Peroxisome Proliferator-Activated Receptor-γ-Mediated Polarization of Macrophages in Leishmania Infection

Infection is the outcome of a contest between a pathogen and its host. In the disease leishmaniasis, the causative protozoan parasites are harbored inside the macrophages. Leishmania species adapt strategies to make the infection chronic, keeping a balance between their own and the host's defense so as to establish an environment that is favorable for survival and propagation. Activation of peroxisome proliferator-activated receptor (PPAR) is one of the tactics used. This ligand-activated nuclear factor curbs inflammation to protect the host from excessive injuries by setting a limit to its destructive force. In this paper, we report the interaction of host PPARs and the pathogen for visceral leishmaniasis, Leishmania donovani, in vivo and in vitro. PPAR expression is induced by parasitic infection. Leishmanial activation of PPARγ promotes survival, whereas blockade of PPARγ facilitates removal of the parasite. Thus, Leishmania parasites harness PPARγ to increase infectivity

Peroxisome Proliferator-Activated Receptor (PPAR): Balance for Survival in Parasitic Infections

Parasitic infections induce a magnitude of host responses. At the opposite ends of the spectrum are those that ensure the host's needs to eliminate the invaders and to minimize damage to its own tissues. This review analyzes how parasites would manipulate immunity by activating the immunosuppressive nuclear factor, peroxisome proliferator-activated receptors (PPARs) with type 2 cytokines and free fatty acids from arachidonic acid metabolism. PPARs limit the action of type 1 immunity, in which classically activated macrophages act through the production of proinflammatory signals, to spare the parasites. They also favor the development of alternately activated macrophages which control inflammation so the host would not be destroyed. Possibly, the nuclear factors hold a pivotal role in the establishment of chronic infection by delicately balancing the pro- and anti-inflammatory signaling mechanisms and their ligands may be used as combination therapeutics to limit host pathology

Nurses\u27 Alumnae Association Bulletin, May 1957

Alumnae Notes Committee Reports Digest of Alumnae Meetings Graduation Awards - 1956 Letter from Hong Kong Leukemia Marriages Necrology New Arrivals Physical Advances at Jefferson President\u27s Message School of Nursing Report Two Year Programs in Nursing White Haven Repor

Ethical considerations in on-ground applications of the ecosystem services concept

The ecosystem services (ES) concept is one of the main avenues for conveying society's dependence on natural ecosystems. On-ground applications of the concept are now widespread and diverse and include its use as a communication tool, for policy guidance and priority setting, and for designing economic instruments for conservation. Each application raises ethical considerations beyond traditional controversies related to the monetary valuation of nature. We review ethical considerations across major on-ground applications and group them into the following categories: anthropocentric framing, economic metaphor, monetary valuation, commodification, sociocultural impact, changes in motivations, and equity implications. Different applications of the ES concept raise different suites of ethical issues, and we propose methods to address the issues most relevant to each application. We conclude that the ES concept should be considered as only one among various alternative approaches to valuing nature and that reliance on economic metaphors can exclude other motivations for protecting ecosystems

Influence of tumour size on the efficacy of targeted alpha therapy with 213Bi-[DOTA0,Tyr3]-octreotate

BACKGROUND: Targeted alpha therapy has been postulated to have great potential for the treatment of small clusters of tumour cells as well as small metastases. (213)Bismuth, an α-emitter with a half-life of 46 min, has shown to be effective in preclinical as well as in clinical applications. In this study, we evaluated whether (213)Bi-[DOTA(0), Tyr(3)]-octreotate ((213)Bi-DOTATATE), a (213)Bi-labelled somatostatin analogue with high affinity for somatostatin receptor subtype 2 (SSTR(2)), is suitable for the treatment of larger neuroendocrine tumours overexpressing SSTR(2) in comparison to its effectiveness for smaller tumours. We performed a preclinical targeted radionuclide therapy study with (213)Bi-DOTATATE in animals bearing tumours of different sizes (50 and 200 mm(3)) using two tumour models: H69 (human small cell lung carcinoma) and CA20948 (rat pancreatic tumour). METHODS: Pharmacokinetics was determined for calculation of dosimetry in organs and tumours. H69- or CA20948-xenografted mice with tumour volumes of approximately 120 mm(3) were euthanized at 10, 30, 60 and 120 min post injection of a single dose of (213)Bi-DOTATATE (1.5–4.8 MBq). To investigate the therapeutic efficacy of (213)Bi-DOTATATE, xenografted H69 and CA20948 tumour-bearing mice with tumour sizes of 50 and 200 mm(3) were administered daily with a therapeutic dose of (213)Bi-DOTATATE (0.3 nmol, 2–4 MBq) for three consecutive days. The animals were followed for 90 days after treatment. At day 90, mice were injected with 25 MBq (99m)Tc-DMSA and imaged by SPECT/CT to investigate possible renal dysfunction due to (213)Bi-DOTATATE treatment. RESULTS: Higher tumour uptakes were found in CA20948 tumour-bearing animals compared to those in H69 tumour-bearing mice with the highest tumour uptake of 19.6 ± 6.6 %IA/g in CA20948 tumour-bearing animals, while for H69 tumour-bearing mice, the highest tumour uptake was found to be 9.8 ± 2.4 %IA/g. Nevertheless, as the anti-tumour effect was more pronounced in H69 tumour-bearing mice, the survival rate was higher. Furthermore, in the small tumour groups, no regrowth of tumour was found in two H69 tumour-bearing mice and in one of the CA20948 tumour-bearing mice. No renal dysfunction was observed in (213)Bi-DOTATATE-treated mice after the doses were applied. CONCLUSIONS: (213)Bi-DOTATATE demonstrated a great therapeutic effect in both small and larger tumour lesions. Higher probability for stable disease was found in animals with small tumours. (213)Bi-DOTATATE was effective in different neuroendocrine (H69 and CA20948) tumour models with overexpression of SSTR(2) in mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-016-0162-2) contains supplementary material, which is available to authorized users

Therapeutic application of CCK2R-targeting PP-F11: influence of particle range, activity and peptide amount

Background: Targeted radionuclide therapy with high-energy beta-emitters is generally considered suboptimal to cure small tumours (90Y, 177Lu or 213Bi, accounting for the radionuclide specific activities (SAs), the tumour absorbed doses and tumour (radio) biology. Methods: Tumour uptake of 111In-PP-F11 was determined in nude mice bearing CCK2 receptor-transfected A431 xenografts at 1 and 4 h post-injection for escalating peptide masses of 0.03 to 15 nmol/mouse. The absorbed tumour dose was estimated, assuming comparable biodistributions of the 90Y, 177Lu or 213Bi radiolabelled peptides. The linear-quadratic (LQ) model was used to calculate the tumour control probabilities (TCP) as a function of tumour mass and growth. Results: Practically achievable maximum SAs for PP-F11 labelled with 90Y and 177Lu were 400 MBq 90Y/nmol and 120 MBq177Lu/nmol. Both the large elution volume from the 220 MBq 225Ac generator used and reaction kinetics diminished the maximum achieved 213Bi SA in practice: 40 MBq 213Bi/nmol. Tumour uptakes decreased rapidly with increasing peptide amounts, following a logarithmic curve with ED50 = 0.5 nmol. At 0.03 nmol peptide, the (300 mg) tumour dose was 9 Gy after 12 MBq 90Y-PP-F11, and for 111In and 177Lu, this was 1 Gy. A curative dose of 60 Gy could be achieved with a single administration of 111 MBq 90Y labelled to 0.28 nmol PP-F11 or with 4 × 17 MBq 213Bi (0.41 nmol) when its α-radiation relative biological effectiveness (RBE) was assumed to be 3.4. Repeated dosing is preferable to avoid complete tumour receptor saturation. Tumours larger than 200 mg are curable with 90Y-PP-F11; the other radionuclides perform better in smaller tumours. Furthermore, 177Lu is not optimal for curing fast-growing tumours. Conclusions: Receptor saturation, specific radiopharmaceutical activities and absorbed doses in the tumour together favour therapy with the CCK2 receptor-binding peptide PP-F11 labelled with 90Y, despite its longer β-particle range in tissue, certainly for tumours larger than 300 mg. The predicted TCPs are of theoretical nature and need to be compared with the outcome of targeted radionuclide experiments

Centimeter to decimeter hollow concretions and voids in Gale Crater sediments, Mars

Voids and hollow spheroids between ∼1 and 23 cm in diameter occur at several locations along the traverse of the Curiosity rover in Gale crater, Mars. These hollow spherical features are significantly different from anything observed in previous landed missions. The voids appear in dark-toned, rough-textured outcrops, most notably at Point Lake (sols 302-305) and Twin Cairns Island (sol 343). Point Lake displays both voids and cemented spheroids in close proximity; other locations show one or the other form. The spheroids have 1-4 mm thick walls and appear relatively dark-toned in all cases, some with a reddish hue. Only one hollow spheroid (Winnipesaukee, sol 653) was analyzed for composition, appearing mafic (Fe-rich), in contrast to the relatively felsic host rock. The interior surface of the spheroid appears to have a similar composition to the exterior with the possible exceptions of being more hydrated and slightly depleted in Fe and K. Origins of the spheroids as Martian tektites or volcanic bombs appear unlikely due to their hollow and relatively fragile nature and the absence of in-place clearly igneous rocks. A more likely explanation to both the voids and the hollow spheroids is reaction of reduced iron with oxidizing groundwater followed by some re-precipitation as cemented rind concretions at a chemical reaction front. Although some terrestrial concretion analogs are produced from a precursor siderite or pyrite, diagenetic minerals could also be direct precipitates for other terrestrial concretions. The Gale sediments differ from terrestrial sandstones in their high initial iron content, perhaps facilitating a higher occurrence of such diagenetic reactions

Outcome Assessment of a Dedicated HIV Positive Health Care Worker Clinic at a Central Hospital in Malawi: A Retrospective Observational Study

BACKGROUND: Malawi has one of the world's lowest densities of Health Care Workers (HCW) per capita. This study evaluates outcomes of a dedicated HCW HIV clinic in Malawi, created at Zomba Central Hospital in January 2007. METHODS AND FINDINGS: Retrospective cohort data was analyzed comparing HCW clinic patient baseline characteristics and treatment outcomes at 18 months after inception, against those attending the general HIV clinic. In-depth interviews and focus group discussions were conducted to explore perceptions of patients and caregivers regarding program value, level of awareness and barriers for uptake amongst HCW. 306 patients were enrolled on antiretroviral therapy (ART) in the HCW HIV clinic, 6784 in the general clinic. Significantly (p<0.01) more HCW clients were initiated on ART on the basis of CD4 as opposed to WHO Stage 3/4 (36% vs.23%). Significantly fewer HCW clients defaulted (6% vs.17%), and died (4% vs.12%). The dedicated HCW HIV clinic was perceived as important and convenient in terms of reduced waiting times, and prompt and high quality care. Improved confidentiality was an appreciated quality of the HCW clinic however barriers included fear of being recognized. CONCLUSIONS/SIGNIFICANCE: Outcomes at the HCW clinic appear better compared to the general HIV clinic. The strategy of dedicated clinics to care for health providers is a means of HIV impact mitigation within human resource constrained health systems in high prevalence settings

Redshift-independent Distances in the NASA/IPAC Extragalactic Database: Methodology, Content, and Use of NED-D

Estimates of galaxy distances based on indicators that are independent of cosmological redshift are fundamental to astrophysics. Researchers use them to establish the extragalactic distance scale, to underpin estimates of the Hubble constant, and to study peculiar velocities induced by gravitational attractions that perturb the motions of galaxies with respect to the "Hubble flow" of universal expansion. In 2006 the NASA/IPAC Extragalactic Database (NED) began making available a comprehensive compilation of redshift-independent extragalactic distance estimates. A decade later, this compendium of distances (NED-D) now contains more than 100,000 individual estimates based on primary and secondary indicators, available for more than 28,000 galaxies, and compiled from over 2000 references in the refereed astronomical literature. This paper describes the methodology, content, and use of NED-D, and addresses challenges to be overcome in compiling such distances. Currently, 75 different distance indicators are in use. We include a figure that facilitates comparison of the indicators with significant numbers of estimates in terms of the minimum, 25th percentile, median, 75th percentile, and maximum distances spanned. Brief descriptions of the indicators, including examples of their use in the database, are given in an appendix