1,721,047 research outputs found
Human tuberculosis I. epidemiology, diagnosis and pathogenetic mechanisms
Full text linkMycobacterium tuberculosis (M. tuberculosis), an almost genetically monomorphic pathogen is a human parasite, transmitted mostly by humans and causes tuberculosis (TB). TB is firmly associated to poverty, although lack of proper nutrition and lowered immune status are contributing factors for disease development. TB remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent and is responsible for nearly 1.5 million deaths annually. Some steps of the progress of our knowledge of M. tuberculosis physiology and its interactions with human beings, are reviewed here. This progress has provided fertile ground for improving diagnosis and cure of TB infection. For TB diagnostics laboratories in high-burden countries, primary isolation is the first step before performing drug susceptibility testing (DST) of M. tuberculosis. IGRA (interferon-release assay)-based tests for diagnosis of active TB are sufficiently fast, specific and sensitive to allow to contain infection and distinguish among latent TB infection and BCG vaccination individuals from those who have clinically resolved M. tuberculosis infection after anti-TB treatment
Human tuberculosis II. m. tuberculosis mechanisms of genetic and phenotypic resistance to anti-tuberculosis drugs
No full textThe great progress of knowledge of both M. tuberculosis physiology and how human host and bacilli interact has provided fertile ground for improving diagnosis and cure of TB infection. Once M. tuberculosis has infected humans, it elaborates strategies for evading the risk to killing by the cells of the host immune system and by the anti-tuberculosis (anti-TB) agents employed to cure infection. These strategies give rise to a bacterial multidrug resistance (MDR) status. This stems firstly from genetic mutations targeting a constellation of drug-processing mechanisms that still need full identification, as drug efflux pumps and drug activating/inactivating enzymes (genetic resistance). Secondly, from the bacterial adaptation to stressful environmental conditions by adopting a temporary dormancy state lasting for decades and characterized by indifference to anti-TB drugs (phenotypic resistance or tolerance). The clarification of the strategies elaborated for surviving by M. tuberculosis has brought to the identification in the last few years of a number of mycobacterial molecular targets worth to exploitation for the development of novel and powerful anti-TB drugs. These targets include drug-efflux pump systems, considered partly responsible for genetic multi-drug resistance, and several enzymes and pump systems, as well, that sustain the metabolic adaptations of M. tuberculosis in the host and give rise to its phenotypic drug resistance
Changes in CSF composition during heat stress and fever in conscious rabbits
No full textElevation of brain temperature after stroke can lead to severe brain injury and even a moderate hyperthermia correlates with increased nervous damage. The role of endogenous cryogens in the pathways that down-regulate body temperature are of overwhelming interest in view of their effectiveness in protecting brain from such damage. The aim of the present work was to study whether heat stress (HS) or fever generates brain homeostatic responses aimed at counteracting the resulting rise in body temperature. Conscious rabbits, with cannulas chronically implanted in the cisterna mayna and lateral ventricle, underwent H S (50 min, 40 degrees C) or were injected with 25 ng of endogenous pyrogen IL-1 beta, while cerebrospinal fluid (CSF) levels of amino acids involved in central mechanisms of thermoregulation like taurine, GABA, aspartate and glutamate were monitored. The concentrations of some CSF cations (Na+, K+, Mg2+ and Ca2+) were also determined in view of their purported role (sodium and calcium in particular) in establishing the thermal set point within the hypothalamus. Results show that during HS-induced hyperthermia, CSF taurine and GABA levels were significantly increased. On the contrary, IL-1 beta caused an increase in CSF taurine and, concurrently, a decrease in CSF GABA. Aspartate and glutamate did not change in both conditions. Furthermore, among CSF cations, only calcium and sodium underwent changes. In particular, calcium content increased both in HS- and febrile-animals, while CSF sodium decreased significantly only under IL-1 beta-Injected treatment. In conclusion, GABA and taurine contribute as endogenous cryogens in a different fashion to the central mechanisms, which regulate dissipation of body heat in hyperthermia or heat production in fever, possibly in coordination with extracellular calcium and sodium
Changes in rectal temperature and ECoG spectral power of sensorimotor cortex elicited in conscious rabbits by i.c.v. injectionof GABA, GABAA and GABAB agonists and antagonists
No full text1. In order to ascertain whether both GABA(A) and GABA(B), or only GABA(B) receptors, directly modulate thermoregulation in conscious rabbits, GABA(A)/GABA(B) agonist and antagonist agents were injected intracerebroventricularly in conscious rabbits while monitoring changes in rectal temperature (RT), gross motor behaviour (GMB) and electrocorticogram (ECoG) power spectra (ps) from sensorimotor cortices. 2. GABA (48 micromol), nipecotic acid (50 nmol), THIP (60 nmol), muscimol (18 nmol) and baclofen (8 nmol) induced hypothermia (-deltaRTmax values of 1.70+/-0.1, 1.4+/-0.2, 1.0+/-0.4, 1.1+/-0.2 and 1.6+/-0.3 degrees C, respectively), accompanied by inhibition of GMB and ECoG synchronization. THIP increased ps at delta frequency band (1.1-3.3 Hz), while GABA, nipecotic acid, muscimol and baclofen did the same at both delta and (4.6-6.5 Hz) frequency bands. ECoG ps changes were concomitant or even preceded hypothermia. 3. Bicuculline (1.8 nmol) induced hyperthermia (deltaRTmax 1.2+/-0.5 degrees C) and slight excitation of GMB, while CGP35348 (1.2 micromol) did not affect RT nor GMB. Both compounds did not affect ECoG ps. 4. Bicuculline potentiated muscimol-induced hypothermia, inhibition of GMB and synchronization of ECoG, while CGP35348 fully antagonized these effects. 5. In conclusion, the present results, while confirming the prevailing role of GABA(B), also outline a direct involvement of GABA(A) receptors in the central mechanisms of thermoregulation. Ascending inhibition towards discrete cortical areas controlling muscular activity and thermogenesis may result from GABA receptor activation in neurones proximal to the ventricles, thus contributing to hypothermia, although hypothermia-induced reduction of neuronal activity of these cortical areas cannot be ruled out
3,5-di-t-butylcatechol (DTCAT) as an activator of rat skeletal muscle ryanodine receptor Ca2+ channel (RyRC)
No full textIn the present study, the effects of 3,5-di-t-butylcatechol (DTCAT) on ryanodine receptor Ca(2+) channel (RyRC) of skeletal muscle sarcoplasmic reticulum (SR) vesicles were investigated, both by monitoring extravesicular Ca(2+) concentration directly with the Ca(2+) indicator dye arsenazo III and by studying the high-affinity [(3)H]ryanodine binding. DTCAT stimulated Ca(2+) release from junctional (terminal cisternae) vesicles in a concentration-dependent manner, with a threshold activating concentration of 30 microM and a pEC(50) value of 3.43+/-0.03 M. The release of Ca(2+) induced by DTCAT was antagonized in a concentration-dependent manner by ruthenium red, thus indicating that RyRC is involved in the mechanism of stimulation. A structure-activity relationship analysis carried out on a limited number of compounds suggested that both hydroxy and t-butyl groups in DTCAT were important for the activation of RyRC. DTCAT inhibited [(3)H]ryanodine binding to SR vesicles with a K(i) of 232.5 microM, thus indicating that it acted directly at the skeletal muscle ryanodine receptor binding site to stimulate Ca(2+) release. In conclusion, the ability of DTCAT to release Ca(2+) from TC vesicles of skeletal muscle is noteworthy in view of its possible use as an alternative compound to either caffeine or halothane for performing the "In vitro contracture test" to diagnose the susceptibility of some patients to develop malignant hyperthermia under particular pharmacological treatments
Increase of extracellular brain calcium involved in interleukin-1 beta-induced pyresis in the rabbit: antagonism by dexamethasone.
No full text1This study investigates the role of extracellular brain calcium in the hyperthermia induced by interleukin-1 beta (IL-1 beta).
2 Intracerebroventricular (i.c.v.) injection of IL-1 beta (12.5 ng kg(-1)) in rabbits caused a prompt and sustained rise in cerebrospinal fluid (CSF) Ca2+ concentration ([Ca2+]) followed by enhanced prostaglandin E(2) (PGE(2)) release and hyperthermia.
3 A linear and significant correlation was observed between the increase in [Ca2+] induced by IL-1 beta and the rise in body temperature.
4 Ventriculo-cisternal perfusion with artificial CSF containing the calcium chelator EGTA (1.3 mM) blocked the IL-1-induced PGE(2) release and countered the febrile response.
5 I.c.v. administration of dexamethasone (Dex) (2.4 and 24 mu g kg(-1)) 100 min prior to IL-1 beta, dose-dependently antagonized the cytokine-induced Ca2+ increase, the PGE(2) release and the febrile response.
6 These results suggest that changes in extracellular brain calcium are involved in the regulation of body temperature. In this light, the antipyretic action of Dex may be related to its effect on Ca2+ uptake
Selective ozone concentrations may reduce the ischemic damage after a stroke
Full text linkStroke is one of the most debilitating diseases, and it is unfortunate that only a small percentage of patients can be treated with thrombolytic agents. Consequently, there is an urgent need of finding an alternative procedure for reoxygenating the so-called penumbra at the earliest time as possible for reducing morbidity and disability. A preliminary, preclinical study has been carried out by using rat hippocampal and cortical brain slices subjected to oxygen-glucose deprivation. Oxygen-ozone gaseous mixture appeared to be effective
in reverting damage of brain tissues, supporting the evaluation of this approach in well-designed clinical trials in stroke patients
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Neuroprotection afforded by GABA against oxygen-glucose deprivation-induced injury in rat cortical brain slices: an hormetic dose-response effect
No full textThe aim of the present investigation was to assess neuroprotection exerted by GABA (100
nM-100 mM) in rat cortical brain slices subjected to oxygen-glucose deprivation and reoxygenation.
Neuronal injury and neuroprotection were assessed by measuring the release of glutamate and lactate
dehydrogenase and tissue water content. Results demonstrate that GABA exerted neuroprotective
effects according to a U-shaped, hormetic-like, concentration-response curve, with an efficacy window
of 10-100 μM concentration. In order to verify whether GABA-neuroprotective effects were GABAAor
GABAB-mediated, Muscimol (GABAA agonist) and Baclofen (GABAB agonist) were tested. Results
demonstrated that only Muscimol exerted neuroprotection according to a U-shaped, hormetic-like,
concentration-response curve, while baclofen was ineffective. In conclusion, the hormetic response of
GABA or GABAA agonists should be taken into consideration when designing experiments aimed at
assessing neuroprotection by these agents against ischemia/reoxygenation injury
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