Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions

Efficacy of a combination of imidacloprid 10%/moxidectin 2.5% spot-on (Advocate® for dogs) in the prevention of canine spirocercosis (Spirocerca lupi)

The nematode Spirocerca lupi is a major canine parasite in warm regions of the world, classically causing parasitic nodules in the esophagus, aortic aneurysms, and spondylitis. This study evaluated the preventive efficacy of monthly treatment with imidacloprid 10%/moxidectin 2.5% spot-on (Advocate® for dogs) administered over a period of 9 months in young dogs naturally exposed to S. lupi on Réunion island. One hundred and twelve puppies, aged from 2.0 to 4.0 months and with a negative spirocerca fecal examination at inclusion, completed the study. They were randomly allocated to two groups. Group A puppies (n = 58) received nine spot-on treatments with Advocate® at the minimum dose of 2.5 mg moxidectin/kg bw at monthly intervals. Control group B puppies (n = 54) received no treatment for S. lupi. During the study, regular clinical and fecal examinations were performed, as was final upper gastrointestinal endoscopy. Endoscopy showed that 19 dogs from group B had spirocerca nodules, corresponding to a prevalence of 35.2% in dogs aged 12 to 14 months. In contrast, only one dog from group A had a nodule, corresponding to a preventive efficacy of 94.7% (p < 0.0001). None of the 378 fecal examinations were positive for spirocerca. This study confirms a high prevalence of canine spirocercosis on Réunion and shows that infestation occurs in very young puppies. Furthermore, it demonstrates that monthly spot-on administration of a combination of imidacloprid 10%/moxidectin 2.5% (Advocate® for dogs) in puppies starting at the age of 2 to 4 months achieves effective and safe prevention of canine spirocercosis

Paired opposing leukocyte receptors recognizing rapidly evolving ligands are subject to homogenization of their ligand binding domains

Some leukocyte receptors come in groups of two or more where the partners share ligand(s) but transmit opposite signals. Some of the ligands, such as MHC class I, are fast evolving, raising the problem of how paired opposing receptors manage to change in step with respect to ligand binding properties and at the same time conserve opposite signaling functions. An example is the KLRC (NKG2) family, where opposing variants have been conserved in both rodents and primates. Phylogenetic analyses of the KLRC receptors within and between the two orders show that the opposing partners have been subject to post-speciation gene homogenization restricted mainly to the parts of the genes that encode the ligand binding domains. Concerted evolution similarly restricted is demonstrated also for the KLRI, KLRB (NKR-P1), KLRA (Ly49), and PIR receptor families. We propose the term merohomogenization for this phenomenon and discuss its significance for the evolution of immune receptors

Earliest evidence for the ivory trade in southern Africa : isotopic and ZooMS analysis of seventh-tenth century AD ivory from KwaZulu-Natal

KwaGandaganda, Ndondondwane and Wosi were major Early Farming Community settlements in what is today the KwaZulu-Natal province of South Africa. These sites have yielded, among other remains, abundant evidence of ivory and ivory working dating to the seventh–tenth centuries ad, pre-dating by approximately 200 years the better-known ivory artefacts from sites in the Limpopo River Valley and surrounding regions. We report the results of carbon, nitrogen and strontium isotope analysis to explore the origins and procurement of this ivory, in combination with Zooarchaeology by Mass Spectrometry (ZooMS) to identify the species of animals from which it was derived. All of the ivory studied using ZooMS was elephant, despite the presence of hippopotamus remains on all three sites. Some ivory was probably obtained from elephant herds that lived close to the sites, in the densely wooded river valleys favoured by both elephants and early farmers. Other material came from savannah environments further afield. Ivory found at these three sites was drawn from different catchments, implying a degree of landscape/resource partitioning even at this early stage. These communities clearly invested substantial effort in obtaining ivory from across the region, which speaks to the importance of this commodity in the economy of the time. We suggest that some ivory items were for local use, but that some may have been intended for more distant markets via Indian Ocean trade

Diet and food strategies in a southern al-Andalusian urban environment during Caliphal period, ecija, Sevilla

The Iberian medieval period is unique in European history due to the widespread socio-cultural changes that took place after the arrival of Arabs, Berbers and Islam in 711 AD. Recently, isotopic research has been insightful on dietary shifts, status, resource availability and the impact of environment. However, there is no published isotopic research exploring these factors in southern Iberian populations, and as the history of this area differs to the northern regions, this leaves a significant lacuna in our knowledge. This research fills this gap via isotopic analysis of human (n = 66) and faunal (n = 13) samples from the 9th to the 13th century Écija, a town renowned for high temperatures and salinity. Stable carbon (δ13C) and nitrogen (δ15N) isotopes were assessed from rib collagen, while carbon (δ13C) values were derived from enamel apatite. Human diet is consistent with C3 plant consumption with a very minor contribution of C4 plants, an interesting feature considering the suitability of Écija to C4 cereal production. δ15N values vary among adults, which may suggest variable animal protein consumption or isotopic variation within animal species due to differences in foddering. Consideration of δ13C collagen and apatite values together may indicate sugarcane consumption, while moderate δ15N values do not suggest a strong aridity or salinity effect. Comparison with other Iberian groups shows similarities relating to time and location rather than by religion, although more multi-isotopic studies combined with zooarchaeology and botany may reveal subtle differences unobservable in carbon and nitrogen collagen studies alone.OLC is funded by Plan Galego I2C mod.B (ED481D 2017/014). The research was partially funded by the projects “Galician Paleodiet” and by Consiliencia network (ED 431D2017/08) Xunta de GaliciaS

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700