The R7 subfamily of RGS proteins assists tachyphylaxis and acute tolerance at mu-opioid receptors.

Members of the R7 subfamily of regulators of G-protein signaling (RGS) proteins (RGS6, RGS7, RGS9-2, and RGS11) are found in the mouse CNS. The expression of these proteins was effectively reduced in different neural structures by blocking their mRNA with antisense oligodeoxynucleotides (ODNs). This was achieved without noticeable changes in the binding characteristics of labeled beta-endorphin to opioid receptors. Knockdown of R7 proteins enhanced the potency of antinociception promoted by morphine and [D-Ala(2), N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO)-both agonists at mu-opioid receptors. The duration of morphine analgesia was greatly increased in RGS9-2 and in RGS11 knockdown mice. The impairment of R7 proteins brought about different changes in the analgesic activity of selective delta agonists. Knockdown of RGS11 reduced [D-Ala(2)]deltorphin II analgesic effects. Those of RGS6 and RGS9-2 proteins caused [D-Ala(2)]deltorphin II to produce a smoothened time-course curve-the peak effect blunted and analgesia extended during the declining phase. RGS9-2 impairment also promoted a similar pattern of change for [D-Pen(2,5)]-enkephalin (DPDPE). RGS7-deficient mice showed an increased response to both [D-Ala(2)]deltorphin II and DPDPE analgesic effects. A single intracerebroventricular (i.c.v.) ED(80) analgesic dose of morphine gave rise to acute tolerance in control mice, but did not promote tolerance in RGS6, RGS7, RGS9-2, or RGS11 knockdown animals. Thus, R7 proteins play a critical role in agonist tachyphylaxis and acute tolerance at mu-opioid receptors, and show differences in their modulation of delta-opioid receptors.     

Preparation of bupivacaine-loaded poly(epsilon-caprolactone) microspheres by spray drying: drug release studies and biocompatibility.

Poly(epsilon-caprolactone) microspheres containing bupivacaine were prepared by the spray-drying process. The average size of drug loaded microspheres was less than 3 microm in diameter, and the percentage of entrapment efficiency was 91 +/- 3%. In vitro drug release kinetic in phosphate buffer at 37 degrees C showed a hyperbolic profile, with a burst-effect during the first hour. Subcutaneous injection of bupivacaine-loaded microspheres in the back of rats caused an increase in drug concentration in plasma. Maximum bupivacaine concentration in plasma was 237 +/- 58 ng/ml at 105 h, and drug was detected in plasma for 16 days. The half-life time of the drug was increased by more than 125 times with regard to that of the drug administered in a solution by intraperitoneal injection. After 30 days of injection, a mass formed by microspheres surrounded by a thin fibrous capsule was observed. Small blood vessels and multinucleate foreign body giant cells with macrophagic function around microspheres were detected. After 60 days of injection a subcutaneous mass was also observed, which was formed of more degraded dispersed microspheres in conjunctive tissue, which had a normal structure. Thus, bupivacaine-loaded poly(epsilon-caprolactone) microspheres could be considered as a device to be used in the treatment of severe pain that is not responsive to opioids for example in cancer-related syndromes or in intractable herpetic neuralgia.     

Can a failed ileal pouch anal anastomosis be left in situ?

OBJECTIVE: Failure after ileal pouch-anal anastomosis (IPAA) is reported with a frequency of 10-20%. The failed IPAA can be excised or defunctioned. Indications for excision and further management of an indefinitely diverted pouch are poorly described. The aim of the present investigation was to investigate pouch-related problems and the histopathological pattern of the pouch mucosa in this group of patients. METHOD: In a cohort of 620 patients having IPAA with a median follow-up of 14 years, 56 patients with failure were identified. The patients with defunctioned pouches were assessed with regard to pouch-related problems and endoscopy with biopsies was performed. Biopsies were stained with haematoxylin-eosin, PAS for neutral mucins and Alcian blue/high iron diamine for sialomucins/sulphomucins. Morphological changes were grouped into three types modified according to Veress and assessed for dysplasia. RESULTS: Twenty-two patients with an indefinitely diverted pouch were found. The follow-up time after surgery for failure was 10 years. Thirteen patients completed the follow-up. Except for two patients with pelvic/perineal pain, there were no clinical problems. The majority of patients displayed mild to moderate macroscopic signs of inflammation. Morphologically, findings ranged from a preserved mucosal pattern to intense inflammatory reaction. No case of dysplasia or carcinoma was found. CONCLUSION: Most patients with an indefinitely diverted pouch had no complaints regarding the pouch. There was no case of dysplasia. Indefinite diversion may be preferable to pouch excision, especially given the associated morbidity.     

Relationship Between Exhaled Carbon Monoxide and Airway Hyperresponsiveness in Asthmatic Patients

The study objectives were to analyze the changes in exhaled carbon monoxide (COex) induced by histamine provocation challenge in asthmatic patients and to evaluate the relationship between COex and airway sensitivity and reactivity. Levels of COex were measured in 105 nonsmoking mildly asthmatic subjects before and after histamine provocation challenge. Dose-response curves were characterized by their sensitivity (PD₂₀) and reactivity. Dose-response slope (DRS), continuous index of responsiveness (CIR), and bronchial reactivity index (BRI) were determined as reactivity indices. Bronchial challenge was positive for 47 subjects and negative for 58. The COex levels rose significantly after bronchial challenge in the positive response group (4.49 ± 0.4 vs. 5.74 ± 0.57 ppm, p = 0.025) and in the negative response group (2.84 ± 0.25 vs 4.00 ± 0.41 ppm, p = 0.000). An inverse relation between basal COex and PD₂₀ was found (r = - 0.318, p = 0.030). In all subjects, a proportional direct relationship between COex and DRS (r = 0.214, p = 0.015), CIR (r = 0.401, p = 0.000), and BRI (r = 0.208, p = 0.012) was observed. On stepwise multiple linear regression analysis, COex only significantly correlated with CIR (multiple r² = 0.174, p = 0.000). In conclusion, exhaled CO determination is a noninvasive inflammatory marker of the respiratory tract, which shows an acceptable association with airway hyperresponsiveness.     

Postoperative pain management—clinical practice is still not optimal

Major progress in clinical pain assessment and management has been achieved in the last decade. More effective analgesic drugs and improved techniques for pain management have been introduced. However, medical reports published during the last few years on postoperative pain management (POPM) indicate that moderate or even severe pain is still rather commonly experienced by surgical patients in the early postoperative period and that worst-pain-episodes may occur even in the late postoperative phase. Insufficient relief of postoperative pain seems a more common problem on surgical wards than on a postanaesthesia care unit (PACU). The aims of POPM are to inhibit autonomic trauma-induced nociceptive impulses that may result in functional disturbances of vital organs and thereby affect the incidence of potentially severe complications influencing clinical outcome. Considering that recent studies continue to show sub-optimal pain management despite the availability of effective drugs and analgesic techniques it must be considered essential to identify possible barriers to effective pain management in clinical practice so that necessary improvements in POPM routines can be carried out.     

Lung Cancer and COPD: a Common Combination

Background and objectiveTo analyse frequency, characteristics and patient survival with lung cancer (LC) and Common Obstructive Pulmonary Disease (COPD), comparing them with patients that do not have COPD.Material and methodsA retrospective study, of patients diagnosed by means of cytohistology. Survival was estimated by the Kaplan-Meier method. Statistical analysis was carried out using SPSS 15.0.ResultsA total of 996 patients were diagnosed, 39.8% with COPD. Mean age70±9.19 years. GOLD stages: I 18.2%, II 53.6%, III 24%, IV 4.2%. The histological types: squamous cell carcinoma 48.2%, adenocarcinoma 22%, and small cell carcinoma 22.5%. Survival was longer in the COPD group.ConclusionsLC and COPD are combined in 39.8%. Squamous cell type is more frequent and survival was longer in the COPD group.     

Program for the Prevention of Smoking in Secondary School Students

Background and ObjectiveSchool smoking prevention programs have never yielded the expected results. The aim of this study was to analyze the efficacy of an intensive smoking prevention program created by the educational community in which it was to be applied.Population and MethodA 3-year smoking prevention program was carried out among the students of Fuentesaúco Secondary School in Zamora, Spain. The Babilafuente Secondary School in Salamanca, Spain was the control group. The program included both prevention and treatment activities. The former were carried out in the school, in out-of-school situations, and in the community. The questionnaire of the European Smoking Prevention Framework Approach was used.ResultsA total of 417 students aged 12 to 17 years participated in the study. Of these, 54.4% belonged to the intervention group and 45.6% to the control group. Smokers represented 36.7% of the population. After the intervention smokers represented 40.1% of the Fuentesaúco students compared with 46.1% of the Babilafuente students, though the difference was not statistically significant. With respect to the cognitive determinants of smoking behavior, after the intervention significant differences in favor of the intervention group were only observed in the subjects’ perception of the behavior of their siblings, peers, and teachers.ConclusionsThe use of smoking prevention programs in schools should be reconsidered, and their evaluation should be based on educational rather than clinical criteria. Proposed changes in the program include decreasing its intensity, starting with students of an earlier age and seeking greater involvement of parents.     

Metformina también como primera elección en pacientes con peso normal. ¿Se ha incrementado su uso?

ObjectiveTo assess whether the release of the new consensus algorithms in August 2006, along with the consensus recommendation of also using metformin as first choice in patients with normal weight, has led to an increase in the use of this drug in the period immediately after.DesignRetrospective longitudinal Study.SitesSantiago de Compostela Health District (A Coruña).ParticipantsUsers of the Galician health service in the Santiago de Compostela Health District.MethodsThe evolution of the monthly number of DHD (Daily Defined Doses/1000 inhabitants/day) of metformin from early 2003 until 12 months after the issuing of new algorithms was analysed graphically and using a multiple regression model.ResultsThe graphical representation of the DHD of metformin over time shows a linear growth for the period, but there is an increasing trend after the publication of the new consensus algorithm. The multiple regression showed that the increase is statistically significant.ConclusionsFollowing the publication of the new consensus algorithm an increasing trend in the use of metformin is observed in the short term.