Enhancement of the toxicity and DNA incorporation of arabinosyl-5-azacytosine and 1-beta-D-arabinofuranosylcytosine by cyclopentenyl cytosine.
We evaluated the interaction of a biochemically active concentration of cyclopentenyl cytosine (CPE-C), an investigational antimetabolite which inhibits CTP synthetase, on the cytotoxicity of arabinosyl-5-azacytosine (Ara-AC) and 1-beta-D-arabinofuranosylcytosine (Ara-C) in HCT 116 colon carcinoma cells. A 3-h exposure to 0.5 microM CPE-C depleted CTP pools by over 90% and decreased dCTP pools by 57%; the effect on CTP pools persisted for up to 24 h following washout of CPE-C. A 3-h pre-exposure to 0.5 microM CPE-C augmented the growth inhibition resulting from a 24-h exposure to Ara-AC. The combination of 1 microM cytidine and deoxycytidine fully reversed the enhancement associated with CPE-C pretreatment, to a level of growth inhibition expected from either CPE-C or Ara-AC alone. A striking enhancement of toxicity was observed in clonogenic studies with pre-exposure to CPE-C at a nonlethal dose followed by either Ara-AC or Ara-C. CPE-C increased the formation of Ara-AC and Ara-C nucleotides by as much as 3-fold, and this was accompanied by increased incorporation of the arabinosyl nucleotides into methanol-precipitable material. Analysis of purified RNase-treated nucleic acids by cesium sulfate density centrifugation confirmed that a 3-h pre-exposure to CPE-C increased [3H]-Ara-C incorporation into DNA at 4 and 24 h by 2.4- and 2.7-fold, respectively. Thus, these studies indicate that CPE-C can function as a biochemical modulator. Following a brief exposure to a nonlethal concentration, CPE-C is capable of augmenting the cytotoxicity and intracellular metabolism of Ara-AC and Ara-C.


[Clinical treatment of inflammatory and benign ulcerous diseases of the stomach and duodenum with a new combination preparation (Aci-Tensilan) (author's transl)].
A gastroduodenal combination preparation was introduced at a deliberately high dosage into a clinical treatment schema. A marked improvement of the subjective symptoms already appeared after a short treatment in hospital, pain in particular being rapidly affected. Younger patients tolerated the preparation excellently, older ones had a marked sedation. Because of the danger of concealment, stenoses in the region of the gastrointestinal tract, ileus and preileus are particular contraindications. The dosage of 3 X 3 to 3 X 4 dragees should be reserved for hospital treatment. The dosage of 3 X 1 dragee for ambulant practice and also for prolonged therapy (ca. 6-8 weeks) is unobjectionable, reference being made to possible initial tiredness and disturbances of accomodation.


Adverse event following immunization or vaccination in children in Minas Gerais: 2015 to 2020.
To describe adverse event following immunization or vaccination in children in Minas Gerais: 2015 to 2020, resulting from immunization errors in children from zero to nine years old. An ecological, descriptive study with a quantitative approach, based on event notifications available in the National Immunization Program Information System. Among the 39,903,277 doses of immunobiologicals in children aged zero to nine, administered in the state of MG, 3,259 events of types of immunization errors were recorded, around 0.008% of the total and, of these, 91.86% did not result in adverse events and 56.02% were children under one year of age. The most frequent diagnosis was application outside the recommended age (29.12%). Among the manifestations, 71.91% were local and systemic, with fever being the most common (40.85%). The study demonstrated that immunization errors were rare and that most of them were not associated with adverse events, which reinforces the safety of the immunization process. This undoubtedly raises reflection on the need and relevance of continuing education for health professionals.


Cardio-respiratory signal extraction from video camera data for continuous non-contact vital sign monitoring using deep learning.
Non-contact vital sign monitoring enables the estimation of vital signs, such as heart rate, respiratory rate and oxygen saturation (SpO2), by measuring subtle color changes on the skin surface using a video camera. For patients in a hospital ward, the main challenges in the development of continuous and robust non-contact monitoring techniques are the identification of time periods and the segmentation of skin regions of interest (ROIs) from which vital signs can be estimated. We propose a deep learning framework to tackle these challenges. This paper presents two convolutional neural network (CNN) models. The first network was designed for detecting the presence of a patient and segmenting the patient's skin area. The second network combined the output from the first network with optical flow for identifying time periods of clinical intervention so that these periods can be excluded from the estimation of vital signs. Both networks were trained using video recordings from a clinical study involving 15 pre-term infants conducted in the high dependency area of the neonatal intensive care unit (NICU) of the John Radcliffe Hospital in Oxford, UK. Our proposed methods achieved an accuracy of 98.8% for patient detection, a mean intersection-over-union (IOU) score of 88.6% for skin segmentation and an accuracy of 94.5% for clinical intervention detection using two-fold cross validation. Our deep learning models produced accurate results and were robust to different skin tones, changes in light conditions, pose variations and different clinical interventions by medical staff and family visitors. Our approach allows cardio-respiratory signals to be continuously derived from the patient's skin during which the patient is present and no clinical intervention is undertaken.


Optokinetic stimulation influences the disturbed perception of body orientation in spatial neglect.
The effect of optokinetic stimulation on the disturbed perception of body orientation in three patients with right brain damage and spatial neglect was examined. The patients were asked to direct a laser point to the position which they felt lay exactly "straight ahead" of their bodies' orientation. Without stimulation they localised the body's sagittal midplane markedly to the right of the objective orientation. The patients' horizontal displacement of the sagittal midplane was reduced by a movement of the surround to the left and worsened by a movement to the right. The findings are consistent with those found in patients with spatial neglect using vestibular and neck proprioceptive stimulation. They show that visual input, together with vestibular and neck proprioceptive input, is used for computing a central representation of egocentric space. In spatial neglect this coordinate transformation works with a systematic error and deviation of the spatial reference frame to the ipsilesional side. The positive effect of optokinetic stimulation in patients with spatial neglect is interpreted with a "correction" of the neural coordinate transformation process by producing asymmetric input at the sensory organs of the contributing channels.


Institutional, policy and farmer responses to drought: El Niño events and rice in the Philippines.
Droughts are common recurring natural hazards in Asia, and El Niño events are particularly severe in the Philippines. This paper explores responses by farm households, irrigation system managers, and macro policymakers in the Philippines to El Niño. In response to the large 1997-98 El Niño, farmers in one major irrigation system significantly diversified their economic activities, hut the drought was so acute that many of these activities were not successful. Communication between meteorologists and irrigation system managers is strong, and irrigation system managers are aware of El Niño events in advance. Communication between irrigation system managers and farmer irrigation associations is also strong, and together they have developed response options that attempt to augment supplies of and more efficiently allocate scarce water. Water pricing is not used, however, and lack of cooperation among farmers results in sub-optimal outcomes. Macro-level policy responses in terms of rice imports and buffer stock management to protect poor consumers have improved substantially over time.


Thioredoxin-mediated redox control of the transcription factor Sp1 and regulation of the thioredoxin gene promoter.
In recent years, redox control has emerged as a fundamental mechanism of gene regulation through transcriptional control. Thioredoxin (Trx) is a dithiol-reducing enzyme known to be involved in the redox regulation of a number of transcription factors, and in this study, we have investigated the redox-dependent regulation of the DNA binding activity of Sp1 by thioredoxin. Electrophoretic mobility shift assays were used to show that both recombinant Sp1 produced in Escherichia coli and endogenous Sp1 expressed by MDA-MB-231 breast cancer cells is subject to redox regulation. We found that thioredoxin alone or in conjunction with the full thioredoxin system (comprising thioredoxin, thioredoxin reductase [TR], and alpha-nicotinamide adenine dinucleotide phosphate [NADPH]) can increase Sp1 DNA binding activity in vitro to an oligonucleotide containing the Sp1 consensus sequence. Furthermore, we have provided evidence that recombinant Sp1 can bind to Sp1 consensus sequences within a 330-base pair (bp) thioredoxin promoter fragment and that this interaction can also be enhanced by the presence of thioredoxin. Luciferase reporter assays using this same minimal thioredoxin promoter region demonstrated that both Sp1 and Sp3 can bind to the promoter and act to enhance transcription. When the three identified Sp1 consensus sequences within the reporter construct were deleted, there was a loss of basal promoter activity, showing that these closely positioned sites are important for regulation of thioredoxin gene expression.


Vortex fluidic high shear induced crystallisation of fullerene C70 into nanotubules.
Hollow C70 nanotubules are formed under high shear within the thin film of a vortex fluidic device (VFD) without the need for using auxiliary reagents, high temperatures and pressures, and/or requiring downstream processing. This novel bottom-up crystallisation process involves intense micro mixing of two liquids (toluene solution of C70 and anti-solvent, isopropyl alcohol) within a thin film in the VFD to precisely control the hierarchical assembly of C70 molecules into hollow nanotubules. The mechanism of self-assembly was consistent with them being a mould of the high shear double helical topological flow from Faraday waves coupled with Coriolis forces generated within the thin film.


[Somatostatin in the treatment of established and severe acute pancreatitis in the rat].
The effects of somatostatin (SS) on the treatment of acute pancreatitis were studied in rats. Acute pancreatitis was established by injecting 5% sodium taurocholate in the biliopancreatic duct. Previously, pancreatic necrosis was determined in this experimental model at several intervals without treatment. Treatment was started according different groups: at 12, 16 and 20 hours after induction of acute pancreatitis (IV bolus of 4 ug/kg body weight followed by a 24h continuous infusion of 4 ug/kg body wt/hour). When somatostatin was initiated at 12 or 16h a decrease in serum amylase and lactodehydrogenase was observed, as well as in pancreatic necrosis resulting in 0% mortality after 24h of treatment. When somatostatin was started at 20h there was no changes in the lethal outcome of the disease.


Term Newborns with relatively low Tissue Oxygen Saturation Levels soon after Birth are predisposed to Neonatal Respiratory Disorders in Low-risk, Elective Cesarean Sections.
Background: Neonatal respiratory disorders, such as transient tachypnea of the newborn and respiratory distress syndrome, occur frequently after an elective cesarean delivery. Although conventional pulse oximetry is recommended for neonatal resuscitation, it often requires several minutes after birth to obtain a reliable signal. In a previous study, we used novel tissue oximetry equipment to detect fetal and neonatal early tissue oxygen saturation (StO2) before and immediately after vaginal delivery. Therefore, we hypothesized that low neonatal StO2 levels measured by tissue oximetry may lead to neonatal respiratory disorder after a scheduled cesarean delivery. Hence, this study aimed to evaluate the StO2 levels measured by tissue oximetry in neonates with or without a respiratory disorder subsequently diagnosed after an elective cesarean delivery. Materials and methods: We enrolled 78 pregnant Japanese women who underwent an elective cesarean section at ≥36 weeks' gestation. After combined spinal and epidural anesthesia were administered to the mother, fetal StO2 levels were measured by tissue oximetry using an examiner's finger-mounted sensor during a pelvic examination immediately before the cesarean section. We measured the neonatal StO2 levels at 1, 3, and 5 minutes after birth and retrospectively compared the fetal and neonatal StO2 levels with the incidence of subsequent diagnoses of neonatal respiratory disorders. Results: The data of StO2 levels in 35 neonates were collected. Seven neonates (respiratory disorder (RD) group) were subsequently diagnosed with respiratory disorders by neonatal medicine specialists, whereas the 28 remaining neonates (NR group) were not. The median fetal StO2 (interquartile range) of the RD and NR groups was 52.0% (41.8%-60.8%) and 42.5% (39.0%-52.5%), respectively (P = 0.12). The median neonatal StO2 (interquartile range) of the RD and NR groups at 1 minute after birth was 42.0% (39.0%-44.0%) and 46.0% (42.0%-49.0%), respectively (P = 0.091). At 3 minutes after birth, the median neonatal StO2 (interquartile range) of the RD and NR groups was 41.0% (39.0%-46.0%) and 47.0% (44.3%-53.5%), respectively (P = 0.004). Finally, at 5 minutes after birth, the median neonatal StO2 (interquartile range) of the RD and NR groups was 45.0% (44.0%-52.0%) and 54.0% (49.3%-57.0%), respectively (P = 0.007). Conclusions: The StO2 values in the RD group were lower than those in the NR group at 3 and 5 minutes after birth, suggesting that neonates with low StO2 levels soon after birth may be predisposed to clinically diagnosed neonatal respiratory disorders.


The pattern of involvement of adult-onset acid maltase deficiency at autopsy.
The autopsy findings in a clinically and biochemically documented case of adult-onset acid maltase deficiency presenting with limb girdle myopathy are presented. The skeletal muscles, tongue, extraocular and smooth muscles of gut and arterioles showed a vacuolar myopathy, most severely affecting proximal skeletal muscles. Muscle spindles were severely affected in all muscles. The heart showed basophilic degeneration and a vacuolar myopathy. The visceral organs and nervous system were morphologically normal. Possible mechanisms for this differential involvement of muscles and tissues are discussed.


Antiepileptic drug treatment of generalized tonic-clonic seizures: An evaluation of regulatory data and five criteria for drug selection.
A generalized tonic-clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper. Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs). (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs. Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices.


The contraction-expansion behaviour in the demosponge Tethya wilhelma is light controlled and follows a diurnal rhythm.
Sponges (phylum Porifera) are metazoans which lack muscles and nerve cells, yet perform coordinated behaviours such as whole-body contractions. Previous studies indicate diurnal variability in both the number of contractions and the expression of circadian clock genes. Here, we show that diurnal patterns are present in the contraction-expansion behaviour of the demosponge Tethya wilhelma, by using infrared videography and a simulated night/day cycle including sunrise and sunset mimics. In addition, we show that this behaviour is at least strongly influenced by ambient light intensity and therefore indicates light-sensing capabilities in this sponge species. This is supported by our finding that T. wilhelma consistently contracts at sunrise, and that this pattern disappears both when the sponge is kept in constant darkness and when it is in constant light.


Uniform data collection in routine clinical practice in cardiovascular patients for optimal care, quality control and research: The Utrecht Cardiovascular Cohort.
Background Cardiovascular disease remains the major contributor to morbidity and mortality. In routine care for patients with an elevated cardiovascular risk or with symptomatic cardiovascular disease information is mostly collected in an unstructured manner, making the data of limited use for structural feedback, quality control, learning and scientific research. Objective The Utrecht Cardiovascular Cohort (UCC) initiative aims to create an infrastructure for uniform registration of cardiovascular information in routine clinical practice for patients referred for cardiovascular care at the University Medical Center Utrecht, the Netherlands. This infrastructure will promote optimal care according to guidelines, continuous quality control in a learning healthcare system and creation of a research database. Methods The UCC comprises three parts. UCC-1 comprises enrolment of all eligible cardiovascular patients in whom the same information will be collected, based on the Dutch cardiovascular management guideline. A sample of UCC-1 will be invited for UCC-2. UCC-2 involves an enrichment through extensive clinical measurements with emphasis on heart failure, cerebral ischaemia, arterial aneurysms, diabetes mellitus and elevated blood pressure. UCC-3 comprises on-top studies, with in-depth measurements in smaller groups of participants typically based on dedicated project grants. All participants are followed up for morbidity and mortality through linkage with national registries. Conclusion In a multidisciplinary effort with physicians, patients and researchers the UCC sets a benchmark for a learning cardiovascular healthcare system. UCC offers an invaluable resource for future high quality care as well as for first-class research for investigators.


Operational implications of using 2006 World Health Organization growth standards in nutrition programmes: secondary data analysis.
To assess the implications of adopting the World Health Organization 2006 growth standards in combination with current diagnostic criteria in emergency and non-emergency child feeding programmes. Secondary analysis of data from three standardised nutrition surveys (n=2555) for prevalence of acute malnutrition, using weight for height z score (<-2 and <-3) and percentage of the median (<80% and <70%) cut-offs for moderate and severe acute malnutrition from the National Center for Health Statistics/WHO growth reference (NCHS reference) and the new WHO 2006 growth standards (WHO standards). Refugee camps in Algeria, Kenya, and Bangladesh. Population Children aged 6-59 months. Important differences exist in the weight for height cut-offs used for defining acute malnutrition obtained from the WHO standards and NCHS reference data. These vary according to a child's height and according to whether z score or percentage of the median cut-offs are used. If applied and used according to current practice in nutrition programmes, the WHO standards will result in a higher measured prevalence of severe acute malnutrition during surveys but, paradoxically, a decrease in the admission of children to emergency feeding programmes and earlier discharge of recovering patients. The expected impact on case fatality rates of applying the new standards in conjunction with current diagnostic criteria is unknown. A full assessment of the appropriate use of the new WHO standards in the diagnosis of acute malnutrition is urgently needed. This should be completed before the standards are adopted by organisations that run nutrition programmes targeting acute malnutrition.


[Research status and outlook of deep learning in oral and maxillofacial medical imaging].
Artificial intelligence, represented by deep learning, has received increasing attention in the field of oral and maxillofacial medical imaging, which has been widely studied in image analysis and image quality improvement. This narrative review provides an insight into the following applications of deep learning in oral and maxillofacial imaging: detection, recognition and segmentation of teeth and other anatomical structures, detection and diagnosis of oral and maxillofacial diseases, and forensic personal identification. In addition, the limitations of the studies and the directions for future development are summarized.


Lactobacillus acidophilus ameliorates H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways.
H. pylori infection may trigger Smad7 and NFκB expression in the stomach, whereas probiotics promote gastrointestinal health and improve intestinal inflammation caused by pathogens. This study examines if probiotics can improve H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways. Challenge with H. pylori increased IL-8 and TNF-α expressions but not TGF-β1 in MKN45 cells. The RNA levels of Smad7 in AGS cells increased after H. pylori infection in a dose-dependent manner. A higher dose (MOI 100) of L. acidophilus pre-treatment attenuated the H. pylori-induced IL-8 expressions, but not TGF-β1. Such anti-inflammatory effect was mediated via increased cytoplasmic IκBα and depletion of nuclear NFκB. L. acidophilus also inhibited H. pylori-induced Smad7 transcription by inactivating the Jak1 and Stat1 pathways, which might activate the TGF-β1/Smad pathway. L. acidophilus pre-treatment ameliorated IFN-γ-induced Smad7 translation level and subsequently reduced nuclear NF-κB production, as detected by western blotting. H. pylori infection induces Smad7, NFκB, IL-8, and TNF-α production in vitro. Higher doses of L. acidophilus pre-treatment reduce H. pylori-induced inflammation through the inactivation of the Smad7 and NFκB pathways.


The Clinical Functional Impairment Scale Development.
The purpose of the project was to review content validity and assess the span of responses for the newly developed Clinical Functional Impairment Scale (CFIS). A cross-sectional, content validity process using focus groups of developmental, behavioral pediatric clinicians was conducted. After qualitative analysis of the focus group data, adjustments were made in the CFIS based on the recommendations of the content experts. A survey was conducted of clinicians participating in the online Society of Developmental and Behavioral Pediatrics Discussion Board. Clinicians reviewed 2 case studies and used the CFIS to score severity and interval change of predetermined functional impairments. The amount of spread in the answers was assessed by calculating the index of dispersion. Qualitative analysis of the focus groups resulted in adjustment to the CFIS to 20 functional impairments, with a 5-point Likert scale of severity and a 7-point Likert scale of interval change. Ninety-four clinicians participated in the survey. The index of dispersion ranged from 0.49 to 0.88. The interval ratings of severity and interval change had lower dispersion ranges. The CFIS uses a mutual prioritization by the family and clinician of the child's functional impairments. The study demonstrated that the clinicians' ratings of the case studies were more variable in the initial symptom severity score than their ratings of symptom severity and interval change in symptoms. Further testing of the CFIS is planned using face-to-face clinical encounters and including parent/caregiver ratings of severity and interval change.


Race and pregnancy-related care in Brazil and South Africa.
This study examines women's use of pregnancy-related medical care in Brazil and South Africa, two multiracial societies with very different histories of race-related legislation that could affect medical care utilization. The analysis uses nationally representative household-level data to show that inequality in the distribution of socioeconomic resources across racial groups and differences in the sociodemographic conditions surrounding individual pregnancies explain much of the racial difference in women's use of prenatal and delivery care in both countries. Even if these characteristics and resources were equalized across women however, the results suggest that non-White South African women would still be less likely than Whites to initiate prenatal care in the first trimester or to have a doctor present at the time of delivery. The mechanisms through which race works to influence the use of care are examined, and the Brazilian and South African contexts are discussed. These findings suggest that although state-sanctioned racism may help to explain the greater racial inequality in stunting in South Africa than in Brazil, reducing the disadvantage for non-Whites in South Africa and Brazil will depend on reducing fundamental inequalities in the distribution of socioeconomic resources and medical services that characterize many nations.


Ultrasonographic and biometric evaluation of the eye and orbit of dogs.
The normal B-scan ultrasonographic anatomic features of the eye and orbit of mesocephalic and dolichocephalic dogs were described. The B-scan appearance of ocular and orbital structures correlated well with the visual morphologic features of the specimens. The eyes of mesocephalic and dolichocephalic dogs were measured by use of ultrasonographic methods; those measurements were compared with direct measurements of the specimens. The 2-tailed Student t-test was used for all statistical analyses (P = 0.05). Measurements made included mid-cornea to anterior lens surface, lens thickness, vitreous body (posterior lens surface to retina), and axial globe length. The A-scan measurements of all 4 ocular distances were significantly different, compared with direct measurements. The B-scan measurements of mid-cornea to anterior lens surface, lens thickness, and vitreous body were significantly different from direct measurements; however, there was no significant difference between B-scan and direct measurements of axial globe length. There was no significant difference between A- and B-scan measurements. These findings suggest that A- and B-scan measurements are similar and that B-scan measurements are reasonably accurate for axial globe determination. Several variables were compared by B-scan and direct measurement methods. The axial globe length of dolichocephalic dogs was significantly longer than that of mesocephalic dogs. The axial globe length of male and female dogs was not significantly different in mesocephalic or dolichocephalic dogs. There was no significant difference in the axial globe length of right and left eyes in mesocephalic or dolichocephalic dogs.


Recreational exercise and occupational activity during pregnancy and birth weight: a case-control study.
Our purpose was to investigate the impact of exercise and occupational activity on birth weight. This case-control study involved singleton infants at > or = 34 weeks' gestation without congenital anomalies. Case subjects had birth weights at <15th percentile for gestational age, and 2 control subjects were selected per case subject. Data were collected by self-completed questionnaire and analyzed by means of logistic regression. Relative to those who participated in structured exercise 3 or 4 times per week during the third trimester, the odds of lower birth weight were substantially increased for those who exercised > or = 5 times per week (adjusted odds ratio, 4.61; 95% confidence interval, 1.73-12.32) and modestly increased for those at the other extreme, who engaged in structured exercise < or = 2 times per week (adjusted odds ratio, 2.64; 95% confidence interval, 1.29-5.39). Other factors of importance to birth weight were maternal height, prepregnancy body mass, pregnancy weight gain, smoking in the third trimester, and nulliparity. Structured exercise frequency during late pregnancy is a determinant of birth weight.


Regularized image recovery in scattering media.
When imaging in scattering media, visibility degrades as objects become more distant. Visibility can be significantly restored by computer vision methods that account for physical processes occurring during image formation. Nevertheless, such recovery is prone to noise amplification in pixels corresponding to distant objects, where the medium transmittance is low. We present an adaptive filtering approach that counters the above problems: while significantly improving visibility relative to raw images, it inhibits noise amplification. Essentially, the recovery formulation is regularized, where the regularization adapts to the spatially varying medium transmittance. Thus, this regularization does not blur close objects. We demonstrate the approach in atmospheric and underwater experiments, based on an automatic method for determining the medium transmittance.


Method for quantifying volumetric lesion change in interval liver CT examinations.
We propose a method of using a relatively low degree of freedom (DOF) warping to accurately measure the interval change of lesions having homogeneous contrast. The setting presented here presupposes the use of interval computed tomography (CT) liver exams. After a 3 x 24 DOF warping of the later examination to match the liver's pose in the earlier exam of the interval pair is performed, the lesion's volume change is estimated using the computed difference volume of the two data sets via a novel method that counts partial volume contributions and is insensitive to slight misregistration. A mathematically generated phantom is used to quantify accuracy in the presence of noise. We also quantify the accuracy of our CT liver registrations using microcoils implanted for chemotherapy. A probabilistic liver atlas is used to support automatic masking and liver-focused registration.


A Missed Summer Wave of the 1918-1919 Influenza Pandemic: Evidence From Household Surveys in the United States and Norway.
Background. Reanalysis of influenza survey data from 1918 to 1919 was done to obtain new insights into the geographic and host factors responsible for the various waves. Methods. We analyzed the age- and sex-specific influenza morbidity, fatality, and mortality for the city of Baltimore and smaller towns and rural areas of Maryland and the city of Bergen (Norway), using survey data. The Maryland surveys captured the 1918 fall wave, whereas the Bergen survey captured 3 waves during 1918-1919. Results. Morbidity in rural areas of Maryland was higher than in the city of Baltimore during the fall of 1918, that was almost equal to that in Bergen during the summer of 1918. In Bergen, the morbidity in the fall was only half of that in the summer, with more females than males just above the age of 20 falling ill, as seen in both regions of Maryland. In contrast, more males than females fell ill during the summer wave in Bergen. Individuals <40 years had the highest morbidity, whereas school-aged children had the lowest fatality and mortality. Conclusion. A previously unrecognized pandemic summer wave may have hit the 2 regions of Maryland in 1918.


Calcium influx factor, further evidence it is 5, 6-epoxyeicosatrienoic acid.
We present evidence in astrocytes that 5,6-epoxyeicosatrienoic acid, a cytochrome P450 epoxygenase metabolite of arachidonic acid, may be a component of calcium influx factor, the elusive link between release of Ca2+ from intracellular stores and capacitative Ca2+ influx. Capacitative influx of extracellular Ca2+ was inhibited by blockade of the two critical steps in epoxyeicosatrienoic acid synthesis: release of arachidonic acid from phospholipid stores by cytosolic phospholipase A2 and cytochrome P450 metabolism of arachidonic acid. AAOCF3, which inhibits cytosolic phospholipase A2, blocked thapsigargin-stimulated release of arachidonic acid as well as thapsigargin-stimulated elevation of intracellular free calcium. Inhibition of P450 arachidonic acid metabolism with SKF525A, econazole, or N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide, a substrate inhibitor of P450 arachidonic acid metabolism, also blocked thapsigargin-stimulated Ca2+ influx. Nano- to picomolar 5, 6-epoxyeicosatrienoic acid induced [Ca2+]i elevation consistent with capacitative Ca2+ influx. We have previously shown that 5, 6-epoxyeicosatrienoic acid is synthesized and released by astrocytes. When 5,6-epoxyeicosatrienoic acid was applied to the rat brain surface, it induced vasodilation, suggesting that calcium influx factor may also serve a paracrine function. In summary, our results suggest that 5,6-epoxyeicosatrienoic acid may be a component of calcium influx factor and may participate in regulation of cerebral vascular tone.


Molecular targets of FTY720 (fingolimod).
FTY720 is a recently approved first line therapy for relapsing forms of multiple sclerosis. In this context, FTY720 is a pro-drug, with its anti-multiple sclerosis, immunosuppressive effects largely elicited following its phosphorylation by sphingosine kinase 2 and subsequent modulation of G protein-coupled sphingosine 1-phosphate (S1P) receptor 1 that induces lymphopenia by altering lymphocyte trafficking. A number of other biological effects of FTY720 have, however, been described, including considerable evidence that this drug also has anti-cancer properties. These other effects of FTY720 are independent of S1P receptors, and appear facilitated by modulation of a range of other recently described protein targets by nonphosphorylated FTY720. Here, we review the direct targets of FTY720 that contribute to its anti-cancer properties. We also discuss other recently described protein effectors that, in combination with S1P receptors, appear to contribute to its immunosuppressive effects.


Toward a better understanding of functional ovarian reserve: AMH (AMHo) and FSH (FSHo) hormone ratios per retrieved oocyte.
Functional ovarian reserve (FOR) has recently been demonstrated to differ with ovarian genotypes of the FMR1 gene and is currently routinely determined with anti-Müllerian hormone (AMH) and FSH. Both, however, reflect distinctively different stages of folliculogenesis. To better understand how AMH and FSH reflect FOR, we evaluated both hormones in association with in vitro fertilization (IVF) by determining how they associate with oocyte yields, considered the most accurate available measure of FOR. Using a series of logistic regressions, we assessed AMH and FSH per oocyte retrieved (AMHo and FSHo) in only first IVF cycles and determined whether at different ages and/or based on ovarian FMR1 genotypes and subgenotypes AMHo and/or FSHo are associated with clinical pregnancy chances in IVF. We investigated 392 consecutive IVF patients of all ages, with among them 60.7% suffering from diminished FOR. Interventions included routine IVF cycles. Clinical pregnancy rate in IVF cycle was assessed. FSHo, but not AMHo, was, overall, statistically associated with pregnancy chances in IVF. This association was further limited to women above age 38 yr. FSHo was also significantly associated with pregnancy chances in women with normal FMR1 genotype, although only almost reaching significance with heterozygous-normal/low. Normal-genotype patients also demonstrate significant interaction between FSHo and age in pregnancy outcome, although insignificant for all other FMR1 genotypes and subgenotypes and universally for AMHo. AMHo and FSHo are representative of distinctively different components of FOR, likely influenced by different ovarian FMR1 genotypes and subgenotypes.


Restoration of expression of signal-transduction molecules in lymphocytes from patients with metastatic renal cell cancer after combination immunotherapy.
A decrease in lymphocyte signal-transduction molecules, described in cancer patients and patients with chronic infectious diseases, has been proposed as a possible mechanism leading to an impaired immune response in cancer patients. Here we report the effects of combination immunotherapy on the levels of T cell receptor zeta chain and p56lck tyrosine kinase in a retrospective study of cryopreserved lymphocytes from 26 metastatic renal cell carcinoma patients treated with high-dose interleukin-2 (IL-2), interferon alpha (IFNalpha) and ex vivo IL-2-activated lymphocytes. Of the 26 patients, 12 were responders (5 complete and 7 partial) and 14 were non-responders (6 stable and 8 with progressive disease). Prior to treatment, 21 of 26 patients (81%) and 13 of 21 patients (62%) respectively expressed zeta chain and p56lck at less than 50% of the levels observed in healthy controls. During therapy, this low zeta chain and p56lck expression increased to at least 50% of normal in 13 of the 21 patients (62%) and in 6 of the 13 patients (46%) respectively; in the remaining patients expression levels remained at 50% of normal or more, or declined. Although, in this limited study, pretreatment levels of and p56lck did not show significant correlation with antitumor response, 4 of 5 patients that achieved a complete response (80%) corrected both zeta chain and p56lck levels to at least 50% of normal, while restoration of both signal-transduction molecules to such levels was only observed in 3 of 7 partial responders (43%), 1 of 5 patients with stable disease (20%) and 2 of 7 patients with progressive disease (29%). Thus, these results suggest that analysis of changes in signal-transduction molecules may a be useful tool for immunological monitoring of patients throughout immunotherapy, and could provide important information for designing new clinical trials that restore impaired signal transduction while activating T cell responses.


[One hundred years of orthopedics in the Netherlands. I. Introduction].
One hundred years ago, on 1 May 1898, the Netherlands Orthopaedic Association was founded. This was prompted by the view that general surgeons paid insufficient attention to the treatment of the locomotor system; they were permitted to join the new association, however, at any rate until 1947. It was especially in the last 30 years that orthopaedic surgery underwent major changes. The most striking novelty was arthroplastic surgery. There have also been developments in the treatment of spinal abnormalities, rheumatological surgery, sports medicine, oncology and traumatology.


Voices of oncology nurses: What is needed to assist patients with advance directives.
The process of completing and executing advance directives (ADs) is not without problems and issues that need to be studied. Nurses, by the nature of their practice, are in a unique position to help patients complete ADs. The findings reported in this article focus on an open-ended question that was part of a larger quantitative survey. The open-ended question, "What do oncology nurses need to increase their ability to assist patients with ADs?" was asked of a random sample of Oncology Nursing Society members. The Knowledge, Attitudinal, Experiential Survey on Advance Directives instrument was used to survey a random sample of oncology nurses in four states: California, Illinois, New York, and Texas. Of the 900 nurses who responded to the survey, 677 (75%) wrote responses to the open-ended question. Grounded theory was used to analyze data to establish and saturate categories. The four topics discussed most often by the nurses were time, education, support, and the nurse's role. Nurses also wrote about philosophical issues related to dying, end-of-life issues, and ADs, as well as institutional issues that have an impact on the assistance they can give patients completing ADs. In addition, the category "communicating" was frequently discussed by nurses. The importance of communication was a thread woven throughout their responses.


Truncal valve repair in an adolescent with severe annular dilatation.
Approximately 20% of patients with truncus arteriosus might need a truncal valve procedure within 20 years after anatomical repair due to regurgitation. These patients commonly develop valve regurgitation due to root dilatation with a sufficient amount of good quality valvular tissue. Thus, the reduction of the truncal annulus is the single most important factor to achieve durable repair, especially in patients in whom the Ross procedure is not an option.


Components of nuclear domain 10 bodies regulate varicella-zoster virus replication.
PML, Sp100, and Daxx are proteins that normally reside within nuclear domains 10 (ND10s). They associate with DNA virus genomes and repress the very early stages of the DNA virus replication cycle. Virus-encoded proteins counteract this innate antiviral response. ICP0, a herpes simplex virus (HSV) immediate-early protein, is necessary and sufficient to dissociate ND10s and target their two major components, PML and Sp100, for proteasomal degradation. In this report, we show that ORF61p, the varicella-zoster virus (VZV) ortholog of ICP0, does not degrade PML and alters Sp100 levels only slightly. Furthermore, we demonstrate that other virus proteins cannot substitute for this lack of function during infection. By using short interfering RNAs, we depleted PML, Sp100, and Daxx and studied their roles in plaquing efficiency, virus protein accumulation, infectious-center titer, and virus spread. The results of these studies show that components of ND10s can accelerate VZV replication but do not ultimately control cell-associated virus titers. We conclude that while both ICP0 and ORF61p activate virus gene expression, they modulate host innate repression mechanisms in two different ways. As a result, HSV and VZV commandeer their host cells by distinct mechanisms to ensure their replication and spread.


Allergen provocation tests in respiratory research: building on 50 years of experience.
The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review.


[Diagnosis and treatment heart and pericardium wounds].
The experience of diagnosis and treatment of heart and pericardium wounds in 152 patients are presented. In obecure diagnosis the authors prefer X-ray examination and echocardiography. Total lethality was 23.6%. Its high level is due to injury of coronary arteries and intracardiac structures, other thoracic and abdominal organs. The left anterolaferal thoracotomy is the optimum approach in wounds of the heart and pericardium. The most frequent complication of postoperative period is pericarditis, its echographic symptoms were revealed in 91% examinys. Non-steroid and steroid antiinflammatory drugs are effective for prophylaxis and treatment of pericarditis.


Transformation pathways in high-pressure solid nitrogen: from molecular N2 to polymeric cg-N.
The transformation pathway in high-pressure solid nitrogen from N2 molecular state to polymeric cg-N phase was investigated by means of ab initio molecular dynamics and metadynamics simulations. In our study, we observed a transformation mechanism starting from molecular Immm phase that initiated with formation of trans-cis chains. These chains further connected within layers and formed a chain-planar state, which we describe as a mixture of two crystalline structures--trans-cis chain phase and planar phase, both with Pnma symmetry. This mixed state appeared in molecular dynamics performed at 120 GPa and 1500 K and in the metadynamics run at 110 GPa and 1500 K, where the chains continued to reorganize further and eventually formed cg-N. During separate simulations, we also found two new phases--molecular P2(1)/c and two-three-coordinated chain-like Cm. The transformation mechanism heading towards cg-N can be characterized as a progressive polymerization process passing through several intermediate states of variously connected trans-cis chains. In the final stage of the transformation chains in the layered form rearrange collectively and develop new intraplanar as well as interplanar bonds leading to the geometry of cg-N. Chains with alternating trans and cis conformation were found to be the key entity--structural pattern governing the dynamics of the simulated molecular-polymeric transformation in compressed nitrogen.


Acculturation, education, nutrition education, and household composition are related to dietary practices among Cambodian refugee women in Lowell, MA.
Refugees in the United States have higher rates of some chronic diseases than US-born residents or other first-generation immigrants. This may be partially a result of dietary practices in the United States. There is limited information about which factors are related to dietary practices in refugee populations, particularly those who have been in the United States for 10 to 20 years. Research with Cambodian communities may be useful for examining the relationship between refugee characteristics and dietary practices. Two focus groups (n=11) and a survey (n=150) of Cambodian refugee women were conducted in Lowell, MA, from 2007 to 2008. χ(2) analyses, t tests, and analysis of variance tests were used to describe differences in dietary practices (24-hour recall and a targeted qualitative food assessment) by group characteristics. Higher acculturation was related to higher likelihood of eating brown rice/whole grains, and to lower likelihood of eating high-sodium Asian sauces. Higher education was related to higher likelihood of eating vegetables and fruits and to eating white rice fewer times. Nutrition education and receiving dietary advice from a health care provider were related to higher likelihood of eating whole grains/brown rice. Having a child at home was related to a higher likelihood of eating fast food. Among Cambodian refugees who have been in the United States for 10 to 20 years, dietary practices appear to have a relationship with acculturation (positive association), the interrupted education common to refugees (negative association), nutrition education from either programs or health care providers (positive association), and having a child at home (negative association).


Polydopamine-Based Multifunctional Platform for Combined Photothermal Therapy, Chemotherapy, and Immunotherapy in Malignant Tumor Treatment.
We designed a multifunctional platform by coloading DOX, an antitumor drug, and imiquimod (R837), an immune adjuvant against Toll-like-receptor-7 (TLR-7), onto polydopamine nanoparticles (PDA NPs), a photothermal therapy (PTT) agent, to develop PDA/DOX&R837 NPs used as combined photothermal therapy, chemotherapy, and immunotherapy in order to enhance the cancer therapeutic effects. For a high delivery to malignant tumors, a folate ligand-receptor recognition molecule was grafted to the nanoparticle surface for a higher cellular uptake efficiency. The particle size, ζ potential, morphology, drug loading content, and drug release profiles of FA-PDA/DOX&R837 NPs were investigated. The antitumor effects under near-infrared (NIR) laser radiation were evaluated, and our results showed that a three-mode strategy combined therapy was significantly superior to single-mode therapy for tumor suppression. The synergetic toxicity of hyperthermia and DOX almost completely eliminated tumors, and together with R837, they further promoted the maturation of dendritic cells to induce a strong antitumor immune response, making tumor recurrence substantially lower than that without R837. This platform can be used as a potential targeted drug delivery system for combined cancer therapy.


Patient self-reports in pharmacoeconomic studies. Their use and impact on study validity.
The validity of estimates of resource utilisation based on patient recall has not been firmly established. A comprehensive literature search was conducted to identify studies that used patient self-reports to derive estimates of healthcare resource utilisation, direct nonmedical costs and indirect costs. Previous work in this area was examined to determine the issues that were most important in determining whether patient self-reports lead to valid and unbiased estimates in cost-effectiveness studies. This study reviews and highlights areas where patient self-reports lead to reliable estimates and where their use may lead to erroneous conclusions. In particular, it is noted that patient recall of resource utilisation declines over time, that the salience of a treatment episode affects recall and that the perceived social acceptability of a condition and other confounding factors may influence patient reporting. Moreover, it appears that not all elements of healthcare consumption are recalled to the same degree: medication use tends to be recalled with less accuracy than hospitalisation. In terms of the potential impact on cost-effectiveness results, the main concern is with problems of validity rather than bias, although bias may occur when the results are applied to league tables.


Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children.
The search for genetic factors predisposing to Attention Deficit Hyperactivity Disorder (ADHD) has focused on genes that regulate dopaminergic pathways such as dopamine receptors and enzymes that regulate levels of dopamine in the synapse. There have been several reports of association between ADHD and polymorphic variants within or near DRD4, DRD5, DAT1, DBH and COMT. In this study we set out to investigate specific alleles of DRD4 and DRD5, previously reported to be associated with ADHD, in a sample of Turkish children with DSM-IV ADHD children, as well as their relation to methylphenidate response and dimensional measures of symptom domains. One hundred and four independent trios and seven dyads were analysed using the transmission disequilibrium test (TDT). We found increased transmission of the DRD4 7-repeat allele (DRD4*7) (TDT chi2 = 2.79, P = 0.047). Given that we were testing specific a priori hypotheses regarding the associated alleles, we have used one-tailed P-values throughout. There was evidence of an interaction with methlyphenidate (MPH) response and analysis of the sample excluding non-responders revealed more significant evidence for the association (TDT chi2 = 4.48, P = 0.017). We also detected a trend for linkage and association in the DRD5 polymorphism (TDT chi2 = 2. 38, P = 0.06). Similar findings were obtained in relation to MPH response as analysis of MPH responders alone gave rise to a more significant association than that of the group as a whole (TDT chi2 = 4.9, P = 0.013). t-Test and logistic regression TDT analyses of DRD4*7 transmission with respect to dimensional rating scales of hyperactivity and impulsivity showed an inverse relation suggesting that in this sample DRD4*7 is associated with a lower level of ADHD symptomatology. While this may be due to stratification along a dimension of severity such that severe cases belong to a more extreme group with other specific genetic and environmental causes, similar to the model for low cognitive ability, it is more likely the result of a chance selection bias in this sample.


[The effect of nootropic agents on brain mitochondrial function in the dynamics of craniocerebral trauma from the age aspect].
A craniocerebral trauma was modelled in experiments on one-month-old rats. Oxidative phosphorylation in the brain mitochondria was studied by polarography 1, 4, 7 days and 4 weeks after the trauma. In the posttraumatic period the animals received piracetam (1 g/kg), picamilon (500 mg/kg), pyriditol (100 mg/kg), pantogam (160 mg/kg), ACTH (5-10) (0.1 mg/kg), nooglutyl (25 mg/kg), and GVS (0.5 mg/kg). It was found that piracetam, picamilon, and nooglutyl have a protective effect on the function of the brain mitochondria during the course of a craniocerebral trauma. Nooglutyl surpasses all the other drugs in its influence on the effectiveness of oxidative phosphorylation of mitochondria in immature rats in the posttraumatic period.


A method for establishing a patient-derived xenograft model to explore new therapeutic strategies for esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of esophageal carcinoma in China. The overall 5-year survival rate of ESCC patients is in the low range of 15-25%. One important reason for the poor prognosis is that the underlying molecular mechanisms are unclear. Furthermore, the development of effective therapeutic strategies to improve patient outcome is needed. Animal models can be beneficial to analyze the molecular mechanisms as well as specific clinical therapeutic strategies for esophageal cancer. In recent years, patient-derived xenografts (PDXs) have been widely used in numerous types of cancers to investigate the basic mechanisms and to conduct preclinical research. Accumulating evidence indicates that the PDX model is an important tool for basic and clinical research. Herein, we successfully established 14 ESCC PDXs. These PDX models preserved the patient pathological characteristics and effectively reflected the patient biological heterogeneity. Cancers exhibit diverse growth rates and tumor texture, even more, they have different signaling pathways. The PDX model is a superior strategy for understanding the underlying molecular mechanisms of ESCC and for screening new therapeutic strategies for ESCC patients.


Micellization of telechelic associative polymers: self-consistent field modeling and comparison with scaling concepts.
We present numerical results from self-consistent field calculations on the micellization of telechelic associative polymers and their mono-functional analogues. These results are confronted with relatively simple scaling concepts. The proportionality of the critical micelle concentration (CMC) with the hydrophilic backbone length, as found in the calculations, shows good correspondence with a scaling argument based on the entropic penalty of loop formation. It is also shown that models for the conformation of spherical brushes can be applied to predict the structure of the flowerlike micelles formed by these telechelic polymers. Furthermore, we find good agreement between the numerical dependence of the aggregation number upon both backbone and terminal hydrophobe length and an analytical expression derived from the well-known Daoud-Cotton model by introducing a correction for the finite size of the micellar core.


[Nonlinear optical absorption characteristics of a novel organic material ZnTBP/CA/PhR].
The measurement of optical absorption spectrum in visible light range of a novel organic material Zn-tetrabenzoporphincrotonic acid/phenoxy resin (ZnTBP/CA/PhR) is reported in this paper. The nonlinear absorption property of the sample illuminated by lasers with different wavelengths was studied. And the absorption alteration and kinetic process of the major spectrum bands were observed. The saturation absorption (SA) and reverse saturation absorption (RSA) appeared as the input fluence increased, and re-reverse saturation absorption process of the material was demonstrated in the experiment. These properties occurred in a broad range of visible spectrum. The paper qualitatively analyses the physical mechanism during the whole course. Based on the nonlinear absorption characteristics, we showed some applications in photonics field of ZnTBP/CA/PhR.


[Post-radiation changes in cardiac contractility and responses mediated by beta adrenergic receptors in mature and old age].
Experiments were performed on isolated perfused hearts of rats of the middle and old age. The animals were irradiated with 60Co gamma-rays at a dose of 1 Gy and a dose rate of 2.7 x 10(-4) Gy/s. This exposure enhanced pacemaking activity and attenuated contractile activity of rat hearts. The biomechanical changes were most distinct in adult rats. It can be assumed that the mechanisms responsible for heart contraction and relaxation as well as for their self-regulation are more resistant to ionizing radiation in old-aged animals. Post-radiation changes of neurohormonal regulation show different age-related features. In adult rats, the exposure caused only a decline of the chronotropic response to stimulation of beta-adrenoreceptors whereas in old animals it produced a decline of inotropic and coronary responses. It is postulated that mechanisms underlying adrenergic effects at the level of the receptor apparatus of coronary vessels and cardiomyocytes experience greater changes in old-aged animals exposed to irradiation.


Management trends for anaplastic meningioma with adjuvant radiotherapy and predictors of long-term survival.
OBJECTIVEThe purpose of this study was to describe effects of adjuvant radiotherapy (RT) for anaplastic meningiomas (AMs) on long-term survival, and to analyze patient and RT characteristics associated with long-term survival.METHODSThe authors queried a retrospective cohort of patients with AM from the National Cancer Database (NCDB) diagnosed between 2004 and 2015 to describe treatment trends. For outcome analysis, patients with at least 10 years of follow-up were included, and they were stratified based on adjuvant RT status and propensity matched to controls for covariates. Survival curves were compared. A data-driven approach was used to find a biologically effective dose (BED) of RT with the largest difference between survival curves. Factors associated with long-term survival were quantified.RESULTSThe authors identified 2170 cases of AM in the NCDB between 2004 and 2015. They observed increased use of adjuvant RT in patients treated with higher doses. A total of 178 cases met the inclusion criteria for outcome analysis. Forty-five percent (n = 80) received adjuvant RT. Patients received a BED of 80.23 ± 16.6 Gy (mean ± IQR). The median survival time was not significantly different (32.8 months for adjuvant RT vs 38.5 months for no RT; p = 0.57, log-rank test). Dichotomizing the patients at a BED of 81 Gy showed maximal difference in survival distribution with a decrease in median survival in favor of no adjuvant RT (31.2 months for adjuvant RT vs 49.7 months for no RT; p = 0.03, log-rank test), but this difference was not significant after false discovery rate correction. Age was a significant predictor for long-term survival.CONCLUSIONSAMs are aggressive tumors that carry a poor prognosis. Conventional adjuvant RT improves local control. However, the effect of adjuvant radiation on overall survival is unclear. Further investigation into this area is warranted.


Distribution of nephrologists and regional variation in the clinical severity of IgA nephropathy at biopsy diagnosis in Japan: a cross-sectional study.
The clinical severity of IgA nephropathy (IgAN) at the time of biopsy diagnosis differs significantly among cases. One possible determinant of any such difference is the time taken for referral from the primary care physician to a nephrologist, but the definitive cause remains unclear. This study examined the contribution of the number of nephrologists per regional population as a potential social factor influencing the clinical severity at diagnosis among patients with IgAN in Japan, which has an ethnically homogeneous population. A cross-sectional study. Patients were registered in the Japan Renal Biopsy Registry (J-RBR), a nationwide multicentre registry, and 6426 patients diagnosed with IgAN were analysed. The facilities registered to the J-RBR were divided into 10 regions and the clinical features of IgAN at biopsy diagnosis, including renal function and level of proteinuria, were examined. Renal prognosis risk at the time of biopsy diagnosis defined by Kidney Disease Improving Global Outcomes guideline 2012. Among the regions, there were significant differences in the estimated glomerular filtration rate (67.5-91.4 mL/min/1.73 m2), urinary protein excretion rate (0.93-1.93 g/day) and renal prognosis risk group distribution at diagnosis. The severity of all clinical parameters was inversely correlated with the number of nephrologists per regional population, which showed an up to 2.7-fold difference among regions. A generalised linear mixed model revealed that a low number of nephrologists per regional population were significantly associated with fulfilment of clinical criteria indicating a very-high-risk renal prognosis (β=-0.484, 95% CI -0.959 to -0.010). Among Japanese patients with IgAN, significant regional differences were detected in clinical severity at the time of diagnosis. Social factors, such as an uneven distribution of nephrologists across regions, may influence the timing of biopsy and determine such differences.


Prospective observational study with an abbreviated protocol in the management of blunt renal injury in children.
There are no published management schemes for blunt renal injuries. We are conducting a 2-center prospective observational study with a fixed management scheme. Children with CT proven renal injuries were enrolled with permission. Ambulation is allowed when able regardless of grade. Discharge occurs when tolerating a diet and pain is controlled regardless of hematuria. Urinalysis occurs at follow up in 2-4weeks and repeated as indicated. Between 9/2008 and 9/2012, 70 patients were enrolled. Mean age was 11.8years (3-17), and 70% were male. The mean grade of injury was 2.8±1.1 [1-5]. One nephrectomy (1.4%) was performed for a grade 5 injury. Other renal interventions included an embolization for the hilar bleed and one cystotomy for a clot. Mean LOS was 2.9days±2.4days. In patients without other major injury, LOS was 1.9±1.7days (0.4-8days). There were 5 (7%) readmissions: 3 for pain, 1 for hematuria, and 1 for a bladder clot. 58 patients (83%) gave urinalysis samples at initial follow up (med 18days), where 31 (53%) were positive for blood. Children with blunt renal injury may benefit from management without strict bedrest guidelines. Hematuria appears to have little influence on recovery.


Phospholipid profiling of plasma from GW veterans and rodent models to identify potential biomarkers of Gulf War Illness.
Gulf War Illness (GWI), which affects at least one fourth of the 700,000 veterans deployed to the Gulf War (GW), is characterized by persistent and heterogeneous symptoms, including pain, fatigue and cognitive problems. As a consequence, this illness remains difficult to diagnose. Rodent models have been shown to exhibit different symptomatic features of GWI following exposure to particular GW agents (e.g. pyridostigmine bromide, permethrin and DEET) and/or stress. Preclinical analyses have shown the activation of microglia and astroglia as a pathological hallmark in these mouse and rat models. Although much has been learned in recent years from these different rodent models and independent clinical studies, characterization studies to identify overlapping features of GWI in animals and humans have been missing. Thus, we aimed to identify biomarkers that co-occur in the plasma of rodent models of GWI and human GWI patients. We observed increases of multiple phospholipid (PL) species across all studied cohorts. Furthermore, these data suggested dysfunction within ether and docosahexaenoic acid and arachidonic acid containing PL species in relation to GWI. As these PL species play a role in inflammatory processes, these findings suggest a possible role for inflammatory imbalance in GWI. Overall, we show that the peripheral lipid disturbances are present both in human GWI patients and in the preclinical rodent models of GWI, highlighting the importance of lipidomics as a potential platform for further biomarker discovery and supporting the value of GW agent exposed models of GWI.


Assay for protein modification by poly-ADP-ribose in vitro.
The enzymatic function of poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) is central to many of its function as a component of DNA repair machinery, modulator of gene transcription, and cell differentiation. While the auto-modification domain of PARP has been shown to be a primary acceptor site of poly-ADP ribose (pADPr), other DNA binding nuclear proteins are also modified by pADPr. It is -generally accepted that pADPr polymer is built upon the carboxyl side chain of specific Glu, Asp, and/or Lys residues within the target protein. Identification of the unique amino acid acceptors of pADPr in these nuclear proteins is an active area of study. Because of the heterogeneity of pADPr chain on modified -protein targets, the resulting modified proteins have unpredictable final masses, making it difficult to -identify acceptor amino acids. Using recombinant proteins, in vitro pADP ribosylation assay and mass spectrometry, we have been able to identify conserved Glu residue in transcription factor NFAT that is enzymatically modified in vitro with pADPr by PARP-1. We discuss this protocol here as a model approach for identifying pADPr acceptors in other nuclear proteins.


Orbital Fat Density as a Diagnostic Tool in Pre-Septal and Orbital Cellulitis.
To evaluate the usefulness of measuring orbital fat density in identifying post-septal involvement when initial differential diagnosis between orbital and periorbital cellulitis (OC and POC) is unclear. Retrospective study of patients with clinical diagnosis of OC or POC who underwent contrast-enhanced computerized tomographic scans over a span of 10 years. Intraconal orbital fat density was measured with Hounsfield units (HU) in six areas on axial scans consisting of nasal and temporal intraconal sites. These measurements correlated with the initial and final diagnoses. Main outcome measures were HU values at the initial and final diagnoses. Fifty-seven patients were included. Mean HU measurement was -52 ± 18 HU for the involved side vs. -63 ± 13 for the uninvolved side (P < .001). The values were higher in cases of a final diagnosis of OC in the involved side (P < .001). The HU values were significantly higher in the nasal vs. the temporal locations of each orbit bilaterally (P < .001). The initial POC diagnosis of 20 patients (35%) was revised to OC. Intraconal fat density measurements can assist in the primary assessment of orbital involvement in patients with an uncertain initial diagnosis, with a HU value higher than -50 is suggestive of orbital involvement.


Electrospun nanofibers in cancer research: from engineering of in vitro 3D cancer models to therapy.
Electrospinning is historically related to tissue engineering due to its ability to produce nano-/microscale fibrous materials with mechanical and functional properties that are extremely similar to those of the extracellular matrix of living tissues. The general interest in electrospun fibrous matrices has recently expanded to cancer research both as scaffolds for in vitro cancer modelling and as patches for in vivo therapeutic delivery. In this review, we examine electrospinning by providing a brief description of the process and overview of most materials used in this process, discussing the effect of changing the process parameters on fiber conformations and assemblies. Then, we describe two different applications of electrospinning in service of cancer research: firstly, as three-dimensional (3D) fibrous materials for generating in vitro pre-clinical cancer models; and secondly, as patches encapsulating anticancer agents for in vivo delivery.


[Detection of Mycoplasma pneumoniae and Chlamydophila pneumoniae in patients with community acquired pneumonia].
A total of 292 patients with pneumonia confirmed by clinical, roentgenological and laboratory methods, admitted to the hospital from closed communities during the one year period, were examined. The sputa of patients with pneumonia in the acute stage were studied in the polymerase chain reaction (PCR). The predominence of M. pneumoniae and C. pneumoniae causualties in autumn and winter period was established. The monitoring of atypical infective agents with the use of the PCR techniques gives evidence for conclusion on their ever growing role in the etiological structure of community acquired pneumonia in groups of closely interacting young people.


Agreement between written and video questions for comparing asthma symptoms in ISAAC.
Phase One of the International Study of Asthma and Allergies in Childhood (ISAAC) has reported the prevalence of asthma, rhinitis and eczema symptoms in children. In 99 centres from 40 countries, a total of just under 317,000 13-14-yr-old children also completed a video questionnaire, showing the symptoms and signs of asthma. This first video sequence has been compared to the ISAAC written question asking about current wheezing to explore variations in agreement and the contribution of each questionnaire to wheezing prevalence between centres, by region and language groups. In general, responses to the video questionnaire gave a lower prevalence than the siritten questionnaire and responses were closely correlated. The overall proportion of agreement was high, mean 0.89. but unbalanced, with good negative agreement but poor positive agreement. Chance corrected agreement using Cohen's kappa coefficient, was generally low, with onl 20 centres with kappa >0.4. The contribution of each questionnaire to wheezing prevalence also varied between centres and suggests that written questions about wheezing are variably understood and interpreted by 13-14 yr olds. International comparisons of wheezing and its audiovisual presentation suggest that adolescents interpret a written question about wheezing differently from its audiovisual presentation and that this interpretation shows variation between centres. This relationship and the interpretation of both written and audiovisual presentation of symptoms requires further study in order to better predict asthma.


Hepatitis C Virus Infection Is Positively Associated with Gallstones in Liver Cirrhosis.
To elucidate the prevalence and risk factors of gallstone disease (GD) among patients with liver disease and explore their association with the aetiology and severity of hepatic injury. We analysed 4,832 subjects of hepatic injury induced by one of the following aetiologies: hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, excessive alcohol consumption. The risk factors significantly associated with GD were analysed using stepwise logistic regression analysis, the influence of aetiology and severity of liver disease on the prevalence of GD were assessed by multiple logistic regression analysis adjusting for confounding factors. Three thousand forty eight patients were of positive HBV surface antigen alone with a prevalence of GD of 18.6%, 526 were tested as positive Anti-HCV alone with a prevalence of GD of 22.4%, and 1,258 were identified with excessive alcohol consumption patterns with a prevalence of GD of 13.5%. In each aetiological category, the prevalence of GD increased by age. Stepwise logistic regression analysis showed that age, female, low-density lipoprotein-cholesterol (LDL-Cho), family history of GD, HBV infection, HCV infection, chronic hepatitis and cirrhosis were independent factors associated with GD. After adjusting for age, LDL-Cho and family history of GD, the prevalence of gallstone disease was significantly associated with HCV-related cirrhosis in both genders, HBV-related cirrhosis in males and alcohol-related cirrhosis in females compared with patients with less severe liver disease [corrected]. After adjusting for gender, age, LDL-Cho and family history of GD, patients with HCV-related cirrhosis (OR 2.66, 95% CI 1.49-3.84) but not HBV-related cirrhosis (OR 1.52, 95% CI 0.73-1.82) were more likely to have GD compared with alcohol-related cirrhosis. HCV infection is positively associated with gallstone formation especially in those with cirrhosis patients.


Overview of the prospective randomized evaluation of the vascular effects of Norvasc (amlodipine) trial: PREVENT.
The Prospective Randomized Evaluation of the Vascular Effects of Norvase (amlodipine) Trial (PREVENT) was designed specifically to assess if amlodipine can be shown to inhibit angiographic progression of lesions 30% or less diameter stenosis. A carotid ultrasound substudy was also undertaken. The antiatherosclerotic effects were discordant in that minor coronary lesions were not affected, whereas carotid intima-media thickness showed significantly less progression in the amlodipine-treated patients. Moreover, significant cardiac events, particularly admissions to hospital for unstable angina and intervention, were significantly reduced in the amlodipine-treated patients. This brief report provides an overview and assessment of the implications of these findings.


Controllable direction of liquid jets generated by thermocavitation within a droplet.
A high-velocity fluid stream ejected from an orifice or nozzle is a common mechanism to produce liquid jets in inkjet printers or to produce sprays among other applications. In the present research, we show the generation of liquid jets of controllable direction produced within a sessile water droplet by thermocavitation. The jets are driven by an acoustic shock wave emitted by the collapse of a hemispherical vapor bubble at the liquid-solid/substrate interface. The generated shock wave is reflected at the liquid-air interface due to acoustic impedance mismatch generating multiple reflections inside the droplet. During each reflection, a force is exerted on the interface driving the jets. Depending on the position of the generation of the bubble within the droplet, the mechanical energy of the shock wave is focused on different regions at the liquid-air interface, ejecting cylindrical liquid jets at different angles. The ejected jet angle dependence is explained by a simple ray tracing model of the propagation of the acoustic shock wave inside the droplet.


Evaluation of continuous non-invasive arterial pressure monitoring during induction of general anaesthesia in patients undergoing cardiac surgery.
Continuous arterial pressure monitoring is essential in cardiac surgical patients during induction of general anaesthesia (GA). Continuous non-invasive arterial pressure (CNAP) monitoring is fast gaining importance due to complications associated with the invasive arterial monitoring. Recently, a new continuous non-invasive arterial pressure device (CNAP™) has been validated perioperatively in non-cardiac surgeries. The aim of our study is to compare and assess the performance of CNAP during GA with invasive arterial pressure (IAP) in patients undergoing cardiac surgeries. Sixty patients undergoing cardiac surgery were included. Systolic, diastolic, and mean arterial pressure (MAP) data were recorded every minute for 20 min simultaneously for both IAP and CNAP™. Statistical analysis was performed using mountain plot and Bland Altman plots for assessing limits of agreement and bias (accuracy) calculation. Totally 1200 pairs of data were analysed. The CNAP™ systolic, diastolic and MAP bias was 5.98 mm Hg, -3.72 mm Hg, and - 0.02 mm Hg respectively. Percentage within limits of agreement was 96.0%, 95.2% and 95.7% for systolic, diastolic and MAP. The mountain plot showed similar results as the Bland Altman plots. We conclude CNAP™ provides real-time estimates of arterial pressure comparable to IAP during induction of GA for cardiac surgery. We recommend CNAP can be used as an alternative to IAP in situations such as cardiac patients coming for non-cardiac surgeries, cardiac catheterization procedures, positive Allen's test, inability to cannulate radial artery and vascular diseases, where continuous blood pressure monitoring is required.


How to measure diffusion coefficients in biofilms: A critical analysis.
Biofilm and granular sludge processes depend on diffusion of substrates. Despite their importance for the kinetic description of biofilm reactors, biofilm diffusion coefficients reported in literature vary greatly. The aim of this simulation study was to determine to what extent the methods that are used to measure diffusion coefficients contribute to the reported variability. Granular sludge was used as a case study. Six common methods were selected, based on mass balances and microelectrodes. A Monte Carlo simulation was carried out to determine the theoretical precision of each method, considering the uncertainty of various experimental parameters. A model-based simulation of a diffusion experiment was used to determine the theoretical accuracy as a result of six sources of error: solute sorption, biomass deactivation, mass transfer boundary layer, granule roughness, granule shape, and granule size distribution. Based on the Monte Carlo analysis, the relative standard deviation of the different methods ranged from 5% to 61%. In a theoretical experiment, the six error sources led to an 37% underestimation of the diffusion coefficient. This highlights that diffusion coefficients cannot be determined accurately with existing experimental methods. At the same time, the need for measuring precise diffusion coefficients as input value for biofilm modeling can be questioned, since the output of biofilm models has a limited sensitivity toward the diffusion coefficient.


Interpretable, probability-based confidence metric for continuous quantitative structure-activity relationship models.
A great deal of research has gone into the development of robust confidence in prediction and applicability domain (AD) measures for quantitative structure-activity relationship (QSAR) models in recent years. Much of the attention has historically focused on structural similarity, which can be defined in many forms and flavors. A concept that is frequently overlooked in the realm of the QSAR applicability domain is how the local activity landscape plays a role in how accurate a prediction is or is not. In this work, we describe an approach that pairs information about both the chemical similarity and activity landscape of a test compound's neighborhood into a single calculated confidence value. We also present an approach for converting this value into an interpretable confidence metric that has a simple and informative meaning across data sets. The approach will be introduced to the reader in the context of models built upon four diverse literature data sets. The steps we will outline include the definition of similarity used to determine nearest neighbors (NN), how we incorporate the NN activity landscape with a similarity-weighted root-mean-square distance (wRMSD) value, and how that value is then calibrated to generate an intuitive confidence metric for prospective application. Finally, we will illustrate the prospective performance of the approach on five proprietary models whose predictions and confidence metrics have been tracked for more than a year.


Outcome of influenza infection: effect of site of initial infection and heterotypic immunity.
An infection established throughout the total respiratory tract of mice with a highly lung adapted influenza virus (H0N1) led to death from viral pneumonia. The 50% lethal dose (LD(50)) was approximately the same as the 50% infectious dose (ID(50)). An infection with the same virus initiated in the nasal mucosa spread to the trachea and lungs over a 3- to 5-day period but was not lethal except at very high infecting doses. The LD(50) was 30,000 times the ID(50). Mice that had recovered from a prior infection with A/PC/73(H3N2) demonstrated enhanced recovery (heterotypic immunity) when challenged with A/PR/8/34(H0N1). Heterotypically immune mice infected while anesthetized with this potentially lethal virus stopped shedding virus from the nose, trachea, and lungs by day 7 and recovered. Heterotypically immune mice, infected awake, stopped shedding virus from the nose by day 5, and, in fact, the virus did not spread to the trachea or lungs. Thus, some of the variation in the severity of influenza infections may be explained by two factors: the site of initial infection and previous infection with heterotypic influenza virus.


Persistent and injury-induced neurogenesis in the vertebrate retina.
The brains of all vertebrates are persistently neurogenic. However, this is not true for the neural retinas. Only three extant classes of vertebrates show significant posthatch/postnatal retinal neurogenesis: amphibians, birds and fish. The retinas of these animals contain an annulus of progenitors at the margin, from which differentiated neurons emerge. In posthatch amphibians and fish the vast majority of the adult retina is added from the margin and neurogenesis is lifelong, whereas in posthatch birds neurogenesis is limited. Unique to fish, rod photoreceptors are added in situ from stem cells within the mature retina. Strikingly, for each class of animal retinal lesions stimulate neuronal regeneration, however the cellular source differs for each: the retinal pigmented epithelium in amphibians and embryonic birds, Müller glia in posthatch birds and intrinsic stem cells in fish. The molecular events surrounding injury-induced neuronal regeneration are beginning to be identified.


Cardiopulmonary coupling during exercise.
Muscular exercise imposes the most potent sustained stress to cellular energetics. At work rates below the anaerobic threshold (i.e. no sustained lactic acidosis), the ventilatory and cardiovascular responses regulate arterial PCO2, [H+] and PO2 at or close to their resting levels in the steady state. However, dynamic forcing and systems-analytic techniques reveal two phases of the non-steady-state response dynamics. In the first phase, increased gas flow to the lungs results solely from increased pulmonary blood flow, with alveolar gas tensions being maintained at their resting levels by a coupled increase in ventilation (VE): evidence for cardiopulmonary coupling being provided by experimentally-altered in man and dog. Arterial chemoreception does not impose humoral feedback control in this phase. Rather, rapid feedforward mechanisms operate, with both intrathoracic (largely cardiac) and exercising-limb mechanoreception proposed as afferent sources. In the second phase, cardiogenic gas flow to the lungs is augmented by altered mixed venous blood gas contents; ventilation responding exponentially with a time constant (tau) which is an inverse function of carotid body gain. The close dynamic coupling of VE with CO2 output (tau VE tau TVCO2) in this phase results in arterial PCO2 and [H+] being maintained close to their resting levels. However, the kinetic dissociation between VE and O2 uptake, with tau VE much greater than tau VO2, leads to an appreciable transient fall of arterial PO2. The respiratory compensation for the sustained lactic acidosis at higher work rates is predominantly mediated by the carotid bodies in man: the aortic bodies subserving no discernible role. Control of the respiratory and circulatory responses to exercise is therefore mediated by both neural and humoral mechanisms: and an important control link appears to couple the responses, via feedforward ventilatory control of cardiac origin.


Role of Reflux in the Pathogenesis of Eosinophilic Esophagitis: Comprehensive Appraisal With Off- and On PPI Impedance-pH Monitoring.
Role of reflux and mechanisms of response to proton pump inhibitor (PPI) therapy in eosinophilic esophagitis (EoE) have not yet been fully elucidated. Comprehensive assessment by impedance-pH monitoring could clarify these issues. Prospective multicenter study comparing EoE patients with healthy controls and gastroesophageal reflux disease cases. Patients with EoE were evaluated off- and on PPI; responsiveness was assessed by histology. Impedance-pH appraisal included chemical clearance, assessed with the postreflux swallow-induced peristaltic wave (PSPW) index, and mucosal integrity measured with mean nocturnal baseline impedance (MNBI). Sixty consecutive patients with EoE were compared with 60 age- and sex-matched healthy controls and 60 subjects with gastroesophageal reflux disease. The number of total refluxes was higher, while the PSPW index was lower in patients with EoE than in healthy controls. Off PPI, a lower MNBI gradient between the mid and distal esophagus distinguished 20 patients with PPI-refractory EoE from 40 patients with PPI-responsive EoE and was a predictor of PPI failure. On PPI, a lower PSPW index was the sole reflux parameter distinguishing PPI-refractory from PPI-responsive EoE; all reflux parameters improved in PPI-responsive patients, whereas the PSPW index was not modified in PPI-refractory cases and was independently associated with PPI-responsiveness. MNBI in the distal and mid esophagus improved much more in PPI-responsive than in PPI-refractory EoE. Reflux plays a role in the pathogenesis of EoE, more relevant in PPI-responsive cases. Low impedance gradient between the mid and distal esophagus may be useful to predict PPI refractoriness. PPIs mainly act by improving chemical clearance, i.e., by an antireflux action supporting long-term prescription in PPI-responsive EoE.


Use of the Internet by physicians in Puerto Rico.
To determine the extent of the use of the Internet by physicians in Puerto Rico to support their clinical practice. Personal interviews were conducted among a representative sample of 385 physicians from different specialties and geographical regions in Puerto Rico. Eighty-one percent physicians who participated in the survey reported the use the Internet in their practices. Rheumatologists, endocrinologists and cardiologists were the specialties with the highest usage rate. Internet use decreased as age of the physicians increased. The great majority of those who use the Internet do it from home (81%) followed by the office (68%). Almost two-thirds used dial-up to connect to the Internet at home or at office. The Internet was used mainly for professional purposes to look for references (92%), communicate with colleagues (33%) and obtain continuing education (31%). There was a high Internet utilization rate among physicians in Puerto Rico, regardless of the specialty. The utilization rate was similar to that reported among physicians from other countries.


Human class I histocompatibility antigens (HLA-A,B,C). A small proportion only is phosphorylated.
Human Class I HLA antigens (HLA-A,B,C) were isolated by immune precipitation from cells labelled with 32P, [35S]methionine or 125I (by lactoperoxidase-catalysed cell-surface iodination) and were analysed using both one- and two-dimensional electrophoretic systems. In several B-lymphoblastoid cell lines and in human peripheral blood lymphocytes the electrophoretic mobility of the 32P-labelled HLA-A,B,C heavy chains consistently differed from that of molecules labelled by other means. Thus the 32P-labelled heavy chains appeared to be larger and to possess a more acidic pI than did heavy chains labelled with [35S]methionine or 125I, or identified by Coomassie Blue staining. Phosphatase treatment of immunoprecipitates, under conditions where 32P-labelled antigens were shown to be dephosphorylated, did not affect the mobilities of the [35S]methionine-labelled heavy chains. On glycosidase treatment, the positions of the 32P-labelled heavy chains were affected by neuraminidase but not by endo-beta-N-acetylglucosaminidase H. These results imply that phosphorylated HLA-A,B,C antigens comprise only a small proportion (relative to the total cellular HLA-A,B,C antigens) of the biosynthetically mature molecules. The possible significance of such heterogeneity is discussed.


Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer.
Loss of Von Hippel-Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia-inducible factor (HIF-α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5-aminoimidazole-4-carboxamide-riboside (AICAR) as AMPK activator are used separately to treat cancer patients. In the current study, the possible additive effect of drug combinations in reducing kidney tumorigenesis was investigated. Treatment with drug combinations significantly decreased cell proliferation, increased cell apoptosis, and abolished Akt phosphorylation and HIF-2α expression in renal cell carcinoma cells, including primary cells isolated from kidney cancer patients. Significant decreases in cell migration and invasion were detected using drug combinations. Drug combinations effectively abolished binding of HIF-2α to the Akt promoter and effected formation of the DNA-protein complex in nuclear extracts from 786-O cells, as demonstrated using electromobility shift assay and examination of Akt promoter activity. Importantly, we tested the effect of each drug and the combined drugs on kidney tumor size in the nude mouse model. Our data show that treatment with rapamycin, AICAR, and rapamycin+AICAR decreased tumor size by 38%, 36%, and 80%, respectively, suggesting that drug combinations have an additive effect in reducing tumor size compared with use of each drug alone. Drug combinations effectively decreased cell proliferation, increased apoptotic cells, and significantly decreased p-Akt, HIF-2α, and vascular endothelial growth factor expression in tumor kidney tissues from mice. These results show for the first time that drug combinations are more effective than single drugs in reducing kidney tumor progression. This study provides important evidence that may lead to the initiation of pre-clinical trials in patients with kidney cancer.


The influence of wound geometry on the measurement of wound healing rates in clinical trials.
The comparison of wound healing rates in clinical trials presents a challenging problem. Wound healing typically has been expressed as a change in area over time or a percent change in area over time. These methods are inaccurate, however, when applied to wounds of varying size and shape. A relatively small amount of healing in a large wound will produce a greater change in area than in a smaller wound. Conversely, measurement of the percent change in area of a wound will tend to exaggerate the healing rates of smaller wounds. A method of calculating average linear healing of the wound edge toward the center of the wound has been proposed that should not be influenced by wound size: D = delatA divided by P, where D = linear healing, deltaA = change in area, and P = mean perimeter. The purpose of this study was to examine linear healing of the wound edge as a method of measuring wound healing in clinical trials. We observed 39 patients with venous stasis ulcers. The area, perimeter, length, and width of each wound were calculated with computerized planimetry. Change in area per day and linear healing rate of the wound edge per day were calculated. Multiple linear regression analysis was used to explore factors that influence wound healing as measured by these methods. The change in area per day was significantly and independently influenced by initial area (p < .0001), perimeter (p < .0001), length (p < .00055), and width (p < .0175). Linear healing per day was not influenced by any geometric variable, including area, perimeter, length, width, and ratio of width to length. Linear healing per day is a valid means of comparing wound healing rates in wounds of different dimensions. Linear healing per unit of time should be preferred to measurements of change in wound area to quantify wound healing rates in clinical trials.


A Nurse-Led Education Program to Improve COVID-19 Prevention Knowledge Among Adolescent Students.
Adolescents are more susceptible than originally thought to COVID-19, and they could play a significant role in community transmission. We aim to evaluate a health education program on students' declarative knowledge and risk awareness concerning COVID-19-related public health recommendations. A quasi-experimental pre-post pilot study was conducted. A number of 487 students aged between 12 and 17 years old participated in an educational program. Following Socratic Method, preventive actions were simulated in order to encourage students to seek answers about the correct application of measures. The program covered 3 prevention areas: (1) practice hygienic handwashing; (2) instruction on the appropriate use of masks; and (3) promotion of physical distancing, and was implemented in class by 3 registered nurses. Following the educational program, declarative knowledge regarding handwashing and mask use improved along with the students' total score. In the pre-test, students 16 years and older as well as female students obtained higher scores in declarative knowledge. Age-dependent differences between groups vanished in the post-test, but girls still achieved better scores. This nurse-led health education program proved to be effective to enhance declarative knowledge about COVID-19-related public health recommendations.


Spontaneous Human Myometrial Contractility in the Third Trimester of Pregnancy in Relation to Past Mode of Delivery.
It is well established that women with a previous vaginal delivery have higher success rates in relation to vaginal birth after cesarean than those without. The aim of this study was to examine the effect of past mode of delivery on contractile parameters of human myometrium in vitro. Myometrial strips were excised from 64 women at cesarean delivery (CD) and recordings of spontaneous contractile activity analyzed and compared across three clinical groups: (1) women with no previous delivery (Group 1); (2) women with CD only (Group 2); and (3) women with a history of vaginal delivery and CD (Group 3). Myometrial samples from women in Group 3, women who had a previous vaginal delivery, had a significantly greater maximum amplitude of contractions (p < 0.05), a greater force (mean contractile force) of contractions (p < 0.01), and a faster rate of rise (p < 0.01) and relaxation of contractions (p < 0.05) than those in Groups 1 and 2. Many of the functional parameters of human uterine contractions are altered, or enhanced, in the women who have had a previous vaginal delivery, when compared with those without. This may partly explain the clinical differences observed in labor.