The Consequences of Contact with the Criminal Justice System for Health in the Transition to Adulthood.
A rapidly growing literature has documented the adverse social, economic and, recently, health impacts of experiencing incarceration in the United States. Despite the insights that this work has provided in consistently documenting the deleterious effects of incarceration, little is known about the specific timing of criminal justice contact and early health consequences during the transition from adolescence to adulthood-a critical period in the life course, particularly for the development of poor health. Previous literature on the role of incarceration has also been hampered by the difficulties of parsing out the influence that incarceration exerts on health from the social and economic confounding forces that are linked to both criminal justice contact and health. This paper addresses these two gaps in the literature by examining the association between incarceration and health in the United States during the transition to adulthood, and by using an analytic approach that better isolates the association of incarceration with health from the multitude of confounders which could be alternatively driving this association. In this endeavor, we make use of variable-rich data from The National Longitudinal Study of Adolescent to Adult Health (n = 10,785) and a non-parametric Bayesian machine learning technique- Bayesian Additive Regression Trees. Our results suggest that the experience of incarceration at this stage of the life course increases the probability of depression, adversely affects the perception of general health status, but has no effect on the probability of developing hypertension in early adulthood. These findings signal that incarceration in emerging adulthood is an important stressor that can have immediate implications for mental and general health in early adulthood, and may help to explain long lasting implications incarceration has for health across the life course.


Demonstration of 5.1 Tbit/s data capacity on a single-wavelength channel.
We have generated a single-wavelength data signal with a data capacity of 5.1 Tbit/s. The enabling techniques to generate the data signal are optical time-division multiplexing up to a symbol rate of 1.28 Tbaud, differential quadrature phase shift keying as data format, and polarisation-multiplexing. For the first time, error-free performance with a bit error rate less than 10(-9) is demonstrated for the 5.1 Tbit/s data signal. This is achieved in a back-to-back configuration using a direct detection receiver based on polarisation- and time-demultiplexing, delay-demodulation and balanced photo-detection.


Multicentre validation of 4-well azole agar plates as a screening method for detection of clinically relevant azole-resistant Aspergillus fumigatus.
Azole-resistant Aspergillus fumigatus is emerging worldwide. Reference susceptibility testing methods are technically demanding and no validated commercial susceptibility tests for moulds currently exist. In this multicentre study a 4-well azole-containing screening agar method was evaluated using clinically relevant isolates. Forty WT and 39 cyp51A mutant A. fumigatus [G54 (n = 10), M220 (n = 10), TR34/L98H (n = 9) and TR46/Y121F/T289A (n = 10)] were tested individually and as simulated mixed samples (sampling 4 WT and 1 mutant colonies). EUCAST MICs were determined following E.Def 9.3. In-house and commercial 4-well plates containing agars supplemented with 4 mg/L itraconazole, 1 mg/L voriconazole, 0.5 mg/L posaconazole and no antifungal, respectively, were evaluated. Growth was scored (0-3) by two independent observers in three laboratories. Inter-plate, inter-observer, essential and categorical agreement, sensitivity and specificity were calculated. CYP51A genotype and antifungal compound-specific MICs and growth patterns were documented. The inter-observer agreement was excellent with 86%-99% identical scores (range 80%-100%) for both plates. The qualitative agreement (no growth versus growth) was excellent (median 95%-100%, range 87%-100%, overall). The overall sensitivity and specificity for the 4-well plate (no growth versus growth) was 99% (range 97%-100%) and 99% (95%-100%), respectively. The sensitivity for simulated WT/mutant specimens was 94% (range 83%-100%) for the WT-TR34/L98H combination, but 100% for the WT/G54W combination. The performance remained unchanged using only itraconazole- and voriconazole-containing agars, but was lower for the other combinations. Implementation of the 4-well screening plate in routine laboratories will allow easy and reliable detection of the most common azole-resistant A. fumigatus.


Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks.
Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or ~ 22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been developed. As such, the search for candidate genes related to the comorbid conditions of asthma and hypertension can help in elucidating the molecular mechanisms underlying the comorbid condition of these two diseases, and can also be useful for genotyping and identifying new drug targets. Using ANDSystem, the reconstruction and analysis of gene networks associated with asthma and hypertension was carried out. The gene network of asthma included 755 genes/proteins and 62,603 interactions, while the gene network of hypertension - 713 genes/proteins and 45,479 interactions. Two hundred and five genes/proteins and 9638 interactions were shared between asthma and hypertension. An approach for ranking genes implicated in the comorbid condition of two diseases was proposed. The approach is based on nine criteria for ranking genes by their importance, including standard methods of gene prioritization (Endeavor, ToppGene) as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analysed genes. According to the proposed approach, the genes IL10, TLR4, and CAT had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the list of top genes is enriched with apoptotic genes and genes involved in biological processes related to the functioning of central nervous system. The application of methods of reconstruction and analysis of gene networks is a productive tool for studying the molecular mechanisms of comorbid conditions. The method put forth to rank genes by their importance to the comorbid condition of asthma and hypertension was employed that resulted in prediction of 10 genes, playing the key role in the development of the comorbid condition. The results can be utilised to plan experiments for identification of novel candidate genes along with searching for novel pharmacological targets.


The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia.
Recent studies suggest that HMG-CoA reductase inhibitors ("statins") may have beneficial effects for patients at risk for some types of infections. We examined the effect of prior outpatient use of statins on mortality for patients hospitalized with community-acquired pneumonia. A retrospective cohort study conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had a chest x-ray consistent with, and had a discharge ICD-9 diagnosis of pneumonia. Subjects were excluded if they were "comfort measures only" or transferred from another acute care hospital. Subjects were considered to be on a medication if they were taking it at the time of presentation. Data was abstracted on 787 subjects at the two hospitals. Mortality was 9.2% at 30-days and 13.6% at 90-days. At presentation 52% of subjects were low risk, 34% were moderate risk, and 14% were high risk based on the pneumonia severity index. In the multivariable regression analysis, after adjusting for potential confounders including a propensity score, the use of statins at presentation (odds ratio 0.36, 95% confidence interval 0.14-0.92) was associated with decreased 30-day mortality. Prior outpatient statin use was associated with decreased mortality in patients hospitalized with community-acquired pneumonia despite their use being associated with comorbid illnesses likely to contribute to increased mortality. Confirmatory studies are needed, as well as research to determine the mechanism(s) of this protective effect.


Using the BITOLA system to identify candidate genes for Parkinson's disease.
Complexity of multifactorial diseases as Parkinson's disease (PD) often complicate identifying causal genetic factors by traditional approaches such as positional cloning and candidate gene analyses. PD is etiologically and genetically complex disease and second most common neurodegenerative disorder after Alzheimer's disease. The most cases of PD are idiopathic and small growing subset of individuals have single gene defect as the cause. The main goal of this research was to identify the potential candidate genes for idiopathic PD by using biomedical discovery support system (BITOLA). For detecting the potential candidate genes for PD was used opened system of bioinformatics tool BITOLA. Data of chromosome location, tissue specific expression of potential candidate genes and their potential association with PD were obtained from Medline, Locus Link, Gene Cards and OMIM. By using BITOLA system is identified 17 genes as potential candidate genes for PD. The role of three genes (MAPT, PARK2, UCHL1) in PD were confirmed earlier. Discovering the novel candidate genes for multifactiorial diseases by using specially mentioned bioinformatics tool BITOLA could offer the new opportunity for researching genetics base of PD without using tissue samples of patients.


High-pressure freezing provides insights into Weibel-Palade body biogenesis.
The Weibel-Palade bodies (WPBs) of endothelial cells play an important role in haemostasis and the initiation of inflammation, yet their biogenesis is poorly understood. Tubulation of their major content protein, von Willebrand factor (VWF), is crucial to WPB function, and so we investigated further the relationship between VWF tubule formation and WPB formation in human umbilical vein endothelial cells (HUVECs). By using high-pressure freezing and freeze substitution before electron microscopy, we visualised VWF tubules in the trans-Golgi network (TGN), as well as VWF subunits in vesicular structures. Tubules were also seen in WPBs that were connected to the TGN by membranous stalks. Tubules are disorganised in the immature WPBs but during maturation we found a dramatic increase in the spatial organisation of the tubules and in organelle electron density. We also found coated budding profiles suggestive of the removal of missorted material after initial formation of these granules. Finally, we discovered that these large, seemingly rigid, organelles flex at hinge points and that the VWF tubules are interrupted at these hinges, facilitating organelle movement around the cell. The use of high-pressure freezing was vital in this study and it suggests that this technique might prove essential to any detailed characterisation of organelle biogenesis.


The animacy continuum in the human ventral vision pathway.
Major theories for explaining the organization of semantic memory in the human brain are premised on the often-observed dichotomous dissociation between living and nonliving objects. Evidence from neuroimaging has been interpreted to suggest that this distinction is reflected in the functional topography of the ventral vision pathway as lateral-to-medial activation gradients. Recently, we observed that similar activation gradients also reflect differences among living stimuli consistent with the semantic dimension of graded animacy. Here, we address whether the salient dichotomous distinction between living and nonliving objects is actually reflected in observable measured brain activity or whether previous observations of a dichotomous dissociation were the illusory result of stimulus sampling biases. Using fMRI, we measured neural responses while participants viewed 10 animal species with high to low animacy and two inanimate categories. Representational similarity analysis of the activity in ventral vision cortex revealed a main axis of variation with high-animacy species maximally different from artifacts and with the least animate species closest to artifacts. Although the associated functional topography mirrored activation gradients observed for animate-inanimate contrasts, we found no evidence for a dichotomous dissociation. We conclude that a central organizing principle of human object vision corresponds to the graded psychological property of animacy with no clear distinction between living and nonliving stimuli. The lack of evidence for a dichotomous dissociation in the measured brain activity challenges theories based on this premise.


Evaluation of glucosinolate variation in a collection of turnip (Brassica rapa) germplasm by the analysis of intact and desulfo glucosinolates.
Glucosinolates (GLS) are secondary metabolites occurring in cruciferous species. These compounds are important for plant defense, human health, and the characteristic flavor of Brassica vegetables. In this study, the GLS in tubers from a collection of 48 turnip ( Brassica rapa ) accessions from different geographic origin were analyzed. Two different methods were used: desulfo GLS were analyzed by high-performance liquid chromatography with a photodiode array detector, and intact GLS were analyzed by accurate mass liquid chromatography-mass spectrometry. For most GLS, desulfo and intact signals correlated well, and the analytical reproducibility for individual GLS was similar for both methods. A total of 11 different GLS was monitored in the turnip tubers, through both intact and desulfo GLS analysis methods. Four clusters of accessions could be clearly distinguished based on GLS composition of the turnip tuber. Clustering based on tuber GLS differed markedly from a previously published clustering based on leaf GLS.


2-Nitroimidazole (EF5) binding predicts radiation resistance in individual 9L s.c. tumors.
The presence of hypoxic tumor cells is known to be an important cause of radiation treatment resistance in vivo. The ability to predict the presence and extent of hypoxic cells in individual tumors would allow the addition of specific "antihypoxia"-based treatment regimes. Hypoxia can be monitored by measuring the binding of 2-nitroimidazoles. We have tested the hypothesis that binding of EF5, a fluorinated derivative of the 2-nitroimidazole, Etanidazole, can predict radioresistance in individual tumors. Fischer rats bearing 9L s.c. tumors were given injections i.v. with EF5 3 h before irradiation and tumor harvest. Tumor cells were dissociated for flow cytometric analysis and plating efficiency studies. EF5 binding was detected via monoclonal antibodies conjugated to the orange emitting dye, Cy3. In air breathing rats, for a given radiation dose, a large amount of variation in plating efficiency was seen. However, there was minimal variability of the plating efficiency for tumors irradiated in euthanized animals (hypoxic tumors; correlation coefficient for the fitted curve = 0.93) and in cells dissociated from tumors and irradiated in suspension (correlation coefficient for the fitted curve = 0.99), suggesting that varying sensitivity to the cell disaggregation technique was not responsible. In contrast, a good correlation between the relative radiation resistance or hypoxic survival and EF5 binding of "moderately" hypoxic cells in air breathing rats was identified using these techniques. In these 9L s.c. tumors, intertumor variation in oxygenation accounted for most of the range in individual tumor radiation response, and this was found to be independent of tumor size. This study provides evidence for the application of EF5 binding with monoclonal antibody detection as an in vivo predictive assay of individual tumor hypoxia and resultant therapy resistance.


Gene expression changes in the prefrontal cortex, anterior cingulate cortex and nucleus accumbens of mood disorders subjects that committed suicide.
Suicidal behaviors are frequent in mood disorders patients but only a subset of them ever complete suicide. Understanding predisposing factors for suicidal behaviors in high risk populations is of major importance for the prevention and treatment of suicidal behaviors. The objective of this project was to investigate gene expression changes associated with suicide in brains of mood disorder patients by microarrays (Affymetrix HG-U133 Plus2.0) in the dorsolateral prefrontal cortex (DLPFC: 6 Non-suicides, 15 suicides), the anterior cingulate cortex (ACC: 6NS, 9S) and the nucleus accumbens (NAcc: 8NS, 13S). ANCOVA was used to control for age, gender, pH and RNA degradation, with P ≤ 0.01 and fold change ± 1.25 as criteria for significance. Pathway analysis revealed serotonergic signaling alterations in the DLPFC and glucocorticoid signaling alterations in the ACC and NAcc. The gene with the lowest p-value in the DLPFC was the 5-HT2A gene, previously associated both with suicide and mood disorders. In the ACC 6 metallothionein genes were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H, MT1X, MT2A) and three were down-regulated in the NAcc (MT1F, MT1G, MT1H). Differential expression of selected genes was confirmed by qPCR, we confirmed the 5-HT2A alterations and the global down-regulation of members of the metallothionein subfamilies MT 1 and 2 in suicide completers. MTs 1 and 2 are neuro-protective following stress and glucocorticoid stimulations, suggesting that in suicide victims neuroprotective response to stress and cortisol may be diminished. Our results thus suggest that suicide-specific expression changes in mood disorders involve both glucocorticoids regulated metallothioneins and serotonergic signaling in different regions of the brain.


Household food insecurity: associations with at-risk infant and toddler development.
In this study, we evaluated the relationship between household food security status and developmental risk in young children, after controlling for potential confounding variables. The Children's Sentinel Nutritional Assessment Program interviewed (in English, Spanish, or Somali) 2010 caregivers from low-income households with children 4 to 36 months of age, at 5 pediatric clinic/emergency department sites (in Arkansas, Massachusetts, Maryland, Minnesota, and Pennsylvania). Interviews included demographic questions, the US Food Security Scale, and the Parents' Evaluations of Developmental Status. The target child from each household was weighed, and weight-for-age z score was calculated. Overall, 21% of the children lived in food-insecure households and 14% were developmentally "at risk" in the Parents' Evaluations of Developmental Status assessment. In logistic analyses controlling for interview site, child variables (gender, age, low birth weight, weight-for-age z score, and history of previous hospitalizations), and caregiver variables (age, US birth, education, employment, and depressive symptoms), caregivers in food-insecure households were two thirds more likely than caregivers in food-secure households to report that their children were at developmental risk. Controlling for established correlates of child development, 4- to 36-month-old children from low-income households with food insecurity are more likely than those from low-income households with food security to be at developmental risk. Public policies that ameliorate household food insecurity also may improve early child development and later school readiness.


New reduced volume preparation regimen in colon capsule endoscopy.
To evaluate the effectiveness of our proposed bowel preparation method for colon capsule endoscopy. A pilot, multicenter, randomized controlled trial compared our proposed "reduced volume method" (group A) with the "conventional volume method" (group B) preparation regimens. Group A did not drink polyethylene glycol electrolyte lavage solution (PEG-ELS) the day before the capsule procedure, while group B drank 2 L. During the procedure day, groups A and B drank 2 L and 1 L of PEG-ELS, respectively, and swallowed the colon capsule (PillCam COLON® capsule). Two hours later the first booster of 100 g magnesium citrate mixed with 900 mL water was administered to both groups, and the second booster was administered six hours post capsule ingestion as long as the capsule had not been excreted by that time. Capsule videos were reviewed for grading of cleansing level. Sixty-four subjects were enrolled, with results from 60 analyzed. Groups A and B included 31 and 29 subjects, respectively. Twenty-nine (94%) subjects in group A and 25 (86%) subjects in group B had adequate bowel preparation (ns). Twenty-two (71%) of the 31 subjects in group A excreted the capsule within its battery life compared to 16 (55%) of the 29 subjects in group B (ns). Of the remaining 22 subjects whose capsules were not excreted within the battery life, all of the capsules reached the left side colon before they stopped functioning. A single adverse event was reported in one subject who had mild symptoms of nausea and vomiting one hour after starting to drink PEG-ELS, due to ingesting the PEG-ELS faster than recommended. Our proposed reduced volume bowel preparation method for colon capsule without PEG-ELS during the days before the procedure was as effective as the conventional volume method.


Cochlear implantation in children and adults in Switzerland.
The cochlear implant (CI) is one of the most successful neural prostheses developed to date. It offers artificial hearing to individuals with profound sensorineural hearing loss and with insufficient benefit from conventional hearing aids. The first implants available some 30 years ago provided a limited sensation of sound. The benefit for users of these early systems was mostly a facilitation of lip-reading based communication rather than an understanding of speech. Considerable progress has been made since then. Modern, multichannel implant systems feature complex speech processing strategies, high stimulation rates and multiple sites of stimulation in the cochlea. Equipped with such a state-of-the-art system, the majority of recipients today can communicate orally without visual cues and can even use the telephone. The impact of CIs on deaf individuals and on the deaf community has thus been exceptional. To date, more than 300,000 patients worldwide have received CIs. In Switzerland, the first implantation was performed in 1977 and, as of 2012, over 2,000 systems have been implanted with a current rate of around 150 CIs per year. The primary purpose of this article is to provide a contemporary overview of cochlear implantation, emphasising the situation in Switzerland.


On the arsenic source mobilisation and its natural enrichment in the sediments of a high mountain cirque in the Pyrenees.
Recently arsenic contamination and its environmental and human health problems have been raising concerns worldwide. The occurrence of natural high levels of arsenic contamination has generally been reported for low altitude environments. Here we report a study conducted to assess the extent of arsenic mobilisation/transportation from previously identified arsenic source areas in a high altitude cirque of the Pyrenees as well as the potential contribution of As by snow. The concentration of arsenic in sediments of several tributaries was enriched up to about ten folds due to mobilisation of arsenic from the source areas within the catchment. The highest arsenic enrichments were found in an area dominated by quartzite and slate formation in the southern side of the basin, and it generally diminished towards the major lake downstream, possible due to mixing with sediments from non-source areas. At these sites arsenic exceeded the hazard quotient (HQ) limits for the protection of aquatic life. The potential hazard of the As-enriched sediments may be further enhanced outside the catchment as samples collected downstream the cirque have also shown arsenic concentration exceeding HQ unity. The arsenic concentrations in the water collected at a number of sites exceeded its guide value for the protection of aquatic life. The potential As contribution by snow in the area was low and was largely of lithospheric origin. The PCA analysis showed strong association of arsenic in sediments with the sediment mineralogical composition (Fe2O3, TiO2 and Mn). Arsenic in water was positively correlated with its concentration in the sediments and could potentially increase if the environmental/climate conditions change.


A source analysis of the late human auditory evoked potentials.
The intracerebral generators of the human auditory evoked potentials were estimated using dipole source analysis of 14-channel scalp recordings. The response to a 400-msec toneburst presented every 0.9 sec could be explained by three major dipole sources in each temporal lobe. The first was a vertically oriented dipole located on the supratemporal plane in or near the auditory koniocortex. This contributed to the scalp-recorded N1 wave at 100 msec. The second was a vertically oriented dipole source located on the supratemporal plane somewhat anterior to the first. This contributed to both the Nl and the sustained potential (SP). The third was a laterally oriented dipole source that perhaps originated in the magnopyramidal temporal field. This contributed a negative wave to the lateral scalp recordings at the latency of 145 msec. A change in the frequency of the toneburst elicited an additional negativity in the scalp-recording -the mismatch negativity (MMN). When the frequency change was large, the mismatch negativity was composed of two distinct sources with sequential but partially overlapping activities. The earlier corresponded to the Nl dipole sources and the later to a more anteriorly located dipole with an orientation more lateral than Nl. Only the later source was active when the frequency change was small. MMN source activities peaked about 15 msec earlier in the contralateral hemisphere, while this difference was only 4 msec for the sources of the Nl.


Strong population structure and shallow mitochondrial phylogeny in the banded guitarfish, Zapteryx exasperata (Jordan y Gilbert, 1880), from the Northern Mexican Pacific.
The northern Mexican Pacific (NMP), the Gulf of California (GC), and Baja California have been recognized as an ecological and evolutionarily dynamic region having experienced significant tectonic and climatic changes leading to the diversification of terrestrial and marine biotas. Zapteryx exasperata is a predominant ray caught in the artisanal fisheries of the NMP. Morphometric and reproductive differences between rays from the GC and the Pacific coast of Baja California (PCBC) regions suggest the presence of distinct populations. We investigate whether this distinction correlates with differences in genetic diversity and differentiation using sequences of the mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit 2 (ND2) gene and the noncoding control region (CR) in 63 specimens. Contrary to our expectations, ND2 bore significantly more diversity (h = 0.76) than CR (h = 0.39). Geographic patterns of diversity of CR were opposite to those of ND2, with GC being significantly less (ND2) and more (CR) diverse than PCBC. The diversity of concatenated haplotypes was high (h = 0.84). Low nucleotide diversity suggests the recent coancestry of haplotypes. Marked genetic structure (Φst = 0.23, P < 0.0001) revealed the existence of reproductive isolation and limited matrilineal gene flow between GC and PCBC, which correlates with their phenotypic distinction. These results suggest the influence of factors such as female reproductive philopatry, and ecological or historical vicariant barriers to gene flow. Our results point to the existence of a distinct management unit of banded guitarfish in each region, and add to the increasing evidence attesting to the diversifying nature of this evolutionarily dynamic region.


Resourcefulness and health practices of diabetic women.
More than one fourth of the millions of Americans with Type 2 diabetes experience depression, of which two thirds are women. Unless the individual is resourceful, coexisting diabetes and depression adversely affect one' health practices. The effects of diabetic and depressive symptoms on health practices and the mediating and moderating role of learned resourcefulness in this relationship were examined in 90 women with Type 2 diabetes. Regression analyses showed direct negative effects of diabetic and depressive symptoms on health practices. The effects of depressive, but not diabetic, symptoms were partially mediated by resourcefulness; no moderating effects were found. The results suggest the need to test interventions to minimize symptoms associated with diabetes, particularly depression. Teaching resourcefulness to Type 2 diabetic women may promote their positive health practices by minimizing their depression.


Effects of fenoterol and ipratropium on respiratory resistance of asthmatics after tracheal intubation.
We have studied the effects of a beta-agonist, fenoterol, and a cholinergic antagonist, ipratropium, on post-intubation total respiratory system resistance (Rrs) in asthmatics who developed increased Rrs after tracheal intubation. Sixteen stable asthmatics in whom Rrs increased after intubation were allocated randomly to receive either 10 puffs of fenoterol (group F) or 10 puffs of ipratropium (group IB) via a metered dose inhaler 5 min after intubation. Anaesthesia was induced and maintained with propofol i.v. Rrs was recorded before treatment and again 5, 15 and 30 min after treatment. Rrs decreased significantly from pretreatment values by mean 53 (SD 8)%, 53 (7)% and 58 (6)% at 5, 15 and 30 min, respectively, in group F, but declined by only 12 (6)%, 15 (4)% and 17 (5)% in group IB. At all times after treatment, patients in the fenoterol group had significantly lower Rrs values than those in the ipratropium group. We conclude that increased Rrs after tracheal intubation in asthmatics can be reduced effectively by treatment with fenoterol. A secondary finding of our study was that even after induction of anaesthesia with propofol, patients with a history of asthma may develop high Rrs.


Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by allographic transplantation of adult subventricular zone-derived neural stem cells.
Neurobehavioral teratogenicity can be reversed with transplantation of neural stem cells. However, the usefulness of this therapy would be greatly enhanced by employing adult stem cells. In pursuit of this this goal, we developed a model that uses subventricular zone (SVZ) cells. HS/Ibg mice were exposed prenatally to chlorpyrifos on gestational days 9-18 (3 mg/kg/day, SC) in order to induce deficits in their performance in the Morris water maze test. Both the control and the exposed offspring were transplanted with SVZ cells (or vehicle) on postnatal day 35; this actually represents an allogenic transplantation, because the HS/Ibg strain is a heterogeneous stock. The transplanted cells were later observed in the host brain by DiI tracing, and their initial differentiation to cholinergic neurons and astrocytes was ascertained. On postnatal day 80, animals that had been exposed prenatally to chlorpyrifos displayed impaired Morris water maze performance, requiring more time to reach the platform. Transplantation of adult SVZ-derived neural stem cells (NSC) reversed the deficits. Applying autologous transplantation provides an important demonstration that the methodological obstacles of immunological rejection and the ethical concerns related to using embryonic stem cells may be successfully bypassed in developing stem cell therapies for neurodevelopmental disorders.


Development of the Visual System in a Burrow-Nesting Seabird: Leach's Storm Petrel.
Little is known about the development of vision in wild birds. It is unknown, for example, whether the ability to see can be predicted by the level of prenatal growth or whether the eyes are open at hatching in a particular species. In this study, we investigated the growth of eyes, the formation of retinal ganglion cell topography, and the appearance of simple, visually guided behaviours in chicks of a small procellariiform seabird, Leach's storm petrel (Oceanodroma leucorhoa). This semi-precocial species, which has a well-developed sense of smell, nests in underground burrows where adults provision chicks for 6-8 weeks in the dark before fledging. Retinal ganglion cell topographic maps revealed that fine-tuning of cell distribution does not happen early in development, but rather that the ganglion cell layer continues to mature throughout provisioning and probably even after fledging. While the olfactory bulbs reached adult size around 7 weeks after hatching, the eyes and telencephalon continued to grow. Optokinetic head response and artificial burrow finding experiments indicated that chicks in the 2nd week after hatching lack even the most basic visually guided behaviours and are probably blind. Thus, vision in Leach's storm petrel chicks starts to function sometime around the 3rd week after hatching, well after the eyes have opened and the olfactory system is functional.


NAD(H)-mediated tetramerization controls the activity of Legionella pneumophila phospholipase PlaB.
The virulence factor PlaB promotes lung colonization, tissue destruction, and intracellular replication of Legionella pneumophila, the causative agent of Legionnaires' disease. It is a highly active phospholipase exposed at the bacterial surface and shows an extraordinary activation mechanism by tetramer deoligomerization. To unravel the molecular basis for enzyme activation and localization, we determined the crystal structure of PlaB in its tetrameric form. We found that the tetramer is a dimer of identical dimers, and a monomer consists of an N-terminal α/β-hydrolase domain expanded by two noncanonical two-stranded β-sheets, β-6/β-7 and β-9/β-10. The C-terminal domain reveals a fold displaying a bilobed β-sandwich with a hook structure required for dimer formation and structural complementation of the enzymatic domain in the neighboring monomer. This highlights the dimer as the active form. Δβ-9/β-10 mutants showed a decrease in the tetrameric fraction and altered activity profiles. The variant also revealed restricted binding to membranes resulting in mislocalization and bacterial lysis. Unexpectedly, we observed eight NAD(H) molecules at the dimer/dimer interface, suggesting that these molecules stabilize the tetramer and hence lead to enzyme inactivation. Indeed, addition of NAD(H) increased the fraction of the tetramer and concomitantly reduced activity. Together, these data reveal structural elements and an unprecedented NAD(H)-mediated tetramerization mechanism required for spatial and enzymatic control of a phospholipase virulence factor. The allosteric regulatory process identified here is suited to fine tune PlaB in a way that protects Legionella pneumophila from self-inflicted lysis while ensuring its activity at the pathogen-host interface.


Dietary fat and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition.
Epidemiologic studies have produced conflicting results with respect to an association of dietary fat with breast cancer. We aimed to investigate the association between fat consumption and breast cancer. We prospectively investigated fat consumption in a large (n = 319,826), geographically and culturally heterogeneous cohort of European women enrolled in the European Prospective Investigation into Cancer and Nutrition who completed a dietary questionnaire. After a mean of 8.8 y of follow-up, 7119 women developed breast cancer. Cox proportional hazard models, stratified by age and center and adjusted for energy intake and confounders, were used to estimate hazard ratios (HRs) for breast cancer. An association between high saturated fat intake and greater breast cancer risk was found [HR = 1.13 (95% CI: 1.00, 1.27; P for trend = 0.038) for the highest quintile of saturated fat intake compared with the lowest quintile: 1.02 (1.00, 1.04) for a 20% increase in saturated fat consumption (continuous variable)]. No significant association of breast cancer with total, monounsaturated, or polyunsaturated fat was found, although trends were for a direct association of risk with monounsaturated fat and an inverse association with polyunsaturated fat. In menopausal women, the positive association with saturated fat was confined to nonusers of hormone therapy at baseline [1.21 (0.99, 1.48) for the highest quintile compared with the lowest quintile; P for trend = 0.044; and 1.03 (1.00, 1.07) for a 20% increase in saturated fat as a continuous variable]. Evidence indicates a weak positive association between saturated fat intake and breast cancer risk. This association was more pronounced for postmenopausal women who never used hormone therapy.


Efficient induction of cell-mediated immunity to varicella-zoster virus glycoprotein E co-lyophilized with a cationic liposome-based adjuvant in mice.
Varicella zoster virus (VZV) is a neurotropic and lymphotropic alpha herpesvirus that causes varicella and herpes zoster (HZ). At a primary infection, VZV causes varicella in young children. Reactivation of latent VZV in sensory ganglia causes painful HZ in elderly people, occasionally leading to a serious complication, postherpetic neuralgia (PHN). A live attenuated VZV vaccine, the first vaccine licensed for the prevention of HZ and PHN is not very effective, while a recombinant subunit vaccine provides higher and longer protection against HZ. In the present study, we developed a new adjuvant system CIA09A, which is composed of cationic liposomes, the Toll-like receptor 4 (TLR4) agonist de-O-acylated lipooligosaccharide, and Quillaja saponin fraction QS-21. We then determined its adjuvant activity for recombinant VZV glycoprotein E (gE) in mice. Co-lyophilization of the liposomal adjuvant formulation with gE did not abolish the immune-stimulating activity. In fact, the CIA09A-adjuvanted gE vaccine was highly effective in eliciting both humoral and cellular immune responses to the recombinant gE protein and VZV in a VZV-primed mouse model. Furthermore, the frequency of gE-specific polyfunctional CD4+ T cells expressing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-2 was significantly increased in mice immunized with the adjuvanted vaccine. These data indicate that co-lyophilization of protein antigens with CIA09A enables development of a liposome-adjuvanted vaccine in a single vial to induce strong cell-mediated immunity required for vaccine efficacy. Thus, the CIA09A-adjuvanted gE vaccine warrants further development as a new prophylactic vaccine against HZ.


Consensus Recommendations for the Diagnosis of Vitreoretinal Lymphoma.
To provide recommendations for diagnosis of vitreoretinal lymphoma (VRL). Literature was reviewed for reports supporting the diagnosis of VRL. A questionnaire (Delphi 1 round) was distributed to 28 participants. In the second round (Delphi 2), items of the questionnaire not reaching consensus (75% agreement) were discussed to finalize the recommendations. Presenting symptoms include floaters and painless loss of vision, vitreous cells organized into sheets or clumps. Retinal lesions are usually multifocal creamy/white in the outer retina. Other findings include retinal lesions with "leopard-skin" appearance and retinal pigment epithelium atrophy. Severe vitreous infiltration without macular edema is the most likely presentation. Diagnostic vitrectomy should be performed. Systemic corticosteroid should be discontinued at least 2 weeks before surgery. An interleukin (IL)-10:IL-6 ratio > 1, positive mutation for the myeloid differentiation primary response 88 gene and monoclonality are indicators of VRL. Multi-modal imaging (optical coherence tomography, fundus autofluorescence) are recommended. A consensus meeting allowed the establishment of recommendations important for the diagnosis of VRL.


Teledermatology to Facilitate Patient Care Transitions From Inpatient to Outpatient Dermatology: Mixed Methods Evaluation.
Both clinicians and patients have increasingly turned to telemedicine to improve care access, even in physical examination-dependent specialties such as dermatology. However, little is known about whether teledermatology supports effective and timely transitions from inpatient to outpatient care, which is a common care coordination gap. Using mixed methods, this study sought to retrospectively evaluate how teledermatology affected clinic capacity, scheduling efficiency, and timeliness of follow-up care for patients transitioning from inpatient to outpatient dermatology care. Patient-level encounter scheduling data were used to compare the number and proportion of patients who were scheduled and received in-clinic or video dermatology follow-ups within 14 and 90 days after discharge across 3 phases: June to September 2019 (before teledermatology), June to September 2020 (early teledermatology), and February to May 2021 (sustained teledermatology). The time from discharge to scheduling and completion of patient follow-up visits for each care modality was also compared. Dermatology clinicians and schedulers were also interviewed between April and May 2021 to assess their perceptions of teledermatology for postdischarge patients. More patients completed follow-up within 90 days after discharge during early (n=101) and sustained (n=100) teledermatology use than at baseline (n=74). Thus, the clinic's capacity to provide follow-up to patients transitioning from inpatient increased from baseline by 36% in the early (101 from 74) and sustained (100 from 74) teledermatology periods. During early teledermatology use, 61.4% (62/101) of the follow-ups were conducted via video. This decreased significantly to 47% (47/100) in the following year, when COVID-19-related restrictions started to lift (P=.04), indicating more targeted but still substantial use. The proportion of patients who were followed up within the recommended 14 days after discharge did not differ significantly between video and in-clinic visits during the early (33/62, 53% vs 15/39, 38%; P=.15) or sustained (26/53, 60% vs 28/47, 49%; P=.29) teledermatology periods. Interviewees agreed that teledermatology would continue to be offered. Most considered postdischarge follow-up patients to be ideal candidates for teledermatology as they had undergone a recent in-person assessment and might have difficulty attending in-clinic visits because of competing health priorities. Some reported patients needing technological support. Ultimately, most agreed that the choice of follow-up care modality should be the patient's own. Teledermatology could be an important tool for maintaining accessible, flexible, and convenient care for recently discharged patients needing follow-up care. Teledermatology increased clinic capacity, even during the pandemic, although the timeliness of care transitions did not improve. Ultimately, the care modality should be determined through communication with patients to incorporate their and their caregivers' preferences.


A photoactive semisynthetic metalloenzyme exhibits complete selectivity for CO2 reduction in water.
A series of artificial metalloenzymes containing a ruthenium chromophore and [NiII(cyclam)]2+, both incorporated site-selectively, have been constructed within an azurin protein scaffold. These light-driven, semisynthetic enzymes do not evolve hydrogen, thus displaying complete selectivity for CO2 reduction to CO. Electrostatic effects rather than direct excited-state electron transfer dominate the ruthenium photophysics, suggesting that intramolecular electron transfer from photogenerated RuI to [NiII(cyclam)]2+ represents the first step in catalysis. Stern-Volmer analyses rationalize the observation that ascorbate is the only sacrificial electron donor that supports turnover. Collectively, these results highlight the important interplay of elements that must be considered when developing and characterizing molecular catalysts.


Efficacy of traditional Chinese medicine for the management of constipation: a systematic review.
The aim of this systematic review was to critically appraise published clinical trials designed to assess the effect of Traditional Chinese Medicine (TCM) on the management of constipation. Databases searched included both English and non-English articles published in the Cochrane library, MEDLINE, CINAHL, AMED, EMBASE, China National Knowledge Infrastructure (CNKI), and the Chinese Electronic Periodical Services (CEPS). Studies reviewed included randomized controlled trials and controlled clinical trials. Methodological quality was assessed using the modified Jadad scale. One hundred and thirty-seven (137) studies met the inclusion criteria, of which 21 were high-quality trials (n = 2449). Eighteen (18) were Chinese herbal medicine (CHM) and 3 were acupuncture trials. The primary outcome measure was total effective rate. CHM was more effective than conventional medicines in eight trials. Of the 10 remaining CHM trials, 9 compared the study CHM with another CHM and the results were significant in 4 trials. The effective rate was significantly higher in the intervention group than in the placebo group in the last CHM study. One (1) of the three acupuncture trials compared acupuncture with a conventional medicine, one trial with Sennae folium, and one trial with deeper acupuncture on Tianshu (ST 25). The therapeutic effect in the treatment group was more effective than that in the control group in all three studies. TCM interventions appear to be useful to manage constipation. Significant positive results were found in 15 high-quality studies. However, only 21 of the 137 publications identified attained high Jadad scores. There was heterogeneity in diagnostic procedures and interventions among the studies. Outcome indicators were also different. Hence, the results should be interpreted cautiously.


The role of the immune system in the generation of neuropathic pain.
Persistent pain is a sequela of several neurological conditions with a primary immune basis, such as Guillain-Barré syndrome and multiple sclerosis. Additionally, diverse forms of injury to the peripheral or the central nervous systems--whether traumatic, metabolic, or toxic--result in substantial recruitment and activation of immune cells. This response involves the innate immune system, but evidence also exists of T-lymphocyte recruitment, and in some patient cohorts antibodies to neuronal antigens have been reported. Mediators released by immune cells, such as cytokines, sensitise nociceptive signalling in the peripheral and central nervous systems. Preclinical data suggest an immune pathogenesis of neuropathic pain, but clinical evidence of a central role of the immune system is less clear. An important challenge for the future is to establish to what extent this immune response initiates or maintains neuropathic pain in patients and thus whether it is amenable to therapy.


Diversity and relationships of cocirculating modern human rotaviruses revealed using large-scale comparative genomics.
Group A rotaviruses (RVs) are 11-segmented, double-stranded RNA viruses and are primary causes of gastroenteritis in young children. Despite their medical relevance, the genetic diversity of modern human RVs is poorly understood, and the impact of vaccine use on circulating strains remains unknown. In this study, we report the complete genome sequence analysis of 58 RVs isolated from children with severe diarrhea and/or vomiting at Vanderbilt University Medical Center (VUMC) in Nashville, TN, during the years spanning community vaccine implementation (2005 to 2009). The RVs analyzed include 36 G1P[8], 18 G3P[8], and 4 G12P[8] Wa-like genogroup 1 strains with VP6-VP1-VP2-VP3-NSP1-NSP2-NSP3-NSP4-NSP5/6 genotype constellations of I1-R1-C1-M1-A1-N1-T1-E1-H1. By constructing phylogenetic trees, we identified 2 to 5 subgenotype alleles for each gene. The results show evidence of intragenogroup gene reassortment among the cocirculating strains. However, several isolates from different seasons maintained identical allele constellations, consistent with the notion that certain RV clades persisted in the community. By comparing the genes of VUMC RVs to those of other archival and contemporary RV strains for which sequences are available, we defined phylogenetic lineages and verified that the diversity of the strains analyzed in this study reflects that seen in other regions of the world. Importantly, the VP4 and VP7 proteins encoded by VUMC RVs and other contemporary strains show amino acid changes in or near neutralization domains, which might reflect antigenic drift of the virus. Thus, this large-scale, comparative genomic study of modern human RVs provides significant insight into how this pathogen evolves during its spread in the community.


The intersection of online social networking with medical professionalism.
To measure the frequency and content of online social networking among medical students and residents. Using the online network Facebook, we evaluated online profiles of all medical students (n = 501) and residents (n = 312) at the University of Florida, Gainesville. Objective measures included the existence of a profile, whether it was made private, and any personally identifiable information. Subjective outcomes included photographic content, affiliated social groups, and personal information not generally disclosed in a doctor-patient encounter. Social networking with Facebook is common among medical trainees, with 44.5% having an account. Medical students used it frequently (64.3%) and residents less frequently (12.8%, p < .0001). The majority of accounts (83.3%) listed at least 1 form of personally identifiable information, only a third (37.5%) were made private, and some accounts displayed potentially unprofessional material. There was a significant decline in utilization of Facebook as trainees approached medical or residency graduation (first year as referent, years 3 and 4, p < .05). While social networking in medical trainees is common in the current culture of emerging professionals, a majority of users allow anyone to view their profile. With a significant proportion having subjectively inappropriate content, ACGME competencies in professionalism must include instruction on the intersection of personal and professional identities.


Anti-Müllerian hormone in grazing dairy cows: Identification of factors affecting plasma concentration, relationship with phenotypic fertility, and genome-wide associations.
The objectives of this study were to (1) characterize the distribution and variability of plasma anti-Müllerian hormone (AMH) concentration; (2) evaluate factors associated with phenotypic variation in plasma AMH; (3) examine the associations between categories of plasma AMH and reproductive outcomes [pregnancy to first artificial insemination (P/AI), and pregnancy rates within 21, 42, and 84 d after the mating start date (MSD)]; (4) estimate pedigree and genomic heritability for plasma AMH; and (5) identify and validate SNP associated with phenotypic variation in plasma AMH. Plasma AMH concentration (pg/mL) was determined from a blood sample collected (mean ± standard deviation) 10 ± 2 d after first insemination at detected estrus (IDE) in 2,628 first- and second-parity Irish dairy cows. Overall, plasma AMH had a positively skewed distribution with mean (± standard deviation), median, minimum, and maximum concentrations of 326 ± 231, 268, 15, and 2,863 pg/mL, respectively. Plasma AMH was greatest for Jersey, followed by Holstein × Jersey, Holstein × Norwegian Red, and Holstein cows (410, 332, 284, and 257 pg/mL, respectively). Second-parity cows had greater plasma AMH than first-parity cows (333 vs. 301 pg/mL, respectively). Samples collected at 7 and 8 d after first IDE had lesser plasma AMH than those collected on d 9, 10, 11, 12, and 13 after first IDE (291 and 297 vs. 317, 319, 331, 337, and 320 pg/mL). Plasma AMH was not associated with either body condition score at first IDE or the interval from calving to MSD. Cows were categorized into low (≤150 pg/mL; n = 526; lowest 20%), intermediate (>150 to ≤461 pg/mL; n = 1,576; intermediate 60%), and high AMH (>461 pg/mL; n = 526; highest 20%) groups based on plasma AMH, and associations with reproductive outcomes were tested. Cows with high and intermediate plasma AMH had 1.42- and 1.51-times-greater odds of becoming pregnant within 84 d after the MSD than those with low plasma AMH (90.3 and 90.8 vs. 86.8%, respectively); however, P/AI and pregnancy rate within 21 and 42 d after the MSD did not differ among AMH categories. Plasma AMH was moderately heritable (pedigree heritability of 0.40 ± 0.06 and genomic heritability of 0.45 ± 0.05), and 68 SNP across Bos taurus autosomes 7 and 11 were associated with phenotypic variation in plasma AMH. Out of 68 SNP, 42 were located in a single quantitative trait locus on Bos taurus autosome 11 that harbored 6 previously identified candidate genes (NR5A1, HSPA5, CRB2, DENND1A, NDUFA8, and PTGS) linked to fertility-related phenotypes in dairy cows.


Neonatal Hypoglycaemia and Visual Development: A Review.
Many newborn babies experience low blood glucose concentrations, a condition referred to as neonatal hypoglycaemia (NH). The effect of NH on visual development in infancy and childhood is of interest because the occipital lobes, which include the primary visual cortex and a number of extrastriate visual areas, may be particularly susceptible to NH-induced injury. In addition, a number of case series have suggested that NH can affect eye and optic nerve development. To review the existing literature concerning the effect of NH on the visual system. A PubMed, Embase, Medline, and Google Scholar literature search was conducted using prespecified MeSH terms. The literature reviewed revealed no clear evidence for an effect of NH on the development of the eye and optic nerve. Furthermore, occipital and occipital-parietal lobe injuries following NH often occurred in conjunction with comorbid conditions and were not clearly linked to subsequent visual dysfunction, possibly due to difficulties in measuring vision in young children and a lack of studies at older ages. A recent, large-scale, prospective study of NH outcomes at 2 years of age found no effect of mild-to-moderate NH on visual development. The effect of NH on visual development is unclear. It is currently unknown whether NH affects visual function in mid-to-late childhood when many visual functions reach adult levels.


Identification of biological functions and gene networks regulated by heat stress in U937 human lymphoma cells.
Although cancer cells exposed to temperatures >42.5°C undergo cell death as the temperature rises, exposure of up to 42.5°C induces slight or no cytotoxicity. The temperature of 42.5°C is, therefore, well known to be the inflection point of hyperthermia. To better understand the molecular mechanisms underlying cellular responses to heat stress at temperatures higher and lower than the inflection point, we carried out global scale microarray and computational gene expression analyses. Human leukemia U937 cells were incubated at 42°C or 44°C for 15 min and cultured at 37°C for 0-6 h. Apoptosis accompanied by the activation of caspase-3 and DNA fragmentation was only observed in cells treated with heat stress at 44°C, but not at 42°C. Although a large number of genes were differentially expressed by a factor of 2.0 or greater, we found substantial differences with respect to the biological functions and gene networks of the genes differentially expressed at the two temperatures examined. Interestingly, we identified temperature-specific gene networks that were considered to be mainly associated with cell death or cellular compromise and cellular function and maintenance at 44°C or 42°C, respectively, by using the Ingenuity pathway analysis tools. These findings provide the molecular basis for a further understanding of the mechanisms of the biological changes that are responsive to heat stress in human lymphoma cells.


Characterization of isoforms of protein 4.1 present in the nucleus.
Although protein 4.1 was originally identified as an element of the erythrocyte membrane skeleton, its presence in most mammalian cell types is now well described. Antibodies raised against erythrocyte protein 4.1 or synthetic peptides corresponding to the spectrin-actin-binding domain of protein 4.1 react with plasma membranes and, unexpectedly, nuclei of different cell types. Nuclear staining was further confirmed in isolated nuclei prepared from rat liver and human leukaemic cell lines. Immunoblot analysis of subcellular fractions derived from these cells revealed three prominent proteins, of 80, 135 and 145 kDa. The structural relationship of the high-molecular-mass proteins with erythrocyte protein 4.1 was demonstrated by peptide mapping. These results indicate that mammalian nucleated cells contain several isoforms of erythrocyte protein 4.1 and that some high-molecular-mass forms may primarily reside in the nucleus.


Aqueous Heck cross-coupling preparation of acrylate-modified nucleotides and nucleoside triphosphates for polymerase synthesis of acrylate-labeled DNA.
Aqueous-phase Heck coupling methodology was developed for direct attachment of butyl acrylate to 5-iodoracil, 5-iodocytosine, 7-iodo-7-deazaadenine, and 7-iodo-7-deazaguanine 2'-deoxyribonucleoside 5'-O-monophosphates (dNMPs) and 5'-O-triphosphates (dNTPs) and compared with the classical approach of phosphorylation of the corresponding modified nucleosides. The 7-substituted 7-deazapurine nucleotides (dA(BA)MP, dA(BA)TP, dG(BA)MP, and dG(BA)TP) were prepared by the direct Heck coupling of nucleotides in good yields (35-55%), whereas the pyrimidine nucleotides reacted poorly and the corresponding BA-modified dNTPs were prepared by triphosphorylation of the modified nucleosides. The acrylate-modified dN(BA)TPs (N = A, C, and U) were good substrates for DNA polymerases and were used for enzymatic synthesis of acrylate-modified DNA by primer extension, whereas dG(BA)TP was an inhibitor of polymerases. The butyl acrylate group was found to be a useful redox label giving a strong reduction peak at -1.3 to -1.4 V in cyclic voltammetry.


EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours.
Chemotherapy-induced neutropenia is not only a major risk factor for infection-related morbidity and mortality, but is also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact on the success of treatment, particularly when treatment intent is either curative or to prolong survival. The incidence of severe or FN can be reduced by prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim, lenograstim or pegfilgrastim. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. While several academic groups have produced evidence-based clinical practice guidelines in an effort to standardise and optimise the management of FN, there remains a need for generally applicable, European-focused guidelines. To this end, we undertook a systematic literature review and formulated recommendations for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. We recommend that patient-related adverse risk factors such as elderly age (>or=65 years), be evaluated in the overall assessment of FN risk prior to administering each cycle of chemotherapy. In addition, when using a chemotherapy regimen associated with FN in >20% patients, prophylactic G-CSF is recommended. When using a chemotherapy regimen associated with FN in 10-20% patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Finally, studies have shown that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications, where indicated.


Implementation of knowledge-based palliative care in nursing homes and pre-post post evaluation by cross-over design: a study protocol.
The demography of the world is changing as the population is ageing. Because of this change to a higher proportion of older people, the WHO has called for improved palliative care for older persons. A large number of all deaths in the industrialised world occur while older people are living in nursing homes and therefore a key question becomes how the principles of palliative care can be implemented in that context. The aims of this study are: a) to describe a model of an educational intervention with the goal of implementing knowledge-based palliative care in nursing homes, and b) to describe the design of the evaluation of the effectiveness regarding the implementation of knowledge-based palliative care. A complex intervention is evaluated by means of a cross-over design. An educational intervention concerning palliative care consisting of five seminars during 6 months for staff and managers has been developed and conducted in 20 nursing homes in two counties. Before the intervention started, the feasibility was tested in a pilot study conducted in nursing homes not included in the main study. The intervention is evaluated through a non-randomized experimental design with intervention and control groups and pre- and post-assessments. The evaluation includes older persons living in nursing homes, next-of-kin, staff and managers. Data collection consists of quantitative methods such as questionnaires and register data and qualitative methods in the form of individual interviews, focus-group interviews and participant observations. The research will contribute to new knowledge about how to implement knowledge-based palliative care in a nursing home setting. A strength of this project is that the Medical Research Council framework of complex intervention is applied. The four recommended stages, Development, Feasibility and piloting, Evaluation and Implementation, are combined for the educational intervention, which functions as a strategy to achieve knowledge-based palliative care in the nursing homes. Implementation is always a question of change and a good theoretical understanding is needed for drawing valid conclusions about the causal mechanisms of change. The topic is highly relevant considering the world's ageing population. The data collection is completed and the analysis is ongoing. NCT02708498 .


Emotional bias and inhibitory control processes in mania and depression.
Despite markedly different clinical presentations, few studies have reported differences in neuropsychological functioning between mania and depression. The disinhibited behaviour characteristic of mania and evidence that subgenual prefrontal cortex is differentially activated in mania and depression both suggest that dissociable deficits will emerge on tasks that require inhibitory control and are subserved by ventromedial prefrontal cortex. Manic patients and controls undertook computerized neuropsychological tests of memory and planning ability. In addition, manic and depressed patients were directly compared with controls on a novel affective shifting task that requires inhibitory control over different components of cognitive and emotional processing. Manic patients were impaired on tests of memory and planning. Importantly, affective shifting performance of manic patients differed from that of depressed patients. Manic patients were impaired in their ability to inhibit behavioural responses and focus attention, but depressed patients were impaired in their ability to shift the focus of attention. Depressed patients exhibited an affective bias for negative stimuli, and we believe this to be the first demonstration of an affective bias for positive stimuli in manic patients. Observed impairments on tests of memory and planning suggest a global pathology for mania consistent with previous profiles for this disorder and similar to established profiles for depression. The results on the affective shifting task demonstrate the presence of mood-congruent bias and dissociable components of inhibitory control in mania and depression. Against a background of memory and planning impairments in the two groups, these findings are consistent with a role for the ventromedial prefrontal cortex in mediating mood-cognition relationships.


Wean earlier and automatically with new technology (the WEAN study). A multicenter, pilot randomized controlled trial.
Automated weaning has not been compared with a paper-based weaning protocol in North America. We conducted a pilot randomized trial comparing automated weaning with protocolized weaning in critically ill adults to evaluate clinician compliance and acceptance of the weaning and sedation protocols, recruitment, and impact on outcomes. From August 2007 to October 2009, we enrolled critically ill adults requiring more than 24 hours of mechanical ventilation and at least partial reversal of the condition precipitating respiratory failure at nine Canadian intensive care units. We randomized patients who tolerated at least 30 minutes of pressure support and either failed or were not yet ready to undergo a spontaneous breathing trial to automated or protocolized weaning. Both groups used pressure support, included spontaneous breathing trials, used a common positive end-expiratory pressure-FI(O(2)) chart, sedation protocol, and criteria for extubation, reintubation, and noninvasive ventilation. We recruited 92 patients (49 automated, 43 protocolized) over 26 months. Adherence to assigned weaning protocols and extreme sedation scale scores fell within prespecified thresholds. Combined physician-respiratory therapist and nurse acceptance scores of the study weaning and sedation protocols, respectively, were not significantly different. Automated weaning patients had significantly shorter median times to first successful spontaneous breathing trial (1.0 vs. 4.0 d; P < 0.0001), extubation (3.0 vs. 4.0 d; P = 0.02), and successful extubation (4.0 vs. 5.0 d; P = 0.01), and underwent fewer tracheostomies and episodes of protracted ventilation. Compared with a standardized protocol, automated weaning was associated with promising outcomes that warrant further investigation. Minor protocol modifications may increase compliance, facilitate recruitment, and enhance feasibility. Clinical trial registered with www.controlled-trials.com (ISRCTN43760151).


Entrapped Sediments as a Source of Phosphorus in Epilithic Cyanobacterial Proliferations in Low Nutrient Rivers.
Proliferations of the benthic mat-forming cyanobacteria Phormidium have been reported in rivers worldwide. Phormidium commonly produces natural toxins which pose a health risk to animal and humans. Recent field studies in New Zealand identified that sites with Phormidium proliferations consistently have low concentrations of water column dissolved reactive phosphorus (DRP). Unlike other river periphyton, Phormidium mats are thick and cohesive, with water and fine sediment trapped in a mucilaginous matrix. We hypothesized that daytime photosynthetic activity would elevate pH inside the mats, and/or night time respiration would reduce dissolved oxygen. Either condition could be sufficient to facilitate desorption of phosphates from sediment incorporated within mats, thus allowing Phormidium to utilize it for growth. Using microelectrodes, optodes and pulse amplitude modulation fluorometry we demonstrated that photosynthetic activity results in elevated pH (>9) during daytime, and that night-time respiration causes oxygen depletion (<4 mg L-1) within mats. Water trapped within the mucilaginous Phormidium mat matrix had on average 320-fold higher DRP concentrations than bulk river water and this, together with elevated concentrations of elements, including iron, suggest phosphorus release from entrapped sediment. Sequential extraction of phosphorus from trapped sediment was used to investigate the role of sediment at sites on the Mangatainoka River (New Zealand) with and without Phormidium proliferations. Deposition of fine sediment (<63 μm) was significantly higher at the site with the most extensive proliferations and concentrations of biological available phosphorus were two- to four- fold higher. Collectively these results provide evidence that fine sediment can provide a source of phosphorus to support Phormidium growth and proliferation.


A reversibly palmitoylated resident protein (p63) of an ER-Golgi intermediate compartment is related to a circulatory shock resuscitation protein.
The recently identified 63 kDa membrane protein, p63, is a resident protein of a membrane network interposed in between rough ER and Golgi apparatus. To characterize p63 at the molecular level a 2.91 kb cDNA encoding p63 has been isolated from a human placenta lambda gt10 cDNA library. Sequence analysis of tryptic peptides prepared from isolated p63 confirmed the identify of the cloned gene. The translated amino acid sequence consists of 601 amino acids (65.8 kDa) with a single putative membrane-spanning region and a N-terminal cytoplasmic domain of 106 amino acids. The human p63 cDNA exhibits a high level of sequence identify to the pig hepatic cDNA 3AL (accession number M27092) whose expression is enhanced after resuscitation from circulatory shock. An additional remarkable feature of p63 is that it becomes reversibly palmitoylated when intracellular protein transport is blocked by the drug brefeldin A. Overexpression of p63 in COS cells led to the development of a striking tubular membrane network in the cytoplasm. This suggests that the protein may be determinant for the structure of the p63 compartment.


Anthropometric, medical history and lifestyle risk factors for myeloproliferative neoplasms in the Iowa Women's Health Study cohort.
Classical myeloproliferative neoplasms (MPNs) are composed of essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), the etiology of which is largely unknown. We investigated the role of anthropometric, medical and lifestyle factors with risk of MPN in a prospective cohort of 27,370 women aged 55-69 years at enrollment. After >250,000 person-years of follow-up, 257 cases of MPN were identified (172 ET, 64 PV, 21 MF). Risk factor profiles were mostly unique for the two most common types, ET and PV. ET was associated with energy balance factors including body mass index (RR = 1.52 for >29.3 vs. <23.4 kg/m(2) ; p-trend = 0.042), physical activity (RR = 0.66 for high vs. low; p-trend = 0.04) and adult onset diabetes (RR = 1.82; p = 0.009), while PV was not. PV was associated with current smoking (RR = 2.83; p-trend = 0.016), while ET was not. Regular use of aspirin was associated with lower risk of ET (RR = 0.68; p = 0.017). These results broadly held in multivariate models. Our results suggest distinct etiologies for these MPN subtypes and raise mechanistic hypotheses related to obesity-related inflammatory pathways for ET and smoking-related carcinogenic pathways for PV. Regular aspirin use may lower risk for ET.


BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the disease.
Breast cancer is a rare disease in men, affecting less than 0.1% of the male population. Two heritable gene defects have been associated with a predisposition to male breast cancer development, ie., germ-line mutations in the breast cancer susceptibility gene BRCA2 and the androgen receptor (AR) gene. In this study, the entire coding regions of BRCA2 and AR were screened for mutations in 34 consecutive male breast cancer patients. Five different truncating BRCA2 mutations were identified in 7 (21%) of the 34 cases, with all mutations being of germ-line origin. Three of the mutated cases carried the same mutation (4186delG), which has been found earlier in two Swedish families with multiple female breast cancer cases. Haplotype analysis supported a common ancestry of 4186delG. One mutation, 6503delTT, was found in a male carrying also a previously identified COOH-terminal polymorphic stop codon (Lys3326ter). No differences were seen between mutation carriers and noncarriers with respect to clinical stage and estrogen or progesterone receptor status. Mutation carriers tended to be younger at diagnosis. No germ-line AR mutations were found in the present material, but the number of AR polyglutamine repeats tended to be lower among mutation carriers. Most surprisingly, only one of the seven BRCA2 mutation carriers had a positive family history of breast cancer, suggesting a lower penetrance of some BRCA2 mutations or an influence of modifying factors for disease development in males and females. The present study implies that approximately one-fifth of all male breast cancer cases in the Swedish population are due to germ-line BRCA2 mutations.


New Ulvaceae (Ulvophyceae, Chlorophyta) from mesophotic ecosystems across the Hawaiian Archipelago.
Ulvalean algae (Chlorophyta) are most commonly described from intertidal and shallow subtidal marine environments worldwide, but are less well known from mesophotic environments. Their morphological simplicity and phenotypic plasticity make accurate species determinations difficult, even at the generic level. Here, we describe the mesophotic Ulvales species composition from 13 locations across 2,300 km of the Hawaiian Archipelago. Twenty-eight representative Ulvales specimens from 64 to 125 m depths were collected using technical diving, submersibles, and remotely operated vehicles. Morphological and molecular characters suggest that mesophotic Ulvales in Hawaiian waters form unique communities comprising four species within the genera Ulva and Umbraulva, each with discrete geographic and/or depth-related distributional patterns. Three genetically distinct taxa are supported by both plastid (rbcL and tufA) and nuclear (ITS1) markers, and are presented here as new species: Umbraulva kaloakulau, Ulva ohiohilulu, and Ulva iliohaha. We also propose a new Umbraulva species (Umbraulva kuaweuweu), which is closely related to subtidal records from New Zealand and Australia, but not formally described. To our knowledge, these are the first marine species descriptions from Hawai'i resulting from the collaboration of traditional Hawaiian nomenclature specialists, cultural practitioners and scientists. The difficulty of finding reliable diagnostic morphological characters for these species reflects a common problem worldwide of achieving accurate identification of ulvalean taxa using solely morphological criteria. Mesophotic Ulvales appear to be distinct from shallow-water populations in Hawai'i, but their degree of similarity to mesophotic floras in other locations in the Pacific remains unknown.


Digital Technologies for Health Workforce Development in Low- and Middle-Income Countries: A Scoping Review.
The collection of journal articles, systematic reviews, and reports published over the last decade that attest to the potential of digital technologies to achieve health workforce improvements across all aspects of the health system is vast. As a capacity-building mechanism, digital technology has potential for low- and middle-income countries (LMICs) to support development of the health workforce, including those health workers based in remote or rural areas, to train, motivate, support, monitor, and pay them. The purpose of this scoping review to present, at a high level, the state of the evidence and best practices in digital strategies for human resources for health and to propose a roadmap for a research agenda to fill identified gaps in the evidence. A variety of peer-reviewed and gray literature sources were searched using selected key terms related to digital health and health workforce, limited to materials published from 2010 to 2018. More than 70 articles, reports, and blog posts were reviewed, with in-depth analysis of 29 articles. Findings show that a range of digital health solutions for health workforce development have been tested and used, such as for health worker training, provider-to-provider communication and professional networking, and supervision of and performance feedback to health workers. There is some evidence of improved efficiency and effectiveness, at least at the level of pilots or small-scale projects. There is, however, a growing urgency in global health to move beyond small-scale demonstration projects and to define the capital and recurring costs of implementation and scale up of digital health interventions, including the return on investment. The next frontier is to select, adapt, and implement at scale those digital health interventions for health worker development and management found to be most promising.


Hyporesponsivity of chronic schizophrenic patients to dextroamphetamine.
Among the evidence supporting the dopamine hypothesis of schizophrenia is the finding that both amphetamine and methylphenidate hydrochloride, potent releasers of dopamine, can cause exacerbation of symptoms in the acute schizophrenic patient. The present report describes three experiments in which the effects of amphetamine in chronic schizophrenic patients were studied. In one of the experiments, orally administered, daily doses of 20 mg of dextroamphetamine sulfate given at 8 PM had little or no effect on the sleep duration of the subjects. In the other two experiments, doses up to 40 mg given orally also had little or no effect on the performance of the subjects on a variety of behavioral tests. There was no evidence of an exacerbation of the disease process in any of the subjects. The most consistent amphetamine effect was a dose-related increase in blood pressure. These results indicate that the chronic schizophrenic patient may be hyporesponsive to amphetamine and suggest that if the dopamine hypothesis is correct, then it must be modified to take into account these findings in the chronic patient.


Gambling Disorder: Exploring Pre-treatment and In-treatment Dropout Predictors. A UK Study.
The aim of this study was to identify predictors of treatment dropout in a sample of gamblers attending a specialist clinic for gambling disorder. We analysed data on 846 treatment-seeking pathological gamblers. Firstly, we investigated differences in socio-demographic and clinical variables between treatment completers and pre-treatment dropouts, as well as between treatment completers and during-treatment dropouts. Subsequently, variables were entered into a multinomial logistic regression model to identify significant predictors of pre-treatment and in-treatment dropout. Overall, 44.8% of clients did not complete the treatment: 27.4% dropped out before starting it, while 17.4% dropped out during the treatment. Younger age and use of drugs were associated with pre-treatment dropout, while family history of gambling disorder, a lower PGSI score, and being a smoker were related with in-treatment dropout. Our findings suggest that pre-treatment dropouts differ from in-treatment dropouts, and, thus, further research will benefit from considering these groups separately. In addition, this newly gained knowledge will also be helpful in increasing treatment retention in specific subgroups of problem gamblers.


Quadricyclane radical cation rearrangements: a computational study of the transformations to 1,3,5-cycloheptatriene and norbornadiene.
An alternative skeletal rearrangement of the quadricyclane radical cation (Q*+) explains the side products formed in the one-electron oxidation to norbornadiene. First, the bicyclo[2.2.1]hepta-2-ene-5-yl-7-ylium radical cation, with an activation energy of 14.9 kcal mol(-1), is formed. Second, this species can further rearrange to 1,3,5-cycloheptatriene through two plausible paths, that is, a multistep mechanism with two shallow intermediates and a stepwise path in which the bicyclo[3.2.0]hepta-2,6-diene radical cation is an intermediate. The multistep rearrangement has a rate-limiting step with an estimated activation energy of 16.5 kcal mol(-1), which is 2.8 kcal mol(-1) lower in energy than the stepwise mechanism. However, the lowest activation energy is found for the Q*+ cycloreversion to norbornadiene that has a transition structure, in close correspondence with earlier studies, and an activation energy of 10.1 kcal mol(-1), which agrees well with the experimental estimate of 9.3 kcal mol(-1). The computational estimates of activation energies were done using the CCSD(T)/6-311+G(d,p) method with geometries optimized on the B3LYP/6-311+G(d,p) level, combined with B3LYP/6-311+G(d,p) frequencies.


Crocodile bites and traditional beliefs in Korogwe District, Tanzania.
To investigate why fatal crocodile bites are increasing in a Tanzanian district and the importance of traditional beliefs and superstitions in determining the residents' response to the crocodiles. Information about beliefs was obtained by interview of Korogwe residents. Human and crocodile fatality statistics were obtained from the Korogwe Department of Natural Resources. Villages within Korogwe District. Population of Korogwe District. Crocodiles have been responsible for 51 deaths in the 52 months from January 1990 to April 1994. Of these, 18 deaths occurred in the first four months of 1994. Local beliefs and superstitions about crocodiles include those about the taming of animals, with implications concerning the choice of victim and the penalties that may ensue if a crocodile is killed. The recent rise in human fatalities is thought to relate to increasing river pollution reducing the fish supply, together with a change in social mores at the riverside which has increased the crocodiles' displeasure. A reliable pumped water supply would reduce the need to draw water and bathe in the river, and eradication of superstition would empower the villagers in the fight against a common enemy.


Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints.
Data on the incidence of symptomatic osteoarthritis (OA) are scarce. We estimated incidence of clinical hip, knee and hand OA, and studied the effect of prevalent OA on joint-specific incident OA. SIDIAP contains primary care records for>5 million people from Catalonia (Spain). Participants aged ≥40 years with an incident diagnosis of knee, hip or hand OA between 2006 and 2010 were identified using International Classification of Diseases (ICD)-10 codes. Incidence rates and female-to-male rate ratios (RRs) for each joint site were calculated. Age, gender and body mass index-adjusted HR for future joint-specific OA according to prevalent OA at other sites were estimated using Cox regression. 3 266 826 participants were studied for a median of 4.45 years. Knee and hip OA rates increased continuously with age, and female-to-male RRs were highest at age 70-75 years. In contrast, female hand OA risk peaked at age 60-64 years, and corresponding female-to-male RR was highest at age 50-55 years. Adjusted HR for prevalent knee OA on risk of hip OA was 1.35 (99% CI 1.28 to 1.43); prevalent hip OA on incident knee OA: HR 1.15 (1.08 to 1.23). Prevalent hand OA predicted incident knee and hip OA: HR 1.20 (1.14 to 1.26) and 1.23 (1.13 to 1.34), respectively. The effect of age is greatest in the elderly for knee and hip OA, but around the menopause for hand OA. OA clusters within individuals, with higher risk of incident knee and hip disease from prevalent lower limb and hand OA.


Regulation of Dauer formation by O-GlcNAcylation in Caenorhabditis elegans.
Modification of proteins at serine or threonine residues with N-acetylglucosamine, termed O-GlcNAcylation, plays an important role in most eukaryotic cells. To understand the molecular mechanism by which O-GlcNAcylation regulates the entry of Caenorhabditis elegans into the non-aging dauer state, we performed proteomic studies using two mutant strains: the O-GlcNAc transferase-deficient ogt-1(ok430) strain and the O-GlcNAcase-defective oga-1(ok1207) strain. In the presence of the dauer pheromone daumone, ogt-1 showed suppression of dauer formation, whereas oga-1 exhibited enhancement of dauer formation. Consistent with these findings, treatment of wild-type N2 worms with low concentrations of daumone and the O-GlcNAcase inhibitor O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) enhanced dauer formation, which was dependent on intact O-GlcNAcylation metabolism. We also found that the treatment of daumone enhanced O-GlcNAcylation in vivo. Seven proteins, identified by coupled two-dimensional electrophoresis/liquid chromatography-mass spectroscopy (LC-MS) analysis, were differentially expressed in oga-1(ok1207) worms compared with wild-type N2 worms. The identities of these proteins suggest that O- GlcNAcylation influences stress resistance, protein folding, and mitochondrial function. Using O-GlcNAc labeling with fluorescent dye combined with two-dimensional electrophoresis/LC-MS analysis, we also identified five proteins that were differentially O-GlcNAcylated during dauer formation. Analysis of these candidate O-GlcNAcylated proteins suggests that O-GlcNAcylation may regulate cytoskeleton modifications and protein turnover during dauer formation.


McMaster-Toronto Arthritis Patient Preference Disability Questionnaire sensitivity to change in low back pain: influence of shifts in priorities.
To assess the sensitivity to change of the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) in chronic low back pain (CLBP) and shifts in patients' priorities of disabling activities over time. A prospective longitudinal survey of 100 patients (38 males) with CLBP in a tertiary care teaching hospital. Evaluation at baseline and 6 months by the MACTAR, Quebec Back Pain Disability Questionnaire (QUEBEC), Hospital Anxiety and Depression scale (HAD), Fear-Avoidance Beliefs Questionnaire (FABQ), Coping Strategies Questionnaire (CSQ), and pain and handicap visual analogue scales (VASs). Patients' perceived improvement or worsening of condition was assessed at 6 months. Effect size (ES) and Standardized response mean (SRM) and effect size (ES) were used to evaluate sensitivity to change of the MACTAR. The MACTAR SRM and ES values (SRM = 0.25; ES = 0.37) were among the highest for the instruments evaluated. For patients considering their condition as improved, the SRM was 0.66 and the ES 1. The 3 disability domains, classified by the International Classification of Functioning, Disability and Health (ICF), most often cited as priorities at baseline remained the most cited at follow-up: mobility (40.9% of patients); community, social and civic life (22.7%); and domestic life (22.4%). At 6 months, 48 patients shifted their priorities, for a decrease in MACTAR SRM and ES values for patients considering their condition improved and an increase in these values for those considering their condition deteriorated. Although the MACTAR has similar sensitivity to change as other outcome measures widely used in CLBP, shifts in patient priorities over time are common and influence scores and sensitivity to change.


Genome-wide analysis of alternative splicing in cow: implications in bovine as a model for human diseases.
Alternative splicing (AS) is a primary mechanism of functional regulation in the human genome, with 60% to 80% of human genes being alternatively spliced. As part of the bovine genome annotation team, we have analysed 4567 bovine AS genes, compared to 16715 human and 16491 mouse AS genes, along with Gene Ontology (GO) analysis. We also analysed the two most important events, cassette exons and intron retention in 94 human disease genes and mapped them to the bovine orthologous genes. Of the 94 human inherited disease genes, a protein domain analysis was carried out for the transcript sequences of 12 human genes that have orthologous genes and have been characterised in cow. Of the 21,755 bovine genes, 4,567 genes (21%) are alternatively spliced, compared to 16,715 (68%) in human and 16,491 (57%) in mouse. Gene-level analysis of the orthologous set suggested that bovine genes show fewer AS events compared to human and mouse genes. A detailed examination of cassette exons across human and cow for 94 human disease genes, suggested that a majority of cassette exons in human were present and constitutive in bovine as opposed to intron retention which exhibited 50% of the exons as present and 50% as absent in cow. We observed that AS plays a major role in disease implications in human through manipulations of essential/functional protein domains. It was also evident that majority of these 12 genes had conservation of all essential domains in their bovine orthologous counterpart, for these human diseases. While alternative splicing has the potential to create many mRNA isoforms from a single gene, in cow the majority of genes generate two to three isoforms, compared to six in human and four in mouse. Our analyses demonstrated that a smaller number of bovine genes show greater transcript diversity. GO definitions for bovine AS genes provided 38% more functional information than currently available in the sequence database. Our protein domain analysis helped us verify the suitability of using bovine as a model for human diseases and also recognize the contribution of AS towards the disease phenotypes.


The resistance of sour orange to Citrus tristeza virus is mediated by both the salicylic acid and RNA silencing defence pathways.
Citrus tristeza virus (CTV) induces in the field the decline and death of citrus varieties grafted on sour orange (SO) rootstock, which has forced the use of alternative decline-tolerant rootstocks in affected countries, despite the highly desirable agronomic features of the SO rootstock. Declining citrus plants display phloem necrosis below the bud union. In addition, SO is minimally susceptible to CTV compared with other citrus varieties, suggesting partial resistance of SO to CTV. Here, by silencing different citrus genes with a Citrus leaf blotch virus-based vector, we have examined the implication of the RNA silencing and salicylic acid (SA) defence pathways in the resistance of SO to CTV. Silencing of the genes RDR1, NPR1 and DCL2/DCL4, associated with these defence pathways, enhanced virus spread and accumulation in SO plants in comparison with non-silenced controls, whereas silencing of the genes NPR3/NPR4, associated with the hypersensitive response, produced a slight decrease in CTV accumulation and reduced stunting of SO grafted on CTV-infected rough lemon plants. We also found that the CTV RNA silencing suppressors p20 and p23 also suppress the SA signalling defence, with the suppressor activity being higher in the most virulent isolates.


Immunoproximity biotinylation reveals the axon initial segment proteome.
The axon initial segment (AIS) is a specialized neuronal compartment required for action potential generation and neuronal polarity. However, understanding the mechanisms regulating AIS structure and function has been hindered by an incomplete knowledge of its molecular composition. Here, using immuno-proximity biotinylation we further define the AIS proteome and its dynamic changes during neuronal maturation. Among the many AIS proteins identified, we show that SCRIB is highly enriched in the AIS both in vitro and in vivo, and exhibits a periodic architecture like the axonal spectrin-based cytoskeleton. We find that ankyrinG interacts with and recruits SCRIB to the AIS. However, loss of SCRIB has no effect on ankyrinG. This powerful and flexible approach further defines the AIS proteome and provides a rich resource to elucidate the mechanisms regulating AIS structure and function.


Virtual caregiver: an ambient-aware elderly monitoring system.
The growing number of elderly population at home and abroad necessitates improved approaches to elderly care provision. Elders, often with cognitive and physical impairment, need assistance in their activities of daily living (ADLs), which is usually provided by human caregivers. As the demand for caregivers assistance increases, the shortage of traditional care resources becomes obvious. In this paper, we present the Virtual Caregiver (ViCare) framework that supports a human caregiver to monitor continuously the elderly by being aware of their surroundings. The ViCare system attempts to understand the elderly persons activities and contexts based on the data captured by the sensors placed in their environment and dynamically decides what services to provide them or whether there is a need to interrupt human caregiver depending on the type of activities. It not only minimizes the cognitive load of the human caregiver but also provides a seamless assistance to the elderly toward their improved health and well-being in their living environment. We conducted the experiments in an instrumented home environment and obtained positive results in terms of the satisfaction of the elderly, interaction event handling, caregivers acceptance and their engagement.


Persistent SARS-CoV-2 infection in patients with secondary antibody deficiency: successful clearance following combination casirivimab and imdevimab (REGN-COV2) monoclonal antibody therapy.
There is growing evidence that antibody responses play a role in the resolution of SARS-CoV-2 infection. Patients with primary or secondary antibody deficiency are at increased risk of persistent infection. This challenging clinical scenario is associated with adverse patient outcome and potentially creates an ecological niche for the evolution of novel SARS-CoV-2 variants with immune evasion capacity. Case reports and/or series have implied a therapeutic role for convalescent plasma (CP) to secure virological clearance, although concerns have been raised about the effectiveness of CP and its potential to drive viral evolution, and it has largely been withdrawn from clinical use in the UK. We report two cases in which persistent SARS-CoV-2 infection was cleared following administration of the monoclonal antibody combination casirivimab and imdevimab (REGN-COV2, Ronapreve). A 55-year-old male with follicular lymphoma, treated with B cell depleting therapy, developed SARS-CoV-2 infection in September 2020 which then persisted for over 200 days. He was hospitalised on four occasions with COVID-19 and suffered debilitating fatigue and malaise throughout. There was no clinical response to antiviral therapy with remdesivir or CP, and SARS-CoV-2 was consistently detected in nasopharyngeal swabs. Intrahost evolution of several spike variants of uncertain significance was identified by viral sequence analysis. Delivery of REGN-COV2, in combination with remdesivir, was associated with clinical improvement and viral clearance within 6 days, which was sustained for over 150 days despite immunotherapy for relapsed follicular lymphoma. The second case, a 68-year-old female with chronic lymphocytic leukaemia on ibrutinib, also developed persistent SARS-CoV-2 infection. Despite a lack of response to remdesivir, infection promptly cleared following REGN-COV2 in combination with remdesivir, accompanied by resolution of inflammation and full clinical recovery that has been maintained for over 290 days. These cases highlight the potential benefit of REGN-COV2 as therapy for persistent SARS-CoV-2 infection in antibody deficient individuals, including after failure of CP treatment. Formal clinical studies are warranted to assess the effectiveness of REGN-COV2 in antibody-deficient patients, especially in light of the emergence of variants of concern, such as Omicron, that appear to evade REGN-COV2 neutralisation.


Myasthenia gravis: steroid-induced effects on lymphocyte subpopulations in myasthenia gravis.
Lymphocyte subpopulations from patients with myasthenia gravis were evaluated during chronic steroid therapy. A marked lymphocytopenia (10-70%) was initially (day 3-21) noticed as well as a preferential depletion of thymus-derived cells which paralleled the clinical deterioration. Thus there was a relative increase in B cells, although their absolute number remained rather constant. These changes were reverted within 2-4 weeks in spite of continuous treatment. These findings are compatible with a release of myasthenic factors (anti-acetylcholine receptor antibodies?) during the initial steroid-induced cell damage, the long-term beneficial effects being due to loss or suppression of autoreactive helper t cells.