Role of TNF-alpha receptors in mice intoxicated with the parkinsonian toxin MPTP

Local application of GABA-potentiating agents can prevent or reduce the development and maintenance of behavioral seizures induced by limbic kindling in rats. Microinjection and lesion studies suggest that the transition zone between anterior and posterior piriform cortex (PC), termed here central PC, is a potential target for transplantation of GABA-producing cells. In the present study, we transplanted conditionally immortalized mouse cortical neurons, engineered with the GABA-synthesizing enzyme GAD(65), to the central PC of rats. Suspensions of 1.5 x 10(5) cells in 1 microl were transplanted bilaterally. Control animals received transplantation of beta-galactosidase (beta-gal)-expressing cells. All rats were subsequently kindled through a chronically implanted electrode placed in the basolateral amygdala. The pre- and postkindling threshold currents for eliciting behavioral seizures were determined before and after kindling. We found the prekindling partial seizure threshold to be significantly increased by about 200% in the rats that received the GABA-producing cells compared to rats receiving beta-gal-producing transplants. After kindling, the seizure threshold tended to be higher by 100% in rats that received GABA-producing cells, although the difference from controls was not statistically significant. GABA-producing transplants had no significant effect on the rate of amygdala kindling, but the latency to the first generalized seizure during kindling was significantly increased in animals receiving GABA-producing cells. The transplanted cells showed long-term GAD(65) expression as verified immunohistologically after termination of the experiments. The findings substantiate and extend previous findings that the central PC is part of the anatomical substrate that facilitates propagation from partial to generalized seizures. The data demonstrate that genetically engineered cells have the potential to raise seizure thresholds when transplanted to the central PC.     

High-grade dysplasia in Barrett's esophagus. The case for esophagectomy

The main principles for optimal management of HGD arising in Barrett's esophagus are that unequivocal diagnosis of HGD is a prerequisite for making the decision of any kind of treatment. HGD must be resected because of the presence of neoplastic cells in the lamina propria in 40% of patients. No reliable endoscopic or endosonographic feature exists that allows accurate prediction of the existence of neoplastic cells within the lamina propria of a patient having HGD in endoscopic biopsy material. Prompt decision to remove an HGD lesion as soon as unequivocal histologic diagnosis has been settled prevents the development of extraesophageal neoplastic spread. Esophagectomy is preferable to endoscopic mucosal excision because approximately 20% of patients who have HGD in preoperative biopsy material carry neoplastic cells beyond the muscularis mucosae. Esophagectomy can be limited to the removal of the esophageal tube without extended lymphadenectomy because 96% of patients who have HGD in endoscopic biopsy samples have a neoplastic process confined to the esophageal wall. Esophageal resection must encompass all the Barrett's area because of the risk for the further development of a second cancer in the metaplastic remnant. Vagus-sparing esophagectomy with colon interposition or elevation of the antrally innervated stomach up to the neck is preferable to conventional esophagectomy with gastric pull up because the former procedure maintains gastric function intact, whereas the latter exposes patients to the risk for the long-term development of reflux esophagitis and even of metaplastic transformation of the proximal esophageal remnant. Subtle details in the understanding of a given patient's clinical course may be critical for making the decision of the most relevant mode of therapy; therefore, patients who have HGD should be treated in dedicated centers, the experience of which offers the best chances of uneventful recovery if the surgical option is retained.     

Second-line drugs used in recent-onset rheumatoid arthritis in Brittany (France)

OBJECTIVE: The management of recent-onset rheumatoid arthritis (RA) is not well standardized. We conducted a survey of drugs prescribed to RA patients in Brittany at presentation and during the first 1 to 3 years of follow-up. METHODS: A cohort of 270 patients with recent-onset inflammatory joint disease was recruited between 1995 and 1997. The evaluation at presentation included a medical history, a thorough physical examination, and a standard battery of investigations. Follow-up at 6-month intervals was offered. At the last visit, between June and December 1999, a panel of five rheumatologists established that 98 patients had RA. RESULTS: At presentation, hydroxychloroquine and injectable gold were the most widely used second-line drugs, and only two patients were offered a combination of second-line drugs. At the last visit, the most commonly used drugs were methotrexate, injectable gold, and hydroxychloroquine (23, 23, and 21 patients, respectively); only three patients were on more than one second-line drug and 38 (38/98, 39%) patients were on glucocorticoid therapy. CONCLUSION: Rheumatologists in Brittany prefer monotherapy with hydroxychloroquine or injectable gold as the initial treatment. Later, they rely mainly on methotrexate, injectable gold, and hydroxychloroquine, often in combination with glucocorticoid therapy.     

Homeostatic regulation of sleep in a genetic model of depression in the mouse: effects of muscarinic and 5-HT1A receptor activation.

In depressed patients, sleep undergoes marked alterations, especially sleep onset insomnia, sleep fragmentation, and disturbances of the Rapid Eye Movement (REM) sleep. Abnormalities of rest-activity rhythms and of hypothalamic-pituitary-adrenocortical function have also been described in these patients. In the present study, we examined the presence of such abnormalities in a recently developed line of mice (Helpless mice-H) that exhibit depression-like behaviors in validated tests, compared to the nonhelpless (NH) line derived from the same colony. Experiments were essentially carried out in females for which previous studies showed marked differences between H and NH lines. Compared to NH mice, the H line exhibited (i) lower basal locomotor activity, (ii) sleep fragmentation, shift towards lighter sleep stages, and facilitation of REM sleep reflected by increased amounts and decreased latency, (iii) larger response to the REM sleep promoting effect of muscarinic receptor stimulation (by arecoline). In contrast, H and NH mice were equally responsive to the REM sleep inhibitory effect of 5-HT1A receptor stimulation (by 8-OH-DPAT). In addition, a deficiency in delta power enhancement after sleep deprivation was observed in the H group, and acute immobilization stress in this group failed to elicit a REM sleep rebound and was associated with a long-lasting raise in serum corticosterone levels. These results further validate H mice as a depression model and suggest they might be of particular interest for investigating the neurobiological mechanisms and possibly genetic substrates underlying sleep alterations associated with depression.     

Sufentanil modifies the antibacterial activity of bupivacaine and ropivacaine

PURPOSE: The purpose of our study was to investigate the effect on the growth of Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Enterococcus faecalis (E. faecalis) of bupivacaine at a final concentration of 0.77 mg.mL(-1), ropivacaine at 1.2 mg.mL(-1), and sufentanil at 0.38 and 0.5 microg.mL(-1) (alone or in combination with bupivacaine and ropivacaine). METHODS: The strains were diluted to approximately 3 x 10(4) cfu.mL(-1) in Mueller-Hinton broth. The anesthetics (0.5 mL) were incubated with the bacterial suspensions (0.5 mL) for 24 hr at 37 degrees C. RESULTS: Bupivacaine inhibited the growth of E. coli (59 +/- 0.8%; P < 0.05) and S. aureus (22 +/- 3.6%; P < 0.05). Ropivacaine also inhibited the growth of E. coli (41 +/- 1.2%; P < 0.05) and S. aureus (25.5 +/- 4.1%; P < 0.05). Both anesthetics were ineffective against E. faecalis. Sufentanil only inhibited S. aureus (13.8 +/- 3.1%; P < 0.05) at a concentration of 0.5 microg.mL(-1). Sufentanil modified the antibacterial activity of bupivacaine and ropivacaine. It increased the inhibitory effect of bupivacaine on E. faecalis and S. aureus by 10 +/- 2.1% (P < 0.05) and on E. coli by 7% (P < 0.05). Sufentanil did not increase the inhibitory effect of ropivacaine on the growth of S. aureus. On the other hand, sufentanil reduced the inhibitory effect of ropivacaine on E. coli by 11% (P < 0.05). CONCLUSION: Both bupivacaine and ropivacaine alone or combined with sufentanil inhibited the growth of E. coli and S. aureus. E. faecalis was partially sensitive to a bupivacaine + sufentanil mixture. Sufentanil had a partial synergistic effect on bupivacaine and a partial antagonistic effect on ropivacaine's antibacterial activity.     

α-Bungarotoxin sensitization in experimental autoimmune myasthenia gravis

A mouse model of MG, termed experimental autoimmune myasthenia gravis (EAMG), can be obtained after immunization with Torpedo acetylcholine receptor (AChR). Although many studies have detailed the consequence of AChR antibodies binding at the neuromuscular junction and the difficulty in obtaining obvious clinical signs, less attention has been focused on the possibility of amplifying the muscular block in order to discriminate between immunized and healthy animals. In the present studies we observe that a single inoculation of α-bungarotoxin (α-bgt) can amplify the neuromuscular block revealed by repetitive nerve stimulation, and induce in EAMG mice a stable muscular weakness state lasting for at least 169 hours instead of 95 hours in normal mice. This model could provide an excellent tool for evaluating drugs active on neuromuscular transmission. © 1993 John Wiley & Soncs, Inc.     

Prognostic significance of a combined clinicopathologic score for response to primary systemic therapy in locally advanced breast cancer

The response to chemotherapy is one of the best indicators of prognosis in locally advanced breast cancer (LABC). The pathologic response (pR) of 108 LABC patients was analysed and compared with their clinical response (cR). Our aim was to define a new combined clinicopathologic response score (cpR) and to explore its correlation with survival data. The 108 stage IIB to IIIB breast carcinomas were first treated with high-dose anthracycline-based chemotherapy. Standard criteria were used to assess cR. Pathologic analysis of surgical specimens allowed the definition of 5 types of pR. Three groups of combined clinicopathologic response were defined. Twenty-two patients (20%) had complete or almost complete pR. Most patients (88, 81%) had partial cR. This large group of partial cR was very heterogeneous, ranging from pR1 to pR5 and from cpR1 to cpR3. In univariate analysis, pR and cpR both strongly correlated with EFS. cR, pR and cpR all correlated with OS. Subgroups of incomplete pathologic responses were not prognostically different. In multivariate analysis, only cpR correlated strongly with both EFS and OS (p<0.002), identifying good (20%), intermediate (61%) and poor (19%) prognosis patients. In conclusion, in 108 stage IIB to IIIB breast cancer patients initially treated by high-dose chemotherapy, combined grading of clinical and pathologic responses in a single score allowed accurate prediction of outcome.     

Subgroup analyses in randomized clinical trials: statistical and regulatory issues

Recently, two CPMP Points to Consider, one on adjustment for baseline covariates and the other on multiplicity issues in clinical trials, have included recommendations on the use of subgroup analysis for regulatory purposes. However, despite their regular use and regulatory attention, the validity and nature of subgroup analyses are still frequently questioned. This article provides guidance on when subgroup analyses can be done, when they should be done, and their interpretation. The validity of common regulatory claims based on subgroup analyses is then discussed.     

Protease-activated receptors: potential therapeutic targets in irritable bowel syndrome?

Protease-activated receptors (PARs) are a family of four G-protein-coupled receptors (PAR-1 to PAR-4) activated by the proteolytic cleavage of their N-terminal extracellular domain. This activation first involves the recognition of the extracellular domain by proteases, such as thrombin, but also trypsin or tryptase which are particularly abundant in the gastrointestinal tract, both under physiological circumstances and in several digestive diseases. Activation of PARs, particularly of PAR-1 and -2, modulates intestinal functions, such as gastrointestinal motility, visceral nociception, mucosal inflammatory response, and epithelial functions (intestinal secretion and permeability). As these physiological properties have been shown to be altered in various extents and combinations in different clinical presentations of irritable bowel syndrome, PARs appear as putative targets for future therapeutic intervention in these patients.