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Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily rising incidence yet no cure. Phosphoinositide 3-kinase-γ (PI3Kγ), a member of a family of lipid kinases expressed primarily in leukocytes, has been the subject of substantial research for its role in inflammatory diseases. However, the role of PI3Kγ inhibition in suppressing autoimmune T1D remains to be explored. We tested the role of the PI3Kγ inhibitor AS605240 in preventing and reversing diabetes in NOD mice and assessed the mechanisms by which this inhibition abrogates T1D. Our data indicate that the PI3Kγ pathway is highly activated in T1D. In NOD mice, we found upregulated expression of phosphorylated Akt (PAkt) in splenocytes. Notably, T regulatory cells (Tregs) showed significantly lower expression of PAkt compared with effector T cells. Inhibition of the PI3Kγ pathway by AS605240 efficiently suppressed effector T cells and induced Treg expansion through the cAMP response element-binding pathway. AS605240 effectively prevented and reversed autoimmune diabetes in NOD mice and suppressed T-cell activation and the production of inflammatory cytokines by autoreactive T cells in vitro and in vivo. These studies demonstrate the key role of the PI3Kγ pathway in determining the balance of Tregs and autoreactive cells regulating autoimmune diabetes. [ABSTRACT FROM AUTHOR]

Climate change has significantly exacerbated the effects of abiotic stresses, particularly high temperatures and drought stresses. This study aims to uncover the mechanisms underlying heat and drought tolerance in lentil accessions. To achieve this objective, twelve accessions were subjected to high-temperature stress (32/20 °C), while seven accessions underwent assessment under drought stress conditions (50% of field capacity) during the reproductive stage. Our findings revealed a significant increase in catalase activity across all accessions under both stress conditions, with ILL7814 and ILL7835 recording the highest accumulations of 10.18 and 9.33 under drought stress, respectively, and 14 µmol H 2 O 2 mg protein -1 min -1 under high temperature. Similarly, ascorbate peroxidase significantly increased in all tolerant accessions due to high temperatures, with ILL6359, ILL7835, and ILL8029 accumulating the highest values with up 50 µmol ascorbate mg protein -1 min -1 . In contrast, no significant increase was obtained for all accessions subjected to water stress, although the drought-tolerant accessions accumulated more APX activity (16.59 t to 25.08 µmol ascorbate mg protein -1 min -1 ) than the sensitive accessions. The accessions ILL6075, ILL7814, and ILL8029 significantly had the highest superoxide dismutase activity under high temperature, while ILL6363, ILL7814, and ILL7835 accumulated the highest values under drought stress, each with 22 to 25 units mg protein -1 . Under both stress conditions, ILL7814 and ILL7835 recorded the highest contents in proline (38 to 45 µmol proline/g FW), total flavonoids (0.22 to 0.77 mg QE g -1 FW), total phenolics (7.50 to 8.79 mg GAE g -1 FW), total tannins (5.07 to 20 µg CE g -1 FW), and total antioxidant activity (60 to 70%). Further, ILL7814 and ILL6338 significantly recorded the highest total soluble sugar content under high temperature (71.57 and 74.24 mg g -1 , respectively), while ILL7835 achieved the maximum concentration (125 mg g -1 ) under drought stress. The accessions ILL8029, ILL6104, and ILL7814 had the highest values of reducing sugar under high temperature with 0.62 to 0.79 mg g -1 , whereas ILL6075, ILL6363, and ILL6362 accumulated the highest levels of this component under drought stress with 0.54 to 0.66 mg g -1 . Overall, our findings contribute to a deeper understanding of the metabolomic responses of lentil to drought and heat stresses, serving as a valuable reference for lentil stress tolerance breeding.

Chickpea is the third most consumed pulse and provides a kit of essential nutrients for an exponential population. High temperatures and drought stress are two major abiotic stresses that cause serious effects on chickpea growth and development. The comprehension of abiotic stresses' impact on chickpea productivity and nutritional quality will permit the selection of promising genotypes. The current study aimed to assess the impact of heat and drought stresses on plant growth, grain yield and its components, grain size, and nutritional quality in chickpea. For this purpose, 43 international chickpea genotypes were evaluated under normal, heat, and combined heat-drought stress conditions. The findings revealed a significant decrease of over 50% in plant height, biological yield, and seed yield under both stress conditions. Grain size and hundred-seed weight were the most heritable traits under normal, heat, and combined heat-drought stress. Proteins were accumulated under both stresses, evolving from 20.26% for normal conditions to 22.19% for heat stress and to 21.94% for combined heat-drought stress. For minerals, significant variation between treatments was observed for Mn, Mg, and Na. Our results also showed a significant impact of genotype and genotype-environment interaction factors only on K content. Using selection indices, 22 genotypes were identified as highly tolerant to the combined heat-drought stress, while eleven genotypes were heat-tolerant. Mineral profile analysis according to the contrasting tolerance clusters revealed decreased potassium content in susceptible genotypes, indicating genetic potential in the studied chickpea collection, ensuring tolerance to both stresses while maintaining good grain quality.

Grasspea ( Lathyrus sativus L.) is recognized as a highly drought-tolerant legume. However, excessive consumption of its seeds and green tissues causes neurolathyrism, a condition characterized by an irreversible paralysis of the legs induced by a neurotoxin amino acid called β-N-oxalyl-L-α, β- diaminopropionic acid (β-ODAP). The present study investigated the effects of heat, and combined heat + drought during the reproductive phase on physiological and phenological parameters, yield-related factors, ODAP content, and seed protein of 24 genotypes representing 11 Lathyrus species under controlled conditions. Analysis of variance revealed a highly significant effect ( p < 0.001) of stress treatments and genotypes for all the traits. In general, heat stress individually or in combination with drought expedited phenology, reduced relative leaf water content, stimulated proline synthesis, and influenced chlorophyll concentration; the effects were more severe under the combined heat + drought stress. ODAP content in seeds ranged from 0.06 to 0.30% under no-stress conditions. However, under heat stress, there was a significant increase of 33% in ODAP content, and under combined stress (heat + drought), the increase reached 83%. Crude protein content ranged from 15.64 to 28.67% among no stress plants and decreased significantly by 23% under heat stress and by 36% under combined stress. The findings of this study also indicated substantial reductions in growth and grain yield traits under both heat stress and combined heat + drought stress. Six accessions namely IG 66026 , IG 65018 , IG 65687 , IG 118511 , IG 64931 , and IG65273 were identified as having the most favorable combination of yield, protein content, and seed ODAP levels across all conditions. ODAP content in these six accessions varied from 0.07 to 0.11% under no stress and remained at moderate levels during both heat stress (0.09-0.14%) and combined stress (0.11-0.17%). IG 66026 was identified as the most stable genotype under drought and heat stress conditions with high protein content, and low ODAP content. By identifying those promising accessions, our results have established a basis for forthcoming grasspea breeding initiatives while paving the way for future research exploration into the fundamental mechanisms driving ODAP variation in the presence of both heat and drought stress conditions.

Human caregivers interacting with children typically modify their speech in ways that promote attention, bonding, and language acquisition. Although this "motherese," or child-directed communication (CDC), occurs in a variety of human cultures, evidence among nonhuman species is very rare. We looked for its occurrence in a nonhuman mammalian species with long-term mother-offspring bonds that is capable of vocal production learning, the bottlenose dolphin ( Tursiops truncatus ). Dolphin signature whistles provide a unique opportunity to test for CDC in nonhuman animals, because we are able to quantify changes in the same vocalizations produced in the presence or absence of calves. We analyzed recordings made during brief catch-and-release events of wild bottlenose dolphins in waters near Sarasota Bay, Florida, United States, and found that females produced signature whistles with significantly higher maximum frequencies and wider frequency ranges when they were recorded with their own dependent calves vs. not with them. These differences align with the higher fundamental frequencies and wider pitch ranges seen in human CDC. Our results provide evidence in a nonhuman mammal for changes in the same vocalizations when produced in the presence vs. absence of offspring, and thus strongly support convergent evolution of motherese, or CDC, in bottlenose dolphins. CDC may function to enhance attention, bonding, and vocal learning in dolphin calves, as it does in human children. Our data add to the growing body of evidence that dolphins provide a powerful animal model for studying the evolution of vocal learning and language.

Purpose: To detect the effect of various types of COVID-19 vaccine on macular and optic disc microvasculature., Method: One hundred subjects receiving various types of COVID-19 vaccine (AstraZeneca, Sinopharm, Sinovac, Pfizer, and Moderna) were included in this study. A complete ophthalmic examination was done which included best-corrected visual acuity measurement, slit-lamp biomicroscopy, intraocular pressure measurement with Goldmann applanation tonometry, and fundus examination. Optical coherence tomography angiography (OCT-A) was done before and 1 week after receiving the vaccine. Superficial and deep macular capillary densities were measured in the form of the whole image, fovea, parafoveal, and perifoveal capillary density. Optic disc vessel density in the form of the whole disc, inside disc, and peripapillary were also measured., Results: The superficial macular vessel densities, (whole image, fovea, parafoveal, and perifoveal) showed statistically non-significant changes with P-values (0.269, 0.167, 0.346, and 0.476) respectively. Also, the deep macular vessel densities showed statistically non-significant changes with P-values (0.491, 0.096, 0.724, and 0.386) for the whole image, fovea, parafoveal, and perifoveal respectively. Moreover, RPC (radial peripapillary capillary) density showed no significant changes either (the whole disc, inside disc, or peripapillary) with P-values (0.807, 0.141, 0.883) respectively., Conclusion: Various types of COVID-19 vaccines had no statistically significant effects on macular or optic disc microvasculature., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

The objective of this work was to establish the bibliometric profile of Tunisian theses in 'general surgery' and to describe their themes, their study designs, and their writing quality. This is a retrospective descriptive bibliometric study, covering all the theses in medicine in the specialty of 'general surgery', defended in the four medical faculties of Tunisia, during the forty last years from 1980 to 2019. During the study period, 739 theses in 'general surgery' were discussed in Tunisia, with an average of 19 theses per year. The most studied research topic was emergencies (41%), followed by common surgical pathologies (26%) and digestive oncology (21.5%). Descriptive studies and case studies represented the majority of study designs with respective proportions of 56.9% and 40.6%. Only 20.7% of these theses had a scientific writing quality deemed satisfactory. The least respected elements in writing their summaries were statistical (confidence intervals and standard deviations) and documentary (keywords). Despite the plethora of themes of Tunisian theses in 'general surgery', their basic methodology and their editorial non conformity require the educational reform of the dissertations, both doctoral students and supervisors, by strengthening their skills in research methodology and scientific communication written.

High temperature during the reproductive stage limits the growth and development of lentil ( Lens culinaris Medikus). The reproductive and seed filling periods are the most sensitive to heat stress, resulting in limited yield and nutritional quality. Climate change causes frequent incidents of heat stress for global food crop production. This study aimed to assess the impact of high temperature during the reproductive stage of lentil on grain yield, nutritional value, and cooking quality. Thirty-six lentil genotypes were evaluated under controlled conditions for their high temperature response. Genotypic variation was significant ( p < 0.001) for all the traits under study. High temperature-induced conditions reduced protein, iron (Fe) and zinc (Zn) concentrations in lentils. Under heat stress conditions, mineral concentrations among lentil genotypes varied from 6.0 to 8.8 mg/100 g for Fe and from 4.9 to 6.6 mg/100 g for Zn. Protein ranged from 21.9 to 24.3 g/100 g. Cooking time was significantly reduced due to high temperature treatment; the range was 3-11 min, while under no stress conditions, cooking time variation was from 5 to 14 min. Phytic acid variation was 0.5-1.2 g/100 g under no stress conditions, while under heat stress conditions, phytic acid ranged from 0.4 to 1.4 g/100 g. All genotypes had highly significant bioavailable Fe and moderately bioavailable Zn under no stress conditions. Whereas under heat stress conditions, Fe and Zn bioavailability was reduced due to increased phytic acid levels. Our results will greatly benefit the development of biofortified lentil cultivars for global breeding programs to generate promising genotypes with low phytic acid and phytic acid/micronutrient ratio to combat micronutrient malnutrition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Choukri, El Haddad, Aloui, Hejjaoui, El-Baouchi, Smouni, Thavarajah, Maalouf and Kumar.)

Background: Waterpipe (shisha) is becoming increasingly popular worldwide, particularly among young people; and in some countries, it is one of the few forms of tobacco use that is increasing. While there is a growing body of evidence of the harms of waterpipe smoke, there is a scarcity of research of interventions to address this form of tobacco consumption., Methods: The Shisha No Thanks project was a co-design social marketing campaign that aimed to raise awareness of the harms of waterpipe smoking among young people from an Arabic speaking background in Sydney, Australia. The campaign distributed material through social media and community events. We evaluated the project through an SMS community panel using a longitudinal study design. The cohort were sent questions before and after the project asking about their awareness of messages of harms, attitudes, intention to reduce waterpipe smoking, and awareness of support services. Data was analysed as matched pre- post- data., Results: The evaluation recruited 133 people to the panel. There was a significantly greater proportion of people who reported seeing, hearing or reading something about the harms of waterpipe smoking after the campaign (67.5%) compared with before (45.0%) (p=0.003). Post-campaign, there were higher proportions of people who strongly agreed that waterpipe smoking causes damage, and that it contains cancer-causing substances, but these increases were not statistically significant. There was low awareness of waterpipe cessation services at baseline and post campaign (22.5%)., Conclusions: The Shisha No Thanks project increased awareness of messages about the harms of waterpipe smoking. Although this is a small study, the longitudinal evaluation findings have international relevance and make a useful contribution to the understanding of the impact such interventions can have in addressing one of the few forms of tobacco use that is growing in both developed and developing countries., (© 2022. The Author(s).)

Raffinose family oligosaccharides (RFOs) are widespread across the plant kingdom, and their concentrations are related to the environment, genotype, and harvest time. RFOs are known to carry out many functions in plants and humans. In this paper, we provide a comprehensive review of RFOs, including their beneficial and anti-nutritional properties. RFOs are considered anti-nutritional factors since they cause flatulence in humans and animals. Flatulence is the single most important factor that deters consumption and utilization of legumes in human and animal diets. In plants, RFOs have been reported to impart tolerance to heat, drought, cold, salinity, and disease resistance besides regulating seed germination, vigor, and longevity. In humans, RFOs have beneficial effects in the large intestine and have shown prebiotic potential by promoting the growth of beneficial bacteria reducing pathogens and putrefactive bacteria present in the colon. In addition to their prebiotic potential, RFOs have many other biological functions in humans and animals, such as anti-allergic, anti-obesity, anti-diabetic, prevention of non-alcoholic fatty liver disease, and cryoprotection. The wide-ranging applications of RFOs make them useful in food, feed, cosmetics, health, pharmaceuticals, and plant stress tolerance; therefore, we review the composition and diversity of RFOs, describe the metabolism and genetics of RFOs, evaluate their role in plant and human health, with a primary focus in grain legumes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elango, Rajendran, Van der Laan, Sebastiar, Raigne, Thaiparambil, El Haddad, Raja, Wang, Ferela, Chiteri, Thudi, Varshney, Chopra, Singh and Singh.)

High temperature and water deficit are among the major limitations reducing lentil ( Lens culinaris Medik.) yield in many growing regions. In addition, increasing atmospheric vapor pressure deficit (VPD) due to global warming causes a severe challenge by influencing the water balance of the plants, thus also affecting growth and yield. In the present study, we evaluated 20 lentil genotypes under field conditions and controlled environments with the following objectives: (i) to investigate the impact of temperature stress and combined temperature-drought stress on traits related to phenology, grain yield, nutritional quality, and canopy temperature under field conditions, and (ii) to examine the genotypic variability for limited transpiration (TR lim ) trait in response to increased VPD under controlled conditions. The field experiment results revealed that high-temperature stress significantly affected all parameters compared to normal conditions. The protein content ranged from 23.4 to 31.9%, while the range of grain zinc and iron content varied from 33.1 to 64.4 and 62.3 to 99.3 mg kg -1 , respectively, under normal conditions. The grain protein content, zinc and iron decreased significantly by 15, 14 and 15% under high-temperature stress, respectively. However, the impact was more severe under combined temperature-drought stress with a reduction of 53% in protein content, 18% in zinc and 20% in iron. Grain yield declined significantly by 43% in temperature stress and by 49% in the combined temperature-drought stress. The results from the controlled conditions showed a wide variation in TR among studied lentil genotypes. Nine genotypes displayed TR lim at 2.76 to 3.51 kPa, with the genotypes ILL 7833 and ILL 7835 exhibiting the lowest breakpoint. Genotypes with low breakpoints had the ability to conserve water, allowing it to be used at later stages for increased yield. Our results identified promising genotypes including ILL 7835, ILL 7814 and ILL 4605 (Bakria) that could be of great interest in breeding for high yields, protein and micronutrient contents under high-temperature and drought stress. In addition, it was found that the TR lim trait has the potential to select for increased lentil yields under field water-deficit environments.

During the COVID-19 pandemic many traditional methods of data collection, such as intercept surveys or focus groups, are not feasible. This paper proposes that establishing community panels through SMS text messages may be a useful method during the pandemic, by describing a case study of how an innovative SMS text message community panel was used for the "Shisha No Thanks" project to collect data from young adults of Arabic-speaking background about their attitudes on the harms of waterpipe smoking. Participants were asked to complete an initial recruitment survey, and then subsequently sent 1 survey question per week. The study recruited 133 participants to the SMS text message community panel and the mean response rate for each question was 73.0% (97.1/133) (range 76/133 [57.1%] to 112/133 [84.2%]). The SMS text message community panel approach is not suited for all populations, nor for all types of inquiry, particularly due to limitations of the type of responses that it allows and the required access to mobile devices. However, it is a rapid method for data collection, and therefore during the COVID-19 pandemic, it can provide service providers and policymakers with timely information to inform public health responses. In addition, this method negates the need for in-person interactions and allows for longitudinal data collection. It may be useful in supplementing other community needs assessment activities, and may be particularly relevant for people who are considered to be more difficult to reach, particularly young people, culturally and linguistically diverse communities, and other groups that might otherwise be missed by traditional methods., (©Lilian Chan, Nouhad El-Haddad, Becky Freeman, Blythe J O'Hara, Lisa Woodland, Ben Harris-Roxas. Originally published in JMIR Formative Research (https://formative.jmir.org), 03.11.2021.)

Objective: To objectively assess the quality of "crisis communication" media, during the COVID-19 pandemic, in the three Greater Maghreb countries (Tunisia, Algeria, Morocco)., Methods: A compliance audit for press releases and epidemiological bulletins was analyzed against a quality benchmark, which had been specifically designed by the authors. This framework, made up of five dimensions and 50 items, graded (0/1), was applied by two researchers in preventive medicine. Multiplying the scores by a coefficient of two resulted in a partial score of 20 points for each dimension and a total score of 100 points for the checklist taken as a whole. The quality of the communication media was considered to be good when exceeding the thresholds of 15/20 for the different dimensions and 75/100 for the entire grid., Results: A total of 141 information media were included in this audit (Tunisia: 60; Algeria: 60; Morocco: 21). The overall median quality score for these media was only 56/100 (IIQ: [46-58]), without major variability between countries. The most appreciated dimension was "maintaining the confidence of the population", with an overall median score of 14/20 (12/20 for epidemiological bulletins and 16/20 for press releases). The most poorly rated dimension was "strengthening community participation", with a median score of only 4/20 (6/20 for epidemiological bulletins and 4/20 for press releases)., Conclusion: The quality of the Maghreb crisis communication media during COVID-19 was insufficient in most of its dimensions and items, particularly from a psychosocial standpoint. Reinforcement of the capacities of communication officers to develop information material and supports during health crises is indispensable and should be considered as an urgent matter., (Copyright © 2021. Published by Elsevier Masson SAS.)

Lentil ( Lens culinaris Medikus) is a protein-rich cool-season food legume with an excellent source of protein, prebiotic carbohydrates, minerals, and vitamins. With climate change, heat, and drought stresses have become more frequent and intense in lentil growing areas with a strong influence on phenology, grain yield, and nutritional quality. This study aimed to assess the impact of heat and drought stresses on phenology, grain yield, and nutritional quality of lentil. For this purpose, 100 lentil genotypes from the global collection were evaluated under normal, heat, and combined heat-drought conditions. Analysis of variance revealed significant differences ( p < 0.001) among lentil genotypes for phenological traits, yield components, and grain quality traits. Under no stress conditions, mineral concentrations among lentil genotypes varied from 48 to 109 mg kg -1 for iron (Fe) and from 31 to 65 mg kg -1 for zinc (Zn), while crude protein content ranged from 22.5 to 32.0%. Iron, zinc, and crude protein content were significantly reduced under stress conditions, and the effect of combined heat-drought stress was more severe than heat stress alone. A significant positive correlation was observed between iron and zinc concentrations under both no stress and stress conditions. Based on grain yield, crude protein, and iron and zinc concentrations, lentil genotypes were grouped into three clusters following the hierarchical cluster analysis. Promising lentil genotypes with high micronutrient contents, crude protein, and grain yield with the least effect of heat and drought stress were identified as the potential donors for biofortification in the lentil breeding program., (Copyright © 2020 Choukri, Hejjaoui, El-Baouchi, El haddad, Smouni, Maalouf, Thavarajah and Kumar.)

Dairy product safety is a global public health issue that demands new approaches and technologies to control foodborne pathogenic microorganisms. Natural antimicrobial agents such as nisin can be added to control the growth of pathogens of concern in dairy foods, namely Listeria monocytogenes and Staphylococcus aureus. However, several factors affect the antimicrobial efficacy of nisin when directly added into the food matrix such as lack of stability at neutral pH, interaction with fat globules, casein, and divalent cations. To overcome these limitations, new and advanced strategies are discussed including nisin encapsulation technology, addition to active packaging, bioengineering, and combination with other antimicrobials. This review highlights advanced technologies with potential to expand and improve the use of nisin as a dairy preservative., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Background: Weight management education is one of the key strategies to assist patients to manage their weight. Educational resources provide an important adjunct in the chain of communication between practitioners and patients. However, one in five Australian adults has low health literacy. The purpose of this study was to assess the readability and analyse the content of weight management resources., Methods: This study is based on the analysis of 23 resources found in the waiting rooms of ten Sydney-based general practices and downloaded from two clinical software packages used at these practices. The reading grade level of these resources was calculated using the Flesch Reading Ease, Flesch-Kincaid Grade Level, Fry Readability Graph, and the Simplified Measure of Gobbledygook. Resources' content was analysed for the presence of dietary, physical activity, and behaviour change elements, as recommended by the Clinical practice guidelines for the management of overweight and obesity in adults, adolescents, and children in Australia., Results: The resources' average reading grade level was for a 10(th) grader (9.5 ± 1.8). These findings highlight that the average reading grade level was two grades higher than the recommended reading grade level for health education resources of 8th grade level or below. Seventy percent of resources contained dietary and behaviour change elements. Physical activity was included in half of the resources. Two messages were identified to be inconsistent with the guidelines and three messages had no scientific basis., Conclusion: A body of evidence now exists that supports the need to develop evidence-based education resources for weight management that place low demand on literacy, without compromising content accuracy. The findings from this study suggest that there is significant room for improvement in the educational resources provided in general practices.

Background: Socioeconomically disadvantaged adults are both more likely to be obese and have lower levels of health literacy. Our trial evaluates the implementation and effectiveness of primary care nurses acting as prevention navigators to support obese patients with low health literacy to lose weight., Methods/design: A pragmatic cluster randomised trial will be conducted. Twenty practices in socioeconomically deprived areas, 10 each in Sydney and Adelaide, will be recruited and randomised to intervention and control groups. Twenty to 40 eligible obese patients aged 40-70 years with a BMI ≥ 30 kg/m(2) and with low health literacy will be enrolled per practice. The intervention is based on the '5As' of the chronic disease model approach - Assess, Advise, Agree, Assist and Arrange - and the recommendations of the 2013 Clinical practice guidelines for the management of overweight and obesity in adults, adolescents and children in Australia. In the intervention practices, patients will be invited to attend a health check with the prevention navigator who will assess the patient's risk and provide brief advice, assistance with goal setting and referral navigation. Provider training and educational meetings will be held. The providers' attitudes to obesity, confidence in treating obesity and preventive care they provide to obese people with low health literacy will be evaluated through questionnaires and interviews. Patients' self-assessment of lifestyle risk factors, perception of preventive care received in general practice, health-related quality of life, and health literacy will be assessed in telephone interviews. Patients' anthropometric measures will be recorded and their health service usage will be determined via linkage to the Australian government-held medical and pharmaceutical data., Discussion: Our trial will provide evidence for the effectiveness of practice nurses as prevention navigators to support better weight management for obese patients with low health literacy., Trial Registration: This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614001021662). Date registered 24/09/2014.

Emerging evidence indicates an association between obesity, metformin use and reduced vitamin B12 status, which can have serious hematologic, neurologic and psychiatric consequences. This study aimed to examine B12 status in obese adolescents with pre-diabetes and/or clinical features of insulin resistance. Serum B12 was measured using chemiluminescence immunoassay in 103 (43 male, 60 female) obese (mean body mass index (BMI) z-score ± SD (2.36 ± 0.29)), adolescents aged 10 to 17 years, median (range) insulin sensitivity index of 1.27 (0.27 to 3.38) and 13.6% had pre-diabetes. Low B12 (<148 pmol/L) was identified in eight (7.8%) and borderline status (148 to 221 pmol/L) in an additional 25 (24.3%) adolescents. Adolescents with borderline B12 concentrations had higher BMI z-scores compared to those with normal concentrations (2.50 ± 0.22 vs. 2.32 ± 0.30, p = 0.008) or those with low B12 concentration (2.50 ± 0.22 vs. 2.27 ± 0.226, p = 0.041). In conclusion, nearly a third of obese adolescents with clinical insulin resistance had a low or borderline serum B12 status. Therefore, further investigations are warranted to explore the cause and the impact of low B12 status in obese pediatric populations.

Transplant glomerulitis is associated with suboptimal graft function. To understand its pathogenesis and to assess the parameters of potential prognostic value, we immunostained 25 paraffin-embedded allograft biopsies showing glomerulitis for markers of complement activation (C4d), cytotoxicity (Granzyme-B), apoptosis (Bcl-XL, Bcl-2, and Fas-L), and endothelial injury (von Willebrand factor). Staining was semiquantitatively assessed in different anatomical compartments, and comparison was made with 40 control allograft biopsies without glomerulitis. Biopsies with glomerulitis had more frequent incidence of "mixed" T-cell and antibody-mediated rejection compared with controls [8/25 (32%) versus 4/40 (10%), P = .046]. Furthermore, they had higher glomerular capillary-C4d scores (1.9 ± 1.1 versus 1.2 ± 1.2, P = .015), which tended to persist when biopsies showing transplant glomerulopathy were excluded. Higher glomerular capillary-C4d scores were observed in samples with versus without donor-specific antibody (2.5 ± 0.9 versus 1.2 ± 1.2, P = .01). Compared with controls, biopsies with glomerulitis had more intraglomerular (4.8 ± 4.5 versus 0.9± 0.8 cells/glomerulus, P < .001) and interstitial mainly peritubular capillary (6.1 ± 4.1 versus 3.2 ± 3.4 cells/hpf, P = .002) Granzyme-B(+) leukocytes. Higher mesangial-von Willebrand factor scores were noted in the glomerulitis group (1.8 ± 1.0 versus 0.8 ± 0.8, P = .003) and correlated with the percentage of inflamed glomeruli (r = 0.54, P < .001). Interstitial-von Willebrand factor was associated with a higher peritubular capillaritis score (interstitial-von Willebrand factor: 1.6 ± 1.2 versus no interstitial-von Willebrand factor: 0.6 ± 0.9, P = .02). Glomerular capillary-Bcl-XL was not associated with accommodation. Finally, no difference in Bcl-2 or Fas-L was observed upon comparing glomerulitis to controls. In conclusion, glomerular injury in transplant glomerulitis appears to be mediated by complement activation and cellular cytotoxicity. Mesangial- or interstitial-von Willebrand factor identified cases with more severe microcirculation injury., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Clinical trials using allogeneic mesenchymal stem cells (MSCs) are ongoing for the purpose of providing therapeutic benefit for a variety of human disorders. Pertinent to their clinical use are the accessibility to sufficient quantities of these cells allowing for repetitive administration, as well as a better understanding of the specific mechanisms by which allogeneic MSCs evade host immune responses that in turn influence their life span following administration. In this report, we sought to characterize and compare human peripheral blood MSCs (hPB-MSCs) with bone marrow-derived MSCs. hPB-MSCs met the established criteria to characterize this cellular lineage, including capacity for self-renewal, differentiation into tissues of mesodermal origin, and expression of phenotypic surface markers. In addition, hPB-MSCs suppressed alloreactive proliferation as well as the production of proinflammatory cytokines. Examination of the mechanisms by which allogeneic MSCs evade the host immune response, which is crucial for their therapeutic use, demonstrated that constitutive expression of serine protease inhibitor 9 (PI-9) on hPB-MSCs and bone marrow-derived MSCs is a major defense mechanism against granzyme B-mediated destruction by NK cells. Similarly, MSCs treated with small interfering RNA for PI-9 increased MSC cellular death, whereas expression of transgenic PI-9 following retroviral transduction protected MSCs. These data significantly advance our understanding of the immunomodulatory role for hPB-MSCs as well as the mechanisms by which they evade host immune responses. These findings contribute to the development of MSC-based therapies for diseases.

Clinical trials using mesenchymal stem cells (MSCs) have been initiated worldwide. An improved understanding of the mechanisms by which allogeneic MSCs evade host immune responses is paramount to regulating their survival after administration. This study has focused on the novel role of serine protease inhibitor (SPI) in the escape of MSCs from host immunosurveillance through the inhibition of granzyme B (GrB). Our data indicate bone marrow-derived murine MSCs express SPI6 constitutively. MSCs from mice deficient for SPI6 (SPI6(-/-)) exhibited a 4-fold higher death rate by primed allogeneic cytotoxic T cells than did wild-type MSCs. A GrB inhibitor rescued SPI6(-/-) MSCs from cytotoxic T-cell killing. Transduction of wild-type MSCs with MigR1-SPI6 also protected MSCs from cytotoxic T cell-mediated death in vitro. In addition, SPI6(-/-) MSCs displayed a shorter lifespan than wild-type MSCs when injected into an allogeneic host. We conclude that SPI6 protects MSCs from GrB-mediated killing and plays a pivotal role in their survival in vivo. Our data could serve as a basis for future SPI-based strategies to regulate the survival and function of MSCs after administration and to enhance the efficacy of MSC-based therapy for diseases.

Polymeric nanoparticles (NPs), prepared via coprecipitation of drugs and polymers, are promising drug delivery vehicles for treating diseases with improved efficacy and reduced toxicity. Here, we report an unprecedented strategy for preparing polylactide-cyclosporine A (PLA-CsA) NPs (termed CsA-NPs) through CsA-initiated ring-opening polymerization of lactide (LA) followed by nanoprecipitation. The resulting CsA-NPs have sub-100 nm sizes and narrow particle size distributions, and release CsA in a sustained manner without a "burst"-release effect. Both free CsA and CsA-NPs displayed comparable suppression of T-cell proliferation and production of inflammatory cytokines in various T-cell assays in a dose-dependent manner. The IC(50) values for CsA and CsA-NPs were 27.5 and 72.0 ng/ml, respectively. As lymph nodes are the main loci for T-cell activation, we coupled dendritic cells (DCs) with CsA-NPs and successfully delivered CsA selectively to the lymph nodes. Our studies indicated that CsA-NPs could be internalized in the DCs with a sustained release of CsA to the culture medium, suppressing alloreactive T-cell proliferation. Allogeneic DCs loaded with CsA-NPs were able to migrate to the draining lymph nodes where the T-cell priming was significantly reduced without any systemic release. This innovative nanoparticulate CsA delivery technology constitutes a strong basis for future targeted delivery of immunosuppressive drugs with improved efficiency and reduced toxicity.

The authors report a retrospective series of 65 cases of renal contusion in children affecting 45 boys and 20 girls between the ages of 10 months and 15 years (mean age: 10 years). The causes of renal trauma were dominated by household accidents (53.8%) and road accidents (33.8%). Associated extrarenal lesions were observed in 21.5% of cases. 55.4% of the 65 contusions were considered to be benign, 27.7% of moderate severity and 16.9% were serious. The blunt trauma affected a pathological kidney in 19 cases. Exclusively medical treatment was recommended in 31 patients, while surgery was indicated in the other 34 patients. Apart from one death in a context of multiple trauma, few complications were observed in the group of operated patients and consisted of 4 cases of urinary fistula and 4 cases of infection, all of which resolved.