Diverse Profiles of Ricin-Cell Interactions in the Lung Following Intranasal Exposure to Ricin

Ricin, a plant-derived exotoxin, inhibits protein synthesis by ribosomal inactivation. Due to its wide availability and ease of preparation, ricin is considered a biothreat, foremost by respiratory exposure. We examined the in vivo interactions between ricin and cells of the lungs in mice intranasally exposed to the toxin and revealed multi-phasic cell-type-dependent binding profiles. While macrophages (MΦs) and dendritic cells (DCs) displayed biphasic binding to ricin, monophasic binding patterns were observed for other cell types; epithelial cells displayed early binding, while B cells and endothelial cells bound toxin late after intoxication. Neutrophils, which were massively recruited to the intoxicated lung, were refractive to toxin binding. Although epithelial cells bound ricin as early as MΦs and DCs, their rates of elimination differed considerably; a reduction in epithelial cell counts occurred late after intoxication and was restricted to alveolar type II cells only. The differential binding and cell-elimination patterns observed may stem from dissimilar accessibility of the toxin to different cells in the lung and may also reflect unequal interactions of the toxin with different cell-surface receptors. The multifaceted interactions observed in this study between ricin and the various cells of the target organ should be considered in the future development of efficient post-exposure countermeasures against ricin intoxication.     

What is and isn’t working: Factors involved in sustaining community‐based health and participation initiatives for people ageing with intellectual and developmental disabilities

As people with intellectual and developmental disabilities (I/DD) age, it is important that I/DD agencies are prepared to support healthy ageing in homes and in communities. This study explored supports and barriers to sustaining community‐based health and participation initiatives (CBHPI) for people ageing with I/DD living in group homes managed by agencies. The study utilized interviews and photovoice with 70 participants—35 individuals with I/DD and 35 management/direct support agency staff. Data were analysed through content analysis and triangulation of data where five themes emerged: Agency values and policies related to healthy ageing; resources and staff competencies; communication between management and staff; community/university partnerships; and peer relations. Findings show that I/DD agencies and people with I/DD value CBHPI, but they find them difficult to sustain due to limited resources and lack of training specific to ageing with I/DD. Conducting system‐level research within I/DD agencies to include first‐person accounts of people with I/DD, staff and management provides insight on how to effectively support the needs of people with I/DD to improve their health and community participation as they age.     

The use of corticosteroids does not influence CD4+ lymphocyte recovery in HIV-infected patients with advanced immunodeficiency

ABSTRACT

Corticosteroids inhibit HIV-related immune activation and seem to have a mild favorable effect on immunological recovery in patients with CD4⁺ counts ≥200?cells/mm³. Data in patients with advanced immunodeficiency are lacking. We analyzed whether corticosteroids negatively influence the short-term CD4⁺ lymphocyte recovery in patients with CD4⁺ cell counts <200?cells/mm³ started on combination antiretroviral therapy (cART). We performed a retrospective cohort analysis including all HIV-infected patients under follow-up in our hospital with a documented episode of Pneumocystis Jirovecii Pneumonia (PJP) in the cART era. CD4⁺ lymphocyte recovery was assessed at three months after the episode of PJP and subsequent start of cART, comparing patients that received adjunctive corticosteroids (AC) versus patients that did not receive corticosteroids (standard care (SC)). In total, 66 patients with an episode of PJP were identified with 38 patients in the AC-group versus 28 patients in the SC-group. Almost all baseline characteristics were similar, including mean CD4⁺ lymphocyte counts. After three months, the mean CD4⁺ cell count did not differ; 222?cells/mm³ for the SC-group versus 259?cells/mm³ for the AC-group (p?=?.29). The use of corticosteroids does not alter CD4⁺ lymphocyte recovery in HIV-infected patients with advanced immunodeficiency in the first months of antiretroviral therapy.     

Expression of the insulin-like growth factors and their receptors in adenocarcinoma of the colon

AIMS: To study changes in the expression of insulin-like growth factors (IGFs) and their receptors, as well as production of the IGF-I and IGF-II polypeptides, in adenocarcinoma of the colon. METHODS: Malignant tissue obtained at operation was used. Total RNA was extracted and specific IGF-I and IGF-II and their receptor mRNAs were measured by a solution hybridisation RNase protection assay. IGF-I and IGF-II polypeptides were measured by specific immunoassays. RESULTS: All normal tissues expressed IGF-II, IGF-I receptor, and IGF-II/mannose-6-phosphate (Man-6-P) receptor. IGF-I mRNA could not be detected but the polypeptide was present in small but equal amounts in normal and malignant tissue. IGF-II was expressed 40 times more abundantly in colonic tumours than in adjacent normal tissue and the concentration of the corresponding polypeptide was twice as high in the malignant tissue. IGF-I receptor expression was increased by a factor of 2.5 and IGF-II/Man-6-P receptor by a factor of 4. CONCLUSIONS: This study confirms that in adenocarcinoma of the human colon there is increased expression of IGF-I receptor and IGF-II. Furthermore, IGF-II/Man-6-P receptor message is increased and the increase in IGF-II message is accompanied by a doubling of the IGF-II protein in the tumour tissue compared with the adjacent normal tissue. These findings suggest that the IGF-II/Man-6-P receptor may also be involved in development of adenocarcinoma of the colon. There is rapidly accumulating evidence implicating the IGF system in the development of malignancy of the large bowel.     

Delays to Care in Pediatric Lupus Patients: Data From the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry

Objective

Prompt treatment for lupus is important to prevent morbidity. A potential barrier to early treatment of pediatric lupus is delayed presentation to a pediatric rheumatologist. To better understand factors contributing to delayed presentation among pediatric lupus patients, we examined differences in demographic and clinical characteristics of lupus patients within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry with regard to time between symptom onset and presentation to a pediatric rheumatologist.

Methods

We analyzed data from 598 CARRA Legacy Registry participants for differences between those who presented early (within <1 month of symptom onset), between 1–3 months (typical presentation), with moderate delays (3–12 months), and with severe delays (≥1 year). Factors associated with early presentation, moderate delay, and severe delay were determined by multinomial logistic regression.

Results

Forty‐four percent of patients presented early, while 23% had moderate delays and 9% had severe delays. Family history of lupus, absence of discoid rash, and location in a state with a higher density of pediatric rheumatologists were associated with earlier presentation. Younger age, low household income (<$25,000 per year), and a family history of lupus were associated with severe delay.

Conclusion

Delays to care ≥1 year exist in a notable minority of pediatric lupus patients from the CARRA Legacy Registry. In this large and diverse sample of patients, access to care and family resources played an important role in predicting time to presentation to a pediatric rheumatologist.

     

Characterization of the Inducer Required for the Development of Macrophage and Granulocyte Colonies

A substance produced by various types of cells can induce from single hematopoietic cells the formation of colonies of normal macrophages and granulocytes. This inducer has been purified 600-fold from serum-free conditioned medium from a tissue culture line of mouse cells. It is shown that the inducer is a protein, with a molecular weight of 65-70,000, whose inducing activity was about 1 ng per colony. Acrylamide gel electrophoresis of this material gave four bands, only one of which contained inducing activity. The purified protein was inactive. Activity was regained by the addition of a low molecular weight cofactor that is present in conditioned medium. Under certain conditions, activity was also regained by the addition of adenosine 3':5'-cyclic monophosphate (cyclic AMP).     

Land,irrigation water,greenhouse gas,and reactive nitrogen burdens of meat,eggs, and dairy production in the United States

Livestock production impacts air and water quality, ocean health, and greenhouse gas (GHG) emissions on regional to global scales and it is the largest use of land globally. Quantifying the environmental impacts of the various livestock categories, mostly arising from feed production, is thus a grand challenge of sustainability science. Here, we quantify land, irrigation water, and reactive nitrogen (Nr) impacts due to feed production, and recast published full life cycle GHG emission estimates, for each of the major animal-based categories in the US diet. Our calculations reveal that the environmental costs per consumed calorie of dairy, poultry, pork, and eggs are mutually comparable (to within a factor of 2), but strikingly lower than the impacts of beef. Beef production requires 28, 11, 5, and 6 times more land, irrigation water, GHG, and Nr, respectively, than the average of the other livestock categories. Preliminary analysis of three staple plant foods shows two- to sixfold lower land, GHG, and Nr requirements than those of the nonbeef animal-derived calories, whereas irrigation requirements are comparable. Our analysis is based on the best data currently available, but follow-up studies are necessary to improve parameter estimates and fill remaining knowledge gaps. Data imperfections notwithstanding, the key conclusion—that beef production demands about 1 order of magnitude more resources than alternative livestock categories—is robust under existing uncertainties. The study thus elucidates the multiple environmental benefits of potential, easy-to-implement dietary changes, and highlights the uniquely high resource demands of beef.Appreciation of the environmental costs of food production has grown steadily in recent years (e.g., refs. 1–3), often emphasizing the disproportionate role of livestock (4–12). Although potentially societally important, to date the impacts of this research on environmental policies (7, 13, 14) and individual dietary choices have been modest. Although pioneering early environmental burden estimates have tended to address wide food classes (notably the animal-based portion of the diet; e.g., refs. 9 and 15), most policy objectives and individual dietary choices are item specific.For example, a person may consider beef and chicken mutually interchangeable on dietary or culinary grounds. However, even if an individual estimate of the environmental cost of one item exists, it is often not accompanied by a directly comparable study of the considered alternative. Even in the unlikely event that both estimates are available, they are unlikely to consider the costs in terms of more than one metric, and often rely on disparate methodologies. Therefore, environmentally motivated dietary choices and farm policies stand to benefit from more finely resolved environutritional information. Although early work yielded a short list of item-specific environmental cost estimates (16), those estimates were often based on meager data, and addressed a single environmental metric (typically energy), thus requiring expansion, updating, and further analysis to enhance statistical robustness (8).Current work in the rapidly burgeoning field of diet and agricultural sustainability falls mostly into two complementary approaches. The first is bottom–up, applying rigorous life cycle assessment (LCA) methods to food production chains (17–22). Whereas early LCAs focused primarily on greenhouse gas (GHG) emissions (23–26), or in some cases GHGs and energy use (5, 27), more recent LCAs often simultaneously address several additional key metrics (17, 19–21, 28, 29), notably land, water, and reactive nitrogen (Nr, nitrogen fertilizer) use. Some studies also include emissions of such undesirable gases (in addition to GHGs) as smog precursors or malodors (30, 31), or adverse contributions to stream turbidity or erosional topsoil loss (e.g., refs. 32–34). This bottom–up approach is extremely important, and is poised to eventually merge with the top–down national efforts described in the next paragraph. This merger is not imminent, however, because the bottom–up approach considers one or at most a handful of farms at a time. Because of wide differences due to geography (35), year-to-year fluctuations (36), and agrotechnological practice (17, 37), numerous LCAs are required before robust national statistics emerge. Eventually, when a large and diverse LCA sample is at hand, the picture at the national level will emerge. Currently, however, the results from an LCA conducted in Iowa, for example, are unlikely to represent Vermont or Colorado. Given the current volume and scope of LCA research, and the complexity and variability of the problem, LCAs are still too few and too local to adequately sample the multifaceted, diverse US food system, and thus to collectively become nationally scalable.The second agricultural sustainability research thrust, into which this study broadly falls, is a top–down analysis of national (10, 16, 38) or global (8, 39–41) production statistics. The top–down approach we follow here is conceptually straightforward, as described schematically in Fig. 1. The environmental needs (land, irrigation water, etc.) of feed production are collected and distributed among the feed-consuming animal categories. This is termed the partitioning step, and is based on information about the number of animals raised or slaughtered mass in each category, as well as the characteristic feed ration in each category. The burdens attributed to each category are divided by the caloric or protein mass output of that animal category, yielding the final result, the environmental burden per consumed unit (e.g., agricultural land needed per ingested kilocalorie of poultry). This method is mainly appealing because it (i) circumvents the variability issues raised above by using national or global aggregations; and (ii) it is based on relatively solid data. For the United States in particular, US Department of Agriculture (USDA) data tend to be temporally consistent, nearly all-inclusive (e.g., records of the main crops are based on close to 100% of the production), and are reported after some (albeit modest) quality control. The key challenge with this approach is obtaining defensible numerical values and uncertainty ranges for the tens if not hundreds of parameters needed in the calculations, many of which are poorly constrained by available data. Such parameters include, for example, the average feed required per animal per day or per kilogram of weight gain, or the relative fraction of pasture in beef and dairy diets. The values vary as a function of, at least, season, geographical location, and agrotechnology used. One research effort, focused on a single location, is unlikely to yield definitive results. Significant progress in both approaches is primarily realized through the tenacious and painstaking amassing of many independent analyses over time; analyses from which robust, meaningful statistics can be derived. Because of the challenges associated with each of the research thrusts discussed above, quantitatively robust, multimetric estimates that are comparable across different categories and represent the average national environmental burdens have yet to be devised. Although estimates of total national energy use and GHG emissions by agriculture do exist (e.g., refs. 4, 5, 42, and 43), they require further statistical evaluation. The costs in terms of land, irrigation water, and Nr are even less certain.Open in a separate windowFig. 1.A simplified schematic representation of the information flow in calculating environmental burdens per consumed calorie or gram of protein. Feed supply and requirements (blue boxes at top) previously yielded (38) the fraction of each feed class consumed by each animal category; e.g., pork requires 23 ± 9% of concentrated feed. Combined with the environmental burdens (green boxes at left; land, irrigation water, and nitrogen fertilizer for each of the three feed classes), these fractions yield the burdens attributed to each animal category. Finally, dividing those overall environmental burdens attributed to each of the five livestock categories by the number of calories (or grams of protein) nationally consumed by humans in the United States, we reach the final result of this paper (yellow box at bottom). Most input data (left and top boxes) is known with relative accuracy based on USDA data, whereas environmental burdens of pasture and average feed requirements are less certain.Applying a top–down, uniform methodology throughout, here we present estimates of land, irrigation water, GHG, and Nr requirements of each of the five main animal-based categories in the US diet—dairy, beef, poultry, pork, and eggs—jointly providing 96% of the US animal-based calories. We do not analyze fish for two reasons. First, during the period 2000–2013, fish contributed ≈14 kcal per person per day, ≈0.5% of the total and 2% of the animal-based energy (750 kcal per person per day) in the mean American diet (44). In addition, data addressing feed use by fisheries and aquaculture are very limited and incomplete (relative to the five categories considered). We do not claim to cover all important environmental impacts of livestock production. Rather, we focus on key metrics that can be reliably defined and quantified at the national level with currently available data.     

A two-pill sublingual misoprostol outpatient regimen following mifepristone for medical abortion through 70 days' LMP: a prospective comparative open-label trial

Objective

To test the effectiveness and acceptability of an outpatient medical abortion protocol with 200 mg mifepristone and 400 mcg sublingual misoprostol at 64–70 days' last menstrual period (LMP) and compare it to the already known efficacy of the 57–63 days' LMP gestational age range.

Study Design

We conducted a prospective, comparative open-label trial in six hospitals and clinics in Ukraine, Georgia, India and Tunisia. We enrolled 714 reproductive age women with pregnancies 57 to 70 days who presented requesting abortion. Medical abortions were managed with the current service delivery protocol (200 mg oral mifepristone followed in 24–48 h by 400 mcg sublingual misoprostol). Data on safety, efficacy and acceptability were collected. The main outcome measure was complete abortion without surgical intervention at any point.

Results

A total of 703 cases were analyzable for efficacy. Success rates did not differ significantly in the two groups [57–63-day group: 94·8%; 64–70-day group: 91.9%; Relative Risk (RR): 0.79 (0.61–1.04)]. Ongoing pregnancy rates also did not differ significantly (57–63 days: 1.8%; 64–70 days: 2.2%; RR: 1.10 (0.65–1.87)].

Conclusion

A medical abortion regimen of 200 mg mifepristone followed in 24–48 h by 400 mcg sublingual misoprostol is effective through 70 days' gestation and may be offered within existing outpatient abortion services.

Implications

A regimen of 200 mg mifepristone followed in 24–48 h by 400 mcg sublingual misoprostol is effective up to 70 days' LMP. The findings have important implications for expanding access to outpatient medical abortion services in settings where the cost of misoprostol is of concern or a two-pill misoprostol regimen is the standard of care.