Isoflurane-induced post-conditioning in senescent hearts is attenuated by failure to activate reperfusion injury salvage kinase pathway.

BACKGROUND: We investigated the cardioprotective effects of isoflurane administered at the onset of reperfusion in senescent rat in vivo, and the activation of the reperfusion injury salvage kinase (RISK) pathway to address a possible mechanism underlying age-related differences. METHODS: Male Wistar rats were assigned to age groups (young, 3-5 months; old, 20-24 months), and randomly selected to receive isoflurane (1 minimum alveolar concentration) or not for 3 min before and 2 min after reperfusion (ISO postC). Rats were subjected to coronary occlusion for 30 min followed by 2 h of reperfusion. Western blot analysis was used to assess the phosphorylation of extracellular signal-regulated kinase (ERK1/2), Akt, and GSK3ß 15 min after reperfusion. RESULTS: Brief administration of isoflurane 3 min before and 2 min after the initiation of early reperfusion reduced infarct size (56 ± 8% of left ventricular area at risk, mean ± standard deviation) compared with controls (68 ± 4%) in young rats, but had no effect in old rats (56 ± 8% in ISO postC and 56 ± 10% in control, respectively). Phosphorylation of ERK1/2, Akt, and GSK3ß were increased in the young ISO postC group but not in the old ISO postC group compared with control groups of the respective ages. CONCLUSIONS: We demonstrated that isoflurane post-conditions the heart in young but not in senescent rats. Failure to activate RISK pathway may contribute to attenuation of isoflurane-induced post-conditioning effect in senescent rats.

Titrated propofol induction vs. continuous infusion in children undergoing magnetic resonance imaging.

BACKGROUND: Propofol is the popular intravenous (i.v.) anaesthetic for paediatric sedation because of its rapid onset and recovery. We compared the efficacy and safety of a single dose and conventional infusion of propofol for sedation in children who underwent magnetic resonance imaging (MRI). METHODS: This was a double-blind, randomized-controlled study. One hundred and sixty children were assigned to group I (single dose) or II (infusion). Sedation was induced with i.v. propofol 2 mg/kg, and supplemental doses of propofol 0.5 mg/kg were administered until adequate sedation was achieved. After the induction of sedation, we treated patients with a continuous infusion of normal saline at a rate of 0.3 ml/kg/h in group I and the same volume of propofol in group II. In case of inadequate sedation, additional propofol 0.5 mg/kg was administered and the infusion rate was increased by 0.05 ml/kg/h. Induction time, sedation time, recovery time, additional sedation and adverse events were recorded. RESULTS: Recovery time was significantly shorter in group I compared with group II [0 (0-3) vs. 1 (0-3), respectively, P<0.001]. Group I (single dose) had significantly more patients with recovery time 0 compared with group II (infusion) (65/80 vs. 36/80, respectively, P<0.001). Induction and sedation times were not significantly different between groups. There was no significant difference in the frequency of additional sedation and adverse events between groups. CONCLUSION: A single dose of propofol without a continuous infusion can provide appropriate sedation in children undergoing MRI for <30 min.

The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy.

OBJECTIVE: To determine if adding etanercept (ETN) to methotrexate (MTX) or MTX to ETN for 52 weeks in rheumatoid arthritis (RA) patients with moderate disease activity provides higher efficacy. METHODS: All patients (n = 227) received open-label ETN 25 mg subcutaneously twice-weekly and MTX orally up to 20 mg weekly for 52 weeks and had completed a 3-year study in which patients received MTX, ETN or combination therapy. Endpoints were based on Disease Activity Score (DAS) and European League Against Rheumatism (EULAR) responses. RESULTS: Patients previously receiving combination therapy (Combination group; n = 96) had a lower disease activity at baseline. The mean DAS for those previously receiving MTX (ETN-added group; n = 55) and previously receiving ETN (MTX-added group; n = 76) were in the moderate disease activity range at baseline; Combination patients had a low disease activity. The greatest increase in DAS remission rates from baseline to week 52 was in the ETN-added group (23.6% to 41.8%, p<0.01), although Combination (37.6% to 50.0%, p<0.01) and MTX-added (26.7% to 36.8%, p = NS) also demonstrated improvements. DAS low disease activity and EULAR responses showed similar results. No new safety issues were identified. CONCLUSION: RA patients who were partial responders to long-term MTX or etanercept monotherapy obtained a higher efficacy with combination therapy. Responses achieved by patients with combination therapy after 3 years in the previous study were sustained or improved during the fourth year of treatment. This trial supports the higher therapeutic effect of combination treatment with etanercept and MTX in RA patients with moderate disease activity despite monotherapy with one of the two agents.

Effects of fentanyl pretreatment on the QTc interval during propofol induction.

Prolongation of the corrected QT (QTc) interval is associated with various anaesthetic drugs. The QTc prolongation may become more exacerbated during laryngoscopy and intubation, which is possibly caused by sympathetic stimulation. The aim of this study was to investigate the effects of fentanyl on the QTc interval during propofol induction in healthy patients. The patients were randomly allocated to receive either fentanyl (n = 25) or saline (n = 25) before induction. The QTc interval was significantly prolonged immediately after intubation in control group compared to preceding values, but it did not change in the fentanyl group. The number of patients with the prolonged QTc interval exceeding 20 ms immediately after intubation compared to the baseline values was 14 in the control group and seven in the fentanyl group. In conclusion, pretreatment with fentanyl 2 microg x kg(-1) significantly attenuated QTc prolongation associated with laryngoscopy and tracheal intubation during propofol induction.

Patient experience in systemic lupus erythematosus: development of novel patient-reported symptom and patient-reported impact measures.

BACKGROUND: Comprehensive assessment of systemic lupus erythematosus (SLE) and its treatment requires patient-reported outcome (PRO) measures to capture impacts and fluctuating symptoms. The objective of this study was to develop PROs, in accordance with the Food and Drug Administration (FDA) PRO Guidance, to assess fluctuations in SLE symptoms and its impact. METHODS: Following independent review board approval, six US rheumatology practices recruited patients with SLE to participate in concept elicitation (CE) interviews, in order to identify important SLE symptoms and their impacts. The SLE Symptom Severity Diary (SSD) and SLE Impact Questionnaire (SIQ) were drafted based on CE interview results and clinician input. The PROs were revised based on patient feedback from cognitive debriefing (CD) interviews, clinician feedback, and a translatability assessment. RESULTS: Forty-one patients completed CE interviews. Commonly-reported symptoms included fatigue (98%), joint pain (93%), and rash (88%). The most frequently reported impact was difficulty with chores/housework (61%). Eighteen patients completed CD interviews. The PROs were considered comprehensive, clear, and relevant.The SSD contains 17 items assessing energy/vitality, joint and muscle pain/stiffness/swelling, flu-like symptoms, cognition, numbness/tingling, skin symptoms and hair loss using an 11-point numeric response scale and a 24-h recall period (with the exception of hair loss). It also evaluates steroid status and dose. The SIQ contains 50 items, uses a 5-point Likert scale and a 7-day recall period, to assess disease impacts including patients' ability to make plans, work, and physical/social/emotional functioning. CONCLUSION: The SSD and SIQ are comprehensive SLE-specific PROs developed in accordance with the FDA PRO Guidance. Following assessment of their measurement properties, they may be useful in clinical studies and clinical practice to measure fluctuations in, and the impact of, symptoms in patients with SLE.

Efficacy and safety of rofecoxib 12.5 mg and celecoxib 200 mg in two similarly designed osteoarthritis studies.

OBJECTIVE: To compare the lower osteoarthritis (OA) dose of rofecoxib to the recommended dose of celecoxib in two identically designed studies. METHODS: Patients with knee OA were randomized (2:2:1 ratio: rofecoxib 12.5 mg once daily (qd), celecoxib 200 mg qd, or placebo, respectively). The primary endpoint was patient global assessment of response to therapy (PGART) averaged over 6 weeks on a five-point scale. Rofecoxib would be declared at least as effective as celecoxib if the lower bound of the 95% confidence interval (95% CI) for difference in means was no lower than -0.5. Additional endpoints included Pain and Physical Function subscales of the Western Ontario and McMaster (WOMAC) OA Index. Adverse experiences (AEs) were recorded and combined from the two studies for analysis. RESULTS: Study 1 enrolled 395 patients (rofecoxib, n = 160; celecoxib, n = 157; placebo, n = 78). Study 2 enrolled 413 patients (rofecoxib, n = 159; celecoxib, n = 169; placebo, n = 85). Rofecoxib 12.5 mg was at least as effective as celecoxib 200 mg by PGART (Study 1 difference -0.09 [95% CI: -0.32, 0.14] and Study 2 difference 0.02 [95% CI: -0.20, 0.24]), and both were significantly (p < 0.001) more effective than placebo. Comparable efficacy was also seen for WOMAC Pain and Physical Function subscales with the active treatments. There was a significantly higher (p < 0.05) incidence of serious AEs with celecoxib than rofecoxib or placebo, none of which was drug-related. There were no significant differences in the pre-specified measurements of safety including drug-related AEs or discontinuations due to AEs, and the medications demonstrated similar safety as assessed by spontaneous reporting. CONCLUSIONS: Rofecoxib 12.5 mg and celecoxib 200 mg provided comparable efficacy over 6 weeks, and both were significantly more efficacious than placebo. The medications demonstrated similar safety compared to one another and placebo. The primary limitations of these studies were that they were only 6 weeks long and were powered for efficacy. Therefore, conclusions about long-term safety cannot be inferred.

Response to belimumab among patients with systemic lupus erythematosus in clinical practice settings: 24-month results from the OBSErve study in the USA.

OBJECTIVE: To examine disease activity and clinical outcomes, and describe overall patterns of systemic lupus erythematosus (SLE) care in patients who received belimumab in a real-world clinical setting. METHODS: This observational cohort study was conducted in US clinical practices. Rheumatologists (n=92) identified adults with SLE who had received ≥8 infusions of belimumab plus standard of care (SoC). Physicians assessed disease outcomes at 6-month intervals using patient medical charts, for up to 24 months. The primary outcome was physician-assessed change in SLE disease. Other outcomes included change in steroid use, laboratory tests and healthcare resource utilisation (HCRU). RESULTS: Of 501 patients (intent-to-treat population (ITT)), 446 were female, mean age was 43.3 years and 98% had moderate/severe disease activity at baseline (first dose of belimumab). Data for 277 patients who completed 24 months of belimumab treatment were available. Among the ITT, a ≥50% improvement in overall clinical response between baseline and month 6 was reported for 48.7% of patients; continued improvement was seen at all subsequent 6-month intervals relative to the previous timepoint. The percentage of patients with moderate/severe disease also decreased at each timepoint. At baseline, 77.0% of patients received steroids at a mean (SD) prednisone equivalent dose of 19.9 (14.39) mg/day, which decreased to 8.4 (7.35) mg/day at month 6 and 6.1 (9.31) mg/day at month 24. Abnormal laboratory values typically associated with SLE also demonstrated improvements at month 6, which continued through 24 months. HCRU decreased over the duration of the study. CONCLUSIONS: Patients with SLE who received belimumab plus SoC for up to 24 months demonstrated improvements in disease severity and laboratory values and a reduction in steroid use and HCRU as early as month 6. Improvements continued through 24 months, providing evidence of reduced disease activity among patients taking belimumab in real-world clinical practice.

CCAAT/enhancer binding protein expression is rapidly extinguished in TA1 adipocyte cells treated with tumor necrosis factor.

Tumor necrosis factor (TNF) has been shown to have diverse effects on a wide variety of cell types. In the mouse adipogenic TA1 cell line, TNF completely abolishes differentiation and reverts fully differentiated fat cells into fibroblasts. This block in differentiation and its reversal is due to the rapid reduction in the expression of adipose-specific genes. This study reports that the transcription factor, CCAAT/enhancer binding protein (C/EBP), previously reported to promote the differentiation of 3T3-L1 adipocytes, is expressed in TA1 cells. During their growth in culture, the levels of C/EBP, as evidenced by its cellular levels of specific mRNA, protein, and DNA binding activity, increase dramatically when cells reach confluence and proceed to differentiate. Addition of TNF to cultured preadipocytes or fully differentiated adipocytes rapidly reduces C/EBP levels and is accompanied by the decrease in expression of adipose-specific genes. C/EBP binding sites occur in several adipose-specific genes, and here it is demonstrated that its presence in a novel adipose-specific gene, Clone 47, also referred to as FSP27, may be responsible for the strong down-regulation of the expression of the Clone 47 (FSP27) promoter-linked chloramphenicol acetyl transferase gene by TNF. This study proposes that the loss of C/EBP in response to TNF treatment may in part explain the loss of the adipocyte differentiated state.

Randomised clinical trial: vercirnon, an oral CCR9 antagonist, vs. placebo as induction therapy in active Crohn's disease.

BACKGROUND: Many patients with active Crohn's disease do not adequately respond to therapies, highlighting the need for new treatments. AIMS: To conduct a randomised, double-blind, placebo-controlled phase 3 study to assess the efficacy and safety of vercirnon, an oral inhibitor of CC chemokine receptor-9, for the treatment of patients with moderately-to-severely active Crohn's disease. METHODS: Patients with a Crohn's Disease Activity Index (CDAI) of 220-450, plus evidence of active disease (endoscopically confirmed or elevation of both C-reactive protein and faecal calprotectin), who had failed corticosteroid or immunosuppressant therapy were enrolled. Patients were equally randomised to receive placebo, vercirnon 500 mg once daily or vercirnon 500 mg twice daily. The primary endpoint was clinical response, defined as a 100-point decrease in CDAI from baseline to week 12. RESULTS: Six hundred and eight patients were randomised. Patient characteristics and baseline demographics were similar among the groups. The proportions of patients achieving a clinical response were 25.1%, 27.6% and 27.2% for placebo, once daily and twice daily respectively; treatment differences were not significant (2.5%; 95% confidence interval, CI -6.1% to 11.0%, P = 0.546 for once daily vs. placebo, and 2.1%; 95% CI -6.5% to 10.7%, P = 0.648 for twice daily vs. placebo). Adverse events were reported in 69.8%, 73.3% and 78.1% with serious adverse events in 8.9%, 5.9%, and 6.0% of patients in the placebo, once-daily and twice-daily groups, respectively. CONCLUSIONS: We did not demonstrate efficacy of vercirnon as an induction therapy in patients with moderately-to-severely active Crohn's disease; its effect in maintenance therapy was not addressed.

Molecular cloning, genomic characterization and expression of novel human alpha1A-adrenoceptor isoforms.

We have isolated and characterized from human prostate novel splice variants of the human alpha1A-adrenoceptor, several of which generate truncated products and one isoform, alpha(1A-4), which has the identical splice site as the three previously described isoforms. Long-PCR on human genomic DNA showed that the alpha(1A-4) exon is located between those encoding the alpha(1A-1) and alpha(1A-3) variants. CHO-K1 cells stably expressing alpha(1A-4) showed ligand binding properties similar to those of the other functional isoforms as well as agonist-stimulated inositol phosphate accumulation. Quantitative PCR analyses revealed that alpha(1A-4) is the most abundant isoform expressed in the prostate with high levels also detected in liver and heart.

Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7b).

1. The rat 5-hydroxytryptamine (5-HT)7 receptor displays two splice variations, a long form, and a truncated splice isoform, arising from the introduction of a stop codon near the carboxy-terminus. The human-5HT7 receptor gene contains at least two introns and encodes a 445 amino acid 5-HT receptor. 2. A truncated splice variation in the human 5-HT7 receptor was isolated from a human placental cDNA library. In accordance with current NC-IUPHAR nomenclature guidelines, it is suggested that this receptor be donated as the h5-HT7b receptor and the long form of the receptor as h5-HT7a. 3. The h5-HT7b receptor was stably expressed in HEK 293 cells and ligand affinities were determined by displacement of [3H]-5-carboxyamidotryptamine (5-CT; Kd = 0.28 +/- 0.6 nM, Bmax = 7.3 +/- 17 pmol mg-1 protein). The rank order of affinities (pKi) for a series of ligands was: 5-carboxamidotryptamine (5-CT, 9.65) > 5-hydroxytryptamine (5-HT, 9.41) > methiothepin (8.87) > mesulergine (7.87) > 8-hydroxy-2 (di-n-propylamino)tetralin (8-OH-DPAT, 6.85) > ketanserin (6.44). 4. The h5-HT7b receptor coupled positively to adenylyl cyclase in HEK 293 cells. This response was elicited by a number of agonists with the following order of potency (pEC50): 5-CT (8.7 +/- 0.11) > 5-MeOT (5-methoxytryptamine; 8.1 +/- 0.20) > 5-HT (7.5 +/- 0.13) tryptamine (5.6 +/- 0.36) > 8-OH-DPAT (5.3 +/- 0.28) > 5-methoxytryptamine (5.0 +/- 0.06). This rank order was comparable to that observed in the radioligand binding studies. 5. In a similar fashion to that described for the 5-HT7a receptor, PCR studies suggested that the 5-HT7b receptor mRNA is found in great abundance throughout the brain, in the small intestine and aorta. 6. It is concluded that the h5-HT7 receptor, like the rat receptor, exists as splice variants exhibiting similar pharmacology, signal transduction and distribution. It is thus likely that there exists a complex physiological role for alternate splicing products of the 5-HT7 receptor gene.

Pharmacological pleiotropism of the human recombinant alpha1A-adrenoceptor: implications for alpha1-adrenoceptor classification.

1. Three fully-defined alpha1-adrenoceptors (alpha1A, alpha1B and alpha1D) have been established in pharmacological and molecular studies. A fourth alpha1-adrenoceptor, the putative alpha1L-adrenoceptor, has been defined in functional but not molecular studies, and has been proposed to mediate contraction of human lower urinary tract tissues; its relationship to the three fully characterized alpha1-adrenoceptors is not known. 2. In the present study, binding affinities were estimated by displacement of [3H]-prazosin in membrane homogenates of Chinese hamster ovary (CHO-K1) cells stably expressing the human alpha1A-, alpha1B- and alpha1D-adrenoceptors and were compared with affinity estimates obtained functionally in identical cells by measuring inhibition of noradrenaline (NA)-stimulated accumulation of [3H]-inositol phosphates. 3. For the alpha1A-adrenoceptor, binding studies revealed a pharmacological profile typical for the classically defined alpha1A-adrenoceptor, such that prazosin, RS-17053, WB 4101, 5-methylurapidil, Rec 15/2739 and S-niguldipine all displayed subnanomolar affinity. A different profile of affinity estimates was obtained in inositol phosphates accumulation studies: prazosin, WB 4101, 5-methylurapidil, RS-17053 and S-niguldipine showed 10 to 40 fold lower affinity than in membrane binding. However, affinity estimates were not 'frameshifted', as tamsulosin, indoramin and Rec 15/2739 yielded similar, high affinity estimates in binding and functional assays. 4. In contrast, results from human alpha1B- and alpha1D-adrenoceptors expressed in CHO-K1 cells gave antagonist affinity profiles in binding and functional assays that were essentially identical. 5. A concordance of affinity estimates from the functional (inositol phosphates accumulation) studies of the alpha1A-adrenoceptor in CHO-K1 cells was found with estimates published recently from contractile studies in human lower urinary tract tissues (putative alpha1L-adrenoceptor). These data show that upon functional pharmacological analysis, the cloned alpha1A-adrenoceptor displays pharmacological recognition properties consistent with those of the putative alpha1L-adrenoceptor. Why this profile differs from that obtained in membrane binding, and whether it explains the alpha1L-adrenoceptor pharmacology observed in many native tissues, requires further investigation.

Dapsone in rheumatoid arthritis.

Dapsone, a synthetic sulfone with chemical similarities to sulfapyridine, has been used for a number of years to treat leprosy and dermatitis herpetiformis. Recently, a number of prospective, randomized, double-blind trials have shown their success in the management of rheumatoid arthritis, with dapsone being superior to placebo and comparable to chloroquine and hydroxychloroquine. Its mode of anti-inflammatory actions in rheumatoid arthritis is not clearly understood, but modulation of neutrophil activity or inhibition of neutrophil inflammatory product formation or release appear to play a role. The major limiting side effect is hemolytic anemia, which may be mitigated through careful patient selection, conservative drug dosing, close monitoring, and possibly, concurrent administration of antioxidants or cytochrome P450 inhibitors. Methemoglobinemia is another common finding among patients receiving dapsone therapy, but rarely does it result in prominent symptoms other than transient pallor. Less common adverse events to dapsone include the idiosyncratic reactions of leukopenia and agranulocytosis, cutaneous eruptions, peripheral neuropathy, psychosis, toxic hepatitis, cholestatic jaundice, nephrotic syndrome, renal papillary necrosis, severe hypoalbuminemia without proteinuria, an infectious mononucleosis-like syndrome, and minor neurological and gastrointestinal complaints. In this report, two patients with advanced rheumatoid arthritis, who were safely and effectively treated with dapsone after failure with other second-line agents, are described and the literature is reviewed. We suggest that dapsone is an effective second-line agent in the treatment of rheumatoid arthritis.

Neurologic complications of rheumatoid arthritis.

Neurologic complications are common extraarticular manifestations of RA, involving both the peripheral and central nervous systems. Because RA patients suffer from pain, stiffness, and weakness, the detection of neurologic impairment is often difficult. Thus, close vigilance and thoughtful use of various diagnostic methods will help in the early diagnosis of cervical spine involvement, compression neuropathies, peripheral neuropathies, myopathies, and central nervous system involvement. Prompt and timely interventions may prevent permanent neurologic sequelae.

Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial.

BACKGROUND: In recent studies of acute pain and primary dysmenorrhea, rofecoxib, a nonsteroidal anti-inflammatory drug that selectively targets the cyclooxygenase-2 enzyme, was found to be similar in efficacy to ibuprofen and naproxen sodium. OBJECTIVE: The purpose of this study was to determine the analgesic efficacy of a single oral dose of rofecoxib 50 mg compared with the combination of codeine 60 mg/acetaminophen 600 mg in a model of postsurgical dental pain. METHODS: In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate or severe pain after the surgical extraction of > or = 2 third molars, at least 1 of which was a mandibular impaction, were randomized to receive placebo, rofecoxib 50 mg, or codeine 60 mg/acetaminophen 600 mg. Patient evaluations of pain intensity, pain relief, and global assessments were recorded throughout the 24-hour period after dosing. The 2-stopwatch method was used to determine time to confirmed perceptible pain relief. The primary end point assessing overall analgesic effect was total pain relief over 6 hours (TOPAR6). Secondary end points were patient global assessment of response to therapy (PGART) at 6 hours, onset of analgesia, peak analgesic effect, and duration of analgesia. RESULTS: A total of 393 patients were enrolled; 182 received rofecoxib, 180 received codeine/acetaminophen, and 31 received placebo. The overall analgesic effect of rofecoxib 50 mg was greater than that of codeine 60 mg/acetaminophen 600 mg for TOPAR6 (12.4 vs 7.0; P < 0.001) and PGART at 6 hours (P < 0.001). The onset of analgesic effect was similar for rofecoxib and codeine/acetaminophen. Peak analgesic effect as measured by peak pain relief scores during the first 6 hours was significantly greater in the rofecoxib group compared with the codeine/acetaminophen group (P < 0.001), as was the duration of analgesic effect measured by the time to rescue analgesia (9.6 hours vs 2.3 hours, P < 0.001). Adverse events were reported in 33.0%, 46.1%, and 32.3% of patients treated with rofecoxib, codeine/acetaminophen, and placebo, respectively. The most common adverse events were nausea (6.0%, 25.0%, and 9.7%, respectively) and vomiting (3.8%, 18.3%, and 6.5%, respectively). Significantly more patients in the codeine/acetaminophen group than in the rofecoxib group experienced adverse events overall (P < 0.050) and nausea in particular (P < 0.001). CONCLUSION: In this study of moderate to severe postoperative dental pain, the analgesic efficacy of rofecoxib 50 mg was greater than that of codeine/acetaminophen, with a lower incidence of adverse events and nausea.

Human cloned alpha1A-adrenoceptor isoforms display alpha1L-adrenoceptor pharmacology in functional studies.

The recombinant alpha1A-adrenoceptor displays a distinct pharmacological profile ('classical alpha1A-adrenoceptor') in homogenate binding assays, but displays the properties of the so-called alpha1L-adrenoceptor in functional studies in whole cells at 37 degrees C. As three splice variants of the human alpha1A-adrenoceptor have been described previously (alpha1A-1, alpha1A-2 and alpha1A-3), we have compared their functional pharmacological profiles, when expressed stably in Chinese hamster ovary (CHO-K1) cells (antagonist inhibition of noradrenaline-stimulated [3H]inositol phosphates accumulation). A fourth, novel isoform (alpha1A-4) has also been studied: alpha1A-4 mRNA predominates in several human tissues including prostate, liver, heart and bladder. In homogenate binding studies, all four isoforms displayed essentially identical affinity profiles, with prazosin (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl)piperazine), tamsulosin (5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2-methoxybenzen esulfonamide), RS-17053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alphad imethyl-1H-indole-3-ethanamine hydrochloride), WB 4101 ((2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride) and 5-Me-urapidil (5-methyl-6[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]amino]-1,3-d imethyuracil) all displaying subnanomolar affinities. In functional studies, noradrenaline accelerated [3H]inositol phosphates production with potencies (p[A]50) of between 5.8 and 6.6. The affinities of prazosin, RS-17053, WB 4101 and 5-Me-urapidil, at antagonizing responses to noradrenaline, were reduced by approximately 10-fold (cf. binding data), while those for tamsulosin and indoramin (N-[1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]benzamide) remained constant or increased, consistent with the previously described alpha1L-adrenoceptor. Thus, all four human recombinant alpha1A-adrenoceptor isoforms display the pharmacology of the alpha1L-adrenoceptor when studied in functional assays, consistent with the hypothesis that the putative alpha1L-adrenoceptor represents a functional phenotype of the alpha1A-adrenoceptor.

Early passive mobilization after digital nerve repair and grafting in a fresh cadaver.

In the clinical management of combined tendon and nerve injuries, there are competing treatment strategies. Isolated tendon injuries should be rapidly mobilized after repair to prevent adhesion formation, whereas isolated nerve repairs are usually immobilized to prevent disruption and to allow axon regrowth. Recommendations in the published literature for the management of combined tendon and nerve injuries are vague and advise up to 3 weeks of immobilization. The goals of this study were to determine which length of nerve gap resulted in rupture of a repair following postoperative mobilization with the modified Duran protocol and with unrestricted motion and to determine whether nerve grafts are at risk of rupture after mobilization. A total of 100 digital nerves from 10 cadaver hands were tested with the modified Duran and the unsplinted protocols. Each digital nerve on each hand was sequentially resected and repaired at five progressively larger gap lengths after testing with both protocols. The mean nerve gaps at which disruption occurred were significantly different between the splinted (9.7 +/- 0.8 mm, n = 100) and unsplinted (7.3 +/- 1.9 mm, n = 100) protocols (t test, p < 0.001). One hundred percent of repairs remained intact, with up to 5 mm of resection with the modified Duran protocol (n = 100) and with up to 2.5 mm of resection with the unsplinted protocol (n = 100). All nerve grafts remained intact after mobilization within a dorsal-blocking splint (n = 100). Considering mechanical integrity of the nerve repair only, these data suggest that early mobilization with tendon protocols may be considered after a nerve injury to avoid the detrimental tendon sequelae that result from immobilization. The adequacy of functional recovery of mobilized nerves is yet to be determined.

Combined Fenton-MF process increases acrylonitrile removal.

The Fenton oxidation process is possessed of the advantages of both oxidation and coagulation processes. In addition to these functions, Fenton's reagent is also a typical initiator of polymerization. The application of the Fenton-microfiltration process for removal of acrylonitrile (AN), which is the major raw material for manufacturing ABS reins, was investigated. As for Fenton oxidation, in the range of pH 2 to pH 4, AN removal efficiency increased as the pH increased. In experiment of the same initial molar ratio of [FeSO4]0/[H2O2]0, the higher dosage can obtain the higher removal efficiency. At pH 4, the AN removal increased as the [H2O2]0 increased for each [FeSO4]0. Acrylic acid and acrylamide were detected in the solution after Fenton oxidation. On the other hand, acrylamide, polyacrylamide, and polyacrylic acid exist in the precipitate after the Fenton oxidation of AN solution. Moreover, it was also found that the operational mode is an important factor of the combined Fenton-MF process.