Vestibular control of entorhinal cortex activity in spatial navigation.
Navigation in rodents depends on both self-motion (idiothetic) and external (allothetic) information. Idiothetic information has a predominant role when allothetic information is absent or irrelevant. The vestibular system is a major source of idiothetic information in mammals. By integrating the signals generated by angular and linear accelerations during exploration, a rat is able to generate and update a vector pointing to its starting place and to perform accurate return. This navigation strategy, called path integration, has been shown to involve a network of brain structures. Among these structures, the entorhinal cortex (EC) may play a pivotal role as suggested by lesion and electrophysiological data. In particular, it has been recently discovered that some neurons in the medial EC display multiple firing fields producing a regular grid-like pattern across the environment. Such regular activity may arise from the integration of idiothetic information. This hypothesis would be strongly strengthened if it was shown that manipulation of vestibular information interferes with grid cell activity. In the present paper we review neuroanatomical and functional evidence indicating that the vestibular system influences the activity of the brain network involved in spatial navigation. We also provide new data on the effects of reversible inactivation of the peripheral vestibular system on the EC theta rhythm. The main result is that tetrodotoxin (TTX) administration abolishes velocity-controlled theta oscillations in the EC, indicating that vestibular information is necessary for EC activity. Since recent data demonstrate that disruption of theta rhythm in the medial EC induces a disorganization of grid cell firing, our findings indicate that the integration of idiothetic information in the EC is essential to form a spatial representation of the environment.


Involvement of FOXO transcription factors, TRAIL-FasL/Fas, and sirtuin proteins family in canine coronavirus type II-induced apoptosis.
n our previous study, we have shown that canine coronavirus type II (CCoV-II) activates both extrinsic and intrinsic apoptotic pathway in a canine fibrosarcoma cell line (A-72 cells). Herein we investigated the role of Sirtuin and Forkhead box O (FOXO) families in this experimental model using Nortern Blot and Western Blot analysis. Our results demonstrated that mitochondrial SIRT3 and SIRT4 protein expression increased from 12 and 24 h post infection (p.i.) onwards, respectively, whereas the nuclear SIRT1 expression increased during the first 12 h p.i. followed by a decrease after 36 h p.i., reaching the same level of control at 48 h p.i. Sirtuins interact with/and regulate the activity of FOXO family proteins, and we herein observed that FOXO3A and FOXO1 expression increased significantly and stably from 12 h p.i. onwards. In addition, CCoV-II induces a remarkable increase in the expression of TNF-related apoptosis-inducing ligand (TRAIL), while we observed a slight up-regulation of FasL/Fas at 36 p.i. with a decrease of both proteins at the end of infection. Furthermore, we found that virus infection increased both bax translocation into mitochondria and decreased bcl-2 expression in cytosol in a time-dependent manner.These data suggest that FOXO transcription factors mediate pro-apoptotic effects of CCoV-II, in part due to activation of extrinsic apoptosis pathway, while some Sirtuin family members (such as SIRT3 and SIRT4) may be involved in intrinsic apoptotic pathway. Moreover, these results propose that TRAIL is an important mediator of cell death induced by CCoV-II during in vitro infection.


Slow gamma rhythms in CA3 are entrained by slow gamma activity in the dentate gyrus.
In hippocampal area CA1, slow (∼25-55 Hz) and fast (∼60-100 Hz) gamma rhythms are coupled with different CA1 afferents. CA1 slow gamma is coupled to inputs from CA3, and CA1 fast gamma is coupled to inputs from the medial entorhinal cortex (Colgin LL, Denninger T, Fyhn M, Hafting T, Bonnevie T, Jensen O, Moser MB, Moser EI. Nature 462: 353-357, 2009). CA3 gives rise to highly divergent associational projections, and it is possible that reverberating activity in these connections generates slow gamma rhythms in the hippocampus. However, hippocampal gamma is maximal upstream of CA3, in the dentate gyrus (DG) region (Bragin A, Jando G, Nadasdy Z, Hetke J, Wise K, Buzsaki G. J Neurosci 15: 47-60, 1995). Thus it is possible that slow gamma in CA3 is driven by inputs from DG, yet few studies have examined slow and fast gamma rhythms in DG recordings. Here we investigated slow and fast gamma rhythms in paired recordings from DG and CA3 in freely moving rats to determine whether slow and fast gamma rhythms in CA3 are entrained by DG. We found that slow gamma rhythms, as opposed to fast gamma rhythms, were particularly prominent in DG. We investigated directional causal influences between DG and CA3 by Granger causality analysis and found that DG slow gamma influences CA3 slow gamma. Moreover, DG place cell spikes were strongly phase-locked to CA3 slow gamma rhythms, suggesting that DG excitatory projections to CA3 may underlie this directional influence. These results indicate that slow gamma rhythms do not originate in CA3 but rather slow gamma activity upstream in DG entrains slow gamma rhythms in CA3.


Protein Corona Modulates Uptake and Toxicity of Nanoceria via Clathrin-Mediated Endocytosis.
Particles present in diesel exhaust have been proposed as a significant contributor to the development of acute and chronic lung diseases, including respiratory infection and allergic asthma. Nanoceria (CeO2 nanoparticles) are used to increase fuel efficiency in internal combustion engines, are present in exhaust fumes, and could affect cells of the airway. Components from the environment such as biologically derived proteins, carbohydrates, and lipids can form a dynamic layer, commonly referred to as the "protein corona" which alters cellular nanoparticle interactions and internalization. Using confocal reflectance microscopy, we quantified nanoceria uptake by lung-derived cells in the presence and absence of a serum-derived protein corona. Employing mass spectrometry, we identified components of the protein corona, and demonstrated that the interaction between transferrin in the protein corona and the transferrin receptor is involved in mediating the cellular entry of nanoceria via clathrin-mediated endocytosis. Furthermore, under these conditions nanoceria does not affect cell growth, viability, or metabolism, even at high concentration. Alternatively, despite the antioxidant capacity of nanoceria, in serum-free conditions these nanoparticles induce plasma membrane disruption and cause changes in cellular metabolism. Thus, our results identify a specific receptor-mediated mechanism for nanoceria entry, and provide significant insight into the potential for nanoparticle-dependent toxicity.


The prosthetic group of methanol dehydrogenase. Purification and some of its properties.
Methanol dehydrogenases isolated from bacteria belonging to different classes of methylotrophs contain the same prosthetic group. A procedure for its purification from whole cells is given. The reduced and oxidized form of the enzyme from Hyphomicrobium X and those of the isolated group are compared and it is concluded that the latter indeed functions in the enzyme. Further evidence is presented that the prosthetic group is not a pterine or lumazine derivative, but a water-soluble nitrogen-containing quinone.


Bayesian inference of causal effects from observational data in Gaussian graphical models.
We assume that multivariate observational data are generated from a distribution whose conditional independencies are encoded in a Directed Acyclic Graph (DAG). For any given DAG, the causal effect of a variable onto another one can be evaluated through intervention calculus. A DAG is typically not identifiable from observational data alone. However, its Markov equivalence class (a collection of DAGs) can be estimated from the data. As a consequence, for the same intervention a set of causal effects, one for each DAG in the equivalence class, can be evaluated. In this paper, we propose a fully Bayesian methodology to make inference on the causal effects of any intervention in the system. Main features of our method are: (a) both uncertainty on the equivalence class and the causal effects are jointly modeled; (b) priors on the parameters of the modified Cholesky decomposition of the precision matrices across all DAG models are constructively assigned starting from a unique prior on the complete (unrestricted) DAG; (c) an efficient algorithm to sample from the posterior distribution on graph space is adopted; (d) an objective Bayes approach, requiring virtually no user specification, is used throughout. We demonstrate the merits of our methodology in simulation studies, wherein comparisons with current state-of-the-art procedures turn out to be highly satisfactory. Finally we examine a real data set of gene expressions for Arabidopsis thaliana.


Optimal P2Y12 inhibition in older adults with acute coronary syndromes: a network meta-analysis of randomized controlled trials.
Dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor on top of aspirin is the cornerstone of therapy after acute coronary syndromes (ACS). Nonetheless, the safest and most efficacious P2Y12 for older patients who are both at high ischaemic and bleeding risk remains uncertain. We aimed to examine the effect of available P2Y12 inhibitors on ischaemic and bleeding endpoints in older adults with ACS. Randomized clinical trials that reported separately the results of adults older >70 years for at least the primary endpoint [composite of death, myocardial infarction (MI), and stroke]. Seven studies (14 485 patients-years) were included. Network meta-analysis showed that prasugrel was associated with similar occurrence of the primary endpoint and of a secondary ischaemic endpoint (composite of MI and stroke) and was most likely the best treatment [Surface Under the Cumulative Ranking curve Analysis (SUCRA) 54.5 and 59.8, respectively]. With regards to major bleedings, clopidogrel showed the highest likelihood of event reduction (SUCRA 70.1%), while ticagrelor of stent thrombosis (SUCRA 55.6%). Our meta-regression with a fixed proportion of patients managed invasively of 100% confirmed these trends with increasing SUCRA. Among older subjects with ACS, DAPT should be balanced upon ischaemic and bleeding risks as prasugrel is associated with the highest probability of reduction of ischaemic events and clopidogrel of bleedings. Ticagrelor had highest SUCRA for stent thrombosis reduction but seems suboptimal in older adults.


Immunoinflammatory role of apolipoprotein E4 in malnutrition and enteric infections and the increased risk for chronic diseases under adverse environments.
Apolipoprotein E plays a crucial role in cholesterol metabolism. The immunomodulatory functions of the human polymorphic APOE gene have gained particular interest because APOE4, a well-recognized risk factor for late-onset Alzheimer's disease, has also been recently linked to increased risk of COVID-19 infection severity in a large UK biobank study. Although much is known about apoE functions in the nervous system, much less is known about APOE polymorphism effects on malnutrition and enteric infections and the consequences for later development in underprivileged environments. In this review, recent findings are summarized of apoE's effects on intestinal function in health and disease and the role of APOE4 in protecting against infection and malnutrition in children living in unfavorable settings, where poor sanitation and hygiene prevail, is highlighted. The potential impact of APOE4 on later development also is discussed and gaps in knowledge are identified that need to be addressed to protect children's development under adverse environments.


Trends in food advertising to children on free-to-air television in Australia.
The issue of marketing unhealthy food to children and its contribution to childhood obesity has become a highly politicised debate in Australia. The aim of this study was to compare recent television food advertising patterns in 2008 to previously published Australian research on television advertising from 2006 and 2007, to examine any changes following policy debates. Television broadcasting was recorded for two weekdays and two weekend days between 6:00 and 22:00 in February 2008 for all three commercial television channels. Food advertisements were classified as core/healthy, non-core/unhealthy or miscellaneous. Television audience data were obtained to determine broadcast periods corresponding to children's peak viewing times. The overall rate of food advertising decreased over time: from seven food advertisements/hour/channel in 2006/07 to five in 2008. However, the relative contribution of non-core food advertising to overall food advertising remained stable. In 2008, the proportion of food advertisements for non-core foods was significantly higher during children's peak viewing times (p<0.01). Australian children remain exposed to a disproportionate volume of television advertisements for unhealthy foods on commercial television, which are shown during time periods when the highest numbers of children are watching. Regulations to limit unhealthy food advertising during the time periods when a significant number of children are watching are required.


The evaluation and management of pheochromocytomas.
Despite the relative infrequency of pheochromocytomas, they remain a potentially curable yet lethal etiology of hypertension. Appropriate utilization of a modern clinical chemistry laboratory and sophisticated radiologic techniques should allow a suspecting physician to establish the presence or absence of such a catecholamine-secreting tumor. The treatment of pheochromocytoma remains surgical; however, strict attention to preoperative details is crucial if mortality is to be minimized. Judicious use of adrenergic blocking agents and measures to ensure a normal circulating blood volume are of utmost importance during the preoperative period. Surgery remains the ultimate diagnostic and therapeutic maneuver. A thorough and meticulous exploration of the entire abdominal cavity and both adrenal beds is essential in all patients with pheochromocytoma. Monitoring of electrocardiographic and hemodynamic parameters is critical during surgery and postoperatively, since changes in cardiovascular stability can be dramatic and rapid. Appropriate measures must be taken to reverse such changes but must be made based on a thorough understanding of the effects of catecholamines, the drugs available to alter these effects, and the potential problems that patients with pheochromocytomas are likely to experience.


Treatment of cutaneous larva migrans.
Cutaneous larva migrans caused by the larvae of animal hookworms is the most frequent skin disease among travelers returning from tropical countries. Complications (impetigo and allergic reactions), together with the intense pruritus and the significant duration of the disease, make treatment mandatory. Freezing the leading edge of the skin track rarely works. Topical treatment of the affected area with 10%-15% thiabendazole solution or ointment has limited value for multiple lesions and hookworm folliculitis, and requires applications 3 times a day for at least 15 days. Oral thiabendazole is poorly effective when given as a single dose (cure rate, 68%-84%) and is less well tolerated than either albendazole or ivermectin. Treatment with a single 400-mg oral dose of albendazole gives cure rates of 46%-100%; a single 12-mg oral dose of ivermectin gives cure rates of 81%-100%.


Bilateral perisylvian infarct: a rare cause and a rare occurrence.
Foix-Chavany-Marie opercular syndrome is a severe form of pseudobulbar palsy occurring due to bilateral anterior opercular lesions. We report a case of a 51-year-old man with sudden onset of inability to speak and dysphagia, and a history of synovial sarcoma of the right hand. Detailed language evaluation was normal. The patient had right upper motor neuron facial paresis and absent gag reflex bilaterally. Magnetic resonance (MR) imaging revealed acute and subacute infarcts involving the bilateral insular cortex. Two-dimensional echocardiography and cardiac MR imaging showed a mobile mass in the left atrium attached to the interatrial septum, which was likely a myxoma. Chest radiograph and computed tomography imaging of the chest revealed multiple cannonball shadows that were suggestive of secondaries in the lung. The probable cause of the cerebral lesions was the mass lesion in the heart or metastatic lesions from the synovial sarcoma. The cardiac surgeon and surgical oncologist recommended palliative care.


One-Step Vapor-Phase Synthesis and Quantum-Confined Exciton in Single-Crystal Platelets of Hybrid Halide Perovskites.
To investigate the quantum confinement effect on excitons in hybrid perovskites, single-crystal platelets of CH3NH3PbBr3 are grown on mica substrates using one-step chemical vapor deposition. Photoluminescence measurements reveal a monotonous blue shift with a decreasing platelet thickness, which is accompanied by a significant increase in exciton binding energy from approximately 70 to 150 meV. Those phenomena can be attributed to the one-dimensional (1D) quantum confinement effect in the two-dimensional platelets. Furthermore, we develop an analytical model to quantitatively elucidate the 1D confinement effect in such quantum wells with asymmetric barriers. Our analysis indicates that the exciton Bohr radius of single-crystal CH3NH3PbBr3 is compressed from 4.0 nm for the thick (26.2 nm) platelets to 2.2 nm for the thin (5.9 nm) ones. The critical understanding of the 1D quantum confinement effect and the development of a general model to elucidate the exciton properties of asymmetric semiconductor quantum wells pave the way toward developing high-performance optoelectronic heterostructures.


Insight into potential mechanisms of hypobaric hypoxia-induced learning and memory deficit - Lessons from rat studies.
Impairment of memory is one of the most frequently reported symptoms during sudden hypoxia exposure in human. Cortical atrophy has been linked to the impaired memory function and is suggested to occur with chronic high-altitude exposure. However, the precise molecular mechanism(s) of hypoxia-induced memory impairment remains an enigma. In this work, we review hypoxia-induced learning and memory deficit in human and rat studies. Based on data from rat studies using different protocols of continuous hypoxia, we try to elicit potential mechanisms of hypobaric hypoxia-induced memory deficit.


Disagreement between symptom-reflux association analysis parameters in pediatric gastroesophageal reflux disease investigation.
To assess the agreement within 3 commonly used symptom-reflux association analysis (SAA) parameters investigating gastroesophageal reflux disease (GERD) in infants. Twenty three infants with suspected GERD were included in this study. Symptom index (SI), Symptom sensitivity index (SSI) and symptom association probability (SAP) related to cough and irritability were calculated after 24 h combined pH/multiple intraluminal impedance (MII) monitoring. Through defined cut-off values, SI, SSI and SAP values are differentiated in normal and abnormal, whereas abnormal values point towards gastroesophageal reflux (GER) as the origin of symptoms. We analyzed the correlation and the concordance of the diagnostic classification of these 3 SAA parameters. Evaluating the GER-irritability association, SI, SSI and SAP showed non-identical classification of normal and abnormal cases in 39.2% of the infants. When irritability was taken as a symptom, there was only a poor inter-parameter association between SI and SSI, and between SI and SAP (Kendall's tau b = 0.37, P < 0.05; Kendall's tau b = 0.36, P < 0.05, respectively). Evaluating the GER-cough association, SI, SSI and SAP showed non-identical classification of normal and abnormal cases in 52.2% of the patients. When cough was taken as a symptom, only SI and SSI showed a poor inter-parameter association (Kendall's tau b = 0.33, P < 0.05). In infants investigated for suspected GERD with pH/MII-monitoring, SI, SSI and SAP showed a poor inter-parameter association and important disagreements in diagnostic classification. These limitations must be taken into consideration when interpreting the results of SAA in infants.


Differentiation of human mesenchymal stem cells on niobium-doped fluorapatite glass-ceramics.
Our goal was to characterize the response of human mesenchymal stem cells (hMSCs) to a niobium-doped fluorapatite-based glass-ceramic (FAp). The glass was prepared by twice melting at 1525 °C for 3 h, and cast into cylindrical ingots later sectioned into discs and heat-treated to promote crystallization of fluorapatite submicrometer crystals. Tissue culture polystyrene (TCP) was used as control. The surface of the FAp discs was either left as-heat treated, ground or etched. Initial cell attachment was assessed at 3 h. Proliferation and alkaline phosphatase (ALP) expression data were collected at days 1, 4, and 8. Cell morphology was examined using SEM, at days 2 and 4. Mineralization was evaluated by Alizarin Red staining and SEM. Initial cell attachment on as heat-treated, etched, or ground surfaces was similar to that of the positive control group (p>0.05). The percentage of area covered by living cells increased significantly on as heat-treated, etched, or ground surfaces between days 1 and 8 (p<0.05). There was no significant difference among groups in cell coverage at day 8, compared to TCP control. SEM revealed well spread polygonal cells with numerous filopodia, either attached to the ceramic surface or connected to neighboring cells. ALP expression at day 8 was significantly higher in osteogenic media compared to growth media on both FAp and control. FAp discs stained positively with Alizarin Red and calcium-rich mineralized granules associated with fibrils were observed by SEM at day 35. hMSCs displayed excellent attachment, proliferation, and differentiation on niobium-doped FAp glass-ceramic.


Screening Autoimmune Anti-neuronal Antibodies in Pediatric Patients with Suspected Autoimmune Encephalitis.
The aim of this study was to identify and describe the pediatric autoimmune encephalitis cases positive for anti-neuronal antibody tests. Screening of six anti-neuronal antibodies in 23 children with suspected autoimmune encephalitis was performed by cell-based indirect immunofluorescence test with patients' serum or cerebrospinal fluid. Among the 23 cases enrolled here, eight patients (35%) were positive for the anti-N-methyl-d-aspartate (NMDA) receptor antibody and one patient (4%) was positive for the anti-contactin-associated protein-like 2 (CASPR2) antibody. In the anti-NMDA receptor antibody-positive group, seizure and movement disorders were the most prominent features and were present in all patients. A tumor was present in only one patient. Three patients with infant- and toddler-onset disease did not exhibit a classic multistage illness. In addition to seizure and dyskinesia, aphasia or mutism without severe consciousness impairment was present in all three patients. These atypical clinical presentations may suggest different pathomechanism of anti-NMDA receptor encephalitis among these age groups. The patient who was positive for the anti-CASPR2 antibody was an 8-year-old girl who presented with fever, encephalopathy, and seizure. Neuromyotonia or other dyskinesia was not present. Eight anti-NMDA receptor antibody positive patients and one CASPR2 positive patient were identified from the screening of six anti-neuronal antibodies in pediatric patients suspected with autoimmune encephalitis. Developmental regression specifically for language skills was suggested as one of the atypical clinical features in infants and toddler onset anti-NMDA receptor antibody positive patients.


[Physiological and hygienic assessment of perception of the information from electronic device for reading (reader)].
A comparison of the legibility of the three different media: paper personal computer (LCD) and the e-reader in schoolchildren (12-14 years of age) was performed. Comprehensive assessment of the reading performance (speed of reading aloud, the number of errors in reading, and integral indicator of the degree of difficulty of visual task), its physiological value (according to data of EEG, EOG and ECG), and subjective preference of type of media by the schoolchildren showed that by the sum of signs e-reader occupies an intermediate position between printed text and the computer screen. The effect of increased emotional intensity of using e-reader (increased motivation), which is manifested in the preservation of the sympathetic nervous system activation after the reading, was obtained. The necessity of additional research has been shown.


People who expect to enter psychotherapy are prone to believing that they have forgotten memories of childhood trauma and abuse.
We asked 1004 undergraduates to estimate both the probability that they would enter therapy and the probability that they experienced but could not remember incidents of potentially life-threatening childhood traumas or physical and sexual abuse. We found a linear relation between the expectation of entering therapy and the belief that one had, but cannot now remember, childhood trauma and abuse. Thus individuals who are prone to seek psychotherapy are also prone to accept a suggested memory of childhood trauma or abuse as fitting their expectations. In multiple regressions predicting the probability of forgotten memories of childhood traumas and abuse, the expectation of entering therapy remained as a substantial predictor when self-report measures of mood, anxiety, post-traumatic stress disorder symptom severity, and trauma exposure were included.


Outcomes associated with transdermal nicotine replacement therapy in a neurosurgery intensive care unit.
The outcomes associated with transdermal nicotine replacement therapy (NRT) in a neurosurgery intensive care unit (ICU) were studied. Data from pharmacy records, neurosurgery ICU admission logs, and computerized patient charts at the University of Illinois Medical Center at Chicago from January 2001 through August 2008 were reviewed for patients older than 18 years who were admitted to the neurosurgery ICU for neurologic insults. Patients were categorized into three groups: smokers who received transdermal NRT (n = 114), smokers who did not receive transdermal NRT (n = 113), and nonsmokers (n = 113). The primary outcome of this study was unfavorable disposition at discharge from the hospital. Secondary outcomes measured included overall mortality; lengths of hospital and neurosurgery ICU stays; and rates of subarachnoid hemorrhage (SAH) rebleeding, angiographic vasospasm, intracerebral hemorrhage rebleeding, and ischemic stroke. Overall, there was no difference in unfavorable discharge disposition among the three groups (p = 0.17). However, the group who received NRT had higher admission rates of SAH, smoked more cigarettes for a longer period of time, and had longer stays in the neurosurgery ICU and hospital compared with the other groups. All patients who received NRT had prolonged hospital (p = 0.014) and neurosurgery ICU (p = 0.006) stays compared with those who did not receive NRT. There were no differences in other secondary outcomes among the groups. There was no significant difference in unfavorable discharge disposition among neurosurgery ICU patients who were smokers treated with NRT, smokers not treated with NRT, and nonsmokers not treated with NRT.


Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urine-derived human interleukin 1 and inhibitor(s).
Interleukin 1 (IL-1) possesses multiple biological activities that may be blocked selectively by different inhibitors. Some known inhibitors block the lymphocyte activating factor (LAF/IL-1) but not the mononuclear cell factor (MCF/IL-1) measured by its capacity to stimulate prostaglandin E2 (PGE2) and collagenase production. The presence of IL-1 in vivo may be difficult to detect due to the presence of inhibitor(s) and the level of the inhibitor(s) may vary depending upon pathological conditions. We have found that urine from three patients with monocytic leukemia (M5) contained high levels of inhibitor(s) of MCF/IL-1, whereas urine of normal subjects did not contain significant amounts. Urine from two patients with other blood neoplasic diseases also contained little inhibitory activity. The MCF/IL-1 inhibitor(s), which also acts on human recombinant IL-1 beta, is approximately 25-35 kD, is not retained on concanavalin A-Sepharose column and can be partially destroyed with urea and boiling. At this stage of the purification the fraction containing the MCF/IL-1 inhibitor(s) also inhibits the LAF/IL-1 assay. However, this inhibitor(s) is probably distinct from other inhibitors already described.


[Structure of the cell wall polysaccharide in the food protein yeast Candida spec H. III. Characterization of different phosphate bonds in the mannan-protein-phosphate complex].
The 31P-NMR spectra of the proteophosphomannan (PPM) and also that of mildly hydrolyzed PPM demonstrated phosphomonoester (in both preparations), acid labile and acid stable phosphodiester linkage, and polyphosphate. Decreasing in size by pronase digestion, separation, purification and characterization of the high and low molecular phosphates by 31P-NMR spectroscopy and chemical analysis revealed the mannan protein is phosphorylated in the N-glycosidically linked carbohydrate parts and in the O-glycosidically linked oligosaccharides. Another phosphate serves as a bridge between the serine of the protein and mannose, mannobioses and mannotrioses and between the threonine and a lipophilic acylglycerid unit. The origin of the polyphosphates has been discussed.


Prediction of the relative blood glucose response of mixed meals using the white bread glycemic index.
Unexpected plasma glucose responses to different mixed meals fed to normal and diabetic volunteers have recently been reported. We have therefore examined in normal volunteers the effect of mixing carbohydrate foods of different glycemic indices (GIs) without the addition of fat and protein. The observed GI of the mixed meal was within 2% of the expected value. In studies in the literature where fat and protein were added to mixed meals, the observed blood glucose responses also related significantly to the meal GIs calculated from the individual foods. Addition of fat and protein in the quantities used did not obscure this relationship. Studies to determine sources of error in comparing glycemic responses showed that type II diabetic patients displayed the least within-individual variation, and type I diabetic patients the most. Expression of results as the GI rather than as absolute glycemic response areas reduced by 50% the between-subject variation. The mean GI values of rice tested in type I and type II patients were similar (82 +/- 22 compared with 74 +/- 19) and the reproducibility 22 mo later in the same group of subjects was excellent (81 +/- 15 compared with 83 +/- 15). However, the lack of precise GI values for all foods fed in the test meals indicates a need for GI values to be derived for a wider range of individual foodstuffs. The GI approach to classifying foods according to physiologic effect may play a useful role in planning meals and diets in which specific blood glucose profiles are required.


Transgenic Cotton: From Biotransformation Methods to Agricultural Application.
Transgenic cotton is among the first transgenic plants commercially adopted around the world. Since it was first introduced into the field in the middle of the 1990s, transgenic cotton has been quickly adopted by cotton farmers in many developed and developing countries. Transgenic cotton has offered many important environmental, social, and economic benefits, including reduced usage of pesticides, indirect increase of yield, minimizing environmental pollution, and reducing labor and cost. Agrobacterium-mediated genetic transformation method is the major method for obtaining transgenic cotton. However, pollen tube pathway-mediated method is also used, particularly by scientists in China, to breed commercial transgenic cotton. Although transgenic cotton plants with disease resistance, abiotic stress tolerance, and improved fiber quality have been developed in the past decades, insect-resistant and herbicide-tolerant cottons are the two dominant cottons in transgenic cotton market.


Assessment of facial form modifications in orthodontics: proposal of a modified computerized mesh diagram analysis.
A modified computerized mesh diagram analysis enables rapid, easy, and independent quantifications of facial size, shape, and head position. A lateral cephalometric radiograph is traced, positioned in natural head position (NHP) according to the NHP registered on a lateral photograph, and superimposed by the standard grid of rectangles determined by the patient's upper face height and face depth. The patient's tracing is compared with a reference tracing of a norm. The two tracings are registered at nasion in NHP, and the size difference of the patient's mesh rectangles from the norm is quantified by a size normalization. The shape discrepancies are evaluated by calculating relevant displacement vectors for each cephalometric landmark, and a global difference factor. This computerized method provides a rapid graphic evaluation of the patient's sagittal and vertical discrepancies and can also be applied to determine the effects of orthodontic therapy and/or growth on the skeletal and dental relationships in a single patient.


Preparing special-needs children for adoption through use of a life book.
Adequate preparation can help assure the success of adoptive placements for special-needs children. One successful method calls for the development of a life book, chronicling the movement of the child through the five stages that will prepare him or her for adoption.


Estimating the prevalence of drug misuse in Dundee, Scotland: an application of capture-recapture methods.
To apply capture-recapture methods to provide an estimate of the prevalence of opiate and benzodiazepine misuse in Dundee, Scotland. A four sample capture-recapture method using data from both statutory and non-statutory data sources to estimate drug misuse prevalence in Dundee between January 1990 and December 1994. Users of benzodiazepines or opiates residing within Dundee. Altogether 855 drug misusers were identified from various sources within Dundee; many were identified from more than one source. Using this data, the estimated unknown population was 1702, giving a total population of 2557 (95% confidence interval (CI) 1974, 3458) who misuse benzodiazepines or opiates. This represents a prevalence of 28.8 (95% CI 22.3, 39.0) per thousand. Capture-recapture techniques can be applied to statutory and non-statutory agency data to produce an estimate of at least certain sections of the drug misusing population. However, it is important to recognise the limitations of this methodology and in future to seek to combine a range of approaches to the problem of estimating prevalence rather than sticking rigidly to any single approach.


Identification of Xenopus laevis mRNAs with homology to repetitive sequences.
Hybrid selection translation experiments have been carried out with genomic and cDNA relatives of two repetitive sequence families. On the basis of the in vitro translation products detected, it was found that transcripts complementary to these repeats are linked to several different mature mRNAs in stage 40 embryos of Xenopus laevis. One repeat hybridizes to mRNAs that direct the synthesis of 17 proteins. The second is present on mRNAs coding for 3 proteins. By estimating the abundance of these proteins among the translation products of total embryonic mRNA, it is inferred that all of the repeat bearing mRNAs are rare, less than one in 20,000 mRNA molecules.


Instrument-free detection of polyphenols with a thread-based analytical device.
We described an instrument-free method for quantitative analysis of the total content of tea polyphenols by measurement of the length of a coloured band. Polyphenols react with ferrous ions to form a colourless ferrous-polyphenols complex on cotton threads, which could be adsorbed on the threads. The complex was then oxidized to form a blue-black ferric-polyphenols complex, generating a blue-black band on the cotton thread. The length of this blue-black band was then measured to detect the total content of polyphenols. The advantages of this method include low cost, rapid analysis, low consumption, easy fabrication and operation. Furthermore, the digital instrument (scanner or camera) as well as the image processing software are not required. This proposed method was used to detect polyphenols in tea leaf extracts with an analytical result agreeing well with that obtained by a standard method, which demonstrates its potential in monitoring of tea leaf quality, especially in resource-limited regions and settings.


Radiographic localization of unerupted mandibular anterior teeth.
The parallax method and the use of 2 radiographs taken at right angles to each other are the 2 methods generally used to accurately localize teeth. For the parallax method, the combination of a rotational panoramic radiograph with an occlusal radiograph is recommended. This combination involves a vertical x-ray tube shift. Three case reports are presented that illustrate: (1) how this combination can accurately localize unerupted mandibular anterior teeth, (2) how a deceptive appearance of the labiolingual position of the unerupted tooth can be produced in an occlusal radiograph, (3) how increasing the vertical angle of the tube for the occlusal radiograph makes the tube shift easier to discern, (4) why occlusal radiographs are preferable to periapical radiographs for tube shifts, and (5) how localization can also be carried out with 2 radiographs at right angles to each other, one of which is an occlusal radiograph taken with the x-ray tube directed along the long axis of the reference tooth.


Dihydro-orotase from Clostridium oroticum. Purification and reversible removal of essential zinc.
A new purification procedure involving five column-chromatography steps is described for dihydro-orotase (L-5,6-dihydro-orotate amidohydrolase, EC 184.108.40.206) from Clostridium oroticum (A.T.C.C. 25750). The native purified enzyme is a dimer of Mr 102 000 and contains 4.0 +/- 0.3 g-atoms of zinc/mol of dimer. These observations agree with those reported previously [Taylor, Taylor, Balch & Gilchrist (1976) J. Bacteriol. 127, 863-873]. It is conclusively demonstrated that dihydro-orotase is a zinc metalloenzyme. Zinc is reversibly removed by treatment with chelators in phosphate buffer at pH 6.5, as demonstrated by atomic absorption spectrophotometry and decrease of enzyme activity. The specific activity is linearly dependent on zinc content. Addition of ZnSO4 to the chelator-treated enzyme results in regain of the normal complement of zinc and enzyme activity. Kinetic properties of the reconstituted enzyme are indistinguishable from those of the native enzyme. The amino acid composition of the homogeneous enzyme suggests that the zinc atoms occupy different environments.


Decidualization Process Induces Maternal Monocytes to Tolerogenic IL-10-Producing Dendritic Cells (DC-10).
Decidualization is a process that involves phenotypic and functional changes of endometrial stromal cells to sustain endometrial receptivity and the participation of immunoregulatory factors to maintain immune homeostasis. In this context, tolerogenic dendritic cells (DCs) can induce regulatory T cells, which are essential to manage the pro- to anti-inflammatory transition during embryo implantation. Recently, Myeloid Regulatory Cells (MRCs) were proposed as immunosuppressants and tolerance-inducer cells, including the DC-10 subset. This novel and distinctive subset has the ability to produce IL-10 and to induce type 1 regulatory T cells (Tr1) through an HLA-G pathway. Here we focus on the impact of the decidualization process in conditioning peripheral monocytes to MRCs and the DC-10 subset, and their ability to induce regulatory T cells. An in vitro model of decidualization with the human endometrial stromal cell line (HESC), decidualized by medroxyprogesterone and dibutyryl-cAMP was used. Monocytes isolated from peripheral blood mononuclear cells from healthy women were cultured with rhGM-CSF + rhIL-4 and then, the effect of conditioned media from decidualized (Dec-CM) and non-decidualized cells (Non-dec-CM) was tested on monocyte cultures. We found that Dec-CM inhibited the differentiation to the CD1a+CD14- immature DC profile in a concentration-dependent manner. Dec-CM also significantly increased the frequency of CD83+CD86low and HLA-DR+ cells in the monocyte-derived culture. These markers, associated with the increased production of IL-10, are consistent with a MRCs tolerogenic profile. Interestingly, Dec-CM treatment displayed a higher expression of the characteristic markers of the tolerogenic DC-10 subset, HLA-G and ILT2/CD85j; while this modulation was not observed in cultures treated with Non-dec-CM. Moreover, when monocyte cultures with Dec-CM were challenged with LPS, they sustained a higher IL-10 production and prevented the increase of CD83, CD86, IL-12p70, and TNF-α expression. Finally, the DC-10 subset was able to induce a CD4+HLA-G+ regulatory T cells subset. These results suggest that the decidualization process might induce different subsets of MRCs, like DC-10, able to induce regulatory T cells as a novel CD4+HLA-G+ subset which might play an immunoregulatory role in embryo implantation.


Nonhelical leash and alpha-helical structures determine the potency of a peptide antagonist of human T-cell leukemia virus entry.
Viral fusion proteins mediate the entry of enveloped viral particles into cells by inducing fusion of the viral and target cell membranes. Activated fusion proteins undergo a cascade of conformational transitions and ultimately resolve into a compact trimer of hairpins or six-helix bundle structure, which pulls the interacting membranes together to promote lipid mixing. Significantly, synthetic peptides based on a C-terminal region of the trimer of hairpins are potent inhibitors of membrane fusion and viral entry, and such peptides are typically extensively alpha-helical. In contrast, an atypical peptide inhibitor of human T-cell leukemia virus (HTLV) includes alpha-helical and nonhelical leash segments. We demonstrate that both the C helix and C-terminal leash are critical to the inhibitory activities of these peptides. Amino acid side chains in the leash and C helix extend into deep hydrophobic pockets at the membrane-proximal end of the HTLV type 1 (HTLV-1) coiled coil, and these contacts are necessary for potent antagonism of membrane fusion. In addition, a single amino acid substitution within the inhibitory peptide improves peptide interaction with the core coiled coil and yields a peptide with enhanced potency. We suggest that the deep pockets on the coiled coil are ideal targets for small-molecule inhibitors of HTLV-1 entry into cells. Moreover, the extended nature of the HTLV-1-inhibitory peptide suggests that such peptides may be intrinsically amenable to modifications designed to improve inhibitory activity. Finally, we propose that leash-like mimetic peptides may be of value as entry inhibitors for other clinically important viral infections.


OnTrackNY's learning healthcare system.
Worldwide, early intervention services for young people with recent-onset psychosis have been associated with improvements in outcomes, including reductions in hospitalization, symptoms, and improvements in treatment engagement and work/school participation. States have received federal mental health block grant funding to implement team-based, multi-element, evidence-based early intervention services, now called coordinated specialty care (CSC) in the USA. New York State's CSC program, OnTrackNY, has grown into a 23-site, statewide network, serving over 1800 individuals since its 2013 inception. A state-supported intermediary organization, OnTrackCentral, has overseen the growth of OnTrackNY. OnTrackNY has been committed to quality improvement since its inception. In 2019, OnTrackNY was awarded a regional hub within the National Institute of Mental Health-sponsored Early Psychosis Intervention Network (EPINET). The participation in the national EPINET initiative reframes and expands OnTrackNY's quality improvement activities. The national EPINET initiative aims to develop a learning healthcare system (LHS); OnTrackNY's participation will facilitate the development of infrastructure, including a systematic approach to facilitating stakeholder input and enhancing the data and informatics infrastructure to promote quality improvement. Additionally, this infrastructure will support practice-based research to improve care. The investment of the EPINET network to build regional and national LHSs will accelerate innovations to improve quality of care.


Two Extremely Rare Case of Carcinosarcoma Ex Pleomorphic Adenoma.
Carcinosarcoma ex pleomorphic adenoma (CCPA), also known as true mixed malignant tumor, is an extremely rare high-grade aggressive tumor. The histopathologic examination is the gold standard for diagnosis and radiologic imaging also plays an important role. CCPA should be considered in the differential diagnosis of salivary gland tumors when there are findings suggestive of malignancy such as necrosis and diffusion limitation on imaging.


Iron supplementation: overcoming technical and practical barriers.
Iron supplementation is probably the best available option to effectively address iron deficiency in pregnant women and young children because it can be targeted specifically to these high-risk groups. However, technical and practical barriers exist: limited information on the effectiveness of supplementation interventions, side effects that affect compliance, and supply/distribution constraints. An innovative approach to addressing these constraints is the use of sprinkles of powdered, microencapsulated ferrous fumarate that can be added directly to any semi-liquid food without changing their taste or consistency. This technique has been tested in initial trials in Ghana and found to be as effective as iron drops. Another approach to improve the effectiveness of iron interventions is through information, education and communication (IEC) programs. These interventions can help modify consumer behavior in some cases, but in some countries, geographic location, variations in language and population size can make the cost of IEC programs very high. IEC strategies in Indonesia aimed at increasing demand for iron supplements by systematic dissemination of specific messages, improving the quality and variety of tablets, increasing the availability and access to supplements by engaging the commercial sector, enrolling traditional birth attendants and other community volunteers in selling supplements. Key issues to be addressed include clarifying optimal starting points and duration of supplementation interventions--based on individual status or population prevalence, defining hemoglobin and ferritin cutoffs at which treatment should be instigated and evaluating the effectiveness of intermittent supplementation with multiple micronutrients.


Early postmolt performance of laying hens fed a low-protein corn molt diet supplemented with corn gluten meal, feather meal, methionine, and lysine.
Commercial White Leghorn hens (65, 63, or 70 wk of age in Experiments 1, 2, and 3, respectively) were induced molted by feed withdrawal until approximately 28% body weight was lost. All hens were then weighed, and seven replicate groups of 12 hens each were fed molt diets. In Experiment 1, three diets consisted of a corn basal diet (7.9% CP) or this diet supplemented with corn gluten meal (CGM) and Lys or feather meal (FM), Met, and Lys. In Experiments 2 and 3, varying levels of FM and FM with Met and Lys were evaluated. A 16% CP corn-soybean meal diet was used as a positive control in all experiments. The molt diets were fed for 17, 15, and 17 d in Experiments 1, 2, and 3, respectively, and production performance was measured for 8 wk from the beginning of feeding the layer diet. In all experiments, hens fed the 16% CP corn-soybean meal molt diet returned to egg production and regained body weight at a faster rate than did hens fed any of the other diets. In Experiment 1, early egg production of hens fed the corn basal diet supplemented with CGM and Lys or supplementation with FM, Met, and Lys was greater (P < 0.05) than that of hens fed the basal diet alone. In Experiment 2, very early egg production (Week 1) and body weight gain were lower (P < 0.05) for hens fed the corn basal diet than for hens fed the basal supplemented with FM, Met, and Lys. The addition of 5.75 or 8.5% FM or 5.75% FM plus Met and Lys generally increased (P < 0.05) early egg production and postmolt body weight gain compared to the corn basal diet in Experiment 3. The present study thus indicated that improved early postmolt performance may be achieved by supplementation of a low-protein corn molt diet with various combinations of CGM, FM, Met, and Lys.


Nodular fasciitis in the pediatric population: a single center experience.
To describe our experience with nodular fasciitis in the pediatric population, in an attempt to contribute additional information that may be used to develop a more comprehensive characterization of the disease. A twenty-year retrospective chart review of patients 18 years or younger diagnosed with nodular fasciitis at a single, large, academic institution. Five patients were treated for nodular fasciitis during the study period. The majority (60%) were male and all presented with rapidly enlarging masses that were excised surgically. The median age at presentation was 14 years. Most (60%) lesions were located in the upper extremities and 80% had no related symptomatology or disability. All lesions were less than 3 cm in greatest dimension and 4 patients had no signs of recurrence (one patient was lost to follow-up). Pathologic, immunohistochemical, and long-term follow-up data were lacking in our cohort. The characteristics of nodular fasciitis in children at our institution are slightly different than those which have been reported thus far based on no patients with head and neck disease or antecedent trauma to the affected area. Due to variability in clinical presentation and histologic findings, additional studies are necessary to provide more practical, consistent and effective management strategies.


Familial risks of esophageal cancer among the Turkmen population of the Caspian littoral of Iran.
In northeastern Iran, there is an area of high incidence of esophageal cancer, which is populated by residents of Turkmen ancestry. Several environmental risk factors for esophageal cancer have been proposed, but the roles of familial and genetic factors have not been studied extensively in the Turkmen population. We evaluated the importance of familial risk factors for esophageal cancer by performing a case-control study of 167 cases of esophageal squamous cell carcinoma and 200 controls of Turkmen ethnicity. Detailed family pedigrees of the cases and controls were constructed, which documented all cancers in first- and second-degree relatives. The actuarial risk of cancer was then estimated in 2,097 first-degree relatives of cases and 2,783 first-degree relatives of the controls. A hazard ratio was constructed, based on a comparison of the 2 cumulative incidence curves. The risk to age 75 of esophageal cancer in the first-degree relatives of Turkmen patients with esophageal cancer was 34% versus 14% for the first-degree relatives of the controls (hazard ratio = 2.3; p = 3 x 10(-8)). Cases (9.6%) reported that their parents were related, versus 2.5% of the controls who reported this. (odds ratio = 4.1; p value = 0.006). Familial factors are important in the etiology of esophageal cancer among the Turkmen residents of Iran. The hazard ratio of 2.3 for cancer among first-degree relatives is consistent with an important contribution of heritable factors. It will be of interest to perform marker studies to establish which genes are responsible.


Chemotactic peptide effects on intestinal electrolyte transport.
The bacterial-derived chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) increases short-circuit current (Isc) and arachidonic acid metabolism (AAM) in rabbit ileum and distal colon. Serosal (s) or mucosal (m) addition of fMLP transiently increases Isc. Half-maximally effective dose and maximal increases in Isc were 32 nM and 84 microA/cm2 in ileum and 234 nM and 80 microA/cm2 in colon, respectively. Piroxicam, a cyclooxygenase inhibitor, diminished the Isc response by 97% in colon and 69% in ileum. Changes in Isc were dependent on Cl- and HCO3- in the bathing media. In ileum, fMLP inhibited m-to-s 36Cl- fluxes and stimulated s-to-m 36Cl- fluxes. These changes in Cl- flux were also inhibited by piroxicam. fMLP stimulated prostaglandin E2 (PGE2) release in intact tissue and in isolated subepithelial components. Increased tissue adenosine 3',5'-cyclic monophosphate levels were detected in intact tissue but not in isolated components. Previous desensitization of ileum to PGE1 inhibited fMLP stimulation of Isc in ileum by 88%. Desensitization to fMLP in ileum failed to alter the effect of PGE1 (10 microM) on Isc. In isolated microsomal membranes of ileal enterocytes, fMLP binding sites could not be demonstrated, suggesting that fMLPs action was initially mediated via stimulation of nonepithelial cell cyclooxygenase activity. The above results indicate that fMLP stimulates net secretion in both ileum and colon probably by the activation of AAM.


Cure of Haemophilus parainfluenzae endocarditis with chloramphenicol.
Haemophilus parainfluenzae is an increasingly reported cause of infective endocarditis. In vitro studies have shown this organism to bae almost universally sensitive to chloramphenicol. However, therapy for H parainfluenzae endocarditis with chloramphenicol as a single agent has been disappointing. This has been attributed to the bacteriostatic activity of chloramphenicol, whereas bactericidal agents are essential for cure of infective endocarditis. We successfully treated a patient with H parainfluenzae endocarditis with chloramphenicol alone after in vitro testing showed chloramphenicol to be bactericidal against the organism. When it is documented that chloramphenicol has bactericidal activity against the causative organism, it alone can be effective therapy for H parainfluenzae endocarditis.


Extension CT scan: its suitability for assessing fusion after posterior lumbar interbody fusion.
Posterior lumbar interbody fusion (PLIF) is a popular procedure for treating lumbar canal stenosis with spinal instability, and several reports concerning fusion assessment methods exist. However, there are currently no definitive criteria for diagnosing a successful interbody fusion in the lumbar spine. We suggested evaluating fusion status using computed tomography (CT) in extension position to detect pseudoarthrosis more precisely. The purpose of this study was to evaluate its usefulness for determining bone union quality after PLIF. Eighty-one patients who underwent PLIF at 97 levels were retrospectively enrolled. The study population included 48 men and 33 women (mean age 58.9 years, range 21-85 years). Patients were followed up for more than 12 months after surgery. The mean follow-up period was 27.6 months (range 14-49 months). Fusion status was evaluated using three ways: flexion-extension radiographs, CT images in flexion and extension position. In the flexion-extension radiographs, mobility of more than 3°, a remaining clear zone, or an uncertain bone connection constituted an incomplete union. For CT images, a remaining clear zone, a gas pattern, or an uncertain bone connection constituted an incomplete union. Flexion-extension radiographs demonstrated a solid fusion in 90.7% of the 97 levels at 10.7 months postoperatively. When fusion was demonstrated on flexion-extension radiographs, the rate of fusion affirmed by flexion CT and extension CT was 87.6 and 69.1% of the levels assessed, respectively. The rate of pseudoarthrosis detected on extension CT images was significantly higher than that on flexion-extension radiographs (P < 0.001) and flexion CT (P < 0.01). The rate of fusion achieved on extension CT was 85.6% at 15.1 months postoperatively. Extension CT could detect pseudoarthrosis more clearly than flexion-extension radiography and flexion CT. The CT images are influenced by body position and dilating anterior disc space in extension CT contributes to detect pseudoarthrodesis. Thus, extension CT was a useful method for assessing fusion status after PLIF.


Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults.
Lateral elbow pain, or tennis elbow, is a common condition causing pain in the elbow and forearm and lack of strength and function of the elbow and wrist. It is often treated with non-steroidal anti-inflammatory drugs (NSAIDs), either orally or by topical application. To assess effectiveness of NSAIDs (oral or topical) in the treatment of adults with lateral elbow pain with respect to symptom (pain) reduction, improvement in function, grip strength and adverse effects. We searched the Musculoskeletal Review Group's trials register database, the Cochrane Clinical Trials Register (Cochrane Library issue 2, 2001), MEDLINE, CINAHL, EMBASE and SCISEARCH up to June 2001. Randomised and pseudo randomised trials in all languages of NSAIDs (oral or topical) compared to placebo or another intervention, or comparing two NSAIDs (oral or topical) to each other, in adults with lateral elbow pain (tennis elbow). Outcomes of interest were pain, function, disability and quality of life, strength, participant satisfaction with treatment and adverse effect. Two reviewers independently applied selection criteria and assessed study quality. Fourteen trials were included in the review. Few trials used intention to treat analysis, and the sample size of most was small. The median follow up was 2 weeks (range 1-12 weeks). There is evidence that topical NSAIDs are significantly more effective than placebo with respect to pain [weighted main difference= -1.88, (95% confidence intervals -2.54 to -1.21)] and participant satisfaction [relative risk 0.39, (95% confidence intervals 0.23 to 0.66)] in the short term, and this finding is robust against the possible bias introduced by the inclusion of unblinded trials and publication bias. The adverse effects reported were minor. Only two included trials assessed the effect of oral NSAID and these were not able to be pooled. There is some evidence for short term benefit with respect to pain and function from oral NSAIDs, but this benefit was not sustained. Significantly more gastrointestinal adverse effects were reported by those taking oral NSAIDs [relative risk = 3.17, (95% confidence intervals 1.35 to 7.41)]. In the short term there may be some advantage in steroid injection over oral NSAID [patient's perception of benefit relative risk = 3.06, (95% confidence intervals 1.55 to 6.06)], but this was not sustained in the longer term. There is some support for the use of topical NSAIDs to relieve lateral elbow pain at least in the short term. There remains insufficient evidence to recommend or discourage the use of oral NSAID, although it appears injection may be more effective than oral NSAID in the short term. A direct comparison between topical and oral NSAID has not been made and so no conclusions can be drawn regarding the best method of administration.


Nonlinear mixed-effects modeling of MNREAD data.
It is often difficult to estimate parameters from individual clinical data because of noisy or incomplete measurements. Nonlinear mixed-effects (NLME) modeling provides a statistical framework for analyzing population parameters and the associated variations, even when individual data sets are incomplete. The authors demonstrate the application of NLME by analyzing data from the MNREAD, a continuous-text reading-acuity chart. The authors analyzed MNREAD data (measurements of reading speed vs. print size) for two groups: 42 adult observers with normal vision and 14 patients with age-related macular degeneration (AMD). Truncated sets of MNREAD data were generated from the individual observers with normal vision. The MNREAD data were fitted with a two-limb function and an exponential-decay function using an individual curve-fitting approach and an NLME modeling approach. The exponential-decay function provided slightly better fits than the two-limb function. When the parameter estimates from the truncated data sets were used to predict the missing data, NLME modeling gave better predictions than individual fitting. NLME modeling gave reasonable parameter estimates for AMD patients even when individual fitting returned unrealistic estimates. These analyses showed that (1) an exponential-decay function fits MNREAD data very well, (2) NLME modeling provides a statistical framework for analyzing MNREAD data, and (3) NLME analysis provides a way of estimating MNREAD parameters even for incomplete data sets. The present results demonstrate the potential value of NLME modeling for clinical vision data.


Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde.
Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity.


The effects of pregnancy on autoimmune diseases.
Internal gestation of a genetically foreign conceptus challenges the maternal host to circumvent immunological processes that recognize and eliminate nonself molecules. Accordingly, human viviparity involves a wide range of immunological modifications. This review examines the relationship between pregnancy and several autoimmune diseases prevalent in women. Pregnancy is associated with improvement in the clinical signs and symptoms of rheumatoid arthritis in more than 70% of patients. Maternal-fetal disparity in alleles of HLA-DRbeta1, DQalpha, and DQbeta has been reported to be associated with pregnancies characterized by remission or improvement. These observations suggest that presentation of fetal DQalpha peptides might correct autoimmunity in patients with RA either by induction of maternal-regulatory T cells, or by affecting the maternal T cell receptor repertoire. In contrast, the course of systemic lupus erythematosus is more variable. Whether flare rates increase during or after pregnancy is unsettled, since individual patient series vary in the characteristics of patients accepted for study and in definitions of flare. Despite a high overall flare rate in some series approaching 60%, recorded flares were usually not severe. Only limited data are available regarding the incidence or outcome for either the mother with scleroderma or her fetus. The extent of diffuse skin disease and systemic involvement, particularly pulmonary, cardiac and renal, may be more important than the duration of the disease; limited disease carries a better prognosis for the mother and fetus. Highly specific autoantibody profiles in the mother (independent of whether she has a clinical disease) are associated with fetal demise and neonatal lupus syndromes, the most serious manifestation of which is isolated congenital heart block. The former is associated with antiphospholipid antibodies and the latter with antibodies directed against SSA/Ro and SSB/La polypeptides.


Neuropharmacological Targets for Drug Action in Vestibular Sensory Pathways.
The use of pharmacological agents is often the preferred approach to the management of vestibular dysfunction. In the vestibular sensory pathways, the sensory neuroepithelia are thought to be influenced by a diverse number of neuroactive substances that may act to enhance or inhibit the effect of the primary neurotransmitters [i.e., glutamate (Glu) and acetylcholine (ACh)] or alter their patterns of release. This review summarizes various efforts to identify drug targets including neurotransmitter and neuromodulator receptors in the vestibular sensory pathways. Identifying these receptor targets provides a strategic basis to use specific pharmacological tools to modify receptor function in the treatment and management of debilitating balance disorders. A review of the literature reveals that most investigations of the neuropharmacology of peripheral vestibular function have been performed using in vitro or ex vivo animal preparations rather than studying drug action on the normal intact vestibular system in situ. Such noninvasive approaches could aid the development of more accurate and effective intervention strategies for the treatment of dizziness and vertigo. The current review explores the major neuropharmacological targets for drug action in the vestibular system.


Childhood trauma and being at-risk for psychosis are associated with higher peripheral endocannabinoids.
Evidence has been accumulating regarding alterations in components of the endocannabinoid system in patients with psychosis. Of all the putative risk factors associated with psychosis, being at clinical high-risk for psychosis (CHR) has the strongest association with the onset of psychosis, and exposure to childhood trauma has been linked to an increased risk of development of psychotic disorder. We aimed to investigate whether being at-risk for psychosis and exposure to childhood trauma were associated with altered endocannabinoid levels. We compared 33 CHR participants with 58 healthy controls (HC) and collected information about previous exposure to childhood trauma as well as plasma samples to analyse endocannabinoid levels. Individuals with both CHR and experience of childhood trauma had higher N-palmitoylethanolamine (p < 0.001) and anandamide (p < 0.001) levels in peripheral blood compared to HC and those with no childhood trauma. There was also a significant correlation between N-palmitoylethanolamine levels and symptoms as well as childhood trauma. Our results suggest an association between CHR and/or childhood maltreatment and elevated endocannabinoid levels in peripheral blood, with a greater alteration in those with both CHR status and history of childhood maltreatment compared to those with either of those risks alone. Furthermore, endocannabinoid levels increased linearly with the number of risk factors and elevated endocannabinoid levels correlated with the severity of CHR symptoms and extent of childhood maltreatment. Further studies in larger cohorts, employing longitudinal designs are needed to confirm these findings and delineate the precise role of endocannabinoid alterations in the pathophysiology of psychosis.


Channel Activities of the Full-Length Prion and Truncated Proteins.
Prion diseases are fatal neurodegenerative disorders characterized by the conversion of the cellular prion protein (PrPC) into a misfolded prion form, which is believed to disrupt the cellular membranes. However, the exact mechanisms underlying prion toxicity, including the formation of membrane pores, are not fully understood. The prion protein consists of two domains: a globular domain (GD) and a flexible N-terminus (FT) domain. Although a proximal polybasic amino acid (FT(23-31) sequence of FT is a prerequisite for cellular membrane permeabilization, other functional domain regions may modulate its effects. Through single-channel electrical recordings and cryo-electron microscopy (cryo-EM), we discovered that the FT(23-50) fragment forms pore-shaped oligomers and plays a dominant role in membrane permeabilization within the full-length mouse prion protein (mPrP(23-230)). In contrast, the FT(51-110) domain or the C-terminal domain downregulate the channel activity of FT(23-50) and mPrP(23-230). The addition of prion mimetic antibody, POM1 significantly amplifies mPrP(23-230) membrane permeabilization, whereas POM1_Y104A, a mutant that binds to PrP but cannot elicit toxicity, has a negligible effect on membrane permeabilization. Additionally, the anti-N-terminal antibody POM2 or Cu2+ binds to the FT domain, subsequently enhancing the FT(23-110) channel activity. Importantly, our setup provides a novel approach without an external fused protein to examine the channel activity of truncated PrP in the lipid membranes. We therefore propose that the primary N-terminal residues are essential for membrane permeabilization, while other functional segments of PrP play a vital role in modulating the pathological effects of PrP-mediated neurotoxicity.


The FXR Agonist, Obeticholic Acid, Suppresses HCC Proliferation & Metastasis: Role of IL-6/STAT3 Signalling Pathway.
The nuclear receptor, farnesoid X receptor (FXR), has been recently considered as a tumor suppressor in HCC. IL-6/Janus kinase 2 (Jak-2)/signal transducer and activator of transcription 3 (STAT3) pathway has been implicated as a key player in many cancer types. This study aimed at investigating the potential effect of the FXR agonist, obeticholic acid (OCA), on HCC and the involvement of IL-6/STAT3 pathway. The potential regulation of STAT3 by its main feedback inhibitor target gene, the suppressor of cytokine signaling 3 (SOCS3), triggered by OCA was also explored. Cytotoxicity studies were performed on HepG2, Huh7, and SNU-449 cell lines using OCA alone and combined with the FXR antagonist guggulsterone (Gugg). OCA cytotoxic effect was significantly hampered in presence of Gugg. OCA also caused cell cycle arrest and inhibited invasion and migration of HCC cells. Decrease in STAT3 phosphorylation and SOCS3 upregulation were also observed. Moreover, Jak-2, IL-1β, and IL-6 levels were decreased. These results were correlated with an upregulation of FXR and small heterodimer partner (SHP) levels. Effects of OCA on IL-6/STAT3 main key players were reversed in presence of Gugg. Overall, these findings suggest a potential effect of OCA in HCC via interfering with IL-6/STAT3 signalling pathway in vitro.


Differential CTLs specific for prostate-specific antigen in healthy donors and patients with prostate cancer.
Induction of CTL responses specific for prostate-specific antigen (PSA)-derived peptides in healthy individuals and patients with prostate cancer (PC) was investigated. Eight PSA-derived peptides that have the potential to bind HLA-A2 molecules were examined. Peripheral blood lymphocytes isolated from HLA-A2-positive volunteers were expanded using autologous mature, PSA-derived peptide-pulsed dendritic cells. The expansion of IFN-gamma-secreting CD8+ T cells specific for three of the eight PSA-derived peptides (PSA-2(108-117), PSA-4(141-150) and PSA-6(146-154)) was detected in healthy individuals, but not in patients with PC. Using HLA-A2/peptide tetramers, the PSA-specific CD8+ T cells were detectable at low frequency both in healthy individuals and patients with PC. Using flow cytometric cytotoxicity assays, the expanded effectors from healthy individuals were able to kill the PSA-expressing epithelial cell line LNCaP and the peptide-pulsed T2 cells in a MHC class I-restricted manner without involving NK activity. However, such killing by effectors expanded from prostatectomized patients involved a complete or a significant NK activity. Specific recognition of PSA-derived peptides in healthy individuals may occur by an adaptive CTL immune response, while such recognition in PC patients may additionally or alternatively be mediated by an innate NK immune response. In conclusion, our work indicates that the PSA-specific CD8+ T cells exist in both healthy individuals and PC patients, but they have impaired function in patients as they failed to release IFN-gamma and to kill targets without involving NK activity.


Quantification of human and animal viruses to differentiate the origin of the fecal contamination present in environmental samples.
Many different viruses are excreted by humans and animals and are frequently detected in fecal contaminated waters causing public health concerns. Classical bacterial indicator such as E. coli and enterococci could fail to predict the risk for waterborne pathogens such as viruses. Moreover, the presence and levels of bacterial indicators do not always correlate with the presence and concentration of viruses, especially when these indicators are present in low concentrations. Our research group has proposed new viral indicators and methodologies for determining the presence of fecal pollution in environmental samples as well as for tracing the origin of this fecal contamination (microbial source tracking). In this paper, we examine to what extent have these indicators been applied by the scientific community. Recently, quantitative assays for quantification of poultry and ovine viruses have also been described. Overall, quantification by qPCR of human adenoviruses and human polyomavirus JC, porcine adenoviruses, bovine polyomaviruses, chicken/turkey parvoviruses, and ovine polyomaviruses is suggested as a toolbox for the identification of human, porcine, bovine, poultry, and ovine fecal pollution in environmental samples.


HIV prevalence, risky behaviors, and discrimination experiences among transgender women in Cambodia: descriptive findings from a national integrated biological and behavioral survey.
Transgender people are disproportionately affected by HIV. Despite their high vulnerability to HIV, lack of adequate epidemiological and surveillance data related to this population in many countries prevents provision of appropriate services. This paper summarizes descriptive findings from a national integrated biological and behavioral survey and discusses policy implications of the findings on HIV prevention among transgender women in Cambodia. This cross-sectional study was conducted between December 2015 and February 2016. Participants were recruited from 20 sites in the capital city and 12 provinces of Cambodia using Respondent Driven Sampling (RDS) method. Behavioral data were collected through structured questionnaire interviews, and rapid finger-prick HIV testing was performed. Descriptive data analyses were conducted using STATA. This study included 1,375 transgender women with a mean age of 25.9 years (SD = 7.1). The overall prevalence of HIV was 5.9%. The prevalence of HIV was significantly higher among urban participants compared to their rural counterparts (6.5 vs. 2.6%, p = 0.02). Almost one in five (19.6%) had never been tested for HIV prior to the study. Overall, 45.0% reported ever using gender affirming hormones. More than one-third (39.1%) reported not using condoms in their last sex, 29.8% had engaged in sex in exchange for money/gifts, and 14.0% reported that they had experienced at least one symptom of sexually transmitted infections (STI) in the past year. About one in ten (10.1%) reported having used some form of amphetamine-type stimulant drugs, while 6.5% reported having sex during or after using illicit drugs. A significant number of participants experienced sexual abuse (39.2%), losing a job (24.3%), or physical abuse (23.6%) because of their transgender identity. In addition, 82.9 and 88.9% would be willing to use the HIV self-test and pre-exposure prophylaxis (PrEP), respectively, if they become available. The high prevalence of HIV, STI, and related risk behaviors among transgender women in Cambodia is of great concern, suggesting an urgent need to further expand tailored prevention interventions for this key population focusing on individual, social, and structural drivers of HIV. HIV self-test and PrEP should be explored as a priority.


Spin-lattice correlation in Eu3+ doped antiferromagnet TmFeO3.
We report the physical properties of Eu-doped bulk TmFeO3 through X-ray diffraction, magnetic susceptibility (χ), Raman scattering and X-ray absorption spectroscopy (XAS) study, which shows a similar orthorhombic structure with the Pbnm space group as TmFeO3. Magnetic measurement on Eu-doped TmFeO3 provides evidence for spin reorientations of Fe3+. Further, the Raman spectra of Eu3+ doped TmFeO3 show significant changes in Raman modes as a function of temperature, which are evidence for strong spin-lattice interaction. From the XAS spectra, the L-edge of Fe provides information on the valence state of Fe, whereas the K-edge of oxygen shows that the compound has a strong influence on the hybridization of the O(2p) state with the 3d states of Fe.


The role of ICAM-1 on T-cells in the pathogenesis of asthma.
The capacity of inflammatory cells to adhere is critical to inflammatory responses and involves an array of adhesion molecules grouped into distinct families. Intercellular adhesion molecule (ICAM)-1 has recently attracted much interest in view of increasing evidence that it plays a prominent role in allergic diseases such as asthma and rhinitis. Apart from its role in adhesion of inflammatory cells to vascular endothelium, the extracellular matrix and epithelium, ICAM-1 mediates T-cell/T-cell, T-cell/target cell and T-cell/B-cell interactions. ICAM-1 on the surface of T-cells is thought to participate in signal transduction and may thus modulate several functions including activation, proliferation, cytotoxicity and cytokine production. Because ICAM-1 is the receptor for the major group of rhinoviruses, the most important cause of acute asthma attacks, binding of rhinovirus (RV) to ICAM-1 on T-cells may, at least theoretically, modulate their function. We review here the role of ICAM-1 in asthma and focus more specifically on its expression on T-cells. We present evidence for a general increase in ICAM-1 expression in this disease including recent observations of enhanced expression on the surface of T-cells in the airways lumen. Whilst the implications of intercellular adhesion molecule- upregulation in asthma remain to be fully elucidated, its participation in cell trafficking and activation are being considered as a target for treatment. We present here early attempts to interfere with intercellular adhesion molecule-1 as an adhesion molecule involved in cell influx and studies aimed preventing virus-induced exacerbations of asthma in children based on the knowledge that intercellular adhesion molecule-1 is the receptor for rhinoviruses.


HPV catch-up vaccination of young women: a systematic review and meta-analysis.
While prophylactic human papilloma virus (HPV) vaccination is considered effective in young girls, it is unclear whether a catch-up vaccination of older girls would be beneficial. We, therefore, aimed to examine the potential health impact of a HPV catch-up vaccination of girls who were too old at the time of vaccine introduction, hence aged 16 and older. We systematically searched the literature for randomized clinical trials (RCTs) that examined the effect of HPV vaccines on overall mortality, cancer mortality and incidence, high-grade cervical intraepithelial neoplasia grade 2 and higher (CIN2+), vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN) grade 2 and higher lesions (VIN2+ and VaIN2+, respectively) genital warts (condyloma). We considered all lesions and those associated with HPV type(s) included in the vaccines. RCTs reporting on serious adverse events were also eligible. Selected publications were assessed for potential risk of bias, and we ascertained the overall quality of the evidence for each outcome using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Meta-analyses were performed, assuming both random and fixed effects, to estimate risk ratios (RR) and corresponding 95% confidence intervals (CI), using intention-to-treat and per-protocol populations. We included 46 publications reporting on 13 RCTs. Most of the RCTs had a maximum follow-up period of four years. We identified no RCT reporting on the effect of HPV catch vaccination on overall and cancer related mortality, and on cervical cancer incidence. We found a borderline protective effect of a HPV catch-up vaccination on all CIN2+, with a pooled RR of 0.80 (95% CI: 0.62-1.02) for a follow-up period of 4 years. A HPV catch-up vaccination was associated with a reduction in VIN2+ and VaIN2+ lesions, and condyloma. No difference in risk of serious adverse events was seen in vaccinated participants versus unvaccinated women (pooled RR of 0.99 (0.91-1.08)). This systematic review indicates that a HPV catch-up vaccination could be beneficial, however the long-term effect of such a vaccination, and its effect on cervical cancer incidence and mortality is still unclear.


[Factors determining the choice of a modality of treatment by dialysis: a study of nine dialysis centers].
The objective of this cross-sectional study in a population of 1472 dialysis patients was to identify the main factors involved in the choice of a specific option for dialysis therapy, taking into account three different types of criteria such as medical dependence (DM), nurse care requirement (SI) and independence for dialysis therapy (CA). Each patient has been analysed, independently of present treatment modality, according to the above three criteria, namely DM, SI and CA. For each type of parameter, patients have been allocated to one of three levels, each level being established to evaluate whether dialytic treatment should be undertaken as hospital centre dialysis (HDC) or in a facility off the hospital. Level 3 of any one category corresponded to the inability of doing haemodialysis at home (HHD) or in self-care unit (AD). Level 2 included patients who could be treated in AD or by peritoneal dialysis (PD) with the assistance of a nurse. CAPD or HHD were considered as potential treatment modalities only in patients qualifying for level 1 of each criterion. In the patient population as a whole, the following treatment options were observed: HHD 3.6%, CAPD 6%, PD 1.8%, AD 16.3% and HDC 72.2%. For medical dependence (DM) there was a relatively even distribution for the three levels in six centres. In contrast, two centres were characterized by a predominance of DM level 3. Differences in DM levels between centres were greatly reduced when considering separately only those patients who were actually treated by CAPD, HDC and AD. SI levels were more uniformly distributed within all centres, and this was true for HCD and AD patients. When considering CA levels in HDC patients, a large predominance of CA level 3 was observed in all centres whereas CA level 1 was nearly in existent. The major finding of this study was that the inability or the refusal of dialysis patients to participate at treatment, independently of medical condition and nurse care requirement, was the main factor in the choice of hospital centre dialysis.


Transformation of radially traveling cylindrical waves between two skew cylindrical coordinate systems.
The transformation of radially traveling cylindrical waves between two cylindrical coordinate systems with skew (nonparallel) axes is derived for the first time to our knowledge. The analytical procedure is based on the complex integral representation of the Hankel function and appropriate contour deformation and change of variables to obtain a final Fourier transform expression of the cylindrical wave in the new system. Scalar and vector waves are considered. This new result is a powerful tool for the rigorous analysis of scattering and coupling in nonparallel optical fiber configurations.


Zn2+'s ability to alter the distribution of Cu2+ among the available binding sites of Aβ(1-16)-polyethylenglycol-ylated peptide: implications in Alzheimer's disease.
The formation of mixed copper(II) and zinc(II) complexes with Aβ(1-16)-PEG has been investigated. The peptide fragment forms stable mixed metal complexes at physiological pH in which the His13/His14 dyad is the zinc(II)'s preferred binding site, while copper(II) coordination occurs at the N-terminus also involving the His6 imidazole. Copper(II) is prevented by zinc(II) excess from the binding to the two His residues, His13 and His14. As the latter binding mode has been recently invoked to explain the redox activity of the copper-Aβ complex, the formation of ternary metal complexes may justify the recently proposed protective role of zinc(II) in Alzheimer's disease. Therefore, the reported results suggest that zinc(II) competes with copper for Aβ binding and inhibits copper-mediated Aβ redox chemistry.


Targeting topoisomerase I: molecular mechanisms and cellular determinants of response to topoisomerase I inhibitors.
Topoisomerase I is required for DNA relaxation during critical cellular functions. The identification of camptothecins as specific enzyme inhibitors and their clinical efficacy have stimulated extensive efforts to exploit topoisomerase I as a tumor target and explain the putative mechanisms of antitumor-specific action. This review provides an overview of the recent achievements in the development of topoisomerase I inhibitors and in the explanation of the biological pathways involved in tumor response. In spite of the difficulty to identify novel topoisomerase I inhibitors with improved pharmacological properties, a growing body of evidence supports the possibility of optimizing the therapeutic profile of available agents. The explanation of defense mechanisms and the molecular determinants of tumor cell response is expected to provide a basis for the design of combination approaches for optimization of topoisomerase I inhibitors-based therapy.


Iron and the liver: update 2008.
The cross-talk which has taken place in recent years between clinicians and scientists has resulted in a greater understanding of iron metabolism with the discovery of new iron-related genes including the hepcidin gene which plays a critical role in regulating systemic iron homeostasis. Consequently, the distinction between (a) genetic iron-overload disorders including haemochromatosis related to mutations in the HFE, hemojuvelin, transferrin receptor 2 and hepcidin genes and (b) non-haemochromatotic conditions related to mutations in the ferroportin, ceruloplasmin, transferrin and di-metal transporter 1 genes, and (c) acquired iron-overload syndromes has become easier. However, major challenges still remain which include our understanding of the regulation of hepcidin production, the identification of environmental and genetic modifiers of iron burden and organ damage in iron-overload syndromes, especially HFE haemochromatosis, indications regarding the new oral chelator, deferasirox, and the development of new therapeutic tools interacting with the regulation of iron metabolism.


Risk of Second Cancer in Hodgkin Lymphoma Survivors and Influence of Family History.
Purpose Although advances in Hodgkin lymphoma (HL) treatment have led to improved disease-free survival, this has been accompanied by an increased risk of second cancers. We sought to quantify the second cancer risks and to investigate the impact of family history. Patients and Methods Using the Swedish Family-Cancer Project Database, we identified 9,522 individuals with primary HL diagnosed between 1965 and 2012. We calculated standardized incidence ratios and cumulative incidence of second cancer in HL survivors and compared the standardized incidence ratios of lung, breast, colorectal, and all second cancers in HL survivors with and without a site-specific family history of cancer. Interactions between family history of cancer and HL treatment were evaluated under additive and multiplicative models. Results Overall, the risk of a second cancer in HL survivors was increased 2.39-fold (95% CI, 2.29 to 2.53). The 30-year cumulative incidence of breast cancer in women diagnosed with HL at younger than 35 years of age was 13.8%. We observed no significant difference in cancer risk over successive time periods. The risk of all second cancers was 1.3-fold higher for HL survivors with a first-degree relative with cancer ( P < .001), with 3.3-fold, 2.1-fold, and 1.8-fold differences shown for lung, colorectal, and breast cancers, respectively. Moreover, a greater than additive interaction between family history of lung cancer and HL treatment was shown ( P = .03). Conclusion HL survivorship is associated with a substantive risk of a second cancer. Notably, the risk is higher in individuals with a family history of cancer. This information should be used to inform risk-adapted therapy and to assist in screening to reduce long-term morbidity and mortality in patients with HL.


Proflavine Uptake and Release in Sensitive and Resistant Escherichia coli.
Both Escherichia coli B and a proflavine-resistant mutant, E. coli B/Pr, took up the same amounts of proflavine when suspended in buffer containing the dye. In growth media, however, sensitive cells took up more proflavine than did resistant cells. Adding growth media or any one of several constituents of these media, including amino acids, glycerol, pyruvic acid, and metabolizable sugars, to resistant cells that had taken up proflavine in buffer caused them to lose the dye, but had less or no effect on sensitive cells. Certian salts caused an equal release of proflavine from resistant and sensitive cells. Proflavine released from resistant cells by glucose was not changed chemically. The effects of temperature and metabolic inhibitors suggest that proflavine uptake is a passive process but that its release may be an active one, dependent on metabolism. Glucose had more effect on the proflavine binding of E. coli B grown in a minimal medium than on that of cells grown in a complex medium. E. coli B was less susceptible to proflavine when growing in a minimal medium. The effects of other synthetic media on proflavine susceptibility of E. coli B were also studied. Deoxyribonucleic acid and envelopes from sensitive and resistant cells bound the same amounts of proflavine, and no difference was seen in the site of dye binding when sensitive and resistant cells that had taken up proflavine in buffer were sonically broken and fractionated. The results suggest that sensitive and resistant cells are equally permeable to proflavine but differ in the ease with which metabolites cause them to release bound proflavine. So far, however, these differences do not account completely for the ability of resistant cells to grow in high proflavine concentrations.