Saudi mothers' preferences about breaking bad news concerning newborns: a structured verbal questionnaire.
Breaking bad news (BBN) to parents whose newborn has a major disease is an ethical dilemma. In Saudi Arabia, BBN about newborns is performed according to the parental preferences that have been reported from non-Arabic/non-Islamic countries. Saudi mothers' preferences about BBN have not yet been studied. Therefore, we aimed to elicit the preferences of Saudi mothers about BBN concerning newborns. We selected a convenience sample of 402 Saudi mothers, aged 18-50 years, who had no previous experience with BBN. We selected them via a simple number-randomization scheme from the premises of a level III Saudi hospital between October of 2009 and January of 2011. We used a hypothetical situation (BBN about trisomy 21) to elicit their preferences about BBN concerning newborns via a structured verbal questionnaire composed of 12 multiple-choice questions. We expressed their preferences as percentages (95% confidence interval), and we used the Kendall's W test (W) to assess the degree of agreement in preferences. The Saudi mothers preferred that BBN be conducted with both parents together (64% [60-69]), albeit with weak levels of agreement (W = 0.29). They showed moderate agreement in their preferences that BBN should be conducted early (79% [75-83], W = 0.48), in detail (81% [77-85], W = 0.52), in person (88% [85-91], W = 0.58), and in a quiet setting (86% [83-90], W = 0.53). With extremely weak agreement, they preferred to have a known person present for support during BBN (56% [51-61], W = 0.01), to have close bodily contact with their babies (66% [61-70], W = 0.10), and to have no another patients present (64% [59-68], W = 0.08). They showed moderate levels of agreement in their desires to detail, in advance, their preferences about process of BBN by giving a reversible, written informed consent that could be utilized for guidance, if needed (80% [76-84], W = 0.36). In our experience, Saudi mothers' preferences about BBN concerning newborns are varied, suggesting that a "one-size-fits-all" approach is inappropriate. A reversible, written informed consent detailing their preferences about BBN that would be kept in their medical records and utilized for guidance, if needed, may be the best solution, given this level of diversity. These findings merit further study.


Dietary Diversity on the Swahili Coast: The Fauna from Two Zanzibar Trading Locales.
Occupants of coastal and island eastern Africa-now known as the 'Swahili coast'-were involved in long-distance trade with the Indian Ocean world during the later first millennium CE. Such exchanges may be traced via the appearance of non-native animals in the archaeofaunal record; additionally, this record reveals daily culinary practises of the members of trading communities and can thus shed light on subsistence technologies and social organisation. Yet despite the potential contributions of faunal data to Swahili coast archaeology, few detailed zooarchaeological studies have been conducted. Here, we present an analysis of faunal remains from new excavations at two coastal Zanzibar trading locales: the small settlement of Fukuchani in the north-west and the larger town of Unguja Ukuu in the south-west. The occurrences of non-native fauna at these sites-Asian black rat (Rattus rattus) and domestic chicken (Gallus gallus), as well as domestic cat (Felis catus)-are among the earliest in eastern Africa. The sites contrast with one another in their emphases on wild and domestic fauna: Fukuchani's inhabitants were economically and socially engaged with the wild terrestrial realm, evidenced not only through diet but also through the burial of a cache of wild bovid metatarsals. In contrast, the town of Unguja Ukuu had a domestic economy reliant on caprine herding, alongside more limited chicken keeping, although hunting or trapping of wild fauna also played an important role. Occupants of both sites were focused on a diversity of near-shore marine resources, with little or no evidence for the kind of venturing into deeper waters that would have required investment in new technologies. Comparisons with contemporaneous sites suggest that some of the patterns at Fukuchani and Unguja Ukuu are not replicated elsewhere. This diversity in early Swahili coast foodways is essential to discussions of the agents engaged in long-distance maritime trade.


[Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic neuroendocrine tumors].
Pancreatic neuroendocrine tumors (PETs) are increasingly recognized. In order to assure an optimal treatment of patients and to propose an efficient diagnostic algorithm we were prompted to organize meetings, with participating experts, specialists in different fields of expertise. The idea for the meetings was to try to give a standardized approach, which would in future help in stratification of PET patients. Results of meetings are given in a form of Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic neuroendocrine tumors.


STX, a Novel Membrane Estrogen Receptor Ligand, Protects Against Amyloid-β Toxicity.
Because STX is a selective ligand for membrane estrogen receptors, it may be able to confer the beneficial effects of estrogen without eliciting the deleterious side effects associated with activation of the nuclear estrogen receptors. This study evaluates the neuroprotective properties of STX in the context of amyloid-β (Aβ) exposure. MC65 and SH-SY5Y neuroblastoma cell lines, as well as primary hippocampal neurons from wild type (WT) and Tg2576 mice, were used to investigate the ability of STX to attenuate cell death, mitochondrial dysfunction, dendritic simplification, and synaptic loss induced by Aβ. STX prevented Aβ-induced cell death in both neuroblastoma cell lines; it also normalized the decrease in ATP and mitochondrial gene expression caused by Aβ in these cells. Notably, STX also increased ATP content and mitochondrial gene expression in control neuroblastoma cells (in the absence of Aβ). Likewise in primary neurons, STX increased ATP levels and mitochondrial gene expression in both genotypes. In addition, STX treatment enhanced dendritic arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites caused by Aβ exposure in Tg2576 neurons. These data suggest that STX can act as an effective neuroprotective agent in the context of Aβ toxicity, improving mitochondrial function as well as dendritic growth and synaptic differentiation. In addition, since STX also improved these endpoints in the absence of Aβ, this compound may have broader therapeutic value beyond Alzheimer's disease.


Older and more mindful? Age differences in mindfulness components and well-being.
Empirical research on the processes through which mindfulness affects well-being is in its infancy. Furthermore, few studies have considered the positive effects of mindfulness on psychological functioning from a lifespan perspective. The present study aimed to examine the role of age in moderating associations of mindfulness components with well-being in the context of a proposed model of mindfulness. A community-based sample of 623 participants aged between 18 and 86 years (M = 48.78, SD = 16.74) was recruited via an internet-based research platform. Participants completed questionnaire measures of mindful characteristics (i.e. present-moment attention, nonjudgment, interoception, acceptance, nonattachment, and decentering), flexible goal adjustment, and well-being. Parallel mediation analyses showed that both present-moment attention and nonjudgment provided significant pathways to (a) flexible goal adjustment through nonattachment and decentering; and (b) well-being through acceptance, nonattachment, and decentering. Furthermore, present-moment attention, nonjudgment, acceptance, nonattachment, and decentering were all positively associated with age. Conditional process analyses revealed that the direct relationships between (1) present-moment attention and well-being, (2) nonjudgment and well-being, and (3) decentering and flexible goal adjustment became stronger with age and were significant for adults from around 40 years of age and older. The findings suggest that the tendency to focus on the present-moment and adopt a nonjudgmental orientation may become especially important for well-being with advancing age, and the ability to appreciate the transitory nature of personal experiences may be particularly important for flexible employment of both goal disengagement and reengagement strategies across the second half of life.


Microbial Colonization on Elastomeric Ligatures during Orthodontic Therapeutics: An Overview.
The current review focuses on the studies conducted on the colonization of microorganisms on orthodontic ligatures during orthodontic treatment. The fixed orthodontic appliances have long been associated with an increase in plaque accumulation, bacterial colonization, and resultant enamel decalcification. Voluminous research has been carried out on the microbial colonization of even newer orthodontic materials such as elastomeric ligatures with an evidence of variably increased microbial counts during orthodontic treatment. However, conclusive material-based data for minimal microbial colonization to establish acceptance criteria for the use of elastomeric ligatures are hardly available. Thus, there is a need for further studies with dual emphasis on exploring microbial associations based on surface chemistries of different elastomers and their requisite modifications for hampering microbial biofilms to evolve efficacious oral health friendly orthodontic ligatures.


How processing may affect milk protein digestion and overall physiological outcomes: A systematic review.
Dairy is one of the main sources for high quality protein in the human diet. Processing may, however, cause denaturation, aggregation, and chemical modifications of its amino acids, which may impact protein quality. This systematic review covers the effect of milk protein modifications as a result of heating, on protein digestion and its physiological impact. A total of 5363 records were retrieved through the Scopus database of which a total of 102 were included. Although the degree of modification highly depends on the exact processing conditions, heating of milk proteins can modify several amino acids. In vitro and animal studies demonstrate that glycation decreases protein digestibility, and hinders amino acid availability, especially for lysine. Other chemical modifications, including oxidation, racemization, dephosphorylation and cross-linking, are less well studied, but may also impact protein digestion, which may result in decreased amino acid bioavailability and functionality. On the other hand, protein denaturation does not affect overall digestibility, but can facilitate gastric hydrolysis, especially of β-lactoglobulin. Protein denaturation can also alter gastric emptying of the protein, consequently affecting digestive kinetics that can eventually result in different post-prandial plasma amino acid appearance. Apart from processing, the kinetics of protein digestion depend on the matrix in which the protein is heated. Altogether, protein modifications may be considered indicative for processing severity. Controlling dairy processing conditions can thus be a powerful way to preserve protein quality or to steer gastrointestinal digestion kinetics and subsequent release of amino acids. Related physiological consequences mainly point towards amino acid bioavailability and immunological consequences.


Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a randomised, open-label, phase 3 trial.
Early combination antiretroviral therapy (cART) initiation at the time of primary HIV-1 infection could restrict the establishment of HIV reservoirs. We aimed to assess the effect of a cART regimen intensified with raltegravir and maraviroc, compared with standard triple-drug cART, on HIV-DNA load. In this randomised, open-label, phase 3 trial, we recruited patients from hospitals across France. Inclusion criteria were primary HIV-1 infection (an incomplete HIV-1 western blot and detectable plasma HIV-RNA), with either symptoms or a CD4+ cell count below 500 cells per μL. Patients were randomly assigned (1:1) to an intensive, five-drug cART regimen (raltegravir 400 mg and maraviroc 150 mg twice daily, and a fixed-dose combination of tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) or a standard triple-drug cART regimen (tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) using a predefined randomised list generated by randomly selected variable block sizes. The primary endpoint was the median number of HIV-DNA copies per 10(6) peripheral blood mononuclear cells (PBMC) at month 24, analysed in the modified intention-to-treat population, defined as all patients who started their assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01033760. Between April 26, 2010, and July 13, 2011, 110 patients were enrolled, of whom 92 were randomly assigned and 90 started treatment (45 in each treatment group). Six (13%) patients in the intensive cART group and two (4%) in the standard cART group discontinued before month 24. At month 24, HIV-DNA loads were similar between groups (2·35 [IQR 2·05-2·50] log₁₀ per 10(6) PBMC in the intensive cART group vs 2·25 [1·71-2·55] in the standard cART group; p=0·21). Eight grade 3-4 clinical adverse events were reported in seven patients in the intensive cART group and seven grade 3-4 clinical adverse events were reported in seven patients in the standard cART group. Three serious clinical adverse events occurred: two (pancreatitis and lipodystrophy) in the standard cART group, which were regarded as treatment related, and one event (suicide attempt) in the intensive cART group that was unrelated to treatment. After 24 months, cART intensified with raltegravir and maraviroc did not have a greater effect on HIV blood reservoirs than did standard cART. These results should help to design future trials of treatments aiming to decrease the HIV reservoir in patients with primary HIV-1 infection. Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck, and ViiV Laboratories.


Anhedonia in schizophrenia: Deficits in both motivation and hedonic capacity.
Anhedonia is one of the core negative symptoms of schizophrenia that affect the ultimate outcome of this disorder. It is unclear whether the motivational or the hedonic component of anhedonia is impaired in patients with schizophrenia. This study examined the deficits in motivation and hedonic capacity in patients with schizophrenia using an Effort-based pleasure experience task (E-pet). Twenty-two schizophrenia patients with prominent negative symptoms, 18 schizophrenia patients without prominent negative symptoms and 29 healthy controls participated in the present study. All of them were administered the E-pet task, which required the participants to make decisions on whether to choose a hard or easy task based on probability and reward magnitude. When making the grip effort allocation decision, schizophrenia patients with prominent negative symptoms were significantly less likely to choose a hard task than healthy controls. As the reward magnitude and the estimated reward value increased, unlike healthy controls, schizophrenia patients with prominent negative symptoms did not increase their hard task choices. They were also significantly less likely to choose a hard task than healthy controls in medium and high probability conditions. When anticipating potential rewards, these patients reported significantly less anticipatory pleasure than healthy controls, even when reward probability and magnitude increased. The pleasure experience rating after obtaining the actual reward was positively correlated with two pleasure experience scales in schizophrenia patients. In conclusion, patients with schizophrenia, especially those with prominent negative symptoms, showed deficits in both reward motivation and anticipatory pleasure experience.


Developmental expression of an amn(+) transgene rescues the mutant memory defect of amnesiac adults.
The Drosophila memory gene amnesiac (amn) has been proposed to encode a neuropeptide protein, which includes regions homologous to vertebrate pituitary adenylyl cyclase-activating peptide (PACAP; Feany and Quinn, 1995). Definitive experiments to link this gene to memory formation, however, have not yet been accomplished (Kandel and Abel, 1995). The experiments described here demonstrate that the putative amn transcript is involved in adult memory formation. With the use of a UAS-amn(+) transgene, we show complete rescue of memory defects in amn(28A), a mutant allele caused by the insertion of a GAL4 enhancer trap transposon (Moore et al., 1998). Study of the amn(28A) reporter reveals widespread expression in the adult brain but also enriched expression in the embryonic and larval nervous systems. To begin addressing the temporal requirement of amn in memory, we asked whether the memory defects could be rescued by restricting transgenic expression to the adult stage. A heat-shock regimen shown previously to rescue fully the amn ethanol sensitivity defect (Moore et al., 1998) failed to rescue the memory defect. These results, coupled with previous genetic and anatomical studies, suggest that adult memory formation and ethanol sensitivity have different temporal and spatial requirements for amn.


Do solitary foraging nocturnal mammals plan their routes?
Large-brained diurnal mammals with complex social systems are known to plan where and how to reach a resource, as shown by a systematic movement pattern analysis. We examined for the first time large-scale movement patterns of a solitary-ranging and small-brained mammal, the mouse lemur (Microcebus murinus), by using the change-point test and a heuristic random travel model to get insight into foraging strategies and potential route-planning abilities. Mouse lemurs are small nocturnal primates inhabiting the seasonal dry deciduous forest in Madagascar. During the lean season with limited food availability, these lemurs rely on few stationary food resources. We radio-tracked seven lemurs and analysed their foraging patterns. First change-points coincided with out-of-sight keystone food resources. Travel paths were more efficient in detecting these resources than a heuristic random travel model within limits of estimated detection distance. Findings suggest that even nocturnal, solitary-ranging mammals with small brains plan their route to an out-of-sight target. Thus, similar ecological pressures may lead to comparable spatial cognitive skills irrespective of the degree of sociality or relative brain size.


High-throughput plasmid DNA purification for 3 cents per sample.
To accommodate the increasingly rapid rates of DNA sequencing we have developed and implemented an inexpensive, expeditious method for the purification of double-stranded plasmid DNA clones. The robust nature, high throughput, low degree of technical difficulty and extremely low cost have made it the plasmid DNA preparation method of choice in both our expressed sequence tag (EST) and genome sequencing projects. Here we report the details of the method and describe its application in the generation of more than 700 000 ESTs at a rate exceeding 16 000 per week.


Mechanics of sphincter action. Studies on the lower esophageal sphincter.
The purpose of this study was to evaluate the mechanical factors involved in the genesis of lower esophageal sphincter pressure. We determined the relationship between intraluminal pressure and inside diameter, estimated the ratio between the wall thickness to inside radius, and calculated the tension in the wall of the lower esophageal sphincter as a function of the inside diameter. Various degrees of circumferential stretch were applied by introducing probes of different diameters in the rat lower esophageal sphincter in vivo. The intraluminal pressure produced by the lower esophageal sphincter around each probe was measured and pressure-diameter curves were constructed during (a) resting state, (b) contraction produced by electrical stimulation, and (c) relaxation produced by esophageal distension. The intraluminal pressure at an inside diameter of 0.5 mm was similar to that at inside diameter of 3.2 mm. This was true for the sphincter at rest as well as upon electrical stimulation. The pressure diameter curve, however, was sigmoid in shape; at first it showed a decline and then an increase followed by decline in pressure again with increasing diameters. The ratio of wall thickness to inside radius or the magnification factor varied with inside diameters as expected and this ratio increased steeply at small inside diameters. The tension diameter curves of the sphincter muscle showed that optimal tension development occurred not near sphincter closure but at a much wider diameter of 3.2 mm and that this muscle developed tension even at small luminal diameters. This behavior of the sphincter muscle ensures effective intraluminal pressure over a wide range of luminal diameters.


[Epidemiological features of exercise-induced bronchial hyperresponsiveness in children aged 13-14 years old in Barcelona (Spain)].
Conclusive data on the risk factors that modify bronchial hyperresponsiveness after airway exposure to modulating triggers (histamine, methacholine and exercise) are lacking. In recent years some risk factors such as air pollution or infection have been questioned and even considered protective. To assess the prevalence of bronchial hyperresponsiveness to exercise among schoolchildren and its association with different risk factors. Three thousand thirty-three schoolchildren aged 13-14 years were studied. Participants answered a questionnaire on respiratory symptoms. A total of 2,842 children underwent exercise challenge testing for bronchial hyperresponsiveness. This study was part of the International Study of Asthma and Allergies in Childhood (ISAAC). A fall in peak expiratory flow rate of (15 % after exercise was found in 324 children (11.4 %), of whom 29 (9 %) also presented symptoms of asthma. Bronchial hyperresponsiveness to exercise was significantly associated with lower age, female sex, high socioeconomic level and attending a private school. No association was found between bronchial hyperresponsiveness and obesity, tobacco or viral infections. These findings are not completely consistent with those of other studies, suggesting that local environmental factors may influence the prevalence of bronchial hyperresponsiveness. Further studies are required to clarify these conflicting data.


An atypical bHLH transcription factor regulates early xylem development downstream of auxin.
The vascular system in plants, which comprises xylem, phloem and vascular stem cells, originates from provascular cells and forms a continuous network throughout the plant body. Although various aspects of vascular development have been extensively studied, the early process of vascular development remains largely unknown. LONESOME HIGHWAY (LHW), which encodes an atypical basic helix-loop-helix (bHLH) transcription factor, plays an essential role in establishing vascular cells. Here, we report the analysis of LHW homologs in relation to vascular development. Three LHW homologs, LONESOME HIGHWAY LIKE 1-3 (LHL1-LHL3), were preferentially expressed in the plant vasculature. Genetic analysis indicated that, although the LHL3 loss-of-function mutant showed no obvious phenotype, the lhw lhl3 double mutant displayed more severe phenotypic defects in the vasculature of the cotyledons and roots than the lhw single mutant. Only one xylem vessel was formed at the metaxylem position in lhw lhl3 roots, whereas the lhw root formed one protoxylem and one or two metaxylem vessels. Conversely, overexpression of LHL3 enhanced xylem development in the roots. Moreover, N-1-naphthylphthalamic acid caused ectopic LHL3 expression in accordance with induced auxin maximum. These results suggest that LHL3 plays a positive role in xylem differentiation downstream of auxin.


Determinants of Acute Diarrhea Among Children Under-Five in Northeast Ethiopia: Unmatched Case-Control Study.
Diarrheal disease is the second leading causes of death among under-five children. Most of the death due to diarrhea is reporting in developing countries. To prevent this highly prevalent problem, identifying the contributing factors across different settings is necessary. Therefore, this study aimed to identify the determinants of acute diarrhea among under-five children in the Northeast part of Ethiopia. An institution-based unmatched case-control study was conducted among 306 under-five children from March to April 2019. A systematic random sampling technique was employed to select study participants. Data were collected by face to face interviews using a pretested structured questionnaire. Data were entered using Epi-info 7 and analyzed with SPSS version 20.0. We applied logistic regression analysis. Those variables with p-value <0.05 were significant determinants of acute diarrhea. Improper child's stool disposal [AOR=4.12; 95% CI (1.25,13.5)], absence of home-based water treatment [AOR=2.85; 95% CI (1.27,6.42)], did not wash hand at critical times [AOR=5.47; 95% CI (1.68,17.8)], did not practice exclusive breastfeed [AOR=3.32; 95% CI (1.21,9.14], unable to get counseling from health professionals [AOR= 3.23; 95%,CI (1.15,13.5)], provide left over food to the child [AOR=2.96; 95% CI (1.19,7.32)], and maternal diarrhea [AOR=6.06; 95% CI (2.42,15.22)] were determinants of acute diarrhea among under five children. Most of the determinants of acute diarrhea could be preventable. Thus, collaborative intervention by emphasizing health education about the importance of personal and environmental hygiene, safe food handling, exclusive breastfeeding practice, and home-based water treatment are essential.


Association between prior-night sleep and next-day fatigue in older adults: a daily diary study.
Fatigue is known as an element of frailty. Sleep problems (e.g., short sleep duration and low sleep quality) can increase fatigue, but the day-to-day relationship between sleep and fatigue has not been studied well in older adults. Using a daily diary method, this study examined the within- and between-person associations between sleep and fatigue in older adults. The study recruited 56 Japanese community dwellers (age: 82-86 years; female: 37.5%). Participants responded to a daily diary questionnaire at the end of each day. Over seven days, time in bed and satisfaction were measured after waking up, whereas fatigue was assessed before going to bed. We included person-level covariates (demographic factors, and physical and mental health) and day-level covariates (time in study, and positive and negative emotions). Multilevel models were estimated to examine within- and between-person associations. At the within-person level, on days following short and long time in bed and days following low levels of sleep satisfaction, individuals felt higher levels of fatigue compared with usual days. At the between-person level, no statistically significant differences in fatigue were observed between individuals with long and short time in bed. The findings suggest that prior-day sleep is associated with next-day fatigue in older adults. Long and short sleep duration and low sleep quality can lead to fatigue. Considering that sleep is a modifiable health behavior, appropriate management of sleep behavior may reduce fatigue.


The expression of SP263 in muscle invasive bladder carcinoma and its relationship with clinicopathological features.
The expression of programmed cell death ligand1 (PDL1) is a research hotspot of immunotherapy. The treatment targeted for its expression has shown effectiveness in many tumors. The aim of the study was to determine PD-L1 expression in urothelial carcinoma (UC) and to compare the PD-L1 expression in muscle invasive bladder carcinoma (MIBC) and upper urinary tract urothelial carcinoma (UTUC). The predictive value of CD8+ tumor-infiltrating lymphocyte (TIL) density for the diagnosis of PD-L1 positivity and the association between CD8+ TIL density and prognosis in MIBC were also explored. Immunohistochemistry (IHC) staining for PD-L1 (SP263), CK5/6, CK20, CD44, and p53 was carried out using a 3D Histech digital scanner to scan and determine CD8+ TIL density. 122 patients received radical cystectomy, and the overall PD-L1 positivity was 34.43% (42/122). PD-L1 positivity in whole sections was higher than in tissue micro-array (TMA) (all P < 0.05). If multiple lesions were detected simultaneously, the number of patients with positive results increased from 42 to 49. The areas under the curve (AUCs) of CD8+ TIL density for the diagnosis of PD-L1 positivity were 0.739, 0.713, and 0.826. Univariate cox regression analysis demonstrated that high CD8+ TIL density and CD8highPDL1+ were protective factors of overall survival (OS), and multivariate cox analyses showed that only CD8+ TIL density was an independent prognostic factor for OS. For UTUC, the overall PD-L1 expression was 40.0% (16/40). Our study results emphasize the importance of detecting PD-L1 expression in multiple tumor lesions from the same patient. In MIBC, CD8+ TIL density could be used as a prognostic marker for predicting the status of PD-L1 expression.


Ultrasmall AGuIX theranostic nanoparticles for vascular-targeted interstitial photodynamic therapy of glioblastoma.
Despite combined treatments, glioblastoma outcome remains poor with frequent local recurrences, indicating that a more efficient and local therapy is needed. In this way, vascular-targeted photodynamic therapy (VTP) could help tumor eradication by destroying its neovessels. In this study, we designed a polysiloxane-based nanoparticle (NP) combining a magnetic resonance imaging (MRI) contrast agent, a photosensitizer (PS) and a new ligand peptide motif (KDKPPR) targeting neuropilin-1 (NRP-1), a receptor overexpressed by angiogenic endothelial cells of the tumor vasculature. This structure achieves the detection of the tumor tissue and its proliferating part by MRI analysis, followed by its treatment by VTP. The photophysical properties of the PS and the peptide affinity for NRP-1 recombinant protein were preserved after the functionalization of NPs. Cellular uptake of NPs by human umbilical vein endothelial cells (HUVEC) was increased twice compared to NPs without the KDKPPR peptide moiety or conjugated with a scramble peptide. NPs induced no cytotoxicity without light exposure but conferred a photocytotoxic effect to cells after photodynamic therapy (PDT). The in vivo selectivity, evaluated using a skinfold chamber model in mice, confirms that the functionalized NPs with KDKPPR peptide moiety were localized in the tumor vessel wall.


Impact of diet on hydrogen sulfide production: implications for gut health.
Excessive hydrogen sulfide (H 2 S) production by the gut microbiota may contribute to the pathogenesis of multiple intestinal diseases, including colon cancer and ulcerative colitis. Therefore, understanding of dietary drivers of H 2 S production has potential implications for nutritional strategies to optimize gut health and treat intestinal diseases. Recent studies support a positive relationship between dietary protein intake and H 2 S production. However, protein rarely exists in isolation in the diet, and dietary fiber intake could reduce H 2 S production in humans and animals, even with ∼30% of calories derived from protein. These findings suggest that increased fiber intake may reduce H 2 S production irrespective of protein intake, enabling the ability to meet the metabolic demands of the illness while supporting gut health. Here we discuss two recent ulcerative colitis diet studies that illustrate this point.


Keeping an eye on serial order: Ocular movements bind space and time.
The present study examined whether traveling through serially-ordered verbal memories exploits overt visuospatial attentional resources. In a three-phase behavioral study, five single-digits were presented sequentially at one spatial location in phase 1, while recognition and verbal recall were tested in phases 2 and 3, respectively. Participants' spontaneous eye movements were registered along with the verbal responses. Results showed that the search and the retrieval of serially-ordered information were mediated by spontaneous ocular movements. Specifically, recognizing middle items of the memorized sequence required longer inspection times and, importantly, a greater involvement of overt attentional resources, than recognizing the serially first-presented item and, to a lesser extent, the last-presented item. Moreover, serial order was found to be spatially encoded from left-to-right, as eye position during vocal responses deviated the more to the right, the later the serial position of the retrieved item in the sequence. These findings suggest that overt spatial attention mediates the scanning of serial order representation.


[Several possible pathogenetic mechanisms of cerebral circulatory disorders].
The author examined the function of the hypothalamic-pituitary-thyroid system (HPTS) in 618 patients with various forms of cerebral circulation disorders and also carried out experiments on 50 rabbits. The results of the clinical-laboratory and experimental studies elicited the role of the HPTS in the pathogenesis of cerebral circulation disorders. HPTS dysfunction was shown to impair the thyroid homeostasis which led to a reduction in the cerebral redox processes, imbalance between the coagulation and anticoagulation systems, and changes in the composition of blood trace elements. All these changes contribute to the development of cerebral circulation disorders.


Thermo-optical behavior of rare-earth-doped low-NA fibers in high power operation.
The influence of the internal temperature gradient in rare-earth-doped low-numerical-aperture fibers on modal properties is analyzed for step-index and photonic crystal fibers. We provide guidelines when a single-mode fiber turns into a multimode fiber and how the mode-field-diameter is affected.


Laser differential confocal lens refractive index measurement.
A new laser differential confocal lens refractive index measurement is proposed, which uses the absolute zero of the differential confocal axial intensity curve to precisely identify the positions of the objective when the measurement pencil is focused on the vertex of the test lens and the reflector with or without the test lens in the measurement light-path, and then uses aberration compensation and ray tracing facet iterative calculation to obtain the refractive index of the test lens, thereby achieving the high-precision noncontact measurement of lens refractive index. The theoretical analyses and preliminary experiments indicate that the accuracy of the approach can reach about 2.5×10(-4).


Cryptic diversity in intestinal protists.
In the past few years our understanding of genetic variation within and between species of intestinal parasitic protists has changed significantly. New species names have been assigned and others have been dropped in response to new data. In this review, I summarise these findings and discuss their implications for future studies. In several cases the findings suggest that caution needs to be exercised to prevent premature conclusions being reached.


Predicted alpha-helix/beta-sheet secondary structures for the zinc-binding motifs of human papillomavirus E7 and E6 proteins by consensus prediction averaging and spectroscopic studies of E7.
The E7 and E6 proteins are the main oncoproteins of human papillomavirus types 16 and 18 (HPV-16 and HPV-18), and possess unknown protein structures. E7 interacts with the cellular tumour-suppressor protein pRB and contains a zinc-binding site with two Cys-Xaa2-Cys motifs spaced 29 or 30 residues apart. E6 interacts with another cellular tumour-suppressor protein p53 and contains two zinc-binding sites, each with two Cys-Xaa2-Cys motifs at a similar spacing of 29 or 30 residues. By using the GOR I/III, Chou-Fasman, SAPIENS and PHD methods, the effectiveness of consensus secondary structure predictions on zinc-finger proteins was first tested with sequences for 160 transcription factors and 72 nuclear hormone receptors. These contain Cys2His2 and Cys2Cys2 zinc-binding regions respectively, and possess known atomic structures. Despite the zinc- and DNA-binding properties of these protein folds, the major alpha-helix structures in both zinc-binding regions were correctly identified. Thus validated, the use of these prediction methods with 47 E7 sequences indicated four well-defined alpha-helix (alpha) and beta-sheet (beta) secondary structure elements in the order beta beta alpha beta in the zinc-binding region of E7 at its C-terminus. The prediction was tested by Fourier transform infrared spectroscopy of recombinant HPV-16 E7 in H2O and 2H2O buffers. Quantitative integration showed that E7 contained similar amounts of alpha-helix and beta-sheet structures, in good agreement with the averaged prediction of alpha-helix and beta-sheet structures in E7 and also with previous circular dichroism studies. Protein fold recognition analyses predicted that the structure of the zinc-binding region in E7 was similar to a beta beta alpha beta motif found in the structure of Protein G. This is consistent with the E7 structure predictions, despite the low sequence similarities with E7. This predicted motif is able to position four Cys residues in proximity to a zinc atom. A model for the zinc-binding motif of E7 was constructed by combining the Protein G coordinates with those for the zinc-binding site in transcription factor TFIIS. Similar analyses for the two zinc-binding motifs in E6 showed that they have different alpha/beta secondary structures from that in E7. When compared with 12 other zinc-binding proteins, these results show that E7 and E6 are predicted to possess novel types of zinc-binding structure.


Increased Gonorrhea Cases - Utah, 2009-2014.
Gonorrhea (caused by infection with Neisseria gonorrhoeae) is the second most commonly reported notifiable disease in the United States (1). Left untreated, gonorrhea is associated with serious long-term adverse health effects, including pelvic inflammatory disease, ectopic pregnancy, and infertility. Infection also facilitates transmission of human immunodeficiency virus (2,3). Effective gonorrhea control relies upon early detection and effective antimicrobial treatment. To assess gonorrhea rate trends in Utah, the Utah Department of Health (UDOH) analyzed Utah National Electronic Disease Surveillance System (UT-NEDSS) data for the state during 2009-2014. After declining during 2009-2011, the statewide gonorrhea rate increased fivefold to 49 cases per 100,000 population in 2014. During 2009-2014, the proportion of cases among women increased from 21% to 39% (decreasing among males from 79% to 61%). Among male patients, the proportion who identified as men who have sex with men (MSM) decreased from 67% to 42%. These demographic changes suggest that increased heterosexual transmission of gonorrhea in Utah might be occurring. Health departments need to work with providers to ensure populations at high risk are being screened and properly treated for gonorrhea. Clinicians need to be aware of increases in the risk for infection among women and non-MSM males when making screening and testing decisions and educate their patients regarding gonorrhea transmission and prevention practices.


The anti-TNF-α antibody infliximab inhibits the expression of fat-transporter-protein FAT/CD36 in a selective hepatic-radiation mouse model.
Previously, we reported a radiation-induced inflammation triggering fat-accumulation through fatty-acid-translocase/cluster of differentiation protein 36 (FAT/CD36) in rat liver. Furthermore, inhibition of radiation-induced FAT/CD36-expression by anti-tumor necrosis factor-α (anti-TNF-α) (infliximab) was shown in vitro. The current study investigates fat-accumulation in a mouse-model of single-dose liver-irradiation (25-Gray) and the effect of anti-TNF-α-therapy on FAT/CD36 gene-expression. Mice livers were selectively irradiated in vivo in presence or absence of infliximab. Serum- and hepatic-triglycerides, mRNA, and protein were analyzed by colorimetric assays, RT-PCR, Immunofluorescence and Western-Blot, respectively. Sudan-staining was used demonstrating fat-accumulation in tissue. In mice livers, early (1-3 h) induction of TNF-α-expression, a pro-inflammatory cytokine, was observed. It was followed by elevated hepatic-triglyceride level (6-12 h), compared to sham-irradiated controls. In contrast, serum-triglyceride level was decreased at these time points. Similar to triglyceride level in mice livers, Sudan staining of liver cryosections showed a quick (6-12 h) increase of fat-droplets after irradiation. Furthermore, expression of fat-transporter-protein FAT/CD36 was increased at protein level caused by radiation or TNF-α. TNF-α-blockage by anti-TNF-α showed an early inhibition of radiation-induced FAT/CD36 expression in mice livers. Immunohistochemistry showed basolateral and cytoplasmic expression of FAT/CD36 in hepatocytes. Moreover, co-localization of FAT/CD36 was detected with α-smooth muscle actin (α-SMA+) cells and F4/80+ macrophages. In summary, hepatic-radiation triggers fat-accumulation in mice livers, involving acute-phase-processes. Accordingly, anti-TNF-α-therapy prevented early radiation-induced expression of FAT/CD36 in vivo.


Patients' assessments of the effectiveness of homeopathic care in Norway: a prospective observational multicentre outcome study.
To evaluate the patient reported effects of homeopathic care 6 months after first consultations. Prospective uncontrolled observational multicentre outcome study. All patients visiting 80 homeopaths all over Norway for the first time in eight different time periods from 1996 to 1998 were approached. Patients wrote down their main complaint and scored its impact on daily living on a 100 mm Visual Analogue Scale (VAS) at the first consultation. Six months later they were asked to score again. The homeopaths recorded treatments given for up to two follow-up consultations. Predefined as a reduction of at least 10 mm in the VAS score between the first consultation and follow-up. Patients 1097 were recruited, 654 completed the follow-up questionnaire. The main complaint improved by at least 10mm on the VAS for 71% (95% confidence interval 67-74%) of patients. The average reduction was 32mm (95% CI 30-35 mm). Fifty-one per cent (95% CI 48-55%) of the patients had an improvement in their general well being of more than 10 mm. The mean reduction in the whole group was 14mm (95% CI 12-16 mm). The proportion of patients using conventional medication reduced from 39% to 16%. Regression analysis showed that lower age and higher baseline score were predictors of better outcome. In this study, seven out of ten patients visiting a Norwegian homeopath reported a meaningful improvement in their main complaint 6 months after the initial consultation.


One-proton catalysis by the alpha-L-arabinofuranosidase III of Monilinia fructigena.
1. Michaelis-Menten parameters for the hydrolysis of p-nitrophenyl alpha-L-arabinofuranoside were measured as a function of pL (pH or pD) in both 1H2O and 2H2O. 2. The variation of both Vmax. and Vmax./Km with pL is sigmoid, the pK governing Vmax. shifting from 6.34 +/- 0.05 in 1H2O to 6.84 +/- 0.07 in 2H2O, and that governing Vmax./Km from 5.89 +/- 0.03 in 1H2O to 6.38 +/- 0.05 in 2H2O. 3. In the plateau regions there is a small inverse solvent isotope effect on Vmax./Km (0.92), and one of 1.45 on Vmax. 4. The variation of Vmax. with isotopic composition is strictly linear, indicating that the isotope effect arises from the transfer of a single proton.


Measles virus breaks through epithelial cell barriers to achieve transmission.
Measles is a highly contagious disease that causes immunosuppression in patients. Measles virus infection has been thought to begin in the respiratory epithelium and then spread to lymphoid tissue. In this issue of the JCI, Leonard et al. provide data to suggest an alternative model of measles virus pathogenesis (see the related article beginning on page 2448). In human primary epithelial cells and rhesus monkeys in vivo, the authors show that initial infection of respiratory epithelium is not necessary for the virus to enter the host but that viral entry into epithelial cells via interaction of the virus with a receptor located on the basolateral side of the epithelium is required for viral shedding into the airway and subsequent transmission.


Lack of short-chain fatty acids and overgrowth of opportunistic pathogens define dysbiosis of neuromyelitis optica spectrum disorders: A Chinese pilot study.
Intestinal microbiota is an important environmental factor in the initiation and progression of autoimmune diseases. However, investigations on the gut microbiome in neuromyelitis optica spectrum disorders (NMOSD) are relatively insufficient, especially for that of the Asia population. To evaluate whether or not the intestinal microbiota of NMOSD patients had specific microbial signatures. Next-generation sequencing and gas chromatography were employed to compare the fecal microbial composition and short-chain fatty acids (SCFAs) spectrum between patients with NMOSD (n = 84) and healthy controls (n = 54). The gut microbial composition of NMOSD distinguished from healthy individuals. Streptococcus, significantly increased in NMOSD, is positively correlated with disease severities (p < 0.05). The use of immunosuppressants results in a decrease of Streptococcus, suggesting that Streptococcus might play a significant role in the pathogenesis of NMOSD. A striking depletion of fecal SCFAs was observed in NMOSD patients (p < 0.0001), with acetate and butyrate showing significantly negative correlation with disease severities (p < 0.05). The fecal organismal structures and SCFAs level of patients with NMOSD were distinctive from healthy individuals. These findings not only could be critical events driving the aberrant immune response responsible for the pathogenesis of these disorders but could also provide suggestions for disease therapy.


Diagnosis of melioidosis by means of an ELISA detecting antibodies toPseudomonas pseudomallei exotoxin. Preliminary assay evaluation.
An ELISA system for the detection of human antibodies toPseudomonas pseudomallei exotoxin is described. Analysis of control sera and sera from patients with culture-positive melioidosis showed that both IgG and IgM antibodies to exotoxin were detectable in patients with melioidosis. This implies that the exotoxin is producedin vivo byP. pseudomallei, and may be involved in the pathogenesis of melioidosis. Furthermore, these rapid and simple assays may prove to be useful for the serodiagnosis of the disease.


Mathematical modeling of influenza A virus dynamics within swine farms and the effects of vaccination.
Influenza A virus infections are widespread in swine herds across the world. Influenza negatively affects swine health and production, and represents a significant threat to public health due to the risk of zoonotic infections. Swine herds can act as reservoirs for potentially pandemic influenza strains. In this study, we develop mathematical models based on experimental data, representing typical breeding and wean-to-finish swine farms. These models are used to explore and describe the dynamics of influenza infection at the farm level, which are at present not well understood. In addition, we use the models to assess the effectiveness of vaccination strategies currently employed by swine producers, testing both homologous and heterologous vaccines. An important finding is that following an influenza outbreak in a breeding herd, our model predicts a persistently high level of infectious piglets. Sensitivity analysis indicates that this finding is robust to changes in both transmission rates and farm size. Vaccination does not eliminate influenza throughout the breeding farm population. In the wean-to-finish herd, influenza infection may persist in the population only if recovered individuals become susceptible to infection again. A homologous vaccine administered to the entire wean-to-finish population after the loss of maternal antibodies eliminates influenza, but a vaccine that only induces partial protection (heterologous vaccine) has little effect on influenza infection levels. Our results have important implications for the control of influenza in swine herds, which is crucial in order to reduce both losses for swine producers and the risk to public health.


[Influence of cattle cord blood fraction below 5 kD on biochemical parameters of blood in experimental chronic stomach ulcer in rats].
Influence of cattle cord blood fraction (below 5 kD) on lipid peroxidation product content and alkaline phosphatase activity-in peripheral blood was studied on the experimental subchronic stomach ulcer model in rats. It has been shown that the fraction administrations normalize thiobarbituric-active product content and alkaline phosphatase activity in blood, which testifies to decreasing inflammatory reaction in the mucous membrane of the stomach. The fraction administrations accelerate the processes of regeneration of the mucous membrane of the stomach up to complete healing of ulcer defects. Cord blood fraction below 5 kD from cattle possesses antiulcer activity which is analogous to the actovegin activity. It has been shown by gel-penetrating chromatography that the pattern of cord blood fraction low molecular substances is different from the actovegin pattern both qualitatively and quantitatively.


Quality of death: assessing the importance placed on end-of-life treatment in the intensive-care unit.
The value of good end-of-life (EOL) care could be underestimated if its effects are assessed using the standard metric of quality-adjusted survival, especially if the time horizon is limited to the duration of the EOL care. This issue is particularly problematic in the intensive-care unit (ICU) where death is frequent, care is difficult, and costs are high. The objectives of this study were to test whether people would trade healthy life expectancy for better EOL care, to understand how much life expectancy they would trade relative to domains of good care, and to determine the association of respondent characteristics to time traded. We used a computerized survey instrument describing hypothetical patient experiences in the ICU used to assess attitudes of a general population sample (n = 104) recruited in Pittsburgh, Pennsylvania. We used life expectancy traded (from a baseline of 80 healthy years followed by a 1-month fatal ICU stay) for improving ICU care in 4 domains: pain and discomfort, daily surroundings, treatment decisions, and family support. Three fourths of respondents (n = 78) were prepared to shorten healthy life for better EOL care. Median time traded in individual domains ranged from 7.2 to 7.7 months overall and 9.6 to 11.4 months when restricted to those willing to trade. Median time traded for improvement in all domains was 8.3 months overall and 24.0 months by those willing to trade. In multivariable analyses, respondents who were older, nonwhite, or had children traded significantly less time, whereas those who did not perceive the ICU to be a caring environment traded more time. Good EOL care is highly valued, both in terms of medical and nonmedical domains, as suggested by previous work and confirmed by our data showing respondents trading quantities of healthy life several times longer than the duration of the EOL period itself. The considerable interperson variation highlights the importance of soliciting individual preferences about EOL care.


Dynamics of surface migration in the weak corrugation regime
We report a systematic study for metal-on-metal surface migration in the weak corrugation regime, i.e., with migration barriers falling below approximately 100 meV. The migration characteristics are elucidated by variable-temperature scanning tunneling microscopy observations in the 50-200 K temperature range, which are analyzed by means of nucleation theory. The results demonstrate that, upon entering the weak corrugation regime, the dynamics of the systems are characterized by increasingly reduced effective preexponential factors, while Arrhenius behavior prevails.


Immune-inducible non-coding RNA molecule lincRNA-IBIN connects immunity and metabolism in Drosophila melanogaster.
Non-coding RNAs have important roles in regulating physiology, including immunity. Here, we performed transcriptome profiling of immune-responsive genes in Drosophila melanogaster during a Gram-positive bacterial infection, concentrating on long non-coding RNA (lncRNA) genes. The gene most highly induced by a Micrococcus luteus infection was CR44404, named Induced by Infection (lincRNA-IBIN). lincRNA-IBIN is induced by both Gram-positive and Gram-negative bacteria in Drosophila adults and parasitoid wasp Leptopilina boulardi in Drosophila larvae, as well as by the activation of the Toll or the Imd pathway in unchallenged flies. We show that upon infection, lincRNA-IBIN is expressed in the fat body, in hemocytes and in the gut, and its expression is regulated by NF-κB signaling and the chromatin modeling brahma complex. In the fat body, overexpression of lincRNA-IBIN affected the expression of Toll pathway -mediated genes. Notably, overexpression of lincRNA-IBIN in unchallenged flies elevated sugar levels in the hemolymph by enhancing the expression of genes important for glucose retrieval. These data show that lncRNA genes play a role in Drosophila immunity and indicate that lincRNA-IBIN acts as a link between innate immune responses and metabolism.


Considerations for the US health-system pharmacist in a world of biosimilars.
As numerous biosimilar products are forecast to enter the US market in the coming years, health-system pharmacists will be faced with novel challenges while incorporating them into clinical practice. The current regulatory approval framework and guidance from the US Food and Drug Administration do not address many real-world scenarios that pharmacists will encounter. We provide an overview of the evolving healthcare landscape shaped by the entry of multiple biosimilars, including for a given reference product, and their impact on the health-system pharmacist with respect to formulary assessment, implementation, and education of various health-system stakeholders, including patients.


Clinicopathologic and gene expression parameters predict liver cancer prognosis.
The prognosis of hepatocellular carcinoma (HCC) varies following surgical resection and the large variation remains largely unexplained. Studies have revealed the ability of clinicopathologic parameters and gene expression to predict HCC prognosis. However, there has been little systematic effort to compare the performance of these two types of predictors or combine them in a comprehensive model. Tumor and adjacent non-tumor liver tissues were collected from 272 ethnic Chinese HCC patients who received curative surgery. We combined clinicopathologic parameters and gene expression data (from both tissue types) in predicting HCC prognosis. Cross-validation and independent studies were employed to assess prediction. HCC prognosis was significantly associated with six clinicopathologic parameters, which can partition the patients into good- and poor-prognosis groups. Within each group, gene expression data further divide patients into distinct prognostic subgroups. Our predictive genes significantly overlap with previously published gene sets predictive of prognosis. Moreover, the predictive genes were enriched for genes that underwent normal-to-tumor gene network transformation. Previously documented liver eSNPs underlying the HCC predictive gene signatures were enriched for SNPs that associated with HCC prognosis, providing support that these genes are involved in key processes of tumorigenesis. When applied individually, clinicopathologic parameters and gene expression offered similar predictive power for HCC prognosis. In contrast, a combination of the two types of data dramatically improved the power to predict HCC prognosis. Our results also provided a framework for understanding the impact of gene expression on the processes of tumorigenesis and clinical outcome.


Models to explore genetics of human aging.
Genetic studies have bestowed insight into the biological mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular and genetic epidemiology provide tools to explore the genetic sources of the variability in biological aging in humans. To be successful, the genetic study of a complex condition such as aging requires the clear definition of essential traits that can characterize the aging process phenotypically. Phenotypes of human aging have long relied on mortality rate or exceptional longevity. Genome-wide association studies (GWAS) have been shown to present an unbiased approach to the identification of new candidate genes for human diseases. The GWAS approach can also be used for positive health phenotypes such as longevity or a delay in age-related chronic disease, as well as for other age related changes such as loss of telomere length or lens transparency. Sequencing, either in targeted regions or across the whole genome can further identify rare variation that may contribute to the biological aging mechanisms. To date, the results of the GWAS for longevity are rather disappointing, possibly in part due to the small number of individuals with GWAS data who have reached advanced old age.Human aging phenotypes are needed that can be assessed prior to death, and should be both heritable and validated as predictors of longevity. Potentially, phenotypes that focus on "successful" or "healthy" aging will be more powerful as they can be measured in large numbers of people and also are clinically relevant.We postulate that construction of an integrated phenotype of aging can be achieved capitalizing on multiple traits that may have weak correlations, but a shared underlying genetic architecture. This is based on a hypothesis that convergent results from multiple individual aging-related traits will point out the pleiotropic signals responsible for the overall rate of aging of the organism. An approach would be to investigate traits that are linked to the state of many vital functions, disability, and ultimately survival rates, to identify common biological pathways that govern aging processes in humans. New composite aging phenotypes must be validated by predicting all-cause mortality, major chronic disease and disability late in life.


[Choice of components and a method of anesthesia in geriatric cancer patients with high cardiovascular risk].
Investigations were made at surgical treatment stages in 102 cancer patients (mean age 72 +/- 5.8 years) at high cardiovascular risk, who received continuous therapy that reduced heart rate and blood pressure, in order to compensate for the course of coronary heart disease and arterial hypertension. The time course of changes in the major circulatory and metabolic parameters was analyzed in patients during operations on the abdomen and small pelvis while using three different multimodal anesthetic techniques (general intravenous anesthesia-based diazepam, propofol, fentanyl, ketamine; sevofluorane-based inhalational; combined epidural and intravenous one). The advantages and limitations of the above methods were shown in patients on cardio- and vasotropic therapies. Correcting modes (transesophageal atrial pacing, morning-dose drug withdrawal) for its possible related bradycardiac and hypotensive disorders, which reduce a risk of perioperative cardiovascular complications, are set forth.


Epigenetic hierarchy within the MAGEA1 cancer-germline gene: promoter DNA methylation dictates local histone modifications.
Gene MAGEA1 belongs to a group of human germline-specific genes that rely on DNA methylation for repression in somatic tissues. Many of these genes, termed cancer-germline (CG) genes, become demethylated and activated in a wide variety of tumors, where they encode tumor-specific antigens. The process leading to DNA demethylation of CG genes in tumors remains unclear. Previous data suggested that histone acetylation might be involved. Here, we investigated the relative contribution of DNA methylation and histone acetylation in the epigenetic regulation of gene MAGEA1. We show that MAGEA1 DNA hypomethylation in expressing melanoma cells is indeed correlated with local increases in histone H3 acetylation (H3ac). However, when MAGEA1-negative cells were exposed to a histone deacetylase inhibitor (TSA), we observed only short-term activation of the gene and detected no demethylation of its promoter. As a more sensitive assay, we used a cell clone harboring a methylated MAGEA1/hph construct, which confers resistance to hygromycin upon stable re-activation. TSA induced only transient de-repression of the transgene, and did not lead to the emergence of hygromycin-resistant cells. In striking contrast, transient depletion of DNA-methyltransferase-1 in the reporter cell clone gave rise to a hygromycin-resistant population, in which the re-activated MAGEA1/hph transgene displayed not only marked DNA hypomethylation, but also significant reversal of histone marks, including gains in H3ac and H3K4me2, and losses of H3K9me2. Collectively, our results indicate that DNA methylation has a dominant role in the epigenetic hierarchy governing MAGEA1 expression.


Dietary n-3 fatty acids affect mRNA level of brown adipose tissue uncoupling protein 1, and white adipose tissue leptin and glucose transporter 4 in the rat.
We examined the effect of dietary fats rich in n-3 polyunsaturated fatty acids (PUFA) on mRNA levels in white and brown adipose tissues in rats. Four groups of rats were fed on a low-fat diet (20 g safflower oil/kg) or a high-fat diet (200 g/kg) containing safflower oil, which is rich in n-6 PUFA (linoleic acid), or perilla (alpha-linolenic acid) or fish oil (eicosapentaenoic and docosahexaenoic acids), both of which are rich in n-3 PUFA, for 21 d. Energy intake was higher in rats fed on a high-safflower-oil diet than in those fed on low-fat or high-fish-oil diet, but no other significant differences were detected among the groups. Perirenal white adipose tissue weight was higher and epididymal white adipose tissue weight tended to be higher in rats fed on a high-safflower-oil diet than in those fed on a low-fat diet. However, high-fat diets rich in n-3 PUFA, compared to a low-fat diet, did not increase the white adipose tissue mass. High-fat diets relative to a low-fat diet increased brown adipose tissue uncoupling protein 1 mRNA level. The increases were greater with fats rich in n-3 PUFA than with n-6 PUFA. A high-safflower-oil diet, compared to a low-fat diet, doubled the leptin mRNA level in white adipose tissue. However, high-fat diets rich in n-3 PUFA failed to increase it. Compared to a low-fat diet, high-fat diets down-regulated the glucose transporter 4 mRNA level in white adipose tissue. However, the decreases were attenuated with high-fat diets rich in n-3 PUFA. It is suggested that the alterations in gene expression in adipose tissue contribute to the physiological activities of n-3 PUFA in preventing body fat accumulation and in regulating glucose metabolism in rats.


Cold War Legacy in Public and Private Health Spending in Europe.
Cold War Era (1946-1991) was marked by the presence of two distinctively different economic systems, namely the free-market (The Western ones) and central-planned (The Eastern ones) economies. The main goal of this study refers to the exploration of development pathways of Public and Private Health Expenditure in all of the countries of the European WHO Region. Based on the availability of fully comparable data from the National Health Accounts system, we adopted the 1995-2014 time horizon. All countries were divided into two groups: those defined in 1989 as free market economies and those defined as centrally-planned economies. We observed six major health expenditures: Total Health Expenditure (% of GDP), Total Health Expenditure (PPP unit), General government expenditure on health (PPP), Private expenditure on health (PPP), Social security funds (PPP) and Out-of-pocket expenditure (PPP). All of the numerical values used refer exclusively to per capita health spending. In a time-window from the middle of the 1990s towards recent years, total health expenditure was rising fast in both groups of countries. Expenditure on health % of GDP in both group of countries increased over time with the increase in the Free-market economies seen to be more rapid. The steeper level of total expenditure on health for the Free-market as of 1989 market economies, is due mainly to a steep increase in both the government and private expenditure on health relative to spending by centrally-planned economies as of the same date, with the out-of-pocket expenditure and the social security funds in the same market economies category following the same steepness. Variety of governments were leading Eastern European countries into their transitional health care reforms. We may confirm clear presence of obvious divergent upward trends in total governmental and private health expenditures between these two groups of countries over the past two decades. The degree of challenge to the fiscal sustainability of these health systems will have to be judged for each single nation, in line with its own local circumstances and perspectives.


[Morphological marker of tumor progression in laryngeal cancer].
Dynamic observation of 32 patients with laryngeal cancer, treated with radiotherapy and combination therapy, was performed using diagnostic technology "Litos-system", including the definition of serum morphotypes by marginal dehydration of biological fluids. In nine of them, on the background of the treatment, there was continued growth of the tumor. In the blood serum seven of nine patients had special microspheroliths, characterized by the presence of "wavy" structures. Such "wavy" microspheroliths could be seen as a harbinger of the continued growth of the tumor, because after their appearance there were detected signs of clinical progression. Apparently, the appearance of mentioned "wavy" structures in the patient's blood is a result of release into the blood of qualitatively new macromolecules produced by a clone of malignant tumor cells.


Third Year Medical School Students' Experiences of Revealing Patients' Stories through Role Playing.
Studying medicine is hard and it takes longer time compared to other majors. In addition, medical students find medical education boring. It is now necessary to turn medical education into an enjoyable and interesting way. The aim of this study is to evaluate the impact of an educational program related to how to learn taking medical history and how an effective patient-doctor interview should be. The program is structured in various scenarios, on the students learning skills, by the "role playing" method. A scenario prepared by the lecturer was employed in this study. While one of the students acted in a doctor role, the other one played in the role of patient's relative. The lecturer always played in the role of patient. After performing the role playing, students' written and oral feedbacks were gathered. Data were analysed by using SPSS 20.0 program. A total of 470 feedbacks (51.3% were given by the female students) were taken from the students. Thirty-three volunteer students, nineteen of them were male, took part in the role playing. In the patient-doctor interview, the field that students were best were greeting the patients and dealing only with patients during the examination. The mean scores were 3.81±0.95 and 3.79±0.94 respectively. The ability to "summarize" and to "address the patient with his/her name" had the lowest scores; the mean scores of the students in these areas were 2.94±1.11 and 2.70±1.31, respectively. Medical education is a long and tough process. Therefore, it should be interesting, attention getting and cheerful. Role playing can be effective in meeting that need.


Inhibition of endothelin-B receptor signaling synergizes with MAPK pathway inhibitors in BRAF mutated melanoma.
The clinical benefit of MAPK pathway inhibition in melanoma patients carrying BRAF mutations is temporal. After the initial response to treatment, the majority of tumors will develop resistance and patients will relapse. Here we demonstrate that the endothelin-endothelin receptor B (ETBR) signaling pathway confers resistance to MAPK pathway inhibitors in BRAF mutated melanoma. MAPK blockade, in addition to being anti-proliferative, induces a phenotypic change which is characterized by increased expression of melanocyte-specific genes including ETBR. In the presence of MAPK inhibitors, activation of ETBR by endothelin enables the sustained proliferation of melanoma cells. In mouse models of melanoma, including patient-derived xenograft models, concurrent inhibition of the MAPK pathway and ETBR signaling resulted in a more effective anti-tumor response compared to MAPK pathway inhibition alone. The combination treatment significantly reduced tumor growth and prolonged survival compared to therapies with MAPK pathway inhibitors alone. The phosphoproteomic analysis revealed that ETBR signaling did not induce resistance towards MAPK pathway inhibitors by restoring MAPK activity, but instead via multiple alternative signaling pathways downstream of the small G proteins GNAq/11. Together these data indicate that a combination of MAPK pathway inhibitors with ETBR antagonists could have a synergistically beneficial effect in melanoma patients with hyperactivated MAPK signaling pathways.


Improving the clinical assessment of consciousness with advances in electrophysiological and neuroimaging techniques.
In clinical neurology, a comprehensive understanding of consciousness has been regarded as an abstract concept--best left to philosophers. However, times are changing and the need to clinically assess consciousness is increasingly becoming a real-world, practical challenge. Current methods for evaluating altered levels of consciousness are highly reliant on either behavioural measures or anatomical imaging. While these methods have some utility, estimates of misdiagnosis are worrisome (as high as 43%)--clearly this is a major clinical problem. The solution must involve objective, physiologically based measures that do not rely on behaviour. This paper reviews recent advances in physiologically based measures that enable better evaluation of consciousness states (coma, vegetative state, minimally conscious state, and locked in syndrome). Based on the evidence to-date, electroencephalographic and neuroimaging based assessments of consciousness provide valuable information for evaluation of residual function, formation of differential diagnoses, and estimation of prognosis.


A communication server for telemedicine applications.
The telemedicine applications, in some cases, need multipoint-to-multipoint communication. To meet the requirement of telemedicine communication, the development of a medical communication server is proposed in this paper. To make a working, as well as cost-effective, communication platform for the telemedicine applications, a specially designed communication server model is proposed in this work. This server is able to provide an effective multipoint-to-multipoint communication service for any level applications in telemedicine. The implementation program of this server is developed in a Windows'95 environment by using a winsocket. The trial application testing in a telemonitoring system is also presented to demonstrate the feasibility of taking such a structure with the server. By using the architecture of such a communication server in telemedicine applications, the multipoint-to-multipoint communication is easily managed and the communication processes are simplified and well controlled by the server.


Regulation of membrane cholecystokinin-2 receptor by agonists enables classification of partial agonists as biased agonists.
Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at understanding the molecular mechanism by which pharmacological compounds regulate their presence at the cell surface is of paramount importance. In this context, using confocal microscopy and bioluminescence resonance energy transfer, we have investigated internalization and intracellular trafficking of the cholecystokinin-2 receptor (CCK2R) in response to both natural and synthetic ligands with different pharmacological features. We found that CCK and gastrin, which are full agonists on CCK2R-induced inositol phosphate production, rapidly and abundantly stimulate internalization. Internalized CCK2R did not rapidly recycle to plasma membrane but instead was directed to late endosomes/lysosomes. CCK2R endocytosis involves clathrin-coated pits and dynamin and high affinity and prolonged binding of β-arrestin1 or -2. Partial agonists and antagonists on CCK2R-induced inositol phosphate formation and ERK1/2 phosphorylation did not stimulate CCK2R internalization or β-arrestin recruitment to the CCK2R but blocked full agonist-induced internalization and β-arrestin recruitment. The extreme C-terminal region of the CCK2R (and more precisely phosphorylatable residues Ser(437)-Xaa(438)-Thr(439)-Thr(440)-Xaa(441)-Ser(442)-Thr(443)) were critical for β-arrestin recruitment. However, this region and β-arrestins were dispensable for CCK2R internalization. In conclusion, this study allowed us to classify the human CCK2R as a member of class B G-protein-coupled receptors with regard to its endocytosis features and identified biased agonists of the CCK2R. These new important insights will allow us to investigate the role of internalized CCK2R·β-arrestin complexes in cancers expressing this receptor and to develop new diagnosis and therapeutic strategies targeting this receptor.


Investigations into the Biosynthesis, Regulation, and Self-Resistance of Toxoflavin in Pseudomonas protegens Pf-5.
Pseudomonas spp. are prolific producers of natural products from many structural classes. Here we show that the soil bacterium Pseudomonas protegens Pf-5 is capable of producing trace levels of the triazine natural product toxoflavin (1) under microaerobic conditions. We evaluated toxoflavin production by derivatives of Pf-5 with deletions in specific biosynthesis genes, which led us to propose a revised biosynthetic pathway for toxoflavin that shares the first two steps with riboflavin biosynthesis. We also report that toxM, which is not present in the well-characterized cluster of Burkholderia glumae, encodes a monooxygenase that degrades toxoflavin. The toxoflavin degradation product of ToxM is identical to that of TflA, the toxoflavin lyase from Paenibacillus polymyxa. Toxoflavin production by P. protegens causes inhibition of several plant-pathogenic bacteria, and introduction of toxM into the toxoflavin-sensitive strain Pseudomonas syringae DC3000 results in resistance to toxoflavin.


Genes encoding ribosomal proteins Rps0A/B of Saccharomyces cerevisiae interact with TOM1 mutants defective in ribosome synthesis.
The Saccharomyces cerevisiae RPS0A/B genes encode proteins of the 40S ribosomal subunit that are required for the maturation of 18S rRNA. We show here that the RPS0 genes interact genetically with TOM1. TOM1 encodes a member of the hect-domain-containing E3 ubiquitin-protein ligase family that is required for growth at elevated temperatures. Mutant alleles of the RPS0 and TOM1 genes have synergistic effects on cell growth at temperatures permissive for TOM1 mutants. Moreover, the growth arrest of TOM1 mutants at elevated temperatures is partially suppressed by overexpression of RPS0A/B. Strains with mutant alleles of TOM1 are defective in multiple steps in rRNA processing, and interactions between RPS0A/B and TOM1 stem, in part, from their roles in the maturation of ribosomal subunits. Ribosome synthesis is therefore included among the cellular processes governed by members of the hect-domain-containing E3 ubiquitin-protein ligase family.


Transjugular biopsy of the liver.
Percutaneous liver biopsy is the procedure of choice for most patients because of its simplicity and the high percentage of adequate biopsies obtained. It is a bedside procedure that does not require specialized equipment or the services of a highly trained angiographer. Nevertheless, complications are not uncommon unless strict contraindications are observed. It is usually recommended that patients be excluded who present with ascites, a prothrombin time less than 50%, a partial thromboplastin time greater than 10 s, or a platelet count less than 50 000. Mahal et al (1979) cite lack of attention to the contraindications as the most important factor in 22 bleeding episodes which occurred following 3800 percutaneous biopsies (0.7%). It is these contraindications that are the main indication for transjugular biopsy. Despite the highly selective nature of the patients who have undergone transjugular biopsy, the frequency of post-biopsy bleeding is only 0.35% and of death 0.13% (Table 1). These figures include the earliest experiences with this technique and can be expected to improve with increased experience and the development of new instruments that make the procedure safer and easier. Transjugular liver biopsy should be an essential procedure in every hospital that is involved in treating patients with liver disease. Unfortunately, although Lebrec et al (1982) estimated that approximately 30% of patients are rejected for percutaneous biopsy because of the presence of contraindications, relatively few centres have adopted this technique. This may be in part due to the reluctance of clinicians to subject their patients to a procedure they perceive as stressful, although a study by Poynard and Lebrec (1982) showed patients rated transjugular biopsy as less painful and inconvenient than percutaneous biopsy.


The relationship between cardiac output and posthyperventilation hyperpnoea in patients with essential hypertension.
Posthyperventilation hyperpnoea (PHVH) is the progressive decline in minute ventilation (V'E) that follows abrupt cessation of voluntary hyperventilation. It has been hypothesized that the increase in cardiac output (CO) during hyperventilation could contribute to the duration of PHVH. This hypothesis was tested by measuring the duration of PHVH in patients with essential hypertension, in whom the increase in CO as a result of various stimuli is less pronounced. Twenty male hypertensives (mean arterial blood pressure+/-SEM: 178/ 107+/-3/1 mmHg), and 12 age-matched male healthy subjects were studied. The study consisted of three periods: control (5 min), voluntary hyperventilation (2 min), and recovery (3 min). V'E, CO, end-tidal CO2 and O2 tensions were measured, and the time constant (tau) of the V'E decay during recovery calculated. The V'E decay was faster in hypertensives (tau: 0-8.4 s) than in healthy subjects (tau: 12-59 s; p<0.01). During voluntary hyperventilation, CO increased to a lesser extent in hypertensives (6.8+0.7 L.min(-1)) than in healthy subjects (12.9+/-1.1 L.min(-1); p<0.01). In hypertensives, changes in CO during voluntary hyperventilation were significantly related to tau (r=0.646; n=20; p=0.002). The less pronounced rise in cardiac output during hyperventilation in hypertensives could account for the shorter duration of posthyperventilation hyperpnoea.


UPL-SFDA: Uncertainty-Aware Pseudo Label Guided Source-Free Domain Adaptation for Medical Image Segmentation.
Domain Adaptation (DA) is important for deep learning-based medical image segmentation models to deal with testing images from a new target domain. As the source-domain data are usually unavailable when a trained model is deployed at a new center, Source-Free Domain Adaptation (SFDA) is appealing for data and annotation-efficient adaptation to the target domain. However, existing SFDA methods have a limited performance due to lack of sufficient supervision with source-domain images unavailable and target-domain images unlabeled. We propose a novel Uncertainty-aware Pseudo Label guided (UPL) SFDA method for medical image segmentation. Specifically, we propose Target Domain Growing (TDG) to enhance the diversity of predictions in the target domain by duplicating the pre-trained model's prediction head multiple times with perturbations. The different predictions in these duplicated heads are used to obtain pseudo labels for unlabeled target-domain images and their uncertainty to identify reliable pseudo labels. We also propose a Twice Forward pass Supervision (TFS) strategy that uses reliable pseudo labels obtained in one forward pass to supervise predictions in the next forward pass. The adaptation is further regularized by a mean prediction-based entropy minimization term that encourages confident and consistent results in different prediction heads. UPL-SFDA was validated with a multi-site heart MRI segmentation dataset, a cross-modality fetal brain segmentation dataset, and a 3D fetal tissue segmentation dataset. It improved the average Dice by 5.54, 5.01 and 6.89 percentage points for the three tasks compared with the baseline, respectively, and outperformed several state-of-the-art SFDA methods.


Differentially DNA methylation changes induced in vitro by traffic-derived nanoparticulate matter.
The cytotoxicity, apoptosis, reactive oxygen species (ROS) and DNA damage induced by the commercial diesel exhaust particulate matter (PM) (SRM2975) with concentrations ranging from 0.1 μg mL-1 to 20 μg mL-1 were assessed in human umbilical vein endothelial cells (HUVECs) in vitro. An epigenetics-wide investigation of DNA methylation profiles was also performed using a new methylation beadchip (Illumina 850 K) to identify the health effects of traffic-derived nanoparticulate matter (nPM) with a concentration of 20 μg mL-1. By characterising its physical and chemical properties, we found that SRM2975 is a highly disordered graphitic structure material with a nanometer dimension and a large surface area. Low levels of traffic-derived nPM (≤10 μg mL-1) induced cell apoptosis and DNA damage as well as increased intracellular ROS levels (p < 0.001). The HUVECs showed a significantly decreased cell viability following their exposure to traffic-derived nPM with a concentration of 20 μg mL-1 (p < 0.001). A total of 149 significant differential methylated probes between the control and traffic-derived nPM treated-cells were identified, among which 86.6% were hypermethylated. A gene ontology (GO) enrichment analysis of differential methylated genes reported that the majority of the enriched GO terms were related to calcium ion and heart muscle, and further Kyoto encyclopaedia of genes and genomes (KEGG) pathway analysis indicated that the top three enriched pathways were involved in three common subtypes of cardiomyopathy. Overall, these results demonstrated that traffic-derived nPM could induce cytotoxic effects and demonstrate robust associations with cardiomyopathy though differential DNA methylation as well as the physiologic process of ROS, oxidative stress, inflammation, cell death and calcium ion channel.


Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo.
Perfluorooctanesulfonate (PFOS) is a well-known contaminant in the environment and it has shown to disrupt multiple biological pathways, particularly those related with lipid metabolism. In this study, we have studied the impact of in ovo exposure to PFOS on lipid metabolism in livers in developing chicken embryos using lipidomics for detailed characterization of the liver lipidome. We used an avian model (Gallus gallus domesticus) for in ovo treatment at two levels of PFOS. The lipid profile of the liver of the embryo was investigated by ultra-high performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry and by gas chromatography mass spectrometry. Over 170 lipids were identified, covering phospholipids, ceramides, di- and triacylglycerols, cholesterol esters and fatty acid composition of the lipids. The PFOS exposure caused dose dependent changes in the lipid levels, which included upregulation of specific phospholipids associated with the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, triacylglycerols with low carbon number and double bond count as well as of lipotoxic ceramides and diacylglycerols. Our data suggest that at lower levels of exposure, mitochondrial fatty acid β-oxidation is suppressed while the peroxisomal fatty acid β -oxidation is increased. At higher doses, however, both β -oxidation pathways are upregulated.


Development of Mefloquine-Based Bifunctional Secondary Amine Organocatalysts for Enantioselective Michael and Friedel-Crafts Reactions.
The chiral framework based on 11-aminomefloquine has been utilized for the first time to construct bifunctional organocatalysts. These catalysts demonstrate high enantioselectivity in both Michael additions and Friedel-Crafts reactions across a variety of substrates, achieving up to >99% ee. The distinctive feature is the incorporation of a secondary amine group, offering unique tight hydrogen-bonding capabilities in the protonated state, as supported by DFT computation. The diversity of these organocatalysts suggests their broad applicability across multiple reaction classes.


Social barriers to a theoretical neuroscience.
Social rather than scientific barriers are impeding neuroscience theory. There are plenty of experimental data and mathematical methods to develop a rigorous, mathematical theory in neuroscience. However, structural mathematical efforts are being suffocated by the requirement to produce numbers immediately. Also theoretical development is tied too closely to one experimental group. The social barriers can be addressed by: (1) judging theory by structural accuracy rather than numerical output; (2) recognizing mathematical theory (not just computational modeling) as a method for producing insight into neurobiological phenomena; (3) funding fundamental theoretical neuroscience and (4) recognizing theoretical neuroscientists as neuroscientists.


Globally altered structural brain network topology in grapheme-color synesthesia.
Synesthesia is a perceptual phenomenon in which stimuli in one particular modality elicit a sensation within the same or another sensory modality (e.g., specific graphemes evoke the perception of particular colors). Grapheme-color synesthesia (GCS) has been proposed to arise from abnormal local cross-activation between grapheme and color areas because of their hyperconnectivity. Recently published studies did not confirm such a hyperconnectivity, although morphometric alterations were found in occipitotemporal, parietal, and frontal regions of synesthetes. We used magnetic resonance imaging surface-based morphometry and graph-theoretical network analyses to investigate the topology of structural brain networks in 24 synesthetes and 24 nonsynesthetes. Connectivity matrices were derived from region-wise cortical thickness correlations of 2366 different cortical parcellations across the whole cortex and from 154 more common brain divisions as well. Compared with nonsynesthetes, synesthetes revealed a globally altered structural network topology as reflected by reduced small-worldness, increased clustering, increased degree, and decreased betweenness centrality. Connectivity of the fusiform gyrus (FuG) and intraparietal sulcus (IPS) was changed as well. Hierarchical modularity analysis revealed increased intramodular and intermodular connectivity of the IPS in GCS. However, connectivity differences in the FuG and IPS showed a low specificity because of global changes. We provide first evidence that GCS is rooted in a reduced small-world network organization that is driven by increased clustering suggesting global hyperconnectivity within the synesthetes' brain. Connectivity alterations were widespread and not restricted to the FuG and IPS. Therefore, synesthetic experience might be only one phenotypic manifestation of the globally altered network architecture in GCS.


Current use of parenteral nutrition in a pediatric hospital. Comparison to the practise 8 years ago.
Parenteral nutrition (PN) has become a mainstay in the treatment of critically ill children, and in the management of extremely premature newborns. We analyse the changes in the profile of pediatric PN in our institution during the last decade. The clinical record of all patients under 16 who received PN in 1994 and 2002 were reviewed. Epidemiological data as well as composition of the solutions were recorded. Student t test and Chi-square were used for comparisons as appropriate. p value < 0.05 was considered as statistically significant. 194 patients received PN in 1994 (123 neonates and 71 children); 186 in 2002 (112 neonates and 74 children). The percentage of inpatients who received PN was 10.7% in 1994 vs 3.7% in 2002 in neonates; 1% in 1994 vs 1.3% in 2002, in infants and children. Gastrointestinal surgery in infants and children and extreme prematurity in newborns were the most frequent indication. All neonates received tailored PN solutions while it was standardised in almost 60% of children. Internal jugular vein in children and peripherally inserted central venous catheters in neonates were the most usual vascular access. Length of PN was 10 +/- 8.7 days in 1994 vs 9.2 +/- 8.2 in 2002 in neonates; 15.2 +/- 14.8 days in 1994 vs 11.0 +/- 14.9 in 2002 in infants and children. 21% of the children presented at least one complication due to PN. There have been very few changes in the use as well as in the profile of the PN practise during the last decade. Gastrointestinal surgery and prematurity were the most frequent indications.


Biphoton manipulation with a fiber-based pulse shaper.
We demonstrate spectral shaping of entangled photons in the telecom band with a programmable, fiber-based optical filter. The fine-resolution spectral control permits implementation of length-40 Hadamard codes, through which we are able to verify frequency anticorrelation with a 20-fold increase in total counts over that permitted by the equivalent pair of monochromators at the same input flux. By programming the complex spectral transmission function corresponding to a Mach-Zehnder interferometer, we also construct variations on Franson interferometers that are free from mechanical instabilities, demonstrating spectral phase independence in the slow-detector limit, in which all temporal features are unobservable. Our configuration furnishes a single, compact arrangement for manipulating telecom biphotons and characterizing their quality.


Tumor Acidity/NIR Controlled Interaction of Transformable Nanoparticle with Biological Systems for Cancer Therapy.
Precisely controlling the interaction of nanoparticles with biological systems (nanobio interactions) from the injection site to biological targets shows great potential for biomedical applications. Inspired by the ability of nanoparticles to alter their physicochemical properties according to different stimuli, we explored the tumor acidity and near-infrared (NIR) light activated transformable nanoparticle DATAT-NPIR&DOX. This nanoparticle consists of a tumor acidity-activated TAT [the TAT lysine residues' amines was modified with 2,3-dimethylmaleic anhydride (DA)], a flexible chain polyphosphoester core coencapsulated a NIR dye IR-780, and DOX (doxorubicin). The physicochemical properties of the nanoparticle can be controlled in a stepwise fashion using tumor acidity and NIR light, resulting in adjustable nanobio interactions. The resulting transformable nanoparticle DATAT-NPIR&DOX efficiently avoids the interaction with mononuclear phagocyte system (MPS) ("stealth" state) due to the masking of the TAT peptide during blood circulation. Once it has accumulated in the tumor tissues, DATAT-NPIR&DOX is reactivated by tumor acidity and transformed into the "recognize" state in order to promote interaction with tumor cells and enhance cellular internalization. Then, this nanoparticle is transformed into "attack" state under NIR irradiation, achieving the supersensitive DOX release from the flexible chain polyphosphoester core in order to increase the DOX-DNA interaction. This concept provides new avenues for the creation of transformable drug delivery systems that have the ability to control nanobio interactions.


'When he's up there he's just happy and content': Parents' perceptions of therapeutic horseback riding.
There is limited global and South African research on parents' perceptions of therapeutic horseback riding (THR), as well as their perceptions of the effect of the activity on their children with disabilities. To explore and describe parents' perceptions and experiences of THR as an activity for their children with disabilities. Twelve parents whose children attend THR lessons at the South African Riding for the Disabled Association in Cape Town were asked to participate in a semi-structured interview. The qualitative data obtained from the interviews were first transcribed and then analysed using thematic analysis to establish parents' perceptions of the THR activity. The main themes that emerged included parental perceived effects of THR on children, parents' personal experiences of the services, and parents' perceived reasons for improvements in the children. The participating parents indicated that THR had had a positive psychological, social and physical effect both on the children participating in the riding, as well as on the parents themselves. According to parents, THR plays an important role in the lives of children with various disabilities and in the lives of their parents. The results of the study address the gap in the literature regarding parents' perceptions of THR.


Nucleotide sequence of a portion of the Autographa californica nuclear polyhedrosis virus genome containing the EcoRI site-rich region (hr5) and an open reading frame just 5' of the p10 gene.
The nucleotide sequence of a 1587 bp region lying within the HindIII-Q fragment of Autographa californica multiple nucleocapsid nuclear polyhedrosis virus (AcMNPV) DNA has been determined. It begins in the EcoRI-S-EcoRI-X region, continues to the HindIII-P/Q boundary and contains an open reading frame that codes for a polypeptide of 240 amino acids (p26). This open reading frame is also included in the 1100 and 1500 base transcripts previously mapped to this region. The sequence reveals that the 5' ends of the 1100 and 1500 base transcripts are located 20 bp downstream from the end of a putative TATA box (TAATTAAAT) and 19 bp upstream from the translation start codon (ATG) of the p26 open reading frame. The translation termination codon (TAA) falls in the immediate 5' flanking region of the major late p10 gene of AcMNPV, 3 bp downstream from the putative TATA box. The probable polyadenylation site for the 1100 base transcript lies 23 bp downstream from the cap site for the 750 and 2500 base transcripts encoding the p10 protein. The 5' flanking region of the p26 open reading frame contains the EcoRI site-rich region, hr5, whose sequence is included here. The EcoRI site-rich region, hr5, consists of six imperfect tandem repeats of a sequence that includes the EcoRI recognition site. These direct repeats also include many inverted repeats.


The Multifaceted Roles of B Cells in the Thymus: From Immune Tolerance to Autoimmunity.
The thymus is home to a significant number of resident B cells which possess several unique characteristics regarding their origin, phenotype and function. Evidence shows that they originate both from precursors that mature intrathymically and as the entry of recirculating mature B cells. Under steady-state conditions they exhibit hallmark signatures of activated B cells, undergo immunoglobulin class-switch, and express the Aire transcription factor. These features are imprinted within the thymus and enable B cells to act as specialized antigen-presenting cells in the thymic medulla that contribute negative selection of self-reactive T cells. Though, most studies have focused on B cells located in the medulla, a second contingent of B cells is also present in non-epithelial perivascular spaces of the thymus. This latter group of B cells, which includes memory B cells and plasma cells, is not readily detected in the thymus of infants or young mice but gradually accumulates during normal aging. Remarkably, in many autoimmune diseases the thymus suffers severe structural atrophy and infiltration of B cells in the perivascular spaces, which organize into follicles similar to those typically found in secondary lymphoid organs. This review provides an overview of the pathways involved in thymic B cell origin and presents an integrated view of both thymic medullary and perivascular B cells and their respective physiological and pathological roles in central tolerance and autoimmune diseases.