The cytoplasmic domain of the polymeric immunoglobulin receptor contains two internalization signals that are distinct from its basolateral sorting signal.
The C-terminal cytoplasmic domain of the polymeric immunoglobulin receptor (pIgR) contains two tyrosine residues, Tyr668 and Tyr734. Previous work identifying Tyr734 as a critical residue in the endocytosis of the pIgR in Madin-Darby canine kidney (MDCK) cells also suggested that a second functional internalization signal was present (Breitfeld, P. P., Casanova, J. E., McKinnon, W. C., and Mostov, K. E. (1990) J. Biol. Chem. 265, 13750-13757). To test this hypothesis, Tyr668 and Tyr734 were mutated singly or together by oligonucleotide-directed mutagenesis of pIgR cDNA, and the mutants were expressed in MDCK cells. The amount of ligand internalized within 5 min from the basolateral membrane by the pIgR in which cytoplasmic tyrosines were mutated separately to Cys668 or Ser734 or together to Cys668, Ser734 was 58, 39, and 20%, respectively, of the internalized by the wild-type pIgR. The cytoplasmic and transmembrane domains of the pIgR, when joined to the external domain of the influenza virus hemagglutinin, retained the capacity to mediate rapid internalization. As with the full-length pIgR, mutation of either tyrosine in the chimera resulted in impairment of endocytosis, with mutation of Tyr734 having a significantly greater effect than mutation on Tyr668 on the initial rate of endocytosis (3 and 44% of control values, respectively). However, unlike the full-length pIgR, mutation of both tyrosines together in the chimera did not reduce internalization further. The two tyrosines in the cytoplasmic sequence of the pIgR, although widely separated in the linear amino acid sequence, both contribute to internalization of the protein, suggesting that both can function as internalization signals. In addition, the correlation between endocytosis and basolateral targeting of the pIgR in MDCK cells was investigated. Neither tyrosine of the cytoplasmic domain was necessary for basolateral targeting of the pIgR.


The effects of age, authority, and gender on perceptions of statutory rape offenders.
Using a sample of 2,838 students from a Southwestern university in the United States, the authors examine the effect of respondent's gender, the adult's gender, the age gap between the adult and teen, and the adult's authority, on students' perceptions of vignettes describing adult-teen sexual relationships. Specifically, the authors investigate four dependent variables related to perceptions of the crime: the adult offender's emotional motivation, whether the adult is a sexual predator, whether the adult should have limited interactions with children, and whether the adult should be included on a sex offender registry. ANOVA analysis revealed that a large age gap between the adult and teen, the presence of authority in the relationship, and respondent's gender were significant predictors of perceptions of the offender as a predator and sex offender. The offender's gender significantly predicted respondents' perceived motivations but had no effect on opinions regarding sex offender registration. The authors discuss the implications of these findings for perceptions of statutory rape.


Numbers of mast cells in the axillary lymph nodes of breast cancer patients.
This retrospective study of surgical specimens from forty-three consecutive patients treated by modified radical mastectomy for carcinoma of the breast shows that those patients surviving for at least sixty months after operation have a significantly greater number of mast cells in their axillary lymph nodes than the nonsurvivors (p less than .001). When expressed as cells/mm2 the survivors are associated with nodal concentrations greater than eleven mast cells per square millimeter while the nonsurvivors haver fewer than eleven mast cells/mm2. The results suggest that the number of nodal mast cells may be a readily quantitated host response of prognostic value in carcinoma of the breast.


Efficacy and feasibility of radiofrequency ablation for hepatocellular carcinoma patients.
Radiofrequency ablation (RFA) is a new treatment which is used to treat hepatocellular carcinoma (HCC). We performed this clinical trial to investigate whether it could reduce the damage of residual liver function. We studied 40 hepatitis-related chronic patients who underwent RFA for hepatocellular carcinoma. Indocyanine green (ICG) test was performed pre and postoperatively. There were 32 males and 8 females with an average age of 53.98+12.59 years who underwent RFA for HCC. The mean preoperative ICGR15 value of 40 of the patients was (10.17+9.54) lower than the postoperative ICG retention rate at 15 min (ICGR15) value (14.95+12.71).Differences between the preoperative ICGR15 and the postoperative ICGR15 values were not significantly different (p=0.074). The 1-, 2- and 3-year survival rates were 98.7%, 88.8% and 76.4%, respectively. The results indicate that RFA is a minimally invasive treatment which provides a possible treatment modality for HCC patients with poor liver function and the efficacy is as well as the surgical treatment for HCC patients within the Milan criteria.


Glucose metabolism among obese and non-obese children of mothers with gestational diabetes.
Abdominal obesity is more closely associated with diabetes than general obesity in adults, however, it is unknown which kind of obesity is more closely associated with abnormal glucose metabolism in children. We recruited 973 children (aged 3.08±1.06) of mothers with prior gestational diabetes mellitus (GDM). Children's height, weight, waist circumstance, fasting glucose and insulin were measured using standardized methods. Logistic regression models were used to assess the single and joint associations of general and abdominal obesity with the risks of hyperglycemia (the upper quartile of fasting glucose), insulin resistance (the upper quartile of homeostatic model assessment of insulin resistance (HOMA-IR)), and β-cell dysfunction (the lower quartile of HOMA-%β). Compared with normal weight children, children with general overweight/obesity had higher levels of HOMA-IR and HOMA-%β, higher ORs for hyperglycemia (1.56, 95% CI 1.06 to 2.30) and insulin resistance (3.44, 95% CI 2.32 to 5.09), but a lower OR for β-cell dysfunction (0.65, 95% CI 0.41 to 1.04). Children with abdominal obesity had an increased risk of insulin resistance (2.54, 95% CI 1.71 to 3.76) but not hyperglycemia and β-cell dysfunction compared with children with normal waist circumstance. In the joint analyses, general overweight children with and without abdominal obesity had an increased risk of hyperglycemia and insulin resistance compared with normal weight children. General obesity was more closely associated with abnormal glucose metabolism than abdominal obesity in children of mothers with GDM.


Analysis of phospholipid metabolism in murine keratinocytes transformed by the v-ras oncogene: relationship of phosphatidylinositol turnover and cytokine stimulation to the transformed phenotype.
Introduction of a v-rasHa oncogene into cultured mouse keratinocytes by transduction with a defective retrovirus is sufficient to transform keratinocytes to the benign phenotype. Transduced keratinocytes overexpress TGF alpha and hyperproliferate in culture medium with 0.05 mM Ca2+. Whereas normal keratinocytes respond to elevated medium Ca2+ by cessation of proliferation and induction of terminal differentiation, v-rasHa keratinocytes are not induced to differentiate by Ca2+. We now demonstrate that v-rasHa keratinocytes have elevated basal levels of phosphatidylinositol, inositol phosphates and diacylglycerols in 0.05 mM Ca2+ medium. Basal turnover of phosphatidylcholine is not altered by the rasHa oncogene. The generation of inositol phosphates is even further stimulated in v-rasHa cells by an increase in extracellular Ca2+ or by exposure to aluminum fluoride. Thus, the v-rasHa gene product does not stimulate the inositol phospholipid pathway maximally and additional phosphatidylinositol is available for turnover in response to inducers of phospholipase C activity. TGF alpha and medium conditioned by v-rasHa keratinocytes, both of which stimulate proliferation of normal cells in 0.05 mM Ca2+, transiently increased phosphatidylinositol turnover in normal keratinocytes but did not inhibit Ca(2+)-induced terminal differentiation. In contrast, sustained elevation in basal phosphatidylinositol metabolism was produced by aluminum fluoride. Combined exposure to aluminum fluoride and exogenous TGF alpha caused hyperproliferation, resistance to Ca(2+)-induced differentiation and morphological changes identical to those of v-rasHa keratinocytes. These results provide a link between the biological consequences of v-rasHa gene expression and biochemical changes which are known to alter the keratinocyte phenotype.


Recurrent Kawasaki disease in a child with retropharyngeal involvement: a case report and literature review.
Kawasaki disease (KD) is a multisystemic vasculitic disease. Recurrent KD is rare and generally presents in a similar clinical picture as the first episode, and early diagnosis with prompt treatment is the key point in preventing associated cardiovascular morbidities. A 9-year-old boy, who was diagnosed with KD when he was 1.5 years' old, was referred to our hospital for surgical drainage of retropharyngeal abscess. He had a 7-day history of high fever, sore throat, left-sided neck swelling, and restricted neck movements. Subsequently, he was diagnosed with recurrent KD and retropharyngeal involvement. He was successfully treated with a single dose of intravenous immunoglobulin (IVIG) and acetyl salicylic acid. Recurrence is rare and occurs most commonly in children. Atypical presentation, incomplete disease, short duration of fever, and reduced response to IVIG treatment were found to be the risk factors for recurrence. KD can occasionally present with clinical and radiographic findings of deep neck bacterial infection. Unusual presentations in KD may cause delay in diagnosis and increase the risk of life-threatening complications. We describe a case of recurrent KD presenting with a clinical picture resembling retropharyngeal infection who fully recovered after 1 dose of IVIG instead of surgical drainage and antibiotic use.


Improving the engagement of Aboriginal families with maternal and child health services: a new model of care.
Access in the early years to integrated community-based services that are flexible in their approach, holistic and culturally strong is a proven critical predictor of a child's successful transition to school and lifelong education and employment outcomes, providing long-term wellbeing. Studies show that participation in maternal and child health (MCH) services in Victoria, Australia, improve health outcomes for children and families, particularly for Aboriginal families. Poorer health outcomes and lower participation rates for these families in MCH services suggest there is a need for an urgent review of the current service model. The purpose of this paper is to outline the Early Assessment Referral Links (EARL) concept that was trialled in the Glenelg Shire in Victoria, Australia (2009-2014) to improve the engagement of Aboriginal families in MCH services. Development of EARL involved the core principles of appreciative inquiry to change existing patterns of conversation and give voice to new and diverse perspectives. A broad cross-section of the Aboriginal community and their early years health service providers were consulted and stakeholders recruited. Regular meetings between these stakeholders, in consultation with the Aboriginal community, were held to identify families that weren't engaged in MCH services and also to identify families who required further assessment, intervention, referral and/or support, ideally from the preconception or antenatal periods. Outcome measures used to evaluate the EARL concept include stakeholder meetings data, numbers of referrals, and participation rates of women and children in MCH services. Participation of Aboriginal women and children in MCH services was consistently above the state average during the pilot period, and significant numbers of Aboriginal women and children were referred to EARL stakeholders and other health professionals via EARL referrals. Additionally, there were increases in Aboriginal children being breastfed, fully immunised and attending Early Start Kindergarten. Identification of Aboriginal women and children at risk of vulnerability also improved with a dramatic increase in referrals for family violence and child protection, and decreased episodes of out-of-home care (OoHC) for children. Evaluation of pilot outcomes indicate that the EARL concept improved women and children's access to and engagement with MCH services, and identified more families at risk of vulnerability than the traditional MCH service model, particularly for Aboriginal women and children.


Microvascular proliferation is associated with aggressive tumour features and reduced survival in lung adenocarcinoma.
Despite new treatment options in lung cancer, there is still a need for better biomarkers to assist in therapy decisions. Angiogenesis has been associated with tumour growth and dissemination, and the vascular proliferation index (VPI) is a valuable prognostic marker in other tumours. Nestin, a marker of immature endothelium, was previously applied in combination with Ki67 for proliferating endothelium as a novel marker (Nestin-Ki67) of ongoing angiogenesis. Here, the prevalence and prognostic impact of vascular proliferation on lung cancer-specific survival (LCSS) in lung adenocarcinomas was studied. Selected tumour slides from a cohort of 210 patients treated surgically for adenocarcinoma at Haukeland University Hospital (Norway) from 1993 to 2010 were stained for Nestin-Ki67. VPI, the ratio between the density of proliferating vessels and the overall microvessel density were used, and the cut-off value was set at 4.4% (upper quartile). High VPI was associated with the presence of blood vessel invasion (p = 0.007) and tumour necrosis (p = 0.007). Further, high VPI was significantly associated with reduced LCSS (p = 0.020). By multivariate analysis, VPI remained an independent prognostic factor for reduced LCSS (HR 1.7; 95% CI 1.04-2.68; p = 0.033) when adjusted for other prognostic clinico-pathological features. In conclusion, microvessel proliferation assessed using the VPI was associated with aggressive tumour features such as blood vessel invasion and tumour necrosis and, independently, decreased LCSS. This marker should be further explored in separate cohorts, and in trials of anti-angiogenesis therapy.


Nexus of poverty, energy balance and health.
Since the inception of planning process in India, health planning was an integral component of socio-economic planning. Recommendations of several committees, policy documents and Millennium development goals were instrumental in development of impressive health infrastructure. Several anti-poverty and employment generation programmes were instituted to remove poverty. Spectacular achievements took place in terms of maternal and child health indicators and expectancy of life at birth. However, communicable diseases and undernutrition remain cause of serious concern and non-communicable diseases are imposing unprecedented challenge to planners and policy makers. Estimates of poverty based on different criteria point that it has remained a sustained problem in the country and emphasizes on revisiting anti-poverty programmes, economic policies and social reforms. Poverty affects purchasing power and thereby, food consumption. Energy intake data has inherent limitations. It must be assessed in terms of energy expenditure. Energy balance has been least explored area of research. The studies conducted in three different representative population group of Eastern Uttar Pradesh revealed that 69.63% rural adolescent girls (10-19 years), 79.9% rural reproductive age group females and 62.3% rural geriatric subjects were in negative energy balance. Negative energy balance was significantly less in adolescent girls belonging to high SES (51.37%), having main occupation of family as business (55.3%), and highest per capita income group (57.1%) with respect to their corresponding sub-categories. In case of rural reproductive age groups, this was maximum (93.0%) in SC/ST category and least (65.7%) in upper caste group. In case of geriatric group, higher adjusted Odd's Ratio for negative energy balance for subjects not cared by family members (AOR 23.43, CI 3.93-139.56), not kept money (AOR 5.27, CI 1.58-17.56), belonging to lower and upper middle SES by Udai Pareekh Classification (AOR 3.73, CI 1.22-11.41), with lowest per capita income (AOR 15.14, CI 2.44-94.14) and in age group >80 years (AOR 5.76, CI 1.03-32.39). Of those in negative energy balance, 70.21% rural adolescent girls and 7 out of 10 geriatric subjects (activity based) were victims of CED. Extent of undernutrition and CED in rural reproductive age group females were more in those caste groups where energy deficit was also of higher magnitude. Energy balance must be visualized giving due consideration to the importance of exercise on human health. The evidence thus generated needs to be translated to the masses based on principles of translational research.


Socio-economic status influences the relationship between obesity and antenatal depression: Data from a prospective cohort study.
Obesity has been associated with increased risk of antenatal depression, but little is known about this relationship. This study tested whether socio-economic status (SES) influences the relationship between obesity and antenatal depression. Data were taken from the Screening for Pregnancy Endpoints (SCOPE) cohort. BMI was calculated from measured height and weight at 15±1 weeks' gestation. Underweight women were excluded. SES was indicated by self-reported household income (dichotomised around the median: low SES ≤£45,000; high SES >£45,000). Antenatal depression was defined as scoring ≥13 on the Edinburgh Postnatal Depression Scale at both 15±1 and 20±1 weeks' gestation, to identify persistently elevated symptoms of depression. Five thousand five hundred and twenty two women were included in these analyses and 5.5% had persistently elevated antenatal depression symptoms. There was a significant interaction between SES and BMI on the risk of antenatal depression (p=0.042). Among high SES women, obese women had approximately double the odds of antenatal depression than normal weight controls (AOR 2.11, 95%CI 1.16-3.83, p=0.014, adjusted for confounders). Among low SES women there was no association between obesity and antenatal depression. The interaction effect was robust to alternative indicators of SES in sensitivity analyses. 1) Antenatal depression was assessed with a self-reported screening measure; and 2) potential mediators such as stigma and poor body-image could not be examined. Obesity was only associated with increased risk of antenatal depression among high SES women in this sample. Healthcare professionals should be aware that antenatal depression is more common among low SES women, regardless of BMI category.


Primary Involvement of Allografted liver in Post-Transplant Lymphoproliferative Disorders, Report of Two Pediatric Cases and Review of the Literature.
Post-transplant lymphoproliferative disorder is a lymphocyte proliferating disease, usually of B cell origin, and rarely of T cell. Involvement of liver itself in liver transplant recipients as the primary organ is not common. Herein we report our experience in two patients who primarily presented in the allografted liver, both of whom were promptly diagnosed after liver biopsy and treated successfully .Now after a few months; both of the patients are alive with normal liver function tests and negative imaging studies.


Evaluation of wastewater contaminant transport in surface waters using verified Lagrangian sampling.
Contaminants released from wastewater treatment plants can persist in surface waters for substantial distances. Much research has gone into evaluating the fate and transport of these contaminants, but this work has often assumed constant flow from wastewater treatment plants. However, effluent discharge commonly varies widely over a 24-hour period, and this variation controls contaminant loading and can profoundly influence interpretations of environmental data. We show that methodologies relying on the normalization of downstream data to conservative elements can give spurious results, and should not be used unless it can be verified that the same parcel of water was sampled. Lagrangian sampling, which in theory samples the same water parcel as it moves downstream (the Lagrangian parcel), links hydrologic and chemical transformation processes so that the in-stream fate of wastewater contaminants can be quantitatively evaluated. However, precise Lagrangian sampling is difficult, and small deviations - such as missing the Lagrangian parcel by less than 1h - can cause large differences in measured concentrations of all dissolved compounds at downstream sites, leading to erroneous conclusions regarding in-stream processes controlling the fate and transport of wastewater contaminants. Therefore, we have developed a method termed "verified Lagrangian" sampling, which can be used to determine if the Lagrangian parcel was actually sampled, and if it was not, a means for correcting the data to reflect the concentrations which would have been obtained had the Lagrangian parcel been sampled. To apply the method, it is necessary to have concentration data for a number of conservative constituents from the upstream, effluent, and downstream sites, along with upstream and effluent concentrations that are constant over the short-term (typically 2-4h). These corrections can subsequently be applied to all data, including non-conservative constituents. Finally, we show how data from other studies can be corrected.


Real-time contrast-enhanced specific ultrasound in staging and follow-up of splenic lymphomas.
From January 2003 to April 2005 we studied 25 lymphoma patients (10 with HD, 4 with low-grade NHL, 6 with high-grade NHL and 5 with chronic lymphatic leukaemia; 14 men, 11 women, age range 28-79 years). After a baseline US study we rapidly injected 4.8 mL of the second-generation microbubble contrast agent SonoVue (Bracco, Italy). Contrast enhanced studies were carried out with the contrast-specific software named Contrast Tuned Imaging (Esaote, Italy) using a continuous, harmonic acquisition and a low acoustic pressure. The CS-US findings were correlated with results of standard tools, including CT, MRI, US follow up. CS-US revealed correctly 47 out of the 52 lesions identified by CT scan, in the absence of false positive findings (sensitivity = 90%; Specificity = 100%, in comparison to CT scan). Complete concordance in evaluating the lesion extension of the CS-US in respect to CT was 88%, while underestimate occurred in 9% and overestimate in 3% of cases. On the contrary, basic sonography defined correctly the dimensional alteration in 52% of the cases, underestimated in 35% and overestimated in 13%, thus showing significantly lower accuracy (chi-square = 30.0, p < 0.001). In our experience, CS-US was superior to conventional sonography even from a qualitative point of view.


[Surgical treatment of critical aortic isthmus stenosis in infancy].
Early and late results of 43 infants (35 under 3 months of age) who underwent different surgical repairs (29 Waldhausen subclavian flap method, 11 resection and end-to-end-anastomosis, 1 Clagett method, 2 Goretex patch) for coarctation of the aorta during the years 1970-1982 are reported. Only one patient had isolated coarctation, five patients had coarctation with patent duct (PDA). Associated cardiac anomalies were found in 37 patients. 17 (39,5%) infants died early after surgery. All were under 3 month of age with severe cardiac anomalies (16x intracardiac, 1x PDA). There were two late deaths after correction of intracardiac defects. In 6 out of 24 surviving patients restenosis developed 1-10 years after repair (3 of 6 patients with end-to-end-anastomosis = 50%, 2 of 10 patients with subclavian flap method = 20%, 1 patient with Goretex-patch). Our results show that coarctation with associated cardiac anomalies in patients under 3 month present higher surgical risk. Subclavian flap technique ist the method of choice for preductal coarctation. Technical difficulties related of this method are discussed in detail.


Low oxygen sensing and balancing in plant seeds: a role for nitric oxide.
Storage product accumulation in seeds of major crop species is limited by their low internal oxygen concentration. Adjustment of energy and storage metabolism to oxygen deficiency (hypoxia) in seeds is highly relevant for agriculture and biotechnology. However, the mechanisms of low-oxygen sensing and balancing remain a mystery. Here, it is shown that normal hypoxia in seeds of soybean (Glycine max) and pea (Pisum sativum) triggers a nitrite-dependent increase in endogenous nitric oxide (NO) concentrations. NO, in turn, reduces the oxygen consumption of seeds, generating a localized decrease in both ATP availability and biosynthetic activity. Increasing oxygen availability reduces endogenous NO concentrations, thereby abolishing mitochondrial and metabolic inhibition. This auto-regulatory and reversible oxygen balancing, via NO, avoids seed anoxia and suggests a key role for NO in regulating storage activity. This hypothesis is reinforced by changes in energy status (ATP:ADP ratio), steady-state metabolite concentrations and biosynthetic fluxes under NO treatment. The proposed mechanism of low-oxygen sensing and balancing in plants offers the prospect of a new field of study in crop biotechnology.


Understanding the role of the state in dietary public health policymaking: a critical scoping review.
Despite evidence that dietary population health interventions are effective and widely accepted, they remain the topic of intense debate centring on the appropriate role of the state. This review sought to identify how the role of the state in intervening in individuals' food practices is conceptualized across a wide range of literatures. We searched 10 databases and 4 journals for texts that debated dietary population health interventions designed to affect individuals' health-affecting food practices. Two co-authors independently screened these texts for eligibility relative to inclusion and exclusion criteria. Thirty-five texts formed our final corpus. Through critical reflexive thematic analysis (TA), we generated 6 themes and 2 subthemes concerning choice, responsibility for health, balancing benefits and burdens of intervention, the use of evidence, fairness, and the legitimacy of the state's actions. Our analysis found that narratives that aim to prevent effective regulation are entrenched in academic literatures. Discourses that emphasized liberty and personal responsibility framed poor health as the result of 'lifestyle choices'. Utilitarian, cost-benefit rationales pervaded arguments about how to best balance the benefits and burdens of state intervention. Claims about fairness and freedom were used to evoke powerful common meanings, and evidence was used politically to bolster interests, particularly those of the food industry. This review identifies and critically analyses key arguments for and against population dietary public health policies. Our findings should motivate public health researchers and practitioners to avoid unreflexively embracing framings that draw on the languages and logics of free market economics.


Induced cold-tolerance mechanisms depend on duration of acclimation in the chill-sensitive Folsomia candida (Collembola).
During cold periods ectotherms may improve low temperature tolerance via rapid cold hardening (RCH) over a period of hours and/or long-term cold acclimation (LTCA) during days, weeks or months. However, the effect of duration and the major underlying mechanisms of these processes are still not fully understood. In the present study, the molecular and biochemical responses to RCH (1-3 h) and LTCA (1-3 days) and the corresponding benefits to survival were investigated using the chill-sensitive collembolan Folsomia candida. We investigated osmolyte accumulation, membrane restructuring and transcription of candidate genes as well as survival benefits in response to RCH and LTCA. RCH induced significant upregulation of targeted genes encoding enzymes related to carbohydrate metabolic pathways and genes encoding small and constitutively expressed heat shock proteins (Hsps), indicating that the animals rely on protein protection from a subset of Hsps during RCH and probably also LTCA. The upregulation of genes involved in carbohydrate metabolic processes initiated during RCH was likely responsible for a transient accumulation of myoinositol during LTCA, which may support the protection of protein and membrane function and structure. Membrane restructuring, composed especially of a significantly increased ratio of unsaturated to saturated phospholipid fatty acids seems to be a mechanism supplementary to activation of Hsps and myoinositol accumulation in LTCA. Thus, the moderate increase in cold shock tolerance conferred by RCH seems to be dominated by effects of Hsps, whereas the substantially better cold tolerance achieved after LTCA is dominated by post-transcriptional processes increasing membrane fluidity and cryoprotectant concentration.


Physical activity during pregnancy and adverse birth outcome: a prospective cohort study in China.
Objectives The relationship between prenatal physical activity (PA) and adverse birth outcomes is still inconclusive. We aimed to investigate the association between PA during pregnancy and adverse birth outcomes by using data from the Guangxi Zhuang birth cohort (GZBC) in China.Study Design A total of 11,292 mother-infant pairs were included from GZBC in China. The information on PA status, intensity, adequacy, and volume and birth outcomes were collected. Multivariable linear and logistic regression models were applied to analyze the effects of PA during pregnancy on birth weight z-scores (BW z-scores) and gestational age and risk of small-for-gestational age (SGA) and preterm birth (PTB), respectively. Cubic spline analysis was conducted to detect a nonlinear dose-response of total weekly activity metabolic equivalents (MET) and birth outcomes.Results Compared to no regular PA during pregnancy, moderate and high-intensity PA (MVPA) was associated with increase BW z-scores (β = 0.08, 95%CI: 0.002, 0.15, p = .044) and associated with a marginal significant decrease in risk of PTB (OR = 0.73, 95%CI: 0.51, 1.05, p = .093). However, PA had no relationship with gestational age and risk of SGA, and Nonlinear relationships were not observed between total weekly activity MET and risk of SGA and PTB.Conclusion These finding shows that PA during pregnancy may increase the BW z-score and reduce risk of PTB, supporting the guidelines that pregnant women should be encouraged to engage in appropriate physical activity during pregnancy in China.


Hippocampal morphometry in schizophrenia by high dimensional brain mapping.
Theories of the pathophysiology of schizophrenia have implicated the hippocampus, but controversy remains regarding hippocampal abnormalities in patients with schizophrenia. In vivo studies of hippocampal anatomy using high resolution magnetic resonance scanning and manual methods for volumetric measurement have yielded inconclusive results, perhaps because of the normal variability in hippocampal volume and the error involved in manual measurement techniques. To resolve this controversy, high dimensional transformations of a computerized brain template were used to compare hippocampal volumes and shape characteristics in 15 matched pairs of schizophrenia and control subjects. The transformations were derived from principles of general pattern matching and were constrained according to the physical properties of fluids. The analysis and comparison of hippocampal shapes based on these transformations were far superior to the comparison of hippocampal volumes or other global indices of hippocampal anatomy in showing a statistically significant difference between the two groups. In the schizophrenia subjects, hippocampal shape deformations were found to be localized to subregions of the structure that send projections to prefrontal cortex. The results of this study demonstrate that abnormalities of hippocampal anatomy occur in schizophrenia and support current hypotheses that schizophrenia involves a disturbance of hippocampal-prefrontal connections. These results also show that comparisons of neuroanatomical shapes can be more informative than volume comparisons for identifying individuals with neuropsychiatric diseases, such as schizophrenia.


Value transfer in ecosystem accounting applications.
Ecosystem accounting is a statistical framework that aims to track the state of ecosystems and ecosystem services, with periodic updates. This framework follows the statistical standard of the System of Environmental Economic Accounting Ecosystem Accounting (SEEA EA). SEEA EA is composed of physical ecosystem extent, condition and ecosystem service supply-use accounts and monetary ecosystem service and asset accounts. This paper focuses on the potential use of the "Value Transfer" (VT) valuation method to produce the monetary ecosystem service accounts, taking advantage of experience with rigorous benefit transfer methods that have been developed and tested over many years in environmental economics. Although benefit transfer methods have been developed primarily for welfare analysis, the underlying techniques and advantages are directly applicable to monetary exchange values required for ecosystem accounting. The compilation of regular accounts is about to become a key area of work for the National Statistical Offices worldwide as well as for the EU Member States in particular, due to the anticipated amendment to regulation on European environmental economic accounts introducing ecosystem accounts. On this basis, accounting practitioners have voiced their concerns in a global consultation during SEEA EA revision, about three issues in particular: the lack of resources, the need for guidelines and the challenge of periodically updating the accounts. We argue that VT can facilitate empirical applications that assess ecosystem services in monetary terms, especially at national scales and in situations with limited expertise and resources available. VT is a low-cost valuation approach in line with SEEA EA requirements able to provide periodic, rigorous and consistent estimates for use in accounts. While some methodological challenges remain, it is likely that VT can help to implement SEEA EA at scale and in time to respond to the pressing need to incorporate nature into mainstream decision-making processes.


Translational competition between related virus RNA species in cell-free systems.
The competition between the RNAs from two tobacco mosaic virus (TMV) strains for translation in rabbit reticulocyte lysate and wheat germ cell-free systems was investigated. The virus translational products were distinguished by the size difference of the I2 polypeptides. The RNAs of the two strains were translated simultaneously if added to the translation system together at the beginning of the reaction. Each of the TMV RNAs could inhibit translation of the other when the reaction was initiated by the RNA of one strain and that of the other strain was added after active translation had commenced. In contrast, translation of alfalfa mosaic virus (AMV) RNA was not appreciably inhibited when its RNA was added after the start of translation of TMV RNA; the addition of TMV RNA to an AMV RNA-initiated reaction also resulted in independent synthesis of the products of both virus RNAs.


QiLing Decoction promotes ferroptosis of castration-resistant prostate cancer cells by inhibiting FSP1 in vitro and in vivo.
QiLing Decoction (QLD) showed therapeutic effects against prostate cancer with an unclear underlying mechanism. This study explored the underlying mechanisms of QLD against castration-resistant prostate cancer (CRPC). Clinical specimens were collected from the patients with CRPC. Stable cells including knockdown and overexpression cell lines were established by plasmid transfection. The xenograft animal model was constructed. Cell viability was determined by using cell-counting kit 8 assay. Biochemical assays were used to determine the levels of iron (Fe2+) and lipid reactive oxygen species (ROS). qRT-PCR and Western blotting were used to determine levels of target genes, respectively. Treatment of QLD inhibited ferroptosis suppressor protein (FSP) 1 at mRNA and protein levels in patients with CRPC. Additionally, cells treated with QLD-containing serum displayed a decrease in cell viability and an increase in Fe2+ and lipid ROS with or without erastin, whereas ferroptosis inhibitor reversed QLD-induced ferroptosis. The regulatory effects of QLD on PC3 cell ferroptosis were associated with its inhibitory effects against FSP1. Consistently, QLD inhibited PC3 tumor growth by inhibiting FSP1. Moreover, treatment of QLD increased the sensitivity of PC3-AbiR cells to abiraterone by inhibiting FSP1. QLD promoted ferroptosis in CRPC cells in part by inhibiting FSP1 in vitro and in vivo.


Maternal obesity increases offspring's mammary cancer recurrence and impairs tumor immune response.
Over 50% of women at a childbearing age in the United States are overweight or obese, and this can adversely affect their offspring. We studied if maternal obesity-inducing high fat diet (HFD) not only increases offspring's mammary cancer risk but also impairs response to antiestrogen tamoxifen. Female rat offspring of HFD and control diet-fed dams, in which estrogen receptor-positive (ER+) mammary tumors were induced with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), exhibited similar initial responses to antiestrogen tamoxifen. However, after tamoxifen therapy was completed, almost all (91%) tumors recurred in HFD offspring, compared with only 29% in control offspring. The increase in local mammary tumor recurrence in HFD offspring was linked to an increase in the markers of immunosuppression (Il17f, Tgfβ1, VEGFR2) in the tumor microenvironment (TME). Protein and mRNA levels of the major histocompatibility complex II (MHC-II), but not MHC-I, were reduced in the recurring DMBA tumors of HFD offspring. Further, infiltration of CD8+ effector T cells and granzyme B+ (GZMB+) cells were lower in their recurring tumors. To determine if maternal HFD can pre-program similar changes in the TME of allografted E0771 mammary tumors in offspring of syngeneic mice, flow cytometry analysis was performed. E0771 mammary tumor growth was significantly accelerated in the HFD offspring, and a reduction in the numbers of GZMB and non-significant reduction of interferon γ (IFNγ) secreting CD8+ T cells in the TME was seen. Thus, consumption of a HFD during pregnancy increases susceptibility of the female rat and mouse offspring to tumor immune suppression and mammary tumor growth and recurrence.


Biophysical investigation of the ironome of human jurkat cells and mitochondria.
The speciation of iron in intact human Jurkat leukemic cells and their isolated mitochondria was assessed using biophysical methods. Large-scale cultures were grown in medium enriched with (57)Fe citrate. Mitochondria were isolated anaerobically to prevent oxidation of iron centers. 5 K Mössbauer spectra of cells were dominated by a sextet due to ferritin. They also exhibited an intense central quadrupole doublet due to S = 0 [Fe(4)S(4)](2+) clusters and low-spin (LS) Fe(II) heme centers. Spectra of isolated mitochondria were largely devoid of ferritin but contained the central doublet and features arising from what appear to be Fe(III) oxyhydroxide (phosphate) nanoparticles. Spectra from both cells and mitochondria contained a low-intensity doublet from non-heme high-spin (NHHS) Fe(II) species. A portion of these species may constitute the "labile iron pool" (LIP) proposed in cellular Fe trafficking. Such species might engage in Fenton chemistry to generate reactive oxygen species. Electron paramagnetic resonance spectra of cells and mitochondria exhibited signals from reduced Fe/S clusters, and HS Fe(III) heme and non-heme species. The basal heme redox state of mitochondria within cells was reduced; this redox poise was unaltered during the anaerobic isolation of the organelle. Contributions from heme a, b, and c centers were quantified using electronic absorption spectroscopy. Metal concentrations in cells and mitochondria were measured using inductively coupled plasma mass spectrometry. Results were collectively assessed to estimate the concentrations of various Fe-containing species in mitochondria and whole cells - the first "ironome" profile of a human cell.


Clinical complications of limb undergone harvesting of great saphenous vein for coronary artery bypass grafting using bridge technique.
The aim of this study was to assess clinical complications of limbs undergone harvesting of the great saphenous vein for venous coronary artery bypass graft surgery using bridge technique. Fourty-four patients who had undergone CABG using the great saphenous vein harvested by the bridge technique over more than 3 months ago were randomly selected. The exclusion criteria were the harvesting of both saphenous veins, prior saphenectomy of the contralateral limb, edema caused by a systemic etiology, such as heart, renal, thyroid or hepatic diseases and venous insufficiency of the lower limbs as characterized by swollen varicose veins both with and without trophic changes. The age, gender, diabetes, time of surgery and occurrence of complications, such as edema, paresthesia, infection, lymphorrhea, erysipelas and deep venous thrombosis, were assessed. The assessment was clinic and diagnosis of the diabetes was performed by the preoperative exams. The chi-square, Fisher and Student's t tests were used for statistical analysis with an alpha error of 5%. The time between surgery and assessment ranged between 3 and 187 months with a mean of 47.3+/-42.5 months. Infections of the saphenous harvest site were detected in 25% of the cases, edema in 52.3%, paresthesia in 29.5%, erysipelas in 9.1%, lymphorrhea in 4.5% and deep venous thrombosis in 2.3%. There was no association between diabetes and complications. The saphenous vein harvesting using bridge technique for coronary artery bypass grafting does not eliminate clinical complications, such as paresthesia, infection and edema of the saphenous vein harvesting site.


Spontaneous remission in adult patients with de novo myelodysplastic syndrome: a possible event.
Spontaneous remission (SR) in de novo myelodysplastic syndromes (MDS) is a rare event, which has been so far described only in children with monosomy 7. The phenomenon is extremely heterogeneous, perhaps depending on different pathogeneses of the disease. We retrospectively evaluated the outcome of 564 consecutive adult patients with primary MDS diagnosed at our Institution in a 12-year period. SR was defined as an unexpected improvement lasting more than 1 year without concomitant treatments other than vitamins or low-dose steroids (in patients with platelets < 50 x 10(9)/L). Nine cases of SR were observed in 3 males and 6 females (median age 38.7 years). At diagnosis, all patients had Hb levels < 10 g/dL and 8/9 required packed red cell transfusions. The median time from diagnosis to SR was 18 months (range 4-46) and all patients had normalization of peripheral blood parameters: in 2 out of 3 patients with karyotypic abnormalities at onset, a cytogenetic remission was documented. The median duration of SR was 56 months; 5 patients are still in SR and 4 patients have relapsed (1 as MDS and 3 as acute myeloid leukemia). SR is a rare (less than 2% in our experience) but possible event also in adult MDS patients. It should be kept in mind in the evaluation of experimental treatments for MDS in which very low rates of complete responses are expected.


Ethnic differences in cardiovascular risk factor burden among middle-aged women: Study of Women's Health Across the Nation (SWAN).
We evaluated ethnic differences in the 10-year risk of myocardial infarction or coronary death derived from Framingham risk equation and in a composite measure of emerging cardiovascular disease risk factors in women and whether statistical adjustments for educational attainment, geographic location, and lifestyle attenuated the magnitude of the ethnic differences in risk. Two thousand eight hundred thirty-four premenopausal women free of stroke, heart disease, or diabetes and aged of 42 to 52 years (1400 whites, 729 African American, 226 Hispanic, 231 Chinese, and 248 Japanese) had measurements of blood pressure, lipids and lipoproteins, waist circumference, glucose, insulin, lipoprotein(a), fibrinogen, factor VII, plasminogen activator inhibitor, tissue-type plasminogen activator antigen, and high-sensitivity C-reactive protein. Framingham risk score and number of risk factors in the top quartile of the distribution of risk factors not included in the Framingham score (called composite burden) were calculated. The unadjusted mean values for the two summary scores were higher among African Americans and Hispanics than other groups. Statistical adjustments for education and geographical site accounted for a majority of the ethnic differences, with an additional small effect of lifestyle for the composite burden score. Largest ethnic differences were apparent for waist circumference, lipoprotein(a), high-sensitivity C-reactive protein, and untreated blood pressure. A substantial part of the risk associated with ethnicity can be attributed to socioeconomic status and geographical location. As the ethnic composition of the United States population becomes more diverse, it is important to appreciate the cardiovascular disease risk factor burden present in some minority groups.


Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development.
The naevoid basal cell carcinoma syndrome (NBCCS) is caused by mutations in the hedgehog receptor PTCH gene. It is characterized by developmental defects and a predisposition to the development of certain tumours, such as basal cell carcinoma, medulloblastoma and meningioma, and potentially fetal rhabdomyomas and embryonal rhabdomyosarcomas. This study aimed to analyse PTCH status in an NBCCS patient with fetal rhabdomyoma and to investigate whether deregulation of hedgehog signalling, as shown by altered expression of hedgehog pathway components and/or genetic imbalances, is a general finding in sporadic rhabdomyomas and rhabdomyosarcomas. The NBCCS patient had a novel PTCH germ-line mutation, 1370insT, and developed a fetal rhabdomyoma that harboured a 30 bp in-frame deletion in the second allele resulting in homozygous inactivation of PTCH. Sporadic rhabdomyomas and rhabdomyosarcomas showed overexpression of PTCH (43/43) and GLI1 (41/43) mRNA, as determined by in situ hybridization, indicating ongoing active hedgehog signalling. Immunohistochemical staining revealed a subgroup of fetal rhabdomyomas and embryonal rhabdomyosarcomas (12/34) lacking PTCH immunoreactivity. Four of nine informative fetal rhabdomyomas and embryonal rhabdomyosarcomas showed loss of heterozygosity (LOH) in the PTCH region with two of these (one fetal rhabdomyoma and one embryonal rhabdomyosarcoma) also showing LOH in the SUFU region. These findings suggest that haploinsufficiency for the two tumour suppressor genes PTCH and SUFU, which are both active in the same signalling pathway, may be important for tumour development. Based on our results we propose that the pathogenesis of rhabdomyoblastic tumours, particularly fetal rhabdomyomas and embryonal rhabdomyosarcomas, involves deregulation of the hedgehog signalling pathway.


Inward rectifier potassium channels.
The past three years have seen remarkable progress in research on the molecular basis of inward rectification, with significant implications for basic understanding and pharmacological manipulation of cellular excitability. Expression cloning of the first inward rectifier K channel (Kir) genes provided the necessary break-through that has led to isolation of a family of related clones encoding channels with the essential functional properties of classical inward rectifiers, ATP-sensitive K channels, and muscarinic receptor-activated K channels. High-level expression of cloned channels led to the discovery that classical inward so-called anomalous rectification is caused by voltage-dependent block of the channel by polyamines and Mg2+ ions, and it is now clear that a similar mechanism results in inward rectification of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-kainate receptor channels. Knowledge of the primary structures of Kir channels and the ability to mutate them also has led to the determination of many of the structural requirements of inward rectification.


COVID-19 and Liver Disease: An Evolving Landscape.
The COVID-19 pandemic has resulted in significant worldwide morbidity and mortality. In this review, we examine the intricate relationships between COVID-19 and liver diseases. While respiratory manifestations of COVID-19 are well known, its impact and consequences in patients with liver diseases remain an area of ongoing investigation. COVID-19 can induce liver injury through various mechanisms and is associated with higher mortality in individuals with preexisting chronic liver disease. Mortality increases with the severity of chronic liver disease and the level of care required. The outcomes in patients with autoimmune hepatitis remain unclear, whereas liver transplant recipients are more likely to experience symptomatic COVID-19 but have comparable outcomes to the general population. Despite suboptimal immunological response, COVID-19 vaccinations are safe and effective in liver disease, although cases of autoimmune hepatitis-like syndrome have been reported. In conclusion, COVID-19 has significant implications in liver diseases; early recognition and treatments are important for improving patient outcomes.


Bridging gaps in multidisciplinary head and neck cancer care: nursing coordination and case management.
Patients with advanced head and neck cancer face not only a life-threatening malignancy, but also a remarkably complex treatment regimen that can affect their cosmetic appearance and ability to speak, breathe, and swallow. These patients benefit from the coordinated interaction of a multidisciplinary team of specialists and a comprehensive plan of care to address their physical and psychosocial concerns, manage treatment-related toxicities, and prevent or limit long-term morbidities affecting health-related quality of life. Although little has been published on patient-provider communication with a multidisciplinary team, evidence has suggested that gaps often occur in communication between patients and providers, as well as between specialists. These communication gaps can hinder the multidisciplinary group from working toward common patient-centered goals in a coordinated "interdisciplinary" manner. We discuss the role of a head-and-neck oncology nurse coordinator at a single institution in bridging gaps across the continuum of care, promoting an interdisciplinary team approach, and enhancing the overall quality of patient-centered head-and-neck cancer care.


Reflex effects on components of synchronized renal sympathetic nerve activity.
The effects of peripheral thermal receptor stimulation (tail in hot water, n = 8, anesthetized) and cardiac baroreceptor stimulation (volume loading, n = 8, conscious) on components of synchronized renal sympathetic nerve activity (RSNA) were examined in rats. The peak height and peak frequency of synchronized RSNA were determined. The renal sympathoexcitatory response to peripheral thermal receptor stimulation was associated with an increase in the peak height. The renal sympathoinhibitory response to cardiac baroreceptor stimulation was associated with a decrease in the peak height. Although heart rate was significantly increased with peripheral thermal receptor stimulation and significantly decreased with cardiac baroreceptor stimulation, peak frequency was unchanged. As peak height reflects the number of active fibers, reflex increases and decreases in synchronized RSNA are mediated by parallel increases and decreases in the number of active renal nerve fibers rather than changes in the centrally based rhythm or peak frequency. The increase in the number of active renal nerve fibers produced by peripheral thermal receptor stimulation reflects the engagement of a unique group of silent renal sympathetic nerve fibers with a characteristic response pattern to stimulation of arterial baroreceptors, peripheral and central chemoreceptors, and peripheral thermal receptors.


GPs could play key role in prostate cancer survivorship programmes.
The number of men living with prostate cancer in the UK is predicted to rise from 255,000 to 416,000 in 2020 and 620,000 by 2030. More than 80% of men diagnosed with prostate cancer can expect to survive for at least five years. Up to 87% of men with prostate cancer may have unmet supportive care needs. Patients regularly cite psychological and sexual issues as the most significant. Poor functional outcomes after treatment such as incontinence and erectile dysfunction have a major impact on quality of life. The traditional model of hospital follow-up fails to deliver optimum patient-centred cancer care. Holistic aspects of care such as psychological needs and factors which may facilitate full rehabilitation of patients back into society may be missed. The key elements of a survivorship programme are: education, intervention, surveillance and co-ordination of care. Interventions which may improve immediate care include: structured holistic needs assessment and care planning, treatment summaries and cancer care reviews, patient education and support events and advice about, and access to, physical activity schemes. Urologists and GPs need to collaborate to establish shared care pathways for prostate cancer patients. Elements of these innovative pathways will include clear follow-up protocols for prostate cancer survivors discharged into the community and rapid access arrangements for patients about whom GPs are concerned.


Stimulation of P(i) transport in opossum kidney cells by hyposmotic media.
Exposure of various cells to hyposmotic media (Hypo) results in a rapid inhibition of both receptor-mediated and fluid-phase endocytosis. We used this maneuver to investigate the role of endocytosis in regulation of Pi transport in opossum kidney (OK) cells. Following exposure to Hypo, Na(+)-dependent Pi uptake increased rapidly, reaching a maximum within 5 min, and remained elevated up to 30 min. This was associated with a simultaneous reduction of horseradish peroxidase uptake. Kinetic studies showed increased apparent Vmax for Pi (9.38 +/- 0.93 vs. 13.08 +/- 1.04 nmol.mg-1.5 min-1 for control and Hypo, respectively; P < 0.05, n = 6) with no change in apparent Km. The effect was specific for Pi with no change in the Na(+)-dependent or -independent uptake of L-proline, L-glutamine, or methyl-alpha-D-glucopyranoside. Stimulation of Pi transport persisted when control and Hypo had identical ionic compositions. Stimulation of Pi transport was rapidly reversed when cells were returned to an isosmotic medium. Preincubation with Hypo at 4 degrees C had no effect on Pi transport. Addition of cycloheximide or actinomycin D did not prevent the increased Pi uptake after exposure to Hypo. The effect also persisted after protein kinase C downregulation. Stimulation of Pi transport by Hypo is consistent with reduced endocytic retrieval of Na(+)-Pi cotransporters from brush-border membrane (BBM), resulting in an increase in their number on the BBM.


Targeting Polo-like kinase in cancer therapy.
Polo-like kinases (Plk) function in mitosis and maintaining DNA integrity. There are four family members, of which Plk1 represents a target for anticancer therapy. Plk1 is only expressed in dividing cells with peak expression during G2/M. Plk1 functions in multiple steps of mitosis, and is overexpressed in many tumor types. Mitotic arrest and inhibition of proliferation, apoptosis, and tumor growth inhibition have been observed in preclinical studies using small interfering RNAs (siRNA) or small molecules that inhibit Plk1. Preclinical studies also show that Plk1 inhibitors may be active against tumors with RAS mutations and that tumor cells with mutations in TP53 are more sensitive to inhibition of Plk1. Several Plk inhibitors are in phase I or II clinical studies. As expected, hematologic toxicity is the primary dose-limiting toxicity. Some patients have achieved clinical response, although in some studies only at doses above the maximum tolerated dose defined in the study. Further evaluation is necessary to discern the clinical utility of Plk1 inhibitors.


Defective antitumor responses in CX3CR1-deficient mice.
Innate immunity is critically important for tumor surveillance and regulating tumor metastasis. Fractalkine (FKN, CX3CL1), operating through the receptor CX3CR1, is an effective chemoattractant and adhesion receptor for NK cells and monocytes, important constituents of the innate immune response. Previous studies have shown that over-expression of CX3CL1 by tumor cells enhances antitumor responses. However, since most tumors do not express CX3CL1, it remains unclear if CX3CL1/CX3CR1 has a role in tumor immunity in the absence of ligand over-expression. To determine the role of CX3CL1 and CX3CR1 in regulating antitumor immune responses, we tested the response of wildtype and CX3CR1-deficient animals to unmanipulated B16 melanoma that does not express CX3CL1. We studied the distribution and trafficking of mononuclear cells (MNC) under homeostatic conditions and in the presence of B16 metastatic melanoma, cytotoxic activity, and cytokine production in wild-type and CX3CR1-deficient animals. We found that B16-treated CX3CR1-/- mice had increased lung tumor burden and cachexia. There was a selective reduction of monocytes and NK cells in the lungs of CX3CR1-deficient animals under homeostatic conditions and in response to B16. CX3CR1-deficient NK cells effectively killed B16 cells in cytotoxicity assays. However, CX3CR1-deficient NK cells exhibited a tumorigenic cytokine production profile with defective IFN-gamma expression and enhanced IL-6 production in response to TLR3 activation with polyIC. Our studies indicate that CX3CR1 is an important contributor to innate immunity at multiple levels. Its role in tumor immunity is not limited by expression of CX3CL1 by tumor cells.


Challenges and opportunities in mapping land use intensity globally.
Future increases in land-based production will need to focus more on sustainably intensifying existing production systems. Unfortunately, our understanding of the global patterns of land use intensity is weak, partly because land use intensity is a complex, multidimensional term, and partly because we lack appropriate datasets to assess land use intensity across broad geographic extents. Here, we review the state of the art regarding approaches for mapping land use intensity and provide a comprehensive overview of available global-scale datasets on land use intensity. We also outline major challenges and opportunities for mapping land use intensity for cropland, grazing, and forestry systems, and identify key issues for future research.


Online tools for individuals with depression and neurologic conditions: A scoping review.
Patients with neurologic conditions commonly have depression. Online tools have the potential to improve outcomes in these patients in an efficient and accessible manner. We aimed to identify evidence-informed online tools for patients with comorbid neurologic conditions and depression. A scoping review of online tools (free, publicly available, and not requiring a facilitator) for patients with depression and epilepsy, Parkinson disease (PD), multiple sclerosis (MS), traumatic brain injury (TBI), or migraine was conducted. MEDLINE, EMBASE, PsycINFO, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL Register of Controlled Trials were searched from database inception to January 2017 for all 5 neurologic conditions. Gray literature using Google and Google Scholar as well as app stores for both Android and Apple devices were searched. Self-management or self-efficacy online tools were not included unless they were specifically targeted at depression and one of the neurologic conditions and met the other eligibility criteria. Only 4 online tools were identified. Of these 4 tools, 2 were web-based self-management programs for patients with migraine or MS and depression. The other 2 were mobile apps for patients with PD or TBI and depression. No online tools were found for epilepsy. There are limited depression tools for people with neurologic conditions that are evidence-informed, publicly available, and free. Future research should focus on the development of high-quality, evidence-based online tools targeted at neurologic patients.


Evaluating success of mobile health projects in the developing world.
Many mobile health (mHealth) projects, typically deploying pilot or small scale implementations, have been undertaken in developing world settings and reported with a widely varying range of claims being made on their effectiveness and benefits. As a result, there is little evidence for which aspects of such projects lead to successful outcomes. This paper describes a literature review of papers from PubMed undertaken to identify strong contributions to execution and evaluation of mHealth projects in developing world settings, and suggests a template for classifying the main success factors to assist with collating evidence in the future.


[Primary structure of rhodopsin. I. Cyanogen bromide degradation peptides].
Carboxymethylated bovine rhodopsin was subjected to cyanogen bromide cleavage at methionine residues. The resultant products were fractionated into the two groups according to the solubility of peptides in 2 M guanidine hydrochloride. Gel-filtration on Bio-Gel P-30 in 80% formic acid of each group followed by rechromatography and high performance liquid chromatography resulted in 15 peptides embracing the whole polypeptide chain of rhodopsin. Amino acid sequence of these peptides was determined.


Immune regulatory cell infusion for graft-versus-host disease prevention and therapy.
Current approaches to prevent and treat graft-versus-host disease (GVHD) after stem cell transplantation rely principally on pharmacological immune suppression. Such approaches are limited by drug toxicity, nonspecific immune suppression, and a requirement for long-term therapy. Our increased understanding of the regulatory cells and molecular pathways involved in limiting pathogenic immune responses opens the opportunity for the use of these cell subsets to prevent and/or GVHD. The theoretical advantages of this approach is permanency of effect, potential for facilitating tissue repair, and induction of tolerance that obviates a need for ongoing drug therapy. To date, a number of potential cell subsets have been identified, including FoxP3+ regulatory T (Treg) and FoxP3negIL-10+ (FoxP3-negative) regulatory T (Tr1), natural killer (NK) and natural killer T (NKT) cells, innate lymphoid cells, and various myeloid suppressor populations of hematopoietic (eg, myeloid derived suppressor cells) and stromal origin (eg, mesenchymal stem cells). Despite initial technical challenges relating to large-scale selection and expansion, these regulatory lineages are now undergoing early phase clinical testing. To date, Treg therapies have shown promising results in preventing clinical GVHD when infused early after transplant. Results from ongoing studies over the next 5 years will delineate the most appropriate cell lineage, source (donor, host, third party), timing, and potential exogenous cytokine support needed to achieve the goal of clinical transplant tolerance.


Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes.
The possible contribution of HLA-DRB3, -DRB4, and -DRB5 alleles to type 1 diabetes risk and to insulin autoantibody (IAA), GAD65 (GAD autoantibody [GADA]), IA-2 antigen (IA-2A), or ZnT8 against either of the three amino acid variants R, W, or Q at position 325 (ZnT8RA, ZnT8WA, and ZnT8QA, respectively) at clinical diagnosis is unclear. Next-generation sequencing (NGS) was used to determine all DRB alleles in consecutively diagnosed patients ages 1-18 years with islet autoantibody-positive type 1 diabetes (n = 970) and control subjects (n = 448). DRB3, DRB4, or DRB5 alleles were tested for an association with the risk of DRB1 for autoantibodies, type 1 diabetes, or both. The association between type 1 diabetes and DRB1*03:01:01 was affected by DRB3*01:01:02 and DRB3*02:02:01. These DRB3 alleles were associated positively with GADA but negatively with ZnT8WA, IA-2A, and IAA. The negative association between type 1 diabetes and DRB1*13:01:01 was affected by DRB3*01:01:02 to increase the risk and by DRB3*02:02:01 to maintain a negative association. DRB4*01:03:01 was strongly associated with type 1 diabetes (P = 10(-36)), yet its association was extensively affected by DRB1 alleles from protective (DRB1*04:03:01) to high (DRB1*04:01:01) risk, but its association with DRB1*04:05:01 decreased the risk. HLA-DRB3, -DRB4, and -DRB5 affect type 1 diabetes risk and islet autoantibodies. HLA typing with NGS should prove useful to select participants for prevention or intervention trials.


[The association of autoimmune thyroiditis with HLA-B8 in the Georgian population].
The study of distribution of HLA antigens among Georgian population in case of autoimmune thyreoiditis revealed a statistically significant association of HLA-B8 antigen with autoimmune thyreoiditis. For statistical analysis we used following criterion: relative risk, attributive risk, preventive fraction, correlation coefficient and immunogenetic correction (P). Without compatibility to these criteria, there were no associations of the HLA antigens with the diseases. Although 8 of the antigens gave relative risk more than one, but only HLA B8 gave real association with autoimmune thyreoiditis. Typing of HLA antigens of class I and class II loci was done by classic microlymphocytotoxic test. The test performed on the lymphocytes from patients with autoimmune thyreoiditis. The character of association of HLA antigens among Georgian population with Hashimoto disease differs in character from other populations that evidently can be explained by the distributional character of HLA antigens among normal Georgian population.


Local adaptation to winter conditions in a passerine spreading north: a common-garden approach.
Sedentary passerine birds living in temperate and boreal regions need a high metabolic capacity for thermogenesis to survive winter conditions. As a consequence of the increased thermogenic capacity, basal energetic demands rise at a time when resources and time to acquire them decrease. In a previous study, great tits (Parus major) from two localities in Fennoscandia with contrasting winter conditions differed in their metabolic response to ambient temperature. To investigate the physiological basis underlying interpopulation differences we performed a common-garden experiment to test whether these differences were genetically based. We found basal metabolic rate to be higher in birds originating from transferred eggs from the southern population compared to the ones from the northern population, contrary to the relationship among birds living in their region of origin. Despite previous evidence suggesting that gene flow prevents local adaptation at the northern range limits of a species expanding northward, we found that great tits differ in their reaction norm to winter conditions according to the population of origin.


A Comparative Study to Assess the Accommodation and Vergence Relationship of Myopia in Indian Adolescent.
Accommodation and Vergence disorder are diverse visual anomalies which can interfere with a child's school performance and impair one's ability to function efficiently. Its association with refractive error and its intervention were studied less in Indian myopia children; hence, there is a need for research in such setting. One hundred and fifty Indian adolescents aged 10 to 17 years were divided into three refractive error groups (high, moderate, and low myopia). Baseline vision examination and a comprehensive binocular vision assessment were performed on all eligible adolescents. Vision therapy was provided to participants whose parents gave consent on behalf of the children. Chi-square analysis was utilized to look at the association between the groups of refractive errors. To compare the mean constants of the experimental and control groups, a two-way RM ANOVA was performed. The most common dysfunction found in low myopia (75.3%), and moderate myopia (54%) was convergence insufficiency. High myopes (62.8%) were found to have combined convergence and accommodative insufficiency followed by accommodative dysfunction (14%) and basic exophoria (6%). In moderate myopia, a significant relationship was found between this dysfunction and refractive error. The experimental group in the overall sample showed statistically significant improvement after vision therapy (P<0.001), in comparison to the control group. Refractive error is linked to accommodative and convergence insufficiency. Thus, vergence and accommodative impairment must be tested for all myopic children, and vision therapy should be advised along with spectacle prescription for efficient binocular vision.


Retorting conditions affect palatability and physical characteristics of canned cat food.
The effects of different temperature and time conditions during retorting of canned cat food on physicochemical characteristics and palatability were examined. For this purpose, lacquer cans containing an unprocessed loaf-type commercial cat food were heated in a pressurised retorting system at three specified temperature-time profiles (113°C/232 min, 120°C/103 min and 127°C/60 min) to equal a similar lethality (F0 value = 30). Physicochemical properties (viscosity, texture, particle size, pH) were determined, and a 10 d three-bowl palatability test was performed with ten European shorthair cats. Retorting at 113°C/232 min resulted in differences in all the physical parameters examined (<viscosity, firmness, adhesiveness, and > particle size). Significant pH differences were observed (6·53, 6·63 and 6·66 for T113/232, 120 and 127°C, respectively). Preference ratios were 0·38, 0·31 and 0·31 for T113/232, 120 and 127°C, respectively (P = 0·067). It can be concluded that different retorting temperature-time profiles with equal F0 value significantly affect physical characteristics and tended to affect palatability of moist cat food.


MicroRNA miR-93-5p regulates expression of IL-8 and VEGF in neuroblastoma SK-N-AS cells.
The role of the microRNA miR-93-5p on the secretome profile and the expression levels of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) was investigated in the neuroblastoma SK-N-AS cell line by Bio-Plex analysis and RT-qPCR. The results indicate that VEGF and IL-8 are the major miR-93-5p molecular targets. This conclusion was based on in vitro transfection with pre-miR-93-5p and anti-miR-93-5p; these treatments inversely modulated both VEGF and IL-8 gene expression and protein release in the neuroblastoma SK-N-AS cell line. Computational analysis showed the presence of miR-93-5p consensus sequences in the 3'UTR region of both VEGF and IL-8 mRNAs, predicting possible interaction with miR-93-5p and confirming a potential regulatory role of this microRNA.


[Sonographic and Doppler color sonographic findings in osteosarcoma].
Till now bone tumors are diagnosed radiologically. In this paper we describe the characteristic sonographic and colour Doppler sonographic features in 5 patients with histologically confirmed osteosarcoma. A large soft tissue tumor with echogenic osteosclerotic areas and echo-free caverns could be shown in all patients. Characteristic signs were destructions of the cortical layer and reactions of the periosteum. Compared to normal tissue an increased number of blood vessels with increased blood flow were visible by colour coded Doppler sonography in the region of the tumor. Sonography and colour coded Doppler sonography are important additions of conventional radiology to describe the structure, extension and blood supply of an osteosarcoma.


Brood Size Affects Future Reproduction in a Long-Lived Bird with Precocial Young.
Estimation of trade-offs between current reproduction and future survival and fecundity of long-lived vertebrates is essential to understanding factors that shape optimal reproductive investment. Black brant geese (Branta bernicla nigricans) fledge more goslings, on average, when their broods are experimentally enlarged to be greater than the most common clutch size of four eggs. Thus, we hypothesized that the lesser frequency of brant clutches exceeding four eggs results, at least partially, from a future reduction in survival, breeding probability, or clutch size for females tending larger broods. We used an 8-year mark-recapture data set (Barker robust design) with 5 years of clutch and brood manipulations to estimate long-term consequences of reproductive decisions in brant. We did not find evidence of a trade-off between reproductive effort and true survival or future initiation date and clutch size. Rather, future breeding probability was maximized ( 0.92±0.03 [SE]) for manipulated females tending broods of four goslings and was lower for females tending smaller (one gosling; 0.63±0.09 [SE]) or larger (seven goslings; 0.52±0.15 [SE]) broods. Our results suggest that demographic trade-offs for female brant tending large broods may reduce the fitness value of clutches larger than four and, therefore, contribute to the paucity of larger clutches. The lack of a trade-off between reproductive effort and survival provides evidence that survival, to which fitness is most sensitive in long-lived animals, is buffered against temporal variation in brant.


Diagnosis of malignant cardiac disease by endomyocardial biopsy.
Among oncology patients, endomyocardial biopsy has been used primarily for the evaluation of anthracycline cardiotoxicity. In addition, however, endomyocardial biopsy may be useful for the detection of malignant cardiac neoplasms. Between 1982 and 1989, metastatic involvement of the heart was diagnosed by endomyocardial biopsy in seven patients at our institution. All except one of these patients were older than 50 years of age and had dyspnea as an initial symptom, and all had a known malignant lesion. Results of endomyocardial biopsy confirmed cardiac involvement by a hematologic malignant lesion in four patients and metastatic melanoma in two patients. In one patient, who had a history of breast cancer and lymphoma, a metastatic neoplasm of uncertain differentiation was observed. Myocyte damage was evident in endomyocardial biopsy specimens from two of the four patients with hematologic malignant disease. Endomyocardial biopsy was performed to confirm the possibility of metastatic involvement in five patients; in the other two, endomyocardial biopsy was performed to determine whether anthracycline cardiotoxicity was present, and metastatic involvement was unanticipated.


Stimulation of renin by acute selective chloride depletion in the rat.
To determine whether acute chloride depletion per se stimulates renin, we produced selective chloride depletion without sodium depletion in rats by peritoneal dialysis (PD) against 0.15 M NaHCO3 or 0.15 M NaNO3. Control rats were dialyzed against 0.15 M NaCl. Plasma renin activity (PRA) was measured before (PRA1) and 105 minutes after (PRA2) PD. Plasma volume was expanded after PD by infusion of salt-free albumin and was measured immediately after PRA2 by [131I]albumin. In experiment 1, rats were prepared on a normal diet. PRA2 (7.0 +/- 1.0 ng/ml per hr, mean +/- SEM) was increased (P less than 0.05) over PRA1 (4.7 +/- 0.7 ng/ml per hr) in Cl-depleted but not in control rats (PRA1 = 5.3 +/- 0.7, PRA2 = 6.1 +/- 0.7, P = NS). In experiment 2, to produce greater chloride depletion, all rats were prepared for 2 weeks on a low salt diet. PRA2 (47 +/- 5 ng/ml per hr) was increased as compared to PRA1 (24 +/- 2 ng/ml per hr, P less than 0.005) in the Cl-depleted group but not in the control group (PRA1 = 24 +/- 3, PRA2 = 27 +/- 6 ng/ml per hr, P = NS). Serum potassium and final plasma volume were slightly but not significantly lower than controls in these Cl-depleted rats. To exclude an additive effect of these two stimuli for renin, in experiment 2a we infused chloride-depleted rats with three times as much albumin as controls and with KHCO3, 100 mEq/liter. Despite volume expansion and potassium loading, PRA2 (41 +/- 6 ng/ml per hr) was significantly elevated as compared to PRA1 (25 +/- 4 ng/ml per hr, P less than 0.01). Since acute metabolic alkalosis also was present in all Cl-depleted renin-stimulated rats, an additional group (2b) was dialyzed against 0.15 M NaNO3; final plasma arterial pH (7.43) was not different from controls (7.42). Nevertheless, PRA2 levels again were higher (36 +/- 6 ng/ml per hr, P less than 0.05) as compared to PRA1 (23 +/- 4 ng/ml per hr). In all experiments, arterial blood pressure, glomerular filtration rate, and filtered sodium load were not different. Free water reabsorption was lower in Cl-depleted than in control rats. We conclude that acute selective chloride depletion per se is a potent stimulus for renin release.


Polymorphisms of MICA recognized by human alloantibodies.
MICA antigens are polymorphic glycoproteins expressed on the surface of human endothelial cells and other cells. Antibodies against MICA have been found in transplant recipients and were found to be associated with decreased survival of kidney allografts. In the present work, we investigated the polymorphisms that are recognized by antibodies against MICA. Soluble MICA recombinant proteins representing 11 common alleles, two hybrid alleles, and two single amino acid mutated alleles were produced. Patterns of reactivity were determined with MICA bound to Luminex beads. In some studies, sera containing antibodies against MICA were absorbed by cell lines transfected with MICA*001, MICA*002, MICA*008, and MICA*009 or with untransfected cells, followed by testing of antibody reactivity against MICA proteins bound to beads. The monoclonal antibodies and sera used in this study were found to recognize up to 14 distinct MICA epitopes as demonstrated by their differential absorption/reactivity patterns. Among these, nine epitopes correlated with a single unique amino acid: one shared two signature amino acids, one shared three signature amino acids in close proximity, and three epitopes involved multiple amino acids in a nonlinear sequence. Two groups of public epitopes (MICA-G1 and MICA-G2) were characterized. MICA shared epitopes were determined by reactivity loss in single MICA antigen bead assays by absorption with MICA transfectants. Since these epitopes may be targets for antibody binding and possibly antibody-mediated allograft rejection, epitope identification may help understand the development of MICA antibodies and to identify suitable donors for sensitized transplant recipients.


Role of ERK signaling in bladder urothelium in response to cyclophosphamide injury.
Mice with inducible urothelial deletion of fibroblast growth factor receptor 2 (ShhCreERT2;Fgfr2Fl/Fl ) injured with cyclophosphamide had aberrant basal cell endoreplication and poor regeneration. The endoreplication correlated with an absence of phosphorylated (activated) ERK expression in urothelium. We assessed whether inhibiting ERK activity phenocopied the urothelial defects in injured Fgfr2 mutant mice. We co-administered cyclophosphamide and an ERK inhibitor (ERKi) systemically in mice and assessed general histology and immunofluorescence for various markers post injury. Since AKT also signals downstream of FGFR2, we assessed effects of an AKT inhibitor (AKTi) on cyclophosphamide injury. ERK knockdown did not affect urothelial injury or proliferation 24 h after cyclophosphamide. Conversely, ERK inhibition led to larger basal cell nuclei, more submucosal hemorrhage and attenuated uroplakin staining 3 days after injury versus vehicle-treated mice. Compared to vehicle-treated mice, ERKi-treated mice had a trend for more Ki67+ urothelial cells and had statistically fewer phospho-Histone H3+ cells normalized to Ki67 and higher basal cell DNA content, consistent with endoreplication 3 days after injury. Ten days after injury, ERKi-treated mice still had signs of poor urothelial regeneration with absent or aberrant expression of differentiation markers and ectopic lumenal expression of keratin 14 (basal progenitor marker). Co-administration of the AKTi led to no apparent urothelial defects 3 days after cyclophosphamide. Thus, ERK knockdown (but not AKT knockdown) leads to urothelial regenerative responses after cyclophosphamide reminiscent of Fgfr2 mutant mice. Together, it appears that FGFR2 acts through ERK to prevent aberrant urothelial basal cell endoreplication and ensure normal regeneration after cyclophosphamide.


[Detection of C-reactive protein in patients with epidemic cerebrospinal meningitis by solid phase radioimmunoassay].
A modified solid phase RIA was developed for the quantification of C-reactive protein in human serum and CSF. The lowest measurable amount detected by this method was 5 ng/ml (0.25 ng/well). The serum levels in 68 healthy blood donors were with in the range from 0.028-3.4 micrograms/ml, with a median value of 0.166 micrograms/ml (mean = 1.57 micrograms/ml); whilst those in 63 patients with epidemic cerebrospinal meningitis were up to 520 micrograms/ml with a median value of 77.5 micrograms/ml (mean = 88.46 micrograms/ml). This is 400-500-fold higher than that of the normal. The levels of CRP in the sera collected during acute stage of the infection (ranged from 28.5-540 micrograms/ml, with a median value of 200 micrograms/ml, mean = 200.6 micrograms/ml) were 400-fold higher than that after recovery (ranged from 0.1-54 micrograms/ml, with a median value of 0.53 micrograms/ml). In addition, lower levels (0.07-150 micrograms/ml, median = 2.07 micrograms/ml) of CRP were detected in CSF. These results markedly revealed that the CRP reflected the characteristics of an acute phase protein in the infection, and would be usefull for the differential diagnosis of bacterial and nonbacterial meningitis, and in monitoring the clinical course of the illness.


Hepatobiliary organoids derived from leporids support the replication of hepatotropic lagoviruses.
The genus Lagovirus of the family Caliciviridae contains some of the most virulent vertebrate viruses known. Lagoviruses infect leporids, such as rabbits, hares and cottontails. Highly pathogenic viruses such as Rabbit haemorrhagic disease virus 1 (RHDV1) cause a fulminant hepatitis that typically leads to disseminated intravascular coagulation within 24-72 h of infection, killing over 95 % of susceptible animals. Research into the pathophysiological mechanisms that are responsible for this extreme phenotype has been hampered by the lack of a reliable culture system. Here, we report on a new ex vivo model for the cultivation of lagoviruses in cells derived from the European rabbit (Oryctolagus cuniculus) and European brown hare (Lepus europaeus). We show that three different lagoviruses, RHDV1, RHDV2 and RHDVa-K5, replicate in monolayer cultures derived from rabbit hepatobiliary organoids, but not in monolayer cultures derived from cat (Felis catus) or mouse (Mus musculus) organoids. Virus multiplication was demonstrated by (i) an increase in viral RNA levels, (ii) the accumulation of dsRNA viral replication intermediates and (iii) the expression of viral structural and non-structural proteins. The establishment of an organoid culture system for lagoviruses will facilitate studies with considerable implications for the conservation of endangered leporid species in Europe and North America, and the biocontrol of overabundant rabbit populations in Australia and New Zealand.


Obesity: an independent predictor of in-hospital postoperative renal insufficiency among patients undergoing cardiac surgery?
We sought to determine, retrospectively, whether obesity was associated with adverse renal outcomes in 17,630 patients who underwent cardiac surgery from January 1995 through December 2006. Obesity was defined as a body mass index > or = 30 kg/m2. The primary outcome was any episode of postoperative renal insufficiency (requiring or not requiring dialysis) before hospital discharge. Outcomes were evaluated in the entire cohort and in subgroups undergoing isolated coronary artery bypass grafting (CABG), isolated valve surgery, and combined CABG and valve surgery. The final analysis included 16,429 patients, 5,124 (31%) of whom were obese. In the entire cohort, obesity was associated both with increased risk of any postoperative renal insufficiency (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.21-1.55) and with increased risk of renal insufficiency not requiring dialysis (OR, 1.41; 95% CI, 1.23-1.62). Obesity was associated with an increased risk of postoperative renal insufficiency in patients undergoing isolated CABG (OR, 1.38; 95% CI, 1.18-1.61), isolated valve surgeries (OR, 1.39; 95% CI, 1.05-1.85), and combined CABG and valve surgeries (OR, 1.35; 95% CI, 0.99-1.83; statistically nonsignificant). Development of postoperative renal insufficiency was associated with a significantly higher mortality rate (P <0.0001) and with a significantly longer hospital stay (23 vs 10.5 days; P <0.0001). We conclude that obesity is associated with a significant increase in postoperative renal insufficiency in cardiac surgery patients, an effect that we attribute to an increase in postoperative renal failure that does not require dialysis.


The Role of Digital Navigators in Promoting Clinical Care and Technology Integration into Practice.
As the role of technology expands in healthcare, so does the need to support its implementation and integration into the clinic. The concept of a new team member, the digital navigator, able to assume this role is introduced as a solution. With a digital navigator, any clinic today can take advantage of digital health and smartphone tools to augment and expand existing telehealth and face to face care. The role of a digital navigator is suitable as an entry level healthcare role, additional training for an experienced clinician, and well suited to peer specialists. To facilitate the training of digital navigators, we draw upon our experience in creating the role and across health education to introduce a 10-h curriculum designed to train digital navigators across 5 domains: (1) core smartphone skills, (2) basic technology troubleshooting, (3) app evaluation, (4) clinical terminology and data, and (5) engagement techniques. This paper outlines the curricular content, skills, and modules for this training and features a rich online supplementary Appendix with step by step instructions and resources.


[The humoral immune response to Epstein-Barr virus in rheumatoid arthritis].
Antibodies to EB virus capsid antigen were assayed for by means of indirect immunofluorescence technique in the serum of 72 rheumatoid arthritis patients; the synovial fluid was tested in parallel with the serum in 18 of these patients. An authentic increase in antibody levels was revealed, as compared to healthy individuals, which is evidence of latent infection activation by EB virus. There was no correlation between the degree to which this activation was pronounced, the rheumatoid factor level in the serum and synovial fluid, and the signs of systemic disease. Half of the rheumatoid synovitis patients were found to have an authentic prevalence of antiviral antibody level in the synovial fluid over that in the serum.


The bioavailability of iron in different weaning foods and the enhancing effect of a fruit drink containing ascorbic acid.
There is limited information on the bioavailability of Fe in infant weaning foods, mainly because of the difficulties of measuring Fe utilization directly in infants. The aim of this study was to develop a safe and relatively noninvasive method for studying Fe bioavailability (measured as percent Fe incorporation into red blood cells) in infants using 54Fe, 57Fe, and 58Fe stable isotopes. Four commonly used weaning foods were selected for study, labeled extrinsically with 57Fe- or 58Fe-enriched ferrous sulfate, and fed to five female and five male 9-mo-old fasting infants, using a multiple-dosing technique. Each food was given three times, labeled with one isotope, with a fruit juice drink containing 50 mg of ascorbic acid, and three times, labeled with a different isotope, with an ascorbic acid-free drink. Fourteen days after the last test meal, a blood sample was obtained from a heel-prick, spiked with a known amount of 54Fe, digested, and purified by ion exchange; isotopic enrichment and total Fe content were measured by quadrupole thermal ionization mass spectrometry. The proportion of administered dose of isotope circulating in the blood was calculated from an estimate of blood volume. The geometric mean bioavailability (range) was 3.0% (1.2-9.5%) in a proprietary dehydrated vegetable product, 3.0% (1.1-21.2%) in Weetabix whole-wheat breakfast cereal, 3.1% (1.2-15.4%) in wholemeal bread, and 4.3% (1.7-10.3%) in baked beans. When taken with the drink containing ascorbic acid, there was a 2-fold increase in bioavailability in all foods except the vegetable meal, presumably because this was already fortified with ascorbic acid.(ABSTRACT TRUNCATED AT 250 WORDS)


Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells.
Respiratory tract resident memory T cells (TRM), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory TRM. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles. Here, we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influenced influenza-specific cell-mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 TRM in the lung and draining lymph nodes. Contralateral, compared with ipsilateral, intramuscular boosting broadened the distribution of lymph node TRM and T follicular helper cells but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory but augmented distribution to the respiratory mucosa. Combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung TRM. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung TRM that can be further expanded by an additional intranasal immunization.


Comparison of reversible and nonreversible aqueous-soluble lipidized conjugates of salmon calcitonin.
Reversible aqueous lipidization (REAL) at the interdisulfide bond has been shown to improve the deliverability of some peptide drugs. Recently, we developed a nonreversible aqueous lipidization method targeted at the interdisulfide bond of salmon calcitonin (sCT). The resultant derivative had comparable hypocalcemic activity to sCT after subcutaneous injection in rats, despite possessing significantly different biophysical properties. The purpose of this study was to conduct a comparative evaluation of the biophysical properties of the reversible aqueous-soluble lipidized sCT (REAL-sCT) and its corresponding nonreversible aqueous-soluble compound (Mal-sCT) with a view to correlate these properties to the bioactivities of the peptides. REAL-sCT and Mal-sCT were successfully synthesized, purified and identified. Both conjugates showed comparable retention times in a C-18 HPLC column, as well as robust helical structures and aggregation behavior in water, although REAL-sCT was shown by dynamic light scattering experiments to form larger aggregates than Mal-sCT in water. The larger particle size of REAL-sCT correlated with its stronger resistance to degradation by intestinal enzymes. Unlike Mal-sCT, REAL-sCT was rapidly converted to sCT in liver juice; however, the regenerated sCT appeared to degrade at a slower rate than unmodified sCT in the liver juice. Compared with sCT, REAL-sCT after subcutaneous injection as an aqueous solution at a dose of 0.15 mg/kg produced a prolonged hypocalcemic activity that lasted at least 24 h in the rat. Using a novel LC-MS/MS method that was developed for this study, we were able to show concomitant increases in REAL-sCT and sCT plasma concentrations with time, the latter prevailing at 10% the molar concentration of the former. In contrast, sCT was not present in the plasma following the subcutaneous injection of Mal-sCT, although a comparable hypocalcemic activity with shorter duration was observed. Oral administration of REAL-sCT and Mal-sCT as aqueous solutions at sCT equivalent dose of 5.0 mg/kg did not produce significant hypocalcemic activity. This study is the first thorough examination of the biophysical characteristics of the corresponding reversible and nonreversible aqueous-soluble lipidized peptide molecules. The results obtained should be useful for the development of the oral formulation of peptide and protein drugs.


A general gelation strategy for 1D nanowires: dynamically stable functional gels for 3D printing flexible electronics.
3D printing of functional inorganic nanowires has been accomplished using extruded nanowire-based inks obtained by incorporating nanofillers into polymeric matrices or thickeners. However, the presence of inactive additives poses a critical challenge for fully realizing the functionality of the nanowires in the printed structures, which remains a fundamental hurdle to overcome. Here, to construct 3D-printed electronics with high performance, we developed a versatile gelation strategy to obtain thixotropic nanowire gels through formation of dynamically stable 3D networks using small amounts of flexible, water-soluble and single-layer 2D nanosheets, such as graphene oxide and MXene, as physical cross-linkers. The nanosheets can knot-tie and stabilize the nanowire junctions in the aqueous suspension, leading to the formation of stable and thixotropic gels with viscosities up to ∼80 000 Pa s at 0.01 s-1 in the absence of polymer thickener. Gels of varioius metallic and semiconductive nanowires have been successfully prepared and printed into 3D and self-supported architectures via extrusion-based 3D-printing. The synergism of nanowires and nanosheets not only conquers the restraints of harsh post-treatments to remove additives after printing, but also maximizes the functionality of the nanowires in the printed architectures. The printed 3D structures solidified by ambient drying, coagulation, or freeze-drying exhibit remarkable functionalities. For example, the electrical conductivity of the 3D-printed silver nanowire-based architectures can reach 40 000 S cm-1. The feasibility of these functional nanowire gels was demonstrated by fabricating a series of printed flexible electronics via extrusion-based 3D-printing.


Molecular genetics of metachromatic leukodystrophy.
Metachromatic leukodystrophy is an autosomal recessive inherited lysosomal storage disease. It can be caused by mutations in two different genes, the arylsulfatase A and the prosaposin gene. These genes encode two proteins that are needed for the proper degradation of cerebroside sulfate, a glycolipid mainly found in the myelin membranes. Deficiency of arylsulfatase A or of a proteolytic product of prosaposin leads to the accumulation of cerebroside sulfate, which causes a lethal progressive demyelination. Mutations in the arylsulfatase A gene are far more frequent than those of the prosaposin gene. So far 31 amino acid substitutions, one nonsense mutation, three small deletions, three splice donor site mutations, and one combined missense/splice donor site mutation have been identified in the arylsulfatase A gene. Two of these mutant alleles are frequent, accounting for about one-half of all mutant alleles, whereas the remainder are heterogeneous. Amino acid substitutions cluster in exons 2 and 3, a region that shows a high degree of conservation among sulfatases of different function and origin. Different mutations are associated with phenotypes of different severity, but there is a remarkable variability of severity when patients with identical genotypes are compared. Demonstration of an arylsulfatase A deficiency is not a proof of metachromatic leukodystrophy, since a substantial deficiency without any clinical consequences is frequent in the general population. This deficiency is caused by an arylsulfatase A allele, which due to certain mutations encodes greatly reduced amounts of functional enzyme. However, these amounts are sufficient to sustain a normal phenotype. In the diagnosis and genetic counseling, these deficiencies must be differentiated from those causing metachromatic leukodystrophy. So far only six patients with mutations in the prosaposin gene have been described, in which three defective alleles two with amino acid substitutions and one with a 33-bp insertion have been identified.