Evaluation of long-term surgical site occurrences in ventral hernia repair: implications of preoperative site independent MRSA infection.

PURPOSE: Previous work demonstrated that prior MRSA infection [MRSA(+)] is associated with 30-day surgical site infection (SSI) following ventral hernia repair (VHR). We aimed to determine the impact of MRSA(+) on long-term wound outcomes after VHR. PARTICIPANTS: A retrospective cohort study was performed at a tertiary center between July 11, 2005, and May 18, 2012, of patients undergoing elective VHR with class I wounds. Patients with documented preoperative MRSA infection at any site (urinary, bloodstream, SSI, etc.) were considered MRSA(+). Primary outcome was 2-year surgical site occurrence (SSO), defined as SSI, cellulitis, necrosis, nonhealing wound, seroma, hematoma, dehiscence, or fistula. SSOs were subdivided into those that required procedural intervention (SSOPI) and those that did not. RESULTS: Among 632 patients, 46 % were female with average age 53 ± 13 years. There were 368 SSOs in 193 patients (31 %); an SSOPI occurred in 9.8 % (n = 62). The most common SSOs were cellulitis (91/632), seroma (91/632), and serous drainage (58/632). The rate of 2-year SSO was higher with MRSA(+) compared to those without (46 vs. 29 %, p = 0.023), attributed to increased soft tissue necrosis, purulent drainage, serous drainage, cellulitis, and fistula. In multivariable analysis, MRSA(+) was not associated with 2-year SSO (HR 1.5, 95 % CI 0.91-2.55, p = 0.113); factors associated with SSO included obesity, immunosuppression, mesh repair, and operative times. CONCLUSIONS: This study is the first to evaluate long-term SSOs and SSOPIs after VHR, highlighting the importance of long-term follow-up. Though not independently associated with SSOs, MRSA(+) may be a marker of hernia complexity.

Use of the H3 receptor antagonist radioligand [3H]-A-349821 to reveal in vivo receptor occupancy of cognition enhancing H3 receptor antagonists.

BACKGROUND AND PURPOSE: The histamine H3 receptor antagonist radioligand [3H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H3 receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 receptor occupancy to blood levels and efficacy in preclinical models. EXPERIMENTAL APPROACH: In vivo cerebral cortical H3 receptor occupancy by [3H]-A-349821 was determined in rats from differences in [3H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 receptors. Comparisons were made to relate antagonist H3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups. KEY RESULTS: In adult rats, [3H]-A-349821, 1.5 microg x kg(-1), penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [3H]-A-349821 levels were twofold higher in the latter. With increasing [3H]-A-349821 doses, cortical H3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [3H]-A-349821 doses, ABT-239 and other H3 receptor antagonists inhibited H3 receptor occupancy by [3H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H3 receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response. CONCLUSIONS AND IMPLICATIONS: When employed as an occupancy radiotracer, [3H]-A-349821 provided valid measurements of in vivo H3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 receptor antagonists.

The histamine H3 receptor: an attractive target for the treatment of cognitive disorders.

The histamine H3 receptor, first described in 1983 as a histamine autoreceptor and later shown to also function as a heteroreceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications including cognition. The purpose of this review is to acquaint the reader with the current understanding of H3 receptor localization and function as a modulator of neurotransmitter release and its effects on cognitive processes, as well as to provide an update on selected H3 antagonists in various states of preclinical and clinical advancement. Blockade of centrally localized H3 receptors by selective H3 receptor antagonists has been shown to enhance the release of neurotransmitters such as histamine, ACh, dopamine and norepinephrine, among others, which play important roles in cognitive processes. The cognitive-enhancing effects of H3 antagonists across multiple cognitive domains in a wide number of preclinical cognition models also bolster confidence in this therapeutic approach for the treatment of attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia. However, although a number of clinical studies examining the efficacy of H3 receptor antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H3 receptor antagonist has been reported to date. The discovery of effective H3 antagonists as therapeutic agents for the novel treatment of cognitive disorders will only be accomplished through continued research efforts that further our insights into the functions of the H3 receptor.

Sensitivity and tolerance to ethanol-induced incoordination and hypothermia in HAFT and LAFT mice.

Acute functional tolerance (AFT) manifests as rapid adaptation during a single ethanol exposure, leading to a decrease in the behavioral response to ethanol. In order to investigate the genetic and environmental components of the development of AFT, mice were selectively bred in replicate from HS/Ibg mice. High (HAFT) and low (LAFT) acute functional tolerance selected lines were bred to differ in the rate of development and magnitude of AFT to ethanol's intoxicating effects using a static dowel-balancing task. In the present set of experiments, HAFT and LAFT mice were tested for development of AFT on a fixed-speed rotarod using a protocol similar to that for which they were selected. HAFT mice developed greater AFT to ethanol than did LAFT mice. In a separate experiment, other mice from these lines were tested for initial sensitivity and the development of chronic tolerance to ethanol-induced hypothermia, and ethanol-induced incoordination in the grid test. Previous research has detected possible common genetic control of these phenotypes. No differences between lines were found in initial sensitivity to ethanol or in the development or magnitude of chronic tolerance in either test. These experiments show that genetic factors influencing the development of acute tolerance to ethanol-induced intoxication are at least partially distinct from those influencing initial sensitivity and the development of chronic tolerance to ethanol-induced hypothermia and incoordination. Furthermore, these experiments show that AFT measured by the stationary dowel generalizes to AFT measured by the fixed-speed rotarod.

Environmental modulation of the response to amphetamine: dissociation between changes in behavior and changes in dopamine and glutamate overflow in the rat striatal complex.

RATIONALE: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. OBJECTIVES: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. METHODS: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. RESULTS: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1-3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). CONCLUSIONS: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex.

Sensitivity to ethanol-induced motor incoordination in 5-HT(1B) receptor null mutant mice is task-dependent: implications for behavioral assessment of genetically altered mice.

Neuromuscular impairment by ethanol likely involves complex effects on balance, gait, muscle strength, and other features of motor coordination. The present experiments showed that relative sensitivity to ethanol-induced motor impairment in serotonin 1B (5-HT(1B)) null mutant and control mice was task dependent. We found that ethanol-treated null mutant mice made fewer missteps on a balance beam than did ethanol-treated wild-type mice, and confirmed a previous finding of their lesser ethanol sensitivity in the grid test. The genotypes did not differ in ethanol sensitivity as measured by the screen test, static dowel, fixed-speed rotarod, accelerating rotarod, grip strength, or loss of righting reflex tests. These experiments suggest that within a behavioral domain, alternative tests of function are not equivalent, so multiple assessment tools should be used to avoid misinterpretation of gene function.

Quantitative trait loci affecting ethanol sensitivity in BXD recombinant inbred mice.

BACKGROUND: Genetic and environmental factors contribute to an individual's sensitivity to ethanol, although the exact genes underlying ethanol's effects are not known. Quantitative trait locus (QTL) mapping is one successful method for provisionally identifying genes participating in the mediation of a given behavior. QTL analyses seek to identify associations between a quantitative response and previously mapped marker genes across genetically diverse individuals. Many QTL analyses have been performed in BXD recombinant inbred (RI) strains of mice derived from a cross of C57BL/6J (B6) and DBA/2J (D2) progenitor strains. METHODS: We conducted a QTL analysis of ethanol-induced loss of righting reflex and ataxia using a panel of 25 BXD RI strains and the progenitors B6 and D2. We measured the duration of loss of righting reflex after injection and blood ethanol concentrations upon regaining of righting reflex. Ataxia was measured as the latency to fall from a vertical screen. RESULTS: Genome-wide QTL analyses correlating strain means with allelic status at >1500 markers identified several associations (p < or = 0.01). These provisional QTLs were on all chromosomes except 2, 5, 12, 13, and X, and several map near potential candidate genes. CONCLUSIONS: These results suggest that ethanol sensitivity is determined by the actions of multiple genes and further suggest their general chromosomal map locations. These provisional linkages will now be confirmed or rejected using additional genetically segregating populations.

Sensitivity and tolerance to ethanol in mouse lines selected for ethanol-induced hypothermia.

Within-family selective breeding techniques have been used to create two lines of mice to be insensitive (HOT) and two lines to be sensitive (COLD) to the hypothermic effects of an acute 3.0-g/kg ethanol (EtOH) injection. Previous studies have found HOT mice to be relatively resistant to the development of tolerance to this effect, whereas COLD mice readily develop tolerance. The breeding program is currently in selected Generation 52, and the HOT and COLD mice differ by about 10 degrees C (average of both replicates) in their selected hypothermic response. Starting with selection Generation 20, separate lines of mice were inbred from the HOT-2 and COLD-2 selected lines, while selection continued for the original two replicate lines of HOT and COLD mice. To assess whether different dose treatments would produce differential tolerance development in the HOT and COLD selected lines, we administered different dose regimens across 5 days to HOT and COLD mice. The COLD mice developed tolerance while the HOT mice did not, regardless of total EtOH administered. In a separate study, we administered EtOH (3.0 g/kg) to mice for 3 days to assess a shorter tolerance paradigm. We also present here responses to the selection dose of 3.0-g/kg EtOH in the inbred HOT (IHOT-2) and COLD (ICOLD-2) mice tested after 41 generations of brother-sister mating. In addition, we report recent attempts to find doses of EtOH that would produce an equivalent initial hypothermic response in each of the six lines (HOT-1, COLD-1, HOT-2, COLD-2, ICOLD-2, and IHOT-2). When doses were selected to produce similar initial hypothermic sensitivity, tolerance was tested by giving three daily doses and examining the attenuation of the hypothermic response on the third day. All three COLD lines developed significant tolerance, while the HOT lines did not. The HOT and COLD mice provide a genetic model to study mechanisms mediating acute EtOH-induced hypothermia as well as tolerance development.

Alcohol and genetics: new animal models.

In recent years, it has become increasingly evident that there is a genetic component to alcoholism. Attempts to isolate alcoholism genes have met with modest success, in part because alcoholism is a multigenic trait. Recently, experimental animal models and novel genetic manipulations have provided several clues as to the specific genes involved in alcoholism, and extensive research has identified many genes that might influence responses to alcohol. Although not all of these might be proven to influence drug sensitivity, research has provided evidence for the involvement of a few genes. Ultimately, findings from animal models that investigate the function of specific genes could aid the development of pharmacotherapies to treat alcohol dependence.

A comparison of two behavioral measures of psychomotor activation following intravenous amphetamine or cocaine: dose- and sensitization-dependent changes.

This paper presents data concerning the dose-effect relationships of intravenously administered amphetamine and cocaine on two widely used measures of psychomotor activation: locomotor crossover activity in neurologically intact rats, and rotational behavior in rats with a unilateral 6-hydroxydopamine lesion. There were marked differences in dose-effect relationships, both as a function of drug and of behavioral measure. Amphetamine produced a linear increase in rotational behavior over a wide range of doses (the highest effective dose was 76.8 times the lowest), but a linear increase in locomotor crossover activity over only a narrow dose range (the highest effective dose was only four times the lowest). In contrast, for cocaine, the dose-effect relationships for the two behaviors were very similar, but for both behaviors the effective dose range was quite narrow, the highest effective dose being only between two and four times the lowest. The data highlight the advantages and disadvantages of these measures as indices of the psychomotor activating effects of psychostimulant drugs.

Injection of the protein kinase C inhibitor Ro31-8220 into the nucleus accumbens attenuates the acute response to amphetamine: tissue and behavioral studies.

The ability of amphetamine to produce heightened locomotor activity is thought to be due to its ability to enhance dopamine release from mesolimbic dopamine neurons. The mechanism by which amphetamine increases dopamine release is not well understood, but is thought to involve exchange diffusion with synaptosomal dopamine through the dopamine transporter. We recently reported that amphetamine-mediated dopamine release in the striatum is also dependent on protein kinase C activity. In the current study, we investigated the role of protein kinase C activity in the acute neurochemical and behavioral response to amphetamine in the nucleus accumbens. Consistent with previous results in the striatum, amphetamine-stimulated dopamine release from nucleus accumbens tissue was inhibited by the specific protein kinase C inhibitor Ro31-8220, but not by the relatively inactive analog bisindoylmaleimide V. In addition, the effects of protein kinase C activity on the acute behavioral response to amphetamine was examined by injecting Ro31-8220 into the nucleus accumbens 15 min prior to intra-accumbens amphetamine. Pretreatment with Ro31-8220 attenuated the motor-stimulant effects of intra-accumbens amphetamine relative to control subjects pretreated with vehicle. Bisindoylmaleimide V did not significantly inhibit the motor-stimulant effects of intra-accumbens amphetamine. These results suggest that the action of amphetamine in the nucleus accumbens in increasing dopamine release and locomotor activity is dependent on protein kinase C activity.

Modulatory effect of environmental stimuli on the susceptibility to amphetamine sensitization: a dose-effect study in rats.

In previous studies the repeated administration of 0.5 to 1.0 mg/kg of amphetamine i.v. failed to induce psychomotor sensitization if the drug was administered to animals living in the test environment (at home). The same doses did induce sensitization if animals were transported to the test environment for each drug treatment. The purpose of the present experiment was to determine the extent to which this effect of environment is dose dependent. Rats either lived in test cages or were transported from the animal colony to test cages where they received an i.v. infusion of one of five doses of amphetamine (0.125, 0.5, 1.0, 4.0 or 8.0 mg/kg) or saline each day for 5 consecutive days. Rotational behavior was used as an index of psychomotor activation. After a 6-day drug-free period all animals were challenged with 0.5 mg/kg of amphetamine to determine the pretreatment dose necessary to induce sensitization. The effect of the drug-treatment environment was to shift the dose-effect curve for the induction of sensitization, such that significantly lower doses were necessary to induce sensitization when amphetamine was given in a novel environment. With high doses, however, sensitization occurred regardless of environmental condition. It is concluded that the circumstances surrounding drug administration can powerfully modulate the ability of psychostimulants to induce sensitization, but this effect is dose dependent.

The influence of environment on the induction of sensitization to the psychomotor activating effects of intravenous cocaine in rats is dose-dependent.

The acute psychomotor response and development of sensitization to amphetamine is attenuated if i.p. injections are given in the cage where a rat lives relative to when injections are given in a novel but physically identical test environment. Furthermore, when the environmental cues predicting i.p. injections are completely eliminated by using remotely activated i.v. injections in the home cage, 1.0 mg/kg amphetamine produces a very small acute response and no sensitization. The same treatments do produce sensitization if i.v. injections are signaled by placement of the rat in a novel test cage. The present experiment was designed to determine if there is a similar effect of environmental condition on the response to i.v. cocaine, and to what extent the effect may be dose-dependent. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated i.v. administrations of one of eight doses of cocaine (0.0, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 7.2 mg/kg) given in the home cage, with infusions of the same doses given in a novel test cage. There was no effect of environment on the acute psychomotor response to cocaine. There was, however, a significant effect of environment on the induction of sensitization. A higher dose of cocaine was required to induce sensitization when i.v. administrations were given in the home cage than when they were given in a physically identical but novel test environment. At high doses, however, cocaine induced sensitization regardless of environmental condition. The results suggest that the effect of this environmental manipulation is to shift the dose-effect curve for the induction of sensitization, and support the notion that the ability of psychostimulant drugs to induce sensitization can be modulated by the circumstances surrounding drug administration.

Modulation of the induction or expression of psychostimulant sensitization by the circumstances surrounding drug administration.

The conditions necessary to induce psychomotor sensitization and to promote its expression are not well understood. Two examples are reviewed here of how the circumstances surrounding drug administration ("set and setting") can powerfully modulate the sensitization produced by psychostimulant drugs, such as amphetamine or cocaine. In the first example it is suggested that repeated exposure to psychostimulant drugs may induce "neural sensitization" (i.e., produce relevant adaptations in the nervous system). The circumstances surrounding drug administration may determine, however, whether neural sensitization is expressed in behavior. In the second example it is suggested that the circumstances surrounding drug administration may determine whether sensitization is induced at all, or at least the rate and extent of sensitization produced by a given dose of a drug. It is concluded that psychomotor sensitization is not an inevitable consequence of exposure to psychostimulant drugs, but is the result of interactions amongst the pharmacological actions of drugs and the circumstances surrounding drug administration.

Fimbria-fornix lesions do not block sensitization to the psychomotor activating effects of amphetamine.

The repeated, intermittent administration of amphetamine produces a long-lasting sensitization to its behavioral activating effects. Excitatory amino acid receptors in the striatum have been implicated in the development of amphetamine sensitization, and one source of excitatory amino acid input to the striatum is the hippocampus. The purpose of this experiment, therefore, was to determine if an intact hippocampal system is necessary for either the development or expression of sensitization to the psychomotor activating effects of amphetamine. Rats received either fimbria-fornix lesions or sham lesions and approximately 2 weeks later received 10 injections of 3.0 mg/kg d-amphetamine or saline (IP) every other day. Rotational behavior was quantified as an index of amphetamine's psychomotor stimulant effects. Animals with a fimbria-fornix lesion were hyperresponsive to an acute injection of amphetamine, but animals with a fimbria-fornix lesion and control animals did not differ in the development of sensitization (i.e., the rate of sensitization). Furthermore, both groups expressed comparable sensitization (relative to their respective saline-pretreated control groups) when given a challenge injection of amphetamine. These results suggest an intact hippocampal system is not necessary for the development or expression of amphetamine sensitization.

Influence of novel versus home environments on sensitization to the psychomotor stimulant effects of cocaine and amphetamine.

The acute psychomotor response (rotational behavior in rats with a unilateral 6-OHDA lesion), and the development of sensitization, were studied in rats that received seven consecutive daily injections of amphetamine (Experiment 1) or cocaine (Experiment 2) either at home or in a 'novel' test environment. The home (HOME) and novel (NOVEL) cages were physically identical, but one group lived and was tested in these cages, whereas the rats in the other group were transported from the stainless steel hanging cages where they lived, to those NOVEl test cages, for each test session. In Exp. 1, the acute psychomotor response to 3.0 mg/kg of amphetamine i.p. and the development of sensitization (increase in the rotational response between the first and the the seventh test session) were greater in the NOVEL than in the HOME environment. In Expt. 2, there were no significant group differences in the acute response to 20 mg/kg of cocaine i.p., but the animals tested in the NOVEL environment showed greater sensitization than animals tested in the HOME environment. In addition, the animals pretreated with cocaine in the NOVEL environment, but not those pretreated with cocaine in the HOME environment, showed conditioned rotational behavior in response to an injection of saline. These data indicate that: (i) sensitization to the psychomotor activating effects of both amphetamine and cocaine is enhanced in a NOVEL environment; (ii) this phenomenon appears to the independent of the effects of the NOVEL environment on the acute response to these drugs; (iii) a robust conditioned psychomotor response to contextual cues develops only when cocaine treatments are given in the NOVEL test environment.