An investigation of lipogenic and glycolytic enzyme activity in the liver of sexually immature and mature domestic fowl.
In the non-laying pullet and the cockerel it was observed that there was no significant variation in the activities of ATP citrate lyase and ;malic' enzyme whereas in the laying hen there was a significantly greater activity of both these enzymes. Parallel increases in liver lipid content in the laying hen were also observed. Three glycolytic enzymes, phosphofructokinase, fructose diphosphate aldolase and pyruvate kinase, did not exhibit any significant variation in enzyme activity with the onset of egg laying. These results are discussed in relation to the hormonal status of the birds and also the demands of egg production for lipid.


Genetic relationships of the dengue virus serotypes.
Previous studies have compared RNA genomes from the different dengue virus serotypes by cDNA-RNA hybridization using dengue-1 virus- and dengue-2 virus-specific cDNA probes. These probes revealed that there is a close genetic relationship between dengue virus serotypes 1 and 4. In this communication, the cDNA-RNA hybridization results using dengue-3- and dengue-4-specific cDNA probes to determine the genetic relatedness of all four dengue virus serotypes are reported. The results indicate that serotypes 1 and 4 are genetically very closely related (sharing about 70% of their genomes as detected by both the dengue-1 and dengue-4 cDNA probes), as are serotypes 3 and 4 (sharing about 50% of their genomes as detected by both the dengue-3 and dengue-4 cDNA probes). Serotype 2 does not seem to be very closely related to the other dengue virus serotypes by cDNA-RNA hybridization analysis.


A competency framework on simulation modelling-supported decision-making for Master of Public Health graduates.
Simulation models are increasingly important for supporting decision-making in public health. However, due to lack of training, many public health professionals remain unfamiliar with constructing simulation models and using their outputs for decision-making. This study contributes to filling this gap by developing a competency framework on simulation model-supported decision-making targeting Master of Public Health education. The study combined a literature review, a two-stage online Delphi survey and an online consensus workshop. A draft competency framework was developed based on 28 peer-reviewed publications. A two-stage online Delphi survey involving 15 experts was conducted to refine the framework. Finally, an online consensus workshop, including six experts, evaluated the competency framework and discussed its implementation. The competency framework identified 20 competencies related to stakeholder engagement, problem definition, evidence identification, participatory system mapping, model creation and calibration and the interpretation and dissemination of model results. The expert evaluation recommended differentiating professional profiles and levels of expertise and synergizing with existing course contents to support its implementation. The competency framework developed in this study is instrumental to including simulation model-supported decision-making in public health training. Future research is required to differentiate expertise levels and develop implementation strategies.


Understanding angiosperm diversification using small and large phylogenetic trees.
How will the emerging possibility of inferring ultra-large phylogenies influence our ability to identify shifts in diversification rate? For several large angiosperm clades (Angiospermae, Monocotyledonae, Orchidaceae, Poaceae, Eudicotyledonae, Fabaceae, and Asteraceae), we explore this issue by contrasting two approaches: (1) using small backbone trees with an inferred number of extant species assigned to each terminal clade and (2) using a mega-phylogeny of 55473 seed plant species represented in GenBank. The mega-phylogeny approach assumes that the sample of species in GenBank is at least roughly proportional to the actual species diversity of different lineages, as appears to be the case for many major angiosperm lineages. Using both approaches, we found that diversification rate shifts are not directly associated with the major named clades examined here, with the sole exception of Fabaceae in the GenBank mega-phylogeny. These agreements are encouraging and may support a generality about angiosperm evolution: major shifts in diversification may not be directly associated with major named clades, but rather with clades that are nested not far within these groups. An alternative explanation is that there have been increased extinction rates in early-diverging lineages within these clades. Based on our mega-phylogeny, the shifts in diversification appear to be distributed quite evenly throughout the angiosperms. Mega-phylogenetic studies of diversification hold great promise for revealing new patterns, but we will need to focus more attention on properly specifying null expectation.


[Profile of the family caregiver caring for patients with sequels of cerebral vascular accident].
This descriptive study using a qualitative approach aimed to identify who are the family caregivers and to understand how the caregiver is chosen amongst the family members of stroke patients. Data were collected by means of a semi-structured questionnaire applied to ten family caregivers. In addition, these caregivers were observed during the interview.The interviews were recorded, transcribed and analyzed. Most of the caregivers who participated in this study were females, married, partners and daughters, with a mean age of 54 years. The statements demonstrated that the "choice" of taking care is not so much an option but closely related to a feeling of obligation. Besides, this choice is also related to the affective relation established with the patient before the illness.


[Placenta percreta with bladder invasion. Case report].
We report a case of a 30-year-old woman, who had two previous caesarean sections, attended for the first time at 18 weeks of gestation. Pelvic ultrasonography and color Doppler imaging showed a placenta percreta invading the urinary bladder. A caesarean section was carried out at 27th week of gestation for preterm premature rupture of membranes. Placental tissue was firmly attached to the anterior surface of the bladder. A cesarean hysterectomy was performed with bilateral anterior internal iliac artery ligation before hysterectomy was finished. The bladder was repaired, leaving a suprapubic catheter.


Associations between alcohol use expectancies and drinking problems among French soldiers.
The aim of the study was to evaluate which alcohol use expectancies could predict harmful use in the French Army to explore some hypotheses concerning socialising or coping effects. A cross-sectional survey, using self-administered questionnaires, was conducted in two Army units in 2011 (n = 249). Hazardous alcohol use and dependence were screened using the Alcohol Use Disorders Identification Test (AUDIT). Alcohol expectancies were measured with the Alcohol Effects Questionnaire (AEFQ). A cluster analysis was performed to identify AEFQ dimensions in our sample. Relationships between AUDIT and AEFQ were explored using multinomial logistic regression. According to AUDIT, 46.6% of soldiers used alcohol without hazard, 26.1% had hazardous use without dependence and 18.1% had use with dependence. The AEFQ had an adequate internal coherence with a 0.78 α coefficient. The scales identified by the cluster analysis in our sample fitted those retained in the originally validated AEFQ, with a correspondence ranging from 60% to 100%. In multivariate analysis, the scale "Social and physical pleasure" was associated with increasing hazardous use and subjects who scored higher on "Global positive" and "Social and physical pleasure" scales were more at risk of dependence. The present study, in line with previous research in terms of importance of alcohol use disorders among military personnel, found that alcohol use expectancies are associated with alcohol misuse among soldiers. This could suggest underlying coping mechanisms towards stress that have to be further explored.


An appraisal of 18F-FDG PET imaging in post-therapy surveillance of uterine cancers: clinical evidence and a research proposal.
Despite important advances in screening for preinvasive forms of uterine cancers and more efficient combined therapy modalities, the surveillance of women previously treated either for a cervical or an endometrial cancer remains problematic. The follow-up protocols commonly applied in practice usually include a physical examination at control visits and clinically oriented morphologic imaging procedures. These routine protocols are, however, not standardized. Moreover, their sensitivity for accurately detecting a recurrent disease is most often suboptimal, especially in asymptomatic patients. On the other hand, the performances of a high-technology imaging such as positron emission tomography (PET) using 18F-fluoro-2-deoxy-d-glucose (18FDG) are nowadays firmly established in the post-treatment monitoring of oncology patients. The purpose of the present paper is to review both the advantages and the limitations of 18FDG PET imaging in the surveillance of women previously treated for uterine cancers. Based on the encouraging literature data, a well-designed research protocol is proposed in order to more objectively assess the contribution of metabolic imaging in the post-therapy management of these gynecological malignancies.


Attention-UNet architectures with pretrained backbones for multi-class cardiac MR image segmentation.
Segmentation architectures based on deep learning proficient extraordinary results in medical imaging technologies. Computed tomography (CT) images and Magnetic Resonance Imaging (MRI) in diagnosis and treatment are increasing and significantly support the diagnostic process by removing the bottlenecks of manual segmentation. Cardiac Magnetic Resonance Imaging (CMRI) is a state-of-the-art imaging technique used to acquire vital heart measurements and has received extensive attention from researchers for automatic segmentation. Deep learning methods offer high-precision segmentation but still pose several difficulties, such as pixel homogeneity in nearby organs. The motivated study using the attention mechanism approach was introduced for medical images for automated algorithms. The experiment focuses on observing the impact of the attention mechanism with and without pretrained backbone networks on the UNet model. For the same, three networks are considered: Attention-UNet, Attention-UNet with resnet50 pretrained backbone and Attention-UNet with densenet121 pretrained backbone. The experiments are performed on the ACDC Challenge 2017 dataset. The performance is evaluated by conducting a comparative analysis based on the Dice Coefficient, IoU Coefficient, and cross-entropy loss calculations. The Attention-UNet, Attention-UNet with resnet50 pretrained backbone, and Attention-UNet with densenet121 pretrained backbone networks obtained Dice Coefficients of 0.9889, 0.9720, and 0.9801, respectively, along with corresponding IoU scores of 0.9781, 0.9457, and 0.9612. Results compared with the state-of-the-art methods indicate that the methods are on par with, or even superior in terms of both the Dice coefficient and Intersection-over-union.


The impact of Covid-19 on children's active travel to school in Vietnam.
This is among the first studies to provide empirical evidence on active school travel rates and determinants before and after the first Covid-19 lockdown in spring 2020. We have collected and analyzed primary survey data on the school travel patterns of 472 school-age children in Hanoi, Vietnam. The findings show that the Covid-19 pandemic has been quite detrimental: once schools reopened, the prevalence of active school travel decreased from 53% to less than 31%. Where parents, especially mothers, did not face barriers to motorized travel, they assumed the role of chauffeur. Parents who were more concerned about community infections were more motivated to shift children to motorized modes. Walking was more affected than cycling because it was seen as more likely to lead to physical contact and virus transmission. Active school travel dropped more steeply in urban districts (as opposed to poorer, non-urban districts) and in those areas where home-school distances were the largest. It appears that the most common perceptions around barriers to active school travel have been exacerbated during the pandemic as parents and children adapt to "the new normal".


Transplantation of insulinoma into the diabetic Syrian hamster.
Syrian hamsters were rendered diabetic with intraperitoneal streptozotocin and were maintained in the diabetic state for a minimum of 14 days. A hamster islet cell tumor was transplanted subcutaneously with a prompt return of water intake (38 +/- 9.1 ml/day to 7.1 +/- 2.2 ml/day, mean +/- SD), urine glucose (4.8 +/- 0.84 g/day to less than 250 mg/day), urine output (37.4 +/- 10.9 ml/day to 7.6 +/- 2.1 ml/day), blood glucose (297 +/- 31.9 mg/dl to 87.6 +/- 28 mg/dl), and weight gain (1.0 to 0.8 g/day) to normal control levels. Histologic examination of the engrafted tumors revealed a well encapsulated tumor with no evidence of metastatic disease. The transplanted insulinomas maintained well differentiated histologic features without evidence of necrosis. Immunopathologic studies failed to reveal any evidence of either humoral or cell mediated immunity directed toward the allograft. Each animal was successfully transplanted with a 1 mm tumor explant. A single rodent tumor donor provided adequate material for engraftment for five recipients. The transplanted insulinomas maintained full functional and enzymatic capabilities. Similar studies utilizing the hamster insulinoma engrafted into the athymic nude mouse showed amelioration of the same diabetic symptomatology. Many of the technical difficulties encountered with whole organ and isolated islet transplantation encourages development of a more practical model. These experimental results suggest an alternative method for supplying the diabetic with an endogenous insulin source.


The steroid-9 alpha-hydroxylation system from Nocardia species.
The steroid 9 alpha-hydroxylase from Nocardia species M117 was found to be an electron-transport chain consisting of an NADH-dependent flavoprotein reductase and two iron-sulfur proteins named protein II and protein III. The components were partially purified. The flavoprotein reductase from Nocardia species M117 was enriched 20-fold to 100 units/mg and protein III 200-fold to 2400 units/mg protein. Protein II has a molecular weight of approximately 214 000. The purification factor of protein II was not determined. The absorption spectrum of protein II shows a maximum at 425 nm in the oxidized form and maxima at 510 nm, 415 nm and 370 nm in the reduced state; whereas protein III has a prominent maximum at 452 nm in the oxidized form and no absorption maximum in the reduced state. Carbon monoxide treatment of the reduced forms of protein II and protein III showed no maximum at 450 nm. Both proteins II and III are sensitive to oxygen. The hydroxylase activity can be reconstituted from the isolated components. Activity of the combined proteins was demonstrated by product analysis and NADH consumption produced by the addition of progesterone. Protein III catalyzes the reduction of cytochrome c in the presence of NADH and Nocardia flavoprotein reductase. The reconstitution of hydroxylase activity from cytochrome-free enzyme preparations excludes the participation of cytochrome P-450 in this steroid hydroxylase system.


IkappaB kinase beta phosphorylates Dok1 serines in response to TNF, IL-1, or gamma radiation.
Dok1 is an abundant Ras-GTPase-activating protein-associated tyrosine kinase substrate that negatively regulates cell growth and promotes migration. We now find that IkappaB kinase beta (IKKbeta) associated with and phosphorylated Dok1 in human epithelial cells and B lymphocytes. IKKbeta phosphorylation of Dok1 depended on Dok1 S(439), S(443), S(446), and S(450). Recombinant IKKbeta also phosphorylated Dok1 or Dok1 amino acids 430-481 in vitro. TNF-alpha, IL-1, gamma radiation, or IKKbeta overexpression phosphorylated Dok1 S(443), S(446), and S(450) in vivo, as detected with Dok1 phospho-S site-specific antisera. Moreover, Dok1 with S(439), S(443), S(446), and S(450) mutated to A was not phosphorylated by IKKbeta in vivo. Surprisingly, mutant Dok1 A(439), A(443), A(446), and A(450) differed from wild-type Dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant Dok1 A(439), A(443), A(446), and A(450) also did not promote cell motility, whereas wild-type Dok1 promoted cell motility, and Dok1 E(439), E(443), E(446), and E(450) further enhanced cell motility. These data indicate that IKKbeta phosphorylates Dok1 S(439)S(443) and S(446)S(450) after TNF-alpha, IL-1, or gamma-radiation and implicate the critical Dok1 serines in Dok1 effects after tyrosine kinase activation.


Cost-utility of add-on omalizumab in difficult-to-treat allergic asthma in Italy.
Omalizumab (OM), an innovative biological treatment for difficult asthma with perennial sensitisations, is an humanized monoclonal anti-IgE antibody that binds free circulating IgE; inhibits mast cell and basophil activation by combining free IgE, leads to IgE receptor down-regulation, thus blocking the inflammatory cascade. To assess real-world cost-utility ofadd-on OM in Italy. changes in clinical and economical outcomes, and in quality of life (QoL) associated with add-on OM in adults (n=23) with severe dfficult asthma were compared with those recorded before OM in the same subjects. Variables were: lung function; IgE levels; health status; ACT score; QoL (SGRQ); n. GP and specialist visits; emergency visits; hospitalizations, and concomitant pharmacological treatments. Further indices were: changes in Health-related QoL; total health-care costs, and incremental cost/utility. Data were statistically compared (Student's T test), and p < 0.01 was accepted for statistical significance. asthma clinical outcomes and patients' health-related quality of life improved significantly by adding OM, and both costs for drugs and hospital care dropped significantly (p < 0.01). The net economic effect was a 350 Euro increase in overall monthly costs; when related to health benefits, it corresponded to an incremental cost/utility ratio ofabout 26,000 Euro/QALY, which represents a quite favourable figure in terms of willingness to pay for health benefits in industrialised countries. Omalizumab added to an optimised therapy significantly improves clinical outcomes in difficult-to-treat, persistent allergic asthma. Costs also increased, but proved justified by health benefits achieved.


Histone Acetyltransferase and Deacetylase Inhibitors-New Aspects and Developments.
Epigenetic processes modulate gene transcription and genomic stability, ensuring proper cell development and differentiation [...].


C1q/TNF-related protein 6 (CTRP6) links obesity to adipose tissue inflammation and insulin resistance.
Obesity is associated with chronic low-grade inflammation, and metabolic regulators linking obesity to inflammation have therefore received much attention. Secreted C1q/TNF-related proteins (CTRPs) are one such group of regulators that regulate glucose and fat metabolism in peripheral tissues and modulate inflammation in adipose tissue. We have previously shown that expression of CTRP6 is up-regulated in leptin-deficient mice and, conversely, down-regulated by the anti-diabetic drug rosiglitazone. Here, we provide evidence for a novel role of CTRP6 in modulating both inflammation and insulin sensitivity. We found that in obese and diabetic humans and mouse models, CTRP6 expression was markedly up-regulated in adipose tissue and that stromal vascular cells, such as macrophages, are a major CTRP6 source. Overexpressing mouse or human CTRP6 impaired glucose disposal in peripheral tissues in response to glucose and insulin challenge in wild-type mice. Conversely, Ctrp6 gene deletion improved insulin action and increased metabolic rate and energy expenditure in diet-induced obese mice. Mechanistically, CTRP6 regulates local inflammation and glucose metabolism by targeting macrophages and adipocytes, respectively. In cultured macrophages, recombinant CTRP6 dose-dependently up-regulated the expression and production of TNF-α. Conversely, CTRP6 deficiency reduced circulating inflammatory cytokines and pro-inflammatory macrophages in adipose tissue. CTRP6-overexpressing mice or CTRP6-treated adipocytes had reduced insulin-stimulated Akt phosphorylation and glucose uptake. In contrast, loss of CTRP6 enhanced insulin-stimulated Akt activation in adipose tissue. Together, these results establish CTRP6 as a novel metabolic/immune regulator linking obesity to adipose tissue inflammation and insulin resistance.


Sex differences in mental rotation tasks: Not just in the mental rotation process!
The paper-and-pencil Mental Rotation Test (Vandenberg & Kuse, 1978) consistently produces large sex differences favoring men (Voyer, Voyer, & Bryden, 1995). In this task, participants select 2 of 4 answer choices that are rotations of a probe stimulus. Incorrect choices (i.e., foils) are either mirror reflections of the probe or structurally different. In contrast, in the mental rotation experimental task (Shepard & Metzler, 1971) participants judge whether 2 stimuli are the same but rotated or different by mirror reflection. The goal of the present research was to examine sources of sex differences in mental rotation, including the ability to capitalize on the availability of structure foils. In 2 experiments, both men and women had greater accuracy and faster reaction times (RTs) for structurally different compared with mirror foils in different versions of the Vandenberg and Kuse Mental Rotation Test (Experiment 1) and the Shepard and Metzler experimental task (Experiment 2). A significant male advantage in accuracy but not response time was found for both trial types. The male advantage was evident when all foils were structure foils so that mental rotation was not necessary (Experiment 3); however, when all foils were structure foils and participants were instructed to look for structure foils a significant sex difference was no longer evident (Experiment 4). Results suggest that the mental rotation process is not the only source of the sex difference in mental rotation tasks. Alternative strategy use is another source of sex differences in these tasks. (PsycINFO Database Record


Rescue bedside laparotomy in the intensive care unit in patients too unstable for transport to the operating room.
The prognoses of critically ill patients with a requirement for emergency laparotomy and severe respiratory and/or hemodynamic instability precluding transport to the operating room (OR) are often fatal without surgery. Attempting emergency surgery at the bedside might equally result in an adverse outcome. However, risk factors and predictors that could support clinical decision making have not been identified so far. This study describes the clinical characteristics, indicative pathophysiology and outcomes in patients undergoing resuscitative laparotomy in the intensive care unit (ICU). This was a retrospective observational study of all critically ill adult patients undergoing resuscitative laparotomy in the ICUs of a German university hospital from January 2005 to July 2013. Clinical characteristics, risk factors, and treatments were compared between survivors and non-survivors. The primary endpoint was 28-day survival. A total of 41 patients with a median age of 64 (21 to 83) were included. The most frequent reasons for ICU admission were sepsis, pneumonia, and pancreatic surgery. All patients were mechanically ventilated, receiving vasopressors, and were in multiple organ failure. Twenty-nine patients (70.7%) were on renal replacement therapy and two patients (4.9%) on extracorporeal membrane oxygenation. The main reasons for surgery were suspected intra-abdominal bleeding (39.0%), suspected intestinal ischemia (24.4%) or abdominal compartment syndrome (24.4%). Twenty-eight-day, ICU and hospital mortalities were 75.6%, 80.5%, and 82.9%, respectively. In six out of ten patients (60%) who survived surgery for more than 28 days, bedside laparotomy was rated as a life-saving procedure by an interdisciplinary group of the investigators. These findings suggest that in selected critically ill patients with a vital indication for emergency laparotomy and severe cardiopulmonary instability precluding transport to the OR, a bedside resuscitative laparotomy in the ICU can be considered as a rescue procedure, even though very high mortality is to be expected.


Lessons from the life of Asia's first female neurosurgeon for modern neurosurgical trainees and educators worldwide.
Surgical specialties, and particularly neurosurgery, have historically had and continue to have poor representation of female trainees. This is especially true of South Asia, considering the added social and cultural expectations for women in this region. Yet it was in India, with its difficult history of gender relations, that Asia's first fully qualified female neurosurgeon, Dr. T. S. Kanaka (1932-2018), took root, flourished, and thereafter played an integral role in helping develop stereotactic and functional neurosurgery in the country. While a few biographical accounts of her exist, highlighted here are the lessons from her illustrious life for neurosurgical trainees and educators worldwide, along with the instances that exemplify those lessons, drawn from several hitherto unutilized primary sources. These lessons are consistent with the factors identified in previous systematic reviews to be contributing to gender disparities in neurosurgery. Many of the virtues that ensured her success are attributes that continue to be critical for a neurosurgical career. Additionally, the circumstances that helped Kanaka succeed have been recounted as considerations for those working to promote diversity and inclusion. Finally, her life choices and sacrifices are described, which are underexplored but relevant concerns for women in neurosurgery.


Replicator-mutator dynamics of linguistic convergence and divergence.
People tend to align their use of language to the linguistic behaviour of their own ingroup and to simultaneously diverge from the language use of outgroups. This paper proposes to model this phenomenon of sociolinguistic identity maintenance as an evolutionary game in which individuals play the field and the dynamics are supplied by a multi-population extension of the replicator-mutator equation. Using linearization, the stabilities of all dynamic equilibria of the game in its fully symmetric two-population special case are found. The model is then applied to an empirical test case from adolescent sociolinguistic behaviour. It is found that the empirically attested population state corresponds to one of a number of stable equilibria of the game under an independently plausible value of a parameter controlling the rate of linguistic mutations. An asymmetric three-population extension of the game, explored with numerical solution methods, furthermore predicts to which specific equilibrium the system converges.


Fatal reactive hemophagocytosis related to disseminated histoplasmosis with endocarditis: an unusual case diagnosed at autopsy.
Reactive hemophagocytic syndrome (RHS) is an uncommon life-threatening disorder. It is believed to be caused by widespread non-neoplastic proliferation and inappropriate activation of mature macrophages, resulting in excessive cytokine activation which leads to hematophagocytosis by cells of the macrophage-monocyte lineage and multiorgan dysfunction. RHS may be associated with infections caused by bacterial, viral and fungal organisms as well as lymphoproliferative disorders, nonhematopoietic malignancies, autoimmune diseases and some therapeutic drugs. Immunosuppression is a frequent underlying condition in RHS. The following case presentation describes a patient with a history of chronic hepatitis C, cryoglobulinemia, renal failure and Staphylococcus aureus perinephric abscess and bacteremia, who, at autopsy, was found to have disseminated histoplasmosis with fungal endocarditis and RHS.


Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch.
Sprouting angiogenesis drives blood vessel growth in healthy and diseased tissues. Vegf and Dll4/Notch signalling cooperate in a negative feedback loop that specifies endothelial tip and stalk cells to ensure adequate vessel branching and function. Current concepts posit that endothelial cells default to the tip-cell phenotype when Notch is inactive. Here we identify instead that the stalk-cell phenotype needs to be actively repressed to allow tip-cell formation. We show this is a key endothelial function of neuropilin-1 (Nrp1), which suppresses the stalk-cell phenotype by limiting Smad2/3 activation through Alk1 and Alk5. Notch downregulates Nrp1, thus relieving the inhibition of Alk1 and Alk5, thereby driving stalk-cell behaviour. Conceptually, our work shows that the heterogeneity between neighbouring endothelial cells established by the lateral feedback loop of Dll4/Notch utilizes Nrp1 levels as the pivot, which in turn establishes differential responsiveness to TGF-β/BMP signalling.


Caregivers' judgments of the functional abilities of the Alzheimer's disease patient: a comparison of proxy reports and objective measures.
The assessment of functional capacity is essential for the diagnosis of dementia by DSM-IV criteria and has important implications for patient intervention and management. Although ratings of functional disability by family or other proxy informants are widely used by clinicians, there have been concerns and empirical evidence that potential reporter biases may result in either overestimation or underestimation of specific functional deficits. In this study, we compared family members' judgments of the functional abilities of seventy-two patients diagnosed with Alzheimer's disease (AD). These judgments were compared to actual objective functional performance on an array of real-world tasks using the Direct Assessment of Functional Status (DAFS) scale. The results indicate that caregivers were extremely accurate in predicting the functional performance of AD patients who were not impaired during objective evaluation. In contrast, caregivers significantly overestimated the ability of impaired AD patients to tell time, to identify currency, to make change for a purchase, and to utilize eating utensils. Higher patient MMSE scores were associated with caregivers' overestimation of functional capacity, while the degree of caregivers' depressive symptoms, as measured by the CES-D depression scale, was not related to either overestimation or underestimation of patients' functional performance.


New threats to health data privacy.
Along with the rapid digitalization of health data (e.g. Electronic Health Records), there is an increasing concern on maintaining data privacy while garnering the benefits, especially when the data are required to be published for secondary use. Most of the current research on protecting health data privacy is centered around data de-identification and data anonymization, which removes the identifiable information from the published health data to prevent an adversary from reasoning about the privacy of the patients. However, published health data is not the only source that the adversaries can count on: with a large amount of information that people voluntarily share on the Web, sophisticated attacks that join disparate information pieces from multiple sources against health data privacy become practical. Limited efforts have been devoted to studying these attacks yet. We study how patient privacy could be compromised with the help of today's information technologies. In particular, we show that private healthcare information could be collected by aggregating and associating disparate pieces of information from multiple online data sources including online social networks, public records and search engine results. We demonstrate a real-world case study to show user identity and privacy are highly vulnerable to the attribution, inference and aggregation attacks. We also show that people are highly identifiable to adversaries even with inaccurate information pieces about the target, with real data analysis. We claim that too much information has been made available electronic and available online that people are very vulnerable without effective privacy protection.


Maize Internode Autofluorescence at the Macroscopic Scale: Image Representation and Principal Component Analysis of a Series of Large Multispectral Images.
A quantitative histology of maize stems is needed to study the role of tissue and of their chemical composition in plant development and in their end-use quality. In the present work, a new methodology is proposed to show and quantify the spatial variability of tissue composition in plant organs and to statistically compare different samples accounting for biological variability. Multispectral UV/visible autofluorescence imaging was used to acquire a macroscale image series based on the fluorescence of phenolic compounds in the cell wall. A series of 40 multispectral large images of a whole internode section taken from four maize inbred lines were compared. The series consisted of more than 1 billion pixels and 11 autofluorescence channels. Principal Component Analysis was adapted and named large PCA and score image montages at different scales were built. Large PCA score distributions were proposed as quantitative features to compare the inbred lines. Variations in the tissue fluorescence were clearly displayed in the score images. General intensity variations were identified. Rind vascular bundles were differentiated from other tissues due to their lignin fluorescence after visible excitation, while variations within the pith parenchyma were shown via UV fluorescence. They depended on the inbred line, as revealed by the first four large PCA score distributions. Autofluorescence macroscopy combined with an adapted analysis of a series of large images is promising for the investigation of the spatial heterogeneity of tissue composition between and within organ sections. The method is easy to implement and can be easily extended to other multi-hyperspectral imaging techniques. The score distributions enable a global comparison of the images and an analysis of the inbred lines' effect. The interpretation of the tissue autofluorescence needs to be further investigated by using complementary spatially resolved techniques.


[Morphologic aspects of the vestibular nerve of the chinchilla].
A quantitative study was made of the number of fibers, their diameters and patterns of distribution in 14 ampullar nerves of chinchilla. The nerves were processed for osmium staining, embedded in plastic and cut serially in 1-micron-thick sections for histologic evaluation. Quantitative evaluation of nerve-fiber characteristics was made with the aid of a laboratory computer and specific programs. The number of the nerve fibers ranged between 1,877 and 2,175. The diameters of the fibers could be as large as 8 microns. The fibers between 2 and 2.5 microns were the most abundant, representing 29.6% of the fiber population. The distribution of fibers in the cristae was size-dependent: 80% of the thin fibers were located at the ends of the nerves, while most of the thick fibers were distributed through the central and intermediate areas.


Diagnostic accuracy of magnetic resonance voiding cystourethrography for detecting vesico-ureteral reflux in children and adolescents.
The purpose of the present study is to determine the accuracy of magnetic resonance voiding cystourethrography (MRVCUG) for diagnosis of vesicoureteral reflux (VUR) in children and adolescents with recurrent urinary tract infection (UTI). During the cross-sectional study from May 2009 to June 2011, 30 patients' (60 kidney-ureter units) MRVCUG findings by 1.5 T magnetic resonance imaging (MRI) were compared with voiding cystourethrography (VCUG) findings in patients with urinary tract infection. The sensitivity, specificity, positive and negative predictive values for MRVCUG were calculated. The sensitivity, specificity, positive and negative predictive values and accuracy for MRVCUG for detecting VUR were respectively 92.68% (95% CI: 80.57-97.48%), 68.42% (95% CI: 46.01-84.64%), 86.36% (95% CI: 71.95-94.33%), 81.25% (95% CI: 53.69-95.02%), and 85% (95% CI: 80.40-89.60%. The level of agreement between MRVCUG and VCUG findings for diagnosis VUR was very good (P < 0.001, according to Cohen's kappa value = 0.638). Studying correlation of low grade VUR (grade I and II) and high grade VUR (grade III-V) showed a very good agreement between MRVCUG and VCUG findings (P < 0.001, Cohen's kappa value = 0.754). MRVCUG could accurately reveal the presence and severity of VUR, especially in cases with high-grade (grade III-V) VUR in both children and adolescents.


Brain peptides and glial growth. I. Glia-promoting factors as regulators of gliogenesis in the developing and injured central nervous system.
Glia-promoting factors (GPFs) are peptides of the central nervous system which accelerate the growth of specific glial populations in vitro. Although these factors were first discovered in the goldfish visual system (Giulian, D., Y. Tomozawa, H. Hindman, and R. Allen, 1985, Proc. Natl. Acad. Sci. USA., 83:4287-4290), we now report similar peptides are found in mammalian brain. The cerebral cortex of rat contains oligodendroglia-stimulating peptides, GPF1 (15 kD) and GPF3 (6 kD), as well as astroglia-stimulating peptides, GPF2 (9 kD) and GPF4 (3 kD). The concentrations of specific GPFs increase in brain during periods of gliogenesis. For example, GPF1 and GPF3 are found in postnatal rat brain during a peak of oligondendroglial growth while GPF2 and GPF4 are first detected at a time of astroglial proliferation in the embryo. Stab wound injury to the cerebral cortices of rats stimulates astroglial proliferation and induces marked elevations in levels of GPF2 and GPF4. Our findings suggest that two distinct classes of GPFs, those acting upon oligodendroglia and those acting upon astroglia, help to regulate cell growth in the developing and injured central nervous system.


Comparison of Allogeneic and Syngeneic Rat Glioma Models by Using MRI and Histopathologic Evaluation.
Research in neurooncology traditionally requires appropriate in vivo animal models, on which therapeutic strategies are tested before human trials are designed and proceed. Several reproducible animal experimental models, in which human physiologic conditions can be mimicked, are available for studying glioblastoma multiforme. In an ideal rat model, the tumor is of glial origin, grows in predictable and reproducible patterns, closely resembles human gliomas histopathologically, and is weakly or nonimmunogenic. In the current study, we used MRI and histopathologic evaluation to compare the most widely used allogeneic rat glioma model, C6-Wistar, with the F98-Fischer syngeneic rat glioma model in terms of percentage tumor growth or regression and growth rate. In vivo MRI demonstrated considerable variation in tumor volume and frequency between the 2 rat models despite the same stereotactic implantation technique. Faster and more reproducible glioma growth occurred in the immunoresponsive environment of the F98-Fischer model, because the immune response is minimized toward syngeneic cells. The marked inability of the C6-Wistar allogeneic system to generate a reproducible model and the episodes of spontaneous tumor regression with this system may have been due to the increased humoral and cellular immune responses after tumor implantation.


A One-Health Approach to Investigating an Outbreak of Alimentary Tick-Borne Encephalitis in a Non-endemic Area in France (Ain, Eastern France): A Longitudinal Serological Study in Livestock, Detection in Ticks, and the First Tick-Borne Encephalitis Virus Isolation and Molecular Characterisation.
Tick-borne encephalitis virus' (TBEV) geographic range and the human incidence are increasing throughout Europe, putting a number of non-endemic regions and countries at risk of outbreaks. In spring 2020, there was an outbreak of tick-born encephalitis (TBE) in Ain, Eastern France, where the virus had never been detected before. All patients but one had consumed traditional unpasteurised raw goat cheese from a local producer. We conducted an investigation in the suspected farm using an integrative One Health approach. Our methodology included (i) the detection of virus in cheese and milk products, (ii) serological testing of all animals in the suspected farm and surrounding farms, (iii) an analysis of the landscape and localisation of wooded area, (iv) the capture of questing ticks and small mammals for virus detection and estimating enzootic hazard, and (v) virus isolation and genome sequencing. This approach allowed us to confirm the alimentary origin of the TBE outbreak and witness in real-time the seroconversion of recently exposed individuals and excretion of virus in goat milk. In addition, we identified a wooded focus area where and around which there is a risk of TBEV exposure. We provide the first TBEV isolate responsible for the first alimentary-transmitted TBE in France, obtained its full-length genome sequence, and found that it belongs to the European subtype of TBEV. TBEV is now a notifiable human disease in France, which should facilitate surveillance of its incidence and distribution throughout France.


Cost-effectiveness of pegfilgrastim versus 6-day filgrastim primary prophylaxis in patients with non-Hodgkin's lymphoma receiving CHOP-21 in United States.
Prophylaxis with granulocyte-colony stimulating factor (G-CSF) reduces the risk of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy. Randomized clinical trials have shown that pegfilgrastim, a 2nd-generation G-CSF, is at least as effective as the 1st-generation G-CSF filgrastim. In the meta-analysis of trials pegfilgrastim performed better than filgrastim with respect to FN risk. The incremental cost-effectiveness of primary prophylaxis (starting in cycle 1 and continuing in subsequent cycles of chemotherapy) with pegfilgrastim versus filgrastim used for 6 days (as is often used in clinical practice) was estimated in patients with aggressive non-Hodgkin's lymphoma (NHL) receiving myelosuppressive chemotherapy in the United States. A decision-analytic model was constructed from a health insurer's perspective with a life-time study horizon. The model considered direct medical costs and outcomes related to reduced FN and potential survival benefits due to reduced FN-related mortality. Inputs for the model were obtained from the medical literature. Sensitivity analyses were conducted across plausible ranges in parameter values. The incremental cost-effectiveness (ICER) of pegfilgrastim versus 6-day filgrastim primary prophylaxis was $2167/FN episode avoided. Adding survival benefit from avoiding FN mortality yielded an ICER of $5532/LY gained or $6190/QALY gained. When the potential benefit of optimized chemotherapy was included, the ICER was $1494/LY gained or $1677/QALY gained. The most influential factors included cost of pegfilgrastim, relative risk of FN between pegfilgrastim and filgrastim, FN case-fatality rate, cost of filgrastim and baseline FN risk. Pegfilgrastim is cost-effective in primary prophylaxis of FN compared to 6 days per cycle of filgrastim, in patients with NHL receiving myelosuppressive chemotherapy (e.g., cyclophosphamide + doxorubicin + vincristine + prednisolone [CHOP-21]) chemotherapy. Study limitations included lack of direct evidence linking G-CSF use with a reduction in FN-related mortality and limited data that show a relationship between relative dose intensity (RDI) and cancer-specific patient survival.


Is motor-imagery brain-computer interface feasible in stroke rehabilitation?
In the past 3 decades, interest has increased in brain-computer interface (BCI) technology as a tool for assisting, augmenting, and rehabilitating sensorimotor functions in clinical populations. Initially designed as an assistive device for partial or total body impairments, BCI systems have since been explored as a possible adjuvant therapy in the rehabilitation of patients who have had a stroke. In particular, BCI systems incorporating a robotic manipulanda to passively manipulate affected limbs have been studied. These systems can use a range of invasive (ie, intracranial implanted electrodes) or noninvasive neurophysiologic recording techniques (ie, electroencephalography [EEG], near-infrared spectroscopy, and magnetoencephalography) to establish communication links between the brain and the BCI system. Trials are most commonly performed on EEG-based BCI in comparison with the other techniques because of its high temporal resolution, relatively low setup costs, portability, and noninvasive nature. EEG-based BCI detects event-related desynchronization/synchronization in sensorimotor oscillatory rhythms associated with motor imagery (MI), which in turn drives the BCI. Previous evidence suggests that the process of MI preferentially activates sensorimotor regions similar to actual task performance and that repeated practice of MI can induce plasticity changes in the brain. It is therefore postulated that the combination of MI and BCI may augment rehabilitation gains in patients who have had a stroke by activating corticomotor networks via MI and providing sensory feedback from the affected limb using end-effector robots. In this review we examine the current literature surrounding the feasibility of EEG-based MI-BCI systems in stroke rehabilitation. We also discuss the limitations of using EEG-based MI-BCI in patients who have had a stroke and suggest possible solutions to overcome these limitations.


Multiple indices of the 'bounce' phenomenon obtained from the same human ears.
Loud low-frequency sounds can induce temporary oscillatory changes in cochlear sensitivity, which have been termed the 'bounce' phenomenon. The origin of these sensitivity changes has been attributed to slow fluctuations in cochlear homeostasis, causing changes in the operating points of the outer hair cell mechano-electrical and electro-mechanical transducers. Here, we acquired three objective and subjective measures resulting in a comprehensive dataset of the bounce phenomenon in each of 22 normal-hearing human subjects. We analysed the level and phase of cubic and quadratic distortion product otoacoustic emissions and the auditory thresholds before and after presentation of a low-frequency stimulus (30 Hz sine wave, 120 dB SPL, 90 s) as a function of time. In addition, the perceived loudness of temporary, tinnitus-like sensations occurring in all subjects after cessation of the low-frequency stimulus was tracked over time. The majority of the subjects (70 %) showed a significant, biphasic change of quadratic, but not cubic, distortion product otoacoustic emissions of about 3-4 dB. Eighty-six percent of the tested subjects showed significant alterations of hearing thresholds after low-frequency stimulation. Four different types of threshold changes were observed, namely monophasic desensitisations (the majority of cases), monophasic sensitisations, biphasic alterations with initial sensitisation and biphasic alterations with initial desensitisation. The similar duration of the three bounce phenomenon measures indicates a common origin. The current findings are consistent with the hypothesis that slow oscillations of homeostatic control mechanisms and associated operating point shifts within the cochlea are the source of the bounce phenomenon.


[Chlamydia trachomatis infection in patients of a health institution of Bogota and Medellin, 2012-2015].
Chlamydia trachomatis presents clinical consequences and it is barely studied in Colombia. To compare the C. trachomatis infection in Bogotá and Medellín with specific frequencies by gender and age group, between 2012-2015. Descriptive study of multiple groups, with 1,660 people in Bogotá and 1,087 in Medellin. Anti-Chlamydia trachomatis test with recombinant antigens MOMP, TARP and CPAF was applied; 100% sensitivity and 99.6% specificity. It was estimated and compared the frequency of infection by gender and age group, by hypothesis testing, confidence intervals and prevalence ratios. The largest proportion were women and people between 30-39 years. The frequency of positive IgG in Bogotá was 15.6% (95% CI = 13.4 to 17.8) in Medellin 16.9% (95% CI = 13.4 to 20.4), while the frequency of positive IgM was 0% in Medellin and 0.2% (95% CI = 0.01-1.0) in Bogotá; it was higher in women. In Bogotá, the frequency was higher in younger than 30 years and lower in older than 50. The high frequency of infection, its greater occurrence in women, the differences found in the age groups, the low number of investigations in Colombia and clinical risks associated with C. trachomatis, show the need to improve surveillance, screening and research in this infection.


Modular and Practical 1,2-Aryl(Alkenyl) Heteroatom Functionalization of Alkenes through Iron/Photoredox Dual Catalysis.
Efficient methods for synthesizing 1,2-aryl(alkenyl) heteroatomic cores, encompassing heteroatoms such as nitrogen, oxygen, sulfur, and halogens, are of significant importance in medicinal chemistry and pharmaceutical research. In this study, we present a mild, versatile and practical photoredox/iron dual catalytic system that enables access to highly privileged 1,2-aryl(alkenyl) heteroatomic pharmacophores with exceptional efficiency and site selectivity. Our approach exhibits an extensive scope, allowing for the direct utilization of a wide range of commodity or commercially available (hetero)arenes as well as activated and unactivated alkenes with diverse functional groups, drug scaffolds, and natural product motifs as substrates. By merging iron catalysis with the photoredox cycle, a vast array of alkene 1,2-aryl(alkenyl) functionalization products that incorporate a neighboring azido, amino, halo, thiocyano and nitrooxy group were secured. The scalability and ability to rapid synthesize numerous bioactive small molecules from readily available starting materials highlight the utility of this protocol.


Adolescents' Views on Active and Non-Active Videogames: A Focus Group Study.
Active games require whole-body movement and may be an innovative tool to substitute sedentary pastime with more active time and may therefore contribute to adolescents' health. To inform strategies aimed at reducing sedentary behavior by replacing non-active with active gaming, perceptions and context of active and non-active gaming are explored. Six focus groups were conducted with adolescents 12-16 years old representing a range of education levels. A semistructured question route was used containing questions about perceptions and the context of gaming. The adolescents had positive attitudes toward active gaming, especially the social interactive aspect, which was greatly appreciated. A substantial number of adolescents enjoyed non-active games more than active ones, mainly because of better game controls and more diversity in non-active games. Active games were primarily played when there was a social gathering. Few game-related rules and restrictions at home were reported. Given the positive attitudes of adolescents and the limited restrictions for gaming at home, active videogames may potentially be used in a home setting as a tool to reduce sedentary behavior. However, to make active games as appealing as non-active games, attention should be paid to the quality, diversity, and sustainability of active games, as these aspects are currently inferior to those of traditional non-active games.


DeltaEF1, a zinc finger and homeodomain transcription factor, is required for skeleton patterning in multiple lineages.
DeltaEF1 is a DNA binding protein containing a homeodomain and two zinc finger clusters, and is regarded as a vertebrate homologue of zfh-1 (zinc finger homeodomain-containing factor-1) in Drosophila. In the developing embryo, deltaEF1 is expressed in the notochord, somites, limb, neural crest derivatives and a few restricted sites of the brain and spinal cord. To elucidate the regulatory function of deltaEF1 in mouse embryogenesis, we generated deltaEF1 null mutant (deltaEF1null(lacZ)) mice. The deltaEF1null(lacZ) homozygotes developed to term, but never survived postnatally. In addition to severe T cell deficiency of the thymus, the deltaEF1null(lacZ) homozygotes exhibited skeletal defects of various lineages. (1) Craniofacial abnormalities of neural crest origin: cleft palate, hyperplasia of Meckel's cartilage, dysplasia of nasal septum and shortened mandible. (2) Limb defects: shortening and broadening of long bones, fusion of carpal/tarsal bone and fusion of joints. (3) Fusion of ribs. (4) Sternum defects: split and asymmetric ossification pattern of the sternebrae associated with irregular sternocostal junctions. (5) Hypoplasia of intervertebral discs. These results indicate that deltaEF1 has an essential role in regulating development of these skeletal structures. Since the skeletal defects were not observed in deltaEF1deltaC727 mice, deltaEF1 bears distinct regulatory activities which are dependent on different domains of the molecule.


Measuring the migration of the components and polyethylene wear after total hip arthroplasty: beads and specialised radiographs are not necessary.
This paper describes the methodology, validation and reliability of a new computer-assisted method which uses models of the patient's bones and the components to measure their migration and polyethylene wear from radiographs after total hip arthroplasty (THA). Models of the patient's acetabular and femoral component obtained from the manufacturer and models of the patient's pelvis and femur built from a single computed tomography (CT) scan, are used by a computer program to measure the migration of the components and the penetration of the femoral head from anteroposterior and lateral radiographs taken at follow-up visits. The program simulates the radiographic setup and matches the position and orientation of the models to outlines of the pelvis, the acetabular and femoral component, and femur on radiographs. Changes in position and orientation reflect the migration of the components and the penetration of the femoral head. Validation was performed using radiographs of phantoms simulating known migration and penetration, and the clinical feasibility of measuring migration was assessed in two patients. Migration of the acetabular and femoral components can be measured with limits of agreement (LOA) of 0.37 mm and 0.33 mm, respectively. Penetration of the femoral head can be measured with LOA of 0.161 mm. The migration of components and polyethylene wear can be measured without needing specialised radiographs. Accurate measurement may allow earlier prediction of failure after THA. Cite this article: Bone Joint J 2017;99-B:1290-7.


The bioaccumulation and biotransformation of tetrabromobisphenol A bis (allyl ether) in common carp (Cyprinus carpio).
Tetrabromobisphenol A bis (allyl ether) (TBBPA-BAE) is an extensively used brominated flame retardant, which has raised considerable concern because of its neurotoxic and endocrine disruption effects on aquatic organisms. However, previous studies mainly focused on the parent compound before modification, tetrabromobisphenol A (TBBPA), and little information is available about the bioconcentration and biotransformation of TBBPA derivatives in fish. In this study, we investigated the tissue-specific uptake, elimination kinetic, and biotransformation of TBBPA-BAE in common carp (Cyprinus carpio). The fish were exposed to TBBPA-BAE at environmentally relevant concentrations (20 μg·L-1) for 28 days, followed by 14 days of depuration. The results showed TBBPA-BAE could rapidly accumulate in common carp. Among the seven tissues studied, the highest concentrations of TBBPA-BAE were observed in the liver (6.00 μg·g-1 wet weight [ww]) on day 24, while the longest residence time was observed in the kidney (t1/2 values of 18.7 days). Biotransformation of TBBPA-BAE was documented in the in vivo experiments, and 14 different phase I and phase II metabolites were identified in the liver. These findings suggest the biotransformation products of TBBPA-BAE should be considered for a comprehensive risk evaluation.


Interleukin 3-dependent hematopoietic progenitor cell lines.
Several biological phenotypes of growth factor-dependent cell lines have been described in recent years, including those with T lymphocyte, neutrophil granulocyte, basophil/mast cell, B lymphocyte, and multipotential stem cell properties. The growth factors for each cell lineage are a subject of intense study. Continuous mouse bone marrow cultures infected with RNA type C viruses (retroviruses) produce nonadherent hematopoietic cells over a longer duration than control cultures. Marrow cultures derived from strains with spontaneously induced ecotropic endogenous retrovirus demonstrate a greater longevity than those from strains with no replicating virus. Cultures infected with murine leukemia virus also generate a greater number, compared with controls, of cloned permanent suspension cell lines dependent for growth on a 41,000-dalton glycoprotein (interleukin 3 [IL 3]). Some are multipotential with capacity for differentiation to erythroid, neutrophil, eosinophil, and basophil/mast cell types. Other cloned IL 3-dependent cell lines are committed to a single pathway. Studies with Friend spleen focus-forming virus indicate that the first effect in the marrow culture is mediated through a subset of adherent hematopoietic stem cells. Bone marrow culture-derived IL 3-dependent cell lines provide a model with which to study the role of viral genes in the control of differentiation and self-renewal capacity of hematopoietic stem cells.


On the evolution of saline tolerance in the larvae of mosquitoes in the genus Ochlerotatus.
We examined physiological and morphological parameters associated with saline tolerance in the larvae of 11 species of mosquito in the genus Ochlerotatus that were collected from the wild in a variety of sites around North America. Saline tolerance was assayed, and all of the species were osmoregulators. Six of the species examined were found to be physiologically restricted to freshwater habitats, while the other five could successfully osmoregulate in both freshwater and saline water, including seawater. All larvae that were obligate freshwater forms had only one rectal segment, while all of the euryhaline osmoregulators had two. We were interested in the evolutionary pathway by which saline tolerance arose in this lineage. DNA sequence data were obtained by polymerase chain reaction amplification and sequencing of the D2 region of the 28s rDNA gene in all of the freshwater and saline-tolerant Ochlerotatus species we studied. When the morphological and physiological characters were mapped on the resultant cladogram, they revealed a complex pattern, with freshwater and saline-water forms being adjacent and interspersed through the tree. The data also demonstrate that saline tolerance has been gained and then lost at least once in this lineage. Two possible evolutionary scenarios are presented, but the one we favor is that saline tolerance arose one time in this lineage and repeated reversions to the freshwater condition have occurred.


Ecological feedback in quorum-sensing microbial populations can induce heterogeneous production of autoinducers.
Autoinducers are small signaling molecules that mediate intercellular communication in microbial populations and trigger coordinated gene expression via 'quorum sensing'. Elucidating the mechanisms that control autoinducer production is, thus, pertinent to understanding collective microbial behavior, such as virulence and bioluminescence. Recent experiments have shown a heterogeneous promoter activity of autoinducer synthase genes, suggesting that some of the isogenic cells in a population might produce autoinducers, whereas others might not. However, the mechanism underlying this phenotypic heterogeneity in quorum-sensing microbial populations has remained elusive. In our theoretical model, cells synthesize and secrete autoinducers into the environment, up-regulate their production in this self-shaped environment, and non-producers replicate faster than producers. We show that the coupling between ecological and population dynamics through quorum sensing can induce phenotypic heterogeneity in microbial populations, suggesting an alternative mechanism to stochastic gene expression in bistable gene regulatory circuits.


pH-responsive cancer-targeted selenium nanoparticles: a transformable drug carrier with enhanced theranostic effects.
Selenium nanoparticles (SeNPs) have been widely used in various biomedical applications, including cancer therapy, diagnosis and drug delivery. Herein, we fabricated a novel type of structure-transformable capsules by decoration of SeNPs with folate-chitosan to form smart-shell nanocapsules (FAC@CurP-SeNPs). The shrink particles could target cancer cells over expressing folate receptor and enter the cells via folate receptor-mediated endocytosis. FAC@CurP-SeNPs were expanded to snowflake particles under acidifying stimulus (pH 5.3), which led to enhanced drug-release over prolonged periods. Treatment with FAC@CurP-SeNPs significantly inhibited the growth of MCF-7 human breast carcinoma cells through induction of apoptosis, which was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. The contribution of extrinsic and intrinsic apoptotic pathways to the cell apoptosis was confirmed by activation of caspase-9 and caspase-8. Internalized FAC@CurP-SeNPs triggers intracellular ROS overproduction, thus activates p53, MAPKs pathways and inhibits NFκB and to promote cell apoptosis. Our results suggest that FAC@CurP-SeNPs may be a candidate for further evaluation as a agent for human cancers, and the strategy to use transformable nanocapsules could be a highly efficient way to enhance controlled drug release and anticancer efficacy.


Prenatal alcohol exposure and offspring hyperactivity: effects of para-chlorophenylalanine and methysergide.
Pregnant Wistar rats were exposed to either a liquid diet containing ethanol, pair-fed an identical diet with sucrose substituted for ethanol, or received ad lib chow and water, during days 6-19 of gestation. Pups were injected with a dose of 100 mg/kg of para-chlorophenylalanine, 48 hr, 24 hr or immediately prior to activity testing at 16, 22 or 28 days of age. Further groups were injected with isotonic saline just prior to activity testing. Pups exposed to alcohol prenatally were more active than controls at 16 days of age. parachlorophenylalanine brought about significant increases in activity when injected 24 or 48 hr prior to testing in 16-day-old pups, and significant increases in activity when injected 24 hr prior to testing in 22- and 28-day-old pups. However, these effects of parachlorophenylalanine were similar regardless of prenatal treatment. In a second study, 16-day-old pups received saline, 0.5, 1.0 or 2.0 mg/kg of methysergide immediately prior to an activity test. Methysergide brought about a dose-related decrease in activity in all three groups of pups. Most importantly, the effects on activity of the methysergide were similar regardless of the treatment received during gestation. These data indicate that the hyperactivity associated with fetal alcohol exposure is unlikely to result from alterations in the ontogeny of a serotonergic system involved in response inhibition.


[Occult papillary thyroid cancer].
The clinical and morphological aspects of occult sclerosing carcinoma of the thyroid are presented on the basis of a ten-year review of the surgically removed thyroids in Geneva and from the study of thyroid glands obtained from 133 consecutive autopsies. The 15 cases found in the surgical material represented 7.7% of all malignant thyroid tumours and one fifth of the papillary carcinomas. Occult tumours are found at a mean age of 46.6 years and predominate in women. Clinically, two thirds presented as nodular goiters, two cases as primary hyperplasia and one as primary hyperparathyroidism. Three out of 15 cases presented clinically with a cervical lymph node metastasis. Treatment was conservative in all cases and consisted of subtotal thyroidectomy and/or elective lymphadenectomy, followed by medical suppression of TSH. Follow-up in 11 cases showed a single recurrence in a cervical lymph node, while the other 10 cases have been disease free for 4 to 13 years. In the autopsy series 3 thyroid glands (2.3%) contained occult tumours, two of which were microcarcinomas. The Genevan series compares with other European and American studies but differs from the much higher incidence in the Japanese.


Machine-learning attacks on interference-based optical encryption: experimental demonstration.
Optical techniques have boosted a new class of cryptographic systems with some remarkable advantages, and optical encryption not only has spurred practical developments but also has brought a new insight into cryptography. However, this does not mean that it is elusive for the opponents to attack optical encryption systems. In this paper, for the first time to our knowledge, we experimentally demonstrate the machine-learning attacks on interference-based optical encryption. Using machine-learning models that are trained by a series of ciphertext-plaintext pairs, an unauthorized person is capable to retrieve the unknown plaintexts from the given ciphertexts without the usage of various different optical encryption keys existing in interference-based optical encryption. In comparison with conventional cryptanalytic methods, the proposed machine-learning-based attacking method can estimate transfer function or point spread function of interference-based optical encryption systems without subsidiary conditions. Simulations and optical experiments demonstrate feasibility and effectiveness of the proposed method, and the proposed machine-learning-based attacking method provides a versatile approach to analyzing the vulnerability of interference-based optical encryption.


Migraine and Cerebrovascular Atherosclerosis in Patients With Ischemic Stroke.
Migraine is a well-established risk factor for ischemic stroke, but migraine is also related to other vascular diseases. This study aims to investigate the association between migraine and cerebrovascular atherosclerosis in patients with acute ischemic stroke. We retrieved data on patients with ischemic stroke from the DUST (Dutch Acute Stroke Study). Migraine history was assessed with a migraine screener and confirmed by telephone interview based on the ICHD criteria (International Classification of Headache Disorders). We assessed intra- and extracranial atherosclerotic changes and quantified intracranial internal carotid artery calcifications as measure of atherosclerotic burden on noncontrast computed tomography and computed tomographic angiography. We calculated risk ratios with adjustments for possible confounders with multivariable Poisson regression analyses. We included 656 patients, aged 18 to 99 years, of whom 53 had a history of migraine (29 with aura). Patients with migraine did not have more frequent atherosclerotic changes in intracranial (51% versus 74%; adjusted risk ratio, 0.82; 95% confidence interval, 0.64-1.05) or extracranial vessels (62% versus 79%; adjusted risk ratio, 0.93; 95% confidence interval, 0.77-1.12) than patients without migraine and had comparable internal carotid artery calcification volumes (largest versus medium and smallest volume tertile, 23% versus 35%; adjusted risk ratio, 0.93; 95% confidence interval, 0.57-1.52). Migraine is not associated with excess atherosclerosis in large vessels in patients with acute ischemic stroke. Our findings suggest that the biological mechanisms by which migraine results in ischemic stroke are not related to macrovascular cerebral atherosclerosis.


In vitro simulation of prepubertal changes in pulsatile luteinizing hormone release enhances progesterone and 17 beta-estradiol secretion from immature rat ovaries.
We have previously demonstrated changes in the episodic pattern of LH secretion in female rats as they approach first ovulation. In the present study, ovaries were taken from peripubertal rats and perifused in vitro with a medium containing FSH and LH. The concentration of FSH in the medium was kept constantly low, whereas the concentration of LH was modulated, simulating as closely as possible the various episodic secretory profiles previously observed in vivo. Medium from the perifusion chambers was collected every 10 min for 5 h and assayed for progesterone (P) and 17 beta-estradiol (E2). Exposure of the ovaries to low amplitude LH pulses (20 ng/ml; comparable to those found in the plasma of peripubertal rats during the morning) did not elicit a significant steroidogenic response. On the other hand, exposure to large amplitude LH pulses (80 ng/ml; as seen during the afternoon) led to a marked increase in the output of both P and E2. Similarly, increased steroid secretion occurred when ovaries were exposed to a 2-h minisurge of LH (160 ng/ml) or to a minisurge preceded by three large amplitude pulses (as seen in some animals during the afternoons of the peripubertal period). Continuous exposure to LH at concentrations similar to either the large amplitude pulses or the LH minisurge increased P and E2 release. However, the increase was not significantly larger than that produced by the discontinuous LH perifusion patterns, even though the total amount of LH reaching the ovaries during the 5-h perifusion period was considerably greater. The results show that episodic LH secretion is functionally much more efficient at eliciting release of P and E2 from immature ovaries than is continuous LH secretion. Furthermore, they strongly suggest that changes in the LH secretory pulse patterns, as seen in vivo close to the time of puberty, are fundamental for the activation of ovarian steroidogenesis that leads to the first preovulatory surge of gonadotropins.


Pharmacogenomics with antidepressants in the STAR*D study.
Major depressive disorder is one of the most common psychiatric disorders worldwide. No single antidepressant has been shown to be more effective than any other in lifting depression, and the effectiveness of any particular antidepressant in an individual is difficult to predict; therefore, doctors must prescribe antidepressants based on educated guesses. SNPs can be used in clinical association studies to determine the contribution of genes to drug efficacy. Evidence is accumulating to suggest that the efficacy of antidepressants results from the combined effects of a number of genetic variants, such as SNPs. Although there are not enough data currently available to prove this hypothesis, an increasing number of genetic variants associated with antidepressant response are being discovered. In this article, we review the pharmacogenomics of the drug efficacy of antidepressants in major depressive disorder. First, we survey the SNPs and genes identified as genetic markers that are correlated and associated with the drug efficacy of antidepressants in the Sequenced Treatment Alternatives for Depression (STAR*D) study. Second, we investigate candidate genes that have been suggested as contributing to treatment-emergent suicidal ideation during the course of antidepressant treatment in the STAR*D study. Third, we briefly describe the pharmacokinetic genes examined in the STAR*D study, and finally, we summarize the limitations with respect to the pharmacogenomics studies in the STAR*D study. Future research with independent replication in large sample sizes is needed to confirm the role of the candidate genes identified in the STAR*D study in antidepressant treatment response.


Risk prediction of hepatotoxicity in paracetamol poisoning.
Paracetamol (acetaminophen) poisoning is the most common cause of acute liver failure in the developed world. A paracetamol treatment nomogram has been used for over four decades to help determine whether patients will develop hepatotoxicity without acetylcysteine treatment, and thus indicates those needing treatment. Despite this, a small proportion of patients still develop hepatotoxicity. More accurate risk predictors would be useful to increase the early detection of patients with the potential to develop hepatotoxicity despite acetylcysteine treatment. Similarly, there would be benefit in early identification of those with a low likelihood of developing hepatotoxicity, as this group may be safely treated with an abbreviated acetylcysteine regimen. To review the current literature related to risk prediction tools that can be used to identify patients at increased risk of hepatotoxicity. A systematic literature review was conducted using the search terms: "paracetamol" OR "acetaminophen" AND "overdose" OR "toxicity" OR "risk prediction rules" OR "hepatotoxicity" OR "psi parameter" OR "multiplication product" OR "half-life" OR "prothrombin time" OR "AST/ALT (aspartate transaminase/alanine transaminase)" OR "dose" OR "biomarkers" OR "nomogram". The search was limited to human studies without language restrictions, of Medline (1946 to May 2016), PubMed and EMBASE. Original articles pertaining to the theme were identified from January 1974 to May 2016. Of the 13,975 articles identified, 60 were relevant to the review. Paracetamol treatment nomograms: Paracetamol treatment nomograms have been used for decades to help decide the need for acetylcysteine, but rarely used to determine the risk of hepatotoxicity with treatment. Reported paracetamol dose and concentration: A dose ingestion >12 g or serum paracetamol concentration above the treatment thresholds on the paracetamol nomogram are associated with a greater risk of hepatotoxicity. Paracetamol elimination half-life: Patients with more severe hepatotoxicity are more likely to have a longer paracetamol elimination half-life. While median elimination half-life increases in those developing hepatotoxicity, there is wide variation in half-life, making this an insensitive parameter to use as a negative risk prediction tool. Prothrombin time (PT): An initially normal PT is associated with a lower risk of developing hepatotoxicity, but cannot be used alone to identify patients not requiring acetylcysteine treatment. Hepatic aminotransferase activity: A normal ALT activity on presentation is associated with a high negative predictive value of hepatotoxicity following paracetamol-poisoning. Psi parameter: The psi parameter takes into account the time from ingestion, the serum paracetamol concentration and the time to initiation of acetylcysteine. A hepatotoxicity risk nomogram based on this parameter may be easier to use, but is limited to acute ingestions. Paracetamol-aminotransferase multiplication product: If a hepatotoxicity risk nomogram is not available, an alternate strategy may be to use the paracetamol-aminotransferase product (<1500 low risk, 1500-10,000 low to moderate risk, >10,000 mg/L × IU/L high risk) to define liver injury risk. Serial blood tests can be performed if patients present prior to 8 h post-overdose for ultimate specificity, or a single blood test can be taken if presenting more than 8 h post-overdose. Patients receiving acetylcysteine within 8 h of their overdose, with a product less than 10,000 mg/L × IU/L have a low likelihood of developing hepatotoxicity. Any clinical trials of intensified treatment (e.g., higher dose) to prevent fulminant hepatic failure might potentially use a product of >10,000 mg/L × IU/L as a criterion for inclusion. The paracetamol-aminotransferase product <1500 mg/L × IU/L may also identify those suitable for an abbreviated acetylcysteine regimen. Newer biomarkers: These show promise in the early identification of patients with a higher risk of developing hepatic injury. Point of care devices measuring paracetamol adducts need further trials. Risk prediction tools can stratify those that are more likely to develop hepatotoxicity. Currently, the paracetamol-aminotransferase multiplication product may be such a tool. Novel biomarkers show promise but need further validation and greater clinical availability. These tools may help inform clinical trials on modified acetylcysteine regimens.


A spectrum of CodY activities drives metabolic reorganization and virulence gene expression in Staphylococcus aureus.
The global regulator CodY controls the expression of dozens of metabolism and virulence genes in the opportunistic pathogen Staphylococcus aureus in response to the availability of isoleucine, leucine and valine (ILV), and GTP. Using RNA-Seq transcriptional profiling and partial activity variants, we reveal that S. aureus CodY activity grades metabolic and virulence gene expression as a function of ILV availability, mediating metabolic reorganization and controlling virulence factor production in vitro. Strains lacking CodY regulatory activity produce a PIA-dependent biofilm, but development is restricted under conditions that confer partial CodY activity. CodY regulates the expression of thermonuclease (nuc) via the Sae two-component system, revealing cascading virulence regulation and factor production as CodY activity is reduced. Proteins that mediate the host-pathogen interaction and subvert the immune response are shut off at intermediate levels of CodY activity, while genes coding for enzymes and proteins that extract nutrients from tissue, that kill host cells, and that synthesize amino acids are among the last genes to be derepressed. We conclude that S. aureus uses CodY to limit host damage to only the most severe starvation conditions, providing insight into one potential mechanism by which S. aureus transitions from a commensal bacterium to an invasive pathogen.


Dynamics in Secondary Metabolite Gene Clusters in Otherwise Highly Syntenic and Stable Genomes in the Fungal Genus Botrytis.
Fungi of the genus Botrytis infect >1,400 plant species and cause losses in many crops. Besides the broad host range pathogen Botrytis cinerea, most other species are restricted to a single host. Long-read technology was used to sequence genomes of eight Botrytis species, mostly pathogenic on Allium species, and the related onion white rot fungus, Sclerotium cepivorum. Most assemblies contained <100 contigs, with the Botrytis aclada genome assembled in 16 gapless chromosomes. The core genome and pan-genome of 16 Botrytis species were defined and the secretome, effector, and secondary metabolite repertoires analyzed. Among those genes, none is shared among all Allium pathogens and absent from non-Allium pathogens. The genome of each of the Allium pathogens contains 8-39 predicted effector genes that are unique for that single species, none stood out as potential determinant for host specificity. Chromosome configurations of common ancestors of the genus Botrytis and family Sclerotiniaceae were reconstructed. The genomes of B. cinerea and B. aclada were highly syntenic with only 19 rearrangements between them. Genomes of Allium pathogens were compared with ten other Botrytis species (nonpathogenic on Allium) and with 25 Leotiomycetes for their repertoire of secondary metabolite gene clusters. The pattern was complex, with several clusters displaying patchy distribution. Two clusters involved in the synthesis of phytotoxic metabolites are at distinct genomic locations in different Botrytis species. We provide evidence that the clusters for botcinic acid production in B. cinerea and Botrytis sinoallii were acquired by horizontal transfer from taxa within the same genus.


Megatrials for bronchodilators in chronic obstructive pulmonary disease (COPD) treatment: time to reflect.
Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality worldwide. Although (long-acting) bronchodilators are used to relieve symptoms, the impact of bronchodilators on COPD mortality remains an unresolved issue. Our aim was to explore the results and the interpretations of the results of studies of bronchodilator treatment from high-impact COPD trials. We searched PubMed and Embase for primary publications of randomized controlled trials with more than 1000 participants with COPD and that studied the effectiveness of long-acting bronchodilator treatment. We assessed population characteristics, primary outcomes, focus of outcomes, and possible bias from concomitant pulmonary medication. We retrieved 5 primary publications of large trials. Participants tended to be patients with rather severe COPD who were cared for at a hospital. Only half of the primary outcomes were statistically significant. Reports tended to focus on statically significant outcomes and not necessarily on primary outcomes or outcomes of the whole study population. The relevance of study outcomes was rarely discussed. The rather small effects of bronchodilators in a COPD population that is not representative for daily care, together with the tendency of relying on statistical rather than clinical significance, hampers translation to the large number of patients with COPD in the community.


Childhood trauma, brain structure and emotion recognition in patients with schizophrenia and healthy participants.
Childhood trauma, and in particular physical neglect, has been repeatedly associated with lower performance on measures of social cognition (e.g. emotion recognition tasks) in both psychiatric and non-clinical populations. The neural mechanisms underpinning this association have remained unclear. Here, we investigated whether volumetric changes in three stress-sensitive regions-the amygdala, hippocampus and anterior cingulate cortex (ACC)-mediate the association between childhood trauma and emotion recognition in a healthy participant sample (N = 112) and a clinical sample of patients with schizophrenia (N = 46). Direct effects of childhood trauma, specifically physical neglect, on Emotion Recognition Task were observed in the whole sample. In healthy participants, reduced total and left ACC volumes were observed to fully mediate the association between both physical neglect and total childhood trauma score, and emotion recognition. No mediating effects of the hippocampus and amygdala volumes were observed for either group. These results suggest that reduced ACC volume may represent part of the mechanism by which early life adversity results in poorer social cognitive function. Confirmation of the causal basis of this association would highlight the importance of resilience-building interventions to mitigate the detrimental effects of childhood trauma on brain structure and function.


Pitfalls and Remedies for Cross Validation with Multi-trait Genomic Prediction Methods.
Incorporating measurements on correlated traits into genomic prediction models can increase prediction accuracy and selection gain. However, multi-trait genomic prediction models are complex and prone to overfitting which may result in a loss of prediction accuracy relative to single-trait genomic prediction. Cross-validation is considered the gold standard method for selecting and tuning models for genomic prediction in both plant and animal breeding. When used appropriately, cross-validation gives an accurate estimate of the prediction accuracy of a genomic prediction model, and can effectively choose among disparate models based on their expected performance in real data. However, we show that a naive cross-validation strategy applied to the multi-trait prediction problem can be severely biased and lead to sub-optimal choices between single and multi-trait models when secondary traits are used to aid in the prediction of focal traits and these secondary traits are measured on the individuals to be tested. We use simulations to demonstrate the extent of the problem and propose three partial solutions: 1) a parametric solution from selection index theory, 2) a semi-parametric method for correcting the cross-validation estimates of prediction accuracy, and 3) a fully non-parametric method which we call CV2*: validating model predictions against focal trait measurements from genetically related individuals. The current excitement over high-throughput phenotyping suggests that more comprehensive phenotype measurements will be useful for accelerating breeding programs. Using an appropriate cross-validation strategy should more reliably determine if and when combining information across multiple traits is useful.


Tight junction defects in patients with atopic dermatitis.
Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJs) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway. We evaluated the expression/function of the TJ protein claudin-1 in epithelium from AD and nonatopic subjects and screened 2 American populations for single nucleotide polymorphisms in the claudin-1 gene (CLDN1). Expression profiles of nonlesional epithelium from patients with extrinsic AD, nonatopic subjects, and patients with psoriasis were generated using Illumina's BeadChips. Dysregulated intercellular proteins were validated by means of tissue staining and quantitative PCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed by using a knockdown approach in primary human keratinocytes. Twenty-seven haplotype-tagging SNPs in CLDN1 were screened in 2 independent populations with AD. We observed strikingly reduced expression of the TJ proteins claudin-1 and claudin-23 only in patients with AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with T(H)2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging SNPs revealed associations with AD in 2 North American populations. Collectively, these data suggest that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.


[Erythropoietin and blood oxygen transport: new sides of well-known problem].
Original results and literature data on the erythropoietin effects and mechanisms of action are analyzed. The action of this substance on blood oxygen transport is not only manifested by direct change in hemoglobin concentration and, correspondingly, by increased oxygen capacity, but is also mediated by modulators of hemoglobinaffinity to oxygen, in particular, via nitric oxide effect on hemoglobin.


Evidence for an active dimer of Escherichia coli beta-galactosidase.
BETA-Galactosidase (EC 184.108.40.206), prepared from strains ML 308 and K12 3300 of Escherichia coli, dissociated into an inactive monomer in the presence of Ag+. When such a monomer preparation is treated with excess of thiol an enzymically active dimer is formed in addition to an active tetramer. It is suggested that Ag+ may be of value in studies on other multimeric proteins as a mild dissociating agent.


Landscape genetic analyses reveal fine-scale effects of forest fragmentation in an insular tropical bird.
Within the framework of landscape genetics, resistance surface modelling is particularly relevant to explicitly test competing hypotheses about landscape effects on gene flow. To investigate how fragmentation of tropical forest affects population connectivity in a forest specialist bird species, we optimized resistance surfaces without a priori specification, using least-cost (LCP) or resistance (IBR) distances. We implemented a two-step procedure in order (i) to objectively define the landscape thematic resolution (level of detail in classification scheme to describe landscape variables) and spatial extent (area within the landscape boundaries) and then (ii) to test the relative role of several landscape features (elevation, roads, land cover) in genetic differentiation in the Plumbeous Warbler (Setophaga plumbea). We detected a small-scale reduction of gene flow mainly driven by land cover, with a negative impact of the nonforest matrix on landscape functional connectivity. However, matrix components did not equally constrain gene flow, as their conductivity increased with increasing structural similarity with forest habitat: urban areas and meadows had the highest resistance values whereas agricultural areas had intermediate resistance values. Our results revealed a higher performance of IBR compared to LCP in explaining gene flow, reflecting suboptimal movements across this human-modified landscape, challenging the common use of LCP to design habitat corridors and advocating for a broader use of circuit theory modelling. Finally, our results emphasize the need for an objective definition of landscape scales (landscape extent and thematic resolution) and highlight potential pitfalls associated with parameterization of resistance surfaces.


Adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a meta-analysis.
The World Health Organization recommends serum ferritin concentrations as the best indicator of iron deficiency (ID). Unfortunately, ferritin increases with infections; hence, the prevalence of ID is underestimated. The objective was to estimate the increase in ferritin in 32 studies of apparently healthy persons by using 2 acute-phase proteins (APPs), C-reactive protein (CRP) and alpha(1)-acid glycoprotein (AGP), individually and in combination, and to calculate factors to remove the influence of inflammation from ferritin concentrations. We estimated the increase in ferritin associated with inflammation (ie, CRP gt 5 mg/L and/or AGP gt 1 g/L). The 32 studies comprised infants (5 studies), children (7 studies), men (4 studies), and women (16 studies) (n = 8796 subjects). In 2-group analyses (either CRP or AGP), we compared the ratios of log ferritin with or without inflammation in 30 studies. In addition, in 22 studies, the data allowed a comparison of ratios of log ferritin between 4 subgroups: reference (no elevated APP), incubation (elevated CRP only), early convalescence (both APP and CRP elevated), and late convalescence (elevated AGP only). In the 2-group analysis, inflammation increased ferritin by 49.6% (CRP) or 38.2% (AGP; both P lt 0.001). Elevated AGP was more common than CRP in young persons than in adults. In the 4-group analysis, ferritin was 30%, 90%, and 36% (all P lt 0.001) higher in the incubation, early convalescence, and late convalescence subgroups, respectively, with corresponding correction factors of 0.77, 0.53, and 0.75. Overall, inflammation increased ferritin by ap 30% and was associated with a 14% (CI: 7%, 21%) underestimation of ID. Measures of both APP and CRP are needed to estimate the full effect of inflammation and can be used to correct ferritin concentrations. Few differences were observed between age and sex subgroups.


Characterization of a mammalian smooth muscle cell line that has retained transcriptional and posttranscriptional potencies.
Unlike skeletal and cardiac muscle cells that differentiate irreversibly, smooth muscle cells (SMCs) retain a high degree of plasticity. During the so-called phenotypic modulation, SMCs can undergo transition between a contractile phenotype and a highly proliferative synthetic phenotype, as apparent from the extinction of numerous smooth muscle (SM) markers when they are passaged in culture. It would be very useful to have an SMC line that can be indefinitely propagated for the cellular and molecular analysis of the mechanisms that underlie the control of SM differentiation. This report describes an immortalized rabbit aorta SMC-derived cell line (U8A4) that has conserved differentiated properties through multiple subcultures. U8A4 cells can grow in the absence of serum and express the SMC markers studied, including SM alpha-actin, SM calponin, SM22alpha, SM alpha-tropomyosin (alpha-TM), SM myosin heavy chain (SM-MHC), and myocardin. U8A4 cells can activate SMC-restricted promoters like those of SM22alpha, SM calponin, and SM-MHC genes as efficiently as described previously for rat SMC lines (PAC1, A7r5, and A10). These cells can also process exogenous alpha-TM transcripts according to an SM-specific pattern. These results demonstrate that the U8A4 cell line constitutes a good alternative model to existing SMC lines that could facilitate the study of the transcriptional and posttranscriptional regulatory mechanisms underlying SMC differentiation.


Liposomal amikacin dry powder inhaler: effect of fines on in vitro performance.
The aim of the present investigation was to prepare and evaluate the influence of adding fines on the in vitro performance of liposomal amikacin dry powder inhaler (AMK LDPI) formulations. Liposomes composed of hydrogenated soyaphosphatidylcholine, cholesterol and saturated soyaphosphatidylglycerol (AMK 1), or stearylamine (AMK 2) were prepared by a reverse phase evaporation technique, extruded to reduce size and separated from unentrapped drug. Purified liposomal dispersion was subjected to lyophilization using optimized cryoprotectant to achieve maximum percentage drug retention (PDR). Lactose carrier in varying mass ratios with or without addition of fines in different mixing sequences was used to formulate AMK LDPI formulations. AMK LDPI formulations were characterized for angle of repose, compressibility index, dispersibility index, scanning electron microscopy, and fine particle fraction (FPF). PDR was found to be 97.6% +/- 2.2% for AMK1 and 98.5% +/- 1.9% for AMK2 using sucrose as optimized cryoprotectant in lipid:sucrose ratio of 1:4. Lactose carrier containing 10% fines (wt/wt) was found to be the optimum blend at 1:5 mass ratio of liposome:lactose. The addition of fines and the order of mixing of fines were found to influence the FPF with significantly different device fractions. FPF of AMK LDPI formulations using Rotahaler as the delivery device at 30, 60, and 90 L/min were found to be 21.85% +/- 2.2% and 24.6% +/- 2.4%, 25.9% +/- 1.8% and 29.2% +/- 2.1%, and 29.5% +/- 2.6% and 34.2% +/- 2.0% for AMK1 and AMK2, respectively. From the studies performed in this investigation, it was observed that liposomal charge, addition of fines and order of mixing fines, has a significant effect (P < .05) on in vitro deposition of drug from LDPI formulation.


Avian malaria co-infections confound infectivity and vector competence assays of Plasmodium homopolare.
Currently, there are very few studies of avian malaria that investigate relationships among the host-vector-parasite triad concomitantly. In the current study, we experimentally measured the vector competence of several Culex mosquitoes for a newly described avian malaria parasite, Plasmodium homopolare. Song sparrow (Melospiza melodia) blood infected with a low P. homopolare parasitemia was inoculated into a naïve domestic canary (Serinus canaria forma domestica). Within 5 to 10 days post infection (dpi), the canary unexpectedly developed a simultaneous high parasitemic infection of Plasmodium cathemerium (Pcat6) and a low parasitemic infection of P. homopolare, both of which were detected in blood smears. During this infection period, PCR detected Pcat6, but not P. homopolare in the canary. Between 10 and 60 dpi, Pcat6 blood stages were no longer visible and PCR no longer amplified Pcat6 parasite DNA from canary blood. However, P. homopolare blood stages remained visible, albeit still at very low parasitemias, and PCR was able to amplify P. homopolare DNA. This pattern of mixed Pcat6 and P. homopolare infection was repeated in three secondary infected canaries that were injected with blood from the first infected canary. Mosquitoes that blood-fed on the secondary infected canaries developed infections with Pcat6 as well as another P. cathemerium lineage (Pcat8); none developed PCR detectable P. homopolare infections. These observations suggest that the original P. homopolare-infected songbird also had two un-detectable P. cathemerium lineages/strains. The vector and host infectivity trials in this study demonstrated that current molecular assays may significantly underreport the extent of mixed avian malaria infections in vectors and hosts.