The Mechanism of Action of Cytokines to Control the Release of Hypothalamic and Pituitary Hormones in Infection

Abstract: During infection, bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause the release of cytokines from immune cells. These cytokines can reach the brain by several routes. Furthermore, cytokines, such as interleukin‐1 (IL‐1), are induced in neurons within the brain by systemic injection of LPS. These cytokines determine the pattern of hypothalamic‐pituitary secretion that characterizes infection. IL‐2, by stimulation of cholinergic neurons, activates neural nitric oxide synthase (nNOS). The nitric oxide (NO) released diffuses into corticotropin‐releasing hormone (CRH)‐secreting neurons and releases CRH. IL‐2 also acts in the pituitary to stimulate adrenocorticotropic hormone (ACTH) secretion. On the other hand, IL‐1α blocks the NO‐induced release of luteinizing hormone‐releasing hormone (LHRH) from LHRH neurons, thereby blocking pulsatile LH but not follicle‐stimulating hormone (FSH) release and also inhibiting sex behavior that is induced by LHRH. IL‐1α and granulocyte macrophage colony‐stimulating factor (GMCSF) block the response of the LHRH terminals to NO. The mechanism of action of GMCSF to inhibit LHRH release is as follows. It acts on its receptors on γ‐aminobutyric acid (GABA)ergic neurons to stimulate GABA release. GABA acts on GABAa receptors on the LHRH neuronal terminal to block NOergic stimulation of LHRH release. IL‐1α inhibits growth hormone (GH) release by inhibiting GH‐releasing hormone (GHRH) release, which is mediated by NO, and stimulating somatostatin release, also mediated by NO. IL‐1α‐induced stimulation of PRL release is also mediated by intra‐hypothlamic action of NO, which inhibits release of the PRL‐inhibiting hormone dopamine. The actions of NO are brought about by its combined activation of guanylate cyclase‐liberating cyclic guanosine monophosphate (cGMP) and activation of cyclooxygenase (COX) and lipoxygenase (LOX) with liberation of prostaglandin E2 and leukotrienes, respectively. Thus, NO plays a key role in inducing the changes in release of hypothalamic peptides induced in infection by cytokines. Cytokines, such as IL‐1β, also act in the anterior pituitary gland, at least in part via induction of inducible NOS. The NO produced inhibits release of ACTH. The adipocyte hormone leptin, a member of the cytokine family, has largely opposite actions to those of the proinflammatory cytokines, stimulating the release of FSHRF and LHRH from the hypothalamus and FSH and LH from the pituitary directly by NO.Fil: McCann, Samuel M.. Pennington Biomedical Research Center; Estados UnidosFil: Kimura, M.. Medical and Dental University; JapónFil: Karanth, S.. Pennington Biomedical Research Center; Estados UnidosFil: Yu, W. H.. Pennington Biomedical Research Center; Estados UnidosFil: Mastronardi, C. A.. Pennington Biomedical Research Center; Estados UnidosFil: Besuhli, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Bringing the Tiger Back from the Brink—The Six Percent Solution

This article does not have an abstract

Oldest known pantherine skull and evolution of the tiger

The tiger is one of the most iconic extant animals, and its origin and evolution have been intensely debated. Fossils attributable to extant pantherine species-lineages are less than 2 MYA and the earliest tiger fossils are from the Calabrian, Lower Pleistocene. Molecular studies predict a much younger age for the divergence of modern tiger subspecies at <100 KYA, although their cranial morphology is readily distinguishable, indicating that early Pleistocene tigers would likely have differed markedly anatomically from extant tigers. Such inferences are hampered by the fact that well-known fossil tiger material is middle to late Pleistocene in age. Here we describe a new species of pantherine cat from Longdan, Gansu Province, China, Panthera zdanskyi sp. nov. With an estimated age of 2.55–2.16 MYA it represents the oldest complete skull of a pantherine cat hitherto found. Although smaller, it appears morphologically to be surprisingly similar to modern tigers considering its age. Morphological, morphometric, and cladistic analyses are congruent in confirming its very close affinity to the tiger, and it may be regarded as the most primitive species of the tiger lineage, demonstrating the first unequivocal presence of a modern pantherine species-lineage in the basal stage of the Pleistocene (Gelasian; traditionally considered to be Late Pliocene). This find supports a north-central Chinese origin of the tiger lineage, and demonstrates that various parts of the cranium, mandible, and dentition evolved at different rates. An increase in size and a reduction in the relative size of parts of the dentition appear to have been prominent features of tiger evolution, whereas the distinctive cranial morphology of modern tigers was established very early in their evolutionary history. The evolutionary trend of increasing size in the tiger lineage is likely coupled to the evolution of its primary prey species

Di­hydro­oxazolones and di­hydro­imidazolo­nes derived from acyl­glycines: syntheses, mol­ecular structures and supra­molecular assembly

Syntheses and structures are described for some alkyl­idene-substituted di­­hydro­oxazolones and di­hydro­imidazoles derived from simple acyl­glycines. A second, triclinic, polymorph of 4-benzyl­idene-2-(4-methyl­phen­yl)-1,3-oxazol-5(4H)-one, C17H13NO2, (I), has been identified and the structure of 2-methyl-4-[(thio­phen-2-yl)methyl­idene]-1,3-oxazol-5(4H)-one, C9H7NO2S, (II), has been rerefined taking into account the orientational disorder of the thienyl group in each of the two independent mol­ecules. The reactions of phenyl­hydrazine with 2-phenyl-4-[(thio­phen-2-yl)methyl­idene]-1,3-oxazol-5(4H)-one or 2-(4-methyl­phen­yl)-4-[(thio­phen-2-yl)methyl­idene]-1,3-oxazol-5(4H)-one yield, respectively, 3-anilino-2-phenyl-5-[(thio­phen-2-yl)methyl­idene]-3,5-di­hydro-4H-imid­azol-4-one, C10H15N3OS, (III), and 3-anilino-2-(4-methyl­phen­yl)-5-[(thio­phen-2-yl)methyl­idene]-3,5-di­hydro-4H-imidazol-4-one, C21H17N3OS, (IV), which both exhibit orientational disorder in their thienyl groups. The reactions of 2-phenyl-4-[(thio­phen-2-yl)methyl­idene]-1,3-oxazol-5(4H)-one with hydrazine hydrate or with water yield, respectively, N-[3-hydrazinyl-3-oxo-1-(thio­phen-2-yl)prop-1-en-2-yl]benzamide and 2-(benzoyl­amino)-3-(thio­phen-2-yl)prop-2-enoic acid, which in turn react, respectively, with thio­phene-2-carbaldehyde to form 2-phenyl-5-[(thio­phen-2-yl)methyl­idene]-3-{[(E)-(thio­phen-2-yl)methyl­idene]­amino}-3,5-di­hydro-4H-imidazol-4-one, C19H13N3OS2, (V), which exhibits orientational disorder in only one of its thienyl groups, and with methanol to give methyl (2Z)-2-(benzoyl­amino)-3-(thio­phen-2-yl)prop-2-enoate, C15H13NO3S, (VI). There are no direction-specific inter­molecular inter­actions in the crystal structure of the triclinic polymorph of (I), but the mol­ecules of (II) are linked by two independent C—H⋯O hydrogen bonds to form C22(14) chains. Compounds (III) and (IV) both form centrosymmetric R22(10) dimers built from N—H⋯O hydrogen bonds, while compound (V) forms a centrosymmetric R22(10) dimer built from C—H⋯O hydrogen bonds. In the structure of compound (VI), a combination of N—H⋯O and C—H⋯π(arene) hydrogen bonds links the mol­ecules into sheets. Comparisons are made with some similar compounds

Ecologists need robust survey designs, sampling and analytical methods

1. Research that yields conflicting results rightly causes controversy. Where methodological weaknesses are apparent, there is ready opportunity for discord within the scientific community, which may undermine the entire study. 2. We use the debate about the role of dingoes Canis dingo in conservation in Australia as a case study for a phenomenon that is relevant to all applied ecologists, where conflicting results have been published in high-quality journals and yet the problems with the methods used in these studies have led to significant controversy. 3. To alleviate such controversies, scientists need to use robust methods to ensure that their results are repeatable and defendable. To date, this has not occurred in Australia’s dingo debate due to the use of unvalidated indices that rely on unsupported assumptions. 4. We highlight the problems that poor methods have caused in this debate. We also reiterate our recommendations for practitioners, statisticians and researchers to work together to develop long-term, multi-site experimental research programmes using robust methods to understand the impacts of dingoes on mesopredators. 5. Synthesis and applications. Incorporating robust methods and appropriate experimental designs is needed to ensure that conservation actions are appropriately focused and are supported with robust results. Such actions will go a long way towards resolving the debate about the role of dingoes in conservation in Australia, and other, ecological debates.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1365-2664hb201

Cameras, Coyotes, and the Assumption of Equal Detectability

Remote cameras are an increasingly important tool in management and wildlife studies. However, we often do not know if they provide an unbiased sample of populations. Using a marked, radio-collared population of coyotes (Canis latrans) of known social status, we evaluated the influence of temporal (daily and seasonal) and spatial (distance between units, habitat, and proximity to human structures) factors on vulnerability to photo-captures. During 8 unbaited camera sessions of 6 weeks each, we obtained 158 coyote photographs at a photo-capture success rate of 1.6%. We were able to identify not only marked individuals, but also a number of uncollared adults through variation in their pelage. Photo-capture of adults peaked 2 weeks after we established camera stations. Annual success for photographing adult coyotes was greatest during March and April, which corresponded with the dispersal season. The majority of photo-captures occurred at night, and adult photo-captures peaked around midnight, with smaller peaks at dawn and dusk. Rather than reflecting a circadian activity pattern, nighttime captures seemed to reflect when adult coyotes were most vulnerable to photo-capture. Characteristics of camera locations, such as amount of human activity, being on roads versus trails, and habitat type, also influenced the number of photo-captures. We conclude that remote cameras do not always provide an unbiased sample of populations and that animal behavior is important to consider when using these systems. Researchers using camera techniques need to carefully consider when, where, and how cameras are placed to reduce this bias

Investigation of in vitro effects of ethephon and chlorpyrifos, either alone or in combination, on rat intestinal muscle contraction

A range of pesticides is widely used in pest management and the chances of exposure to multiple organophosphorus (OP) compounds simultaneously are high, especially from dietary and other sources. Although health hazards of individual OP insecticides have been relatively well characterized, there is lesser information on the interactive toxicity of multiple OP insecticides. The aim of this study is to elicit the possible interactions in case combined exposure of an OP pesticide chlorpyrifos (CPF) and a plant growth regulator ethephon (ETF) which are used worldwide. The ileum segments of 3 months old Wistar Albino male rats were used in isolated organ bath containing Tyrode solution. ETF and CPF were incubated (10−7 M concentration) separately or in combination with each other to ileum and their effects on acetylcholine-induced contractions were studied. The data obtained from this study show that, single and combined exposure to the agents caused agonistic interactions with regard to potency of ACh whereas they caused a decrease on Emax value of ACh. These findings suggest that exposure to these agents which have direct and indirect cholinergic effects, may cause developing clinical responses with small doses and earlier but the extent of toxicity will be lower

Congenital anomalies of the male urethra

The spectrum of congenital anomalies of the male urethra is presented. The embryologic basis of each anomaly, when known, is discussed. Clinical and imaging features of each entity are presented

Ibrutinib for Relapsed / Refractory CLL: A UK and Ireland Analysis of Outcomes in 315 patients

In 2014, ibrutinib was made available for relapsed/refractory chronic lymphocytic leukaemia (CLL) patients. The UK CLL Forum collected data from UK/Ireland patients with a minimum of 1 year follow-up with pre-planned primary endpoints; the number of patients still on therapy at 1 year (Discontinuation Free Survival; DFS) and 1 year overall survival (OS). With a median 16 months follow-up, data on 315 patients demonstrated 1 year DFS of 73.7% and 1 year OS of 83.8%. Patients with better pre-treatment performance status (PS 0/1 vs 2+) had superior DFS (77.5% vs 61.3%;p14 days and had OS of 89.7%, while 26% of patients had dose reductions and 13% had temporary treatment breaks >14 days. We could not demonstrate a detrimental effect of dose reductions alone (1 year OS: 91.7%), but patients who had first year treatment breaks > 14 days, particularly permanent cessation of ibrutinib had both reduced 1 year OS (68.5%) and also a statistically significant excess mortality rate beyond one year. Although outcomes appear inferior to the RESONATE trial (1 year OS;90%: PFS;84%), this may partly reflect the inclusion of PS 2+ patients and that 17.5% of patients permanently discontinued ibrutinib due to an event other than disease progression

Relational approaches to poverty in rural India: social, ecological and technical dynamics

Poverty is now widely recognised as multidimensional, with indicators including healthcare, housing and sanitation. Yet, relational approaches that foreground political-cultural processes remain marginalised in policy discourses. Focusing on India, we review a wide range of relational approaches to rural poverty. Beginning with early approaches that focus on structural reproduction of class, caste and to a lesser extent gender inequality, we examine new relational approaches developed in the last two decades. The new approaches examine diverse ways in which poverty is experienced and shapes mobilisations against deprivation. They draw attention to poor people’s own articulations of deprivation and alternate conceptions of well-being. They also show how intersecting inequalities of class, caste and gender shape governance practices and political movements. Despite these important contributions, the new relational approaches pay limited attention to technologies and ecologies in shaping the experience of poverty. Reviewing studies on the Green Revolution and wider agrarian transformations in India, we then sketch the outlines of a hybrid relational approach to poverty that combines socio-technical and -ecological dynamics. We argue that such an approach is crucial to challenge narrow economising discourses on poverty and to bridge the policy silos of poverty alleviation and (environmentally) sustainable development