Search PubMed⌕ Search

Biomedical subjects

A Fisher

Publications and source records attributed to A Fisher.

At least 19 recordsLinked to original sources
PubMed2007

Perioperative acute upper gastrointestinal haemorrhage in older patients with hip fracture: incidence, risk factors and prevention.

BACKGROUND: No specific preventive strategy exists for acute gastrointestinal haemorrhage in hip fracture patients. AIMS: To determine the effectiveness of prophylactic use of proton pump inhibitors in patients with risk factors for acute gastrointestinal haemorrhage. METHODS: Prospective two-stage study of 822 consecutive older (> or =60 years) hip fracture patients. RESULTS: Acute gastrointestinal haemorrhage occurred in 16 (3.9%) of 407 patients and was associated with increased length of hospital stay (28.7 vs. 15.9; P = 0.0027) and mortality (18.8% vs. 4.3%; P = 0.043). Multiple analysis identified five independent risk factors for acute gastrointestinal haemorrhage: pre-existing peptic ulcer (OR 4.3; P = 0.043), current smoking (OR 3.1; P = 0.023), post-operative use of an antiplatelet agent (OR 6.5; P = 0.046), post-operative use of non-steroidal anti-inflammatory drug/cyclo-oxygenase-2 inhibitor (OR 4.9; P = 0.06) and blood group O (OR 1.7; P = 0.046). These risk factors were highly sensitive and had a negative predictive value of 99.8%. Prophylactic use of proton pump inhibitors in patients with risk factor for acute gastrointestinal haemorrhage significantly reduced the incidence of this complication (0.72% in treated patients vs. 13.4% in untreated; P < 0.001); the number needed to treat was 7.9. Conclusions In older hip fracture patients perioperative acute gastrointestinal haemorrhage occurs in 3.9% and is associated with poor outcome. Preventive proton pump inhibitor therapy in patients at risk of acute gastrointestinal haemorrhage is effective and safe.

Aged↗
PubMed2006

Characterization of Clostridial botulinum neurotoxin channels in neuroblastoma cells.

The channel and chaperone activities of Clostridial botulinum neurotoxin (BoNT) A were investigated in Neuro 2a neuroblastoma cells under conditions that closely emulate those prevalent at the endosome. Channel activity occurs in bursts interspersed between periods of little or no activity. The channels are voltage dependent, opening only at negative voltages. Within bursts, the channel resides preferentially in the open state. The channels open to a main conductance of 105 +/- 5 pS or 65 +/- 4 pS in 200 mM CsCl or NaCl, respectively. The BoNT channels display a conspicuous subconductance of 10 +/- 2 pS. The neuroblastoma cell line appears, therefore, to be a suitable system to characterize the BoNT channel and to pursue evaluation of plausible strategies for targeted drug delivery thereby minimizing the requirement for in vivo animal testing.

Animals↗
PubMed2006

Microcebus murinus: a useful primate model for human cerebral aging and Alzheimer's disease?

Age-associated dementia, in particular Alzheimer's disease (AD), will be a major concern of the 21st century. Research into normal brain aging and AD will therefore become increasingly important. As for other areas of medicine, the availability of good animal models will be a limiting factor for progress. Given the complexity of the human brain, the identification of appropriate primate models will be essential to further knowledge of the disease. In this review, we describe the features of brain aging and age-associated neurodegeneration in a small lemurian primate, the Microcebus murinus, also referred to as the mouse lemur. The mouse lemur has a relatively short life expectancy, and animals over 5 years of age are considered to be elderly. Among elderly mouse lemurs, the majority show normal brain aging, whereas approximately 20% develop neurodegeneration. This Microcebus age-associated neurodegeneration is characterized by a massive brain atrophy, abundant amyloid plaques, a cytoskeletal Tau pathology and a loss of cholinergic neurons. While elderly mouse lemurs with normal brain aging maintain memory function and social interaction, animals with age-associated neurodegeneration lose their cognitive and social capacities and demonstrate certain similarities with age-associated human AD. We conclude that M. murinus is an interesting primate model for the study of normal brain aging and the biochemical dysfunctions occurring in age-associated neurodegeneration. Mouse lemurs might also become an increasingly important model for the development of novel treatments in this domain.

Aging↗
PubMed2005

Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation.

BACKGROUND: Cathepsin K (catK), a lysosomal cysteine protease, was identified in a gene-profiling experiment that compared human early plaques, advanced stable plaques, and advanced atherosclerotic plaques containing a thrombus, where it was highly upregulated in advanced stable plaques. METHODS AND RESULTS: To assess the function of catK in atherosclerosis, catK(-/-)/apolipoprotein (apo) E(-/-) mice were generated. At 26 weeks of age, plaque area in the catK(-/-)/apoE(-/-) mice was reduced (41.8%) owing to a decrease in the number of advanced lesions as well as a decrease in individual advanced plaque area. This suggests an important role for catK in atherosclerosis progression. Advanced plaques of catK(-/-)/apoE(-/-) mice showed an increase in collagen content. Medial elastin fibers were less prone to rupture than those of apoE(-/-) mice. Although the relative macrophage content did not differ, individual macrophage size increased. In vitro studies of bone marrow derived-macrophages confirmed this observation. Scavenger receptor-mediated uptake (particularly by CD36) of modified LDL increased in the absence of catK, resulting in an increased macrophage size because of increased cellular storage of cholesterol esters, thereby enlarging the lysosomes. CONCLUSIONS: A deficiency of catK reduces plaque progression and induces plaque fibrosis but aggravates macrophage foam cell formation in atherosclerosis.

Animals↗
PubMed2005

Effect of socioeconomic status on objectively measured physical activity.

BACKGROUND: A socioeconomic gradient in childhood obesity is known to be present by the age of school entry in the UK. The origin of this gradient is unclear at present, but must lie in socioeconomic differences in habitual physical activity, sedentary behaviour, or dietary intake. AIMS: To test the hypothesis that habitual physical activity and/or sedentary behaviour are associated with socioeconomic status (SES) in young Scottish children. METHODS: Observational study of 339 children (mean age 4.2 years, SD 0.3) in which habitual physical activity and sedentary behaviour were measured by accelerometry over six days (study 1). In a second study, 39 pairs of children of distinctly different SES (mean age 5.6 years, SD 0.3) were tested for differences in habitual physical activity and sedentary behaviour by accelerometry over seven days. RESULTS: In study 1, SES was not a significant factor in explaining the amount of time spent in physical activity or sedentary behaviour once gender and month of measurement were taken into account. In study 2, there were no significant differences in time spent in physical activity or sedentary behaviour between affluent and deprived groups. CONCLUSION: Results do not support the hypothesis that low SES in young Scottish children is associated with lower habitual physical activity or higher engagement in sedentary behaviour.

Body Mass Index↗
PubMed2005

Electron-temperature and energy-flow history in an imploding plasma.

The time-dependent radial distribution of the electron temperature in a 0.6 micros, 220-kA gas-puff z-pinch plasma is studied using spatially-resolved observations of line emission from singly to fivefold ionized oxygen ions during the plasma implosion, up to 50 ns before maximum compression. The temperature obtained, together with the previously determined radial distributions of the electron density, plasma radial velocity, and magnetic field, allows for studying the history of the magnetic-field energy coupling to the plasma by comparing the energy deposition and dissipation rates in the plasma. It is found that at this phase of the implosion, approximately 65% of the energy deposited in the plasma is imparted to the plasma radial flow, with the rest of the energy being converted into internal energy and radiation.

Journal Article↗
PubMed2005

A review of self-management interventions for panic disorders, phobias and obsessive-compulsive disorders.

OBJECTIVE: To review current evidence for the clinical and cost-effectiveness of self-management interventions for panic disorder, phobias and obsessive-compulsive disorder (OCD). METHOD: Papers were identified through computerized searches of databases for the years between 1995 and 2003, manual searches and personal contacts. Only randomized-controlled trials were reviewed. RESULTS: Ten studies were identified (one OCD, five panic disorder, four phobias). Effective self-management interventions included cognitive-behavioural therapy (CBT) and exposure to the trigger stimuli for phobias and panic disorders. All involved homework. There was evidence of effectiveness in terms of improved symptoms and psychological wellbeing when compared with standard care, waiting list or relaxation. Brief interventions and computer-based interventions were effective for most participants. In terms of quality, studies were mainly based on small samples, lacked long-term follow-up, and failed to address cost-effectiveness. CONCLUSION: Despite the limitations of reviewed studies, there appears to be sufficient evidence to warrant greater exploration of self-management in these disorders.

Cognitive Behavioral Therapy↗
PubMed2004

Bier's block; 100 years old and still going strong!

In August 1908 Karl August Bier, Professor of Surgery in Berlin, described a new method of producing analgesia of a limb which he named 'vein anesthesia'. Bier first presented his new method of intravenous regional anesthesia (IVRA) at the 37th Congress of the German Surgical Society on 22 April, 1908, only 10 years after his significant communication on spinal anesthesia (1). His method, which now bears his name, consisted of occluding the circulation in a segment of the arm with two tourniquets and then injecting a dilute local anesthetic through a venous cut-down in the isolated segment. Bier had the good fortune to use procaine, the first safe injectable local anesthetic that had been synthesized by Einhorn in 1904.

Adjuvants, Anesthesia↗
PubMed2003

The substance P (NK1) receptor antagonist L-760735 inhibits fear conditioning in gerbils.

The ability of the substance P (NK(1) receptor) antagonist (SPA) L-760735 to inhibit conditioned fear was assessed in gerbils using a four plate apparatus. Animals that had been treated with diazepam (3 mg/kg) or L-760735 (3 mg/kg) 30 min before a 3 min conditioning session in the apparatus exhibited a release of plate crossings during the retest session approximately 3 h later. Plate crossings were also increased when animals received diazepam or L-760735 30 min before the retest session. In contrast, fluoxetine and venlafaxine (30 mg/kg) did not exhibit anxiolytic-like effects. During the retest session, gerbils drummed their hind feet on the floor; this behaviour was not observed spontaneously in gerbils that were naïve to the apparatus. Foot drumming was abolished by pretreatment with L-760735 or diazepam (3 mg/kg) but was markedly increased following administration of fluoxetine or venlafaxine (30 mg/kg). Foot drumming elicited by aversive conditioning alone or in combination with fluoxetine was abolished by administration of L-760735 and by amygdala lesions involving the basolateral and lateral nuclei, indicating that this behaviour is an alarm signal or fear response mediated via release of substance P in brain circuits involving the amygdala. The observations provide further evidence for an anxiolytic-like profile of SPAs in preclinical assays and demonstrate a clear difference between the actions of SPAs and established antidepressant drugs.

Amygdala↗
PubMed2003

A history of neuraxial administration of local analgesics and opioids.

The history of intrathecal and epidural anaesthesia is in parallel with the development of general anaesthesia. As ether anaesthesia (1846) is considered the first modern anaesthetic since its use by Morton 157 yr ago, so Bier made history by using cocaine for intrathecal anaesthesia in 1898. The first published report on opioids for intrathecal anaesthesia belongs to a Romanian surgeon, Racoviceanu-Pitesti, who presented his experience at Paris in 1901. It was almost a century before the opioids were used for epidural analgesia. Behar and his colleagues published the first report on the epidural use of morphine for the treatment of pain in The Lancet in 1979. Epidural and intrathecal opioids are today part of a routine regimen for intra- and postoperative analgesia. Over the last 30 yr, the use of epidural opioids has became a standard for analgesia in labour and delivery, and for the management of chronic pain. Finally, epidural opioids have been shown to have a pre-emptive effect, when used before major surgery. We present the evolution of neuraxial anaesthesia and the history of intrathecal and epidural administration of opioids.

Analgesia, Epidural↗
PubMed2003

P-Glycoprotein efflux reduces the brain concentration of the substance P (NK1 receptor) antagonists SR140333 and GR205171: a comparative study using mdr1a-/- and mdr1a+/+ mice.

Investigation of the antidepressant-like actions of substance P (NK1 receptor) antagonists has been hindered by the few available compounds that bind with high affinity to the rat and mouse NK1 receptor, as these are the most commonly used preclinical species. The best available compounds for such studies are SR140333 and GR205171. However, SR140333 does not penetrate the central nervous system (CNS) after systemic administration, and GR205171 is active only at high doses, where unspecific pharmacological effects occur, so that changes in behaviour cannot be attributed to selective NK1 receptor blockade. These compounds may be substrates for P-glycoprotein (P-gp) and hence are actively excluded from the brain. The present studies used mdr1a-/- mice, a spontaneously occurring mutant that is deficient in P-gp, to examine the CNS penetration of SR140333 and GR205171. Following systemic administration of SR140333 and GR205171 (0.01-10 mg/kg i.v.), considerably higher drug concentrations were achieved in the brains of mdr1a-/- than in mdr1a+/+ mice, and this corresponded with a greater ability to inhibit NK1-agonist-induced behaviours in the mdr1a-/- mutants. Moreover, an NK1-receptor-specific inhibition of aggressive behaviour by GR205171 (10 mg/kg) could be demonstrated in mdr1a-/-, but not mdr1a+/+, mice. These findings suggest that P-gp deficient mice may have useful applications in behavioural pharmacology studies, especially when highly brain-penetrant compounds are not yet available.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Impact of muscarinic agonists for successful therapy of Alzheimer's disease.

The M1 muscarinic agonists AF102B, AF150(S) & AF267B--i) restored cognitive impairments in several animal models for AD with an excellent safety margin; ii) elevated alpha-APPs levels; iii) attenuated vicious cycles induced by A beta, and inhibited A beta- and oxidative stress-induced apoptosis; and iv) decreased tau hyperphosphorylation. AF150(S) and AF267B were more effectve than rivastigmine and nicotine in restoring memory impairments in mice with small hippocampi. In apolipoprotein E-knockout mice, AF150(S) restored cognitive impairments and cholinergic hypofunction and decreased tau hyperphosphorylation. In aged microcebes, AF150(S) restored cognitive and behavioral impairments and decreased tau hyperphosphorylation, paired helical filaments and astrogliosis. In rabbits, AF267B & AF150(S) decreased CSF A beta(1-42 & 1-40), while AF102B reduced A beta(1-40). Finally AF102B decreased CSF A beta(total) in AD patients. Taken together, M1 agonists may represent a unique therapy in AD due to their beneficial effects on three major hallmarks of AD--cholinergic hypofunction, A beta and tau protein hyperphosphorylation.

Aged↗
PubMed2001

The mutational spectrum of human malignant autosomal recessive osteopetrosis.

Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogeneous autosomal recessive disorder of bone metabolism, which, if untreated, has a fatal outcome. Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, are responsible for a subset of this condition. By sequencing the ATP6i gene in arOP patients from 44 unrelated families with a worldwide distribution we have now established that ATP6i mutations are responsible for approximately 50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions, two insertions, 10 nonsense substitutions and 21 mutations in splice sites) are predicted to cause severe abnormalities in the protein product and are likely to represent null alleles. In addition, we have also analysed nine unrelated arOP patients from Costa Rica, where this disease is apparently much more frequent than elsewhere. All nine Costa Rican patients bore either or both of two missense mutations (G405R and R444L) in amino acid residues which are evolutionarily conserved from yeast to humans. The identification of ATP6i gene mutations in two families allowed us for the first time to perform prenatal diagnosis: both fetuses were predicted not to be affected and two healthy babies were born. This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe condition.

Amino Acid Sequence↗
PubMed2001

Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists.

Overproduction of the peptide amyloid beta (A beta) is a critical event in Alzheimer's disease (AD). Systemic administration of 3 M1-selective muscarinic agonists, AF102B, AF150S and AF267B, decreased cerebrospinal fluid (CSF) A beta concentrations; levels of CSF secreted beta-APP were not significantly altered. Rabbits treated for 5 days with s.c. injections of each drug (2 mg/kg/day) had levels of CSF A beta which were between 55 and 71% of control for A beta 1-40 and between 59 and 84% of control for A beta 1--42.

Alzheimer Disease↗
PubMed2001

Plasma dynamics in capillary discharge soft x-ray lasers.

The dynamics and stability of collapsing gas columns, generated by a fast capillary discharge setup, are studied for obtaining soft x-ray amplification in highly ionized ions. Electron temperature and density measurements at the peak of the compression stage are used for tuning the discharge parameters. Once the needed conditions were achieved, strong amplification of the 3s-3p transition in Ne-like Ar ions at 469 A is observed. A gain coefficient of >0.75 cm(-1) and a beam divergence of <5 mrad are measured along plasma columns of <150 microm diameter and up to 165 mm length.

Journal Article↗
PubMed2001

Use of muscarinic agonists in the treatment of Sjögren's syndrome.

Two muscarinic agonists (pilocarpine and cevimeline) have recently been approved for the treatment of symptoms of xerostomia in Sjögren's syndrome (SS). These agents stimulate the M1 and M3 receptors present on salivary glands, leading to increased secretory function. The use of these agents emphasizes the importance of neuroendocrine mechanisms in SS, which is considered an autoimmune disorder. We review recent studies on the release of cytokines and metalloproteinases in SS-affected glands and their influence on the release of and response to neurotransmitters. Also, we review the structure and function of muscarinic receptors as they may relate to SS and the potential use of novel muscarinic agonists in SS.

Humans↗