Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation

Mevalonate kinase (MK) is an essential enzyme in the isoprenoid biosynthesis pathway which produces numerous biomolecules (isoprenoids) involved in a variety of cellular processes. The indispensability of MK and isoprenoid biosynthesis for human health is demonstrated by the identification of its deficiency as the biochemical and molecular cause of the inherited autoinflammatory disorders mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. Since the discovery of the genetic defect, considerable progress has been made in understanding the molecular, biochemical and immunological basis of MK deficiency. Important questions such as which specific protein(s) and/or signaling pathway(s) are affected, however, remain unanswered. Resolving the complete pathophysiology of this disorder is a major challenge, but eventually will give insight into the in vivo role of MK and isoprenoid biosynthesis in inflammation and fever. This may open novel options for antiinflammatory therapies in general. Here, we give a general introduction on isoprenoid biosynthesis, the regulation thereof and deficiencies therein. We review the molecular, biochemical and immunological aspects of MK deficiency and discuss the relations between isoprenoid biosynthesis and inflammation. Finally, we compare MK deficiency with other autoinflammatory syndromes.     

Depletion of hypothalamic norepinephrine reduces the fever induced by polyriboinosinic acid: polyribocytidylic acid (Poly I:Poly C) in rats

Summary Administration of either Poly I:Poly C (0.05–0.50 g) or norepinephrine (2–8 g) into the anterior hypothalamic area produced a dose-related fever in rats. The fever induced by Poly I:Poly C was attenuated after selective depletion of norepinephrine in the hypothalamus. However, selective depletion of hypothalamic norepinephrine did not affect the fever induced by intrahypothalamic norepinephrine. The data indicate that Poly I:Poly C may act to induce fever through the endogenous release of norepinephrine from the rat's hypothalamus.This work was supported by grants from the National Science Council (Taipei, Republic of China).     

Absence of endotoxin-fever but not hyperthermia in Brattleboro rats

Summary I. c. v. administration of bacterial endotoxin produced a fever in the Long-Evans rat but not in the Brattleboro rat. Similar administration of arachidonic acid, prostaglandin E₂, prostacyclin, dibutyryl cAMP, norepinephrine, morphine and -endorphin caused hyperthermia in both Long-Evans and Brattleboro rats. Variable doses of exogenous arginine vasopressin (AVP) when centrally administered with endotoxin caused fever in the Brattleboro rat. It is suggested that AVP may play an important role in the production and release of endogenous pyrogen.     

Course of fever response to repeated administration of sublethal doses of lipopolysaccharides,polyinosinic: Polycytidylic acid and muramyl dipeptide to rabbits

Summary The purpose of the present study was to examine the development of tolerance to three structurally dissimilar pyrogens, i.e., lipopolysaccharide (LPS), muramyl dipeptide (MDP) and polyinosinic: polycytidylic acid (poly I:C) in rabbits. The possibility of pyrogenic cross-tolerance among these agents has also been studied. It was observed that repeated injection of sublethal doses of LPS and MDP was connected with the changing of biphasic fever to monophasic. The consequence of this was a drop in the fever index. In contrast to LPS and MDP, the repeated administration of poly I:C did not result in such changes. Successive injections of this pyrogen always evoked biphasic fever. We also demonstrated that pyrogenic cross-tolerance between LPS and MDP did not occur. The cross-tolerance between LPS and MDP did not occur. The cross-tolerance among pyrogens was possible if they originated from the same class, for example endotoxin fromSalmonella abortus eq. and endotoxin fromEscherichia coli.     

Depletion of hypothalamic norepinephrine reduces the fever induced by polyriboinosinic acid: polyribocytidylic acid (Poly I:Poly C) in rats

Administration of either Poly I:Poly C (0.05-0.50 micrograms) or norepinephrine (2-8 micrograms) into the anterior hypothalamic area produced a dose-related fever in rats. The fever induced by Poly I:Poly C was attenuated after selective depletion of norepinephrine in the hypothalamus. However, selective depletion of hypothalamic norepinephrine did not affect the fever induced by intrahypothalamic norepinephrine. The data indicate that Poly I:Poly C may act to induce fever through the endogenous release of norepinephrine from the rat's hypothalamus.     

Absence of endotoxin-fever but not hyperthermia in Brattleboro rats

I.c.v. administration of bacterial endotoxin produced a fever in the Long-Evans rat but not in the Brattleboro rat. Similar administration of arachidonic acid, prostaglandin E2, prostacyclin, dibutyryl cAMP, norepinephrine, morphine and beta-endorphin caused hyperthermia in both Long-Evans and Brattleboro rats. Variable doses of exogenous arginine vasopressin (AVP) when centrally administered with endotoxin caused fever in the Brattleboro rat. It is suggested that AVP may play an important role in the production and release of endogenous pyrogen.     

The role of orientation experiments in discovering mechanisms

Many types of experiments have been recognized in the literature. One important type we discuss in this article is the orientation experiment. While orientation experiments are like other types of experiments in that they are tests for causal relevance, they also have other qualities. One important (but not the only) goal of these experiments is to offer a rough, qualitative characterization of the mechanism responsible for a capacity of interest, effectively constraining future research. This makes them particularly useful during the early stages of investigation, when an explanandum-phenomenon has just been identified and several (often competing) hypotheses as to the qualitative character of the mechanism responsible for it are proposed. We illustrate our claims, and explicate a number of additional aims that orientation experiments can sometimes serve, by considering three case studies from different era's, namely the discovery of the mechanisms responsible for i) the capacity of eels to produce numbing sensations (17th and 18th century), ii) puerperal fever in Semmelweis' Vienna Maternity Hospital (19th century), and iii) the capacity of pigeons to home (20th century).     

Isolation in east Senegal of a yellow fever virus strain from a pool of Aedes belonging to the subgenus Diceromyia]

During an epidemiological survey of yellow fever in Eastern Senegal, one strain of yellow fever virus was isolated in December 1976 from wild Mosquitoes. This first isolate obtained in nature from Aedes subgenus Diceromyia shows the primordial part these vectors may have in the area studied. It corroborates the existence of a selvatic focus of yellow fever in this region. It also gives information on the transmission cycle in a dry area.     

Immunological sensitization following inapparent infection with dengue virus type 3 in rhesus monkeys

Summary Rhesus monkeys previously given dengue virus type 3, without apparent viremia or antibody response, exhibited a secondary-type response upon reinoculation. These data suggest that monkeys can be immunologically sensitized to dengue virus without detectable antibody production.The authors wish to express their deepest gratitude to Alma Till man, Carlie White, Annie McCoy, Francis Brisset, Albert Jackson and Becky Kagarise for their devoted technical assistance. This research was supported in part by the U.S. Army Medical Research and Development Command under Contract No. DADA-16-69-C-9048 and DAMD-17-74-C-4005 and by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Public Health Service, under Research Grant No. 5-R22-AI02686-13,-14 and-15, and Training Grant No. 5-T01-AI-00110-14.     

Microsomal glutathione S-transferases: selective up-regulation of leukotriene C4 synthase during lipopolysaccharide-induced pyresis

Cysteinyl-leukotrienes (cys-LTs) are potent smooth muscle contracting agents, which play key roles in inflammatory and allergic diseases. The committed step in cys-LT biosynthesis is catalyzed by leukotriene C₄ synthase (LTC4S) as well as microsomal glutathione S-transferase type 2 (MGST2) and type 3 (MGST3). Here we report that intraperitoneal injections of lipopolysaccharide in rats lead to a strong increase of LTC4S messenger RNA (mRNA) levels after approximately 1 h, particularly in the heart, brain, adrenal glands and liver, without any significant effect on MGST2 and MGST3 mRNA levels. After 6 h, LTC4S mRNA returns to basal levels, concomitant with a 4.9-, 4.0-, 2.9- and 2.3-fold induction of LTC4S protein in brain, heart, liver and adrenal gland, respectively. Hence, challenge with lipopolysaccharide in vivo causes an organ-selective, local priming for leukotriene C₄ synthesis. Moreover, these data suggest that LTC4S and cys-LTs may be involved in acute systemic inflammatory responses such as fever and tachycardia.Received 12 August 2004; received after revision 27 October 2004; accepted 1 November 2004     

A strain of amaril virus isolated from Aedes africanus in the Ivory Coast]

The yellow fever virus has been isolated from a pool of Aedes africanus caught on men in a region situated between forest and savannah near Touba, in the Ivory Coast. This isolation, occurring at an interepidemic period, proves for the first time in West Africa, the part played by this mosquito in the transmission of the yellow fever virus.     

Course of fever response to repeated administration of sublethal doses of lipopolysaccharides, polyinosinic:polycytidylic acid and muramyl dipeptide to rabbits

The purpose of the present study was to examine the development of tolerance to three structurally dissimilar pyrogens, i.e., lipopolysaccharide (LPS), muramyl dipeptide (MDP) and polyinosinic:polycytidylic acid (poly I:C) in rabbits. The possibility of pyrogenic cross-tolerance among these agents has also been studied. It was observed that repeated injection of sublethal doses of LPS and MDP was connected with the changing of biphasic fever to monophasic. The consequence of this was a drop in the fever index. In contrast to LPS and MDP, the repeated administration of poly I:C did not result in such changes. Successive injections of this pyrogen always evoked biphasic fever. We also demonstrated that pyrogenic cross-tolerance between LPS and MDP did not occur. The cross-tolerance between LPS and MDP did not occur. The cross-tolerance among pyrogens was possible if they originated from the same class, for example endotoxin from Salmonella abortus eq. and endotoxin from Escherichia coli.     

The insecticidal potential of venom peptides

Pest insect species are a burden to humans as they destroy crops and serve as vectors for a wide range of diseases including malaria and dengue. Chemical insecticides are currently the dominant approach for combating these pests. However, the de-registration of key classes of chemical insecticides due to their perceived ecological and human health risks in combination with the development of insecticide resistance in many pest insect populations has created an urgent need for improved methods of insect pest control. The venoms of arthropod predators such as spiders and scorpions are a promising source of novel insecticidal peptides that often have different modes of action to extant chemical insecticides. These peptides have been optimized via a prey–predator arms race spanning hundreds of millions of years to target specific types of insect ion channels and receptors. Here we review the current literature on insecticidal venom peptides, with a particular focus on their structural and pharmacological diversity, and discuss their potential for deployment as insecticides.     

Fever and survival in the rat. Metabolic versus temperature response

Summary In infected rats, survival was directly proportional to the metabolic cost of fever (O₂%°C) during its rising phase and inversely proportional to the height of fever. It is suggested that some febrile, metabolic response may be beneficial, while the rise in temperature may be harmful for the host animal.I thank Dr W. Mannheim from the Institute of Hygiene for kindly furnishing the cultures ofS. enteritidis. This work was supported by the Schwerpunktprogramm Temperaturregulation und-adaptation of the DFG.     

Isolation of the yellow fever virus from an egg-cluster and the larvae of the tick Amblyomma variegatum]

The yellow fever virus is isolated in natura from eggs of a Tick Amblyomma variegatum. It is then isolated from larvae issued from the same egg-cluster and also from blood of a monkey bitten by larvae of the same origin. It is reported that the same virus has been previously obtained from adults of the same species of Tick. An acarine appears for the first time as a sylvatic vector and reservoir (at least temporary) of yellow fever.     

Lack of pyrogenic tolerance transmission between brain and periphery in the rabbit

Summary Successive injections of lipopolysaccharide (LPS) either intravenously (i.v.) or intracerebroventricularly (i.c.v.) induced pyrogenic tolerance to LPS in rabbits. Tolerance was shown by a decrease of the magnitude of the fever response to repeated doses of LPS, irrespective of the route of pyrogen administration. A significantly greater and more dramatic decrease of the fever index, however, was observed in rabbits made tolerant to pyrogen given i.v. than when the pyrogen was given i.c.v. Transmission of the pyrogenic toleraance between brain and peripheral tissues, however, has not been ascertained.     

Lack of pyrogenic tolerance transmission between brain and periphery in the rabbit

Successive injections of lipopolysaccharide (LPS) either intravenously (i.v.) or intracerebroventricularly (i.c.v.) induced pyrogenic tolerance to LPS in rabbits. Tolerance was shown by a decrease of the magnitude of the fever response to repeated doses of LPS, irrespective of the route of pyrogen administration. A significantly greater and more dramatic decrease of the fever index, however, was observed in rabbits made tolerant to pyrogen given i.v. than when the pyrogen was given i.c.v. Transmission of the pyrogenic tolerance between brain and peripheral tissues, however, has not been ascertained.     

Saving the mutual manipulability account of constitutive relevance

Constitutive mechanistic explanations are said to refer to mechanisms that constitute the phenomenon-to-be-explained. The most prominent approach of how to understand this relation is Carl Craver's mutual manipulability approach (MM) to constitutive relevance. Recently, MM has come under attack (Baumgartner and Casini 2017; Baumgartner and Gebharter 2015; Harinen 2014; Kästner 2017; Leuridan 2012; Romero 2015). It is argued that MM is inconsistent because, roughly, it is spelled out in terms of interventionism (which is an approach to causation), whereas constitutive relevance is said to be a non-causal relation. In this paper, I will discuss a strategy of how to resolve this inconsistency—so-called fat-handedness approaches (Baumgartner and Casini 2017; Baumgartner and Gebharter 2015; Romero 2015). I will argue that these approaches are problematic. I will present a novel suggestion for how to consistently define constitutive relevance in terms of interventionism. My approach is based on a causal interpretation of manipulability in terms of causal relations between the mechanism's components and what I will call temporal EIO-parts of the phenomenon. Still, this interpretation accounts for the fundamental difference between constitutive relevance and causal relevance.     

Pharmacogenetics and disease genetics of complex diseases

Advances in technologies and the availability of a single nucleotide polymorphism (SNP) map are beginning to show the true potential for the human genome project to affect patient healthcare. A whole genome scan, the use of 100,000–300,000 SNPs across the genome, is now possible. Use of traditional approaches and the whole genome scan will result in identification of disease susceptibility genes and development of many new treatments in the longer term. In the shorter term, the goal will be to predict those patients at risk to experience an adverse reaction or those with a high probability for improved efficacy (i.e. pharmacogenetics). As progress is made in the area of disease genetics and pharmacogenetics, our understanding of disease susceptibility and its interrelationship with drug response will improve, making targeted therapy (i.e. the right drug to the right patient) a reality.Received 19 December 2002; received after revision 14 February 2003; accepted 20 February 2003     

Prostaglandin E1-induced fever in rabbits pretreated with p-chlorophenylalanine

Summary The prostaglandin E₁-induced fever was neither potentiated nor attenuated at all levels of the ambient temperatures (2, 22 and 32°C) studied after pretreatment of the conscious rabbits with p-chlorophenylalanine, when compared to the untreated control.This work was supported by grants from National Science Council of Republic of China and John B. Pierce Foundation (New Haven, USA). The author is grateful to Drs J. D. Hardy, J. T. Stitt and C. Y. Chai for their advice.