Long-term outcome of a prospective randomized trial of conversion from cyclosporine to azathioprine treatment one year after renal transplantation

BACKGROUND: Since the introduction of cyclosporine (CsA), 1-year renal allograft survival has improved, but concern persists about the long-term adverse effects of CsA, especially with respect to renal function and blood pressure. This randomized controlled trial was set up to establish whether withdrawal of CsA would alter long-term outcome. METHODS: Adult patients who, at 1 year after renal transplantation, had a stable serum creatinine of less than 300 micromol/L and who had not had acute rejection within the last 6 months were eligible for entry. Patients were randomized either to continue on CsA (n=114) or to stop CsA and start azathioprine (Aza, n=102). All patients remained on prednisolone. Median follow-up was 93 months after transplantation (range: 52-133 months). RESULTS: There was no significant difference in actuarial 10-year patient or graft survival (Kaplan-Meier), despite an increased incidence of acute rejection within the first few months after conversion. Median serum creatinine was lower in the Aza group (Aza: 119 micromol/L; CsA. 153 micromol/L at 5 years after randomization, P=0.0002). The requirement for antihypertensive treatment was also reduced after conversion to Aza; 75% of patients required antihypertensive treatment at the start of the study, decreasing to 55% from 1 year after randomization in the Aza group and increasing to >80% in the CsA group (55% (Aza) and 84% (CsA) at 5 years after randomization, P<0.005). CONCLUSIONS: Conversion from CsA to Aza at 1 year after renal transplantation results in improvement in both blood pressure control and renal allograft function, and is not associated with significant adverse effects on long-term patient or graft survival.     

Topical gentamicin and ethacrynic acid: effects on cochlear function

OBJECTIVE: To determine whether concurrent intravenous administration of the loop diuretic ethacrynic acid potentiates the toxicity of the aminoglycoside antibiotic gentamicin applied topically on the round window. STUDY DESIGN: The authors studied the effects on cochlear sensitivity of co-administered intracardiac ethacrynic acid (40 mg/kg) and high-dose topical gentamicin solution (100%) applied to the round window. Comparisons were made with animals receiving ethacrynic acid plus systemic gentamicin (100 mg/kg); topical gentamicin alone; systemic gentamicin alone; and intravenous ethacrynic acid alone. METHODS: Experiments were carried out on pigmented guinea pigs weighing 400 to 500 g. Changes in cochlear function were characterized by monitoring shifts in compound action potential (CAP) thresholds by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. RESULTS: After 20 days animals receiving ethacrynic acid in combination with topical gentamicin to the round window failed to demonstrate a significant deterioration in cochlear sensitivity, whereas all animals receiving systemic gentamicin plus ethacrynic acid experienced profound increases in CAP thresholds. CONCLUSIONS: This study supports the contention that ethacrynic acid potentiates aminoglycoside ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph. In addition, this study answers important clinical concerns regarding the safety of the use of topical aminoglycoside agents in combination with loop diuretics.     

Antisense inhibition of striatal GABAA receptor proteins decreases GABA-stimulated chloride uptake and increases cocaine sensitivity in rats

The functional status of striatal GABAA receptors appears to be inversely related to the magnitude of cocaine-induced behaviors. Exposure of striatum to antisense oligodeoxynucleotides (ASODNs) targeted to the mRNAs for the alpha 2 and the beta 3 subunits of the GABAA receptor should decrease expression of receptor proteins and therefore might be expected to increase cocaine sensitivity. ASODNs, scrambled ODNs or saline were injected into right lateral ventricle of rats and behavioral responses to cocaine were tested 18-20 h after treatment. Animals injected separately with alpha 2 or beta 3 ASODNs exhibited increased behavioral sensitivity to cocaine compared to rats injected with saline or scrambled ODNs including performing more 360 degrees turns to the left than to the right. There was significantly less GABA-stimulated Cl uptake in right striatum compared to left striatum of ASODN-treated rats with no significant difference between sides in control animals. Specific binding to benzodiazepine and convulsant sites on the GABAA receptor was not selectively altered by ASODN treatment. Combined alpha 2 beta 3 ASODN treatment did not affect either cocaine sensitivity or GABAA receptor function. There was no difference between the density of Nissl stained cells in the left and right edges of striatum in control or ASODN-treated rats indicating the absence of significant neurotoxic effects of the ASODN treatment. Injection of fluorescein-conjugated ASODNs indicated that ASODN is present in striatum at times during which behavioral and neurochemical indices of GABA receptor function are decreased. Thus, the functional status of GABAA receptors in striatum may be involved in determining cocaine sensitivity.     

The use of controlled-release oxycodone for the treatment of chronic cancer pain: a randomized, double-blind study

1. We have studied the effects of muscarinic cholinoceptor agonists and subtype-preferring antagonists on the isometric contraction of smooth muscle strips from dog prostate. 2. Acetylcholine and carbachol induced contraction of prostate strips from the peripheral zone, ('the capsule'). Bethanechol contracted the tissue but not at lower doses. McN-A-343 and oxotremorine-M showed the same effects. 3. Blocking alpha- and beta-adrenoceptors with phentolamine and propranolol, respectively, did not modify carbachol-induced contractions. 4. The nicotinic receptor blocker, hexamethonium (10(-6)-10(-4) M) did not affect the contractile response evoked by a single dose of carbachol (10(-5) M), whilst the muscarinic receptor antagonist, atropine (10(-11)-10(-9) M), inhibited it in a competitive manner. 5. The muscarinic M1 (pirenzepine), M2 [AF-DX 116, himbacine (M2/M4) and methoctramine], M3 (HHSID and f-F-HHSID), and putative M4 (tropicamide) antagonists reduced significantly the carbachol-induced contractions. The pIC50 values were: atropine (10.01) > himbacine (8.3) > methoctramine (7.85) > AF-DX 116 (7.60) > HHSID (7.21) > p-F-HHSID (7.10) > pirenzepine (7.30) > tropicamide (7.00). 6. The antagonist profile indicates that an predominant M2 receptor subtype could mediate the muscarinic contraction in the canine prostate.     

The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis

OBJECTIVE: To determine whether sulfasalazine is better than placebo in slowing disability progression in MS. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 199 patients with active relapsing-remitting (n = 151) or progressive (n = 48) MS were evaluated at 3-month intervals for a minimum of 3 years (94% completed 3 years of follow-up; mean follow-up, 3.7 years). MRI studies were performed at 6-month intervals on a subset of 89 patients. RESULTS: Sulfasalazine failed to slow or prevent disability progression as measured by the primary outcome (confirmed worsening of the Expanded Disability Status Scale [EDSS] score by at least 1.0 point on two consecutive 3-month visits). Sulfasalazine influenced favorably a number of secondary outcomes during the first 18 months of the trial (e.g., annualized relapse rate, proportion of relapse-free patients; progressive subgroup only: rate of EDSS progression at 1 and 2 years, median time to EDSS progression) but these positive findings were not sustained into the second half of the trial. CONCLUSIONS: Sulfasalazine does not prevent EDSS score progression in the subset of MS patients studied by this protocol. Treatments may improve relapse-related outcomes in MS, at least temporarily, without providing sustained slowing of EDSS progression. Phase III MS trials should be of sufficient length to determine a meaningful impact on disease course.     

Complete physical map of the common deletion region in Williams syndrome and identification and characterization of three novel genes

Williams syndrome (WS) is a contiguous gene deletion disorder caused by haploinsufficiency of genes at 7q11.23. We have shown that hemizygosity of elastin is responsible for one feature of WS, supravalvular aortic stenosis (SVAS). We have also implicated LIM-kinase 1 hemizygosity as a contributing factor to impaired visual-spatial constructive cognition in WS. However, the common WS deletion region has not been completely characterized, and genes for additional features of WS, including mental retardation, infantile hypercalcemia, and unique personality profile, are yet to be discovered. Here, we present a physical map encompassing 1.5 Mb DNA that is commonly deleted in individuals with WS. Fluorescence in situ hybridization analysis of 200 WS individuals shows that WS individuals have the consistent deletion interval. In addition, we identify three novel genes from the common deletion region: WS-betaTRP, WS-bHLH, and BCL7B. WS-betaTRP has four putative beta-transducin (WD40) repeats, and WS-bHLH is a novel basic helix-loop-helix leucine zipper (bHLHZip) gene. BCL7B belongs to a novel family of highly conserved genes. We describe the expression profile and genomic structure for each of these genes. Hemizygous deletion of one or more of these genes may contribute to developmental defects in WS.     

The syntaxin Tlg1p mediates trafficking of chitin synthase III to polarized growth sites in yeast

Tlg1p and Tlg2p, members of the syntaxin family of SNAREs in yeast, have been implicated in both endocytosis and the retention of late Golgi markers. We have investigated the functions of these and the other endocytic syntaxins Pep12p and Vam3p. Remarkably, growth is possible in the absence of all four proteins. In the absence of the others, Pep12p and Tlg1p can each create endosomes accessible to the endocytic tracer dye FM4-64. However, although Pep12p is required for the ligand-induced internalization of the alpha factor receptor and its passage via Pep12p-containing membranes to the vacuole, Tlg1p is not. In contrast, Tlg1p is required for the efficient localization of the catalytic subunit of chitin synthase III (Chs3p) to the bud neck, a process that involves endocytosis and polarized delivery of Chs3p. In wild-type cells, internalized Chs3p cofractionates with Tlg1p and Tlg2p, and in a strain lacking the other endocytic syntaxins, either Tlg1p or Tlg2p is sufficient for correct localization of the enzyme. Pep12p is neither necessary nor sufficient for this process. We conclude that there are two endocytic routes in yeast that can operate independently and that Tlg1p is located at the junction of one of these with the polarized exocytic pathway.     

Pharmacokinetics and pharmacodynamics of sibrafiban (Ro 48-3657), an orally active IIb/IIIa antagonist, administered alone or in combination with heparin, aspirin, and recombinant tissue-type plasminogen activator in beagles

OBJECTIVE: The study aimed to determine the effectiveness of prophylactic medical intervention in reducing the incidence of cystoid macular edema (CME) and the effectiveness of medical treatment for chronic CME after cataract surgery. DESIGN: The study design was a systematic review and meta-analysis of published reports of randomized clinical trials (RCTs). PARTICIPANTS: Sixteen RCTs involving 2898 eyes examining the effectiveness of medical prophylaxis of CME and 4 RCTs involving 187 eyes testing the effectiveness of medical treatment of chronic CME were used in the study. INTERVENTIONS: Medical prophylaxis of treatment (cyclo-oxygenase inhibitors or corticosteroids) versus control (placebo or active treatment) was performed. MAIN OUTCOME MEASURES: Incidence of angiographically diagnosed CME, incidence of clinically significant CME, and vision were measured. RESULTS: Thirty-six articles reported testing a prophylactic medical intervention for CME after cataract surgery. The incidence of CME varied extensively across studies and was related to the study design used. Summary odds ratios (OR) indicated that prophylactic intervention was effective in reducing the incidence of both angiographic CME (OR = 0.36; 95% confidence interval [CI] = 0.28-0.45) and clinically relevant CME (OR = 0.49; 95% CI = 0.33-0.73). There also was a statistically significant positive effect on improving vision (OR = 1.97; 95% CI = 1.14-3.41). A combination of the results of the four RCTs testing medical therapy for chronic CME indicated a treatment benefit in terms of improving final visual acuity by two or more Snellen lines (OR = 2.67; 95% CI = 1.35-5.30). Assessment of the quality of the 20 RCTs included in the meta-analyses indicated problems in the design, execution, and reporting of a number of trials. CONCLUSION: A combination of the results from RCTs indicates that medical prophylaxis for aphakic and pseudophakic CME and medical treatment for chronic CME are beneficial. Because most of the RCTs performed to date have problems related to quality, a well-designed RCT is needed to confirm this result, using clinical CME and vision as outcomes.