified double-lumen catheter (versus standard double-lumen catheter: MD 16.00 hours, 95% CI 13.49 to 18.51; 1 study, 262 circuits) may prolong circuit lifespan. However, higher blood flow may not increase circuit lifespan (versus standard blood flow: MD 0.64, 95% CI -3.37 to 4.64; 2 studies, 499 circuits; I² = 70%). More and shorter hollow fibre filters (versus standard filters: MD -5.87 hours, 95% CI -10.18 to -1.56; 1 study, 6 circuits) may reduce circuit lifespan. Death from any cause was reported in four comparisons We are uncertain whether CVVHDF versus CVVH, CVVHD versus CVVH or CVVHDF, longer versus a shorter catheter, or surface-modified double-lumen catheters versus standard double-lumen catheters reduced death due to any cause, in very low certainty evidence. Recovery of kidney function was reported in three comparisons. We are uncertain whether CVVHDF versus CVVH, CVVHDF versus CVVH, or surface-modified double-lumen catheters versus standard double-lumen catheters increased recovery of kidney function. Vascular access complications were reported in two comparisons. Low certainty evidence indicated using a longer catheter (versus a shorter catheter: RR 0.40, 95% CI 0.22 to 0.74) may reduce vascular access complications, however the use of surface-modified double lumen catheters versus standard double-lumen catheters may make little or no difference to vascular access complications. The use of CVVHDF as compared with CVVH, pre-dilution haemofiltration, a longer catheter, and surface-modified double-lumen catheter may be useful in prolonging the circuit lifespan, while higher blood flow and more and shorter hollow fibre filter may reduce circuit life. The Overall, the certainty of evidence was assessed to be low to very low due to the small sample size of the included studies. Data from future rigorous and transparent research are much needed in order to fully understand the effects of non-pharmacological interventions in preventing circuit coagulation amongst people with AKI receiving CKRT.


Anorexia Nervosa and Osteoporosis: Pathophysiology and Treatment.
Anorexia nervosa (AN) affects 2.9 million people, many of whom experience bone loss and increased fracture risk. In this article, we review data on the underlying pathophysiology of AN-related osteoporosis and possible approaches to disease management. Available research suggests that low body weight and decreased gonadal function are the strongest predictors of bone loss and fractures in patients with AN. Additionally, other metabolic disturbances have been linked to bone loss, including growth hormone resistance, low leptin concentrations, and hypercortisolemia, but those correlations are less consistent and lack evidence of causality. In terms of treatment of AN-related bone disease, weight gain has the most robust impact on bone mineral density (BMD). Restoration of gonadal function seems to augment this effect and may independently improve BMD. Bisphosphonates, insulin-like growth factor 1 supplementation, and teriparatide may also be reasonable considerations, however need long-term efficacy and safety data.


Infectious and neoplastic diseases of the sphenoid sinus--a report of 10 cases.
Sphenoid opacifications may be discovered during the radiological work up of patients presenting with fever, headache, or neurological changes. While most of these patients do not require surgical intervention, prompt assessment and management is nevertheless required. Ten patients who underwent sphenoidotomy for drainage or biopsy at Montefiore Hospital during a 4-year period from September 1995 through January 2000 are presented. Nine out of 10 patients had predisposing factors such as AIDS, diabetes, leukemia, and end-stage renal disease. The most common presentation was altered mental status. One patient rapidly developed cavernous sinus thrombosis. Microbiology of sphenoid cultures included various fungi, Mycobacterium avium intracellulare, coagulase negative Staphylococci, and Corynebacterium. Neoplastic processes included non-Hodgkin's lymphoma and sinonasal undifferentiated carcinoma. When evaluating hospitalized patients with sphenoid sinus disease, a thorough history and a bedside nasal endoscopy should be performed. Conservative management in the form of intravenous antibiotics and topical decongestion should always be the first line of treatment. Those patients with clinical or radiological evidence of disease extending beyond the confines of the sphenoid sinus require immediate surgical intervention.


Active immunotherapy in treatment of acute leukaemia.
Active non-specific immunotherapy has been used to prolong remissions in acute lymphoblastic leukaemia. The series reported here used Bordetella pertussis vaccine in a controlle trial after intensive chemotherapy. Possibly immunotherapy delayed the onset of relapse in the treated patients, but no long-term remissions were obtained. Further work is needed to establish the role of immunotherapy in general, and the use of B. pertussis vaccine in particular, in the treatment of acute leukaemia.


Lymphomas in E mu-Pim1 transgenic mice exposed to pulsed 900 MHZ electromagnetic fields.
Whether radiofrequency (RF) fields are carcinogenic is controversial; epidemiological data have been inconclusive and animal tests limited. The aim of the present study was to determine whether long-term exposure to pulse-modulated RF fields similar to those used in digital mobile telecommunications would increase the incidence of lymphoma in E mu-Pim1 transgenic mice, which are moderately predisposed to develop lymphoma spontaneously. One hundred female E mu-Pim1 mice were sham-exposed and 101 were exposed for two 30-min periods per day for up to 18 months to plane-wave fields of 900 MHz with a pulse repetition frequency of 217 Hz and a pulse width of 0.6 ms. Incident power densities were 2.6-13 W/m2 and specific absorption rates were 0.008-4.2 W/kg, averaging 0.13-1.4 W/kg. Lymphoma risk was found to be significantly higher in the exposed mice than in the controls (OR = 2.4. P = 0.006, 95% CI = 1.3-4.5). Follicular lymphomas were the major contributor to the increased tumor incidence. Thus long-term intermittent exposure to RF fields can enhance the probability that mice carrying a lymphomagenic oncogene will develop lymphomas. We suggest that such genetically cancer-prone mice provide an experimental system for more detailed assessment of dose-response relationships for risk of cancer after RF-field exposure.


[Long-term effects of tinnitus retraining therapy involving monaural noise generators].
We have previously reported on the effects of tinnitus retraining therapy (TRT) involving monaural noise generators (NGs) up to 24 months after the start of treatment (Eur Arch Otorhinolaryngol. 2013 Feb; 270(2) : 443-8.) but very few reports exist about the long-term effects of TRT for periods of over 2 years. The aim of this study was to report the effects of TRT involving monaural NGs more than 24 months after the start of treatment. Thirty-three patients with chronic tinnitus were included in this study. All received directive counseling and monaural NGs without any other combination treatment. Effects were evaluated with the Tinnitus Handicap Inventory (THI) at their final visits to our clinic (average 31 months after the start of treatment). The average THI scores significantly improved from 55.3 +/- 19.7 at baseline to 33.5 +/- 23.3 at their final visits. Seventeen patients (52%) improved by more than 20 points from the baseline. Eleven patients who were treated with TRT for more than 3 years were individually observed in a detailed manner. Some of them experienced aggravation of their symptoms after 2 years' successful treatments. This study suggests that, although TRT seems effective more than 2 years after the start of treatment, the clinical course of each patient can vary and we need to follow them periodically depending on their situations and symptoms.


The Role of Social Support in Motivating Reductions in Alcohol Use: A Test of Three Models of Social Support in Alcohol-Impaired Drivers.
Social support has been linked to many therapeutic benefits (e.g., treatment retention, reduced posttreatment relapse) for individuals with alcohol use disorder. However, the positive impacts of social support have not been well understood in the context of alcohol-impaired driving. This article examines the role of social support in motivating those with histories of driving while intoxicated (DWI) arrest to reduce alcohol use by testing 3 major models of social support: the Main-Effects model, the Buffering model, and the Optimal Matching model. One hundred and nineteen participants with histories of DWI arrest were recruited from a correctional treatment facility (n = 59) and the local community (n = 60). Participants completed interviews to assess alcohol consumption, psychiatric/physical conditions, and psychosocial factors associated with drinking behavior (e.g., social support, alcohol-related problems, and motivation to change). Hierarchical regression analyses were conducted to test the 3 models. Additionally, the relative magnitude of the effects of general and recovery-specific social support was compared based on the approach of statistical inference of confidence intervals. Overall social support was positively associated with some motivation to change (i.e., importance of change, confidence in change) among alcohol-impaired drivers, supporting the Main-Effects model. However, the impact of overall social support on motivation to change was not moderated by alcohol-related problems of individuals arrested for DWI, which did not confirm the Buffering model. Last, recovery-specific social support, rather than general social support, contributed to increasing motivation to reduce alcohol use, which supported the Optimal Matching model. These findings highlight the benefits of social support (i.e., increased motivation to change alcohol use) for alcohol-impaired drivers. Regardless of the severity of alcohol-related problems of alcohol-impaired drivers, social support had direct positive impacts on motivation to change. In particular, the results underscore that social support can be more effective when it is matched to the recovery effort of individuals, which is consistent with the Optimal Matching model.


Experience in fostering regional collaboration and Coordination to use data for battling infectious diseases in sub-Saharan Africa.
The emergence of COVID-19 highlights globalisation realties, where diseases may emerge from anywhere and rapidly spread globally. Lessons emphasise the necessity for strengthening regional and global collaboration and coordination to allow rapid risk identification, resource mobilisation and joint actions. We report the experience of the Regional Action through Data (RAD) partnership in fostering regional cooperation and collaboration to use data for battling infectious diseases and the effects of COVID-19. The Partnership comprised;BoadReach company, The West African Health Organization (WAHO) and the Intergovernmental Authority on Development (IGAD); Duke University Global Health Centre and the Jembi Health Systems, South Africa. To address the problem of limited used of data to drive performance in healthcare service delivery in sub-Saharan Africa; by changing how and why data is collected, analysed, and then used to achieve results. 1. Regional level: To equip and empower IGAD and WAHO with evidence-based analytics to drive data use for evidence-based policy and program action in public health (regional level). 2. Patient-provider level: To deploy and implement a digital health solution for child-hood vaccination services focused on mobile cross-border populations along the Uganda-Kenya border.Engagement approaches used included; meetings, workshops, technical working groups, establishing monitoring system and annual implementation revision. Targeted training and capacity building were conducted. All activities were built on existing systems and structures to strengthen ownership and sustainability. 1. Regional health data sharing and protection policy, 2. Strengthened regional health information platform. Patient provider level: Deployment of a cloud based digital health solution to enhance childhood access to vaccination services for cross border populations of Kenya and Uganda, 3. Both regions developed resource mobilisation plans for sustainability.RAD established the foundation for building trust and strengthening regional collaboration and coordination in health in Sub-Saharan Africa.


cDNA cloning, gene organization and expression analysis of human peptidylarginine deiminase type VI.
Peptidylarginine deiminase (PAD) catalyzes the post-translational modification of protein through the conversion of arginine to citrulline in the presence of calcium ions. Human, similar to rodents, has four isoforms of PAD (type I, II, III and IV/V), each of which is distinct in substrate specificity and tissue specific expression. In our large-scale sequencing project, we identified a new human PAD cDNA from a human fetal brain cDNA library. The putative protein encoded by this cDNA is designated hPADVI. Expression analysis of hPADVI showed that it is mainly expressed in adult human ovary and peripheral blood leukocytes. We conclude that hPADVI may be orthologous to mouse ePAD, basing on sequence comparison, chromosome localization and exon-intron structure analysis. PAD-mediated deimination of epithelial cell keratin resulting in cytoskeletal remodeling suggests a possible role for hPADVI in cytoskeletal reorganization in the egg and in early embryo development. This study describes a new important member of the human PAD family.


Whole genome sequencing and comparative genomics of closely related Fusarium Head Blight fungi: Fusarium graminearum, F. meridionale and F. asiaticum.
The Fusarium graminearum species complex is composed of many distinct fungal species that cause several diseases in economically important crops, including Fusarium Head Blight of wheat. Despite being closely related, these species and individuals within species have distinct phenotypic differences in toxin production and pathogenicity, with some isolates reported as non-pathogenic on certain hosts. In this report, we compare genomes and gene content of six new isolates from the species complex, including the first available genomes of F. asiaticum and F. meridionale, with four other genomes reported in previous studies. A comparison of genome structure and gene content revealed a 93-99% overlap across all ten genomes. We identified more than 700 k base pairs (kb) of single nucleotide polymorphisms (SNPs), insertions, and deletions (indels) within common regions of the genome, which validated the species and genetic populations reported within species. We constructed a non-redundant pan gene list containing 15,297 genes from the ten genomes and among them 1827 genes or 12% were absent in at least one genome. These genes were co-localized in telomeric regions and select regions within chromosomes with a corresponding increase in SNPs and indels. Many are also predicted to encode for proteins involved in secondary metabolism and other functions associated with disease. Genes that were common between isolates contained high levels of nucleotide variation and may be pseudogenes, allelic, or under diversifying selection. The genomic resources we have contributed will be useful for the identification of genes that contribute to the phenotypic variation and niche specialization that have been reported among members of the F. graminearum species complex.


Long lasting near-obstruction stenosis of mesencephalic aqueduct without development of hydrocephalus--case report.
The aim of this study is to present the five-year longitudinal magnetic resonance imaging (MRI) follow up of a patient with incidental finding of near-obstruction stenosis of the aqueduct of Sylvius due to a large pineal cyst. The patient was scanned 3 times on a 3T MR device using a set of standard structural sequences supplemented with high-resolution constructive interference of steady state (CISS) T2 sequence for precise delineation of the aqueduct of Sylvius and cardiac-gated phase-contrast sequences for the analysis of cerebrospinal fluid (CSF) movement. On all MR scans, the size of the pineal cyst and severity of near-obstruction aqueductal stenosis did not show any morphological changes. There was no significant ventricular enlargement although structural CISS sequence showed a near-obstruction stenosis and cardiac-gated phase-contrast sequences did not detect CSF movement through the aqueduct of Sylvius. Our findings are contradictory to the classic hypothesis of CSF physiology based on secretion, circulation, and absorption of CSF, which states that the impairment of CSF circulation through the aqueduct of Sylvius inevitably leads to a hypertensive hydrocephalus development involving the third and the lateral ventricle. Our research group previously proposed a new hypothesis of CSF physiology, which offers more suitable explanation for such clinical cases.


Antimicrobial resistance, penicillin-binding protein sequences, and pilus islet carriage in relation to clonal evolution of Streptococcus pneumoniae serotype 19A in Russia, 2002-2013.
Clonal changes of serotype 19A pneumococci have been appreciated in conjunction with growing prevalence of this serotype after implementation of the seven-valent pneumococcal conjugate vaccine (PCV7). In the present study, we characterized serotype 19A pneumococci collected in Russia within a decade preceding the implementation of PCV vaccination and described their clonal evolution. We retrospectively analyzed non-invasive serotype 19A isolates collected in 2002-2013. All isolates were subjected to multilocus sequence typing, antimicrobial susceptibility testing, determination of macrolide resistance genotype, molecular detection of pilus islet (PI) carriage, sequencing of penicillin-binding protein (PBP) genes. A total of 49 serotype 19A isolates represented 25 sequence types, of which 14 were newly described. The majority of isolates were distributed among clonal complex (CC) 663 (28%), CC230 (25%), CC156, and CC320 (14% each). CC663 and CC156 dominated in 2003, but were replaced by CC230 and CC320 later on; CC320 was only evident starting 2010. All isolates of CC663 and CC156 carried PI1; CC320 possessed both PI1 and PI2. The overall rate of altered amino acids in penicillin-nonsusceptible isolates was 13·9%, 7·2%, and 8·7% for PBP1a, PBP2b, and PBP2x, respectively. Our findings demonstrate that the clonal structure of serotype 19A pneumococci may evolve without PCV pressure.


Isolation of a Sulfur-oxidizing Bacterium That can Grow under Alkaline pH, from Corroded Concrete.
To study the early stages of concrete corrosion by bacteria, sulfur-oxidizing bacterium strain RO-1, which grows in an alkaline thiosulfate medium (pH 10.0) was isolated from corroded concreate and characterized. Strain RO-1 was a Gram negative, rod-shaped bacterium (0.5-0.6×0.9-1.5 μm). The mean G+C content of the DNA of strain RO-1 was 65.0 mol%. Optimum pH and temperature for growth were 8.0. and 30-37°C, respectively. When grown in thiosulfate medium with pH 10.0, growth rate of the strain was 48% of that observed at the optimum pH for growth. Strain RO-1 used sulfide, thiosulfate, and glucose, but not elemental sulfur or tetrathionate, as a sole energy source. Strain RO-1 grew under anaerobic conditions in pepton-NO3 (-) medium containing sodium nitrate as an electron acceptor, and had enzyme activities that oxidized sulfide, elemental sulfur, thiosulfate, sulfite, and glucose, but not tetrathionate. The bacterium had an activity to assimilate (14)CO2 into the cells when thiosulfate was used as an energy source. These results suggest that strain RO-1 is Thiobacillus versutus. Strain RO-1 exuded Ca(2+) from concrete blocks added to thiosulfate medium with pH 9.0 and the pH of the medium decreased from 9.0 to 5.5 after 22 days of cultivation. In contrast, Thiobacillus thiooxidans strain NB1-3 could not exude Ca(2+) in the same thiosulfate medium, suggesting that strain RO-1, but not T. thiooxidans NB1-3, is involved in the early stage of concrete corrosion because concrete structures just after construction contain calcium hydroxide and have a pH of 12-13.


Intestinal Epithelial Cell Autophagy Is Required to Protect against TNF-Induced Apoptosis during Chronic Colitis in Mice.
Genome-wide association studies have linked polymorphisms in the autophagy gene ATG16L1 with susceptibility to inflammatory bowel disease (IBD). However, the cell-type-specific effects of autophagy on the regulation of chronic intestinal inflammation have not been investigated. Here, we assessed the effect of myeloid-specific or intestinal epithelial cell (IEC)-specific deletion of Atg16l1 on chronic colitis triggered by the intestinal opportunistic pathogen Helicobacter hepaticus in mice. Although Atg16l1 deficiency in myeloid cells had little effect on disease, mice selectively lacking Atg16l1 in IECs (Atg16l1VC) developed severely exacerbated pathology, accompanied by elevated pro-inflammatory cytokine secretion and increased IEC apoptosis. Using ex vivo IEC organoids, we demonstrate that autophagy intrinsically controls TNF-induced apoptosis and in vivo blockade of TNF attenuated the exacerbated pathology in Atg16l1VC mice. These findings suggest that the IBD susceptibility gene ATG16L1 and the process of autophagy within the epithelium control inflammation-induced apoptosis and barrier integrity to limit chronic intestinal inflammation.


Efficiently Combining Water Reuse and Desalination through Forward Osmosis-Reverse Osmosis (FO-RO) Hybrids: A Critical Review.
Forward osmosis (FO) is a promising membrane technology to combine seawater desalination and water reuse. More specifically, in a FO-reverse osmosis (RO) hybrid process, high quality water recovered from the wastewater stream is used to dilute seawater before RO treatment. As such, lower desalination energy needs and/or water augmentation can be obtained while delivering safe water for direct potable reuse thanks to the double dense membrane barrier protection. Typically, FO-RO hybrid can be a credible alternative to new desalination facilities or to implementation of stand-alone water reuse schemes. However, apart from the societal (public perception of water reuse for potable application) and water management challenges (proximity of wastewater and desalination plants), FO-RO hybrid has to overcome technical limitation such as low FO permeation flux to become economically attractive. Recent developments (i.e., improved FO membranes, use of pressure assisted osmosis, PAO) demonstrated significant improvement in water flux. However, flux improvement is associated with drawbacks, such as increased fouling behaviour, lower rejection of trace organic compounds (TrOCs) in PAO operation, and limitation in FO membrane mechanical resistance, which need to be better considered. To support successful implementation of FO-RO hybrid in the industry, further work is required regarding up-scaling to apprehend full-scale challenges in term of mass transfer limitation, pressure drop, fouling and cleaning strategies on a module scale. In addition, refined economics assessment is expected to integrate fouling and other maintenance costs/savings of the FO/PAO-RO hybrid systems, as well as cost savings from any treatment step avoided in the water recycling.


Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction.
Monoamine-based treatments for depression have evolved greatly over the past several years, but shortcomings such as suboptimal efficacy, treatment lag, and residual cognitive dysfunction are still significant. Preclinical and clinical studies using compounds directly targeting glutamatergic neurotransmission present new opportunities for antidepressant treatment, with ketamine having a surprisingly rapid and sustained antidepressant effect that is presumably mediated through glutamate-dependent mechanisms. While direct modulation of glutamate transmission for antidepressant and cognition-enhancing actions may be hampered by nonspecific effects, indirect modulation through the serotonin (5-HT) system may be a viable alternative approach. Based on localization and function, 5-HT can modulate glutamate neurotransmission at least through the 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors, which presents a rational pharmacological opportunity for modulating glutamatergic transmission without the direct use of glutamatergic compounds. Combining one or more of these glutamate-modulating 5-HT targets with 5-HT transporter inhibition may offer new therapeutic opportunities. The multimodal compounds vortioxetine and vilazodone are examples of this approach with diverse mechanisms, and their different clinical effects will provide valuable insights into serotonergic modulation of glutamate transmission for the potential treatment of depression and associated cognitive dysfunction.


The risk of MTBE relative to other VOCs in public drinking water in California.
Ongoing publicity about methyl tertiary butyl ether (MTBE) suggests that this chemical is of greater concern than other contaminants commonly found in drinking water. The purpose of this article is to evaluate the available MTBE data in context with other volatile organic compounds (VOCs) that are detected in public drinking water sources in California. We find that of the 28 VOCs with a primary maximum contaminant level (MCL) in California, 21 were found in 50 or more drinking water sources from 1985 to 2002. Over the last 10 years, the most frequently detected VOCs were chloroform, tetrachloroethylene (PCE), and trichloroethylene (TCE), which were found in about 9-15% of all sampled drinking water sources. These same chemicals were found to have the highest mean detected concentrations over the last 5 years, ranging from 13 to 15 microg/L. Many VOCs were also found to routinely exceed state and federal drinking water standards, including benzene and carbon tetrachloride. By comparison, MTBE was found in approximately 1% of sampled drinking water sources for most years, and of those drinking water sources found to contain MTBE from 1998 to 2002, over 90% had detected concentrations below California's primary MCL of 13 microg/L. Relative to the other VOCs evaluated, MTBE has the lowest estimated California cancer potency value, and was found to pose one of the least cancer risks from household exposures to contaminated drinking water. These findings suggest that MTBE poses an insignificant threat to public drinking water supplies and public health in California, particularly when compared to other common drinking water contaminants.


Pseudohypoaldosteronism type 1 and respiratory distress syndrome.
We present a patient born at 31 weeks gestation with respiratory distress syndrome (RDS) which did not respond to surfactant. He also developed hyponatremia, hyperkalemia and dehydration with increased sweat electrolytes despite high levels of serum aldosterone, thus systemic pseudohypoaldosteronism type 1 (PHA-1) diagnosis was made. Systemic PHA-1 is caused by mutations of amiloride-sensitive epithelial sodium channel (ENaC) genes. Because ENaC is a rate-limiting step for sodium absorption by epithelial cells, not only of the renal tubule but also of the lung epithelium, patients with PHA-1 with pulmonary symptoms have sometimes been reported. However, our patient appears to be the second reported human case of both neonatal RDS and PHA-1, and the first description, with increased sweat electrolytes, of a premature baby with systemic PHA-1 and RDS.


Pertussis.
Pertussis continues to be an important public-health issue. The high immunization coverage rates achieved, mainly in industrialized countries, have certainly decreased the spread of the pathogen. However, as immunity wanes, adolescents and adults play an important role in the dynamics of the infection. The surveillance system has several limitations and the underestimation of pertussis in adolescents, young adults and adults is mainly related to the atypical clinical characteristics of cases and the lack of lab confirmation. The real epidemiological impact of pertussis is not always perceived. The unavailability of comprehensive data should not hamper the adoption of active prophylactic measures designed to avoid the impact of waning immunity against pertussis. Different immunization strategies have been suggested and/or already adopted such as immunization of newborns, pre-school and school children, adolescents, adults, healthcare workers, childcare workers, pregnant women, cocoon strategy. Prevention of pertussis requires an integrated approach and the adoption of different immunization strategies, with the objective of achieving and maintaining high coverage rates.


High trait rumination is associated with blunted nighttime diastolic blood pressure dipping.
Blunted blood pressure (BP) dipping during nighttime sleep has been associated with an increased risk of cardiovascular events. Psychological traits have been associated with prolonged cardiovascular activation and a lack of cardiovascular recovery. This activation may extend into nighttime sleep and reduce BP dipping. This study aims to evaluate the association between trait rumination and nighttime BP dipping. Sixty women scoring either high or low on trait rumination underwent one 24-h ambulatory BP monitoring session. Self-reported wake and sleep times were used to calculate nighttime BP. High trait rumination was associated with less diastolic blood pressure (DBP) dipping relative to low trait rumination. Awake ambulatory BP, asleep systolic blood pressure (SBP) and DBP, and asleep SBP dipping were not associated with trait rumination. In a sample of young women, high trait rumination was associated with less DBP dipping, suggesting that it may be associated with prolonged cardiovascular activation that extends into nighttime sleep, blunting BP dipping.


Posttranscriptional cell cycle-dependent regulation of human FANCC expression.
The Fanconi Anemia (FA) Group C complementation group gene (FANCC) encodes a protein, FANCC, with a predicted M(r) of 63,000 daltons. FANCC is found in both the cytoplasmic and the nuclear compartments and interacts with certain other FA complementation group proteins as well as with non-FA proteins. Despite intensive investigation, the biologic roles of FANCC and of the other cloned FA gene products (FANCA and FANCG) remain unknown. As an approach to understanding FANCC function, we have studied the molecular regulation of FANCC expression. We found that although FANCC mRNA levels are constant throughout the cell cycle, FANCC is expressed in a cell cycle-dependent manner, with the lowest levels seen in cells synchronized at the G1/S boundary and the highest levels in the M-phase. Cell cycle-dependent regulation occurred despite deletion of the 5' and 3' FANCC untranslated regions, indicating that information in the FANCC coding sequence is sufficient to mediate cell cycle-dependent regulation. Moreover, inhibitors of proteasome function blocked the observed regulation. We conclude that FANCC expression is controlled by posttranscriptional mechanisms that are proteasome dependent. Recent work has demonstrated that the functional activity of FA proteins requires the physical interaction of at least FANCA, FANCC, and FANCG, and possibly of other FA and non-FA proteins. Our observation of dynamic control of FANCC expression by the proteasome has important implications for understanding the molecular regulation of the multiprotein complex. (Blood. 2000;95:3970-3977)


Slow light with a swept-frequency source.
ct: We introduce a new concept for stimulated-Brillouin-scattering-based slow light in optical fibers that is applicable for broadly-tunable frequency-swept sources. It allows slow light to be achieved, in principle, over the entire transparency window of the optical fiber. We demonstrate a slow light delay of 10 ns at 1.55 μm using a 10-m-long photonic crystal fiber with a source sweep rate of 400 MHz/μs and a pump power of 200 mW. We also show that there exists a maximal delay obtainable by this method, which is set by the SBS threshold, independent of sweep rate. For our fiber with optimum length, this maximum delay is ~38 ns, obtained for a pump power of 760 mW.


Association between sleep duration and sleep quality, and metabolic syndrome in Taiwanese police officers.
This study's objective was to examine association between sleep duration and sleep quality, and metabolic syndrome (MetS) and its components in Taiwanese male police officers. Male police officers who underwent annual health examinations were invited to join the study and eventually a total of 796 subjects was included in it. The study subjects were divided into 5 groups according to the length (duration) of sleep: < 5, 5-5.9, 6-6.9, 7-7.9 and ≥ 8 h per day, and the global Pittsburgh Sleep Quality Index was used to categorize their sleep quality as good or poor. To analyze the association between sleep problems and MetS, adjusted odds ratio and respective 95% confidence intervals (CI) were computed. The prevalence of MetS in Taiwanese male police officers was 24.5%. Abdominal obesity had the highest proportion (36.2%) among 5 components of MetS. More than 1/2 of the police officers (52.3%) had poor sleep quality. Police officers with higher scores of sleep disturbances had a higher prevalence of MetS (p = 0.029) and abdominal obesity (p = 0.009). After adjusting for age, low-density lipoprotein cholesterol, smoking status, alcohol drinking habit, physical habitual exercise, snoring and type of shift work, the police officers who slept less than 5 h were 88% more likely to suffer from abdominal obesity than those who slept 7-7.9 h (95% CI: 1.01-3.5). Sleep quality was not associated with MetS and its components. The police officers who slept less than 5 h were more likely to experience abdominal obesity in Taiwan, and those with higher scores of sleep disturbances had a higher prevalence of MetS and abdominal obesity. It is recommended that police officers with short sleep duration or sleep disturbances be screened for MetS and waist circumference in order to prevent cardiovascular diseases.


Functional characterization of the Saccharomyces cerevisiae protein Chl1 reveals the role of sister chromatid cohesion in the maintenance of spindle length during S-phase arrest.
Metaphase cells have short spindles for efficient bi-orientation of chromosomes. The cohesin proteins hold sister chromatids together, creating Sister Chromatid Cohesion (SCC) that helps in the maintenance of short spindle lengths in metaphase. The budding yeast protein Chl1p, which has human homologs, is required for DNA damage repair, recombination, transcriptional silencing and aging. This protein is also needed to establish SCC between sister chromatids in S-phase. In the present study we have further characterized Chl1p for its role in the yeast Saccharomyces cerevisiae when cells are under replication stress. We show that when DNA replication is arrested by hydroxyurea (HU), the chl1 mutation causes growth deficiency and a mild loss in cell viability. Although both mutant and wild-type cells remained arrested with undivided nuclei, mutant cells had mitotic spindles, which were about 60-80% longer than wild-type spindles. Spindle extension occurred in S-phase in the presence of an active S-phase checkpoint pathway. Further, the chl1 mutant did not show any kinetochore-related defect that could have caused spindle extension. These cells were affected in the retention of SCC in that they had only about one-fourth of the normal levels of the cohesin subunit Scc1p at centromeres, which was sufficient to bi-orient the chromosomes. The mutant cells showed defects in SCC, both during its establishment in S-phase and in its maintenance in G2. Mutants with partial and pericentromeric cohesion defects also showed spindle elongation when arrested in S-phase by HU. Our work shows that Chl1p is required for normal growth and cell viability in the presence of the replication block caused by HU. The absence of this protein does not, however, compromize the replication checkpoint pathway. Even though the chl1 mutation gives synthetic lethal interactions with kinetochore mutations, its absence does not affect kinetochore function; kinetochore-microtubule interactions remain unperturbed. Further, chl1 cells were found to lose SCC at centromeres in both S- and G2 phases, showing the requirement of Chl1p for the maintenance of cohesion in G2 phase of these cells. This work documents for the first time that SCC is an important determinant of spindle size in the yeast Saccharomyces cerevisiae when genotoxic agents cause S-phase arrest of cells.


Nuclear Factor-Y in Mouse Pancreatic β-Cells Plays a Crucial Role in Glucose Homeostasis by Regulating β-Cell Mass and Insulin Secretion.
Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The current study was undertaken in a conditional knockout of Nf-ya specifically in pancreatic β-cells (Nf-ya βKO) to define the essential physiological role of NF-Y in β-cells. Nf-ya βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca2+ influx in response to glucose, which was associated with an inefficient glucose uptake into β-cells due to a decreased expression of GLUT2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islet homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.


Evaluate the Feasibility of Using Frontal SSVEP to Implement an SSVEP-Based BCI in Young, Elderly and ALS Groups.
This paper studies the amplitude-frequency characteristic of frontal steady-state visual evoked potential (SSVEP) and its feasibility as a control signal for brain computer interface (BCI). SSVEPs induced by different stimulation frequencies, from 13 ~ 31 Hz in 2 Hz steps, were measured in eight young subjects, eight elders and seven ALS patients. Each subject was requested to participate in a calibration study and an application study. The calibration study was designed to find the amplitude-frequency characteristics of SSVEPs recorded from Oz and Fpz positions, while the application study was designed to test the feasibility of using frontal SSVEP to control a two-command SSVEP-based BCI. The SSVEP amplitude was detected by an epoch-average process which enables artifact-contaminated epochs can be removed. The seven ALS patients were severely impaired, and four patients, who were incapable of completing our BCI task, were excluded from calculation of BCI performance. The averaged accuracies, command transfer intervals and information transfer rates in operating frontal SSVEP-based BCI were 96.1%, 3.43 s/command, and 14.42 bits/min in young subjects; 91.8%, 6.22 s/command, and 6.16 bits/min in elders; 81.2%, 12.14 s/command, and 1.51 bits/min in ALS patients, respectively. The frontal SSVEP could be an alternative choice to design SSVEP-based BCI.


Duplicate polyphenol oxidase genes on barley chromosome 2H and their functional differentiation in the phenol reaction of spikes and grains.
Polyphenol oxidases (PPOs) are copper-containing metalloenzymes encoded in the nucleus and transported into the plastids. Reportedly, PPOs cause time-dependent discoloration (browning) of end-products of wheat and barley, which impairs their appearance quality. For this study, two barley PPO homologues were amplified using PCR with a primer pair designed in the copper binding domains of the wheat PPO genes. The full-lengths of the respective PPO genes were cloned using a BAC library, inverse-PCR, and 3'-RACE. Linkage analysis showed that the polymorphisms in PPO1 and PPO2 co-segregated with the phenol reaction phenotype of awns. Subsequent RT-PCR experiments showed that PPO1 was expressed in hulls and awns, and that PPO2 was expressed in the caryopses. Allelic variation of PPO1 and PPO2 was analysed in 51 barley accessions with the negative phenol reaction of awns. In PPO1, amino acid substitutions of five types affecting functionally important motif(s) or C-terminal region(s) were identified in 40 of the 51 accessions tested. In PPO2, only one mutant allele with a precocious stop codon resulting from an 8 bp insertion in the first exon was found in three of the 51 accessions tested. These observations demonstrate that PPO1 is the major determinant controlling the phenol reaction of awns. Comparisons of PPO1 single mutants and the PPO1PPO2 double mutant indicate that PPO2 controls the phenol reaction in the crease on the ventral side of caryopses. An insertion of a hAT-family transposon in the promoter region of PPO2 may be responsible for different expression patterns of the duplicate PPO genes in barley.


Vena caval filter placement by intravascular ultrasound.
Placement of vena caval filters under fluoroscopic surveillance incurs significant expense and potential risks associated with the transportation of critically ill patients. Intravascular ultrasound (IVUS) allows direct intraluminal visualization of the vena cava and the renal veins. The purpose of this study is to evaluate the accuracy of vena caval filter placement under IVUS in an animal model. Fifteen Simon-Nitinol venal cava filters (C.R. Bard, Inc., Covington, GA) were placed under IVUS guidance into four anesthetized sheep. Twelve were placed transfemorally, and three were placed transjugularly. Accuracy of placement was confirmed with fluoroscopy by measurement between the filter tip and the targeted side branch. The vena caval filters placed femorally averaged 0.33+/-0.42 cm distance from the target vein side branch. Jugular approach filter placement was less accurate. Although two out of three filters placed from the jugular vein were correctly positioned, the distance from the target vein side branch was much greater averaging 2.5+/-1.04 cm. Femoral placement of vena caval filters under IVUS is extremely accurate. The transjugular route, however, was technically challenging and standard fluoroscopic vena caval filter placement appears to be more appropriate. Our success with the femoral approach merits further clinical investigation in the use of IVUS for critically ill patients that would benefit from bedside vena caval filter placement.


Stochastic fluctuations in the susceptible-infective-recovered model with distributed infectious periods.
We investigate a stochastic model of infection dynamics based on the Susceptible-Infective-Recovered (SIR) model, where the distribution of the recovery times can be tuned, interpolating between exponentially distributed recovery times, as in the standard SIR model, and recovery after a fixed infectious period. This is achieved by introducing L infective classes, as compared to 1 in the standard model. For large populations, the spectrum of fluctuations around the deterministic limit of the model can be computed analytically. The demographic stochasticity has the effect of transforming the decaying oscillations of the deterministic model into sustained oscillations in the stochastic formulation. We find that the amplification of these stochastic oscillations increases with L , as well as their coherence in frequency. For large values of L (of the order of 10 and greater), the height and position of the peak of the power spectra changes little and is described well by the model with fixed recovery period (L-->infinity) . In this limit we give a closed-form expression for the power spectrum of fluctuations of infective individuals.