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At least 451 records · Page 25Linked to original sources

PubMed1987

Miconazole: a cost-effective antifungal genitourinary irrigant.

Miconazole was used as a fungistatic genitourinary irrigant in the management of 10 patients with persistent candiduria. All patients were in the older age group, with a mean age of 77.6 years, and they were debilitated by a variety of medical problems, including major surgery, neoplasia, recurrent bacterial infection, diabetes or other metabolic dysfunction. Miconazole at a concentration of 50 mcg. per ml. was administered continuously during 24 hours for 5 consecutive days via a urethral catheter. Candiduria resolved in 8 of the 10 patients, with 1 requiring a second course of miconazole at a concentration of 100 mcg. per ml. Two patients manifested other foci of infection, necessitating intravenous and intravesical amphotericin B. Stability studies showed that the miconazole irrigation solutions maintain their antifungal activity for 11 days at room temperature. The 5-day cost (drug and materials) of the miconazole irrigation at 50 mcg. per ml. was $17.75 versus $76.75 for an equal course of therapy with amphotericin B. In addition, compared to amphotericin B as an antifungal genitourinary irrigant, miconazole is prepared more easily, requires less labor and preparation time, and does not require refrigeration or protection from light. These clinical observations indicate that miconazole is a cost-effective antifungal genitourinary irrigant.

Aged↗

PubMed2000

Evidence that Alzheimer's disease is a microvascular disorder: the role of constitutive nitric oxide.

Evidence is fast accumulating which indicates that Alzheimer's disease is a vascular disorder with neurodegenerative consequences rather than a neurodegenerative disorder with vascular consequences. It is proposed that two factors need to be present for AD to develop: (1) advanced ageing, (2) presence of a condition that lowers cerebral perfusion, such as a vascular-risk factor. The first factor introduces a normal but potentially insidious process that lowers cerebral blood flow in inverse relation to increased ageing; the second factor adds a crucial burden which further lowers brain perfusion and places vulnerable neurons in a state of high energy compromise leading to a cascade of neuronal metabolic turmoil. Convergence of the two factors above will culminate in a critically attained threshold of cerebral hypoperfusion (CATCH). CATCH is a hemodynamic microcirculatory insufficiency that will destabilize neurons, synapses, neurotransmission and cognitive function, creating in its wake a neurodegenerative state characterized by the formation of senile plaques, neurofibrillary tangles, amyloid angiopathy and in some cases, Lewy bodies. Since any of a considerable number of vascular-related conditions must be present in the ageing individual for cognition to be disturbed, CATCH identifies an important aspect of the heterogeneic disease profile assumed to be present in the AD syndrome. It is proposed that CATCH initiates AD by distorting regional brain capillary structure involving endothelial cell shape changes and impairment of nitric oxide (NO) release which affect signaling between the immune, cardiovascular and nervous systems. Evidence is presented that in many tissues there is a basal level of NO being produced and that the actions of several signaling molecules may initiate increases in basal NO levels. Moreover, these temporary increases in basal NO levels exert inhibitory cellular actions, via cellular conformational changes. Findings indicate that (a) constitutive NO is responsible for a basal or 'tonal' level of NO; (b) this NO keeps particular types of cells in a state of inhibition and (c) activation of these cells occurs through disinhibition. Consequently, tissues not maintaining a basal NO level are more prone to excitatory, immune, vascular and neural influences. Under such circumstances, these tissues cannot be down-regulated to normal basal levels, thus prolonging their excitatory state. Thus, the clinical convergence of advanced ageing in the presence of a chronic, pre-morbid vascular risk factor, can, in time, contribute to an endotheliopathy involving basal NO deficit, to the degree where regional metabolic dysfunction leads to cognitive meltdown and to progressive neurodegeneration characteristic of Alzheimer's disease.

Alzheimer Disease↗

PubMed2000

Unchanged total number of neurons in motor cortex and neocortex in amyotrophic lateral sclerosis: a stereological study.

Modern stereological methods provide precise and reliable estimates of the number of neurons in specific regions of the brain. The total number of neurons in the neocortex and motor cortex from eight patients suffering from amyotrophic lateral sclerosis (ALS) and nine controls was estimated. No attempt was made to estimate subpopulations of neurons such as the number of giant pyramidal cells of Betz. No difference was found in the average number of neurons in neocortex in ALS and controls, 21.7 and 22.3 x 10(9), respectively, and 1.33 and 1.29 x 10(9) in motor cortex, respectively. In the light of our stereological measurements, results obtained from in-vivo proton magnetic resonance spectroscopy (1H-MRS), suggesting neuronal loss in ALS, may instead be due to neuronal metabolic dysfunction and/or alteration in the size or the volume fraction of the neurons.

Aged↗

PubMed1999

Postnatal development of cytochrome oxidase activity in fiber tracts of the rat brain.

This paper describes postnatal changes in cytochrome oxidase (C.O.) activity in developing fiber tracts. Quantitative histochemistry was used to measure changes in C.O. activity in nine white matter regions at postnatal days (P) 7, 12, 17, 30, and 60 in the rat. At P7, enzyme activity was maximal in the spinal trigeminal tract, medial longitudinal fasciculus, and cerebellar white matter. At P12, maximal levels were measured in the medial lemniscus and cerebral peduncle. C.O. activity increased from low levels at P7 to maximal levels by P17 in the hippocampal commissure, posterior and anterior corpus callosum, and anterior commissure. In all nine regions, C.O. activity decreased by P60. Thus, peaks in C.O. activity shifted as a function of postnatal age in a caudo-rostral direction. The regional heterogeneity in the age of onset in C.O. fluctuations suggests that vulnerability to injury and metabolic dysfunction during the perinatal period will differentially affect white matter structures, depending on the age of onset of such disruptions.

Aging↗

PubMed2002

Regulation of lipolysis: natriuretic peptides and the development of cachexia.

The development of cachexia is commonly seen in many pathological states and is associated with a markedly impaired prognosis. Loss of fat tissue appears to be of particular pathophysiological importance in this setting. Lipolysis is closely regulated in health; the major established pathways involving catecholamines (stimulation of lipolysis) and insulin (inhibition of lipolysis). The wasting process in cachexia is associated with marked metabolic dysfunction, and loss of this tight regulatory control. Natriuretic peptides are a family of related peptides with important vasodilatory, natriuretic and diuretic properties. It has recently been shown that natriuretic peptides are also potent stimuli for lipolysis in humans. In this respect, atrial and brain natriuretic peptide appear to have the greatest lipolytic effect, and are similar in potency to catecholamines. Elevated levels of circulating natriuretic peptides are found in several pathological states, and generally reflect disease severity. This article will provide a concise review of the regulation of lipolysis in humans, concentrating on the role of the natriuretic peptides. The relevance of natriuretic peptides to the development of cachexia will be discussed.

Adipose Tissue↗

PubMed1987

[Significance of clinical and biological markers in autistic syndromes in children].

Several biological theories were proposed to explain symptoms of childhood autism in terms of monoamine metabolic dysfunction. Clinical, electrophysiological and biochemical markers which support the dopaminergic hypothesis will be given in this paper. A factorial analysis, performed on the 'behavior summarized evaluation' (BSE, scoring behavioral data), exhibits a first component corresponding to the autistic DSM III criteria, and also shows that the disturbances of attention and perception belonged to this component. So, as well as communication, selective attention, perception and gestures, usually considered as regulated by the dopaminergic system are deeply modified and appeared as primary symptoms in autistic syndromes. Many electrophysiological data recorded in autistic children suggest both faulty modulation of sensory input and deficiency in dealing with sensory cross-modal association which have been related to a dysfunctioning of the dopaminergic system. Elevated homovanillic acid levels, the main dopamine metabolite, have been attributed to a reduced re-uptake of dopamine related to a 'longer occupation' of the receptors which is in agreement with the electrophysiological 'sensory overload'. The relationships found between these markers are discussed. Such an approach would contribute to a better understanding of the underlying mechanism of autism.

Autistic Disorder↗

PubMedDate not supplied

Tau aggregation in the hippocampal formation: an ageing or a pathological process?

Tauopathy is a concept to describe different genetic or metabolic dysfunctions of tau proteins that generate most of the known dementing disorders. Tauopathy is a degenerating process that also affects the entorhinal formation, and then the hippocampal formation in ageing. In Alzheimer's disease (AD), a disease due to APP dysfunction, a similar tauopathy process in observed in neocortical areas, well correlated to cognitive impairment. One important gap of knowledge is the relationship between tauopathy in the hippocampal formation, ageing, AD, and cognitive impairment. Here we show that the multidisciplinary analysis of numerous brains from non-demented and demented patients suggests the following observations: tauopathy of the hippocampal formation in humans is age-related but not an age-dependent process, also independent of AD, but amplified by APP dysfunctions. Tauopathy in the entorhinal and hippocampal formation could be another type of pathological dysfunction of tau proteins, and a therapeutic target to delay AD. Relevant animal models are desperately needed to address this issue.

Aged↗

PubMed2002

Mental status changes in children with systemic cancer.

Mental status changes are second only to headaches as a cause of neurologic consultation in children with systemic cancer, but the literature on these patients is sparse. This study consisted of a review of the consultations because of changes in mental status in patients with pediatric cancer, with analysis of clinical presentation, etiology, underlying cancer, and neuroradiologic findings. Hematologic cancers were the underlying disorder in slightly more than one half of the patients. The majority of children suffered from iatrogenically induced encephalopathy, predominantly opioid-related. Several drugs were associated with depressed sensorium, but a pure metabolic deficit was rare. One third of the patients had multiple causative factors. Neuroimaging studies were particularly helpful in children with unexplained somnolence but were less useful if the patient had hallucinations. The absence of localizing signs in children with unexplained somnolence or stupor did not exclude the presence of structural disease. Altered mental status is frequently observed in children being actively treated for systemic cancer. The majority of children suffer from iatrogenically induced encephalopathy, predominantly opioid-related. The presence of hallucinations favors a toxic-metabolic dysfunction, especially if associated with myoclonus. Under those circumstances a neuroimaging study is usually unrewarding. If the main complaint is unexplained somnolence without hallucinations or delusions, the performance of a brain imaging study is mandatory, even in the absence of localizing signs.

Adolescent↗

PubMed1996

Effect of estrogen withdrawal on blood pressure and insulin resistance in sucrose-fed juvenile rats.

We have previously shown that juvenile Sprague-Dawley rats, fed a diet in which complex carbohydrates are replaced by sucrose, develop insulin resistance and hypertension. These conditions develop despite the absence of genetic predisposition to either. When studied with the euglycemic hyperinsulinemic clamp technique, these rats have reduced insulin-stimulated glucose utilization, but normal suppression of hepatic glucose output. In the young sucrose-fed rats, it was noted that the degree of blood pressure elevation was greater in males than in females. The purpose of this study was to test the hypothesis that estrogen withdrawal increases insulin resistance and hypertension. Female rats were randomized at weaning (3 weeks of life) to receive control diet or sucrose diet. Animals were assessed with weekly weight and indirect tail-cuff blood pressure. At 8 weeks of life, the sucrose-fed rats were randomized to receive bilateral oophorectomy or sham surgery (anesthesia and uterine horn exposure without removal of the ovaries). At 13 to 14 weeks of life, all animals were fasted overnight, and had an oral glucose tolerance test while conscious. Weight and weight gain were not different among the groups over the 11 week study period. Animals fed the sucrose diet developed significantly higher blood pressure than animals fed the control diet; oophorectomized animals had higher blood pressure than sham-operated animals (P <.0001). Sucrose-fed oophorectomized animals developed fasting and glucose-stimulated hyperinsulinemia. Estrogen withdrawal augments blood pressure in juvenile rats made insulin resistant and hypertensive with a sucrose diet. Estrogen withdrawal in these animals also induces fasting and glucose-stimulated hyperinsulinemia, which are signs of worsening insulin resistance. Androgen:estrogen imbalance increases metabolic dysfunction and worsens hypertension in this animal model.

Animals↗

PubMed1994

Oxygen-free radicals and myocardial nerve fibers endings.

Previous data from our laboratory have shown that electrolysis-induced oxygen free radicals (OFR) and ischemia/reperfusion (I/R) injury both produced a significant decrease of myocardial noradrenaline (NA) stocks in the isolated perfused rat heart. Therefore, we carried out the present study by immuno- and fluorescence histochemistry techniques to demonstrate the possibility that fibers nerve endings of the heart may be injured and to evaluate the subsequent damages. Isolated rat hearts were perfused according to the Langendorff technique and subdivided into i) control; ii) electrolyzed (two platinum electrodes, DC current, 10 mA, 1 min); iii) xanthine and xanthine oxidase (X-XO) perfusion for 30 min, and iv) 30 min global ischemia followed by 5 min reperfusion. Results indicate that in the last three groups myocardial fibers were altered. However, in electrolyzed hearts and those submitted to X-XO perfusion, but not in the I/R model, a disruption of many of the nerve fibers could be noted. Thus, NA leakage may be due to a neural injury when OFR are generated exogenously, whereas in the I/R model NA overflow may be explained by a metabolic dysfunction such as the inversion of the uptake I carrier. The major conclusion of this study is that OFR as generated exogenously (by electrolysis or by X-XO) cannot be considered to closely mimic the conditions of I/R injury, at least as concerns neural injury.

Animals↗

PubMedDate not supplied

Atherogenesis and its relationship to coronary risk factors.

A new model for the development of atherosclerosis is emerging (1,2). This development process, called atherogenesis, is now thought to begin with metabolic dysfunction of the endothelial cells that line the innermost portion of the arterial wall. Endothelial dysfunction precedes visible changes in endothelial structure. Dysfunctional endothelium loses its ability to maintain vascular smooth muscle relaxation and instead promotes vasospasm, chemotaxis and inflammation, platelet aggregation, and diminished clot lysis. Endothelial dysfunction appears to occur diffusely, rather than discretely, in affected vessels. Accordingly, local anatomical interventions, such as bypass surgery or angioplasty, can be expected to have only limited success in the treatment of patients with atherosclerotic disease. More definitive treatments must be directed at the risk factors initiating or enhancing atherogenesis. Such interventions are more likely to be medical than surgical or mechanical. With appropriate understanding of the underlying process of atherogenesis and its clinical manifestations, such medical interventions can be carried out within the boundaries of everyday practice.

Arteriosclerosis↗

PubMed2003

Drug discovery in the ubiquitin regulatory pathway.

The ubiquitin system has been implicated in the pathogenesis of numerous disease states, including oncogenesis, inflammation, viral infection, CNS disorders and metabolic dysfunction. Ubiquitin conjugation and deconjugation to substrate proteins is carried out by multiple families of proteins, each with a defined role in the enzymatic cascade. This conjugation-deconjugation system parallels the kinase-phosphatase system in that both alter protein function by the addition and removal of post-translational modifiers. Our understanding of ubiquitin biology and strategies to interfere pharmacologically with the ubiquitin regulatory machinery is progressing rapidly. In light of increased interest in ubiquitin pathways as drug targets, we review the ubiquitin enzymatic cascades, highlighting therapeutic opportunities and enzymatic mechanisms. We also discuss the challenges of targeting this class of enzymes with small molecules, as well as current approaches and progress in drug discovery.

Humans↗

PubMed2002

The genetics of sleep disorders.

The contribution of genetic components to the pathology of sleep disorders is increasingly recognised as important. Genetic studies have identified genes that may be important in the regulation of circadian rhythms, which in turn determine the time of sleep onset and waking. Recent studies have shown that mutations in hPER2 are associated with autosomal-dominant familial advanced-sleep-phase syndrome. Genetic studies in a canine model of narcolepsy and in knock-out mice have led to the identification of the hypothalamic hypocretin (orexin) neurotransmitter system as a key target for human narcolepsy. The contribution of genetic factors to obstructive sleep apnoea syndrome (OSAS) has led to a better understanding of this complex disorder that may be part of a larger syndrome associated with respiratory, cardiovascular, and metabolic dysfunction. The aim of this review is to discuss the current knowledge on the role of genetic factors in sleep disorders, in particular circadian disorders, narcolepsy, restless-legs syndrome, and OSAS.

Animals↗

PubMed1977

Urinary mucopolysaccharides in acheiropodia.

Urinary mucopolysaccharides from three patients with acheiropodia were qualitatively and quantitatively analysed by agar gel electrophoresis coupled with enzymatic degradation. Although no abnormal pattern was characterized, eventual metabolic dysfunction detected only in bone/cartilage tissues could not be ruled out.

Abnormalities, Multiple↗

PubMed2004

Mitochondrial myopathies and anaesthesia.

The mitochondrial myopathies consist of a heterogeneous group of disorders caused by structural and functional abnormalities in mitochondria leading to involvement of the nervous system and muscles as well as other organ systems. The peculiar genetic characteristics of mitochondrial DNA impart distinctive properties to these disorders. The pathophysiology is presented. The methods employed in making the correct diagnosis, the preoperative patient assessment and correction of metabolic dysfunctions and anaesthetic techniques used, are highlighted. The conditions are briefly reviewed and suggestions are made for the safe anaesthetic management of affected patients.

Anesthesia, Conduction↗

PubMed2003

NMR spectroscopic-based metabonomic studies of urinary metabolite variation in acclimatizing germ-free rats.

Understanding metabolic variation in "normal" animals is critical to the evaluation of drug-induced metabolic perturbation related to toxicity or pharmacology. NMR spectroscopic-based metabonomic methods were used to evaluate the acclimatization pathways of germ-free (axenic) rats to standard laboratory conditions concomitant with the associated development of gut microfloral communities. Urine samples from male Fischer 344 germ-free rats were collected over 21 days following introduction to a standard laboratory environment and analyzed using NMR spectroscopy. NMR spectra were data-reduced and analyzed using principal component analysis to visualize the changes in the host metabolic trajectory over the course of the study. At days 2 and 6 of the acclimatization process, there were marked episodes of glycosuria. In comparison to the concentrations in the 0-6 h samples, there was a reduction in the level of the tricarboxylic acid cycle intermediates (citrate, 2-oxoglutarate, and succinate) from 6 h to day 6, after which there was a sustained increase until the end of the study. The concentrations of hippurate and trimethylamine N-oxide increased over the course of the study in comparison to the levels at 0-6 h, with the most pronounced increase in the former between days 17 and 21. Phenylacetylglycine levels increased after 6 h whereas 3-hydroxypropionic acid was observed at day 12 and increased up to day 17. By day 21, the urinary metabolic profile was within the control range when compared to historical data, implying the establishment of a stable gut microflora. Although the metabolic alterations caused by the microbial alterations were not as substantial as those from metabolic dysfunction, their presence does have an effect on the interpretation of the profiles, the state of the animal, and the mechanism for the cause of such alterations. Furthermore, the use of oral drug delivery will have an effect on the microbial state, not only as a direct influence of the drug but also from it's associated vehicle. Such effects are likely to be observed particularly in the area of preclinical investigation where the data from these studies are of particular relevance.

Acclimatization↗

PubMed1998

Molecular cloning of a novel heat induced/chilling tolerance related cDNA in tomato fruit by use of mRNA differential display.

Chilling injury was circumvented by heat-treating mature green tomatoes (Lycopersicon esculentum, cv. Mountain Springs) at 42 degrees C for two days prior to storing them at 2 degrees C for one or two weeks, whereas fruits stored at 2 degrees C without preheating developed typical chilling injury symptoms and failed to ripen at 20 degrees C. Using mRNA differential display and screening of the cDNA libraries, we have cloned from tomato fruit a full-length HCT1 cDNA (heat induced/chilling tolerance related). The protein ( 17.6 kDa) predicted from coding region of HCT1 cDNA has high identity with class II cytosolic small HSPs. The gene corresponding to HCT1 cDNA was termed as LeHSP 17.6. Southern-blot hybridization indicates that LeHSP 17.6 belongs to a two-member gene family. Northern blot analysis indicates the heat-induced transcript of the LeHSP 17.6 remains up-regulated during subsequent exposure of the fruit to chilling temperatures for at least one week and upon transfer to ripening temperatures for one day. Fruits which were only chilled show a low level of expression of the LeHSP 17.6 transcript. We hypothesize that LeHSP 17.6 may be involved in protecting the cell from metabolic dysfunctions leading to ripening failure caused by chilling injury. This is the first report of a class II cytosolic smHSPs encoding gene in tomato.

Amino Acid Sequence↗

PubMed1998

Free radicals as mediators of neuronal injury.

1. Free radicals may play an important role in several pathological conditions of the central nervous system (CNS) where they directly injure tissue and where their formation may also be a consequence of tissue injury. 2. Free radicals produce tissue damage through multiple mechanisms, including excito-toxicity, metabolic dysfunction, and disturbance of intracellular homeostasis of calcium. 3. Oxidative stress can significantly worsen acute insults, such as ischemia, as well as chronic neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease. 4. For instance, recent findings suggest a causal role for chronic oxidative stress in familial ALS, as this disease is linked to missence mutations of the copper/zinc superoxide dismutase (SOD). 5. Thus, therapeutic approaches which limit oxidative stress may be potentially beneficial in several neurological diseases.

Amyotrophic Lateral Sclerosis↗