Upper gastrointestinal safety of oral bisphosphonate in hospitalized patients.

Oral bisphosphonates are effective medications for the prevention of fractures in people suffering from osteoporosis. They are associated with gastrointestinal adverse reactions the most severe being an esophageal ulcer. It is unclear if oral bisphosphonates have a similar gastrointestinal safety profile in the hospital setting as in the community setting because hospitalized patients are often bedridden which may hinder proper drug administration. INTRODUCTION: To evaluate the incidence of upper gastrointestinal symptoms in hospitalized patients taking oral bisphosphonate. METHODS: This single-center prospective cohort study included hospitalized adult patients actively taking risedronate or alendronate. Upper gastrointestinal symptoms were actively assessed at the baseline and 1 to 5 h following the administration of the oral bisphosphonate. RESULTS: A total of 298 patients were included in the study. The mean age was 64 ± 15 years. During the follow-up period, gastric and esophageal symptoms affected 32 patients (10.7%). Epigastric burning, dysphagia, and regurgitation were reported in 4.4% (n = 13), 3% (n = 9), 2.7 (n = 8), and 2.3% (n = 7) patients, respectively. Heartburn, retro-sternal pain, and odynophagia were observed in 1.7% (n = 5), 1.7% (n = 5), and 0.3% (n = 1) patients. CONCLUSION: The incidence of adverse reaction was similar to that reported in community trials. The administration of oral bisphosphonate in hospitalized patients does not represent an additional risk for upper gastrointestinal adverse events. Treatment should be optimized during the hospital stay to improve the pharmacological management of osteoporosis.

A requirement for epigenetic modifications during noradrenergic stabilization of heterosynaptic LTP in the hippocampus.

Beta-adrenergic receptor (b-AR) activation by noradrenaline (NA) enhances memory formation and long-term potentiation (LTP), a form of synaptic plasticity characterized by an activity-dependent increase in synaptic strength. LTP is believed to be a cellular mechanism for contextual learning and memory. In the mammalian hippocampus, LTP can be observed at multiple synaptic pathways after strong stimulation of a single synaptic pathway. This heterosynaptic LTP is believed to involve synaptic tagging of active synapses and capture of plasticity-related proteins that enable heterosynaptic transfer of persistent potentiation. These processes may permit distinct neural pathways to associate information transmitted by separate, but convergent, synaptic inputs. We had previously shown that transcription and epigenetic modifications were necessary for stabilization of homosynaptic LTP. However, it is unclear whether transfer of LTP to a second, heterosynaptic pathway involves b-ARs signalling to the nucleus. Using electrophysiologic recordings in area CA1 of murine hippocampal slices, we show here that pharmacologically inhibiting b-AR activation, transcription, DNA methyltransferase or histone acetyltransferase activation, prevents stabilization of heterosynaptic LTP. Our data suggest that noradrenergic stabilization of heterosynaptic ("tagged") LTP requires not only transcription, but specifically, DNA methylation and histone acetylation. NA promotes stable heterosynaptic plasticity through engagement of nuclear processes that may contribute to prompt consolidation of short-term memories into resilient long-term memories under conditions when the brain's noradrenergic system is recruited.

Comparative plasticity of brain synapses in inbred mouse strains.

One niche of experimental biology that has experienced considerable progress is the neurobiology of learning and memory. A key contributor to such progress has been the widespread use of transgenic and 'knockout' mice to elucidate the mechanisms of identifiable phenotypes of learning and memory. Inbred mouse strains are needed to generate genetically modified mice. However, genetic variations between inbred strains can confound the interpretation of cellular neurophysiological phenotypes of mutant mice. It is known that altered physiological strength of synaptic transmission ('synaptic plasticity') can modify and regulate learning and memory. Characterization of the synaptic phenotypes of inbred mouse strains is needed to identify the most appropriate strains to use for generating mutant mouse models of memory function. More importantly, comparative electrophysiological analyses of inbred mice per se can also shed light on which forms of synaptic plasticity underlie particular types of learning and memory. Many such analyses have focused on synaptic plasticity in the hippocampus because of the critical roles of this brain structure in the formation and consolidation of long-term memories. Comparative electrophysiological data obtained from several inbred mouse strains are reviewed here to highlight the following key notions: (1) synaptic plasticity is influenced by the genetic backgrounds of inbred mice; (2) the plasticity of hippocampal synapses in inbred mice is ;tuned' to particular temporal patterns of activity; (3) long-term potentiation, but not long-term depression, is a cellular correlate of behavioural memory performance in some strains; (4) synaptic phenotyping of inbred mouse strains can identify cellular models of memory impairment that can be used to elucidate mechanisms that may cause specific memory deficits.

A novel antigenic variant of Canine parvovirus from a Vietnamese dog.

Nine isolates of Canine parvovirus (CPV) were obtained from Vietnamese dogs and cats. One canine isolate showed a unique antigenic property which indicates a novel antigenic variant of CPV-2b when examined with hemagglutination inhibition tests using our monoclonal antibodies, 21C3 and 19D7, which were recently developed. This isolate had an amino acid substitution of residue 426, Asp to Glu, and the same substitution has recently been found in CPV from Italian dogs. This study first showed that such substitution caused an antigenic difference demonstrable by monoclonal antibodies and that a similar evolution may have occurred in CPV in Vietnam.

Multidisciplinary approaches for investigating the mechanisms of hippocampus-dependent memory: a focus on inbred mouse strains.

Inbred mouse strains differ in genetic makeup and display diverse learning and memory phenotypes. Mouse models of memory impairment can be identified by examining hippocampus-dependent memory in multiple strains. These mouse models may be used to establish the genetic, molecular, and cellular correlates of deficits in learning or memory. In this article, we review research that has characterized hippocampal learning and memory in inbred mouse strains. We focus on two well-established behavioral tests, contextual fear conditioning and the Morris water maze (MWM). Selected cellular and molecular correlates of good and poor memory performance in inbred strains are highlighted. These include hippocampal long-term potentiation, a type of synaptic plasticity that can influence hippocampal learning and memory. Further methods that might help to pinpoint the anatomical loci, and genetic and cellular/molecular factors that contribute to memory impairments in inbred mice, are also discussed. Characterization of inbred mouse strains, using multidisciplinary approaches that combine cellular, genetic, and behavioral techniques, can complement directed mutagenesis to help identify molecular mechanisms for normal and abnormal memory functions.

Phenylethylidenehydrazine, a novel GABA-transaminase inhibitor, reduces epileptiform activity in rat hippocampal slices.

Phenylethylidenehydrazine (PEH), an analog of the monoamine oxidase inhibitor, beta-phenylethylhydrazine (phenelzine), inhibits the gamma-aminobutyric acid (GABA) catabolic enzyme GABA-transaminase and increases brain levels of GABA. GABA is the predominant fast inhibitory transmitter counteracting glutamatergic excitation, and increased neural GABA could influence a wide range of synaptic and circuit properties under both physiologic and pathophysiologic conditions. To examine the scope of these effects, we applied PEH (or vehicle) to rat hippocampal slices and measured basal glutamatergic transmission, synaptic plasticity, and epileptiform activity using extracellular field and whole cell patch clamp recordings. In vitro pre-treatment with PEH (100 microM) increased the GABA content of hippocampal slices by approximately 60% over vehicle-treated controls, but it had no effect on basal field excitatory postsynaptic potentials, tonic GABA currents, paired-pulse facilitation, or long-term potentiation. In contrast, pre-incubation with PEH caused a dose- and time-dependent reduction in epileptiform burst frequency induced by superfusion with Mg2+-free or high-K+ artificial cerebrospinal fluid. Thus, the inhibitory effects of PEH are state-dependent: hyper-excitation during epileptiform bursting was reduced, whereas synaptic transmission and plasticity were unaffected.

Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases.

Protein kinases critically regulate synaptic plasticity in the mammalian hippocampus. Cyclic-AMP dependent protein kinase (PKA) is a serine-threonine kinase that has been strongly implicated in the expression of specific forms of long-term potentiation (LTP), long-term depression (LTD), and hippocampal long-term memory. We review the roles of PKA in activity-dependent forms of hippocampal synaptic plasticity by highlighting particular themes that have emerged in ongoing research. These include the participation of distinct isoforms of PKA in specific types of synaptic plasticity, modification of the PKA-dependence of LTP by multiple factors such as distinct patterns of imposed activity, environmental enrichment, and genetic manipulation of signalling molecules, and presynaptic versus postsynaptic mechanisms for PKA-dependent LTP. We also discuss many of the substrates that have been implicated as targets for PKA's actions in hippocampal synaptic plasticity, including CREB, protein phosphatases, and glutamatergic receptors. Future prospects for shedding light on the roles of PKA are also described from the perspective of specific aspects of synaptic physiology and brain function that are ripe for investigation using incisive genetic, cell biological, and electrophysiological approaches.

Behavioural and physiological characterization of inbred mouse strains: prospects for elucidating the molecular mechanisms of mammalian learning and memory.

With the advent of recombinant DNA methodology, it has become possible to dissect the molecular mechanisms of complex traits, including brain function and behaviour. The increasing amount of available information on the genomes of mammalian organisms, including our own, has facilitated this research. The present review focuses on a somewhat neglected area of genetics, one that involves the study of inbred mouse strains. It is argued that the use of inbred mice is complementary to transgenic approaches in the analysis of molecular mechanisms of complex traits. Whereas transgenic technology allows one to manipulate a single gene and investigate the in vivo effects of highly specific, artificially induced mutations, the study of inbred mouse strains should shed light on the roles of naturally occurring allelic variants in brain function and behaviour. Systematic characterization of the behavioural, electrophysiological, neurochemical, and neuroanatomical properties of a large number of inbred strains is required to elucidate mechanisms of mammalian brain function and behaviour. In essence, a 'mouse phenome' project is needed, entailing the construction of databases to investigate possible causal relationships amongst the phenotypical characteristics. This review focuses on electrophysiological and behavioural characterization of mouse strains. Nevertheless, it is emphasized that the full potential of the analysis of inbred mouse strains may be attained if techniques of numerous disciplines, including gene expression profiling, biochemical analysis, and quantitative trait loci (QTL) mapping, to name but a few, are also included.

Infrarenal aortic stenosis: value of stent placement after percutaneous transluminal angioplasty failure.

PURPOSE: To evaluate the long-term clinical and hemodynamic effectiveness of aortic stent placement in cases of failure of intended infrarenal percutaneous transluminal aortic angioplasty (PTAA). MATERIALS AND METHODS: Fifty-three patients who underwent technically successful PTAA were compared with 24 patients who underwent aortic stent placement because of PTAA failure (19 patients) or ulcerated lesions (five patients) that otherwise would have been treated surgically because of the embolization hazard associated with PTAA alone. Clinical patency was defined as the absence or improvement of symptoms after the intervention. Hemodynamic patency was defined as a normal Doppler waveform in the common femoral arteries, an ankle-brachial index greater than 0.95, or the absence of a thigh-brachial pressure gradient. RESULTS: Three-year clinical and hemodynamic patency rates, respectively, were 85% and 79% for PTAA and 69% and 43% for aortic stent placement. No morbidity was encountered. With use of the Cox proportional hazards model, two significant risk factors were retained for restenosis: unchanged smoking habit (P =.04) and small dilatation diameter (P =.001). Aortic stent placement, performed in patients with a smaller aortic diameter (10.3 vs. 12.7 mm for PTAA), appeared to be a predictive factor for restenosis by using univariate analysis. By using the Cox proportional hazards model, however, the restenosis rates after PTAA and aortic stent placement were not significantly different. CONCLUSION: When aortic diameter is taken into consideration, there is no evidence that clinical outcome after secondary aortic stent placement would be poorer than technically successful PTAA.

Environmental enrichment modifies the PKA-dependence of hippocampal LTP and improves hippocampus-dependent memory.

cAMP-dependent protein kinase (PKA) is critical for the expression of some forms of long-term potentiation (LTP) in area CA1 of the mouse hippocampus and for hippocampus-dependent memory. Exposure to spatially enriched environments can modify LTP and improve behavioral memory in rodents, but the molecular bases for the enhanced memory performance seen in enriched animals are undefined. We tested the hypothesis that exposure to a spatially enriched environment may alter the PKA dependence of hippocampal LTP. Hippocampal slices from enriched mice showed enhanced LTP following a single burst of 100-Hz stimulation in the Schaffer collateral pathway of area CA1. In slices from nonenriched mice, this single-burst form of LTP was less robust and was unaffected by Rp-cAMPS, an inhibitor of PKA. In contrast, the enhanced LTP in enriched mice was attenuated by Rp-cAMPS. Enriched slices expressed greater forskolin-induced, cAMP-dependent synaptic facilitation than did slices from nonenriched mice. Enriched mice showed improved memory for contextual fear conditioning, whereas memory for cued fear conditioning was unaffected following enrichment. Our data indicate that exposure of mice to spatial enrichment alters the PKA dependence of LTP and enhances one type of hippocampus-dependent memory. Environmental enrichment can transform the pharmacological profile of hippocampal LTP, possibly by altering the threshold for activity-dependent recruitment of the cAMP-PKA signaling pathway following electrical and chemical stimulation. We suggest that experience-dependent plasticity of the PKA dependence of hippocampal LTP may be important for regulating the efficacy of hippocampus-based memory.

Genetic and pharmacological demonstration of differential recruitment of cAMP-dependent protein kinases by synaptic activity.

cAMP-dependent protein kinase (PKA) is believed to play a critical role in the expression of long-lasting forms of hippocampal long-term potentiation (LTP). Can distinct patterns of synaptic activity induce forms of LTP that require different isoforms of PKA? To address this question, we used transgenic mice that have genetically reduced hippocampal PKA activity, and a specific pharmacological inhibitor of PKA, Rp-cAMPS. Transgenic mice [R(AB) mice] that express an inhibitory form of a particular type of regulatory subunit of PKA (type-Ialpha) showed significantly reduced LTP in area CA1 of hippocampal slices as compared with slices from wild-type mice. This impairment of LTP expression was evident when LTP was induced by applying repeated, temporally spaced stimulation (4 1-s bursts of 100-Hz applied once every 5 min). In contrast, LTP induced by applying just 60 pulses in a theta-burst pattern was normal in slices from R(AB) mice as compared with slices from wild-type mice. We found that Rp-cAMPS blocked the expression of LTP induced by both spaced tetra-burst and compressed theta-burst stimulation in hippocampal slices of wild-type and R(AB) mice, respectively. Since Rp-cAMPS is a PKA inhibitor that is not selective for any particular isoform of PKA and these R(AB) mice show reduced hippocampal PKA activity resulting from genetic manipulation of a single isoform of PKA regulatory subunit, our data support the idea that distinct patterns of synaptic activity can produce different forms of LTP that significantly engage different isoforms of PKA. In particular, theta-burst LTP significantly recruits isoforms of PKA containing regulatory subunits other than the mutant RIalpha subunit, whereas tetra-burst LTP requires PKA isoforms containing the mutant RIalpha subunit. Thus, altering both the total amount of imposed synaptic activity and the temporal spacing between bursts of imposed activity may subtly modulate the PKA dependence of hippocampal LTP by engaging distinct isoforms of PKA. In a broader context, our findings suggest that synaptic plasticity in the mammalian brain might be importantly regulated by activity-dependent recruitment of different isoforms of key signal transduction molecules.

Differential maintenance and frequency-dependent tuning of LTP at hippocampal synapses of specific strains of inbred mice.

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be "tuned" to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.

Strain-dependent differences in LTP and hippocampus-dependent memory in inbred mice.

Many studies have used "reverse" genetics to produce "knock-out" and transgenic mice to explore the roles of various molecules in long-term potentiation (LTP) and spatial memory. The existence of a variety of inbred strains of mice provides an additional way of exploring the genetic bases of learning and memory. We examined behavioral memory and LTP expression in area CA1 of hippocampal slices prepared from four different inbred strains of mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J. We found that LTP induced by four 100-Hz trains of stimulation was robust and long-lasting in C57BL/6J and DBA/2J mice but decayed in CBA/J and 129/SvEms-+(Ter?)/J mice. LTP induced by one 100-Hz train was significantly smaller after 1 hr in the 129/SvEms-+(Ter?)/J mice than in the other three strains. Theta-burst LTP was shorter lasting in CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J mice than in C57BL/6J mice. We also observed specific memory deficits, among particular mouse strains, in spatial and nonspatial tests of hippocampus-dependent memory. CBA/J mice showed defective learning in the Morris water maze, and both DBA/2J and CBA/J strains displayed deficient long-term memory in contextual and cued fear conditioning tests. Our findings provide strong support for a genetic basis for some forms of synaptic plasticity that are linked to behavioral long-term memory and suggest that genetic background can influence the electrophysiological and behavioral phenotypes observed in genetically modified mice generated for elucidating the molecular bases of learning, memory, and LTP.

Maturation of neuromuscular transmission during early development in zebrafish.

We have examined the rapid development of synaptic transmission at the neuromuscular junction (NMJ) in zebrafish embryos and larvae by patch-clamp recording of spontaneous miniature endplate currents (mEPCs) and single acetylcholine receptor (AChR) channels. Embryonic (24-36 h) mEPCs recorded in vivo were small in amplitude (<50 pA). The rate of mEPCs increased in larvae (3.5-fold increase measured by 6 days), and these mEPCs were mostly of larger amplitude (10-fold on average) with (

Infrarenal aortic stenosis: long-term clinical and hemodynamic results of percutaneous transluminal angioplasty.

PURPOSE: To evaluate the safety and long-term clinical and hemodynamic results of percutaneous transluminal angioplasty (PTA) of the infrarenal aorta. MATERIALS AND METHODS: During nearly 10 years, 102 patients with symptomatic infrarenal atherosclerotic aortic stenosis underwent PTA. Follow-up information was available in 92 patients (17 men, 75 women; mean age, 51.9 years). Stenosis involved the aortic bifurcation in 18 patients and only the infrarenal abdominal aorta in 74 patients. Technical success was defined as residual stenosis less than 50% or a pressure gradient less than 10 mm Hg after PTA. Clinical patency was defined as the absence or improvement of symptoms after PTA. Hemodynamic patency was defined as a normal Doppler waveform in the common femoral arteries, an ankle-brachial ratio greater than 0.95, or the absence of a thigh-brachial pressure gradient. RESULTS: Technical success was achieved in 78 patients after PTA. After 10 years, primary clinical and hemodynamic patency rates were 72% and 46%, respectively. After a mean follow-up of 51 months, 15 of the 22 symptomatic recurrences were due to aortic restenosis; 11 of these were treated with repeated PTA with or without stent placement, and three eventually required aortic surgery. No morbidity was encountered. CONCLUSION: Infrarenal aortic PTA proved to be safe and provided durable, long-term clinical improvement. In this group of relatively young patients, the clinical patency rate of PTA was equivalent to that of aortic surgery but with less morbidity.

Synaptic physiology and mitochondrial function in crayfish tonic and phasic motor neurons.

Phasic and tonic motor neurons of crustaceans differ strikingly in their junctional synaptic physiology. Tonic neurons generally produce small excitatory postsynaptic potentials (EPSPs) that facilitate strongly as stimulation frequency is increased, and normally show no synaptic depression. In contrast, phasic neurons produce relatively large EPSPs with weak frequency facilitation and pronounced depression. We addressed the hypothesis that mitochondrial function is an important determinant of the features of synaptic transmission in these neurons. Mitochondrial fluorescence was measured with confocal microscopy in phasic and tonic axons and terminals of abdominal and leg muscles after exposure to supravital mitochondrial fluorochromes, rhodamine-123 (Rh123) and 4-diethylaminostyryl-N-methylpyridinium iodide (4-Di-2-Asp). Mitochondria of tonic axons and neuromuscular junctions had significantly higher mean Rh123 and 4-Di-2-Asp fluorescence than in phasic neurons, indicating more accumulation of the fluorochromes. Mitochondrial membrane potential, which is responsible for Rh123 uptake and is related to mitochondrial oxidative activity (the production of ATP by oxidation of metabolic substrates), is likely higher in tonic axons. Electron microscopy showed that tonic axons contain approximately fivefold more mitochondria per microm2 cross-sectional area than phasic axons. Neuromuscular junctions of tonic axons also have a much higher mitochondrial content than those of phasic axons. We tested the hypothesis that synaptic fatigue resistance is dependent on mitochondrial function in crayfish motor axons. Impairment of mitochondrial function by uncouplers of oxidative phosphorylation, dinitrophenol or carbonyl cyanide m-chlorophenylhydrazone, or by the electron transport inhibitor sodium azide, led to marked synaptic depression of a tonic axon and accelerated depression of a phasic axon during maintained stimulation. Iodoacetate, an inhibitor of glycolysis, and chloramphenicol, a mitochondrial protein synthesis inhibitor, had no significant effects on either mitochondrial fluorescence or synaptic depression in tonic or phasic axons. Collectively, the results provide evidence that mitochondrial oxidative metabolism is important for sustaining synaptic transmission during maintained stimulation of tonic and phasic motor neurons. Tonic neurons have a higher mitochondrial content and greater oxidative activity; these features are correlated with their greater resistance to synaptic depression. Conversely, phasic neurons have a lower mitochondrial content, less oxidative activity, and greater synaptic fatigability.