Classical and alternative components of the mitochondrial respiratory chain in pathogenic fungi as potential therapeutic targets

The frequency of opportunistic fungal infection has increased drastically, mainly in patients who are immunocompromised due to organ transplant, leukemia or HIV infection. In spite of this, only a few classes of drugs with a limited array of targets, are available for antifungal therapy. Therefore, more specific and less toxic drugs with new molecular targets is desirable for the treatment of fungal infections. In this context, searching for differences between mitochondrial mammalian hosts and fungi in the classical and alternative components of the mitochondrial respiratory chain may provide new potential therapeutic targets for this purpose.

BLOCKING CENTRAL LEUKOTRIENES SYNTHESIS AFFECTS VASOPRESSIN RELEASE DURING SEPSIS

Recent studies revealed that vasopressinergic neurons have a high content of cys-leukotriene C(4) (LTC(4)) synthase, a critical enzyme in cys-leukotriene synthesis that may play a role in regulating vasopressin secretion. This study investigates the role of this enzyme in arginine vasopressin (AVP) release during experimentally induced sepsis. Male Wistar rats received an i.c.v. injection of 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2, 2-dimethylpropanoic acid (MK-886) (1.0 mu g/kg), a leukotrienes (LTs) synthesis inhibitor, or vehicle, 1 h before cecal ligation and puncture (CLP) or sham operation. In one group of animals the survival rate was monitored for 3 days. In another group, the animals were decapitated at 0, 4, 6, 18 and 24 h after CLP or sham operation, and blood was collected for hematocrit, serum sodium and nitrate, plasma osmolality, protein and AVP determination. A third group was used for blood pressure measurements. The neurohypophysis was removed for quantification of AVP content, and the hypothalamus was dissected for LTC4 synthase analysis by Western blot. Mortality after CLP was reduced by the central administration of MK-886. The increase in plasma AVP levels and hypothalamus LTC4 synthase content in the initial phase of sepsis was blocked, whereas the decrease in neurohypophyseal AVP content was partially reversed. Also the blood pressure drop was abolished in this phase. The increase of serum nitric oxide and hematocrit was reduced, and the decrease in plasma protein and osmolality was not affected by the LTs blocker. In the final phase of sepsis, the plasma AVID level and the hypothalamic LTC4 synthase content were at basal levels. The central administration of MK-886 increased the hypothalamic LTC4 synthase content but did not alter the plasma and neurohypophysis AVID levels observed, or the blood pressure during this phase. These results suggest that the central LTs are involved in the vasopressin release observed during sepsis. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.

Movements of feral camels in central Australia determined by satellite telemetry

Movements of two female one-humped camels in central Australia were tracked using satellite telemetry between March 1986 and July 1987. During that time both animals travelled a minimum distance of over 1000 km within a radius of 125 km for one animal, and 200 km for the other. However, their movements were uite punctuated and both animals spent periods of up to several months in rleatively small areas before moving over longer distances to new areas. Both camels moved at greater rates overnight. An activity index, probably measuring feeding rate, declined during the study period for both animals. Patchy and sporadic rainfall may explain some of these results.

Respiratory and cardiovascular responses to hypoxia in the Australian lungfish

Simultaneous measurements of pulmonary blood flow (qPA), coeliacomesenteric blood flow (qCoA), dorsal aortic blood pressure (PDA), heart rate (fH) and branchial ventilation frequency (fv) were made in the Australian lungfish, /Neoceratodus forsteri, /during air breathing and aquatic hypoxia. The cho­linergic and adrenergic influences on the cardiovascular system were investigated during normoxia using pharmacological agents, and the presence of catecholamines and serotonin in different tissues was investi­gated using histochemistry. Air breathing rarely occurred during normoxia but when it did, it was always associated with increased pulmonary blood flow. The pulmonary vasculature is influenced by both a cho­linergic and adrenergic tonus whereas the coeliacomesenteric vasculature is influenced by a β-adrenergic vasodilator mechanism. No adrenergic nerve fibers could be demonstrated in /Neoceratodus /but catecholamine-containing endothelial cells were found in the atrium of the heart. In addition, serotonin-­immunoreactive cells were demonstrated in the pulmonary epithelium. The most prominent response to aquatic hypoxia was an increase in gill breathing frequency followed by an increased number of air breaths together with increased pulmonary blood flow. It is clear from the present investigation that /Neoceratodus /is able to match cardiovascular performance to meet the changes in respiration during hypoxia.

Central Cardiovascular Anatomy and Function in Crocodilia

Abstract: Among the vertebrates, crocodilians have the most complex anatomy of the heart and outflow channels. Their cardiovascular anatomy may also be the most func­tionally sophisticated, combining as it does the best features of both reptilian and mammalian (and avian) systems. The puzzlingly complex "plumbing" of crocodilians has fascinated ana­tomists and physiologists for a very long time, the first paper being that by Panizza (1833). Gradually, with the application of successive techniques of investigation as they became available, its functional significance has become reasonably clear, and the complexity is now revealed as a cardiovascular system of considerable elegance. In this paper I will review the main anatomical features of the heart and outflow channels, discuss what is known about the way they work, and speculate about the probable functional significance.

Central and peripheral mediation of human force sensation following eccentric or concentric contractions

Fatigue was induced in the triceps brachii of the experimental arm by a regimen of either eccentric or concentric muscle actions. Estimates of force were assessed using a contralateral limb-matching procedure, in which target force levels (25 %, 50 % or 75 % of maximum) were defined by the unfatigued control arm. Maximum isometric force-generating capacity was reduced by 31 % immediately following eccentric contractions, and remained depressed at 24 (25 %) and 48 h (13 %) post-exercise. A less marked reduction (8.3 %) was observed immediately following concentric contractions. Those participants who performed prior eccentric contractions, consistently (at all force levels), and persistently (throughout the recovery period), overestimated the level of force applied by the experimental arm. In other words, they believed that they were generating more force than they actually achieved. When the forces applied by the experimental and the control arm, were each expressed as a proportion of the maximum force that could be attained at that time, the estimates matched extremely closely. This outcome is that which would be expected if the estimates of force were based on a sense of effort. Following eccentric exercise, the amplitude of the EMG activity recorded from the experimental arm was substantially greater than that recorded from the control arm. Cortically evoked potentials recorded from the triceps brachii (and extensor carpi radialis) of the experimental arm were also substantially larger than those elicited prior to exercise. The sense of effort was evidently not based upon a corollary of the central motor command. Rather, the relationship between the sense of effort and the motor command appears to have been altered as a result of the fatiguing eccentric contractions. It is proposed that the sense of effort is associated with activity in neural centres upstream of the motor cortex.

Changes in neutrophil surface receptor expression, degranulation, and respiratory burst activity following moderate and high intensity exercise

Intense exercise stimulates the systemic release of a variety of factors that alter neutrophil surface receptor expression and functional activity. These alterations may influence resistance to infection after intense exercise. The aim of this study was to examine the influence of exercise intensity on neutrophil receptor expression, degranulation (measured by plasma and intracellular myeloperoxidase concentrations), and respiratory burst activity. Ten well-trained male runners ran on a treadmill for 60 min at 60% [moderate-intensity exercise (MI)] and 85% maximal oxygen consumption [high-intensity exercise (HI)]. Blood was drawn immediately before and after exercise and at 1 h postexercise. Immediately after HI, the expression of the neutrophil receptor CD16 was significantly below preexercise values (P < 0.01), whereas MI significantly reduced CD35 expression below preexercise values (P < 0.05). One hour after exercise at both intensities, there was a significant decline in CD11b expression (P < 0.05) and a further decrease in CD16 expression compared with preexercise values (P < 0.01). CD16 expression was lower 1 h after HI than 1 h after MI (P < 0.01). Immediately after HI, intracellular myeloperoxidase concentration was less than preexercise values (P < 0.01), whereas plasma myeloperoxidase concentration was greater (P < 0.01), indicating that HI stimulated neutrophil degranulation. Plasma myeloperoxidase concentration was higher immediately after HI than after MI (P < 0.01). Neutrophil respiratory burst activity increased after HI (P < 0.01). In summary, both MI and HI reduced neutrophil surface receptor expression. Although CD16 expression was reduced to a greater extent after HI, this reduction did not impair neutrophil degranulation and respiratory burst activity.

Children’s respiratory health and daily particulate levels in ten non-urban communities

We conducted a study to assess the association between the acute respiratory health of children and the levels of particulates in communities near and away from active opencast coal mines. The study enrolled children aged 1–11 years from the general population of five socioeconomically matched pairs of nonurban communities in northern England. Diaries of respiratory events were collected for 1405 children, and information was collected on the consultations of 2442 children with family/general practitioners over the 6-week study periods during 1996–1997, with concurrent monitoring of particulate levels. The associations found between daily PM10 levels and respiratory symptoms were frequently small and positive and sometimes varied between communities. The magnitude of these associations were in line with those from previous studies, even though daily particulate levels were low, and the children were drawn from the general population, rather than from the population with respiratory problems. The associations among asthma reliever use, consultations with general practitioners, and daily particulate levels were of a similar strength but estimated less precisely. The strength of association between all respiratory health measures and particulate levels was similar in communities near and away from opencast coal mining sites.

Increased apoptosis of T lymphocytes and macrophages in the central and peripheral nervous systems of Lewis rats with experimental autoimmune encephalomyelitis treated with dexamethasone

Using light and electron microscopic histological and immunocytochemical techniques, we investigated the effects of the glucocorticoid dexamethasone on T cell and macrophage apoptosis in the central nervous system (CNS) and peripheral nervous system (PNS) of Lewis rats with acute experimental autoimmune encephalomyelitis (EAE) induced with myelin basic protein (MBP). A single subcutaneous injection of dexamethasone markedly augmented T cell and macrophage apoptosis in the CNS and PNS and microglial apoptosis in the CNS within 6 hours (h). Pre-embedding immunolabeling revealed that dexamethasone increased the number of apoptotic CD5+ cells (T cells or activated B cells), αβ T cells, and CD11b+ cells (macrophages/microglia) in the meninges, perivascular spaces, and CNS parenchyma. The induction of increased apoptosis was dose-dependent. Daily dexamethasone treatment suppressed the neurological signs of EAE. However, the daily injection of a dose of dexamethasone (0.25 mg/kg). which, after a single dose, did not induce increased apoptosis in the CNS or PNS, was as effective in inhibiting the neurological signs of EAE as the high dose (4 mg/kg), which induced a marked increase in apoptosis. This indicates that the beneficial clinical effect of glucocorticoid therapy in EAE does not depend on the induction of increased apoptosis. The daily administration of dexamethasone for 5 days induced a relapse that commenced 5 days after cessation of treatment, with the severity of the relapse tending to increase with dexamethasone dosage.

Mice expressing the E7 oncogene of HPV16 in epithelium show central tolerance, and evidence of peripheral anergising tolerance, to E7-encoded cytotoxic T-lymphocyte epitopes

In order to derive mice which expressed both the E7 open reading frame transgene of human papillomavirus type 16 in skin and MHC class 1 restriction elements for several E7-encoded cytotoxic T-lymphocyte (CTL) epitopes, K14.HPV16E7 mice which express E7 in basal keratinocytes were crossed to the F1 generation with A2.1 K-b transgenic mice which express the MHC binding cleft domains of human HLA A*0201, and murine H-2(b). F1 mice (denoted K14E7xA2.1) expressed E7 in the thymus at least as early as 2-5 days before birth. Immunisation of FVBxA2.1 control mice (transgenic for HLA A*0201 and H-2(b) but not for E7), with two HLA A*0201-restricted epitopes of E7 and one H-2(b)-restricted CTL epitope of E7, gave strong primary CTL responses recognising epitope-pulsed or constitutively E7-expressing syngeneic target cells. In contrast, in immunised K14E7xA2.1 mice, the CTL responses to the H-2(b) epitope and one of the HLA A*0201 CTL epitopes were strongly down-regulated, and to the other HLA A*0201 epitope, completely abolished, as demonstrated by percentage specific killing by bulk splenocyte cultures in cyrotoxicity assays, and by CTL precursor frequency analysis, In thymus-transplanted bone marrow radiation chimeras in which the immune system of K14E7xA2.1 mice was replaced by a FVBxA2.1 immune system, specific immunisation did not result in reemergence of strong E7-directed CTL responses. In agreement with these in vitro findings, specific immunisation failed to significantly alter the course of E7-associated tumour development in K14E7xA2.1 mice. These data are consistent with a model of central deletional CTL tolerance to E7-encoded epitopes recognised in the context of two distinct MHC class 1 restriction elements, and with the possibility of peripheral T-cell anergy maintained by expression of E7 in the skin. (C) 1998 Academic Press.

Nest temperature and respiratory gases during natural incubation in the broad-shelled river turtle, Chelodina expansa (Testudinata : Chelidae)

Temperature was monitored in three natural nests, and oxygen and carbon dioxide partial pressure monitored in one natural nest of the broad-shelled river turtle, Chelodina expansa, throughout incubation. Nest temperature decreased after nest construction in autumn, remained low during winter and gradually increased in spring to a maximum in summer. In a nest where temperature was recorded every hour, temperature typically fluctuated through a 2 degrees C cycle on a daily basis throughout the entire incubation period, and the nest always heated faster than it cooled. Oxygen and carbon dioxide partial pressures in this nest were similar to soil oxygen and carbon dioxide partial pressures for the first 5 months of incubation, but nest respiratory gas tensions deviated from the surrounding soil over the last three months of incubation. Nest respiratory gas tensions were not greatly different from those in the atmosphere above the ground except after periods of rain. After heavy rain during the last 3 months of incubation the nest became moderately hypoxic (P-O2 similar to 100 Torr) and hypercapnic (P-CO2 similar to 50 Torr) for several successive days. These short periods of hypoxia and hypercapnia were not lethal.

The respiratory risks of cannabis smoking

Cannabis users have recently been told that cannabis smoking is ª relatively harmlessº 1 and presents ª minimal danger to the lungsº .2 These statements seem at odds with the similarities between the carcinogens and other toxic constituents in tobacco and cannabis smoke, the fact that un® ltered cannabis smoke contains more of some carcinogens than ® ltered tobacco smoke3,4 and other evidence that chronic cannabis smoking has adverse respiratory effects.5

Presynaptic long-term depression at a central glutamatergic synapse: a role for CaMKII

CaMKII is a calcium-activated kinase that is abundant in neurons and has been strongly implicated in memory and learning. Here we show that low-frequency stimulation of glutamatergic afferents in hippocampal slices from juvenile domestic chicks results in long-term depression of synaptic transmission. This reduction does not require activation of NMDA or metabotropic glutamate receptors and does not require a rise in postsynaptic calcium. However, buffering presynaptic calcium prevents the reduction of the excitatory postsynaptic potential or current that is induced by low-frequency stimulation. in addition, application of the calmodulin antagonist calmidazolium, or the specific CaMKII antagonist KN-93, completely blocks long-term depression. These findings demonstrate a newsy discovered form of long-term synaptic depression in the avian hippocampus.

Size of the first spring generation of Helicoverpa punctigera (Wallengren) (Lepidoptera : Noctuidae) and winter rain in central Australia

Serious infestations of Helicoverpa punctigera are experienced yearly in the eastern cropping regions of Australia. Regression analysis was used to determine whether the size of the first generation in spring (G(1)), which is comprised mostly of immigrants from inland Australia, was related to monthly rainfall in inland winter breeding areas. Data from two long series of light-trap catches at Narrabri in New South Wales (NSW) and Turretfield in South Australia (SA) were used in the analyses. The size of G1 at Narrabri in each year was significantly regressed on the amount of rainfall in western Queensland and NSW in May and June. The size of G1 at Turretfield each year was significantly regressed on the amount of rain in May, June and July in western Queensland and NSW and also in the desert of central Western Australia. Low r(2) values of the regressions suggest that rainfall data for more sites, as well as biological and other physical factors, such as temperature, evaporation, and prevailing wind systems, may need to be included to improve forecasts of the potential magnitude of the infestations in coastal cropping regions.