Biomedical subjects

L Urban

Publications and source records attributed to L Urban.

At least 19 recordsLinked to original sources

PubMed2006

Cardiac troponins--biochemical markers of cardiac toxicity after cytostatic therapy.

Cardiotoxicity is a serious adverse effect of chemotherapy that encompasses a spectrum of disorders, ranging from relatively benign arrhythmias to potentially lethal conditions such as myocardial ischemia/infarction and cardiomyopathy. The toxicity of chemotherapeutic drugs can cause loss of myocytes' sarcolemmal integrity, release of bioactive markers into the extracellular environment (tissue and circulation) and ultimately leading to the necrosis of myocytes. The extent and severity of the necrosis can be monitored by the levels of bioactive markers. Therefore current research is aimed at finding biochemical markers with absolute cardiac specificity, high sensitivity and predictive value that can be used in early detection of patients with treatment-induced myocardial damage. Routinely used biomarkers like CK, CK-MB, and myoglobin do not meet the stated criteria. Their role in early diagnosis of chemotherapy- induced myocardial toxicity is controversial and limited. However, cardiac troponins, new nonconventional markers, have shown promising results in assessment and monitoring of both, early and late, clinical and subclinical damage to myocardium after chemotherapy. The article reviews clinical studies evaluating the role of cardiac troponins in the diagnosis of cardiotoxicity and their use in the management of cancer survivors.

Animals↗

PubMed2005

Body surface integral maps in patients with arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: The aim of this study was to evaluate changes in QRST integral maps in patients with ARVC. BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive disorder of predominantly right ventricle characterized with arrhythmic events possibly leading to sudden cardiac death. QRST integral maps reflect local disparities of ventricular repolarization and resulting vulnerability to arrhythmias. METHODS: A group of 8 patients with ARVC and a control group of 8 patients with a concealed accessory pathway were studied. Body surface mapping was performed using a 63-lead Savard's system. RESULTS: Mean QRST integral map of patients with ARVC showed abnormal characteristics. The area of negativity was larger than normal and extended to lower border of thorax. Departure map of the mean QRST integral map of patients with ARVC showed areas with departure index < 2 and > 2 in lower part of chest and upper part of back. When statistically analyzed, areas with p < 0.05 covered nearly lower half of chest and upper half of back. CONCLUSIONS: We consider body surface QRST integral mapping to be an adequate method for evaluation of dispersion of ventricular repolarization in ARVC patients (Tab. 1, Fig. 5, Ref. 17).

Adolescent↗

PubMed2004

Interaction of gamma-aminobutyric acid receptor type B receptors and calcium channels in nociceptive transmission studied in the mouse hemisected spinal cord in vitro: withdrawal symptoms related to baclofen treatment.

An in vitro mouse hemisected spinal cord was used to characterize the gamma-aminobutyric acid receptor type B (GABA(B)) modulation of the ventral root potential (VRP) in response to electrical stimulation of the dorsal root (DR). Low-intensity (LI) and high-intensity (HI) stimulation induced VRPs with progressively higher amplitude and duration. Repetitive HI-stimulation of the DR (1-10 Hz) produced windup. The selective GABA(B) receptor agonist, CGP35024, inhibited the VRPs in a dose-dependent manner. The inhibitory action of CGP35024 was blocked by CGP52432, a potent GABA(B) receptor antagonist. Following washout of the GABA(B) receptor agonist, VRPs and windup were significantly enhanced. The rebound increase of the VRP following removal of CGP35024 was also blocked by the GABA(B) receptor antagonist, CGP52432. This phenomenon is not linked to receptor desensitization, but rather due to GABA(B) receptor-induced hyperactivity of N-, P/Q-type Ca(2+) channels, as omega-CgTx GVIA and MVIIC abolished/prevented the increase. The 'rebound' enhancement of the spinal transmission after exposure to GABA(B) agonists sheds light on the possible mechanism of the severe withdrawal effects after abrupt termination of baclofen treatment in patients suffering from multiple sclerosis.

Action Potentials↗

PubMed2004

Inhibitory effect of flowering and early fruit growth on leaf photosynthesis in mango.

Carbohydrate and nitrogen contents, chlorophyll fluorescence and gas exchange were measured in leaves from both vegetative and reproductive terminal shoots of 12-year-old flowering mango trees. Reproductive shoot leaves were close to swelling floral buds, inflorescences or panicles bearing set fruits. Leaves close to inflorescences had lower rates of mitochondrial respiration (Rd) and net photosynthesis (Anet), and lower stomatal conductance (gs) and quantum efficiency of photosystem II under actinic light than vegetative shoot leaves. Leaf nitrogen concentration, which decreased from the beginning until the end of flowering, was lower in leaves close to inflorescences than in vegetative shoot leaves. However, these differences and changes were counterbalanced by an increase in leaf mass-to-area ratio so that leaf nitrogen per unit leaf area (Na) remained nearly constant during the whole flowering period, except in leaves close to panicles bearing set fruits. Net CO2 assimilation rate simulated by a biochemical model of leaf photosynthesis (Urban et al. 2003) was much higher than Anet measured at an ambient CO2 partial pressure (Ca) of either 36 or 70 Pa. The overestimation of Anet was more pronounced in leaves close to inflorescences, to panicles bearing set fruits and to reversing inflorescences (characterized by the appearance of leaves in terminal positions on inflorescences) than in vegetative shoot leaves. It is concluded that low Anet in leaves close to inflorescences was probably due neither to changes in Na nor to a decrease in Rubisco activity induced by low gs, but rather to a decrease in electron flow in photosystem II. This decrease was not directly associated with higher starch or soluble sugar contents.

Chlorophyll↗

PubMed2003

A biochemical model of photosynthesis for mango leaves: evidence for the effect of fruit on photosynthetic capacity of nearby leaves.

Variations in leaf nitrogen concentration per unit mass (Nm) and per unit area (Na), mass-to-area ratio (Ma), total nonstructural carbohydrates (Ta), and photosynthetic capacity (maximum carboxylation rate, electron transport capacity, rate of phosphate release in triose phosphate utilization and dark respiration rate) were studied within the digitized crowns of two 3-year-old mango trees (Mangifera indica L.) on La Réunion Island. Additional measurements of Nm, Na, Ma, Ta and photosynthetic capacities were performed on young, fully expanded leaves of 11-year-old mango trees. Leaves of similar gap fractions were taken far from and close to developing fruits. Unlike Nm, both Na and Ta were linearly correlated to gap fraction. Similar relationships were found for all leaves whatever their age and origin, except for Ta, for which we found a significant tree effect. Photosynthetic capacity was nonlinearly correlated to Na, and a unique relationship was obtained for all types of leaves. Photosynthetic acclimation to light was mainly driven by changes in Ma, but allocation of total leaf N between the different photosynthetic functions also played a substantial role in acclimation to the lowest irradiances. Leaves close to developing fruits exhibited a higher photosynthetic capacity than other leaves, but similar Ta. Our data suggest that Ta does not control photosynthetic capacity in mango leaves. We used the data to parameterize a biochemically based model of photosynthesis and an empirical stomatal conductance model, allowing accurate predictions of net photosynthesis of leaves in field-grown mango trees.

Carbohydrates↗

PubMed2002

A rat model of bone cancer pain.

This study describes the first known model of bone cancer pain in the rat. Sprague-Dawley rats receiving intra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells developed behavioural signs indicative of pain, including: mechanical allodynia, difference of weight bearing between hind paws and mechanical hyperalgesia. The development of the bone tumour and structural damage to the bone was monitored by radiological analysis, quantitative measurement of mineral content and histology. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) syngeneic MRMT-1 cells produced a rapidly expanding tumour within the boundaries of the tibia, causing severe remodelling of the bone. Radiographs showed extensive damage to the cortical bone and the trabeculae by day 10-14 after inoculation of 3 x 10(3) MRMT-1 cells, and by day 20, the damage was threatening the integrity of the tibial bone. While both mineral content and mineral density decreased significantly in the cancerous bone, osteoclast numbers in the peritumoural compact bone remained unchanged. However, tartarate-resistant acid phosphatase staining revealed a large number of polykariotic cells, resembling those of osteoclasts within the tumour. No tumour growth was observed after the injection of heat-killed MRMT-1 cells. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) MRMT-1 cells, heat-killed cells or vehicle did not show changes in body weight and core temperature over 19-20 days. The general activity of animals after injection with live or heat-killed MRMT-1 cells was higher than that of the control group, however, the activity of the MRMT-1 treated group declined during the progress of the disease. Rats receiving intra-tibial injections of MRMT-1 cells displayed the gradual development of mechanical allodynia and mechanical hyperalgesia/reduced weight bearing on the affected limb, beginning on day 12-14 or 10-12 following injection of 3 x 10(3) or 3 x 10(4) cells, respectively. These symptoms were not observed in rats receiving heat-killed cells or vehicle. Behavioural data suggest a reasonable time window for evaluation of anti-nociceptive agents between day 14 and 20 after cancer cell inoculation in this model. Acute treatment with morphine (1-3mg/kg, subcutanously (s.c.)) produced a dose-dependent reduction in the response frequency of hind paw withdrawal to von Frey filament stimulation 17 or 19 days following intra-tibial injections of 3 x 10(3) MRMT-1 cells. A significant reduction in the difference in hind limb weight bearing was also observed. Acute treatment with celebrex (10-30 mg/kg, s.c.) did not affect mechanical allodynia or difference in weight bearing in rats 20 days following treatment with 3 x 10(3) MRMT-1 cells. Although the pathophysiology of cancer pain is largely unknown, significant enhancement of glial fibrillary acidic protein (GFAP) staining in the corresponding segments of the ipsilateral spinal cord highlights the possible involvement of astrocytes. In summary, the induction of bone cancer in the rat by the syngeneic MRMT-1 mammary tumour cell line provides a valid pre-clinical model for pain associated with bone metastases. Significant mechanical hyperalgesia and allodynia develops in association with the progression of the tumour in the bone marrow cavity, while the general condition of the animal remains satisfactory. While acute treatment with morphine has some analgesic effect on hind limb sparing the selective COX-2 inhibitor, celebrex, has no influence on the pain-related behavioural changes in this model.

Analgesics, Opioid↗

PubMed2002

Cannabinoid 1 receptors are expressed by nerve growth factor- and glial cell-derived neurotrophic factor-responsive primary sensory neurones.

Expression of the cannabinoid 1 (CB1) receptor and its regulation were studied in the different nociceptive and non-nociceptive sub-populations of cultured primary sensory neurones of adult rats. Bandairaea simplicifolia isolectin B4 (IB4) binding and calcitonin gene-related peptide (CGRP) immunostaining were used to distinguish between the glial cell-derived neurotrophic factor (GDNF)- and nerve growth factor (NGF)-responsive nociceptive and the non-nociceptive primary sensory neurones while a specific CB1 receptor antibody was used to study the expression of the CB1 receptor protein. About half of the total number of primary sensory neurones (47+/-3.2%) cultured for 1 day in the presence of both neurotrophic factors (50 ng/ml each) showed CB1 receptor-like immunostaining, whereas 21.8+/-3.3% and 32.7+/-5.6% of the neurones showed CGRP-like immunopositivity and IB4 binding, respectively. A proportion of the CB1 receptor-like immunopositive neurones was immunostained for CGRP (31.7+/-5%) and IB4 (48.2%+/-7.5), with a minimal (1%) co-expression of CGRP and IB4 binding. About a fifth of the CB1 receptor-like immunopositive neurones did not show either CGRP-like immunostaining or IB4 binding. To find out whether CB1 receptor expression in nociceptive primary sensory neurones is regulated by GDNF or NGF, cultures were grown in the presence or absence of the neurotrophic factors for 7 days. Vanilloid receptor 1 (VR1) immunostaining was used as a control marker to monitor the effect of the neurotrophins. In cultures maintained in the presence of both factors (50 ng/ml each) 51+/-2.6% and 42.4+/-1.2% of the cells showed CB1 receptor-like and VR1-like immunostaining, respectively. In cultures grown for 7 days in the absence of either of the neurotrophic factors the relative number of VR1-like immunopositive cells decreased to 13.4+/-2.7%, whereas the relative number of CB1 receptor-like immunopositive neurones was unchanged (50.6+/-1.1%). Our data suggest that the CB1 receptor is expressed in all of the three major sub-populations of primary sensory neurones and that the CB1 receptor expression is not regulated by either NGF or GDNF.

Animals↗

PubMed2002

Interaction of group I mGlu and NMDA receptor agonists within the dorsal horn of the spinal cord of the juvenile rat.

1. The modulatory effects of mGlu receptors on NMDA-induced potential changes in spinal motoneurones were studied in vitro. 2. Selective activation of mGlu5 receptors by 10 microM (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG; EC(50)=280 +/- 24 microM) did not produce any change in the ventral root potential. However, the same concentration of CHPG (10 min perfusion) significantly attenuated the NMDA-induced ventral root depolarization (VRD). The effect persisted for 10 min after washout. NMDA-induced responses returned to control in 30 min. Brief co-application of CHPG and NMDA did not alter the NMDA-induced response indicating lack of direct receptor interaction. 3. The attenuating effect of CHPG on the NMDA-induced VRD was inhibited by the mGluR5 receptor antagonist, 2-methyl-6-phenyl-ethynylpyridine (MPEP). 4. In the presence of CGP56433A, a GABA(B) receptor antagonist, the NMDA-induced VRD was unchanged. However, NMDA-induced responses were potentiated after 10 min co-application of CHPG and CGP56433A. 5. (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC), a group II mGlu receptor agonist did not attenuate the NMDA-induced response. 6. Under normal physiological conditions group I mGlu receptor agonists activate at least two populations of neurones: (1) GABA-ergic cells, which could release GABA and inhibit dorsal horn neurones, and (2) deep dorsal horn neurones/motoneurones which express NMDA receptors. Therefore, activation of mGlu5 receptors located on GABA-ergic interneurones could influence any direct potentiating interaction between mGlu5 and NMDA receptors in spinal cord and result in depression of the VRD. In the presence of a GABA(B) receptor antagonist, the direct synergistic interaction is unmasked. These data suggest that group I mGlu receptors provide a complex modulation of spinal synaptic processes.

Animals↗

PubMed2001

Possible mechanisms of cannabinoid-induced antinociception in the spinal cord.

Anandamide is an endogenous ligand at both the inhibitory cannabinoid CB(1) receptor and the excitatory vanilloid receptor 1 (VR1). The CB(1) receptor and vanilloid VR1 receptor are expressed in about 50% and 40% of dorsal root ganglion neurons, respectively. While all vanilloid VR1 receptor-expressing cells belong to the calcitonin gene-related peptide-containing and isolectin B4-binding sub-populations of nociceptive primary sensory neurons, about 80% of the cannabinoid CB(1) receptor-expressing cells belong to those sub-populations. Furthermore, all vanilloid VR1 receptor-expressing cells co-express the cannabinoid CB(1) receptor. In agreement with these findings, neonatal capsaicin treatment that induces degeneration of capsaicin-sensitive, vanilloid VR1 receptor-expressing, thin, unmyelinated, nociceptive primary afferent fibres significantly reduced the cannabinoid CB(1) receptor immunostaining in the superficial spinal dorsal horn. Synthetic cannabinoid CB(1) receptor agonists, which do not have affinity at the vanilloid VR1 receptor, and low concentrations of anandamide both reduce the frequency of miniature excitatory postsynaptic currents and electrical stimulation-evoked or capsaicin-induced excitatory postsynaptic currents in substantia gelatinosa cells in the spinal cord without any effect on their amplitude. These effects are blocked by selective cannabinoid CB(1) receptor antagonists. Furthermore, the paired-pulse ratio is increased while the postsynaptic response of substantia gelatinosa neurons induced by alpha-amino-3-hydroxy-5-methylisoxasole-propionic acid (AMPA) in the presence of tetrodotoxin is unchanged following cannabinoid CB(1) receptor activation. These results strongly suggest that the cannabinoid CB(1) receptor is expressed presynaptically and that the activation of these receptors by synthetic cannabinoid CB(1) receptor agonists or low concentration of anandamide results in inhibition of transmitter release from nociceptive primary sensory neurons. High concentrations of anandamide, on the other hand, increase the frequency of miniature excitatory postsynaptic currents recorded from substantia gelatinosa neurons. This increase is blocked by ruthenium red, suggesting that this effect is mediated through the vanilloid VR1 receptor. Thus, anandamide at high concentrations can activate the VR1 and produce an opposite, excitatory effect to its inhibitory action produced at low concentrations through cannabinoid CB(1) receptor activation. This "dual", concentration-dependent effect of anandamide could be an important presynaptic modulatory mechanism in the spinal nociceptive system.

Analgesics↗

PubMed2001

Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)).

GABA(B) (gamma-aminobutyric acid type B) receptors are important for keeping neuronal excitability under control. Cloned GABA(B) receptors do not show the expected pharmacological diversity of native receptors and it is unknown whether they contribute to pre- as well as postsynaptic functions. Here, we demonstrate that Balb/c mice lacking the GABA(B(1)) subunit are viable, exhibit spontaneous seizures, hyperalgesia, hyperlocomotor activity, and memory impairment. Upon GABA(B) agonist application, null mutant mice show neither the typical muscle relaxation, hypothermia, or delta EEG waves. These behavioral findings are paralleled by a loss of all biochemical and electrophysiological GABA(B) responses in null mutant mice. This demonstrates that GABA(B(1)) is an essential component of pre- and postsynaptic GABA(B) receptors and casts doubt on the existence of proposed receptor subtypes.

Animals↗

PubMed2001

The neurogenic contribution to synovial leucocyte infiltration and other outcome measures in a guinea pig model of arthritis.

A neurogenic contribution to joint inflammation has been demonstrated in rat adjuvant arthritis, however as inflammatory mechanisms vary between species it is unclear whether these observations can be applied more generally. The aim of this study was to assess the neurogenic contribution to cellular infiltration and other outcome measures in a guinea pig model of arthritis. Compared to arthritic controls, animals pre-treated with capsaicin at doses sufficient to reduce sensory activity exhibited a significant attenuation of both mechanical and thermal hyperalgesia. Measures of inflammation, including swelling and radiological scores were also improved. Furthermore, capsaicin selectively reduced synovial T cell infiltration whereas no difference was seen with respect to synovial macrophages. These observations confirm a neurogenic component in guinea pig arthritis and indicate a selective sensory influence on T cell activity within the chronically inflamed joint. As T cells are strongly implicated in the pathogenesis of rheumatic disease, such an influence may serve to explain some of the clinical features observed in these disorders.

Animals↗

PubMed2001

Metabotropic glutamate receptor subtype 5 (mGlu5) and nociceptive function. I. Selective blockade of mGlu5 receptors in models of acute, persistent and chronic pain.

The excitatory neurotransmitter, glutamate, is particularly important in the transmission of pain information in the nervous system through the activation of ionotropic and metabotropic glutamate receptors. A potent, subtype-selective antagonist of the metabotropic glutamate-5 (mGlu5) receptor, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has now been discovered that has effective anti-hyperalgesic effects in models of inflammatory pain. MPEP did not affect rotarod locomotor performance, or normal responses to noxious mechanical or thermal stimulation in naïve rats. However, in models of inflammatory pain, systemic administration of MPEP produced effective reversal of mechanical hyperalgesia without affecting inflammatory oedema. In contrast to the non-steroidal anti-inflammatory drugs, indomethacin and diclofenac, the maximal anti-hyperalgesic effects of orally administered MPEP were observed without acute erosion of the gastric mucosa. In contrast to its effects in models of inflammatory pain, MPEP did not produce significant reversal of mechanical hyperalgesia in a rat model of neuropathic pain.

Animals↗

PubMed2001

mGlu5 receptors and nociceptive function II. mGlu5 receptors functionally expressed on peripheral sensory neurones mediate inflammatory hyperalgesia.

Previous studies have demonstrated that the metabotropic glutamate receptor subtype 5 (mGlu5 receptor) is expressed in the cell bodies of rat primary afferent neurones. We have further investigated the function and expression of mGlu5 receptors in primary afferent neurones, and their role in inflammatory nociception. Freund's complete adjuvant-induced inflammatory hyperalgesia of the rat hind paw was significantly reduced by intraplantar, but not by intracerebroventricular or intrathecal microinjection of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). Pharmacological comparison in vivo of the nociceptive effects of glutamate, and ionotropic and metabotropic glutamate (mGlu) receptor agonists applied to the rat hind paw, indicated that group I mGlu receptor agonists induce a dose-dependent decrease in paw withdrawal threshold (mechanical hyperalgesia). Group I mGlu agonist-induced hyperalgesia was inhibited by co-microinjection of MPEP, but not by the mGlu1 receptor antagonist (S)-4-carboxy-phenylglycine (4-CPG). Carrageenan-induced inflammatory hyperalgesia was inhibited by pre-treatment of the inflamed hind paw with MPEP, but not following MPEP injection into the contralateral hind paw. Dorsal horn neurones receiving peripheral nociceptive and non-nociceptive afferent input were recorded in anaesthetized rats following microinjection of CHPG into their peripheral receptive fields. CHPG significantly increased the frequency and duration of firing of dorsal horn wide dynamic range (WDR) neurones and this activity was prevented by co-administration of CHPG and MPEP into their receptive fields. Immunohistochemical experiments revealed the co-expression of mGlu5 receptor protein and betaIII tubulin in skin from naive rats, indicating the constitutive expression of mGlu5 receptors on peripheral neurones. Double-labelling of adult rat DRG cells with mGlu5 receptor and vanilloid receptor subtype 1 antisera also supports the expression of mGlu5 receptors on peripheral nociceptive afferents. These results suggest that mGlu5 receptors expressed on the peripheral terminals of sensory neurones are involved in nociceptive processes and contribute to the hyperalgesia associated with inflammation.

Analgesics, Opioid↗

PubMed2001

Laparoscopic cholecystectomy in patients with early cirrhosis.

Traditionally, cholecystectomy in cirrhotic patients has been reserved for patients with severe biliary disease, because of the high morbidity and mortality in cirrhotic patients undergoing this procedure. Laparoscopic cholecytectomy (LC) was originally contraindicated in cirrhotic patients because of the associated portal hypertension and coagulopathy. This study examined the safety of LC in Child's class A patients.A review was conducted of all patients with cirrhosis who underwent cholecystectomy at our hospital between 1990 and 1998.Fifteen patients with cirrhosis had their gallbladder removed laparoscopically during that time period. All patients were Child's class A. The average age was 59 (range, 36-85). The operative indications included acute cholecystitis (5 patients), biliary pacreatitis (4 patients), biliary colic (5 patients), and cholangitis (1 patients). Six patients had known cirrhosis, and 9 were examined intraoperatively. The average operative time was 105 minutes. None of the patients required a blood transfusion. No intraoperative or postoperative complications occurred. No deaths occurred. Postoperative stay was 3 days or less in all but 3 patients.These results compare favorably to other published studies from outside of the United States. Based on our findings, we believe LC can be performed safely in patients with class A cirrhosis.

Journal Article↗

PubMed2001

The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain.

We have examined the effects of cannabinoid agonists on hyperalgesia in a model of neuropathic pain in the rat and investigated the possible sites of action. The antihyperalgesic activity of the cannabinoids was compared with their ability to elicit behavioural effects characteristic of central cannabinoid activity. WIN55,212-2 (0.3-10 mg kg(-1)), CP-55,940 (0.03-1 mg kg(-1)) and HU-210 (0.001-0.03 mg kg(-1)) were all active in a 'tetrad' of tests consisting of tail-flick, catalepsy, rotarod and hypothermia following subcutaneous administration, with a rank order of potency in each of HU-210 > CP-55,940 > WIN55,212-2. The effects of WIN55,212-2 in each assay were blocked by the Cannabinoid1 (CB1) antagonist SR141716A. In the partial sciatic ligation model of neuropathic pain WIN55,212-2, CP-55,940 and HU-210 produced complete reversal of mechanical hyperalgesia within 3 h of subcutaneous administration with D50 values of 0.52, 0.08 and 0.005 mg kg(-1), respectively. In this model WIN55,212-2 was also effective against thermal hyperalgesia and mechanical allodynia. WIN55,212-2 produced pronounced reversal of mechanical hyperalgesia following intrathecal administration that was blocked by the CB1 antagonist SR141716A. Following intraplantar administration into the ipsilateral hindpaw, WIN55,212-2 produced up to 70% reversal of mechanical hyperalgesia, although activity was also observed at high doses following injection into the contralateral paw. The antihyperalgesic effect of WIN55,212-2 injected into the ipsilateral paw was blocked by subcutaneously administered SR141716A, but was not affected by intrathecally administered SR141716A. These data show that cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of neuropathic pain. This activity is likely to be mediated via an action in both the CNS and in the periphery.

Analgesics↗

PubMed2001

Laparoscopic cholecystectomy: fundus-down approach.

BACKGROUND AND PURPOSE: Laparoscopic cholecystectomy (LC) is the primary treatment of gallstone disease. Although refinements have made it safer, bile duct injury remains more common than with the open approach. The major difference in these techniques is that open cholecystectomy approaches the gallbladder from the fundus downward, whereas conventional laparoscopic cholecystectomy proceeds in the reverse direction. A handful of fundus-down techniques appear in the literature. The use of special instruments or port sites is common. We present a technique that is safe and utilizes instruments familiar to the surgeon performing conventional LC. PATIENTS AND METHODS: Fifty consecutive LCs were included in the study. The variables monitored were age, comorbidities, postoperative diagnosis, pathologic diagnosis, length of operation, hospital length of stay, and complications. RESULTS: The average operating time for chronic cholecystitis was 1 hour, and the average time for acute cholecystitis was less than 2 hours. Except for one early case of bleeding, in which the procedure was completed using the familiar conventional method, no complications and no unusual technical difficulties were encountered. There were no differences between conventional and fundus-down LC with regard to time and complications. CONCLUSIONS: This technique is safe and has several benefits: (1) standard trocar sites that offer the surgeon flexibility in the approach; (2) the ability to resect as much cystic duct as desired; and (3) utilization of standard instruments familiar to the surgeon, thus avoiding costly special instruments. The approach may offer the benefit of reducing the rate of common bile duct injury to that of open cholecystectomy.

Bile Ducts↗

PubMed2001

Cannabinoid-induced presynaptic inhibition of glutamatergic EPSCs in substantia gelatinosa neurons of the rat spinal cord.

The effect of cannabinoids on excitatory transmission in the substantia gelatinosa was investigated using intracellular recording from visually identified neurons in a transverse slice preparation of the juvenile rat spinal cord. In the presence of strychnine and bicuculline, perfusion of the cannabinoid receptor agonist WIN55,212-2 reduced the frequency and the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Furthermore, the frequency of miniature EPSCs (mEPSCs) was also decreased by WIN55,212-2, whereas their amplitude was not affected. Similar effects were reproduced using the endogenous cannabinoid ligand anandamide. The effects of both agonists were blocked by the selective CB(1) receptor antagonist SR141716A. Electrical stimulation of high-threshold fibers in the dorsal root evoked a monosynaptic EPSC in lamina II neurons. In the presence of WIN55,212-2, the amplitude of the evoked EPSC (eEPSCs) was reduced, and the paired-pulse ratio was increased. The reduction of the eEPSC following CB(1) receptor activation was unlikely to have a postsynaptic origin because the response to AMPA, in the presence of 1 microM TTX, was unchanged. To investigate the specificity of this synaptic inhibition, we selectively activated the nociceptive C fibers with capsaicin, which induced a strong increase in the frequency of EPSCs. In the presence of WIN55,212-2, the response to capsaicin was diminished. In conclusion, these results strongly suggest a presynaptic location for CB(1) receptors whose activation results in inhibition of glutamate release in the spinal dorsal horn. The strong inhibitory effect of cannabinoids on C fibers may thereby contribute to the modulation of the spinal excitatory transmission, thus producing analgesia at the spinal level.

Analgesics↗

PubMed2000

Differential role of neurokinin receptors in human lymphocyte and monocyte chemotaxis.

The precise nature of neurokin receptor involvement in human immune cell chemotaxis is unclear. This study therefore sought to directly compare the chemotactic effects of neurokinins on human T lymphocytes and monocytes. Substance P was found to have a similar dose-dependent chemotactic action on T lymphocyte and monocyte populations. In contrast, T lymphocytes were found to be more responsive than monocytes both to the highly selective NK-1 agonist, [Sar(9)Met O(2)(11)]-substance P, and also to the NK-2 selective agonist, beta-alanine neurokinin A((4-10)). Consistent with these findings, substance P-induced chemotaxis of both T lymphocyte and monocytes was attenuated by the selective NK-1 antagonist LY303870. However, the selective NK-2 antagonist MEN 10,376 was only effective in inhibiting the T lymphocyte response. The study confirms that neurokinins have chemotactic actions on immune cells and indicates important functional differences between human T lymphocyte and monocyte responses. This provides a potential mechanism by which the nervous system can selectively influence cellular recruitment in inflammatory disease.

Chemotaxis, Leukocyte↗