Titanium oxide film for the bottom antireflective layer in deep ultraviolet lithography.
Titanium oxide thin film, fabricated with tetraisopropyltitanate and oxygen by electron cyclotron resonance-plasma-enhanced chemical vapor deposition, is investigated as a potential candidate for the antireflective layer in KrF excimer laser (248-nm) lithography. The oxygen flow-rate dependence of the optical properties such as the refractive index (n) and the extinction coefficient (k) of the film at the 248-nm wavelength has been characterized, and the films with the expected combinations of n and k values for the antireflective layer have been deposited. Simulation results indicate that reflectance values of less than 4% and as low as 1.2% can be reached at the interface between the photoresist and the film postulating the structures of the photoresist/300-A TiO(x) film/c-Si substrate and the W-Si substrate, respectively, by selected proper combinations of n and k values. Moreover the reflectance can be further reduced to almost zero by changing the film thickness. Thus it is found that titanium oxide thin films can be used as the bottom antireflective layer in KrF excimer laser lithography.


Multiplexing of six micro-displacement suspended-core Sagnac interferometer sensors with a Raman-Erbium fiber laser.
This work experimentally demonstrates a long-range optical fiber sensing network for the multiplexing of fiber sensors based on photonic crystal fibers. Specifically, six photonic crystal fiber sensors which are based on a Sagnac interferometer that includes a suspended-core fiber have been used. These sensors offer a high sensitivity for micro-displacement measurements. The fiber sensor network presents a ladder structure and its operation mode is based on a fiber ring laser which combines Raman and Erbium doped fiber amplification. Thus, we show the first demonstration of photonic crystal fiber sensors for remote measurement applications up to 75 km.


Social Factors and Older Adults' Use of Wearable Activity Trackers: Before and During the First Wave of the COVID-19 Pandemic.
Wearable activity trackers (WAT) have shown high potential to improve health in the aging population. Evidence links various social factors with WAT use in older adults, but mainly within small samples and the prevalence of their WAT use during the COVID-19 is unknown. We reported WAT use prevalence before and during the first wave of COVID-19 and examined social factors associated with WAT use frequency using a nationally representative sample of 3302 U.S. older adults. We used Multinomial Logistic Regression to identify social factors associated with WAT use frequency. Only 10.3% of pre-COVID-19 and 10.9% of first-wave subsamples were frequent WAT users. Older adults aged 75 and above and those with low incomes were less likely to frequently use WATs. Our findings suggest socioeconomic and age disparities in WAT use among older Americans. Future studies should focus on enhancing low-income older adults' WAT adoption to enable equal access to WAT-related health benefits.


Molecular genetic identification of Avena chromosomes related to the group 1 chromosomes of the Triticeae.
A collection of 19 wheat (Triticum aestivum) probes, detecting sequences in the seven homoeologous groups of chromosomes, were hybridized to DNA from the 'Kanota' series of oat monosomic lines (Avena byzantina) to investigate their use for identifying groups of homoeologous oat chromosomes. Three probes from homoeologous group 1 of wheat, psr161, psr162, and psr121, mapped among the set of oat chromosomes 1C, 14, and 17. One homoeologous group 6 probe, psr167, mapped to oat chromosomes 1C and 17. Two oat probes that had previously been shown to map to oat chromosomes 1C, 14, and 17 were then hybridized to DNA from the 'Chinese Spring' wheat ditelosomics. They localized to homoeologous group 1 wheat chromosomes, one to the short arm and one to the long arm. These results reveal that in hexaploid oat there is a group of three chromosomes that correspond at least in part to homoeologous group 1 of wheat. The remaining wheat probes identifying other wheat homoeologous sets did not detect a complete series of homoeologous chromosomes in oat. This was presumably due to the incomplete status of the 'Kanota' monosomic series, chromosomal rearrangement in Avena, weak hybridization signals owing to low probe-target sequence homology, and (or) detection of only two hybridization bands by the wheat probe.


Heterogeneity of root and nerve ultrasound pattern in CIDP patients.
The few published ultrasound (US) studies on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) report diffusely increased cross-sectional area (CSA) of nerves. The data are, however, heterogeneous and correlations with clinical history or disease severity are lacking. Thirty-four patients with CIDP underwent US nerve evaluation by two neurologists blinded to clinical data. US nerve pattern for each patient was defined by a third neurologist blinded to clinical data. Three US classes were identified based on CSA and echogenicity: large nerves with hypoechoic nerves/fascicles (class 1); large nerves with heterogeneous hypo- and hyperechoic fascicles (class 2); normal size nerve but abnormal hyperechoic array (class 3). In all patients, US nerve changes were observed: in most of the cases, enlarged nerves or nerve segments were observed. The three 'classes' of US nerve changes significantly correlated (R: 0.68, p<0.001) with disease duration, but not with age or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. US may be of adjunctive diagnostic value in CIDP assessment. Nerve morphological changes may mirror the underlying pathophysiological mechanisms and seem to correlate with disease duration. These results offer the possibility of exploring the use of US to assess CIDP disease activity and treatment.


Human myeloperoxidase gene: molecular cloning and expression in leukemic cells.
We have molecularly cloned the human myeloperoxidase (MPO) gene from the lambda gt11 expression library by screening with an affinity-purified MPO antibody. The cDNA clone of the MPO gene was used to study MPO gene expression in leukemic cells. The amino acid sequence predicted from the nucleotide sequence of the cDNA clone pMP401 matched exactly the 23 amino acid sequence of the NH2-terminal of the 60,000 MPO subunit. We found that MPO cDNA hybridized to a single EcoRI genomic band of 19 kb, indicating that the MPO gene represents a single gene in the human genome. Northern blot analysis of RNA isolated from leukemic cell lines and acute myelogenous leukemia (AML) patients' samples shows that MPO gene expression correlated with myeloid lineage. The intensity of MPO mRNA expression on Northern blot correlated with the level of MPO expression by cytochemical staining. Multiple species of MPO mRNA were found. This indicates that a single MPO gene may encode different RNA species through a mechanism of posttranscriptional processing or that multiple transcriptional start/termination sites exist in the MPO gene.


Strictinin, a novel ROR1-inhibitor, represses triple negative breast cancer survival and migration via modulation of PI3K/AKT/GSK3ß activity.
Triple Negative Breast Cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by the absence of hormone receptors usually targeted by hormone therapies like Tamoxifen. Because therapy success and survival rates for TNBC lag far behind other breast cancer subtypes, there is significant interest in developing novel anti-TNBC agents that can target TNBC specifically, with minimal effects on non-malignant tissue. To this aim, our study describes the anti-TNBC effect of strictinin, an ellagitanin previously isolated from Myrothamnus flabellifolius. Using various in silico and molecular techniques, we characterized the mechanism of action of strictinin in TNBC. Our results suggest strictinin interacts strongly with Receptor Tyrosine Kinase Orphan like 1 (ROR1). ROR1 is an oncofetal receptor highly expressed during development but not in normal adult tissue. It is highly expressed in several human malignancies however, owing to its numerous pro-tumor functions. Via its interaction and inhibition of ROR1, strictinin reduced AKT phosphorylation on ser-473, inhibiting downstream phosphorylation and inhibition of GSK3β. The reduction in AKT phosphorylation also correlated with decreased cell survival and activation of the caspase-mediated intrinsic apoptotic cascade. Strictinin treatment also repressed cell migration and invasion in a beta-catenin independent manner, presumably via the reactivated GSK3ß's repressing effect on microtubule polymerization and focal adhesion turnover. This could be of potential therapeutic interest considering heightened interest in ROR1 and other receptor tyrosine kinases as targets for development of anti-cancer agents. Further studies are needed to validate these findings in other ROR1-expressing malignancies but also in more systemic models of TNBC. Our findings do however underline the potential of strictinin and other ROR1-targeting agents as therapeutic tools to reduce TNBC proliferation, survival and motility.


Morphological Analysis of the Olfactory System of the Pig-Nosed Turtle, Carettochelys insculpta.
The turtle olfactory organ consists of the upper (UCE) and lower (LCE) chamber epithelium, projecting to the ventral and dorsal parts of the olfactory bulbs, respectively. The UCE is associated with glands, contains ciliated olfactory receptor neurons, and is assumed to detect odorants primarily in air, while the LCE is devoid of glands, contains microvillous olfactory receptor neurons, and is assumed to detect odorants primarily in water. Examining the olfactory system of the pig-nosed turtle, Carettochelys insculpta, this study found that both the upper and lower chambers of the nasal cavity were lined with sensory epithelium devoid of associated glands and contained ciliated olfactory receptor neurons. Moreover, the olfactory bulbs were not divided into dorsal and ventral parts. These results suggest that the olfactory system of the pig-nosed turtle is a single system specialized for detecting odorants in water.


Leiomyoma mimicking an incarcerated inguinal hernia: A rare complication of laparoscopic hysterectomy.
A 52-year-old, obese, female patient was referred for a right inguinal mass, which appeared seven months after a laparoscopic hysterectomy, which was performed because of myomatosis. Despite several examinations, including ultrasound, computed tomography (CT)-Scan, positron emission tomography (PET)-CT, and ultrasound-guided biopsy, the diagnosis remained unclear until surgical exploration, which disclosed a well-encapsulated solid tumour corresponding to a fibrotic leiomyoma. Spilling of leiomyoma cells is a rare and unusual complication of laparoscopic surgery. Tumour development in the inguinal canal after laparoscopic gynaecological surgery should be kept in mind in the differential diagnosis of inguinal hernia and other uncommon pathologies.


Autohydrolysis of plant xylans by apoplastic expression of thermophilic bacterial endo-xylanases.
The genes encoding the two endo-xylanases XynA and XynB from the thermophilic bacterium Dictyoglomus thermophilum were codon optimized for expression in plants. Both xylanases were designed to be constitutively expressed under the control of the CaMV 35S promoter and targeted to the apoplast. Transient expression in tobacco and stable expression in transgenic Arabidopsis showed that both enzymes were expressed in an active form with temperature optima at 85 degrees C. Transgenic Arabidopsis accumulating heterologous endo-xylanases appeared phenotypically normal and were fully fertile. The highest xylanase activity in Arabidopsis was found in dry stems indicating that the enzymes were not degraded during stem senescence. High levels of enzyme activity were maintained in cell-free extracts from dry transgenic stems during incubation at 85 degrees C for 24 h. Analysis of cell wall polysaccharides after heat treatment of wildtype and transgenic extracts from dry stems showed a decrease in the molecular weight of xylans from transgenic stems.


Research approaches in illicit drug use: a critical review.
Research approached and substantive findings pertaining to determinants of the nonmedical use of illicit psychoactive drugs are reviewed. Discussion focuses upon the dimensions of drug use as a behaviorial phenomenon, the findings and limitations of four basic approaches to research in the ares--sociocultural, psychopathological, functionalist, and social learning-- and upon methodological problems. Drug use must be treated as a multidimensional phenomenon, with analyses extending well beyond simple user vs. nonuser comparisons or arbitrary categories of users. Research must be conducted within a coherent field-theoretical conceptual framework, directed toward the formulation of nomothetic laws concerning patterns of drug use. Inadequacies in sampling and measurement and the absence of longitudinal design have compromised the utility of a vast research literature.


[Disorder of Ca2+ deposition in the myocardial mitochondria and sarcoplasmic reticulum in sudden death from ischemic heart disease].
The content of Ca2+ was reduced in myocardiocyte mitochondria and sarcoplasmatic reticulum, and increased in the supra-sedimentary fluid following the sedimentation of sarcoplasmatic reticulum in cases of sudden coronary death, an evidence of disturbed Ca2+ deposition in subcellular myocardial fractions and elevated Ca2+ concentration in myocardiocyte sarcoplasm. The demonstrated disturbances of Ca2+ deposition may be responsible for cardiac contractility disorders, and incomplete diastolic relaxation of the myocardium, and thus provide an essential element of thanatogenesis of the sudden coronary death.


Precise in vivo genome editing via single homology arm donor mediated intron-targeting gene integration for genetic disease correction.
In vivo genome editing represents a powerful strategy for both understanding basic biology and treating inherited diseases. However, it remains a challenge to develop universal and efficient in vivo genome-editing tools for tissues that comprise diverse cell types in either a dividing or non-dividing state. Here, we describe a versatile in vivo gene knock-in methodology that enables the targeting of a broad range of mutations and cell types through the insertion of a minigene at an intron of the target gene locus using an intracellularly linearized single homology arm donor. As a proof-of-concept, we focused on a mouse model of premature-aging caused by a dominant point mutation, which is difficult to repair using existing in vivo genome-editing tools. Systemic treatment using our new method ameliorated aging-associated phenotypes and extended animal lifespan, thus highlighting the potential of this methodology for a broad range of in vivo genome-editing applications.


Metabolomics comparison of red cells stored in four additive solutions reveals differences in citrate anticoagulant permeability and metabolism.
Metabolomics studies have revealed transition points in metabolic signatures of red cells during storage in SAGM, whose clinical significance is unclear. We set out to investigate whether these transition points occur independent of storage media and define differences in the metabolism of red cells in additive solutions. Red cell concentrates were stored in SAGM, AS-1, AS-3 or PAGGSM, and sampled fourteen times spanning Day 1-46. Following quality control, the samples were split into extracellular and intracellular aliquots. These were analysed with ultra-high-performance liquid chromatography coupled to mass spectrometry analysis affording quantitative metabolic profiles of both intra- and extracellular red cell metabolites. Differences were observed in glycolysis, purine salvage, glutathione synthesis and citrate metabolism on account of the storage solutions. Donor variability however hindered the accurate characterization of metabolic transition time-points. Intracellular citrate concentrations were increased in red cells stored in AS-3 and PAGGSM media. The metabolism of citrate in red cells in SAGM was subsequently confirmed using 13 C citrate isotope labelling and shown to originate from citrate anticoagulant. Metabolic signatures that discriminate between 'fresh' and 'old' stored red cells are dependent upon additive solutions. Specifically, the incorporation and metabolism of citrate in additive solutions with lower chloride ion concentration is altered and impacts glycolysis.


Pulmonary arterial hypertension in interferonophaties: a case report and a review of the literature.
Pulmonary arterial hypertension consists in an increase of mean pulmonary arterial pressure (PAPm ≥ 25 mmHg), and may lead to right ventricular failure. Pulmonary arterial hypertension can arise in several disorders, encompassing inflammatory conditions and connective tissue diseases. The occurrence of pulmonary arterial hypertension has recently been reported in monogenic interferonopathies and in systemic lupus erythematosus, highlighting the pathogenic role of type I interferons and paving the way to therapies aimed at inhibiting interferon signaling. We describe a 17-year-old boy with DNase II deficiency, presenting a clinical picture with significant overlap with systemic lupus erythematosus. During treatment with the Janus kinase inhibitor ruxolitinib, he developed pulmonary arterial hypertension, raising the question whether it could represent a sign of insufficient disease control or a drug-related adverse event. The disease even worsened after drug withdrawal, but rapidly improved after starting the drug again at higher dosage. Pulmonary arterial hypertension can complicate type I interferonopathies. We propose that ruxolitinib was beneficial in this case, but the wider role of Janus kinase inhibitors for the treatment of pulmonary arterial hypertension is not clear. For this reason, a strict cardiologic evaluation must be part of the standard care of subjects with interferonopathies, especially when Janus kinase inhibitors are prescribed.


The views of quality improvement professionals and comparative effectiveness researchers on ethics, IRBs, and oversight.
Recently, there have been increasing numbers of activities labeled as either quality improvement (QI) or comparative effectiveness research (CER), both of which are designed to learn what works and what does not in routine clinical care settings. These activities can create confusion for researchers, Institutional Review Board members, and other stakeholders as they try to determine which activities or components of activities constitute clinical practices and which constitute clinical research requiring ethical oversight and informed consent. We conducted a series of semi-structured focus groups with QI and CER professionals to understand their experiences and views of the ethical and regulatory challenges that exist as well as the formal or informal practices and criteria they and their institutions use to address these issues. We found that most participants have experienced challenges related to the ethical oversight of QI and CER activities, and many believe that current regulatory criteria for distinguishing clinical practice from clinical research requiring ethical oversight are confusing. Instead, many participants described other criteria that they believe are more ethically appropriate. Many also described developing formal or informal practices at their institutions to navigate which activities require ethical oversight. However, these local solutions do not completely resolve the issues caused by the blurring of clinical practice and clinical research, raising the question of whether more foundational regulatory changes are needed.


Decade of experience with vascular rings at a single institution.
Over the past decade, the diagnostic workup of vascular rings has changed at our institution. Despite surgical intervention, we have observed long-term aerodigestive issues in some patients. In an effort to better characterize these pre- and postoperative issues, we reviewed a decade of experience at our institution. We performed a complete chart review of all patients identified as having surgical intervention for vascular ring between January 1993 and December 2003. A questionnaire was mailed to the family of each patient to ascertain a subjective assessment of long-term postoperative issues. Thirty-eight patients were reviewed and categorized as to specific arch anomaly. Associated cardiac anomalies were present in 29% of patients. Chronic feeding difficulties persisted in 18% of patients, and airway issues remained in nearly half of the patients. Patients with underlying genetic syndromes had less resolution of symptoms compared with nonsyndromic children. Chronic respiratory symptoms were present in 80% of patients operated <6 months, 15% if operated between 6 months and 3 years, and 42% of patients operated after 3 years of age. Aerodigestive issues may persist after vascular ring division despite initial improvement. Accurate preoperative anatomic imaging is imperative to surgical planning.


[Microcirculatory bed in the capsules of certain glands].
The capsules of the thyroid, submaxillary salivary, pancreatic gland of adults and the thymus of children were studed. The preparation were impregnated with silver nitrate after Kuprijanov and stained with haematoxiline-eosin. Different constructions of them microcirculatory bed depending on the character of the tissue and the functional activity of the organ were found. The value of the total cross section of the vessels of the microcirculatroy bed calculated in the capillary link allowed a comparisonof the degree of blood supply of the sheaths. The vascular bed of the sheaths served as anadditional way for the blood supply of the organ, a distribution basin and the site ofcollection of the blood, flowing from the parenchyma through collateral vessels.


[Morphologic changes in the myocardium following acute blood loss and subsequent resuscitation].
An electron microscopic investigation on reparative regeneration of the myocardium has been performed in dogs survived after clinical death resulted from loss of blood. Some regenerative processes already begin on the first hours after reanimation and they proceed on the background of certain distrophic and destructive changes. On the 3d-7th days of the restorative period, the intracellular regeneration of cardiomyocytes increases considerably; it is demonstrated by newly formed myofilaments in the foci of myofibrillar lysis, increasing content of small mitochondria, hyperplasia of the granular endoplasmic reticulum. Simultaneously, a great number of secondary lysosomes is forming; as a result, the cells are releasing themselves from the substances formed after decomposition and decay of some organelles. Myelin-like bodies are observed to be pushed out of the cardiomyocytes into the intercellular space. In fact, by the end of the second week after total ischemia the structure of the cardiac muscle is fully normalized. T-system of cardiomyocytes is the one which is the slowest to restore.


Strength of association between body mass index and physical function scores in paediatric burn patients: A National Institute on Disability, Independent Living, and Rehabilitation Research Burn Model System study.
Increased body weight has been associated with reduced muscle wasting in the early catabolic phase after a severe burn. Yet, overweight and obese non-burn children often exhibit impaired musculoskeletal function, which may lead to poor physical function (PF). We aimed to determine the association between body mass index (BMI) at discharge and self-reported PF and caregiver proxy-reported PF during recovery of burned children. This is a retrospective multisite longitudinal study in paediatric burn patients ((8-17 y old at time of burn). PF outcome measures were self-reported mobility, proxy-reported mobility, and upper extremity PF evaluated using PROMIS measures at 6-, 12-, and 24-months after injury. Primary exposure variable was BMI-for-age at discharge. A total of 118 paediatric patients, aged 11.7 ± 3.3 y, with burns covering 37.6 ± 18.8% of their total body surface area (TBSA) and BMI-for-age of 23.1 ± 5.4 kg/m2 at discharge were analyzed. BMI at discharge was not significantly associated with self-reported mobility scores 6 months after burn (beta coefficient =-0.23, p = 0.31), had a positive effect on mobility at 12 months (beta = 0.46, p = 0.05), and no effect at 24 months after injury (beta=-0.10, p = 0.60), when adjusted for burn size. BMI did not have a significant effect on proxy-reported mobility or upper extremity PF. A greater BMI at discharge was associated with improved self-reported PF at 12 months after burn but not at 6 months or 24 months, which suggests a faster recovery of PF in paediatric patients of larger body weight. Our data suggests that a larger body weight does not compromise the recovery of PF after burn.


A comparison of the effect of two regimens of infestation on the development of resistance by cattle to the cattle tick, Boophilus microplus (Can.).
The development of resistance to Boophilus microplus by cattle was studied using sets of cattle twins, in stalls. One twin from each set received 3 infestations of 40,000 larvae and the other a continuous infestation of 1,000 larvae a day over the same period. Sets of twins were then challenged with 1,000 larvae a day for 40 days and 2 field infestations of 20,000 larvae. Correlations of ranking for resistance made at 40-day periods during daily infestations of 1,000 larval ticks or for corresponding intermittent infestations of 40,000 larvae were low until animals had received 120,000 larvae. Thereafter irrespective of method of infestation correlations of ranking were relatively high (r = 0.61-0.96) between periods of infestations or method of infestation including 2 field infestations. Fewer adult female ticks matured on the daily infested animals than on the intermittently infested animals during the treatment period, but animals developed a similar resistance level whether infested with either technique.


Developing an FHIR-Based Computational Pipeline for Automatic Population of Case Report Forms for Colorectal Cancer Clinical Trials Using Electronic Health Records.
The Fast Healthcare Interoperability Resources (FHIR) is emerging as a next-generation standards framework developed by HL7 for exchanging electronic health care data. The modeling capability of FHIR in standardizing cancer data has been gaining increasing attention by the cancer research informatics community. However, few studies have been conducted to examine the capability of FHIR in electronic data capture (EDC) applications for effective cancer clinical trials. The objective of this study was to design, develop, and evaluate an FHIR-based method that enables the automation of the case report forms (CRFs) population for cancer clinical trials using real-world electronic health records (EHRs). We developed an FHIR-based computational pipeline of EDC with a case study for modeling colorectal cancer trials. We first leveraged an existing FHIR-based cancer profile to represent EHR data of patients with colorectal cancer, and then we used the FHIR Questionnaire and QuestionnaireResponse resources to represent the CRFs and their data population. To test the accuracy of and overall quality of the computational pipeline, we used synoptic reports of 287 Mayo Clinic patients with colorectal cancer from 2013 to 2019 with standard measures of precision, recall, and F1 score. Using the computational pipeline, a total of 1,037 synoptic reports were successfully converted as the instances of the FHIR-based cancer profile. The average accuracy for converting all data elements (excluding tumor perforation) of the cancer profile was 0.99, using 200 randomly selected records. The average F1 score for populating nine questions of the CRFs in a real-world colorectal cancer trial was 0.95, using 100 randomly selected records. We demonstrated that it is feasible to populate CRFs with EHR data in an automated manner with satisfactory performance. The outcome of the study provides helpful insight into future directions in implementing FHIR-based EDC applications for modern cancer clinical trials.


Managing complications of chronic pancreatitis: a guide for the gastroenterologist.
Chronic pancreatitis is a heterogeneous and complex syndrome that, in most cases, causes pain as a cardinal symptom and affects both the morphology and function of the pancreas, leading to several serious complications. The present review, based on a non-systematic PubMed search updated to June 2023, aims to present the current available evidence on the role of gastroenterologists in the diagnosis and treatment of both local and systemic complications by either endoscopic or medical treatments. At diagnosis and during chronic pancreatitis follow-up, particular care is needed to consider not only the clinically manifest signs and symptoms of the disease, such as pain, jaundice, gastrointestinal obstruction, and pseudocysts, which require multidisciplinary discussion to establish the best treatment option (endoscopic or surgical), but also less evident systemic complications. Pancreatic exocrine and endocrine insufficiency, together with chronic inflammation, addiction, and dysbiosis, contribute to malnutrition, sarcopenia, and osteopathy. These complications, in turn, increase the risk of infection, thromboembolic events, and death. Patients with chronic pancreatitis also have an increased risk of psychiatric disorders and pancreatic cancer onset. Overall, patients with chronic pancreatitis should receive a holistic evaluation, considering all these aspects, possibly through multidisciplinary care in dedicated expert centers.


Neuronal elements that mediate escape swimming and suppress feeding behavior in the predatory sea slug Pleurobranchaea.
1. The white, bilaterally paired A1 interneurons of the cerebropleural ganglion of Pleurobranchaea californica fire rhythmic bursts of action potentials during escape swimming behavior. We studied the role of the A1s in swimming behavior and pattern generation in whole animal and isolated CNS preparations. 2. The escape swim is a cyclic sequence of dorsal and ventral flexions of the body. During the swim, A1 bursts precede and accompany the dorsal flexion phase of the cycle. Hyperpolarization of A1 to prevent spike activity interrupts swimming behavior in the whole animal and fictive swimming in the isolated CNS. Stimulated A1 activity was not observed to cause swimming in whole animals, and was only occasionally sufficient to trigger fictive swimming activity in the isolated CNS. 3. In quiescent whole animal preparations, stimulation of a single A1 normally causes a single dorsal flexion followed by body flexion to the side contralateral to the stimulated cell; characteristically, A1 spike activity stimulates feedback inhibition coinciding with the end of dorsal flexion and the onset of contralateral flexion. 4. A1 spike activity suppresses feeding behavior and causes proboscis retraction in whole animal preparations induced to feed. A1 activity also suppresses fictive feeding driven by stimulation of the critical phasic paracerebral neurons (PCps) of the motor network of feeding in the isolated CNS. Concomitantly, A1 spikes cause potent inhibition of the PCp interneurons. 5. The A1s are specifically excited by noxious mechanical and chemical stimuli, but are not affected by feeding stimuli or the occurrence of feeding behavior. 6. We conclude that the A1 neurons are elements of an escape swimming pattern generator, and that they are probably homologous to the similar C2 neurons of the nudibranch Tritonia diomedea. One of their functions outside of generating the swim pattern may be the suppression of feeding behavior in response to noxious stimulation. These observations provide a neural mechanism for the original observations of the dominance of escape swimming behavior over feeding.


The dendritic ERGIC: Microtubule and actin cytoskeletons participate in stop-and-go movement of mobile carriers between stable structures.
The endoplasmic reticulum (ER)-to-Golgi intermediate compartment (ERGIC) is a membranous organelle that mediates protein transport between the ER and the Golgi apparatus. In neurons, clusters of these vesiculotubular structures are situated throughout the cell in proximity to the ER, passing cargo to the cis-Golgi cisternae, located mainly in the perinuclear region. Although ERGIC markers have been identified in neurons, the distribution and dynamics of neuronal ERGIC structures have not been characterized yet. Here, we show that long-distance ERGIC transport occurs via an intermittent mechanism in dendrites, with mobile elements moving between stationary structures. Slow and fast live-cell imaging have captured stable ERGIC structures remaining in place over long periods of time, as well as mobile ERGIC structures advancing very short distances along dendrites. These short distances have been consistent with the lengths between the stationary ERGIC structures. Kymography revealed ERGIC elements that moved intermittently, emerging from and fusing with stationary ERGIC structures. Interestingly, this movement apparently depends not only on the integrity of the microtubule cytoskeleton, as previously reported, but on the actin cytoskeleton as well. Our results indicate that the dendritic ERGIC has a dual nature, with both stationary and mobile structures. The neural ERGIC network transports proteins via a stop-and-go movement in which both the microtubule and the actin cytoskeletons participate.


"Pop-out" method of levonorgestrel implant removal.
The "pop-out" technique is a method of levonorgestrel implant removal that uses digital pressure to direct implants through a small skin incision. This technique was developed, theoretically, to cause less bruising and patient discomfort by avoiding the use of instruments. The pop-out technique is the primary method used for levonorgestrel implant removal in the Magee-Womens Hospital resident clinic. We performed a retrospective analysis of levonorgestrel implant removals performed between July 1, 1995, and December 31, 1998. Of the 168 removals included in this analysis, 38 were performed by one of two attending physicians, and 130 were performed by the residents with attending supervision. The average time for removal was 12 +/- 5 min (range 2.25-27 min) when the "pop-out" method could be used to remove all six implants, and 14 +/- 7 min (range 2.25-59 min) for all removals. The removal time for residents was inversely proportional to the anticipated level of difficulty of the removal and to the number of previous removals performed. The removal time was significantly faster when residents were supervised by one of the attending physicians as compared with the other attending physician. Only 0.7% (7/1,008) of levonorgestrel implants were fragmented during removal. This review shows that the "pop-out" method is a reasonable alternative to other proposed methods of primary implant removal. The difference in the level of expertise of the attending physician may significantly influence removal time when training clinicians in levonorgestrel implant removal.


The N1 domain of human lactoferrin is required for internalization by caco-2 cells and targeting to the nucleus.
Human lactoferrin (hLf) has been shown to interact with cells from the Caco-2 human small intestinal cell line. There currently is little information about the molecular details of its interaction. As a first step toward detailed characterization of this interaction, we used a series of Lf chimeras to analyze which part of Lf is responsible for the interaction with Caco-2 cells. Recombinant chimeric proteins consisting of segments of hLf and bovine transferrin (bTf) were produced in a baculovirus-insect cell system and purified by a combination of cation exchange chromatography and immobilized bTf antibody affinity chromatography. Each chimera was labeled with a green fluorescent dye to monitor its interaction with Caco-2 cells. Similarly, the intestinal Lf receptor (LfR), also known as intelectin, was probed with an anti-LfR antibody that was detected with a secondary antibody conjugated with a red-color fluorescent dye. The results demonstrated that chimeric proteins containing the N-lobe or the N1.1 subdomain of Lf bound as well as intact Lf to Caco-2 cells. Confocal microscopy analysis revealed that these proteins, along with the LfR, were internalized and targeted to the nucleus. These results indicate that the N1.1 subdomain of hLf is sufficient for binding, internalization, and targeting to the nucleus of Caco-2 cells.


Failure of surface ring mutant strains of Helicobacter mustelae to persistently infect the ferret stomach.
Helicobacter mustelae, the gastric pathogen of ferrets, produces an array of surface ring structures which have not been described for any other member of the genus Helicobacter, including H. pylori. The unique ring structures are composed of a protein named Hsr. To investigate whether the Hsr rings are important for colonization of the ferret stomach, ferrets specific pathogen free for H. mustelae were inoculated with an Hsr-deficient mutant strain or the wild-type H. mustelae strain. Quantitative cultures from antral biopsy specimens obtained at 3, 6, and 9 weeks postinoculation demonstrated no significant difference in the levels of bacteria in the ferrets that received the Hsr-negative strain and the ferrets infected with the parent strain. However, when the ferrets were biopsied at 12 and 15 weeks and necropsied at 18 weeks after infection, the levels of bacteria of the Hsr-negative strain in the stomach antrum were significantly reduced. This decline contrasted the robust antral colonization by the wild-type strain. The Hsr-negative strain did not efficiently colonize the gastric body of the study ferrets. Histological examination at 18 weeks postinoculation revealed minimal gastric inflammation in the animals that received the mutant H. mustelae strain, a finding consistent with its waning infection status, whereas lesions characteristic of helicobacter infection were present in ferrets infected with the wild-type strain. Scant colonization by the Hsr-negative H. mustelae strain at the end of the 18-week study, despite initial successful colonization, indicates an inability of the mutant to persist, perhaps due to a specific host response.


Sexually Transmitted Infections Detected by Multiplex Real Time PCR in Asymptomatic Women and Association with Cervical Intraepithelial Neoplasia.
To determine the frequency of sexually transmitted infections (STIs) in asymptomatic women and the association of STIs with cervical intraepithelial neoplasia (CIN). A cross-sectional study was performed, enrolling women examined in a general gynecology clinic and in a colposcopy referral center from October 2014 to October 2015. The colposcopy group consisted of 71 women, and the general gynecology group consisted of 55 women. Cervical samples were collected for cervical cytology and a multiplex real-time polymerase chain reaction (PCR) was developed to detect human papillomavirus (HPV) and the STIs caused by the following microorganisms: Chlamydia trachomatis, Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma urealyticum, and Neisseria gonorrhoeae. A multivariate analysis was performed by logistic regression, considering the significance level of 0.05. The general frequency of STIs was: 46.8% (HPV); 27.8% (C. trachomatis); 28.6% (M. genitalium); 0.8% (M. hominis); 4.8% (U. urealyticum); and 4.8% (N. gonorrhoeae). The significant risk factors for CIN were: HPV infection (odds ratio [OR] = 2.53; p = 0.024); C. trachomatis (OR = 3.04; p = 0.009); M. genitalium (OR = 2.37; p = 0.04); and HPV and C. trachomatis coinfection (OR = 3.11; p = 0.023). After the multivariate analysis, a significant association was found between HPV and CIN (OR = 2.48; 95% confidence interval [95%CI]: 1.04-5.92; p = 0.04); and between C. trachomatis and CIN (OR = 2.69; 95%CI: 1.11-6.53; p = 0.028). The frequency of STIs was high in asymptomatic patients. Infections by HPV and C. trachomatis were independently associated with the presence of CIN. The high frequency of STIs in asymptomatic women suggests the need for routine screening of these infections.


The global epidemiology of waterpipe smoking.
In the past decade, waterpipe smoking (a.k.a. hookah, shisha, narghile) has become a global phenomenon. In this review, we provide an updated picture of the main epidemiological trends in waterpipe smoking globally. Peer-reviewed publications indexed in major biomedical databases between 2004 and 2014. Search keywords included a combination of: waterpipe, hookah, shisha along with epidemiology, patterns, prevalence and predictors. We also used different spellings of waterpipe terms commonly used. The focus was on studies with large representative samples, national data or high-quality reports that illuminated aspects of the epidemiology and trends in waterpipe smoking. Multiple researchers extracted the data independently and collectively decided on the most important and pertinent studies to include in the review. Waterpipe smoking has become a global phenomenon among youth. The global waterpipe epidemic is likely driven by (1) the introduction of manufactured flavoured tobacco (Maassel); (2) the intersection between waterpipe's social dimension and thriving café culture; (3) the evolution of mass communication media; (4) the lack of regulatory/policy framework specific to the waterpipe. Waterpipe smoking is becoming the most popular tobacco use method among youth in the Middle East, and is quickly gaining popularity elsewhere. Important patterns of waterpipe smoking include the predominance among younger, male, high socioeconomic, and urban groups. Intermittent and social use are also noted patterns. Waterpipe smoking has become a global public health problem. Developing surveillance, intervention and regulatory/policy frameworks specific to the waterpipe has become a public health priority.


[Discitis in brucellosis is not responsive to anti-brucella treatment].
A 14-year-old girl with fever and low back pain was diagnosed as having brucellosis and diskitis. Treatment with doxycycline and gentamicin had no effect nor was there any improvement when the treatment was changed to doxycycline and rifampicin. With cessation of this treatment and administration of cloxacillin fever was reduced and the back pain disappeared. After 12 days of i.v. cloxacillin, she was released from hospital with instructions to continue cloxacillin orally for another 4 weeks. We conclude that when a patient is suffering from brucellosis and diskitis and does not respond to the usual anti-brucellosis treatment, an anti-staphylococcal preparation should be added.


Do physician communication skills influence screening mammography utilization?
The quality of physician communication skills influences health-related decisions, including use of cancer screening tests. We assessed whether patient-physician communication examination scores in a national, standardized clinical skills examination predicted future use of screening mammography (SM). Cohort study of 413 physicians taking the Medical Council of Canada clinical skills examination between 1993 and 1996, with follow up until 2006. Administrative claims for SM performed within 12 months of a comprehensive health maintenance visit for women 50-69 years old were reviewed. Multivariable regression was used to estimate the relationship between physician communication skills exam score and patients' SM use while controlling for other factors. Overall, 33.8 % of 96,708 eligible women who visited study physicians between 1993 and 2006 had an SM in the 12 months following an index visit. Patient-related factors associated with increased SM use included higher income, non-urban residence, low Charlson co-morbidity index, prior benign breast biopsy and an interval >12 months since the previous mammogram. Physician-related factors associated with increased use of SM included female sex, surgical specialty, and higher communication skills score. After adjusting for physician and patient-related factors, the odds of SM increased by 24 % for 2SD increase in communication score (OR: 1.24, 95 % CI: 1.11 - 1.38). This impact was even greater in urban areas (OR 1.30, 95 % CI: 1.16, 1.46) and did not vary with practice experience (interaction p-value 0.74). Physicians with better communication skills documented by a standardized licensing examination were more successful at obtaining SM for their patients.


Multi-locus models of genetic risk of disease.
Evidence for genetic contribution to complex diseases is described by recurrence risks to relatives of diseased individuals. Genome-wide association studies allow a description of the genetics of the same diseases in terms of risk loci, their effects and allele frequencies. To reconcile the two descriptions requires a model of how risks from individual loci combine to determine an individual's overall risk. We derive predictions of risk to relatives from risks at individual loci under a number of models and compare them with published data on disease risk. The model in which risks are multiplicative on the risk scale implies equality between the recurrence risk to monozygotic twins and the square of the recurrence risk to sibs, a relationship often not observed, especially for low prevalence diseases. We show that this theoretical equality is achieved by allowing impossible probabilities of disease. Other models, in which probabilities of disease are constrained to a maximum of one, generate results more consistent with empirical estimates for a range of diseases. The unconstrained multiplicative model, often used in theoretical studies because of its mathematical tractability, is not a realistic model. We find three models, the constrained multiplicative, Odds (or Logit) and Probit (or liability threshold) models, all fit the data on risk to relatives. Currently, in practice it would be difficult to differentiate between these models, but this may become possible if genetic variants that explain the majority of the genetic variance are identified.


A single conserved amino acid in the coat protein gene of pea seed-borne mosaic potyvirus modulates the ability of the virus to move systemically in Chenopodium quinoa.
Two isolates of pea seed-borne mosaic potyvirus, DPD1 and NY, which both infect pea (Pisum sativum) systemically, differ in their ability to move long distance in Chenopodium quinoa. DPD1 spreads to uninoculated leaves, whereas NY is restricted to the inoculated leaves. The NY isolate was found to move from cell to cell infecting all parts of the inoculated leaves, including the petiole. The coat protein (CP) coding region was identified as the determinant of long-distance movement. Virus chimeras containing the CP coding sequence of NY were restricted to inoculated leaves, whereas chimeras containing the CP coding sequence of DPD1 infected C. quinoa systemically. Mutational analysis of the CP demonstrated that changing the serine at position 47 of the NY CP to proline was sufficient to permit systemic spread of the NY(S47P) mutant. The reverse mutant, DPD1(P47S), in which the proline at position 47 of the CP was changed to serine, was restricted to inoculated leaves. The movement characteristics and CP sequences of 10 additional PSbMV isolates were determined. All isolates caused systemic infection in pea. In C. quinoa 6 of the isolates that were restricted to inoculated leaves had a serine at position 47. Two isolates that infected C. quinoa systemically had a proline at position 47. Two isolates, S6 and NEP-1, infected C. quinoa systemically, but had a serine at position 47 of the CP. This shows that although a proline/serine difference at position 47 of the CP determined systemic spread of the isolates DPD1 and NY, this amino acid alone does not govern the spread of PSbMV in C. quinoa.


A novel injectable borate bioactive glass cement as an antibiotic delivery vehicle for treating osteomyelitis.
A novel injectable cement composed of chitosan-bonded borate bioactive glass (BG) particles was evaluated as a carrier for local delivery of vancomycin in the treatment of osteomyelitis in a rabbit tibial model. The setting time, injectability, and compressive strength of the borate BG cement, and the release profile of vancomycin from the cement were measured in vitro. The capacity of the vancomycin-loaded BG cement to eradicate methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis in rabbit tibiae in vivo was evaluated and compared with that for a vancomycin-loaded calcium sulfate (CS) cement and for intravenous injection of vancomycin. The BG cement had an injectability of >90% during the first 3 minutes after mixing, hardened within 30 minutes and, after hardening, had a compressive strength of 18 ± 2 MPa. Vancomycin was released from the BG cement into phosphate-buffered saline for up to 36 days, and the cumulative amount of vancomycin released was 86% of the amount initially loaded into the cement. In comparison, vancomycin was released from the CS cement for up 28 days and the cumulative amount released was 89%. Two months post-surgery, radiography and microbiological tests showed that the BG and CS cements had a better ability to eradicate osteomyelitis when compared to intravenous injection of vancomycin, but there was no significant difference between the BG and CS cements in eradicating the infection. Histological examination showed that the BG cement was biocompatible and had a good capacity for regenerating bone in the tibial defects. These results indicate that borate BG cement is a promising material both as an injectable carrier for vancomycin in the eradication of osteomyelitis and as an osteoconductive matrix to regenerate bone after the infection is cured.


[The principal arthropod vectors of disease. What are the risks of travellers' to be bitten? To be infected?].
Many blood-sucking arthropods are potential vectors of disease. To become a vector, the arthropod must be susceptible to the infective agent and must survive the incubation period so as to transmit the pathogens to a host. While some arthropod associated diseases affect only man (e.g. malaria) most of these diseases are (anthropo-) zoonoses with man often an accidental host. The risk of contamination depends on the one hand on the biting behaviour of the vector, its biology and distribution, and on the other hand on the sites visited by the traveller, the length of his stay, his activities, the conditions of sleeping accommodation. The risk of contracting malaria is very high in tropical Africa, in the forest area of South America and South East Asia, in Papua New Guinea. Malaria can be prevented if measures (e.g. pyrethroid impregnated bed nets, repellents) are taken to avoid bites of Anopheline mosquitoes between sunset and sunrise, but appropriate chemoprophylaxis must not be neglected. Lethal cases of yellow fever among unvaccinated travellers still occur despite a strict international regulation on vaccination requirements. Dengue is a major health problem in intertropical areas. As no vaccine is available, personal protection measures are recommended against daytime-biting mosquitoes, including the use of protective clothing, repellents. Other arthropod borne diseases among travellers are less common but the risks increase during adventure trips (e.g. zoonotic leishmaniasis, tick-borne relapsing fever) and humanitarian actions (e.g. risk of louse-borne typhus during visits of overcrowded prisons). Tick-borne diseases receive nowadays more attention. These diseases are not only restricted to some occupations (farmers, veterinarians) but also ramblers and campers are at risk. Attached ticks should be removed rapidly and carefully, since several hours of attachment are needed for transmission of spirochetes of LYME disease.


MS-Based in Situ Proteomics Reveals AMPylation of Host Proteins during Bacterial Infection.
Bacteria utilize versatile strategies to propagate infections within human cells, e.g., by the injection of effector proteins, which alter crucial signaling pathways. One class of such virulence-associated proteins is involved in the AMPylation of eukaryotic Rho GTPases with devastating effects on viability. In order to get an inventory of AMPylated proteins, several technologies have been developed. However, as they were designed for the analysis of cell lysates, knowledge about AMPylation targets in living cells is largely lacking. Here, we implement a chemical-proteomic method for deciphering AMPylated host proteins in situ during bacterial infection. HeLa cells treated with a previously established cell permeable pronucleotide probe (pro-N6pA) were infected with Vibrio parahaemolyticus, and modified host proteins were identified upon probe enrichment and LC-MS/MS analysis. Three already known targets of the AMPylator VopS-Rac1, RhoA, and Cdc42-could be confirmed, and several other Rho GTPases were additionally identified. These hits were validated in comparative studies with V. parahaemolyticus wild type and a mutant producing an inactive VopS (H348A). The method further allowed to decipher the sites of modification and facilitated a time-dependent analysis of AMPylation during infection. Overall, the methodology provides a reliable detection of host AMPylation in situ and thus a versatile tool in monitoring infection processes.


Total internal reflection enabled wide-field coherent anti-Stokes Raman scattering microscopy.
Wide-field coherent anti-Stokes Raman scattering (CARS) microscopy offers an attractive means for the rapid and simultaneous acquisition of vibrationally resolved images across a large field of view. A major challenge in the implementation lies in how to achieve sufficiently strong excitation fields necessary to drive the third-order optical responses over the large focal region. Here, we report a new wide-field CARS microscope enabled by a total internal reflection excitation scheme using a femtosecond Ti:Sapphire oscillator to generate pump and broadband near-infrared Stokes pulses. The spectrally broad Stokes pulse, in combination with its inherent chirp, offers not only access to a wide range of Raman modes spanning ∼1000 to ∼3500cm-1 but also a straightforward means to select vibrational transitions within this range by simply varying the time delay between the pulses. The unique capabilities of this wide-field CARS microscope were validated by acquiring high-quality CARS images from the model and complex biological samples on conventional microscope coverslips.


Effect of AI Explanations on Human Perceptions of Patient-Facing AI-Powered Healthcare Systems.
Ongoing research efforts have been examining how to utilize artificial intelligence technology to help healthcare consumers make sense of their clinical data, such as diagnostic radiology reports. How to promote the acceptance of such novel technology is a heated research topic. Recent studies highlight the importance of providing local explanations about AI prediction and model performance to help users determine whether to trust AI's predictions. Despite some efforts, limited empirical research has been conducted to quantitatively measure how AI explanations impact healthcare consumers' perceptions of using patient-facing, AI-powered healthcare systems. The aim of this study is to evaluate the effects of different AI explanations on people's perceptions of AI-powered healthcare system. In this work, we designed and deployed a large-scale experiment (N = 3,423) on Amazon Mechanical Turk (MTurk) to evaluate the effects of AI explanations on people's perceptions in the context of comprehending radiology reports. We created four groups based on two factors-the extent of explanations for the prediction (High vs. Low Transparency) and the model performance (Good vs. Weak AI Model)-and randomly assigned participants to one of the four conditions. Participants were instructed to classify a radiology report as describing a normal or abnormal finding, followed by completing a post-study survey to indicate their perceptions of the AI tool. We found that revealing model performance information can promote people's trust and perceived usefulness of system outputs, while providing local explanations for the rationale of a prediction can promote understandability but not necessarily trust. We also found that when model performance is low, the more information the AI system discloses, the less people would trust the system. Lastly, whether human agrees with AI predictions or not and whether the AI prediction is correct or not could also influence the effect of AI explanations. We conclude this paper by discussing implications for designing AI systems for healthcare consumers to interpret diagnostic report.


Microrheology and ROCK signaling of human endothelial cells embedded in a 3D matrix.
Cell function is profoundly affected by the geometry of the extracellular environment confining the cell. Whether and how cells plated on a two-dimensional matrix or embedded in a three-dimensional (3D) matrix mechanically sense the dimensionality of their environment is mostly unknown, partly because individual cells in an extended matrix are inaccessible to conventional cell-mechanics probes. Here we develop a functional assay based on multiple particle tracking microrheology coupled with ballistic injection of nanoparticles to measure the local intracellular micromechanical properties of individual cells embedded inside a matrix. With our novel assay, we probe the mechanical properties of the cytoplasm of individual human umbilical vein endothelial cells (HUVECs) embedded in a 3D peptide hydrogel in the presence or absence of vascular endothelial growth factor (VEGF). We found that VEGF treatment, which enhances endothelial migration, increases the compliance and reduces the elasticity of the cytoplasm of HUVECs in a matrix. This VEGF-induced softening response of the cytoplasm is abrogated by specific Rho-kinase (ROCK) inhibition. These results establish combined particle-tracking microrheology and ballistic injection as the first method able to probe the micromechanical properties and mechanical response to agonists and/or drug treatments of individual cells inside a matrix. These results suggest that ROCK plays an essential role in the regulation of the intracellular mechanical response to VEGF of endothelial cells in a 3D matrix.


[Microalbuminuria and urinary albumin excretion: French guidelines].
Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hour-urine sample. Values defining microalbuminuria are: - 24-hour urine sample: 30-300 mg/24 hours - Morning urine sample: 20-200 mg/mL or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mol (women). - Timed urine sample: 20-200 mug/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans. In diabetic subjects, microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is also a marker of CV and renal risk in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. In non-diabetic subjects, microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of the renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence or elevation of UAE overtime is associated with deleterious outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive subjects with 1 or 2 CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic, non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome as it is in diabetic or hypertensive subjects. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is annually recommended in all subjects with microalbuminuria. in patients with microalbuminuria, weight reduction, sodium restriction (< 6 g/day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of ACEI or ARB are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non-diabetic subjects, any of the five classes of anti-hypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or beta-blockers) can be used.


Long non-coding RNA LINC01287 promotes breast cancer cells proliferation and metastasis by activating Wnt/ß-catenin signaling.
Long noncoding RNA (lncRNAs) frequently exhibited abnormal levels in numerous tumors and other diseases in current biological researches. LINC01287, a newly discovered lncRNA, has been found to act as an oncogene in hepatocellular carcinoma. The aim of this research was to explore the expressions and functions of LINC01287 in breast cancer (BC). The relative expressions of LINC01287 in BC tissues and cells were determined using RT-PCR. The associations between the LINC01287 expression, the clinicopathological factors, and the overall survival of BC patients were statistically examined. The apoptosis and proliferation abilities of MCF-7 and MDA-MB-468 cells were analyzed by MTT and flow cytometry assay after LINC01287 knockdown. The effects of LINC01287 in migration and invasion were determined using wound-healing and transwell assays. The protein expressions of the Wnt/β-catenin pathway were determined using Western blot. We showed that the levels of LINC01287 were significantly upregulated in BC tissues and BC cell lines, and the abnormal expressions of LINC01287 were correlated with TNM stage and lymph node metastasis. A distinct difference was observed and indicated that BC patients with higher LINC01287 expressions had significantly shorter overall survival than patients with lower LINC01287 expressions. The multivariate analysis demonstrated that LINC01287 expression was independently correlated with the overall survival. Si-LINC01287 transfection significantly inhibited the proliferation and metastasis of BC cells, and further promoted apoptosis. Besides, the knockdown of LINC01287 suppressed Wnt/β-catenin activation and affected the expressions of β-catenin, cyclin D1, and c-myc. Our findings indicated that the new lncRNA LINC01287 was correlated with poor clinical outcome and may function as a novel prognostic biomarker and therapeutic target in the development of antineoplastic therapies for BC.


Fasciolopsiasis: is it a controllable food-borne disease?
Fasciolopsiasis, endemic to the Orient and Southeast Asia, is a snail-transmitted, intestinal, food-borne parasitic zoonosis caused by a trematode, Fasciolopsis buski, which also infects farm pigs. Fasciolopsiasis remains a public health problem despite changes in eating habits, alterations in social and agricultural practices, health education, industrialization, and environmental alterations. The disease occurs focally and is most prevalent in school-age children. In foci of parasite transmission, the prevalence of infection in children ranges from 57% in mainland China to 25% in Taiwan and from 50% in Bangladesh and 60% in India to 10% in Thailand. Control programs implemented for food-borne zoonoses are not fully successful for fasciolopsiasis because of century-old traditions of eating raw aquatic plants and using untreated water. Fasciolopsiasis is aggravated by social and economic factors such as poverty, malnutrition, an explosively growing free-food market, a lack of sufficient food inspection and sanitation, other helminthiases, and declining economic conditions.


Acute intraperitoneal rupture of hydatid cysts.
Rupture into the abdominal cavity is a rare but serious complication of hydatid disease. The cysts may be ruptured after a trauma, or spontaneously as a result of increased intracystic pressure. Rupture of the hydatid cyst requires emergency surgical intervention. Seventeen patients received surgical treatment for intraperitoneal rupture of the cysts over a period of 18 years. Age, gender, time to surgery from the onset of the symptoms, laboratory findings, diagnostic procedures, surgical treatment modalities, in-hospital stay, morbidity, mortality and recurrence were evaluated retrospectively. Five cases (29.4%) had a history of blunt abdominal trauma. Ultrasonography scans revealed intra-abdominal fluid in all cases. Intraperitoneal multiple cysts with heterogeneous cavity or cystic structures in the liver were shown in 14 cases. Computed tomography and magnetic resonance imaging showed multiple cystic lesions in the liver and peritoneum with intra-abdominal free fluid. Procedures to fill the cystic cavities were applied after removal of the intraperitoneal fluid. Four patients (23.5%) died in the early postoperative period. A total of nine morbidities developed in six patients (35.3%). Median hospital stay was 18 days and median follow-up was 78 months. Intra-abdominal recurrence occurred in one case (7.7%). Rupture of hydatid cysts into the peritoneal cavity, although rare, presents a challenge for surgeons. This pathology should be included in the differential diagnosis of acute abdomen in endemic areas. Computed tomography scan, in addition to clinical presentation, is essential for diagnosis. Emergency surgery is the main treatment for acute ruptured hydatid cysts. The morbidity and mortality rates of surgical interventions for ruptured hydatid cysts are higher than the rates for elective uncomplicated cases.


Quantification of serotonin O-sulphate by LC-MS method in plasma of healthy volunteers.
The objective of this study was to test the hypothesis that serotonin O-sulphate (5-HT-SO4) could be quantified in human plasma using modern liquid chromatography-mass spectrometry (LC-MS) method as well as develop and validate that method. First, a suitable LC-MS method for detection of 5-HT-SO4 in human plasma samples was developed and validated. Second, a Pilot phase involving four healthy volunteers was executed, where a basal plasma level of 5-HT-SO4 was measured for all subjects and for one after the intake of 100 mg of a 5-hydroxytryptophan (5-HTP) -containing food supplement used to promote serotonergic stimulation of the central nervous system. The basal level of 0.9-2.8 ng/mL of 5-HT-SO4 was observed. The changes of plasma 5HT-O-SO4 showed 1.2 ng/mL before and 22.6 ng/mL 1 h after stimulation. Finally, nine healthy volunteers were selected for the Study phase, where a basal plasma level of 5-HT-SO4 was measured before and after the intake of 5-HTP. One hour after stimulation, six study subjects showed a decrease in 5-HT-SO4 levels while three subjects showed an increase. The changes of plasma 5HT-O-SO4 from the Study phase showed an average 5-HT-SO4 level of 19.2 ng/mL before and 15.7 ng/mL 1 h after stimulation indicating ability of method to emphasize quantitative changes. This was the first study in which naturally occurring 5-HT-SO4 was detected in the samples of human plasma obtained from healthy volunteers. The method developed herein is specific to the measurement of 5-HT-SO4, sensitive enough to quantify intra-individual changes in the samples of plasma and opens up new possibilities to evaluate pathways of serotonin metabolism by minimally invasive methods. The discovery of novel biomarkers using such approaches is increasingly required to expedite development of mechanism-based therapeutics and patient stratification.


Advanced statistics: statistical methods for analyzing cluster and cluster-randomized data.
Sometimes interventions in randomized clinical trials are not allocated to individual patients, but rather to patients in groups. This is called cluster allocation, or cluster randomization, and is particularly common in health services research. Similarly, in some types of observational studies, patients (or observations) are found in naturally occurring groups, such as neighborhoods. In either situation, observations within a cluster tend to be more alike than observations selected entirely at random. This violates the assumption of independence that is at the heart of common methods of statistical estimation and hypothesis testing. Failure to account for the dependence between individual observations and the cluster to which they belong can have profound implications on the design and analysis of such studies. Their p-values will be too small, confidence intervals too narrow, and sample size estimates too small, sometimes to a dramatic degree. This problem is similar to that caused by the more familiar "unit of analysis error" seen when observations are repeated on the same subjects, but are treated as independent. The purpose of this paper is to provide an introduction to the problem of clustered data in clinical research. It provides guidance and examples of methods for analyzing clustered data and calculating sample sizes when planning studies. The article concludes with some general comments on statistical software for cluster data and principles for planning, analyzing, and presenting such studies.


Integrating a hand held computer and stethoscope into a fetal monitor.
This article presents procedures for modifying a hand held computer or personal digital assistant (PDA) into a versatile device functioning as an electronic stethoscope for fetal monitoring. Along with functioning as an electronic stethoscope, a PDA can provide a useful information source for a medical trainee. Feedback from medical students, residents and interns suggests the device is well accepted by medical trainees.


[Transcatheter embolization of tumors of the muscular and skeletal systems].
The value of transcatheter embolisation of tumours of the musculoskeletal system is discussed on the basis of 26 cases. All procedures were performed following diagnostic angiography (DSA). By preoperative vascular occlusion it was possible to prevent major blood loss during surgery, provided the operation was carried out within three days of embolisation. Reduction in size of some large inoperable metastases before radio-iodine therapy is another indication for embolisation. As a palliative measure, vascular occlusion can be used for reducing otherwise untreatable skeletal pain and for the management of arteriovenous malformations. Bleeding from a tumour can be controlled by vascular occlusion. Our results indicate that transcatheter embolisation is an effective and reliable technique.


[Epidemiological and economic impact of tetanus vaccination in Colombian adults].
Assess the potential epidemiological and economic impact of vaccinating the over-15 Colombian population against tetanus with a booster dose every 10 years. A cost-effectiveness analysis of tetanus vaccination with a booster dose every 10 years was conducted in Colombia and compared with the current strategy (2, 4, 6, 18, and 60 months). Estimates of the burden of disease were based on three official data sources. A Markov model from the perspective of the third party payer was developed. The time horizon was the lifetime of a person. Deterministic and probabilistic sensitivity analyses were conducted. In Colombia, 30 to 48 cases of tetanus resulting in 9.6 to 10.1 deaths are reported each year. Although booster vaccination for the entire population was cost-effective (the cost per disability-adjusted life year [DALY] avoided was US$ 11,314 in the entire population), gender-based differentiation of the results showed that it would not be cost-effective in women (cost per DALY avoided was US$ 4,903 in men and US$ 22,332 in women). This is the first study that evaluates the cost-effectiveness of a tetanus vaccine booster dose every 10 years in a developing country. Use of this measure would be cost-effective in Colombia, especially for men. As a result of the gender-based differences in the results, any decision about its use in women of childbearing age should take current vaccination into account.


High-dose deferoxamine treatment (intravenous) for thalassaemia patients with cardiac complications.
As a means to manage cardiac conditions, we determined the effects of high-dose intravenous (IV) deferoxamine in 15 thalassaemia patients with cardiomyopathy and high ferritin and haemoglobin levels. The patients received IV deferoxamine, 130 mg/kg per day over 10-14 hours (maximum 5 g) for 5 consecutive days. All patients underwent a full evaluation before receiving deferoxamine, and 2 days and 1 month after completing the treatment. Visual and auditory examinations were done to detect any side-effects. After treatment, cardiovascular symptoms decreased considerably and systolic function showed significant improvement, but there was no significant effect on diastolic function, electrocardiography and physical findings. There were no significant side-effects reported.


Decades of emerging infectious disease, food safety, and antimicrobial resistance response in Vietnam: The role of One Health.
Since facing outbreaks of severe acute respiratory syndrome and avian influenza A in 2003, Vietnam has increasingly applied a One Health approach to address emerging infectious diseases of animal origin. Here, we reflect on the challenges and opportunities of One Health in the context of zoonoses, food safety, and antimicrobial resistance, drawing on a stocktake of One Health training, policy, and research in Vietnam. We also report on the results of a virtual consultation workshop held on July 2021 with representatives from 32 institutions in Vietnam to explore future One Health directions. As Vietnam approaches nearly two decades of disease preparedness and response, we hope our experiences can provide practical insights to support countries in developing coordination mechanisms and moving the One Health agenda forward toward better public health outcomes.


A Novel Integrated Pharmacokinetic-Pharmacodynamic Model to Evaluate Combination Therapy and Determine In Vivo Synergism.
Understanding pharmacokinetic (PK)-pharmacodynamic (PD) relationships is essential in translational research. Existing PK-PD models for combination therapy lack consideration of quantitative contributions from individual drugs, whereas interaction factor is always assigned arbitrarily to one drug and overstretched for the determination of in vivo pharmacologic synergism. Herein, we report a novel generic PK-PD model for combination therapy by considering apparent contributions from individual drugs coadministered. Doxorubicin (Dox) and sorafenib (Sor) were used as model drugs whose PK data were obtained in mice and fit to two-compartment model. Xenograft tumor growth was biphasic in mice, and PD responses were described by three-compartment transit models. This PK-PD model revealed that Sor (contribution factor = 1.62) had much greater influence on overall tumor-growth inhibition than coadministered Dox (contribution factor = 0.644), which explains the mysterious clinical findings on remarkable benefits for patients with cancer when adding Sor to Dox treatment, whereas there were none when adding Dox to Sor therapy. Furthermore, the combination index method was integrated into this predictive PK-PD model for critical determination of in vivo pharmacologic synergism that cannot be correctly defined by the interaction factor in conventional models. In addition, this new PK-PD model was able to identify optimal dosage combination (e.g., doubling experimental Sor dose and reducing Dox dose by 50%) toward much greater degree of tumor-growth inhibition (>90%), which was consistent with stronger synergy (combination index = 0.298). These findings demonstrated the utilities of this new PK-PD model and reiterated the use of valid method for the assessment of in vivo synergism. SIGNIFICANCE STATEMENT: A novel pharmacokinetic (PK)-pharmacodynamic (PD) model was developed for the assessment of combination treatment by considering contributions from individual drugs, and combination index method was incorporated to critically define in vivo synergism. A greater contribution from sorafenib to tumor-growth inhibition than that of coadministered doxorubicin was identified, offering explanation for previously inexplicable clinical observations. This PK-PD model and strategy shall have broad applications to translational research on identifying optimal dosage combinations with stronger synergy toward improved therapeutic outcomes.


[The Free Trade Area of the Americas (FTAA) and the health sector in Latin America].
The Free Trade Area of the Americas-FTAA, which will be implemented in 2005, is the closest expression of economic globalization we will have. In this paper the debate about the neo liberal tendency of globalization is considered: on one side are the defendants of trade, competition and market liberalization; on the other side, those who claim for global social justice, for an alternative globalization, for reaching the ideal of justice in the planet, seriously affected by the free trade agreements, in the absence of a global political power capable of distributing richness. The debate permanently animates this essay on the FTAA which starts with the government proposals and the scope that the interventions of the U.S.A. and the trans-nationals have on the decisions of our countries, besides pointing out to the negative effects that the North American Free Trade Agreement-NAFTA has had on health. Most of the affirmations on the FTAA and its impact on health are derived from its analysis and the new relationships imposed on world trade through organisms as the World Trade Organization-WTO.


Molecular cloning and sequence analysis of a cDNA for factor V activating enzyme.
The complete amino acid sequence of a factor V activator (VLFVA) is deduced from the nucleotide sequence of a cDNA encoding the enzyme. The cDNA was isolated by PCR screening a venomous gland cDNA library of Central Asian Vipera lebetina snake. The full-length cDNA clone, derived from two overlapping fragments, comprises 1563 basepairs which encode an open reading frame of 259 amino acids. The amino acid sequence of VLFVA (235 amino acids) shows significant homology with snake venom and mammalian serine proteinases. It contains 12 half-cysteines which form, by analogy with other serine proteinases, 6 disulfide bridges. VLFVA has the catalytic triad His43-Asp88-Ser182. The amino terminal amino acid valine is preceded by 24 amino acids: a putative signal peptide of 18, mainly hydrophobic, amino acids and an activating peptide of 6, mainly hydrophilic amino acid residues. This is the first cloned factor V activating enzyme from snake venom.


Inhaled underground subway dusts may stimulate multiple pathways of cell death signals and disrupt immune balance.
In this study, we aimed to identify a toxic mechanism and the potential health effects of ambient dusts in an underground subway station. At 24 h exposure to human bronchial epithelial (BEAS-2B) cells (0, 2.5, 10, and 40 μg/mL), dusts located within autophagosome-like vacuoles, whereas a series of autophagic processes appeared to be blocked. The volume, potential and activity of mitochondria decreased in consistent with a condensed configuration, and the percentage of late apoptotic cells increased accompanying S phase arrest. While production of reactive oxygen species, expression of ferritin (heavy chain) protein, secretion of IL-6, IL-8 and matrix metalloproteinases, and the released LDH level notably increased in dust-treated cells (40 μg/mL), intracellular calcium level decreased. At day 14 after a single instillation to mice (0, 12.5, 50, and 200 μg/head), the total number of cells increased in the lungs of dust-treated mice with no significant change in cell composition. The pulmonary levels of TGF-β, GM-CSF, IL-12 and IL-13 clearly increased following exposure to dusts, whereas that of CXCL-1 was dose-dependently inhibited. Additionally, the population of cytotoxic T cells in T lymphocytes in the spleen increased relative to that of helper T cells, and the levels of IgA and IgM in the bloodstream were significantly reduced in the dust-treated mice. Subsequently, to improve the possibility of extrapolating our findings to humans, we repeatedly instilled dusts (1 time/week, 4 weeks, 0.25 and 1.0 mg/head) to monkeys. The total number of cells, the relative portion of neutrophils, the level of TNF-α significantly increased in the lungs of dust-treated monkeys, and the expression of cytochrome C was enhanced in the lung tissues. Meanwhile, the pulmonary level of MIP-α was clearly reduced, and the expression of caveolin-1 was inhibited in the lung tissues. More importantly, inflammatory lesions, such as granuloma, were seen in both mice and monkeys instilled with dusts. Taken together, we conclude that dusts may impair the host's immune function against foreign bodies by inhibiting the capacity for production of antibodies. In addition, iron metabolism may be closely associated with dust-induced cell death and inflammatory response.


Clostridium ljungdahlii represents a microbial production platform based on syngas.
Clostridium ljungdahlii is an anaerobic homoacetogen, able to ferment sugars, other organic compounds, or CO(2)/H(2) and synthesis gas (CO/H(2)). The latter feature makes it an interesting microbe for the biotech industry, as important bulk chemicals and proteins can be produced at the expense of CO(2), thus combining industrial needs with sustained reduction of CO and CO(2) in the atmosphere. Sequencing the complete genome of C. ljungdahlii revealed that it comprises 4,630,065 bp and is one of the largest clostridial genomes known to date. Experimental data and in silico comparisons revealed a third mode of anaerobic homoacetogenic metabolism. Unlike other organisms such as Moorella thermoacetica or Acetobacterium woodii, neither cytochromes nor sodium ions are involved in energy generation. Instead, an Rnf system is present, by which proton translocation can be performed. An electroporation procedure has been developed to transform the organism with plasmids bearing heterologous genes for butanol production. Successful expression of these genes could be demonstrated, leading to formation of the biofuel. Thus, C. ljungdahlii can be used as a unique microbial production platform based on synthesis gas and carbon dioxide/hydrogen mixtures.


DNA Nanodevices with Selective Immune Cell Interaction and Function.
DNA nanotechnology produces precision nanostructures of defined chemistry. Expanding their use in biomedicine requires designed biomolecular interaction and function. Of topical interest are DNA nanostructures that function as vaccines with potential advantages over nonstructured nucleic acids in terms of serum stability and selective interaction with human immune cells. Here, we describe how compact DNA nanobarrels bind with a 400-fold selectivity via membrane anchors to white blood immune cells over erythrocytes, without affecting cell viability. The selectivity is based on the preference of the cholesterol lipid anchor for the more fluid immune cell membranes compared to the lower membrane fluidity of erythrocytes. Compacting DNA into the nanostructures gives rise to increased serum stability. The DNA barrels furthermore functionally modulate white blood cells by suppressing the immune response to pro-inflammatory endotoxin lipopolysaccharide. This is likely due to electrostatic or steric blocking of toll-like receptors on white blood cells. Our findings on immune cell-specific DNA nanostructures may be applied for vaccine development, immunomodulatory therapy to suppress septic shock, or the targeting of bioactive substances to immune cells.


Glaucoma Patient Preferences for Video Education on Eye Drop Technique.
Glaucoma patients express a strong need for practical instruction on instilling eye drops correctly. To maximize the benefit of a video intervention to improve eye drop technique, patients recommend that video education be provided both in the clinic setting and online. The purposes of this study were to (1) describe glaucoma patients' perspectives on how to improve an online eye drop technique video and how to disseminate it to other glaucoma patients and (2) examine how these perspectives differ across demographics. Glaucoma patients (N = 43) who viewed an online eye drop technique educational video as part of a randomized controlled trial were interviewed to assess their overall rating of the video on a 4-point scale, with whom they had watched the video, whether they would recommend the video to others, how the video helped them, how they would recommend improving the video, and how they would like the video to be disseminated to other glaucoma patients. Patients' mean (SD) rating of the video was 3.4 (0.8), with a higher mean rating of 3.8 among African Americans (P = .02). All 43 patients said that they would recommend that others watch the video. Patients most commonly said that the video helped them learn to block the tear duct correctly, put the cap down on its side, mix the medication correctly, and close the eye after instillation. Patients preferred viewing the video in the doctor's office examination room and a website. Eye drop technique videos should be disseminated in the doctor's office and online. Health systems that integrate educational videos into their everyday practice may be able to use technique videos to improve patient technique at low cost and little time burden to the provider.


Superparamagnetic iron oxide nanoparticles (SPION) for the treatment of antibiotic-resistant biofilms.
Bacterial infections caused by antibiotic-resistant strains are of deep concern due to an increasing prevalence, and are a major cause of morbidity in the United States of America. In particular, medical device failures, and thus human lives, are greatly impacted by infections, where the treatments required are further complicated by the tendency of pathogenic bacteria, such as Staphylococcus aureus, to produce antibiotic resistant biofilms. In this study, a panel of relevant antibiotics used clinically including penicillin, oxacillin, gentamicin, streptomycin, and vancomycin are tested, and although antibiotics are effective against free-floating planktonic S. aureus, either no change in biofilm function is observed, or, more frequently, biofilm function is enhanced. As an alternative, superparamagnetic iron oxide nanoparticles (SPION) are synthesized through a two-step process with dimercaptosuccinic acid as a chelator, followed by the conjugation of metals including iron, zinc, and silver; thus, the antibacterial properties of the metals are coupled to the superparamagnetic properties of SPION. SPION might be the ideal antibacterial treatment, with a superior ability to decrease multiple bacterial functions, target infections in a magnetic field, and had activity better than antibiotics or metal salts alone, as is required for the treatment of medical device infections for which no treatment exists today.


Purification of the 22000- and 20000-mol.wt. forms of human somatotropin and characterization of their binding to liver and mammary binding sites.
Quantitative data concerning the binding of 22000-mol.wt. human somatotropin and its 20000-mol.wt. variant are described using pregnant-rabbit liver and mammary-gland receptors. The purification and the complete chemical characterization of both human somatotropin and its 20000-mol.wt. variant is also presented. Contamination of the 20000-mol.wt.-variant preparation by 22000-mol.wt. hormone was found to be 0.5% by weight as measured in radioimmunoassay using monoclonal antibody. Labelling of human somatotropin and its 20000-mol.wt. variant using the Iodogen method is described as well as the characterization of the binding to pregnant-rabbit liver and mammary-gland receptor preparations. The maximum binding capacity of the 125I-labelled human somatotropin was between 50 and 60% to liver particulate receptor, whereas that of the 20000-mol.wt. variant was 30%. The specificity of binding of both forms to rabbit hepatic and mammary-gland receptor was found to be similar for both proteins in the same system. The affinity constants and capacity were respectively 0.7 X 10(10)M-1 and 815 fmol/mg of protein for human somatotropin and 0.6 X 10(10)M-1 and 1.250 fmol/mg of protein for the 20000-mol.wt. variant. These data suggest that both proteins behave as partial agonists to the receptors studied.


Identification and characterisation of high affinity nucleoside and nucleobase transporters in Toxoplasma gondii.
The protozoan parasite Toxoplasma gondii depends upon salvaging the purines that it requires. We have re-analysed purine transport in T. gondii and identified novel nucleoside and nucleobase transporters. The latter transports hypoxanthine (TgNBT1; K(m)=0.91+/-0.19 microM) and is inhibited by guanine and xanthine: it is the first high affinity nucleobase transporter to be identified in an apicomplexan parasite. The previously reported nucleoside transporter, TgAT1, is low affinity with K(m) values of 105 and 134 microM for adenosine and inosine, respectively. We have now identified a second nucleoside transporter, TgAT2, which is high affinity and inhibited by adenosine, inosine, guanosine, uridine and thymidine (K(m) values 0.28-1.5 microM) as well as cytidine (K(i)=32 microM). TgAT2 also recognises several nucleoside analogues with therapeutic potential. We have investigated the basis for the broad specificity of TgAT2 and found that hydrogen bonds are formed with the 3' and 5' hydroxyl groups and that the base groups are bound through H-bonds with either N3 of the purine ring or N(3)H of the pyrimidine ring, and most probably pi-pi-stacking as well. The identification of these high affinity purine nucleobase and nucleoside transporters reconciles for the first time the low abundance of free nucleosides and nucleobases in the intracellular environment with the efficient purine salvage carried out by T. gondii.


Impact of Quercetin against Salmonella Typhimurium Biofilm Formation on Food-Contact Surfaces and Molecular Mechanism Pattern.
Quercetin is an active nutraceutical element that is found in a variety of foods, vegetables, fruits, and other products. Due to its antioxidant properties, quercetin is a flexible functional food that has broad protective effects against a wide range of infectious and degenerative disorders. As a result, research is required on food-contact surfaces (rubber (R) and hand gloves (HG)) that can lead to cross-contamination. In this investigation, the inhibitory effects of quercetin, an antioxidant and antibacterial molecule, were investigated at sub-MIC (125; 1/2, 62.5; 1/4, and 31.25; 1/8 MIC, μg/mL) against Salmonella Typhimurium on surfaces. When quercetin (0−125 μg/mL) was observed on R and HG surfaces, the inhibitory effects were 0.09−2.49 and 0.20−2.43 log CFU/cm2, respectively (p < 0.05). The results were confirmed by field emission scanning electron microscopy (FE-SEM), because quercetin inhibited the biofilms by disturbing cell-to-cell connections and inducing cell lysis, resulting in the loss of normal cell morphology, and the motility (swimming and swarming) was significantly different at 1/4 and 1/2 MIC compared to the control. Quercetin significantly (p < 0.05) suppressed the expression levels of virulence and stress response (rpoS, avrA, and hilA) and quorum-sensing (luxS) genes. Our findings imply that plant-derived quercetin could be used as an antibiofilm agent in the food industry to prevent S. Typhimurium biofilm formation.


Blood transfusions using 27 gauge PICC lines: a retrospective clinical study on safety and feasibility.
Blood transfusions are required by most extremely low birth weight (ELBW) infants, but sometimes an adequate peripheral venous access cannot be achieved. Under these circumstances, we used 27 Gauge (G) peripherally inserted central catheter (PICC) lines that are routinely inserted on the second day of life. Due to their narrow lumen, hemolysis of transfused erythrocytes was a major concern. We therefore performed a retrospective study in ELBW infants to analyze the incidence, safety and feasibility of PRBC transfusions via 27 G PICC lines. ELBW infants admitted from 08/2011-07/2012 were screened for packed red blood cell (PRBC) transfusions. Those applied via 27 G PICC lines were identified. For analysis of transfusion safety (hemolysis), hemoglobin and potassium levels as well as cardiovascular variables (invasive mean arterial blood pressure and heart rate) were evaluated before and after transfusion. For analysis of transfusion feasibility, catheter removal after transfusion and the reason for removal were recorded. A total of 648 transfusions were applied in 110 ELBW infants. 27 infants (24%) received no transfusion. In 12/83 (14.5%) infants who received PRBCs, transfusions were applied using a 27 G PICC line (38/648, 5.9%). Patients who received PRBCs via the PICC line were smaller at birth (582 g [range 380-752 g] vs. 710 g [430-972 g]; 23+6 [23+1-27+6] vs. 26+0 [23+1-31+4]) and required a higher number of PRBC transfusions (n=13 vs. n=5) overall. Transfusion analysis showed an appropriate increase of blood hemoglobin levels and stable potassium levels as well as cardiovascular parameters. 4/38 of PICC lines were removed within 24 h after transfusion, one due to occlusion (15 h after transfusion). We conclude that PRBC transfusions via 27 G PICC lines were feasible and performed without signs of hemolysis in ELBW infants. Our findings may help clinicians in the management of ELBW infants requiring transfusions if a peripheral venous access is not achievable.


Factors influencing variation in implementation outcomes of the redesigned community health fund in the Dodoma region of Tanzania: a mixed-methods study.
Micro-health insurance (MHI) has been identified as a possible interim solution to foster progress towards Universal Health Coverage (UHC) in low- and middle- income countries (LMICs). Still, MHI schemes suffer from chronically low penetration rates, especially in sub-Saharan Africa. Initiatives to promote and sustain enrolment have yielded limited effect, yet little effort has been channelled towards understanding how such initiatives are implemented. We aimed to fill this gap in knowledge by examining heterogeneity in implementation outcomes and their moderating factors within the context of the Redesigned Community Health Fund in the Dodoma region in Tanzania. We adopted a mixed-methods design to examine implementation outcomes, defined as adoption and fidelity of implementation (FOI) as well as their moderating factors. A survey questionnaire collected individual level data and a document review checklist and in-depth interview guide collected district level data. We relied on descriptive statistics, a chi square test and thematic analysis to analyse our data. A review of district level data revealed high adoption (78%) and FOI (77%) supported also by qualitative interviews. In contrast, survey participants reported relatively low adoption (55%) and FOI (58%). Heterogeneity in adoption and FOI was observed across the districts and was attributed to organisational weakness or strengths, communication and facilitation strategies, resource availability (fiscal capacity, human resources and materials), reward systems, the number of stakeholders, leadership engagement, and implementer's skills. At an individual level, heterogeneity in adoption and FOI of scheme components was explained by the survey participant's level of education, occupation, years of stay in the district and duration of working in the scheme. For example, the adoption of job description was statistically associated with occupation (p = 0.001) and wworking in the scheme for more than 20 months had marginal significant association with FOI (p = 0.04). The study demonstrates that assessing the implementation processes helps to detect implementation weaknesses and therefore address such weaknesses as the interventions are implemented or rolled out to other settings. Attention to contextual and individual implementer elements should be paid in advance to adjust implementation strategies and ensure greater adoption and fidelity of implementation.


WashU Epigenome Browser update 2019.
The WashU Epigenome Browser (https://epigenomegateway.wustl.edu/) provides visualization, integration and analysis tools for epigenomic datasets. Since 2010, it has provided the scientific community with data from large consortia including the Roadmap Epigenomics and the ENCODE projects. Recently, we refactored the codebase, redesigned the user interface, and developed various novel features. New features include: (i) visualization using virtual reality (VR), which has implications in biology education and the study of 3D chromatin structure; (ii) expanded public data hubs, including data from the 4DN, ENCODE, Roadmap Epigenomics, TaRGET, IHEC and TCGA consortia; (iii) a more responsive user interface; (iv) a history of interactions, which enables undo and redo; (v) a feature we call Live Browsing, which allows multiple users to collaborate remotely on the same session; (vi) the ability to visualize local tracks and data hubs. Amazon Web Services also hosts the redesign at https://epigenomegateway.org/.