Adult exogenous lipoid pneumonia: A rare and underrecognized entity in cytology - A case series.
Exogenous lipoid pneumonia (ELP) is a rare benign entity without specific clinical or imaging presentation. Although cytological studies - either bronchoalveolar lavage (BAL) or fine-needle aspiration (FNA) - may be pursued in patients with ELP, a definitive diagnosis is frequently rendered only on histology. The aim of this study is to highlight the cytological features of ELP. A search of cytopathology (CP) and surgical pathology (SP) diagnoses of ELP was conducted. The corresponding clinical and imaging features were obtained, and the morphology, particularly the presence and size of the intracytoplasmic vacuoles and background, was assessed. Nine cases of ELP were identified, including eight with corresponding CP and SP. A neoplasm was suspected in three based on imaging, but ELP was not in the differential clinically or radiographically in any. Among the cases, six patients had BALs and three FNAs. All of the samples showed multiple large vacuoles within macrophages with at least some equal to or larger than the size of the cell nucleus. Similar vacuoles were noted extracellularly on smears. ELP is typically described in case reports in the clinical or radiological literature. To the best of our knowledge, this represents the largest series of adult ELP in CP. When large vacuoles are present in macrophages in cytology specimens, at least a suspicion of ELP can be suggested to initiate appropriate therapy, identify/remove the inciting agent, and preclude a more invasive procedure.


[Evaluation of drug administration through enteral feeding tubes in hospitalized patients].
To describe the administration of drugs through nasogastric tubes by the nursing staff of a tertiary hospital and to identify the most common administration errors. An observational study was carried out between November of 2010 and March of 2011. The study population was the nursing staff of the hospital. A questionnaire was created asking about the daily practice of drugs administration through the nasogastric tube; a score was assigned to each question. A document on correct administration techniques of drugs through the nasogastric tube was elaborated, which served for the comparison of the answers obtained. A total of 162 surveys were answered. Most of the staff (44.5%) had a deficient knowledge on the proper administration techniques. 69.7% of the staff stated to have grinded some time a tablet with enteric coverage, and 66.2% a tablet with modified release. A significant lower number of perceived obstructions per month was obtained in those nurses with higher degree of knowledge, in those consulting the Pharmacy Department when they had doubts, and in those never having grinded a tablet with enteric coverage of modified release. It is observed that the knowledge on proper administration of drugs through the nasogastric tube by the nursing staff is deficient; therefore, it would be convenient to carry out specific training courses as well as a closer collaboration between the Pharmacy department and the Nursing units.


N-methyl-D-aspartate exposure blocks glutamate toxicity in cultured cerebellar granule cells.
Exposure of cultured cerebellar granule cells to glutamate results in a concentration-dependent (EC50 = 22.7 +/- 0.4 microM) and delayed (24-72 hr) neurotoxicity, which is blocked by the specific N-methyl-D-aspartate (NMDA) receptor antagonists 2-amino-5-phosphovalerate and MK-801 but is unaffected by the non-NMDA receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 6,7-dinitroquinoxaline-2,3-dione. Although glutamate toxicity in these cells is mediated by the NMDA subtype of glutamate receptor, pretreatment of cerebellar granule cells with subtoxic concentrations of NMDA markedly antagonizes the neurotoxic actions of glutamate, with an IC50 of 55 +/- 4 microM. The neuroprotective effect of NMDA requires a preincubation time of approximately 120 min to be fully manifested and does not require the presence of NMDA during glutamate exposure. These data demonstrate that NMDA receptors mediate both neurotoxicity and neuroprotection in cerebellar granule cells. Among four glutamate receptor agonists tested (NMDA, quisqualate, ibotenate, and kainate), only NMDA was able to provide a robust neuroprotection against glutamate toxicity. Quisqualate was neither neurotoxic nor neuroprotective, whereas ibotenate, which was nontoxic by itself, induced a small degree of neuroprotection. In contrast, kainate, which was neurotoxic to cerebellar granule cells, also provided considerable neuroprotection against glutamate toxicity. Because preincubation of cerebellar granule cells with NMDA fails to alter NMDA receptor-mediated phosphoinositide hydrolysis or the specific binding of [3H]MK-801 to NMDA receptors, it appears that the neuroprotective effects of NMDA are not due to NMDA receptor desensitization.


Obesity, heuristic reasoning and the organisation of communicative embarrassment in diagnostic radiography.
This paper, the second of three arising from a broader qualitative study, explores difficulties emerging around radiographer-patient communication regarding obesity in hospital-based encounters, and the situated strategies found by experienced radiographers for handling such situations. Semi-structured interviews with eight clinicians working in plain radiography (mean experience = 21.56 years) were analysed using Interpretative Phenomenological Analysis (IPA), so as to highlight the practical, nuanced and real-world experiences of these individuals regarding obesity communication. Participants generally viewed communicating with obese patients as a potential interpersonal 'minefield'. Most reported having had negative experiences in which patients had acted with denial or outright aggression during examinations but, conversely, all reported cases in which patients had been frank and open about their obesity, and even been happy to joke about it. Equally, all participants were able to document a range of communicative strategies for effectively handling potentially difficult situations. Results further indicate that the documented communicative problems and embarrassment for the patient only generally arose within specific material contexts; i.e. when equipment is inadequate or multiple exposures are necessary. It is concluded that, while participants largely expected any interaction about obesity with a patient to be embarrassing for both parties, their actual experience was much more varied. This indicates a more complex communicative environment than may be expected, and also a potential metacognitive availability heuristic in play - something that might be clarified with future quantitative investigation.


Early Pleistocene large mammals from Maka'amitalu, Hadar, lower Awash Valley, Ethiopia.
The Early Pleistocene was a critical time period in the evolution of eastern African mammal faunas, but fossil assemblages sampling this interval are poorly known from Ethiopia's Afar Depression. Field work by the Hadar Research Project in the Busidima Formation exposures (~2.7-0.8 Ma) of Hadar in the lower Awash Valley, resulted in the recovery of an early Homo maxilla (A.L. 666-1) with associated stone tools and fauna from the Maka'amitalu basin in the 1990s. These assemblages are dated to ~2.35 Ma by the Bouroukie Tuff 3 (BKT-3). Continued work by the Hadar Research Project over the last two decades has greatly expanded the faunal collection. Here, we provide a comprehensive account of the Maka'amitalu large mammals (Artiodactyla, Carnivora, Perissodactyla, Primates, and Proboscidea) and discuss their paleoecological and biochronological significance. The size of the Maka'amitalu assemblage is small compared to those from the Hadar Formation (3.45-2.95 Ma) and Ledi-Geraru (2.8-2.6 Ma) but includes at least 20 taxa. Bovids, suids, and Theropithecus are common in terms of both species richness and abundance, whereas carnivorans, equids, and megaherbivores are rare. While the taxonomic composition of the Maka'amitalu fauna indicates significant species turnover from the Hadar Formation and Ledi-Geraru deposits, turnover seems to have occurred at a constant rate through time as taxonomic dissimilarity between adjacent fossil assemblages is strongly predicted by their age difference. A similar pattern characterizes functional ecological turnover, with only subtle changes in dietary proportions, body size proportions, and bovid abundances across the composite lower Awash sequence. Biochronological comparisons with other sites in eastern Africa suggest that the taxa recovered from the Maka'amitalu are broadly consistent with the reported age of the BKT-3 tuff. Considering the age of BKT-3 and biochronology, a range of 2.4-1.9 Ma is most likely for the faunal assemblage.


Synchronous endometrial and cervical tumors in a 26-year-old nullipara: diagnostic modalities updated.
Proton magnetic resonance spectroscopy (MRS), performed on conventional magnetic resonance imaging (MRI) scanners, provides useful information at the biochemical level. MRS has been used to measure tissue concentrations of proton-containing compounds such as organic and amino acids, and sugars in living tissues. We have used MRS in a 26-year-old female with suspected cervical and endometrial carcinomas. With the use of the above mentioned technique, biochemical differences in the endometrium and the cervix tissues were detected. The presented case is the first virgin patient in the relevant literature in whom endometrial and cervical carcinoma was detected. Choline (Cho), creatine (Cr), N-acetylaspartate (NAA), lipid and lactate region of the MRS spectrum suggested that the technique could be used as an indicator of metabolic alterations in the cervical and endometrial tumor cells.


Clinical, electrophysiological findings and evaluation of prognosis of patients with Guillain-Barré syndrome.
Kılıç B, Güngör S, Özgör B. Clinical, electrophysiological findings and evaluation of prognosis of patients with Guillain-Barré syndrome. Turk J Pediatr 2019; 61: 200-208. Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy characterized by frequent rapid progressive, ascending, symmetric weakness and areflexia. We aimed to evaluate the etiology, clinical and electrophysiological findings with treatment and prognosis of the patients with GBS in our clinic. Patients who were diagnosed with GBS in our clinic between 2009 and 2017 were evaluated retrospectively. The study included 20 female and 25 male patients. The most frequent symptom was the absence of walking (95.5%). All of the patients had muscle weakness on examination; in addition to that hyperesthesia (31%), autonomic symptoms (13.3%), sensory loss (11.1%), ataxia (11.1%), bilateral facial nerve palsy (6.6%), oculomotor nerve palsy (2.2%), and multiple cranial nerve involvement (2.2%) were the other detected findings. Ventilation support was required in 6 cases (13.3%). Acute motor axonal neuropathy (AMAN) was found in 20 patients (44.5%), acute inflammatory demyelinating polyradiculoneuropathy (AIDP) was found in 24 patients (53.3%), and acute motor and sensory axonal neuropathy (AMSAN) was only present in 1 patient (2.2%). Intravenous immunoglobulin (IVIG) was administered to 33 of the patients (73.3%). The mean hospital stay was 8.4±3.5 (2-17 days), and the relationship between the duration of hospital stay and the treatment given was statistically significant (p = 0.001). Complete remission was observed in 37 patients (82.3%) and the remaining 5 children (11.1%) experienced incomplete recovery. Three patients (6.7%) died of treatment-resistant hypotension, arrhythmia and severe pulmonary infection. The short duration of neurological deficit following infection, clinical stage of application, need for mechanical ventilation, dysautonomia, cranial nerve involvement, and current subtype were the negative prognostic factors. Although GBS is a self-limiting disease, early diagnosis and treatment are very important to reduce hospital stay with morbidity and mortality. Patients expected to be at high risk should be monitored closely.


The effect of culinary doses of spices in a high-saturated fat, high-carbohydrate meal on postprandial lipemia and endothelial function: a randomized, controlled, crossover pilot trial.
Previously it has been shown that incorporation of >11 g of spices into a mixed meal blunts postprandial lipemia, which may reduce acute endothelial impairment. The effect of lower doses of spices remains unclear. The aim was to examine the postprandial effect of a meal high in saturated fat and carbohydrate inclusive of spices (2 g or 6 g) or exclusive of spices (0 g) on flow mediated dilation (FMD), lipids and lipoproteins, glucose, and insulin in men at-risk for cardiovascular disease. A 3-period randomized, controlled, crossover, pilot study was conducted. In random order, subjects consumed a high-saturated fat, high-carbohydrate meal (1076 kcal, 39 g saturated fat, 98 g carbohydrate) with 0 g, 2 g and 6 g of mixed spices. After meal consumption, blood was drawn hourly for 4 hours and FMD was measured at 2 and 4 hours. Serum lipids and lipoproteins, and insulin were measured in the fasting state and at each post-meal time point; plasma glucose was also assessed at each time point. Subjects were 13 men aged 52 ± 9 years that were overweight or obese (29.9 ± 3.1 kg m-2), and had an enlarged waist circumference (102.2 ± 8.9 cm). Time (p < 0.05) and treatment (p < 0.05) effects existed for FMD and triglycerides; no time by treatment interactions were detected. Post hoc testing showed that the meal with 6 g of spices lessened the postprandial reduction in FMD compared to the meal with no spices (-0.87 ± 0.32%; p = 0.031); no other pairwise differences were observed. Triglyceride levels were lower following the meal with 2 g of spices vs. the no spice meal (-18 ± 6 mg dL-1; p = 0.015); no difference was observed between the meal with 6 g of spice and the no spice meal (-13 ± 6 mg dL-1; p = 0.12). Glucose and insulin were unaffected by the presence of spices in the meal. In conclusion, this study provides preliminary evidence suggesting that lower doses of spices (2 and 6 g) than previously tested may attenuate postprandial lipemia and impairments in endothelial function caused by a high-saturated fat, high-carbohydrate meal.


'Read me to resilience': Exploring the use of cultural stories to boost the positive adjustment of children orphaned by AIDS.
The study explored whether and how culturally sensitive stories can encourage resilience in young children orphaned by AIDS. The purpose of the investigation was allied to the paradigm of positive psychology, which focuses on the promotion of potential strengths to buffer children against adversity, as well as on social ecological understandings of resilience, which emphasise that social ecologies have a duty to facilitate children's positive adjustment to adversity. A pre-post-intervention evaluation was used to gather qualitative data on orphaned children's resilience to AIDS-related adversity by employing participatory visual methods. The intervention, called Read-me-to-Resilience (Rm2R), consisted of telling 22 culturally sensitive stories to the children. We compared the pre- and post-intervention data for each participant before thematically analysing the total findings. Our analysis indicates that the children's resilience had been bolstered in the period between the pre-test and post-test. We conclude that culturally relevant stories could be used by South African caregivers, service providers, and educators as an accessible, inexpensive and ready-made tool to directly empower children who have been orphaned by AIDS.


First Report of Cladosporium Leaf Spot of Spinach Caused by Cladosporium variabile in the Winter Spinach Production Region of California and Arizona.
In December 2011, symptoms typical of Cladosporium leaf spot caused by Cladosporium variabile (4) were observed in organic "baby leaf" spinach (Spinacia oleracea) crops of the cultivars Amazon, Missouri, Tasman, and Tonga in the Imperial Valley (Imperial County, CA and Yuma County, AZ). Leaves had small, circular lesions (1 to 3 mm in diameter), some of which had progressed to necrotic, bleached lesions surrounded by a thin dark margin. The incidence of symptoms in affected crops was ≤20%. Fungal isolates resembling C. variabile were recovered by surfacesterilizing sections (5 mm2) of symptomatic leaf tissue in 0.6% NaOCl, triple-rinsing the sections in sterile water, and plating the sections onto water agar and potato dextrose agar amended with 100 ppm chloramphenicol (cPDA). Single-spore transfers made onto cPDA were maintained at 24 ± 2°C with a natural day/night cycle. Each isolate produced slow growing cultures consisting of dense masses of dark conidiophores (≤350 μm long) with chains of up to three dematiaceous (olive) conidia, and almost no mycelium. Torulose (coiled) aerial hyphae developed from the apices of conidiophores after 5 to 7 days, and distinguished the isolates as C. variabile, not C. macrocarpum (2,4). Pathogenicity was tested for each of six single-spore isolates using 36-dayold plants of the spinach cultivar Carmel. The plants were enclosed in clear plastic bags overnight and inoculated the next day with the isolates of C. variabile by atomizing approximately 30 ml of a spore suspension (1.0 × 106 conidia/ml in sterile water amended with 0.01% Tween 20) of the appropriate isolate onto the upper and lower leaf surfaces of each of five plants/isolate. Five control plants were inoculated similarly with sterile water + 0.01% Tween 20. The plants were resealed in plastic bags for 72 h and then placed on a greenhouse bench. Pinpoint, sunken lesions developed within 4 to 7 days on the leaves of plants inoculated with each of the six test isolates. Lesions developed into dry, circular spots typical of Cladosporium leaf spot. Symptoms were not observed on control plants. After 20 days, C. variabile was reisolated from lesions caused by all six isolates, but not from control plants. Although Cladosporium leaf spot has been reported in the Salinas Valley of California (4), to our knowledge, this is the first report of the disease on spinach crops in the Imperial Valley of California and Arizona, the primary winter, fresh market spinach production region of the United States. Inoculum of C. variabile may have been introduced to this region on spinach seed lots (3), because even seed infestation levels <0.1% could lead to seed transmission (1) under the dense planting populations (≤9 million seeds/ha) and overhead irrigation typical of "baby leaf" spinach crops in this region. Fungicides can be used to manage Cladosporium leaf spot in conventional spinach crops (1), but management in certified organic crops may be more challenging. References: (1) L. J. du Toit et al. Fung. Nemat. Tests 59:V115, 2004. (2) M. B. Ellis. Page 315 in: Dematiaceous Hyphomycetes. Commonwealth Mycological Institute, Surrey, England, 1971. (3) P. Hernandez-Perez. Page 79 in: Management of Seedborne Stemphylium botryosum and Cladosporium variabile Causing Leaf Spot of Spinach Seed Crops in Western Washington, MS thesis, Pullman, WA, 2005. (4) P. Hernandez-Perez and L. J. du Toit. Plant Dis. 90:137, 2006.


Association between Elder Abuse and Metabolic Syndromes: Findings from the Chicago Health and Aging Project.
Elder abuse and metabolic syndromes are both important public health issues and are associated with increased morbidity and mortality. This study aimed to examine the associations between elder abuse and risk for metabolic syndromes. The Chicago Health and Aging Project (CHAP) cohort is a population-based study (n = 4,586). We identified 676 participants with some form of elder abuse reported to a social services agency. The primary independent variable was elder abuse reported to a social services agency. Outcomes were metabolic syndrome as categorized by World Health Organization (WHO), American Heart Association (AHA) and International Diabetes Federation (IDF) criteria. Bivariate and logistic regression analyses were used to assess the association between elder abuse and different definitions of metabolic syndromes. In the bivariate analyses, elder abuse victims were more likely than those without elder abuse to have metabolic syndromes [22.4 vs. 10.7% (WHO), 50.7 vs. 40.0% (AHA) and 47.7 vs. 33.5% (IDF)]. After adjusting for potential confounding factors, elder abuse was associated with an increased risk for metabolic syndromes according to WHO [OR, 3.95 (2.86-5.47)], AHA [OR, 2.03 (1.56-2.64)] and IDF [OR, 2.55 (1.97-3.29)] criteria. Interaction term analyses indicate that the association between elder abuse and metabolic syndromes may be moderated by sociodemographic characteristics but not by health-related or psychosocial factors. Elder abuse is associated with an increased risk for metabolic syndromes. Research is needed to examine the association between elder abuse and cardiovascular disease.


Deep Learning for EEG Seizure Detection in Preterm Infants.
EEG is the gold standard for seizure detection in the newborn infant, but EEG interpretation in the preterm group is particularly challenging; trained experts are scarce and the task of interpreting EEG in real-time is arduous. Preterm infants are reported to have a higher incidence of seizures compared to term infants. Preterm EEG morphology differs from that of term infants, which implies that seizure detection algorithms trained on term EEG may not be appropriate. The task of developing preterm specific algorithms becomes extra-challenging given the limited amount of annotated preterm EEG data available. This paper explores novel deep learning (DL) architectures for the task of neonatal seizure detection in preterm infants. The study tests and compares several approaches to address the problem: training on data from full-term infants; training on data from preterm infants; training on age-specific preterm data and transfer learning. The system performance is assessed on a large database of continuous EEG recordings of 575[Formula: see text]h in duration. It is shown that the accuracy of a validated term-trained EEG seizure detection algorithm, based on a support vector machine classifier, when tested on preterm infants falls well short of the performance achieved for full-term infants. An AUC of 88.3% was obtained when tested on preterm EEG as compared to 96.6% obtained when tested on term EEG. When re-trained on preterm EEG, the performance marginally increases to 89.7%. An alternative DL approach shows a more stable trend when tested on the preterm cohort, starting with an AUC of 93.3% for the term-trained algorithm and reaching 95.0% by transfer learning from the term model using available preterm data. The proposed DL approach avoids time-consuming explicit feature engineering and leverages the existence of the term seizure detection model, resulting in accurate predictions with a minimum amount of annotated preterm data.


Cause-specific mortality in Africa and Asia: evidence from INDEPTH health and demographic surveillance system sites.
Because most deaths in Africa and Asia are not well documented, estimates of mortality are often made using scanty data. The INDEPTH Network works to alleviate this problem by collating detailed individual data from defined Health and Demographic Surveillance sites. By registering all deaths over time and carrying out verbal autopsies to determine cause of death across many such sites, using standardised methods, the Network seeks to generate population-based mortality statistics that are not otherwise available. To build a large standardised mortality database from African and Asian sites, detailing the relevant methods, and use it to describe cause-specific mortality patterns. Individual demographic and verbal autopsy (VA) data from 22 INDEPTH sites were collated into a standardised database. The INDEPTH 2013 population was used for standardisation. The WHO 2012 VA standard and the InterVA-4 model were used for assigning cause of death. A total of 111,910 deaths occurring over 12,204,043 person-years (accumulated between 1992 and 2012) were registered across the 22 sites, and for 98,429 of these deaths (88.0%) verbal autopsies were successfully completed. There was considerable variation in all-cause mortality between sites, with most of the differences being accounted for by variations in infectious causes as a proportion of all deaths. This dataset documents individual deaths across Africa and Asia in a standardised way, and on an unprecedented scale. While INDEPTH sites are not constructed to constitute a representative sample, and VA may not be the ideal method of determining cause of death, nevertheless these findings represent detailed mortality patterns for parts of the world that are severely under-served in terms of measuring mortality. Further papers explore details of mortality patterns among children and specifically for NCDs, external causes, pregnancy-related mortality, malaria, and HIV/AIDS. Comparisons will also be made where possible with other findings on mortality in the same regions. Findings presented here and in accompanying papers support the need for continued work towards much wider implementation of universal civil registration of deaths by cause on a worldwide basis.


pyHVis3D: visualising molecular simulation deduced H-bond networks in 3D: application to T-cell receptor interactions.
Hydrogen bonds (H-bonds) play an essential role for many molecular interactions but are also often transient, making visualising them in a flexible system challenging. We provide pyHVis3D which allows for an easy to interpret 3D visualisation of H-bonds resulting from molecular simulations. We demonstrate the power of pyHVis3D by using it to explain the changes in experimentally measured binding affinities for three T-cell receptor/peptide/MHC complexes and mutants of each of these complexes. pyHVis3D can be downloaded for free from http://opig.stats.ox.ac.uk/resources. firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


The topogenic function of S4 promotes membrane insertion of the voltage-sensor domain in the KvAP channel.
Voltage-dependent K+ (KV) channels control K+ permeability in response to shifts in the membrane potential. Voltage sensing in KV channels is mediated by the positively charged transmembrane domain S4. The best-characterized KV channel, KvAP, lacks the distinct hydrophilic region corresponding to the S3-S4 extracellular loop that is found in other K+ channels. In the present study, we evaluated the topogenic properties of the transmembrane regions within the voltage-sensing domain in KvAP. S3 had low membrane insertion activity, whereas S4 possessed a unique type-I signal anchor (SA-I) function, which enabled it to insert into the membrane by itself. S4 was also found to function as a stop-transfer signal for retention in the membrane. The length and structural nature of the extracellular S3-S4 loop affected the membrane insertion of S3 and S4, suggesting that S3 membrane insertion was dependent on S4. Replacement of charged residues within the transmembrane regions with residues of opposite charge revealed that Asp72 in S2 and Glu93 in S3 contributed to membrane insertion of S3 and S4, and increased the stability of S4 in the membrane. These results indicate that the SA-I function of S4, unique among K+ channels studied to date, promotes the insertion of S3 into the membrane, and that the charged residues essential for voltage sensing contribute to the membrane-insertion of the voltage sensor domain in KvAP.


Megakaryocyte Potentiating Factor as a Predictive Biomarker for Therapies Against Malignant Mesothelioma.
Effective biomarkers for malignant mesothelioma (MM) are needed for clinical management and the development of mesothelin-targeted therapies. We evaluated serum megakaryocyte potentiating factor (MPF) as a biomarker predictive of treatment outcome in patients with MM and for developing mesothelin-targeted therapies. Serial serum samples from patients with MM in two clinical trials of an antimesothelin immunotoxin were tested with our clinically validated MPF assay. Correlative studies were performed to determine the test effectiveness in treatment monitoring and outcome prediction. MPF was further evaluated for an association with response to an antimesothelin therapy and for disease monitoring. There was a significant reduction of serum MPF in patients with elevated baseline and radiologic response, with an average change from -52% to -78% after one to six cycles. Using a -50% change as the cutoff, patients with MM with positive MPF response had significantly improved progression-free survival (P < .001), with the median extended from 1.9 to 11.3 months. These patients with MPF response further exhibited improved overall survival (P = .004), with the median extended from 8.8 to 22.3 months. In patients with refractory MM, there was an association between elevated pretreatment serum MPF and radiologic response to an antimesothelin therapy (P = .033). Furthermore, in these response patients, serum MPF was monitored between 32.2 and 63.8 months and was found to reflect treatment response and disease progression. At a cutoff of -50% change after receiving systemic therapies, a reduction in MPF was associated with improved clinical outcome, both progression-free survival and overall survival. An elevated baseline serum MPF was associated with a response to an antimesothelin therapy in patients with refractory MM; however, this finding needs to be confirmed in another study.


Preparation of Beebread Caviar from Buckwheat Honey through Immobilization with Sodium Alginate.
Honeys have a pleasant taste and a wide range of use. They are characterized by a relatively high consumption compared to bee pollen or beebread. Honeys are the most popular bee products. Considering health reasons, beebread exhibits the strongest properties as it has the highest nutritional value as well as strong detoxifying, antioxidant, and antiradical properties. Despite having such valuable properties, consumption of beebread is negligible; sometimes, it is limited only to supplementation in case of diseases. This paper proposes a new food product, that is, beebread caviar made from buckwheat honey. The expiry date and sensory and physicochemical quality of beebread caviar have been determined in this study. Beebread caviar, obtained by immobilization on alginate carrier, contained 0.34 mg GAE/mL extract. It remained stable until five days after preparation. Its total acidity was 33.7 mval/kg. Its extract content was 22.53%. Caviar had a high overall sensory score of 4.8 points on a 5-point scale. Beebread caviar can be successfully classified as probiotic food because beebread contains a large amount of lactic acid. In the form of caviar, a new, attractive, and convenient form of beebread consumption could become one of the products of comfortable and functional food.


Cognitive-behavioural therapy reduces unwanted thought intrusions in generalized anxiety disorder.
Voluntary attempts to suppress certain thoughts can paradoxically increase their intrusive return. Particular impairments in thought suppression are thought to be key mechanisms in the pathogenesis of mental disorders. To assess the role of this processing bias in the maintenance of generalized anxiety disorder (GAD), we investigated whether it is susceptible to cognitive-behavioural treatment (CBT). 22 GAD patients and 22 healthy controls (HC) were tested twice within 15 weeks, with patients receiving CBT in between. A subset of patients was additionally tested while waiting for treatment to control for retest effects. Using a mental control paradigm, we measured intrusion frequency during the voluntary suppression of thoughts related to (a) the individual main worry topic, (b) a negative non-worry topic, and (c) a neutral topic. Self-reported worry was measured before and after treatment, and at 6-months follow-up. Compared to HC, GAD showed specifically more worry-related intrusions. CBT reduced this bias to a healthy level, over and above mere test-retest effects. This study could not clarify whether the demonstrated effect mediates other changes, or how it relates to other cognitive biases in GAD. The results indicate that thought suppression processes are not only impaired in GAD, but that the impairment is specific to the patients' worries, and that it can be successfully targeted by CBT. This highlights the importance of thought suppression processes in the maintenance of GAD.


Acellular vaccines for preventing whooping cough in children.
Routine use of whole-cell pertussis (wP) vaccines was suspended in some countries in the 1970s and 1980s because of concerns about adverse effects. Following this action, there was a resurgence of whooping cough. Acellular pertussis (aP) vaccines, containing purified or recombinant Bordetella pertussis (B. pertussis) antigens, were developed in the hope that they would be as effective, but less reactogenic than the whole-cell vaccines. This is an update of a Cochrane review first published in 1999, and previously updated in 2012. In this update, we included no new studies. To assess the efficacy and safety of acellular pertussis vaccines in children and to compare them with the whole-cell vaccines. We searched CENTRAL (2013, Issue 12), MEDLINE (1950 to January week 2, 2014), EMBASE (1974 to January 2014), Biosis Previews (2009 to January 2014) and CINAHL (2009 to January 2014). We selected double-blind randomised efficacy and safety trials of aP vaccines in children up to six years old, with active follow-up of participants and laboratory verification of pertussis cases. Two review authors independently extracted data and assessed the risk of bias in the studies. Differences in trial design precluded a meta-analysis of the efficacy data. We pooled the safety data from individual trials using a random-effects meta-analysis model. We included six efficacy trials with a total of 46,283 participants and 52 safety trials with a total of 136,541 participants. Most of the safety trials did not report the methods for random sequence generation, allocation concealment and blinding, which made it difficult to assess the risk of bias in the studies. The efficacy of multi-component (≥ three) vaccines varied from 84% to 85% in preventing typical whooping cough (characterised by 21 or more consecutive days of paroxysmal cough with confirmation of B. pertussis infection by culture, appropriate serology or contact with a household member who has culture-confirmed pertussis), and from 71% to 78% in preventing mild pertussis disease (characterised by seven or more consecutive days of cough with confirmation of B. pertussis infection by culture or appropriate serology). In contrast, the efficacy of one- and two-component vaccines varied from 59% to 78% against typical whooping cough and from 41% to 58% against mild pertussis disease. Multi-component acellular vaccines are more effective than low-efficacy whole-cell vaccines, but may be less effective than the highest-efficacy whole-cell vaccines. Most systemic and local adverse events were significantly less common with aP vaccines than with wP vaccines for the primary series as well as for the booster dose. Multi-component (≥ three) aP vaccines are effective in preventing whooping cough in children. Multi-component aP vaccines have higher efficacy than low-efficacy wP vaccines, but they may be less efficacious than the highest-efficacy wP vaccines. Acellular vaccines have fewer adverse effects than whole-cell vaccines for the primary series as well as for booster doses.


Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling.
Systemic delivery of a complementary cDNA library expressed from the vesicular stomatitis virus (VSV) treats tumors by vaccinating against a wide range of tumor associated antigens (TAAs). For subcutaneous B16 melanomas, therapy was achieved using a specific combination of self-TAAs (neuroblastoma-Ras, cytochrome c, and tyrosinase-related protein 1) expressed from VSV. However, for intracranial B16 tumors, a different combination was therapeutic (consisting of VSV-expressed hypoxia-inducible factor [HIF]-2α, Sox-10, c-Myc, and tyrosinase-related protein 1). Therefore, we tested the hypothesis that tumors of different histological types growing in the brain share a common immunogenic signature which can be exploited for immunotherapy. Syngeneic tumors, including GL261 gliomas, in the brains of immune competent mice were analyzed for their antigenic profiles or were treated with systemic viroimmunotherapy. Several different histological types of tumors growing intracranially, as well as freshly resected human brain tumor explants, expressed a HIF-2α(Hi) phenotype imposed by brain-derived CD11b+ cells. This location-specific antigen expression was exploited therapeutically against intracranial GL261 gliomas using systemically delivered VSV expressing HIF-2α, Sox-10, and c-Myc. Viroimmunotherapy was enhanced by immune checkpoint inhibitors, associated with the de-repression of antitumor T-helper cell type 1 (Th1) interferon-γ and Th17 T cell responses. Since different tumor types growing in the same location in the brain share a location-specific phenotype, we suggest that antigen-specific immunotherapies should be based upon expression of both histological type-specific tumor antigens and location-specific antigens. Our findings support clinical application of VSV-TAA therapy with checkpoint inhibition for aggressive brain tumors and highlight the importance of the intracranial microenvironment in sculpting a location-specific profile of tumor antigen expression.


The growth-inhibitory protein Nogo is involved in midline routing of axons in the mouse optic chiasm.
We have investigated the role of Nogo, a protein that inhibits regenerating axons in the adult central nervous system, on axon guidance in the developing optic chiasm of mouse embryos. Nogo protein is expressed by radial glia in the midline within the optic chiasm where uncrossed axons turn, and the Nogo receptor (NgR) is expressed on retinal neurites and growth cones. In vitro neurite outgrowth from both dorsonasal and ventrotemporal retina was inhibited by Nogo protein, and this inhibition was abolished by blocking NgR activity. In slice cultures of the optic pathway, blocking NgR with a peptide antagonist produced significant reduction in the uncrossed projection but had no effect on the crossing axons. This result was confirmed by treating cultures with an anti-Nogo functional blocking antibody. In vitro coculture assays of retina and optic chiasm showed that NgR was selectively reduced on neurites and growth cones from dorsonasal retina when they contacted chiasm cells, but not on those from ventrotemporal retina. These findings provide evidence that Nogo signaling is involved in directing the growth of axons in the mouse optic chiasm and that this process relies on a differential regulation of NgR on axons from the dorsonasal and ventrotemporal retina.


Dietary Phytochemicals and Cancer Chemoprevention: A Perspective on Oxidative Stress, Inflammation, and Epigenetics.
Oxidative stress occurs when cellular reactive oxygen species levels exceed the self-antioxidant capacity of the body. Oxidative stress induces many pathological changes, including inflammation and cancer. Chronic inflammation is believed to be strongly associated with the major stages of carcinogenesis. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a crucial role in regulating oxidative stress and inflammation by manipulating key antioxidant and detoxification enzyme genes via the antioxidant response element. Many dietary phytochemicals with cancer chemopreventive properties, such as polyphenols, isothiocyanates, and triterpenoids, exert antioxidant and anti-inflammatory functions by activating the Nrf2 pathway. Furthermore, epigenetic changes, including DNA methylation, histone post-translational modifications, and miRNA-mediated post-transcriptional alterations, also lead to various carcinogenesis processes by suppressing cancer repressor gene transcription. Using epigenetic research tools, including next-generation sequencing technologies, many dietary phytochemicals are shown to modify and reverse aberrant epigenetic/epigenome changes, potentially leading to cancer prevention/treatment. Thus, the beneficial effects of dietary phytochemicals on cancer development warrant further investigation to provide additional impetus for clinical translational studies.


Ginsenoside Rb1 eliminates HIV-1 (D3)-transduced cytoprotective human macrophages by inhibiting the AKT pathway.
Abstract Acquired immunodeficiency syndrome patients treated with red ginseng, which contains protopanxadiol and protopanaxatriol ginsenosides as its main constituents, have been reported to remain healthy for >20 years in the absence of highly active antiretroviral therapy. Of these ginsenosides, ginsenoside Rh1, a protopanaxatriol ginsenoside, is known to eliminate cytoprotective HIV-1-infected macrophages by inhibiting pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK-1) phosphorylation. In this study, we investigated the capacity of ginsenoside Rb1, a protopanaxadiol ginsenoside, to eliminate cytoprotective primary human macrophages. We found that ginsenoside Rb1 could also eliminate cytoprotective primary human macrophages infected with HIV-1 D3. Ginsenoside Rb1 inhibited lipopolysaccharide/cycloheximide-induced AKT and glycogen synthase kinase-3β phosphorylation in the D3-transduced macrophages, but not the phosphorylation of PDK-1 and phosphoinositide-3-kinase (PI3K). Furthermore, we also observed that a combined treatment with ginsenoside Rb1 and miltefosine synergistically abolished the cytoprotective CHME5 cells expressing HIV-1 tat. Based on these findings, we can conclude that ginsenoside Rb1 can eliminate cytoprotective macrophages infected with HIV-1 by inhibiting the AKT pathway.


Community understanding of the concept of pre-referral treatment and how this impacts on referral related decision-making following the provision of rectal artesunate: a qualitative study in western Uganda.
Successful pre-referral treatment with rectal artesunate (RA) for suspected severe malaria requires operational linkages between community health workers (CHWs) and referral facilities, acceptance of pre-referral treatment and adherence to referral practices by CHWs and caregivers. This qualitative study investigated how community understanding of the concept of 'pre-referral treatment' is used in referral related decision-making following provision of RA in Uganda. Narrative interviews were conducted with 30 caregivers of children under five who received RA within the previous three months and the 30 associated CHWs who provided the treatment. Nineteen focus group discussions incorporating vignettes from the interviews were held with further caregivers, and 12 with CHWs and women representatives. Twenty traditional healers were targeted for semi-structured interview. Thematic analysis followed a 'meaning-based' approach. CHWs were aware of essential information to be given to caregivers on prescribing RA as indicated by the job aid, specifically urgency for referral, yet there was insufficient emphasis on RA not being a full treatment for severe malaria. Information shared by the CHW appeared to be influenced by the perceived urgency with which the CHW needed to act and the time of day or night the child was seen. Seven of the 32 caregivers did not complete referral post RA administration. Caregivers seemed more likely to adhere to referral advice if they perceived their child's condition to be severe. Previous caregiver experience and CHW comparisons with Artemisinin-based Combination Therapy (ACT) as a treatment for uncomplicated malaria appeared to raise misperceptions that RA is a complete treatment for severe malaria, thus reducing likelihood to complete referral. CHW implication, or caregiver interpretation, of the need to monitor the child, and some prescription of ACT post RA administration, also confused the need for referral. Both CHWs and caregivers requested further information about the role of RA. CHW advice should emphasise RA as providing temporary relief prior to facility-based treatment, the importance of referral whether or not a change is seen in the child's condition, and the dangers of not completing referral. Social behaviour change communication, training and support supervision activities could help promote these messages.


Effect of high-intensity intermittent exercise on postprandial plasma triacylglycerol in sedentary young women.
High-intensity intermittent exercise (HIIE) such as the 30-s Wingate test attenuates postprandial triacylglycerol (TG), however, the ability of shorter versions of HIIE to reduce postprandial TG is undetermined. Thus, the effect of 8-s sprinting bouts of HIIE on blood TG levels of 12 females after consumption of a high-fat meal (HFM) was examined. Twelve young, sedentary women (BMI 25.1 ± 2.3 kg/m²; age 21.3 ± 2.1 years) completed a maximal oxygen uptake test and then on different days underwent either an exercise or a no-exercise postprandial TG condition. Both conditions involved consuming a HFM after a 12-hr fast. The HFM, in milkshake form provided 4170 kJ (993 Kcal) of energy and 98 g fat. Order was counter-balanced. In the exercise condition participants completed 20-min of HIIE cycling consisting of repeated bouts of 8 s sprint cycling (100-115 rpm) and 12 s of active rest (easy pedaling) 14 hr before consuming the HFM. Blood samples were collected hourly after the HFM for 4 hr. Total postprandial TG was 13% lower, p = .004, in the exercise (5.84 ± 1.08 mmol L⁻¹ 4 h⁻¹) compared with the no-exercise condition (6.71 ± 1.63 mmol L⁻¹ 4 h⁻¹). In conclusion, HIIE significantly attenuated postprandial TG in sedentary young women.


Identification of differentially expressed genes and pathways for risk stratification in HPV-associated cancers governing different anatomical sites.
Human papillomavirus (HPV) is the major cause of cervical cancer (CC) etiology; its contribution to head and neck cancer (HNC) incidence is steadily increasing. As individual patients' response to the treatment of HPV-associated cancer is variable, there is a pressing need for the identification of biomarkers for risk stratification that can help determine the intensity of treatment. We have previously reported a novel prognostic and predictive indicator (HPPI) scoring system in HPV-associated cancers regardless of anatomical location by analyzing The Cancer Genome Atlas and Gene Expression Omnibus databases. In the present study, we comprehensively investigated the association of group-specific expression patterns of common differentially expressed genes (DEGs) between high- and low-risk groups in HPV-associated CC and HNC, identifying molecular biomarkers and pathways for risk stratification. Among the 174 identified DEGs, the expression of genes associated with extracellular matrix (ECM)-receptor interaction pathway (ITGA5, ITGB1, LAMB1, and LAMC1) was increased in high-risk groups in both HPV-associated CC and HNC, while the expression of genes associated with T-cell immunity (CD3D, CD3E, CD8B, LCK, and ZAP70) was decreased and vice versa. The individual genes showed significant prognostic impact on HPV-associated cancers but not on HPV-negative cancers. The expression levels of identified genes were similar between HPV-negative and HPV-associated high-risk groups with distinct expression patterns only in HPV-associated low-risk groups. Each group of genes showed negative correlations and distinct patterns of immune cell infiltration in tumor microenvironments. These results allowed us to identify molecular biomarkers and pathways for risk stratification in HPV-associated cancers regardless of anatomical location. The identified targets were found to be selectively working in only HPV-associated cancers and not in HPV-negative cancers, indicating the possibility of selective targets governing HPV-infective tumor microenvironments.


Tumor necrosis factor alpha activity in genital tract secretions of guinea pigs infected with chlamydiae.
Previous studies using the guinea pig model of chlamydial genital infection demonstrated that primary infection is associated with a marked acute inflammatory response early on, while chronic inflammation appears later, at a time when the level of infection is reduced. Challenge infections result primarily in a chronic inflammatory response. The stimuli that initiate inflammation and lead to tissue damage have not been defined. We investigated the possibility that tumor necrosis factors (TNFs) play a role in the inflammatory response to chlamydial genital tract infection. Cytotoxicity assays for TNF were performed on genital tract secretions collected from female guinea pigs during infection with the Chlamydia psittaci agent of guinea pig inclusion conjunctivitis. During the early days of primary infection, high levels of TNF-alpha were detected in genital tract secretions from inbred S2 strain and outbred Hartley strain guinea pigs. Significantly lower levels of TNF-alpha were detected in secretions from both strains during challenge infection. In general, the intensity of the TNF-alpha response was proportional to the intensity of infection. High TNF-alpha levels were present during primary infection at a time of marked neutrophil influx. Thus, TNF-alpha may play an important role in the response to primary chlamydial genital tract infection.


Institute for Quality and Efficiency in Health Care: Germany.
The Institute for Quality and Efficiency in Health Care (IQWiG) was established in 2004 to provide Germany's Federal Joint Committee with evidence-based evaluations of the benefits and cost benefits of health services, and functions in an advisory role. IQWiG reviews available evidence and produces recommendations after an extensive process of consultation with experts and stakeholders. IQWiG's recommendations are then considered by the Joint Committee in issuing coverage and payment directives. Under German law, insurance funds must cover any service that is medically necessary, which means that cost-effectiveness analysis can only be used to exclude a treatment from coverage if at least one equivalent alternative exists.


Mobile phone text-messaging interventions aimed to prevent cardiovascular diseases (Text2PreventCVD): systematic review and individual patient data meta-analysis.
A variety of small mobile phone text-messaging interventions have indicated improvement in risk factors for cardiovascular disease (CVD). Yet the extent of this improvement and whether it impacts multiple risk factors together is uncertain. We aimed to conduct a systematic review and individual patient data (IPD) meta-analysis to investigate the effects of text-messaging interventions for CVD prevention. Electronic databases were searched to identify trials investigating a text-messaging intervention focusing on CVD prevention with the potential to modify at least two CVD risk factors in adults. The main outcome was blood pressure (BP). We conducted standard and IPD meta-analysis on pooled data. We accounted for clustering of patients within studies and the primary analysis used random-effects models. Sensitivity and subgroup analyses were performed. Nine trials were included in the systematic review involving 3779 participants and 5 (n=2612) contributed data to the IPD meta-analysis. Standard meta-analysis showed that the weighted mean differences are as follows: systolic blood pressure (SBP), -4.13 mm Hg (95% CI -11.07 to 2.81, p<0.0001); diastolic blood pressure (DBP), -1.11 mm Hg (-1.91 to -0.31, p=0.002); and body mass index (BMI), -0.32 (-0.49 to -0.16, p=0.000). In the IPD meta-analysis, the mean difference are as follows: SBP, -1.3 mm Hg (-5.4 to 2.7, p=0.5236); DBP, -0.8 mm Hg (-2.5 to 1.0, p=0.3912); and BMI, -0.2 (-0.8 to 0.4, p=0.5200) in the random-effects model. The impact on other risk factors is described, but there were insufficient data to conduct meta-analyses. Mobile phone text-messaging interventions have modest impacts on BP and BMI. Simultaneous but small impacts on multiple risk factors are likely to be clinically relevant and improve outcome, but there are currently insufficient data in pooled analyses to examine the extent to which simultaneous reduction in multiple risk factors occurs. CRD42016033236.


Spectrum of myelinated pulmonary afferents (II).
Recently, it has been recognized that a single airway sensory unit may contain multiple receptive fields and that each field houses at least one encoder. Since some units respond to both lung inflation and deflation, we hypothesized that these units contain heterogeneous encoders for sensing inflation and deflation, respectively. Single unit activities were recorded from the cervical vagus nerve in anesthetized, open chest, and mechanically ventilated rabbits. Fifty-two airway sensory units with multiple receptive fields that responded to both lung inflation and deflation were identified. Among them, 13 units had separate receptive fields for inflation and deflation, where one of the fields could be blocked by local injection of 2% lidocaine (10 μl). In 8 of the 13 units, the deflation response was blocked without affecting the unit's response to inflation, whereas in the remaining five units, the inflation response was blocked without affecting the deflation response. Our results support the hypothesis that a single mechanosensory unit may contain heterogeneous encoders that can respond to either inflation or deflation.


Kinetic evidence for interdomain communication in the allosteric regulation of alpha-isopropylmalate synthase from Mycobacterium tuberculosis.
The enzyme alpha-isopropylmalate synthase from Mycobacterium tuberculosis (MtIPMS) has been identified as a possible target for the design of new antitubercular therapeutics. Recently, it was shown that MtIPMS is subject to slow-onset, feedback inhibition by l-leucine, the first instance of an allosteric regulator utilizing this mechanism. Structural studies are inconsistent with canonical allosteric mechanisms, including changes to the quaternary structure or large, rigid-body conformational changes to the enzyme upon l-leucine binding. Thus, the allosteric regulation may result from a discrete inhibitory signal transmitted to the active site upon l-leucine binding in the regulatory domain, a distance of more than 50 A. To test this mechanism, site-directed mutagenesis was employed to construct enzymes with substitutions at phylogenetically conserved active site residues near the interface of the catalytic and linker domains. The substitutions had wide-ranging effects on the kinetics of l-leucine inhibition, with some modest effects on the kinetic parameters of catalysis. The most dramatic result was the finding that the Y410F mutant form of MtIPMS is insensitive to l-leucine inhibition, suggesting that this residue has completely uncoupled the inhibitory signal to the active site. Overall, the data are consistent with a mechanism of allosteric regulation described by the interdomain communication of the inhibitory signal from the regulatory to catalytic domain and implicate the interactions between the linker and catalytic domains as critical determinants of inhibitory signal transmission.


The population effect of crime and neighbourhood on physical activity: an analysis of 15,461 adults.
Area-based interventions offer the potential to increase physical activity for many sedentary people in countries such as the UK. Evidence on the effect of individual and area/neighbourhood influences on physical activity is in its infancy, and despite its value to policy makers a population focus is rarely used. Data from a population-based health and lifestyle survey of adults in northwest England were used to analyse associations between individual and neighbourhood perceptions and physical activity. The population effect of eliminating a risk factor was expressed as a likely effect on population levels of physical activity. Of the 15,461 responders, 21,923 (27.1%) were physically active. Neighbourhood perceptions of leisure facilities were associated with physical activity, but no association was found for sense of belonging, public transport or shopping facilities. People who felt safe in their neighbourhood were more likely to be physically active, but no associations were found for vandalism, assaults, muggings or experience of crime. The number of physically active people would increase by 3290 if feelings of "unsafe" during the day were removed, and by 11,237 if feelings of "unsafe" during the night were removed. An additional 8342 people would be physically active if everyone believed that they were "very well placed for leisure facilities". Feeling safe had the potential largest effect on population levels of physical activity. Strategies to increase physical activity in the population need to consider the wider determinants of health-related behaviour, including fear of crime and safety.


CD300LF Polymorphisms of Inbred Mouse Strains Confer Resistance to Murine Norovirus Infection in a Cell Type-Dependent Manner.
Human norovirus is the leading cause of gastroenteritis worldwide, yet basic questions about its life cycle remain unanswered due to an historical lack of robust experimental systems. Recent studies on the closely related murine norovirus (MNV) have identified CD300LF as an indispensable entry factor for MNV. We compared the MNV susceptibilities of cells from different mouse strains and identified polymorphisms in murine CD300LF which are critical for its function as an MNV receptor. Bone marrow-derived macrophages (BMDMs) from I/LnJ mice were resistant to infection from multiple MNV strains which readily infect BMDMs from C57BL/6J mice. The resistance of I/LnJ BMDMs was specific to MNV, since the cells supported infection of other viruses comparably to C57BL/6J BMDMs. Transduction of I/LnJ BMDMs with C57BL/6J CD300LF made the cells permissible to MNV infection, suggesting that the cause of resistance lies in the entry step of MNV infection. In fact, we mapped this phenotype to a 4-amino-acid difference at the CC' loop of CD300LF; swapping of these amino acids between C57BL/6J and I/LnJ CD300LF proteins made the mutant C57BL/6J CD300LF functionally impaired and the corresponding mutant of I/LnJ CD300LF functional as an MNV entry factor. Surprisingly, expression of the I/LnJ CD300LF in other cell types made the cells infectible by MNV, even though the I/LnJ allele did not function as an MNV receptor in macrophage-like cells. Correspondingly, I/LnJ CD300LF bound MNV virions in permissive cells but not in nonpermissive cells. Collectively, our data suggest the existence of a cell type-specific modifier of MNV entry.IMPORTANCE MNV is a prevalent model system for studying human norovirus, which is the leading cause of gastroenteritis worldwide and thus a sizeable public health burden. Elucidating mechanisms underlying susceptibility of host cells to MNV infection can lead to insights on the roles that specific cell types play during norovirus pathogenesis. Here, we show that different alleles of the proteinaceous receptor for MNV, CD300LF, function in a cell type-dependent manner. In contrast to the C57BL/6J allele, which functions as an MNV entry factor in all tested cell types, including human cells, I/LnJ CD300LF does not function as an MNV entry factor in macrophage-like cells but does allow MNV entry in other cell types. Together, these observations indicate the existence of cell type-specific modifiers of CD300LF-dependent MNV entry.


Survival of Salmonella enterica Typhimurium in water amended with manure.
Outbreaks of Salmonella enterica have been associated with water sources. Survival of S. enterica in various environments has been studied but survival in water has rarely been attempted. In two separate experiments, we examined the survival of S. enterica Typhimurium in clean spring water at various eutrophication levels and temperatures. In the first experiment, lasting for 135 days, survival of S. enterica (10(10) CFU/ml) in water with 0, 50, 100, 500, and 1,000 mg/liter of added carbon at 7, 17, and 27°C was monitored weekly. In the second experiment, lasting for 3 weeks, survival of S. enterica in water at 0, 100, and 200 mg/ liter of added carbon and 27°C was studied daily. Each experiment had four replicates. Dissolved organic carbon was measured daily in each experiment. At the beginning, midpoint, and end of the survival study, microbial communities in both experiments were assessed by denaturing gradient gel electrophoresis (DGGE). Even at minimal carbon concentrations, S. enterica survived for at least 63 d. Survival of Salmonella was highly dependent on eutrophication levels (as measured by dissolved organic carbon) and temperature, increasing at high eutrophication levels, but decreasing at high temperatures. Survival was also strongly affected by microbial competition or predation.


The clinical effectiveness of static resting splints in early rheumatoid arthritis: a randomized controlled trial.
To evaluate the effectiveness of static resting splints in early RA. A multicentre, randomized, trial was conducted. Patients (n = 120) received either static resting splints [positioned with the wrist in neutral, MCP joint (MCPJ) and IP joint (IPJ) in a maximum of 60 degrees and 30 degrees of flexion, respectively] plus standardized occupational therapy or standardized occupational therapy alone. Change in grip strength (Ns), structural impairment (MCPJ ulnar deviation), applied dexterity (Button Board), self-report hand ability [Michigan Hand Outcomes Questionnaire (MHQ)], hand pain and morning hand stiffness were assessed at 0 and 12 months. Data for 56 (97%) splinted and 60 (97%) control group patients were analysed. Splint wear adherence was moderate; 24.5% 'never wore' the splints. The adjusted mean difference between groups for handgrip was -14.2 Ns (P = 0.342; 95% CI -43.7, 5.4); MCPJ ulnar deviation -1.1 degrees (P = 0.657; 95% CI = -6.2, 3.9); dexterity 0.1 s (P = 0.975; 95% CI = -6.6, 6.8) and self-report ability -3.0 on the MHQ score (P = 0.426; 95% CI -10.5, 4.5). Pain scores were unchanged in either group (P = 0.15). The occurrence of morning hand stiffness was reduced in a small group of splinted patients (P = 0.021), but the duration shortened in control patients (P = 0.010). There was no significant difference between the two interventions on grip strength, deformity, hand function and pain. The data favoured the control group and this study suggests that resting splints should not be used as a routine treatment of patients with early RA.


Family Man in the Other America: New Opportunities, Motivations, and Supports for Paternal Caregiving.
This analysis draws on longitudinal, qualitative interviews with disadvantaged mothers and fathers who participated in the Fragile Families Study (a U.S. birth cohort study) to examine how issues related to men's employment, social support, skills, and motivation facilitated their care of young children in different relationship contexts. Interviews with parents indicate that while some motivated and skilled men actively chose to become caregivers with the support of mothers, others developed new motivations, skills, and parenting supports in response to situations in which they were out of work or the mother was experiencing challenges. These findings suggest that disadvantaged men who assume caregiving responsibilities take different paths to involvement in the early years after their child's birth. Policies that overlook paternal caregivers may not only miss the opportunity to support relationships that benefit at-risk children but also unintentionally undermine this involvement.


Oxytocin Effect on Collective Decision Making: A Randomized Placebo Controlled Study.
Collective decision making often benefits both the individuals and the group in a variety of contexts. However, for the group to be successful, individuals should be able to strike a balance between their level of competence and their influence on the collective decisions. The hormone oxytocin has been shown to promote trust, conformism and attention to social cues. We wondered if this hormone may increase participants' (unwarranted) reliance on their partners' opinion, resulting in a reduction in collective benefit by disturbing the balance between influence and competence. To test this hypothesis we employed a randomized double-blind placebo-controlled design in which male dyads self-administered intranasal oxytocin or placebo and then performed a visual search task together. Compared to placebo, collective benefit did not decrease under oxytocin. Using an exploratory time dependent analysis, we observed increase in collective benefit over time under oxytocin. Moreover, trial-by-trial analysis showed that under oxytocin the more competent member of each dyad was less likely to change his mind during disagreements, while the less competent member showed a greater willingness to change his mind and conform to the opinion of his more reliable partner. This role-dependent effect may be mediated by enhanced monitoring of own and other's performance level under oxytocin. Such enhanced social learning could improve the balance between influence and competence and lead to efficient and beneficial collaboration.


Active Wnt signaling in response to cardiac injury.
Although the contribution of Wnt signaling in infarct healing is suggested, its exact role after myocardial infarction (MI) still needs to be unraveled. We evaluated the cardiac presence of active Wnt signaling in vivo following MI, and investigated in which cell types active Wnt signaling was present by determining Axin2 promoter-driven LacZ expression. C57BL/6 Axin2-LacZ reporter mice were sacrificed at days 0, 1, 3, 7, 14, and 21 after LAD ligation. Hearts were snap-frozen for immunohistochemistry (IHC) or enzymatically digested to obtain a single cell suspension for flow cytometric analysis. For both FACS and IHC, samples were stained for beta-galactosidase and antibodies against Sca-1, CD31, ckit, and CD45. Active Wnt signaling increased markedly in the myocardium, from 7 days post-MI onwards. Using Sca-1 and CD31, to identify progenitor and endothelial cells, a significant increase in LacZ+ cells was found at 7 and 14 days post-MI. LacZ+ cells also increased in the ckit+ and CD45+ cell population. IHC revealed LacZ+ cells co-expressing Sca, CD31, CD45, vWF, and alphaSMA in the border zone and the infarcted area. Wnt signaling increased significantly after MI in Sca+- and CD31+-expressing cells, suggesting involvement of Wnt signaling in resident Sca+ progenitor cells, as well as endothelial cells. Moreover, active Wnt signaling was present in ckit+ cells, leukocytes, and fibroblast. Given its broad role during the healing phase after cardiac injury, additional research seems warranted before a therapeutic approach on Wnt to enhance cardiac regeneration can be carried out safely.


ROLE OF THE GAMETE MEMBRANES IN FERTILIZATION IN SACCOGLOSSUS KOWALEVSKII (ENTEROPNEUSTA). I. THE ACROSOMAL REGION AND ITS CHANGES IN EARLY STAGES OF FERTILIZATION.
Previous electron microscope studies of sperm-egg association in the annelid Hydroides revealed novel aspects with respect to the acrosomal region. To determine whether these aspects were unique, a comparable study was made of a species belonging to a widely separated phylum, Hemichordata. Osmium tetroxide-fixed polyspermic material of the enteropneust, Saccoglossus, was used. The acrosomal region includes the membrane-bounded acrosome, with its large acrosomal granule and shallow adnuclear invagination, and the periacrosomal material which surrounds the acrosome except at the apex; here, the acrosomal membrane lies very close to the enclosing sperm plasma membrane. After reaching the egg envelope, the spermatozoon is activated and undergoes a series of changes: the apex dehisces and around the resulting orifice the acrosomal and sperm plasma membranes form a continuous mosaic membrane. The acrosomal granule disappears. Within 7 seconds the invagination becomes the acrosomal tubule, spans the egg envelopes, and meets the egg plasma membrane. The rest of the acrosomal vesicle everts. The periacrosomal mass changes profoundly: part becomes a fibrous core (possibly equivalent to a perforatorium); part remains as a peripheral ring. The basic pattern of structure and sperm-egg association in Saccoglossus is the same as in Hydroides. Previous evidence from four other phyla as interpreted here also indicates conformity to this pattern. The major role of the acrosome is apparently to deliver the sperm plasma membrane to the egg plasma membrane.


Characteristics of vegetarian adolescents in a multiethnic urban population.
To examine the prevalence of adolescents' vegetarianism in a multiethnic, urban population, and its correlates with demographic, personal, weight-related, and behavioral factors. Self-report and anthropometric data were collected from a representative sample of 4746 adolescents from 31 public middle schools and high schools in the Twin Cities area of Minnesota. Students answered questions concerning vegetarianism, food and weight, and health behaviors. Height and weight were directly measured. Comparisons were made between self-reported vegetarians and nonvegetarians; these analyses also assessed gender and race/ethnicity interactions. In the second set of analyses, demographic and behavioral characteristics of more restricted and semi-vegetarians were examined. Analyses were done by logistic regression. Teenage vegetarians comprise about 6% of the sample. The vegetarians were more likely than nonvegetarians to be female, not black, weight- and body-conscious, dissatisfied with their bodies, and involved in a variety of healthy and unhealthy weight control behaviors. Vegetarians more often reported having been told by a physician that they had an eating disorder and were more likely to have contemplated and attempted suicide. Vegetarian males were found to be an especially high risk group for unhealthy weight control practices. Few ethnic group differences among vegetarians were noted. Adolescents who did not eat chicken and fish were at lower risk than those who also ate chicken and fish. Adolescent vegetarians are at greater risk than others for involvement in unhealthy and extreme weight control behaviors. Vegetarian males are at particularly high risk. Vegetarianism among adolescents may therefore be a signal for preventive intervention. Adolescents who choose to become vegetarians may also need to learn how to healthfully do so.


Association of Parental Incarceration With Psychiatric and Functional Outcomes of Young Adults.
In 2016, an estimated 8% of US children younger than 18 years had experienced the incarceration of a parent, and rates were substantially higher among children from racial and ethnic minority backgrounds and disadvantaged groups. Little is known about whether parental incarceration during childhood is associated with adult psychiatric problems and functional outcomes. To examine whether parental incarceration is associated with increased levels of psychiatric diagnosis and poor outcomes in health, legal, financial, and social domains in adulthood. This cohort study used data from the community-representative, prospective, longitudinal Great Smoky Mountains Study. Children and their parents were interviewed up to 8 times from January 1993 to December 2000 (ages 9-16 years; 6674 observations of 1420 participants) using the Child and Adolescent Psychiatric Assessment, which assessed parental incarceration, childhood psychiatric diagnoses, and other adversities. Young adults were followed up at ages 19, 21, 25, and 30 years from January 1999 to December 2015 (4556 observations of 1334 participants) to assess psychiatric diagnoses and functional outcomes indicative of a disrupted transition to adulthood. Data analysis was conducted from June 2018 to June 2019. By age 16 years, 475 participants (weighted percentage, 23.9%) had a parental figure who had been incarcerated, including 259 young men (22.2%) and 216 young women (25.5%). Parental incarceration was associated with higher prevalence of childhood psychiatric diagnoses (eg, any depressive diagnosis: adjusted odds ratio [aOR], 2.5; 95% CI, 1.3-4.6; P = .006; attention-deficit/hyperactivity disorder: aOR, 2.3; 95% CI, 1.0-5.5; P = .06; and conduct disorder: aOR, 2.5; 95% CI, 1.4-4.3; P = .001). After accounting for childhood psychiatric diagnoses and adversity exposure, parental incarceration remained associated with increased odds of having an adult anxiety disorder (aOR, 1.7; 95% CI, 1.0-3.0; P = .04), having an illicit drug use disorder (aOR, 6.6; 95% CI, 2.6-17.0; P < .001), having a felony charge (aOR, 3.4; 95% CI, 1.8-6.5; P < .001), incarceration (aOR, 2.8; 95% CI, 1.4-5.4; P = .003), not completing high school (aOR, 4.4; 95% CI, 2.2-8.8; P < .001), early parenthood (aOR, 1.7; 95% CI, 1.0-3.0; P = .04), and being socially isolated (aOR, 2.2; 95% CI, 1.2-4.0; P = .009). This study suggests that parental incarceration is associated with a broad range of psychiatric, legal, financial, and social outcomes during young adulthood. Parental incarceration is a common experience that may perpetuate disadvantage from generation to generation.


Psychological distress and negative appraisals in survivors of severe acute respiratory syndrome (SARS).
Severe acute respiratory syndrome (SARS) is a novel disease. The authors have limited knowledge of its impact on mental health. The present study aimed to examine the level and extent of psychological distress of SARS survivors following 1-month recovery, to explore patients' negative appraisals of the impact of SARS, and to evaluate the associations between psychological distress and negative appraisals. The Beck Anxiety Inventory, the Beck Depression Inventory, and a newly developed measure, the SARS Impact Scale (SIS), were mailed to 453 Hong Kong Chinese SARS survivors discharged from hospital for 4 weeks or more. A total of 425 patients received the questionnaires and 180 (mean age 36.9 years; 120 women) gave valid replies. The response rate was 42.4 %. The participants also represented 13.6 % of all adult survivors in Hong Kong. About 35 % of respondents reported 'moderate to severe' or 'severe' ranges of anxiety and/or depressive symptoms. It was found that those working as healthcare workers or having family members killed by SARS were more prone to develop subsequent high levels of distress. Factor analyses extracted three meaningful factors of the SIS, namely 'survival threat', 'physical impact', and 'social impact'. Negative appraisals at the acute phase and 1-month recovery significantly accounted for substantial portions of variances for anxiety and depressive symptoms, after the effects of other psychosocial variables were controlled. Psychological distress of SARS survivors at 1-month recovery is real and significant. Negative appraisals may play a pivotal role in the development of psychological distress for SARS survivors, at least in the short term.


Randomized phase II study of fulvestrant and erlotinib compared with erlotinib alone in patients with advanced or metastatic non-small cell lung cancer.
This open-label, randomized phase II trial evaluated antitumor efficacy of an antiestrogen, fulvestrant, in combination with human epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in advanced non-small cell lung cancer (NSCLC) patients. Patients with advanced or metastatic NSCLC, ECOG 0-2, previous chemotherapy unless patient refusal, and no prior EGFR-directed therapy were randomized 2:1 to erlotinib 150 mg oral daily plus 500 mg intramuscular fulvestrant on day 1, 15, 29 and every 28 days thereafter or erlotinib alone 150 mg oral daily. The primary end point was objective response rate (ORR); secondary endpoints included progression free survival (PFS) and overall survival (OS). Among 106 randomized patients, 100 received at least one dose of study drug. ORR was 16.4% (11 of 67 patients) for the combination versus 12.1% (4 of 33 patients) for erlotinib (p = 0.77). PFS median 3.5 versus 1.9 months [HR = 0.86, 95% CI (0.52-1.43), p = 0.29] and OS median 9.5 versus 5.8 months [HR = 0.92, 95% CI (0.57-1.48), p = 0.74] numerically favored the combination. In an unplanned subset analysis, among EGFR wild type patients (n = 51), but not EGFR mutant patients (n = 17), median PFS was 3.5 versus 1.7 months [HR = 0.35, 95% CI (0.14-0.86), p = 0.02] and OS was 6.2 versus 5.2 months [HR = 0.72, 95% CI (0.35-1.48), p = 0.37] for combined therapy versus erlotinib, respectively. Notably, EGFR WT patients were more likely to be hormone receptor-positive (either estrogen receptor α- and/or progesterone receptor-positive) compared to EGFR mutant patients (50% versus 9.1%, respectively) (p = 0.03). Treatment was well tolerated with predominant grade 1-2 dermatologic and gastrointestinal adverse effects. Addition of fulvestrant to erlotinib was well tolerated, with increased activity noted among EGFR wild type patients compared to erlotinib alone, albeit in an unplanned subset analysis.


An observational cohort study of numbers and causes of preventable general hospital admissions in people with and without intellectual disabilities in England.
Hospital admissions for preventable reasons [ambulatory care sensitive (ACS) conditions] can indicate gaps in access to or quality of primary care. This paper seeks to document the numbers and causes of these admissions in England for people with intellectual disabilities (ID) compared with those without. Observational cohort study of number and duration of emergency admitted patient episodes for ACS conditions, overall and by cause, using the Clinical Practice Research Datalink GOLD primary care database and the linked Hospital Episode Statistics Admitted Patient Care dataset. The study covered 5.2% of the population of England from April 2010 to March 2014 giving a total population base of 59 280 person-years for people with ID and 11 103 910 for people without identified ID. The rate of emergency admissions for ACS conditions for people with ID was 77.5 per 1000 person-years. As a crude comparison, this was 3.0 times the rate for those without ID, but standardising for the distinct demography of this group, the number of episodes was 4.8 times that expected if they had the same age-specific and sex-specific rates. Stay durations for these episodes were longer for both young-age and working-age people with ID. Overall people with ID used 399.8 bed-days per 1000 person-years. As a crude comparison, this is 2.8 times the figure for people without ID. Standardising for their age and sex profile, it is 5.4 times the number expected if they had the same age-specific and sex-specific rates. For patients with ID, 16.6% (one in six) of all admitted patient episodes and 24.3% (one in four) of in-patient care days for people with ID were for ACS conditions. Corresponding figures for those without ID were 8.3% (one in 12) and 14.4% (one in seven). The difference in rates between those with and without ID was most marked in people of working age. The three most common causes of emergency episodes for ACS conditions in people with ID were convulsions and epilepsy, influenza pneumonia and aspiration pneumonitis. Influenza pneumonia was also a common cause for people without ID. Episodes for convulsions and epilepsy and aspiration pneumonitis were specifically associated with people with ID. Rates of hospital admissions for ACS conditions provide an important indicator of health literacy, basic self-care (or support by carers) and the accessibility of primary care. High rates are seen for some conditions specifically associated with premature death in people with ID. Local monitoring of these figures could be used to indicate the effectiveness of local primary health services in providing support to people with ID.


Prevalence of Parasitic Contamination in Salad Vegetables Collected from Supermarkets and Street Vendors in Amman and Baqa'a - Jordan.
One of the main ways in transmitting parasites to humans is through consuming contaminated raw vegetables. The aim of this study was to evaluate the prevalence of parasitological contamination (helminthes eggs, Giardia and Entamoeba histolytica cysts) of salad vegetables sold at supermarkets and street vendors in Amman and Baqa'a – Jordan. A total of 133 samples of salad vegetables were collected and examined for the prevalence of parasites. It was found that 29% of the samples were contaminated with different parasites. Of the 30 lettuce, 33 tomato, 42 parsley and 28 cucumber samples examined the prevalence of Ascaris spp. eggs was 43%, 15%, 21% and 4%; Toxocara spp. eggs was 30%, 0%, 0% and 4%; Giardia spp. cysts was 23%, 6%, 0% and 0%; Taenia/Echinococcus eggs was 20%, 0%, 5% and 0%; Fasciola hepatica eggs was 13%, 3%, 2% and 0%; and E. histolytica cysts was 10%, 6%, 0% and 0%, respectively. There was no significant difference in the prevalence of parasite in salad vegetables either between supermarkets and street vendors, or between Amman and Baqa'a, Ascaris spp. was found to be the highest prevalent parasite in salad vegetables from supermarkets and street vendors and from Amman and Baqa'a. Our results pointed out that, the parasitic contamination of salad vegetables found in our study might be caused by irrigating crops with faecal contaminated water. We concluded that salad vegetables sold in Amman and Baqa'a may cause a health risk to consumers.


Diabetes mellitus and cancer risk: pooled analysis of eight cohort studies in Japan.
Although a growing body of evidence suggests a link between diabetes and cancer, it is not clear whether diabetes independently increases the risk of cancer. We conducted a comprehensive assessment of the association between pre-existing diabetes and total and site-specific cancer risk based on a pooled analysis of eight cohort studies in Japan (>330 000 subjects). We estimated a summary hazard ratio by pooling study-specific hazard ratios for total and site-specific cancer by using a random-effects model. A statistically increased risk was observed for cancers at specific sites, such as colon (hazard ratio; HR = 1.40), liver (HR = 1.97), pancreas (HR = 1.85) and bile duct (HR = 1.66; men only). Increased risk was also suggested for other sites, and diabetes mellitus was associated with an overall 20% increased risk in total cancer incidence in the Japanese population. The association between these two diseases has important implications for reiterating the importance of controlling lifestyle factors and may suggest a possible strategy for cancer screening among patients with diabetes. Studies continuously investigating the risk factors for diabetes are also important.


Cytoprotection of kidney epithelial cells by compounds that target amino acid gated chloride channels.
Glycine, strychnine and certain chloride channel blockers were reported to protect cells against lethal cell injury. These effects have been attributed to interactions with membrane proteins related to CNS glycine gated chloride channel receptors. We have investigated the pharmacology of these actions. Madin-Darby canine kidney (MDCK) epithelial cells were depleted of adenosine triphosphate (ATP) by incubation in glucose free medium containing a mitochondrial uncoupler. Medium Ca2+ was adjusted to 100 nM in the presence of an ionophore such that intracellular Ca2+ did not increase, and Ca(2+)-related injury mechanisms were inhibited. This permitted more sensitive quantitation of protection against cell injury attributable to glycine or other agents whose actions might be related to those of the amino acid. Two classes of compounds showed cytoprotective activity in this system: (1) ligands at chloride channel receptors, such as glycine, strychnine and avermectin B1a; (2) chloride channel blockers, including cyanotriphenylboron and niflumic acid, both of which are known to bind to channel domains of CNS glycine receptors. Morphological and functional studies showed that the compounds preserved plasma membrane integrity, but permitted cell swelling. Substitution of medium chloride by gluconate, or chloride salts by sucrose, did not substantially modify lethal damage or its prevention by glycine or other drugs. The compounds did not modify ATP declines. At least for some compounds, cytoprotection appeared to be specific to structural features on the molecules. These observations are consistent with the hypothesis that a plasma membrane protein related to glycine-gated chloride channel receptors plays a significant role in cell injury, but indicate that the mechanisms of injury and protection by compounds active in this system are not related to chloride fluxes.


Spread of herbicide-resistant weedy rice (red rice, Oryza sativa L.) after 5 years of Clearfield rice cultivation in Italy.
The weedy relative of cultivated rice, red rice, can invade and severely infest rice fields, as reported by rice farmers throughout the world. Because of its close genetic relationship to commercial rice, red rice has proven difficult to control. Clearfield (Cl) varieties, which are resistant to the inhibiting herbicides in the chemical group AHAS (acetohydroxyacid synthase), provide a highly efficient opportunity to control red rice infestations. In order to reduce the risk of herbicide resistance spreading from cultivated rice to red rice, stewardship guidelines are regularly released. In Italy, the cultivation of Cl cultivars started in 2006. In 2010, surveillance of the possible escape of herbicide resistance was carried out; 168 red rice plants were sampled in 16 fields from six locations containing Cl and traditional cultivars. A first subsample of 119 plants was analysed after herbicide treatment and the resistance was found in 62 plants. Of these 119 plants, 78 plants were randomly selected and analysed at the level of the AHAS gene to search for the Cl mutation determining the resistant genotype: the Cl mutation was present in all the resistant plants. Nuclear and chloroplast microsatellite markers revealed a high correlation between genetic similarity and herbicide resistance. The results clearly show that Cl herbicide-resistant red rice plants are present in the field, having genetic relationships with the Cl variety. Finding plants homozygous for the mutation suggests that the crossing event occurred relatively recently and that these plants are in the F2 or later generations. These observations raise the possibility that Cl red rice is already within the cultivated rice seed supply.


Competition among physicians, revisited.
Ten years ago we developed a model of demand inducement in the physician services market and explored the properties of that model. We found that predictions concerning physicians' prices, workloads, and income were ambiguous and in many cases were consistent with those derived from a standard monopoly pricing model. Spurred in part by our work, numerous empirical studies of the demand inducement model have been conducted. These studies found little evidence of demand inducement for primary care physician services. Demand inducement may exist in the market for surgical services, but its extent is less than previously estimated. We disagree with those who say that physicians generate demand to avoid price controls and that national health care spending is proportional to the number of physicians; the evidence does not support these arguments. Substantial uncertainty may surround the physician's choice of diagnosis and treatment mode. However, this does not imply a breakdown of the agency relationship. In this paper we extend our earlier model of demand inducement to include variations in the quantity of services (which was previously assumed to be less than socially ideal). Using the model, we conclude that the major objection to government price setting is not that physicians will get around the controls by inducing demand; rather, price controls result in a quantity and quality of physicians' services that is not ideal and may be inferior to those provided in an unregulated monopoly.


Meaning of dependency on care as narrated by 10 patients.
This article is part of an ongoing study that aims to illuminate the meaning of dependency on care. The aim of this particular study is to disclose the meaning of dependency on care as narrated by patients. We conducted interviews with patients (six men and four women) who had been in medical or surgical wards for at least 14 days. Seven of the patients were also interviewed one week after discharge. The participants ranged in age from 41 to 84 years old. The interviews were tape-recorded and transcribed verbatim. A phenomenological-hermeneutic approach was used to interpret the resulting text. The results show that to be dependent on care is to face the inevitability of not being able to manage by oneself--it is being attached to the nurses and bound to the care they offer. Being dependent on care involves a struggle to get care without treading on the nurses' toes. The nurses are one's lifelines and getting care is essential, no matter what. It is better to receive any form of care, good or bad, than to receive nothing. Being dependent on care is to be exposed and subjected to a nurse's ability and benevolence. One comprehensive understanding of the meaning of dependency on care is simply that "one does not saw off the branch one is sitting on." Furthermore, dependency on care involves a struggle to move forward in a life that hurts. Patients lose much of their freedom of choice in daily life and grieve their loss of ability and value. Patients may be able, however, to see things they would have never noticed earlier in life. Dependency on care is understood as one kind of "limit situation." Patients who are dependent on care may reevaluate their potential in life and gain another perspective on life.


"Lucy" (A.L. 288-1) had five sacral vertebrae.
A "long-backed" scenario of hominin vertebral evolution posits that early hominins possessed six lumbar vertebrae coupled with a high frequency of four sacral vertebrae (7:12-13:6:4), a configuration acquired from a hominin-panin last common ancestor (PLCA) having a vertebral formula of 7:13:6-7:4. One founding line of evidence for this hypothesis is the recent assertion that the "Lucy" sacrum (A.L. 288-1an, Australopithecus afarensis) consists of four sacral vertebrae and a partially-fused first coccygeal vertebra (Co1), rather than five sacral vertebrae as in modern humans. This study reassesses the number of sacral vertebrae in Lucy by reexamining the distal end of A.L.288-1an in the context of a comparative sample of modern human sacra and Co1 vertebrae, and the sacrum of A. sediba (MH2). Results demonstrate that, similar to S5 in modern humans and A. sediba, the last vertebra in A.L. 288-1an exhibits inferiorly-projecting (right side) cornua and a kidney-shaped inferior body articular surface. This morphology is inconsistent with that of fused or isolated Co1 vertebrae in humans, which either lack cornua or possess only superiorly-projecting cornua, and have more circularly-shaped inferior body articular surfaces. The level at which the hiatus' apex is located is also more compatible with typical five-element modern human sacra and A. sediba than if only four sacral vertebrae are present. Our observations suggest that A.L. 288-1 possessed five sacral vertebrae as in modern humans; thus, sacral number in "Lucy" does not indicate a directional change in vertebral count that can provide information on the PLCA ancestral condition.


Leveraging electrokinetics for the active control of dendritic fullerene-1 release across a nanochannel membrane.
General adoption of advanced treatment protocols such as chronotherapy will hinge on progress in drug delivery technologies that provide precise temporal control of therapeutic release. Such innovation is also crucial to future medicine approaches such as telemedicine. Here we present a nanofluidic membrane technology capable of achieving active and tunable control of molecular transport through nanofluidic channels. Control was achieved through application of an electric field between two platinum electrodes positioned on either surface of a 5.7 nm nanochannel membrane designed for zero-order drug delivery. Two electrode configurations were tested: laser-cut foils and electron beam deposited thin-films, configurations capable of operating at low voltage (≤1.5 V), and power (100 nW). Temporal, reproducible tuning and interruption of dendritic fullerene 1 (DF-1) transport was demonstrated over multi-day release experiments. Conductance tests showed limiting currents in the low applied potential range, implying ionic concentration polarization (ICP) at the interface between the membrane's micro- and nanochannels, even in concentrated solutions (≤1 M NaCl). The ability of this nanotechnology platform to facilitate controlled delivery of molecules and particles has broad applicability to next-generation therapeutics for numerous pathologies, including autoimmune diseases, circadian dysfunction, pain, and stress, among others.


Gluten-induced RNA methylation changes regulate intestinal inflammation via allele-specific XPO1 translation in epithelial cells.
Coeliac disease (CD) is a complex autoimmune disorder that develops in genetically susceptible individuals. Dietary gluten triggers an immune response for which the only available treatment so far is a strict, lifelong gluten free diet. Human leucocyte antigen (HLA) genes and several non-HLA regions have been associated with the genetic susceptibility to CD, but their role in the pathogenesis of the disease is still essentially unknown, making it complicated to develop much needed non-dietary treatments. Here, we describe the functional involvement of a CD-associated single-nucleotide polymorphism (SNP) located in the 5'UTR of XPO1 in the inflammatory environment characteristic of the coeliac intestinal epithelium. The function of the CD-associated SNP was investigated using an intestinal cell line heterozygous for the SNP, N6-methyladenosine (m6A)-related knock-out and HLA-DQ2 mice, and human samples from patients with CD. Individuals harbouring the risk allele had higher m6A methylation in the 5'UTR of XPO1 RNA, rendering greater XPO1 protein amounts that led to downstream nuclear factor kappa B (NFkB) activity and subsequent inflammation. Furthermore, gluten exposure increased overall m6A methylation in humans as well as in in vitro and in vivo models. We identify a novel m6A-XPO1-NFkB pathway that is activated in CD patients. The findings will prompt the development of new therapeutic approaches directed at m6A proteins and XPO1, a target under evaluation for the treatment of intestinal disorders.


Optical trapping and integration of semiconductor nanowire assemblies in water.
Semiconductor nanowires have received much attention owing to their potential use as building blocks of miniaturized electrical, nanofluidic and optical devices. Although chemical nanowire synthesis procedures have matured and now yield nanowires with specific compositions and growth directions, the use of these materials in scientific, biomedical and microelectronic applications is greatly restricted owing to a lack of methods to assemble nanowires into complex heterostructures with high spatial and angular precision. Here we show that an infrared single-beam optical trap can be used to individually trap, transfer and assemble high-aspect-ratio semiconductor nanowires into arbitrary structures in a fluid environment. Nanowires with diameters as small as 20 nm and aspect ratios of more than 100 can be trapped and transported in three dimensions, enabling the construction of nanowire architectures that may function as active photonic devices. Moreover, nanowire structures can now be assembled in physiological environments, offering new forms of chemical, mechanical and optical stimulation of living cells.


Radioprotective Effect of Hesperidin: A Systematic Review.
Background and objectives: Ionizing radiation (IR) has been of immense benefit to man, especially for medical purposes (diagnostic imaging and radiotherapy). However, the risks of toxicity in healthy normal cells, leading to cellular damage as well as early and late side effects, have been major drawbacks. The aim of this study was to evaluate the radioprotective effect of hesperidin against IR-induced damage. Materials and Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were applied in reporting this study. A search was conducted using the electronic databases PubMed, Scopus, Embase, Google Scholar, and www.ClinicalTrials.gov for information about completed or ongoing clinical trials. Results: From our search results, 24 studies involving rats, mice, and cultured human and animal cells were included. An experimental case-control design was used in all studies. The studies showed that the administration of hesperidin reduced oxidative stress and inflammation in all investigated tissues. Furthermore, it increased 30-day and 60-day survival rates and protected against DNA damage. The best radioprotection was obtained when hesperidin was administered before irradiation. Conclusions: The results of the included studies support the antioxidant, anti-inflammatory, and antiapoptotic abilities of hesperidin as a potential radioprotective agent against IR-induced damage. We recommend future clinical trials for more insights.