Electronic speckle pattern interferometry: a novel non-invasive tool for studying drug transport rate through free films.

In this work, Electronic Speckle Pattern Interferometry (ESPI) is presented as a non-invasive tool to study drug transport in controlled release systems. ESPI is shown to be a feasible tool to measure drug film permeability via comparison with an ordinary diaphragm cell. A specially designed cuvette was used in the release study: the polymeric film separated the donor and the receiving chambers of the cuvette to create a diffusion cell with no mixing in the two chambers. Thus, the cuvette mimicked a coated system immersed in a stagnant bulk liquid. Concentration profile data were obtained for the two compartments. Using these data, it was possible to visually discriminate between a film subject only to diffusion and a film subject to diffusion as well as osmotic effects. Moreover, using the concentration profile data collected at different time intervals, it was possible to follow the film properties in terms of drug permeability, thus studying how drug permeability depended on drug concentration. Compared to other measuring techniques, ESPI offers the advantages that no invasive measurements are needed, and that no sampling and calibration are required. Furthermore, the permeability can be measured with no influence of mass transfer in the boundary layers.     

Treatment of severe encephalopathy after porta-systemic anastomosis by suppression of the shunt

Encephalopathy is the most common complication after total portal by-pass operation. 5-15% of patients have severe and intractable encephalopathy. Many medical and surgical procedures were proposed to prevent and treat this complication but none of these were effective. Two cases of patients with severe encephalopathy after side to side portal by-pass are presented. They were treated with the procedure proposed by Bismuth; it consists of a gradual suppression of the anastomosis associated with esophagogastric devascularization. In the first case we obtained the regression of encephalopathy while the second patient died portal thrombosis (probably due to this procedure) two months after surgery. Validity and efficacy of this procedure must be evaluated with a higher number of patients. This surgical technique should lead to choose the type of portal by-pass: side to side portal by-pass operation allows according to Bismuth's procedure to reestablish an hepatopetal flow.     

Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin a

Subunit intranasal vaccines offer the prospect of inducing combined systemic-mucosal immunity against mucosally transmitted infections such as human immunodeficiency virus. However, although human studies have demonstrated the induction of active immunity, secretory immunoglobulin A (sIgA) responses are variable, and no study has demonstrated protection by accepted vaccine-licensing criteria as measured by direct toxin-neutralizing activity. Using the genetically inactivated mutant diphtheria toxoid CRM(197) in a bioadhesive polycationic polysaccharide chitosan delivery system, we found that a single nasal immunization was well tolerated and boosted antitoxin neutralizing activity in healthy volunteers, which could be further boosted by a second immunization. The neutralizing activity far exceeded accepted protective levels and was equivalent to that induced by standard intramuscular vaccine and significantly greater than intranasal immunization with CRM(197) in the absence of chitosan. A striking but unexpected observation was that although unilateral intranasal immunization induced circulating antitoxin antibody-secreting cells, a nasal antitoxin sIgA response was seen only after the second immunization and only in the vaccinated nostril. If these data are reproduced in larger studies, an intranasal diphtheria vaccine based on CRM(197)-chitosan could be rapidly licensed for human use. However, a restricted sIgA response suggests that care must be taken in the priming-boosting strategy and clinical sampling techniques when evaluating such vaccines for the induction of local mucosal immunity.     

CCL22-induced responses are powerfully enhanced by synergy inducing chemokines via CCR4: evidence for the involvement of first beta-strand of chemokine

In an attempt to clarify how cells integrate the signals provided by multiple chemokines expressed during inflammation, we have uncovered a novel mechanism regulating leukocyte trafficking. Our data indicate that the concomitant exposure to CCR4 agonists and CXCL10/IP-10 strongly enhances the chemotactic response of human T lymphocytes. This enhancement is synergistic rather than additive and occurs via CCR4 since it persists after CXCR3 blockade. Besides chemotaxis, other cellular responses are enhanced upon stimulation of CCR4-transfected cells with CCL22/MDC plus CXCL10. Several other chemokines in addition to CXCL10 were able to increase CCL22-mediated chemotaxis. The first beta-strand of the chemokine structure is highly and specifically implicated in this phenomenon, as established using synergy-inducing and non-synergy-inducing chimeric chemokines. As shown in situ for skin from atopic and allergic contact dermatitis patients, this organ becomes the ideal environment in which skin-homing CCR4(+) T lymphocytes can accumulate under the stimulus offered by CCR4 agonists, together with the synergistic chemokines that are concomitantly expressed. Overall, our results indicate that chemokine-induced synergism strengthens leukocyte recruitment towards tissues co-expressing several chemokines.     

Heterotopic mesenteric ossification. Description of a case

We describe a case of heterotopic mesenteric ossification presented in a 25 year-old male who underwent laparotomy for a fire-gun injury. Two weeks later he experienced small bowel obstruction and for this reason he has been operated five times with removal of segments of small bowel. Now, nine months later, he needs ileostomy to avoid another obstruction.     

Structure-activity relationships in 1,4-benzodioxan-related compounds. 6. Role of the dioxane unit on selectivity for alpha(1)-adrenoreceptor subtypes.

WB 4101-related benzodioxans 3-9 were synthesized, and their biological profiles at alpha(1)-adrenoreceptor subtypes and 5-HT(1A) serotoninergic receptors were assessed by binding assays in CHO and HeLa cells membranes expressing the human cloned receptors. Furthermore, receptor selectivity of selected benzodioxan derivatives was further determined in functional experiments in isolated rat vas deferens (alpha(1A)) and aorta (alpha(1D)) and guinea pig spleen (alpha(1B)), in additional receptor binding assays in rat cortex membranes containing alpha(2)-adrenoreceptors and 5-HT(2) serotoninergic receptors, and in rat striatum membranes containing D(2) dopaminergic receptors. An analysis of the results of receptor binding experiments for benzodioxan-modified derivatives 3-9 showed high affinity and selectivity toward the alpha(1a)-adrenoreceptor subtype for compounds 3-5 and 7 and a reversed selectivity profile for 9, which was a selective alpha(1d) antagonist. Furthermore, the majority of structural modifications performed on the prototype 1 (WB 4101) led to a marked decrease in the affinity for 5-HT(1A) serotoninergic receptors, which may have relevance in the design of selective alpha(1A)-adrenoreceptor antagonists. The exception to these findings was the chromene derivative 8, which exhibited a 5-HT(1A) partial agonist profile.     

Grasper trauma during laparoscopic cholecystectomy

BACKGROUND: The present study characterized the histopathological nature of laparoscopic grasper trauma during laparoscopic cholecystectomy in a prospective, blinded trial in order to establish a model for laparoscopic grasper trauma. The null hypothesis that graspers cause no histologically distinct tissue injury was tested. METHODS: The gall bladders of 19 patients undergoing laparoscopic cholecystectomy were examined. The area of gall bladder that had been grasped by Debakey laparoscopic forceps was excised (sample), along with an area of gall bladder that had not been grasped (control). Paired specimens were examined by a pathologist (blinded) to identify which was 'sample' and which was 'control' and to assess for histological markers of crushed tissue injury. The data were analysed by chi-squared or Fisher's exact tests. RESULTS: The pathologist was able to identify the sample (gripped) specimen in 13 of the 19 cases. In the remaining six cases the pathologist was unable to determine the specimen that had been gripped due to either absence of damage (four cases), or severe inflammation precluding assessment (two cases). The ability of the pathologist to distinguish the sample from the control specimen was significant (chi-squared test, P = 0.003). Of the histological markers of crushed tissue injury, focal thinning of the gall bladder wall and epithelial loss were present in significantly more sample (gripped) specimens than control specimens (chi-squared test, P = 0.0002 and P < 0.0001, respectively). CONCLUSIONS: Laparoscopic graspers cause tissue trauma that can be assessed histologically. The current study presents a relevant, reproducible, ethically acceptable human model for assessing the interaction between laparoscopic graspers and soft tissues.     

Synthesis and Antimuscarinic Activity of Derivatives of 2-Substituted-1,3-Dioxolanes

Geometric cis, trans isomers, derivatives of 2-substituted-1,3-dioxanes were designed and studied as antimuscarinic agents. The synthesized compounds were evaluated as perchlorides and methiodides by functional tests with rabbit vas deferens (putative M₁), guinea-pig heart (M₂) and guinea-pig ileum (M₃). The effect of the replacement of a trimethylammonium group with a dimethysulfonium in the two rings was also evaluated. Pharmacological results indicate that the 1,3-dioxane nucleus shows the highest stereoselective values on the studied receptors.     

Relationship between focal cortical dysplasia and epilepsy‐associated low‐grade tumors: an immunohistochemical study

We retrospectively analyzed 29 seizure‐associated temporal lobe low‐grade tumors to evaluate the utility of CD34 and bcl‐2 expression in clarifying the relationship of these tumors with different classes of focal cortical dysplasia (FCD). CD34 immunostained 75% of gangliogliomas (GG) and 60% of pleomorphic xanthoastrocytomas. FCD type IIIb [i.e. abnormal cortical layering associated with a glioneuronal tumor, according to the new International League Against Epilepsy (ILAE) classification] presented CD34‐immunopositive cells in 2/9 (22.2%) cases, whereas FCD type II in 6/7 (85.7%) cases, a difference statistically significant (p = 0.0117). Bcl‐2 immunostained 9/12 (75%) gangliogliomas and 2/3 (66.6%) gangliocytomas. The cases of FCD type IIIb resulted negative for Bcl‐2, whereas 4/7 cases (57.1%) of FCD type II showed immunopositive cells. These differences in Bcl‐2 expression between FCD type IIIb and FCD type II resulted statistically significant (p = 0.0088). Abnormal cortical layering, overall, represents the kind of FCD more commonly associated with seizure‐related low‐grade tumors, whereas FCD type II is more frequently associated with GG. The profile of CD34 and Bcl‐2 expression exhibited by GG is more similar to that observed in FCD type II. Such immunoprofile suggests the existence of a common pathogenesis linking glioneuronal tumors and FCD type II.