Neurogenesis paradoxically decreases both pattern separation and memory interference.
The hippocampus has been the focus of memory research for decades. While the functional role of this structure is not fully understood, it is widely recognized as being vital for rapid yet accurate encoding and retrieval of associative memories. Since the discovery of adult hippocampal neurogenesis in the dentate gyrus by Altman and Das in the 1960's, many theories and models have been put forward to explain the functional role it plays in learning and memory. These models postulate different ways in which new neurons are introduced into the dentate gyrus and their functional importance for learning and memory. Few if any previous models have incorporated the unique properties of young adult-born dentate granule cells and the developmental trajectory. In this paper, we propose a novel computational model of the dentate gyrus that incorporates the developmental trajectory of the adult-born dentate granule cells, including changes in synaptic plasticity, connectivity, excitability and lateral inhibition, using a modified version of the Restricted Boltzmann machine. Our results show superior performance on memory reconstruction tasks for both recent and distally learned items, when the unique characteristics of young dentate granule cells are taken into account. Even though the hyperexcitability of the young neurons generates more overlapping neural codes, reducing pattern separation, the unique properties of the young neurons nonetheless contribute to reducing retroactive and proactive interference, at both short and long time scales. The sparse connectivity is particularly important for generating distinct memory traces for highly overlapping patterns that are learned within the same context.


Preserved otolith function in patients with cerebellar atrophy and bilateral vestibulopathy.
Cerebellar degeneration affects vestibular function. For instance, with lesions of the cerebellar flocculus, the ability to adaptively modify the VOR gain is markedly reduced, and cerebellar patients may even demonstrate severe vestibular deficits. We report five patients (m=3, f=2) with cerebellar disease, in whom search-coil head impulse testing revealed reduced gains of the angular VOR, while sacculus-mediated myogenic potentials were normal. Preserved static ocular counterroll in roll-tilt positions and prominent gravity-dependent modulation of downbeat nystagmus (DBN) along the pitch plane demonstrated the integrity of otolith (OL) function in these patients as well. Probably, at least in some cerebellar patients with marked floccular atrophy, the dissociation between impaired semicircular canal (SCC) function and preserved OL function may be explained by a predilection of the atrophic process for the flocculus and brainstem neurons involved in angular VOR gain control, while structures mediating OL function remain widely spared by the cerebellar degeneration. The exact pathomechanism leading to the vestibular impairment remains unclear: both a primary multi-system-type atrophy involving cerebellar and brainstem vestibular structures as well as a mechanism of secondary retrograde degeneration of floccular brainstem target neurons mediating SCC function seem plausible.


Transvaginal Mesh and Transanal Resection to Treat Outlet Obstruction Constipation Caused by Rectocele.
BACKGROUND The aim of this study was to evaluate the curative effect of transvaginal mesh repair (TVMR) and stapled transanal rectal resection (STARR) in treating outlet obstruction constipation caused by rectocele. MATERIAL AND METHODS Patients who had outlet obstruction constipation caused by rectocele were retrospectively analyzed and 39 patients were enrolled the study. Patients were assigned to either the TVMR or STARR group. Postoperative factors such as complications, pain, recurrence rate, and operative time were compared between the 2 groups. RESULTS Total effective rate was 100% in both groups. No long-term chronic pain occurred and discomfort rate of tenesmus was higher in the STARR group than in the TVMR group. Postoperative defecography showed that the rectocele depth was significantly reduced, and the prolapse of the rectal mucosa and the lower rectal capacity was also decreased. Four cases had mesh exposure in the TVMR group and 2 cases in the STARR group had anastomotic bleeding after the surgery. CONCLUSIONS For outlet obstruction constipation caused by rectocele, TVMR and STARR both obtained satisfactory results. Although TVMR is complex with longer operative time and hospitalization period, its long-term effect is better than that of STARR.


Transcriptional Modulation of the ERK1/2 MAPK and NF-κB Pathways in Human Urothelial Cells After Trivalent Arsenical Exposure: Implications for Urinary Bladder Cancer.
Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk of urinary bladder (UB) cancers in humans. The exact role of specific iAs metabolite(s) in As-mediated carcinogenesis remains largely unknown. Experimental evidence suggests that trivalent arsenicals, namely arsenite (iAsIII) and two of its metabolites, monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII), are possible proximate UB carcinogens. Here, we used a transcriptomics approach to examine perturbed molecular pathways in a human urothelial cell line (UROtsa) after short-term exposure to iAsIII, MMAIII and DMAIII. Molecular pathways containing genes that encode proteins implicated in UB cancer development were perturbed by both MMAIII and DMAIII. These pathways included those of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK 1/2 MAPK) and nuclear factor kappa beta (NF-κB). Together, these results may inform the current understanding of effects in the UB induced by acute As exposure and the relationship of these effects with As-mediated carcinogenesis.


Thermal Decoherence and Disorder Effects on Chiral-Induced Spin Selectivity.
We use a nonlinear master equation formalism to account for thermal and disorder effects on spin-dependent electron transport in helical organic molecules coupled to two ideal leads. The inclusion of these two effects has important consequences in understanding the observed length and temperature dependence of spin polarization in experiments, which cannot be accounted for in a purely coherent tunneling model. Our approach considers a tight-binding helical Hamiltonian with disordered onsite energies to describe the resulting electronic states when low-frequency interacting modes break the electron coherence. The high-frequency fluctuating counterpart of these interactions, typical of intramolecular modes, is included by means of temperature-dependent thermally activated transfer probabilities in the master equation, which lead to hopping between localized states. We focus on the spin-dependent conductance and the spin-polarization in the linear regime (low voltage), which are analyzed as a function of the molecular length and the temperature of the system. Our results at room temperature agree well with experiments because our model predicts that the degree of spin-polarization increases for longer molecules. Also, this effect is temperature-dependent because thermal excitation competes with disorder-induced Anderson localization. We conclude that a transport mechanism based on thermally activated hopping in a disordered system can account for the unexpected behavior of the spin polarization.


Regulation of calcium concentration in voltage-clamped smooth muscle cells.
The regulation of intracellular calcium concentration in single smooth muscle cells was investigated by simultaneously monitoring electrical events at the surface membrane and calcium concentration in the cytosol. Cytosolic calcium concentration rose rapidly during an action potential or during a voltage-clamp pulse that elicited calcium current; a train of voltage-clamp pulses caused further increases in the calcium concentration up to a limit of approximately 1 microM. The decline of the calcium concentration back to resting levels occurred at rates that varied with the calcium concentration in an apparently saturable manner. Moreover, the rate of decline at any given calcium concentration was enhanced after a higher, more prolonged increase of calcium. The process responsible for this enhancement persisted for many seconds after the calcium concentration returned to resting levels. Thus, the magnitude and duration of a calcium transient appear to regulate the subsequent calcium removal.


Salivary Biomarkers for Alzheimer's Disease and Related Disorders.
The search for accessible and cost-effective biomarkers to complement current cerebrospinal fluid (CSF) and imaging biomarkers in the accurate detection of Alzheimer disease (AD) and other common neurodegenerative disorders remains a challenging task. The advances in ultra-sensitive detection methods has highlighted blood biomarkers (e.g. amyloid-β and neurofilament light) as a valuable and realistic tool in a diagnostic or screening process. Saliva, however, is also a rich source of potential biomarkers for disease detection and offers several practical advantages over biofluids that are currently examined for neurodegenerative disorders. However, while this may be true for the general population, challenges in collecting saliva from an elderly population should be seriously considered. In this review, we begin by discussing how saliva is produced and how age-related conditions can modify saliva production and composition. We then focus on the data available which support the concept of salivary amyloid-β, tau species and novel biomarkers in detecting AD and alpha-synuclein (α-syn) in Parkinson's disease (PD).


Emotion Recognition Using Smart Watch Sensor Data: Mixed-Design Study.
Research in psychology has shown that the way a person walks reflects that person's current mood (or emotional state). Recent studies have used mobile phones to detect emotional states from movement data. The objective of our study was to investigate the use of movement sensor data from a smart watch to infer an individual's emotional state. We present our findings of a user study with 50 participants. The experimental design is a mixed-design study: within-subjects (emotions: happy, sad, and neutral) and between-subjects (stimulus type: audiovisual "movie clips" and audio "music clips"). Each participant experienced both emotions in a single stimulus type. All participants walked 250 m while wearing a smart watch on one wrist and a heart rate monitor strap on the chest. They also had to answer a short questionnaire (20 items; Positive Affect and Negative Affect Schedule, PANAS) before and after experiencing each emotion. The data obtained from the heart rate monitor served as supplementary information to our data. We performed time series analysis on data from the smart watch and a t test on questionnaire items to measure the change in emotional state. Heart rate data was analyzed using one-way analysis of variance. We extracted features from the time series using sliding windows and used features to train and validate classifiers that determined an individual's emotion. Overall, 50 young adults participated in our study; of them, 49 were included for the affective PANAS questionnaire and 44 for the feature extraction and building of personal models. Participants reported feeling less negative affect after watching sad videos or after listening to sad music, P<.006. For the task of emotion recognition using classifiers, our results showed that personal models outperformed personal baselines and achieved median accuracies higher than 78% for all conditions of the design study for binary classification of happiness versus sadness. Our findings show that we are able to detect changes in the emotional state as well as in behavioral responses with data obtained from the smartwatch. Together with high accuracies achieved across all users for classification of happy versus sad emotional states, this is further evidence for the hypothesis that movement sensor data can be used for emotion recognition.


Comparison of various surface textured layer in InGaN LEDs for high light extraction efficiency.
The various surface texturing effects of InGaN light emitting diodes (LEDs) have been investigated by comparison of experimented data and simulated data. The single-layer and double-layer texturing were performed with the help of ITO nanospheres using wet etching, where the ITO ohmic contact layer and the p-GaN layer are textured using ITO nanospheres as an etch mask. In case of single-layer texturing, p-type GaN layer texturing was more effective than ITO ohmic contact layer texturing. The maximum enhancement of wall-plug efficiency of double-layered textured LEDs is 40% more than conventional LEDs, after packaging at an injected current of 20 mA. The increase of light scattering at the textured GaN surfaces is a major reason for increasing the light extraction efficiency of LEDs.


Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical applications.
Molecular hydrogen (H2) was believed to be inert and nonfunctional in mammalian cells. We overturned this concept by demonstrating that H2 reacts with highly reactive oxidants such as hydroxyl radical ((•)OH) and peroxynitrite (ONOO(-)) inside cells. H2 has several advantages exhibiting marked effects for medical applications: it is mild enough neither to disturb metabolic redox reactions nor to affect signaling by reactive oxygen species. Therefore, it should have no or little adverse effects. H2 can be monitored with an H2-specific electrode or by gas chromatography. H2 rapidly diffuses into tissues and cells to exhibit efficient effects. Thus, we proposed the potential of H2 for preventive and therapeutic applications. There are several methods to ingest or consume H2: inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-dissolved saline (H2-saline), taking an H2 bath, or dropping H2-saline onto the eyes. Recent publications revealed that, in addition to the direct neutralization of highly reactive oxidants, H2 indirectly reduces oxidative stress by regulating the expression of various genes. Moreover, by regulating gene expression, H2 functions as an anti-inflammatory, antiallergic, and antiapoptotic molecule, and stimulates energy metabolism. In addition to growing evidence obtained by model animal experiments, extensive clinical examinations were performed or are under way. Since most drugs specifically act on their specific targets, H2 seems to differ from conventional pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has potential for clinical applications for many diseases.


Variation in clutch size in relation to nest size in birds.
Nests are structures built to support and protect eggs and/or offspring from predators, parasites, and adverse weather conditions. Nests are mainly constructed prior to egg laying, meaning that parent birds must make decisions about nest site choice and nest building behavior before the start of egg-laying. Parent birds should be selected to choose nest sites and to build optimally sized nests, yet our current understanding of clutch size-nest size relationships is limited to small-scale studies performed over short time periods. Here, we quantified the relationship between clutch size and nest size, using an exhaustive database of 116 slope estimates based on 17,472 nests of 21 species of hole and non-hole-nesting birds. There was a significant, positive relationship between clutch size and the base area of the nest box or the nest, and this relationship did not differ significantly between open nesting and hole-nesting species. The slope of the relationship showed significant intraspecific and interspecific heterogeneity among four species of secondary hole-nesting species, but also among all 116 slope estimates. The estimated relationship between clutch size and nest box base area in study sites with more than a single size of nest box was not significantly different from the relationship using studies with only a single size of nest box. The slope of the relationship between clutch size and nest base area in different species of birds was significantly negatively related to minimum base area, and less so to maximum base area in a given study. These findings are consistent with the hypothesis that bird species have a general reaction norm reflecting the relationship between nest size and clutch size. Further, they suggest that scientists may influence the clutch size decisions of hole-nesting birds through the provisioning of nest boxes of varying sizes.


Disseminated cutaneous sporotrichosis in patient with alcoholism.
Sporotrichosis is the most prevalent subcutaneous mycosis and is characterized by a subacute or chronic development of a cutaneous or subcutaneous nodular lesion. It is caused by the dimorphic fungus Sporothrix spp, which may manifest in different clinical forms. The disseminated cutaneous form is uncommon and is more likely to occur in immunocompromised patients. We report a 47-year-old male patient with multiple cutaneous and subcutaneous nodules. The patient was diagnosed with disseminated cutaneous sporotrichosis based on the isolation and identification of Sporothrix spp. The patient was treated with potassium iodide, which resulted in clinical improvement of the lesions.


Osteopathy for musculoskeletal pain patients: a systematic review of randomized controlled trials.
The objective of this systematic review was to assess the effectiveness of osteopathy as a treatment option for musculoskeletal pain. Six databases were searched from their inception to August 2010. Only randomized clinical trials (RCTs) were considered if they tested osteopathic manipulation/mobilization against any control intervention or no therapy in human with any musculoskeletal pain in any anatomical location, and if they assessed pain as an outcome measure. The selection of studies, data extraction, and validation were performed independently by two reviewers. Studies of chiropractic manipulations were excluded. Sixteen RCTs met the inclusion criteria. Their methodological quality ranged between 1 and 4 on the Jadad scale (max = 5). Five RCTs suggested that osteopathy compared to various control interventions leads to a significantly stronger reduction of musculoskeletal pain. Eleven RCTs indicated that osteopathy compared to controls generates no change in musculoskeletal pain. Collectively, these data fail to produce compelling evidence for the effectiveness of osteopathy as a treatment of musculoskeletal pain.


Mobile DNA can drive lineage extinction in prokaryotic populations.
Natural selection ultimately acts on genes and other DNA sequences. Adaptations that are good for the gene can have adverse effects at higher levels of organization, including the individual or the population. Mobile genetic elements illustrate this principle well, because they can self-replicate within a genome at a cost to their host. As they are costly and can be transmitted horizontally, mobile elements can be seen as genomic parasites. It has been suggested that mobile elements may cause the extinction of their host populations. In organisms with very large populations, such as most bacteria, individual selection is highly effective in purging genomes of deleterious elements, suggesting that extinction is unlikely. Here we investigate the conditions under which mobile DNA can drive bacterial lineages to extinction. We use a range of epidemiological and ecological models to show that harmful mobile DNA can invade, and drive populations to extinction, provided their transmission rate is high and that mobile element-induced mortality is not too high. Population extinction becomes more likely when there are more elements in the population. Even if elements are costly, extinction can still occur because of the combined effect of horizontal gene transfer, a mortality induced by mobile elements. Our study highlights the potential of mobile DNA to be selected at the population level, as well as at the individual level.


Novel animal glioma models that separately exhibit two different invasive and angiogenic phenotypes of human glioblastomas.
Invasive behaviors of malignant gliomas are fundamental traits and major reasons for treatment failure. Delineation of invasive growth is important in establishing treatment for gliomas and experimental neuro-oncology could benefit from an invasive glioma model. In this study, we established two new cell line-based animal models of invasive glioma. Two cell lines, J3T-1 and J3T-2, were derived from the same parental canine glioma cell line, J3T. These cells were inoculated to establish brain tumors in athymic mice and rats. Pathologic samples of these animal gliomas were examined to analyze invasive patterns in relation to angiogenesis, and were compared with human glioblastoma samples. The molecular profiles of these cell lines were also shown. Histologically, J3T-1 and J3T-2 tumors exhibited different invasive patterns. J3T-1 cells clustered around newly developed vessels at tumor borders, whereas J3T-2 cells showed diffuse single cell infiltration into surrounding healthy parenchyma. In human malignant glioma samples, both types of invasion were observed concomitantly. Molecular profiles of these cell lines were analyzed by immunocytochemistry and with quantitative reverse transcription polymerase chain reaction. Vascular endothelial growth factor, matrix metalloproteinase-9, hypoxia-inducible factor-1, and platelet-derived growth factor were overexpressed in J3T-1 cells rather than in J3T-2 cells, whereas integrin αvβ3, matrix metalloproteinase-2, nestin, and secreted protein acidic and rich in cysteine were overexpressed in J3T-2 cells rather than in J3T-1 cells. These animal models histologically recapitulated two invasive and angiogenic phenotypes, namely angiogenesis-dependent and angiogenesis-independent invasion, also observed in human glioblastoma. These cell lines provided a reproducible in vitro and in vivo system to analyze the mechanisms of invasion and angiogenesis in glioma progression.


The ability of anaesthetists to identify the position of the right internal jugular vein correctly using anatomical landmarks.
We performed a study of 85 consenting anaesthetists to assess their ability to locate the right internal jugular vein using a landmark technique. Initially, a questionnaire was completed ascertaining previous user experience. An ultrasound probe, using the midpoint as an 'imaginary needle', was placed on the neck of a healthy volunteer (with previously confirmed normal anatomy) and the image recorded. Both anaesthetist and volunteer were blinded to the screen until the image was stored. Anaesthetists were grouped into those in training before 2002 (Pre-2002, n = 58), when National Institute for Health and Clinical Excellence guidelines recommending ultrasound guidance were published, and those training after this time point (Post-2002, n = 27). The success rate for identifying the internal jugular vein using the landmark technique was 36/58 (62%) in the Pre-2002 group and 6/27 (22%) in the Post-2002 group (p < 0.001). Three participants in each group would have hit the carotid artery (5% Pre-2002 and 11% Post-2002 respectively; p = 0.2). The advent of routine use of ultrasound has resulted in a cohort of anaesthetists who are unable to use a landmark technique effectively or safely. This has significant training implications.


The arsenic for phosphorus swap is accidental, rather than a facultative one, and the question whether arsenic is nonessential or toxic is quantitative, not a qualitative one.
Arsenic shares many physicochemical properties with phosphorus, so that arsenic can be taken up inadvertently by cells through the pathways for phosphorus. As a phosphate analog, arsenate competes with phosphate and enters cells via phosphate transporters. In the cell, arsenate can be recognized as a substrate by enzymes that usually use phosphate as a substrate. The phosphate for arsenate swap results in wasteful 'futile cycles' in metabolic pathways, uncoupled oxidative phosphorylation and extreme DNA instability. The disrupting metabolic effects of arsenic have an evolutionary meaning, so that all living organisms-from chemoautotrophic organisms that grow by reducing or oxidizing arsenic to metazoan--carry highly conserved arsenic resistance genes. Arsenic resistance can result from different strategies including selective transport to maximize phosphate uptake and minimize entry of arsenate, active transport to export arsenate, arsenic storage in specialized compartments, enzyme selectivity toward phosphate, and increased efficiency of DNA repair systems. None of these strategies is infallible, though, and susceptibility to arsenic toxicity varies between taxa in many orders of magnitude. Even arsenic-hypertolerant organisms will stop to grow and will eventually die when exposed to arsenic over species-specific resistance limits. The arsenic for phosphorus swap is an accidental one, it does not warrant a conclusion in favor of the essentiality of arsenic to life as we know it.


Effect of venous superdrainage on a four-territory skin flap survival in rats.
In a previous report, the authors demonstrated that distal arterial supercharging is more effective at increasing flap survival. There is no doubt of the benefit of arterial augmentation in flap surgery, but the effect of venous superdrainage is still controversial. The purpose of this study was to investigate how venous augmentation could generate larger flap survival areas with different superdrainage positions in rats. A four-territory skin flap, developed by the authors, was used. Forty rats were divided into four groups, as follows: group 1, flaps based only on the deep circumflex iliac artery and vein; group 2, flaps superdrained with the ipsilateral superficial inferior epigastric vein; group 3, flaps superdrained with the contralateral superficial inferior epigastric vein; and group 4, flaps superdrained with the contralateral deep circumflex iliac vein. On the fourth postoperative day, the flaps were assessed by measurements of necrosis and survival areas. Vascular changes produced by venous augmentation were evaluated angiographically. Compared with group 1 (mean flap survival, 37.8 +/- 5.0 percent), the flap survival areas were significantly greater in the superdrainage flap groups (group 2, 57.4 +/- 6.5 percent, p < 0.001; group 3, 72.4 +/- 21.3 percent, p < 0.001, and group 4, 89.2 +/- 18.8 percent; p < 0.001). Angiographic assessment of the flaps revealed dilatation of the choke vein between the territories and reorientation of dilated veins along the long axes of the flaps. This study demonstrates that venous augmentation is also effective for increasing flap survival, and the distal procedure is more effective than the proximal procedure in arterial supercharging.


Localization of nigral dopamine-sensitive adenylate cyclase on neurons originating from the corpus striatum.
Nigral basal adenylate cyclase and dopamine-sensitive adenylate cyclase, glutamate decarboxylase, choline acetyltransferase, and tyrosine hydroxylase activities were measured in rats with hemitransections at various levels or with electrolytic lesions of the medial forebrain bundle or the crus cerebri. The loss of nigral dopamine-sensitive adenylate cyclase activity after the various brain lesions was correlated with loss of nigral glutamic acid decarboxylase but not that of tyrosine hydroxylase; nigral choline acetyltransferase was unaffected in all cases. The data indicate that the nigral dopamine-sensitive adenylate cylase activity may be localized on neurons afferent to the nigra, probably originating from the globus pallidus and possibly from the tail of the caudate. The results suggest that dopamine, released from nigral dendrites, may influence dopaminergic activity indirectly by modulating impulses transmitted to the nigrostriatal neurons through the crus cerebri.


Estimated mortality and hospital admission due to rotavirus infection in the WHO European region.
In 2006 two rotavirus vaccines were licensed for use in young children in Europe. This study aimed to estimate the mortality and hospital admissions due to rotavirus in children aged <5 years in the WHO European region using data from routine sources and published literature. We grouped 49/52 countries in the region by their World Bank Gross National Income (GNI) per capita. We obtained for children aged <5 years: populations, hospital discharges for diarrhoeal disease, estimated mortality rates and the percentage of deaths attributable to diarrhoeal disease, from WHO data sources or published literature, and combined them to estimate country-specific diarrhoeal disease mortality. Rotavirus-attributable percentages of hospital admissions due to diarrhoeal disease were obtained through a literature search, and an income-group median applied to countries in each GNI category. In the countries we studied in the WHO European region, rotavirus infection causes an estimated 6550 deaths (range 5671-8989) and 146 287 (range 38 374-1 039 843) hospital admissions each year in children aged <5 years. Hospital admission rates were similar across income groups (medians 2.0, 2.8, 4.2 and 1.9/1000 per year in low-, lower-middle-, upper-middle- and high-income countries, respectively). Seven countries, mostly in the low- and lower-middle-income groups, accounted for 93% of estimated deaths. Disease burden varied dramatically by income level in the European region. Rotavirus vaccination in Azerbaijan, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan and Turkey could potentially prevent 80% of all regional rotavirus deaths. Data from low-income countries is still sparse, and improved disease burden studies are required to better inform regional vaccine policy.


The Brazilian Portuguese Version of the DISCERN Instrument: Translation Procedures and Psychometric Properties.
To report on the translation procedures and psychometric properties of the DISCERN tool in Brazilian Portuguese. Three people translated the DISCERN from English into Brazilian Portuguese. A committee of experts and community representatives evaluated the quality of the 3 versions in 2 online voting rounds. Two native speakers back-translated the questionnaire into English. We compared these versions to the original DISCERN and made small adjustments. The final Brazilian Portuguese version of DISCERN was tested twice by journalism students to evaluate the quality of a text about smoking cessation treatments. We evaluated participants' health literacy with the Short Assessment of Health Literacy for Portuguese-Speaking Adults (SAHL-PA) tool, assessed the internal consistency of the translated questionnaire with the Cronbach test, and measured its reproducibility with the intraclass correlation coefficient (ICC). We then investigated the relationship between DISCERN and SAHL-PA scores and demographic variables. The participants (n = 126) had no difficulty in using the questionnaire. Cronbach's alpha was 0.865 (95% confidence interval [CI], 0.826-0.898), and the ICC between the 2 evaluations was 0.845 (CI 0.717-0.912). The mean health literacy of the participants was adequate. There was no correlation between the DISCERN score and the SAHL-PA score, age, or sex (P > .05). The Brazilian Portuguese version of the DISCERN questionnaire has excellent internal consistency and good reproducibility. The evaluators' ages, sex, and health literacy did not interfere with the score resulting from the evaluation of the quality of the text.


Involvement of the Septo-Hippocampal Cholinergic Pathway in Association with Septal Acetylcholinesterase Upregulation in a Mouse Model of Tauopathy.
Cholinergic cell loss in the basal forebrain, the major source of hippocampal cholinergic projections, has been implicated in Alzheimer's disease. To examine whether the septohippocampal pathway is involved in tauopathy model mice and to elucidate the tau-associated mechanism underlying cholinergic alteration. Adult (6 to 8 months old) and old (16 to 18 months old) transgenic mice expressing wild-type human tau, Tg601, were examined using Ex vivo diffusion tensor magnetic resonance imaging (DTI) and 2-[18F]fluoro- 2-deoxy-D-glucose positron emission tomography (FDG-PET). Choline acetyltransferase (ChAT)-positive neurons in the medial septum (MS) were counted by stereological methods. Acetylcholinesterase (AChE) activity and AChE mRNA in 6 brain regions were measured. Ex vivo DTI revealed that the number of fractional anisotropy (FA) streamlines in the septohippocampal tract decreased with age in Tg601 mice. The FA value in the septum was lower in old Tg601 mice than in non-tg mice. A voxel-based statistical analysis of FDG-PET revealed the presence of low glucose uptake areas, involving the MS in adults, and spread over regions including the hippocampal dentate gyrus in old mice. In the MS, the number of choline acetyltransferase (ChAT)-positive neurons decreased in old Tg601 mice. AChE activity and AChE mRNA T transcripts were exclusively higher in the septum. The upregulation of AChE in the septum may result in the selective degeneration of the septohippocampal cholinergic pathway in the tauopathy mouse model.


Sodium alginate hydrogel-based bioprinting using a novel multinozzle bioprinting system.
Bioprinting is a technology for constructing bioartificial tissue or organs of complex three-dimensional (3-D) structure with high-precision spatial shape forming ability in larger scale than conventional tissue engineering methods and simultaneous multiple components composition ability. It utilizes computer-controlled 3-D printer mechanism or solid free-form fabrication technologies. In this study, sodium alginate hydrogel that can be utilized for large-dimension tissue fabrication with its fast gelation property was studied regarding material-specific printing technique and printing parameters using a multinozzle bioprinting system developed by the authors. A sodium alginate solution was prepared with a concentration of 1% (wt/vol), and 1% CaCl(2) solution was used as cross-linker for the gelation. The two materials were loaded in each of two nozzles in the multinozzle bioprinting system that has a total of four nozzles of which the injection speed can be independently controlled. A 3-D alginate structure was fabricated through layer-by-layer printing. Each layer was formed through two phases of printing, the first phase with the sodium alginate solution and the second phase with the calcium chloride solution, in identical printing pattern and speed condition. The target patterns were lattice shaped with 2-mm spacing and two different line widths. The nozzle moving speed was 6.67 mm/s, and the injection head speed was 10 µm/s. For the two different line widths, two injection needles with inner diameters of 260 and 410 µm were used. The number of layers accumulated was five in this experiment. By varying the nozzle moving speed and the injection speed, various pattern widths could be achieved. The feasibility of sodium alginate hydrogel free-form formation by alternate printing of alginate solution and sodium chloride solution was confirmed in the developed multinozzle bioprinting system.


Hypertension and Dementia: A comprehensive review from the HOPE Asia Network.
Approximately 365 million people in Asia were classified as elderly in 2017. This number is rising and expected to reach approximately 520 million by 2030. The risk of hypertension and cognitive impairment/dementia increases with age. Recent data also show that the prevalence of hypertension and age-related dementia are rising in Asian countries. Moreover, not many people in Asian countries are aware of the relationship between hypertension and cognitive impairment/dementia. Furthermore, hypertension control is poorer in Asia than in developed countries. Hypertension is known to be a major risk factor for damage to target organs, including the brain. Decreased cognitive function can indicate the presence of target organ damage in the brain. Twenty-four-hour blood pressure profiles and blood pressure variability have been associated with cognitive impairment and/or silent cerebral diseases, such as silent cerebral infarction or white matter lesions, which are predisposing conditions for cognitive impairment and dementia. Hypertension that occurs in midlife also affects the incidence of cognitive impairments in later life. Managing and controlling blood pressure could preserve cognitive functions, such as by reducing the risk of vascular dementia and by reducing the global burden of stroke, which also affects cognitive function.


msgbsR: An R package for analysing methylation-sensitive restriction enzyme sequencing data.
Genotyping-by-sequencing (GBS) or restriction-site associated DNA marker sequencing (RAD-seq) is a practical and cost-effective method for analysing large genomes from high diversity species. This method of sequencing, coupled with methylation-sensitive enzymes (often referred to as methylation-sensitive restriction enzyme sequencing or MRE-seq), is an effective tool to study DNA methylation in parts of the genome that are inaccessible in other sequencing techniques or are not annotated in microarray technologies. Current software tools do not fulfil all methylation-sensitive restriction sequencing assays for determining differences in DNA methylation between samples. To fill this computational need, we present msgbsR, an R package that contains tools for the analysis of methylation-sensitive restriction enzyme sequencing experiments. msgbsR can be used to identify and quantify read counts at methylated sites directly from alignment files (BAM files) and enables verification of restriction enzyme cut sites with the correct recognition sequence of the individual enzyme. In addition, msgbsR assesses DNA methylation based on read coverage, similar to RNA sequencing experiments, rather than methylation proportion and is a useful tool in analysing differential methylation on large populations. The package is fully documented and available freely online as a Bioconductor package ( https://bioconductor.org/packages/release/bioc/html/msgbsR.html ).


CD1a promotes systemic manifestations of skin inflammation.
Inflammatory skin conditions are increasingly recognised as being associated with systemic inflammation. The mechanisms connecting the cutaneous and systemic disease are not well understood. CD1a is a virtually monomorphic major histocompatibility complex (MHC) class I-like molecule, highly expressed by skin and mucosal Langerhans cells, and presents lipid antigens to T-cells. Here we show an important role for CD1a in linking cutaneous and systemic inflammation in two experimental disease models. In human CD1a transgenic mice, the toll-like receptor (TLR)7 agonist imiquimod induces more pronounced splenomegaly, expansion of the peripheral blood and spleen T cell compartments, and enhanced neutrophil and eosinophil responses compared to the wild-type, accompanied by elevated skin and plasma cytokine levels, including IL-23, IL-1α, IL-1β, MCP-1 and IL-17A. Similar systemic escalation is shown in MC903-induced skin inflammation. The exacerbated inflammation could be counter-acted by CD1a-blocking antibodies, developed and screened in our laboratories. The beneficial effect is epitope dependent, and we further characterise the five best-performing antibodies for their capacity to modulate CD1a-expressing cells and ameliorate CD1a-dependent systemic inflammatory responses. In summary, we show that a therapeutically targetable CD1a-dependent pathway may play a role in the systemic spread of cutaneous inflammation.


Ultrasound guided electrocoagulation in patients with chronic non-insertional Achilles tendinopathy: a pilot study.
High resolution colour Doppler ultrasound shows intratendinous Doppler activity in patients with chronic Achilles tendinopathy. Treatment of this neovascularisation with sclerosing therapy seems to relieve the pain. However, the procedure often has to be repeated. To investigate the effect of electrocoagulation of the neovessels on tendon pain and tendon vascularity in patients with chronic Achilles tendinopathy. Colour Doppler ultrasound guided electrocoagulation was used on vessels in the ventral portion of the Achilles tendon in 11 patients (seven men, four women, mean age 41 years) with painful chronic mid-portion Achilles tendinosis. A unipolar coagulation device was used. One patient dropped out after two months (dissatisfied with the results). The remaining 10 patients (91%) were satisfied. These 10 patients were still satisfied at six months of follow up and had returned to their previous level of activity. All 10 patients were "cured" after one treatment. The patient who dropped out received two treatments because of lack of progress. There was significantly reduced pain (Likert pain scale, 0-10) during activity, from a median of 7 (range 4 to 10) at baseline to 0 (0 to 8) at six months' follow up (p<0.005); and at rest, from 1.5 (1 to 5) to 0 (0 to 8) (p = 0.005). In all patients, vascularisation was unchanged at the six months follow up, with no significant change in semiquantitative or quantitative colour scoring. Coagulation in the area with vessels entering the tendon appears to be effective treatment for painful chronic mid-tendinous Achilles tendinopathy. No effect on the intratendinous Doppler activity could be detected, suggesting that the effect is independent of changes in blood flow. Localisation of hyperaemia appears to be the key to the pathology and for targeting the treatment. One explanation could be that the effect is obtained by destruction of nerves accompanying the vessels.


Series: The research agenda for general practice/family medicine and primary health care in Europe. Part 2. Results: Primary care management and community orientation.
At the WONCA Europe conference 2009 the recently published 'Research Agenda for General Practice/Family Medicine and Primary Health Care in Europe' was presented. It is a background paper and reference manual, providing advocacy of general practice/family medicine (GP/FM) in Europe. The Research Agenda summarizes the evidence relating to the core competencies and characteristics of the WONCA Europe definition of GP/FM, and its implications for general practitioners/family doctors, researchers and policy makers. The European Journal of General Practice publishes a series of articles based on this document. In a first article, background, objectives, and methodology were discussed. In this second article, the results for the core competencies 'primary care management' and 'community orientation' are presented. Though there is a large body of research on various aspects of 'primary care management', it represents a very scattered rather than a meta view. Many studies focus on care for specific diseases, the primary/secondary care interface, or the implications of electronic patient records. Cost efficiency or process indicators of quality are current outcomes. Current literature on community orientation is mainly descriptive, and focuses on either care for specific diseases, or specific patient populations, or on the uptake of preventive services. Most papers correspond poorly to the WONCA concept. For both core competencies, there is a lack of research with a longitudinal perspective and/or relevant health or quality of life outcomes as well as research on patients' preferences and education for organizational aspects of GP/FM.


Synergism of Alkaline Extract of the Leaves of Sasa senanensis Rehder and Antiviral Agents.
Previous studies have shown a much greater antiviral activity of alkaline extract of the leaves of Sasa senanensis Rehder (SE) against human immunodeficiency virus (HIV), compared to lignin precursors, tannins and flavonoids, suggesting its possible application to oral diseases. Systematic comparative study with herpes simplex virus (HSV) has been limited compared to that with HIV. In the present study, we investigated whether combination of SE with other popular antiviral agents further enhances their individual activity. Cell viability of mock-infected, HIV-infected and HSV-infected cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The antiviral activity was evaluated by the selectivity index, defined as the ratio of 50% cytotoxic concentration to 50% effective concentration. Synergy between SE and antiviral agents was evaluated by MacSynerg and CompuSyn software. SE showed potent anti-HIV activity, although its activity was two-orders lower than that of azidothymidine, 2',3'-dideoxycytidine dextran sulfate and curdlan sulfate. Combination of SE with these antiviral agents produced synergistic effects. Using a newly established MTT assay system for anti-HSV activity, SE and acyclovir were found to have synergistic anti-HSV activity. The present study suggests the possible efficacy of the clinical application of SE combined with antiviral agents.


13C-urea breath test for Helicobacter pylori: cut-off point determination by cluster analysis.
1. This study was performed on a large set of 13C-urea breath test results to determine the optimal cut-off point of the test for the diagnosis of Helicobacter pylori (Hp) infection. 2. The following steps were applied to three sets of urea breath test results obtained in three groups of subjects (696 adults before anti-Hp treatment, 1056 adults after anti-Hp treatment and 173 children under 17 years of age): (1) demonstrate the distribution of urea breath test results as a mix of two normal populations (Hp negative and Hp positive) by logarithmic transformation of the results in each group of subjects; (2) apply statistical cluster analysis to determine the separation point between Hp-negative and -positive populations; (3) calculate the mean and SD of each population, and use these parameters in the equation of the normal distribution to establish the frequency curves of Hp-negative and -positive populations; and (4) determine the cut-off point of the urea breath test as the intersection of the two curves, and the risks of error related to it. 3. The optimal cut-off point was found at +3.00 delta/1000, with a risk of false-negative or -positive response of the urea breath test of less than 3%. From this, a cut-off point of +3.00 delta/1000 for the 13C-urea breath test is recommended, with an indetermined zone between +2.5 and +3.5 delta/1000 to account for the spontaneous variation of 13CO2 in breath and the limits of GC-isotope ratio-MS analytical precision.


The dynamics of the Hg + Br2 reaction: elucidation of the reaction mechanism for the Br exchange reaction.
In spite of its importance in the Hg atmospheric chemistry, the dynamics of the Hg + Br2 → HgBr + Br reaction is poorly understood. In this article, we have carried out a comprehensive study of the reaction mechanism of this reaction by means of quasiclassical trajectories (QCTs) on an existing ab initio potential energy surface (PES). The reaction has a non trivial dynamics, as a consequence of its large endothermicity, the presence of a deep potential well, and the competition between the Br exchange and the collision induced dissociation processes. Our calculations demonstrate that insertion is only relevant at energies just above the reaction threshold and that, at energies above 2.3 eV, HgBr formation typically takes place via a sort of frustrated dissociation. In order to compare directly with the results obtained in extensive cross molecular beam experiments for the homologous reaction with I2, angular distributions in the laboratory frame for Hg + Br2 have been simulated under similar experimental conditions. The lack of agreement at the highest energies considered suggests that either the two reactions have substantially different mechanisms or that calculations on a single PES cannot account for the dynamics at those energies.


Transmission of viral disease to the recipient through the donor liver.
Morbidity and mortality after liver transplantation continue to be significantly influenced by infectious complications. A particular concern is transmission of pathogens through the graft, which may cause significant disease in the recipient. For frequently transmitted herpes viruses with high seroprevalence such as cytomegalovirus, Epstein-Barr virus and human herpes viruses 6 and 7, significance, diagnosis, spectrum of disease in the recipient, prophylaxis and therapy are well established. Less is known about rare viruses such as West Nile virus, rabies virus, human choriomeningitis virus, human herpes virus 8 and human T-cell lymphoma 1, which are in many cases fatal. A plenitude of other viruses that potentially can be transmitted with a donor liver may exist, for which no detailed information is currently available. Grafts from anti-hepatitis B virus core antibody positive donors can be safely used when using lamivudine/hepatitis B immunoglobulin prophylaxis; hepatitis C virus positive organs should be given to hepatitis C virus positive individuals only. With the utilization of increasingly extended criteria donors, the risk for transmission of viruses with the graft may become a more common complication. These viruses will include rare and new pathogens and testing donors for these viruses may become necessary.


Oseltamivir-resistant influenza A (H1N1) virus strain with an H274Y mutation in neuraminidase persists without drug pressure in infected mallards.
Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate [OC]), stockpiled as Tamiflu for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may exert evolutionary pressure on avian IAV in waterfowl, resulting in the development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In this in vivo mallard (Anas platyrhynchos) study, we tested whether an OC-resistant avian IAV (H1N1) strain with an H274Y mutation in the neuraminidase (NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for the neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission among 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV that is induced by exposure of the natural host to OC can persist in the absence of the drug. Thus, there is a risk that human-pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir-resistant pandemic IAV would pose a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment, and surveillance for resistant IAVs in wild birds.


Novel interleukin-2 receptor subunit detected by cross-linking under high-affinity conditions.
Interleukin-2 (IL-2) binds to both high- and low-affinity classes of IL-2 receptors on activated T lymphocytes. Only the high-affinity receptors are involved in receptor-mediated endocytosis and normally transduce the mitogenic signals of IL-2; however, the structural features distinguishing the high- and low-affinity receptors are unknown. When 125I-labeled IL-2 was chemically cross-linked to activated human T lymphocytes, two major bands were identified. First, as predicted, a 68- to 72-kilodalton band, consisting of IL-2 (15.5 kilodaltons) cross-linked to the IL-2 receptor (55 kilodaltons), was observed. Second, an unpredicted 85- to 92-kilodalton moiety was detected. This band was not present when IL-2 was cross-linked to transfected C127 cells, which exclusively express low-affinity receptors. The data presented are most consistent with the existence of a 70- to 77-kilodalton glycoprotein subunit (p70) which, upon associating with the 55-kilodalton low-affinity receptor (p55), transforms it into a high-affinity site. It is proposed that p55 and p70 be referred to as the alpha and beta subunits, respectively, of the high-affinity IL-2 receptor.


Clustering of Domain-Specific Sedentary Behaviors and Their Association With Physical Function Among Community-Dwelling Older Adults.
The present study examined the cluster of domain-specific sedentary behaviors (SBs) and their associations with physical function among community-dwelling older adults to identify the target groups that require intervention for SBs. A total of 314 older adults who participated in a population-based cross-sectional survey and an on-site functional assessment in Matsudo City in Chiba participated in this study. Participants were asked to report the daily average of 6 domain-specific SBs. To identify the cluster of domain-specific SBs, hierarchical cluster analysis was performed using the Ward method. Analysis of covariance adjusted for sociodemographic factors, exercise habit, chronic disease, and total SB time was performed to examine the associations between each cluster and physical functional status. The average age of the participants was 74.5 (5.2) years. The 4 clusters identified were leisure cluster, low cluster, work and personal computer use cluster, and television viewing cluster. The analysis of covariance adjusted for covariates showed that grip strength (P = .01), maximum walking speed (P = .03), and 1-leg standing time (P = .03) were significantly poorer in the television viewing cluster than other clusters. It has been concluded that the television viewing group identified as a high-risk group of physical functional decline; therefore, interventions targeting this group are needed to prevent physical functional decline.


Lipopolysaccharide and tumor necrosis factor-alpha induce lipopolysaccharide receptor expression on bone marrow cells by different mechanisms.
Two cell types, monocytes/macrophages and neutrophilic granulocytes, play a prominent role in the pathogenic effects of endotoxins during Gram-negative infections. We previously established that nanomolar concentrations of LPS induce the expression of new specific LPS-binding sites (LpsR) in bone marrow granulocytes of LPS-responsive mice. To examine this induction process further, we asked whether it, like other LPS activities, can be mediated by TNF-alpha. We report that exogenous rTNF-alpha can induce LpsR expression in bone marrow cells (BMC) from both LPS-responsive (C3H/HeOU) and LPS-hyporesponsive (C3H/HeJ) mice. In BMC, LPS elicited a down-regulation of the TNF-alpha receptors (TNF-R) without direct binding to TNF-R. On the other hand, taxol, a microtubule stabilizer that has shown LPS mimetic activity in macrophages, was unable to elicit LpsR expression or induce TNF-R down-regulation in BMC. Thus, unlike the LPS-signaling receptor of macrophages, that of BMC is apparently not functionally associated with microtubules. The LPS-induced expression of LpsR was inhibited only partially with an anti-TNF-alpha serum, and with dexamethasone, suggesting that an autocrine activity of endogenous TNF-alpha cannot alone account for the LPS effect. Comparative analyses also indicated that dexamethasone inhibited the LPS-induced increase of LpsR, but enhanced the number of TNF-induced LpsR+ BMC. Furthermore, the synthetic lipid PPDm2 (a 1,4-bisphosphorylated and N,N-diacylated derivative of 2,3-diamino-2,3-dideoxy-D-glucose) inhibited LPS-induced, but not TNF-induced, expression of LpsR. These data show that in BMC, LPS and TNF-alpha induce LpsR expression by different mechanisms.


Fibre types in human lumbar back muscles.
The distribution of histochemically identified muscle fibre types was studied in biopsy samples from the two main muscles in the lumbar region of the human erector spinae, the multifidus and the longissimus, in 16 healthy subjects (nine males and seven females, age 20-30 years). Muscle fibres were classified as types I, IIA, IIB or IIC on the basis of the pH lability of their myofibrillar ATPases. There were no differences between the multifidus and the longissimus muscles in the relative occurrence of type I (62 vs. 57%), type IIA (20 vs. 22%) or type IIB fibres (18 vs. 22%), or in the absolute size of fibres (range of mean least diameters 58-66 micron). The oxidative potential (NADH-diaphorase staining intensity) was high in type I and low in type II fibres, irrespective of subgroups, in both muscles. In the females, the type I fibres occupied a relatively larger area (70-75 vs. 54-58% for the males) although the relative number of type I fibres was the same in both sexes. This was due to smaller type II fibres in the females resulting in higher type I/type II area ratios (1.70-1.90 vs. 0.88-0.92 for males). This suggests a difference in functional capacity of lumbar back muscles between males and females. On the other hand, the similarity in histochemical fibre-type distribution between the multifidus and the longissimus muscles does not give support for a functional differentiation between these two anatomically different parts of the lumbar erector spinae in man.


Determining stakeholder priorities and core components for school-based identification of mental health difficulties: A Delphi study.
Only approximately half of children and young people (CYP) with mental health difficulties access mental health services in England, with under-identification of need as a contributing factor. Schools may be an ideal setting for identifying mental health difficulties in CYP, but uncertainty remains about the processes by which these needs can best be identified and addressed. In this study, we conducted a two-round, three-panel Delphi study with parents, school staff, mental health practitioners, and researchers to inform the development of a program to identify mental health difficulties in primary schools. We aimed to assess and build consensus regarding (a) the aims of such a program, (b) identification model preferences, (c) key features of the identification model, and (d) key features of the implementation model. A total of 54 and 42 participants completed the Round 1 and 2 questionnaires, respectively. In general, responses indicated that all three panels supported the idea of school-based identification of mental health difficulties. Overall, 53 of a possible 99 items met the criteria for inclusion as program core components. Five main priorities emerged, including that (a) the program should identify children experiencing mental health difficulties across the continuum of severity, as well as children exposed to adversity, who are at greater risk of mental health difficulties; (b) the program should train staff and educate pupils about mental health in parallel; (c) parental consent should be obtained on an opt-out basis; (d) the program must include clear mechanisms for connecting identified pupils to care and support; and (e) to maximize implementation success, the program needs to lie within a school culture that values mental health and wellbeing. In highlighting these priorities, our study provides needed stakeholder consensus to guide further development and evaluation of mental health interventions within schools.


Afterpains: a comparison between active and expectant management of the third stage of labor.
Management of the third stage of labor, the period following the birth of the infant until delivery of the placenta, is crucial. Active management using synthetic oxytocin has been advocated to decrease blood loss. It has been suggested, but not studied, that oxytocin may increase afterpains. The aim of this study was to compare women's experience of pain intensity when the third stage of labor was managed actively and expectantly and their experience of afterpains. A single-blind, randomized, controlled trial was performed at two delivery units in Sweden in a population of healthy women with normal, singleton pregnancies, gestational age of 34 to 43 weeks, cephalic presentation, and expected vaginal delivery. Women (n=1,802) were randomly allocated to either active management or expectant management of the third stage of labor. Afterpains were assessed by Visual Analog Scale (VAS) and the Pain-o-Meter (POM-WDS) 2 hours after delivery of the placenta and the day after childbirth. At 2 hours after childbirth, women in the actively managed group had lower VAS pain scores than expectantly managed women (p=0.014). Afterpains were scored as more intense the day after, compared with 2 hours after, childbirth in both groups. Multiparas scored more intense afterpains, compared with primiparas, irrespective of management (p<0.001). Active management of the third stage of labor does not provoke more intense afterpains than expectant management.


Avoiding Crowded Places During COVID-19: Common Sense or a Complex Strategic Decision?
Introduction: Following a period of strict lockdowns during the COVID-19 pandemic, most countries introduced policies in which citizens were expected to avoid crowded places using common sense, as advised by the WHO. We argue that the ambiguity in the recommendation to "avoid crowded places" implicitly forces individuals to make a complex strategic decision. Methods: Using a Dutch representative sample of 1,048 participants [42% male, mean age=43.78years (SD=12.53), we examine the effect of context on the decision to visit a hypothetical recreational hotspot under the policy recommendation to "avoid crowded places." We randomize four levels of context on the crowdedness "on the streets" (no context, low, medium, and high context). Subsequently, participants are asked to estimate the percentage of others going out in the same situation. Finally, we assess the impact of a selection of personal characteristics on the likelihood of visiting a crowded place. Results: Respondents are proportionally more likely to go in a low context and high context, compared to no context (diff=0.121, p<0.000, and diff=0.034, p<0.05, respectively) and middle context (diff=0.125, p<0.000, and diff=0.037, p<0.05, respectively). Low context information also decreases the expectation of others going out (-2.63%, z=4.68, p<0.000). High context information increases the expected percentage of others going out (significant only for medium to high context; 2.94%, z=7.34, p<0.001). Furthermore, we show that education, age, and health and risk attitude are all predictive of the likelihood to visit a crowded place, notwithstanding the context. Discussion: Although there is a strong inclination to avoid crowded places during the COVID-19 pandemic (81%), we find two context-driven exceptions: when people expect to avoid crowded spots (in the "low" context, i.e., strategical decision-making) and when people expect others to go (social influence). The freedom provided by ambiguous public policy is implicitly asking more from the population than it initially seems. "Use your common sense" is often the accompanied advice, but our results show that more and better information concerning the context is essential to enable us to make an optimal decision for ourselves, and for society.


Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation-positive families?
Women who carry BRCA mutations are advised to begin breast cancer screening based on the age-specific risks of breast cancer development. It is not clear to what extent the family history of breast cancer influences age of onset. We evaluated the use of family history to predict the age of breast cancer onset in BRCA mutation carriers. Pedigrees from an Ontario-based registry were reviewed to identify the index case of breast cancer (most recent diagnosis) and other family cases of breast cancer. The youngest age of breast cancer diagnosis and mean age at breast cancer diagnosis in the other family cases were compared to the age of onset in the index case. The 260 BRCA1 and 213 BRCA2 pedigrees were reviewed. In BRCA2 families, the index case was diagnosed on average at 44.4 years when the youngest reported family case was less than or equal to 35 years, compared to 51.9 years when the earliest cases were diagnosed after age 50 (p = 0.04). A modest trend was seen for BRCA1 carriers, but this was not statistically significant. To a small extent, the onset of breast cancer in a BRCA2 mutation carrier can be predicted from her family history of cancer, however, the trend is modest and should not alter clinical recommendations regarding initiation of screening.


The Impact of Anti-Retroviral Therapy on Tuberculosis Detection at the National Level in South Africa.
Human immunodeficiency virus/tuberculosis (HIV/TB) coinfection is particularly prevalent in South Africa, where TB has been the leading cause of death for more than a decade. The 2004-2008 national rollout of antiretroviral therapy (ART) provides a unique opportunity to examine the population-level impact of ART on the TB epidemic. We performed longitudinal regression analysis to follow the evolution of TB outcomes before and after the introduction of ART using a large data set from the National Health Laboratory Service. This is the first study to produce estimates of the impact of the ART rollout by exploiting staggered timing and geographic variation in the rollout. After ART became available in a health facility, 3.7% (P < 0.0001) more patients were tested for TB and 3.2% (P < 0.0001) more received repeat testing; however, there was a steep rise in testing before the introduction of ART. Although the number of TB-positive patients increased by 4.3% (P = 0.0002) in the first year post-ART, the TB rate among tested patients fell by 2 percentage points (8%, P = 0.001) after 2 years. Sputum smear testing declined relative to more technologically advanced diagnostics post-ART. Antiretroviral therapy availability increased the attention to TB screening and drew new patients into the health-care system. Small increases in the numbers of repeat patients are indicative of retention in care. The decline in TB rates post-ART suggests that the reduction in TB risk due to improved immune functioning and health-care contact likely outweighed the increased TB risk because of the longer lifespan of ART initiators.


Olanzapine exposure diminishes perfusion and decreases volume of sensorimotor cortex in rats.
Olanzapine is a frequently used atypical antipsychotic drug known to exert structural brain alterations in animals. This study investigated whether chronic olanzapine exposure alters regional blood brain perfusion assessed by Arterial Spin Labelling (ASL) magnetic resonance imaging (MRI) in a validated model of olanzapine-induced metabolic disturbances. An effect of acute olanzapine exposure on brain perfusion was also assessed for comparison. Adult Sprague-Dawley female rats were treated by intramuscular depot olanzapine injections (100 mg/kg every 14 days) or vehicle for 8 weeks. ASL scanning was performed on a 9.4 T Bruker BioSpec 94/30USR scanner under isoflurane anesthesia. Serum samples were used to assay leptin and TNF-α level while brains were sliced for histology. Another group received only one non-depot intraperitoneal dose of olanzapine (7 mg/kg) during MRI scanning, thus exposing its acute effect on brain perfusion. Both acute and chronic dosing of olanzapine resulted in decreased perfusion in the sensorimotor cortex, while no effect was observed in the piriform cortex or hippocampus. Furthermore, in the chronically treated group decreased cortex volume was observed. Chronic olanzapine dosing led to increased body weight, adipose tissue mass and leptin level, confirming its expected metabolic effects. This study demonstrates region-specific decreases in blood perfusion associated with olanzapine exposure present already after the first dose. These findings extend our understanding of olanzapine-induced functional and structural brain changes.


Observation of the dynamical Casimir effect in a superconducting circuit.
One of the most surprising predictions of modern quantum theory is that the vacuum of space is not empty. In fact, quantum theory predicts that it teems with virtual particles flitting in and out of existence. Although initially a curiosity, it was quickly realized that these vacuum fluctuations had measurable consequences--for instance, producing the Lamb shift of atomic spectra and modifying the magnetic moment of the electron. This type of renormalization due to vacuum fluctuations is now central to our understanding of nature. However, these effects provide indirect evidence for the existence of vacuum fluctuations. From early on, it was discussed whether it might be possible to more directly observe the virtual particles that compose the quantum vacuum. Forty years ago, it was suggested that a mirror undergoing relativistic motion could convert virtual photons into directly observable real photons. The phenomenon, later termed the dynamical Casimir effect, has not been demonstrated previously. Here we observe the dynamical Casimir effect in a superconducting circuit consisting of a coplanar transmission line with a tunable electrical length. The rate of change of the electrical length can be made very fast (a substantial fraction of the speed of light) by modulating the inductance of a superconducting quantum interference device at high frequencies (>10 gigahertz). In addition to observing the creation of real photons, we detect two-mode squeezing in the emitted radiation, which is a signature of the quantum character of the generation process.


Impact of the nature and size of the polymeric backbone on the ability of heterobifunctional ligands to mediate shiga toxin and serum amyloid p component ternary complex formation.
Inhibition of AB(5)-type bacterial toxins can be achieved by heterobifunctional ligands (BAITs) that mediate assembly of supramolecular complexes involving the toxin's pentameric cell membrane-binding subunit and an endogenous protein, serum amyloid P component, of the innate immune system. Effective in vivo protection from Shiga toxin Type 1 (Stx1) is achieved by polymer-bound, heterobifunctional inhibitors-adaptors (PolyBAITs), which exhibit prolonged half-life in circulation and by mediating formation of face-to-face SAP-AB(5) complexes, block receptor recognition sites and redirect toxins to the spleen and liver for degradation. Direct correlation between solid-phase activity and protective dose of PolyBAITs both in the cytotoxicity assay and in vivo indicate that the mechanism of protection from intoxication is inhibition of toxin binding to the host cell membrane. The polymeric scaffold influences the activity not only by clustering active binding fragments but also by sterically interfering with the supramolecular complex assembly. Thus, inhibitors based on N-(2-hydroxypropyl) methacrylamide (HPMA) show significantly lower activity than polyacrylamide-based analogs. The detrimental steric effect can partially be alleviated by extending the length of the spacer, which separates pendant ligand from the backbone, as well as extending the spacer, which spans the distance between binding moieties within each heterobifunctional ligand. Herein we report that polymer size and payload of the active ligand had moderate effects on the inhibitor's activity.


The Cost-Effectiveness of Prostate Cancer Detection with the Use of Prostate Health Index.
Clinical trial results suggested that prostate-specific antigen (PSA) screening can reduce prostate cancer mortality. Nevertheless, because the specificity of the PSA test for cancer detection is low, it leads to many negative biopsies. The Beckman Coulter Prostate Health Index (PHI) testing demonstrates improved specificity compared with the PSA-only screening and therefore may improve the cost-effectiveness of prostate cancer detection. To examine the cost-effectiveness of adding PHI testing to improve cancer detection for men with elevated serum PSA. A microsimulation model, based on the results of the European Randomized Study of Screening for Prostate Cancer trial, was used to evaluate the effects of PSA screening and PHI reflex testing. We predicted the numbers of prostate cancers, negative biopsies, deaths, quality-adjusted life-years gained, and cost-effectiveness of both PSA (cutoff 3 ng/mL) and PHI (cutoff 25) testing methods for a European population, screened from age 50 to 75 years at 4-year intervals. When the PHI test was added to the PSA screening, for men with a PSA between 3 and 10 ng/mL, the model predicted a 23% reduction in negative biopsies. This would lead to a 17% reduction in costs for diagnostics and 1% reduction in total costs for prostate cancer. The cost-effectiveness (3.5% discounted) was 11% better. Limitations found were the modeling assumptions on the sensitivity and specificity of PHI by tumor stage and cutoff values. Compared with PSA-only screening, the use of a PHI test can substantially reduce the number of negative biopsies and improve the cost-effectiveness of prostate cancer detection.


Materials: tribology experiment in zero gravity.
A tribology experiment in zero gravity was performed during the orbital flight of Spacelab 1 to study the motion of liquid lubricants over solid surfaces. The absence of a significant gravitational force facilitates studies of the motion of liquid lubricants over solid surfaces as controlled by interfacial and capillary forces. Observations were made of phenomena associated with the liquid on one solid surface and also with the liquid between a pair of closely spaced surfaces. Typical photographic records obtained on Spacelab 1 are described.


Molecular-Atomic Transition along the Deuterium Hugoniot Curve with Coupled Electron-Ion Monte Carlo Simulations.
We have performed simulations of the principal deuterium Hugoniot curve using coupled electron-ion Monte Carlo calculations. Using highly accurate quantum Monte Carlo methods for the electrons, we study the region of maximum compression along the Hugoniot, where the system undergoes a continuous transition from a molecular fluid to a monatomic fluid. We include all relevant physical corrections so that a direct comparison to experiment can be made. Around 50 GPa we find a maximum compression of 4.85. This compression is approximately 5.5% higher than previous theoretical predictions and 15% higher than the most accurate experimental data. Thus first-principles simulations encompassing the most advanced techniques are in disagreement with the results of the best experiments.


In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance.
The advent of hyperpolarized (13)C magnetic resonance (MR) has provided new potential for the real-time visualization of in vivo metabolic processes. The aim of this work was to use hyperpolarized [1-(13)C]pyruvate as a metabolic tracer to assess noninvasively the flux through the mitochondrial enzyme complex pyruvate dehydrogenase (PDH) in the rat heart, by measuring the production of bicarbonate (H(13)CO(3)(-)), a byproduct of the PDH-catalyzed conversion of [1-(13)C]pyruvate to acetyl-CoA. By noninvasively observing a 74% decrease in H(13)CO(3)(-) production in fasted rats compared with fed controls, we have demonstrated that hyperpolarized (13)C MR is sensitive to physiological perturbations in PDH flux. Further, we evaluated the ability of the hyperpolarized (13)C MR technique to monitor disease progression by examining PDH flux before and 5 days after streptozotocin induction of type 1 diabetes. We detected decreased H(13)CO(3)(-) production with the onset of diabetes that correlated with disease severity. These observations were supported by in vitro investigations of PDH activity as reported in the literature and provided evidence that flux through the PDH enzyme complex can be monitored noninvasively, in vivo, by using hyperpolarized (13)C MR.


Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE study.
While there have been advances in prophylaxis and management of venous thromboembolism (VTE), there are a dearth of data from the perspective of a community-wide study, on the epidemiology, management, and outcomes of patients with a first episode of deep vein thrombosis (DVT) or pulmonary embolism (PE). The purpose of this population-based observational study was to describe trends in the incidence rates, clinical profile, management, and outcomes for patients with VTE. The medical records of Worcester (MA) metropolitan area residents with ICD-9 codes consistent with possible VTE during 1999, 2001, and 2003 were independently validated and reviewed by trained abstractors. A total of 1,567 persons with first-time VTE were identified. Incidence rates (per 100,000) of VTE were stable between 1999 (109) and 2003 (117). A considerable proportion of patients treated for VTE had events of unclear clinical significance (e.g., isolated calf DVT, unconfirmed "possible" PE). By 2003, low-molecular-weight heparin was increasingly utilized as acute therapy and more than 25% of patients with VTE were managed as outpatients. Cumulative rates of recurrent VTE and major bleeding following initial VTE were high (approximately 16% and 12%, respectively, mean follow-up 1,216 days) and did not change significantly between 1999 and 2003. Our data suggest that while the incidence rates of VTE remain high, and outcomes suboptimal, there have been marked changes in its management. Whether these changes will result in future declines in VTE incidence and/or improved outcomes in the community setting will require further surveillance.


Cell surface sialic acid influences tumor cell recognition in the mixed lymphocyte reaction.
The Ia+ B cell lymphoma, AKTB-1b, fails to stimulate thymic lymphocytes in a one-way mixed lymphocyte reaction unless pretreated with sialidase or inhibitors of N-linked oligosaccharide processing. A comparison of different sialidases and sialyltransferases suggests that the removal of only a subset of total surface sialic acid, rather than net desialylation of the cell surface, is required. Three sialidases were compared, including Vibrio cholerae (VC) and Clostridium perfringens (CP), which will cleave alpha 2-3, alpha 2-6, and alpha 2-8, sialic acid linkages, and Newcastle Disease virus (NDV), which will remove only alpha 2-3 and alpha 2-8 linked sialic acid. When treated with equivalent units of sialidase, CP-, VC-, and NDV-treated cells were 24-fold, sixfold, and threefold better stimulators than untreated cells. In contrast, VC released 1.3-fold and 2.5-fold more sialic acid per cell than did CP or NDV, respectively. Furthermore, VC was superior in reducing the levels of binding of the sialic acid-specific lectin, Limulus polyphemus agglutinin, in exposing Gal beta 1-3GalNAc and Gal beta 1-4GlcNAc residues, and in desialylating gangliosides. Two-dimensional gel analysis indicated that VC and CP were both equal and superior to NDV in the desialylation of iodinatable cell-surface proteins, including H-2Kk, I-A beta k, and a highly sialylated 65,000 dalton protein of unknown identity. Maximal resialylation of CP-treated cells with exogenously added CMP-NANA and either the alpha 2-3(Gal beta 1-3GalNAc) or alpha 2-6(Gal beta 1-4GlcNAc) sialyltransferase did not reduce the stimulatory capacity of these cells. However, resialylation of VC-treated cells with just CMP-NANA alone resulted in 49% reversal of their stimulatory capacity, and no additional reversal could be achieved with either of the sialyltransferases. Although the alpha 2-6(Gal beta 1-4GlcNAc) sialyltransferase was capable of adding back approximately 10% of the sialic acid removed, the endogenous activity added back approximately 0.1% of the total sialic acid removed. SDS-PAGE gels of the sialylated cells indicated that the exogenously added sialyltransferase labeled many different proteins, whereas the endogenous activity labeled far fewer proteins, predominantly in 46,000 and 25,000 m.w. range. Both the desialylation and resialylation data suggest that the sialidase-dependent stimulation is due to the desialylation of specific membrane structures. Together with previous studies, these data suggest that the sialic acids involved are probably alpha 2-6 linked to N-linked glycosyl moieties.


Melanocortinergic activation by melanotan II inhibits feeding and increases uncoupling protein 1 messenger ribonucleic acid in the developing rat.
The hypothalamic neurocircuitry that regulates energy homeostasis in adult rats is not fully developed until the third postnatal week. In particular, fibers from the hypothalamic arcuate nucleus, including both neuropeptide Y (NPY) and alpha-MSH fibers, do not begin to innervate downstream hypothalamic targets until the second postnatal week. However, alpha-MSH fibers from the brainstem and melanocortin receptors are present in the hypothalamus at birth. The present study investigated the melanocortin system in the early postnatal period by examining effects of the melanocortin receptor agonist melanotan II (MTII) on body weight, energy expenditure, and hypothalamic NPY expression. Rat pups were injected ip with MTII (3 mg/kg body weight) or saline on postnatal day (P) 5 to P6, P10-P11, or P15-P16 at 1700 and 0900 h and then killed at 1300 h. Stomach weight and brown adipose tissue uncoupling protein 1 mRNA were determined. In addition, we assessed central c-Fos activation 90 min after MTII administration and hypothalamic NPY mRNA after twice daily MTII administration from P5-P10 or P10-P15. MTII induced hypothalamic c-Fos activation as well as attenuating body weight gain in rat pups. Stomach weight was significantly decreased and uncoupling protein 1 mRNA was increased at all ages, indicating decreased food intake and increased energy expenditure, respectively. However, MTII had no effect on NPY mRNA levels in any hypothalamic region. These findings demonstrate that MTII can inhibit food intake and stimulate energy expenditure before the full development of hypothalamic feeding neurocircuitry. These effects do not appear to be mediated by changes in NPY expression.


The Medicare Prescription Drug Improvement and Modernization Act: prescription drugs and academic medicine.
The Medicare Prescription Drug, Improvement, and Modernization Act (MMA) provides universally available prescription drug benefits to elderly and disabled Medicare beneficiaries for the first time. This paper first discusses three controversial features of this legislation: (1) the form of the prescription drug benefit package; (2) the use of competing private plans; and (3) the uncertainty about the future cost of the new prescription drug benefit. The paper then evaluates the implications for academic medicine of the prescription drug benefit and other MMA legislative provisions aimed at improving the quality of medical practice and shifting away from acute care. Ultimately, the health of seniors and the efficient use of public funds in the new prescription drug benefit depend centrally on the prescribing practices of physicians. Academic medicine should turn its attention to training the next generation of physicians to be more effective agents and advocates for their patients in their use of pharmaceuticals.


The Men Who Have Sex with Men HIV Care Cascade in Rio de Janeiro, Brazil.
Brazil has a concentrated HIV epidemic and men who have sex with men (MSM) are disproportionately affected. Yet, no data is available on the HIV care cascade for this population. This study aimed to assess the HIV care cascade among MSM newly diagnosed through innovative testing strategies in Rio de Janeiro. Data from 793 MSM and travestites/transgender women (transwomen) tested for HIV at a non-governmental LGBT organization and a mobile testing unit located at a gay friendly venue were analyzed. A 12-month-after-HIV-diagnosis-censored cohort was established using CD4, viral load and combination antiretroviral therapy (cART) longitudinal data from those diagnosed with HIV. A cross-sectional HIV care cascade was built using this data. The relative risks of achieving each cascade-stage were estimated using generalized linear models according to age, self-declared skin-color, education, history of sexually transmitted diseases (STD), drug use and prior HIV testing. From Jan-2013 to Jan-2014, 793 MSM and transwomen were tested, 131 (16.5%) were HIV-infected. As of January 2015, 95 (72.5%) were linked to HIV care, 90 (68.7%) were retained in HIV care, 80 (61.1%) were on cART, and 50 (38.2%) were virally suppressed one year after HIV diagnosis. Being non-white (Relative risk [lower bound; upper bound of 95% confidence interval] = 1.709 [1.145; 2.549]) and having a prior HIV-test (1.954 [1.278; 2.986]) were associated with an HIV-positive diagnosis. A higher linkage (2.603 [1.091; 6.211]) and retention in care (4.510 [1.880; 10.822]) were observed among those who were older than 30 years of age. Using community-based testing strategies, we were able to access a high-risk MSM population and a small sample of transwomen. Despite universal care coverage and the test-and-treat policy adopted in Brazil, the MSM cascade of care indicates that strategies to increase linkage to care and prompt cART initiation targeted to these populations are critically needed. Interventions targeting non-white and young MSM should be prioritized.


Annexin A1-containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair.
Epithelial restitution is an essential process that is required to repair barrier function at mucosal surfaces following injury. Prolonged breaches in epithelial barrier function result in inflammation and further damage; therefore, a better understanding of the epithelial restitution process has potential for improving the development of therapeutics. In this work, we demonstrate that endogenous annexin A1 (ANXA1) is released as a component of extracellular vesicles (EVs) derived from intestinal epithelial cells, and these ANXA1-containing EVs activate wound repair circuits. Compared with healthy controls, patients with active inflammatory bowel disease had elevated levels of secreted ANXA1-containing EVs in sera, indicating that ANXA1-containing EVs are systemically distributed in response to the inflammatory process and could potentially serve as a biomarker of intestinal mucosal inflammation. Local intestinal delivery of an exogenous ANXA1 mimetic peptide (Ac2-26) encapsulated within targeted polymeric nanoparticles (Ac2-26 Col IV NPs) accelerated healing of murine colonic wounds after biopsy-induced injury. Moreover, one-time systemic administration of Ac2-26 Col IV NPs accelerated recovery following experimentally induced colitis. Together, our results suggest that local delivery of proresolving peptides encapsulated within nanoparticles may represent a potential therapeutic strategy for clinical situations characterized by chronic mucosal injury, such as is seen in patients with IBD.


Image reconstruction of optical computed tomography by using the algebraic reconstruction technique for dose readouts of polymer gel dosimeters.
Optical computed tomography (optical CT) has been proven to be a useful tool for dose readouts of polymer gel dosimeters. In this study, the algebraic reconstruction technique (ART) for image reconstruction of gel dosimeters was used to improve the image quality of optical CT. Cylindrical phantoms filled with N-isopropyl-acrylamide polymer gels were irradiated using a medical linear accelerator. A circular dose distribution and a hexagonal dose distribution were produced by applying the VMAT technique and the six-field dose delivery, respectively. The phantoms were scanned using optical CT, and the images were reconstructed using the filtered back-projection (FBP) algorithm and the ART. For the circular dose distribution, the ART successfully reduced the ring artifacts and noise in the reconstructed image. For the hexagonal dose distribution, the ART reduced the hot spots at the entrances of the beams and increased the dose uniformity in the central region. Within 50% isodose line, the gamma pass rates for the 2 mm/3% criteria for the ART and FBP were 99.2% and 88.1%, respectively. The ART could be used for the reconstruction of optical CT images to improve image quality and provide accurate dose conversion for polymer gel dosimeters.


NMR spectroscopic investigation of mobility and hydrogen bonding of the chromophore in the binding pocket of phytochrome proteins.
For a complete understanding of the light reception of phytochrome proteins, a detailed study of the structure and dynamics of the binding pocket at atomic resolution is required. Structures from X-ray crystallography and NMR spectroscopy are available and have been able to provide a picture of the binding pocket. NMR spectroscopy has, in addition, shown that the chromophore exhibits noticeable dynamics in the binding pocket of the cyanobacterial phytochrome Cph1. Herein, NMR spectroscopy is used to investigate further the mobility of the chromophore by analyzing the line widths of the resonances of the chromophore in various environments, in particular other protein environments. It is shown that the chromophore exhibits a different mobility in the binding pocket of the bacterial phytochrome Agp1 than in that of the cyanobacterial phytochrome Cph1. Finally, it is shown that NMR spectroscopy is capable of detecting hydrogen bonds in the binding pocket of phytochromes by observing slow exchange of protons in the amino acid side chains.


Endogenous expression levels of autoantigens influence success or failure of DNA immunizations to prevent type 1 diabetes: addition of IL-4 increases safety.
Administration of autoantigens through DNA immunizations or via the oral route can prevent progression of islet destruction and lower the incidence of type 1 diabetes in animal models. This beneficial effect is mediated by autoreactive regulatory CD4 lymphocytes, and it is known that their induction depends on the precise dose and route of antigen administration. However, it is not clear which endogenous factors determine when such immunizations lead to activation of regulatory versus aggressive autoreactive lymphocytes and how a deleterious outcome can be avoided. Here we describe novel observations made in an animal model for virally induced type 1 diabetes, showing that the endogenous expression levels of the islet antigens and glutamic acid decarboxylase determine whether immunization with these antigens is beneficial or detrimental. Lower expression levels in beta-cells support immune regulation resulting in induction of autoreactive, regulatory cells characterized by increased IL-4 production (Th2-like), whereas higher levels favor Th1-like autoaggressive responses characterized by augmented IFN-gamma generation. Co-immunization with an IL-4-expressing plasmid reduces the risk of augmenting autoaggression and in this way increases the safety margin of this immune-based therapy. Our findings will be of importance for designing safe antigen-specific interventions for human type 1 diabetes.


Vitamin B12 deficiency presenting as acute ataxia.
A previously healthy 7-year-old Caucasian boy was hospitalised for evaluation of acute ataxia and failure to thrive, initially suspicious for an intracranial mass. Weight and body mass index were below the third percentile and he demonstrated loss of joint position and vibratory sense on examination. Laboratory studies revealed megaloblastic anaemia while an initial MRI of the brain showed no evidence of mass lesions or other abnormalities. A dietary history revealed the child subscribed to a restrictive vegan diet with little to no intake of animal products or other fortified foods. The child was diagnosed with presumed vitamin B12 deficiency and was treated with intramuscular B12 injections. Neurological symptoms resolved promptly within several days after starting therapy. This case underlines the importance of assessing nutritional status in the evaluation of neurological dysfunction in the pediatric patient.


Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues.
X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.


Laser ranging error budget for the TOPEX/POSEIDON satellite.
A laser ranging error budget is detailed, and a specific error budget is derived for the TOPEX/POSEIDON satellite. A ranging uncertainty of 0.76 cm is predicted for TOPEX/POSEIDON at 20 degrees elevation using the presently designed laser retroreflector array and only modest improvements in present system operations. Atmospheric refraction and satellite attitude effects cause the predicted range error to vary with satellite elevation angle from 0.71 cm at zenith to 0.76 cm at 20 degrees elevation. This a priori error budget compares well with the ~1.2-cm rms a posteriori polynomial orbital fit using existing data taken for an extant satellite of similar size and orbit.


Resistance to quaternary ammonium compounds in food-related bacteria.
Microbial resistance to antimicrobial agents continues to be a major problem. The frequent use and misuse of disinfectants based on quaternary ammonium compounds (QACs) in food-processing industries have imposed a selective pressure and may contribute to the emergence of disinfectant-resistant microorganisms. A total number of 1,325 Gram-negative isolates (Escherichia coli, other coliforms Vibrio spp., and Aeromonas spp.) and 500 Enterococcus spp. from food and food-processing industries and fish farming were screened for natural resistance to the QAC-based disinfectant benzalkonium chloride (BC). Of the 1,825 isolates, 16 strains, mainly from meat retail shops, showed low-level resistance to BC. None of the Enterococcus spp. from broiler, cattle, and pigs, the antibiotic-resistant E. coli from pig intestine and fish pathogens Vibrio spp. and Aeromonas spp. from the Norwegian fish farming industry were resistant to BC. The BC-resistant strains were examined for susceptibility to 15 different antibiotics, disinfectants, and dyes. No systematic cross-resistance between BC and any of the other antimicrobial agents tested was detected. Stable enhanced resistance in Enterobacter cloacae isolates was demonstrated by step-wise adaptation in increasing concentrations of BC. In conclusion, BC resistance among food-associated Gram-negative bacteria and Enterococcus spp. is not frequent, but resistance may develop to user concentrations after exposure to sublethal concentrations of BC.