A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation.

A previous nonblinded, randomized, single-center renal transplantation trial of single-dose rabbit anti-thymocyte globulin induction (SD-rATG) showed improved efficacy compared with conventional divided-dose (DD-rATG) administration. The present multicenter, double-blind/double-dummy STAT trial (Single dose vs. Traditional Administration of Thymoglobulin) evaluated SD-rATG versus DD-rATG induction for noninferiority in early (7-day) safety and tolerability. Ninety-five patients (randomized 1:1) received 6 mg/kg SD-rATG or 1.5 mg/kg/dose DD-rATG, with tacrolimus-mycophenolate maintenance immunosuppression. The primary end point was a composite of fever, hypoxia, hypotension, cardiac complications, and delayed graft function. Secondary end points included 12-month patient survival, graft survival, and rejection. Target enrollment was 165 patients with an interim analysis scheduled after 80 patients. Interim analysis showed primary end point noninferiority of SD-rATG induction (p = 0.6), and a conditional probability of <1.73% of continued enrollment producing a significant difference (futility analysis), leading to early trial termination. Final analysis (95 patients) showed no differences in occurrence of primary end point events (p = 0.58) or patients with no, one, or more than one event (p = 0.81), or rejection, graft, or patient survival (p = 0.78, 0.47, and 0.35, respectively). In this rigorously blinded trial in adult renal transplantation, we have shown SD-rATG induction to be noninferior to DD-rATG induction in early tolerability and equivalent in 12-month safety. (Clinical Trials.gov #NCT00906204.).

Brachial artery low-flow-mediated constriction is increased early after coronary intervention and reduces during recovery after acute coronary syndrome: characterization of a recently described index of vascular function.

AIMS: The endothelium plays a role in regulating vascular tone. Acute and dynamic changes in low-flow-mediated constriction (L-FMC) and how it changes with regard to traditional flow-mediated dilatation (FMD) have not been described. We aimed to investigate the changes in brachial artery L-FMC following percutaneous coronary intervention (PCI) and during recovery from non-ST-segment elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: FMD was performed in accordance with a previously described technique in patients before and after PCI and in the recovery phase of NSTEMI, but in addition, L-FMC data were acquired from the last 30 s of cuff inflation. About 135 scans were performed in 96 participants (10 healthy volunteers and 86 patients). Measurement of brachial L-FMC was reproducible over hours. L-FMC was greater among patients with unstable vs. stable coronary atherosclerosis (-1.33 ±1.09% vs. -0.03 ± 1.26%, P < 0.01). Following PCI, FMD reduced (4.43 ± 2.93% vs. 1.66 ± 2.16%, P < 0.01) and L-FMC increased (-0.33 ± 0.76% vs. -1.63 ± 1.15%, P = 0.02). Furthermore, during convalescence from NSTEMI, L-FMC reduced (-1.37 ± 1.19% vs. 0.01 ± 0.82%, P = 0.02) in parallel with improvements in FMD (2.54 ± 2.19% vs. 5.15 ± 3.07%, P < 0.01). CONCLUSION: Brachial L-FMC can be measured reliably. Differences were observed between patients with stable and unstable coronary disease. L-FMC was acutely increased following PCI associated with reduced FMD and, in the recovery from NSTEMI, L-FMC reduced associated with increased FMD. These novel findings characterize acute and subacute variations in brachial L-FMC. The pathophysiological and clinical implications of these observations require further study.

Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period.

New onset diabetes after transplantation (NODAT) and impaired fasting glucose (IFG) are common in kidney transplant recipients (KTRs). Calcinuerin inhibitor (CNI) therapy is a causal risk factor. NODAT is associated with increased mortality and diminished graft survival. We studied the incidence of NODAT and IFG in KTRs before and after a medically indicated switch of CNI therapy from cyclosporine (CsA) to tacrolimus (Tac). The study population consisted of 704 nondiabetic KTRs. Of them, 171 underwent conversion from CsA to Tac (group I) and 533 remained on the CsA since transplantation (Group II). Time-dependent Cox regression and generalized estimating equations were used to account for sequential CNI exposure. NODAT and IFG occurred in 15.2% and 22.1% of group I subjects and 15.6% and 25.8% of group II subjects, respectively (p = 0.90 for NODAT and p = 0.38 for IFG). Accounting for equal follow-up time since conversion from CsA to Tac, the adjusted 5-year NODAT-free survival was 87.4% and 91.4% in group I and group II, respectively (p = 0.90). In conclusion, conversion to Tac, compared to continuous exposure to CsA, carries quantitatively similar risk of impaired glucose metabolism in KTRs in the late posttransplant period.

Severe Hyperkalemia Complicating Voriconazole Treatment in a Kidney Transplant Recipient With Histoplasmosis: A Case Report.

Voriconazole is an antifungal agent that is commonly used in immunocompromised patients who develop fungal infections. We report a case of severe recurrent hyperkalemia that developed after starting voriconazole for the treatment of histoplasmosis in a kidney transplant patient who was maintained on tacrolimus-based immunosuppression. Hyperkalemia developed despite reducing the tacrolimus dose to maintain levels in a low therapeutic range. Although interactions between azoles and calcineurin inhibitors are widely recognized, this is the 1st report describing new-onset hyperkalemia following initiation of voriconazole in a kidney transplant patient receiving tacrolimus.

Ruptured sinus of Valsalva aneurysm presenting as ST-elevation myocardial infarction.

BACKGROUND: A 52-year-old man presented with central chest pain, which he had experienced for 8 h. He had no other associated symptoms and no prior history of cardiovascular disease. INVESTIGATIONS: Electrocardiography, chest radiography, coronary angiography, aortic angiography, echocardiography, CT thorax with contrast. DIAGNOSIS: Ruptured aneurysm of the sinus of Valsalva. MANAGEMENT: Emergency sternotomy and pericardiotomy, followed by aortic root replacement.

Mortality experience in recipients undergoing repeat transplantation with expanded criteria donor and non-ECD deceased-donor kidneys.

Nearly one-quarter of the kidney transplant waiting list is composed of repeat transplantation candidates. Survival following retransplantation using expanded criteria donor (ECD) kidneys has not been adequately studied. Using data from the Scientific Registry of Transplant Recipients, we analyzed mortality after retransplantation with ECD and non-ECD deceased-donor kidneys. Adult patients who experienced graft failure and were relisted for transplantation between 1995 and 2004 were studied (n=9641). Follow-up began at the date of relisting and continued until death or the end of the observation period (December 31, 2004), with censoring at living-donor transplantation. Sequential stratification (an extension of Cox regression) was used to compare mortality between patients receiving an ECD retransplant and those remaining on the waiting list or receiving a non-ECD retransplant (conventional therapy). Of 2908 retransplantations, 292 used ECD kidneys. Survival after ECD retransplantation was approximately equal to that of conventional therapy, with an adjusted hazard ratio of 0.98 (p=0.88). In contrast, non-ECD retransplant recipients experienced a significant reduction in mortality (HR=0.44; p<0.0001). Based on these national data, recipients of ECD retransplantation do not have a survival advantage relative to conventional therapy, whereas non-ECD retransplantation is associated with a significant survival advantage.

Percutaneous coronary intervention of a circumflex chronic total occlusion using an epicardial collateral retrograde approach.

Antegrade disobliteration of a chronic total coronary occlusion (CTO) may be technically difficult in spite of the use of customized equipment. Retrograde approaches via intramyocardial septal or bypass grafts have been described. We report a successful Percutaneous intervention of a proximal circumflex CTO using a retrograde approach via an epicardial collateral.

Selection of diquat resistance photosynthesis mutants from maize.

Resistance of a seedling to the herbicide 1,1'-ethylene-2,2'-dipyridylium bromide (diquat) can be used as a selective technique for photosynthesis mutants in Zea mays L. Diquat requires reduction by the light reaction in order to kill leaf cells and, therefore, nonphotosynthetic mutants survive. This technique was tested using known mutants and is applicable to larger samples of plants than previous techniques. Resistance to diquat should allow selection of mutants on the oxidizing side of photosystem II which are not previously available in higher plants.

Acid-bath Phosphorylation in Heptane-extracted Chloroplasts.

When spinach (Spinacia oleracea) chloroplast fragments were lyophilized and extracted with n-heptane, acid-bath phosphorylation was significantly reduced. Phosphorylation could be restored to these chloroplasts, if the extracted material (containing quinones, carotenoids, and other lipids) was added back to dry preparation before rehydration. The results reported suggest it was not quinones which were required for restoration of acid-bath phosphorylation but lipids. It is suggested that the lipids which were extracted by n-heptane serves as structural role in the thylakoid membrane.

The Differentiation of Pigmentation in Flower Parts, IV. Flavonoid Elaborating Enzymes From Petals of Impatiens balsamina s.

Extracts of the flower petals of Impatiens balsamina L. contain enzymes which catalyze the glycosylation of phenolic compounds. Enzymes have been extracted which glycosylate hydroquinone to arbutin and at least 3 different flavonols to the 3-monoglucoside. The hydroquinone glucosylating enzyme is similar to enzymes previously described except that it requires an unidentified low molecular weight cofactor. The glucosylation of flavonols follows normal enzyme kinetics; it requires a nucleotide diphosphate glucose donor for activity, and is made more evident by the presence of glucono-1:5-lactone, an inhibitor of endogenous glucosidases. It is suggested that the flavonol glucosylating enzyme acts naturally to glucosylate a precursor of both flavonols and anthocyanins to the 3-monoglucoside. The only elaboration of an anthocyanin observed with petal extracts was an acylation of pelargonidin-3-monoglucoside.

Chloroplast Reactions of Photosynthetic Mutants in Zea mays.

Three seedling lethal mutants of Zea mays with impaired photosynthesis are described. These recessive mutants were selected on the basis of high chlorophyll fluorescence. They have normal chlorophyll pigmentation but are unable to fix CO(2) fully. Evidence is presented from fluorescence characteristics of isolated chloroplasts that both photosystem I and II mutants were isolated. Using conventional measures of photosynthetic electron transport, we suggest that the photosystem I mutant has limited ability to reduce NADP. The other two mutants are clearly blocked in photosystem II, one possibly lacking the primary electron acceptor.

Nuclear gene-regulated expression of chloroplast genes for coupling factor one in maize.

In order to gain a better understanding of the interaction between the chloroplast and nuclear genomes in controlling the expression of plastid genes and the biosynthesis of chloroplast proteins, maize (Zea mays) nuclear gene mutant hcf(*)-38, in which alpha and beta subunits of coupling factor one (CF(1)) are almost completely missing was studied. The mutant possesses all the other subunits of CF(1) but several peptides of photosystem II are present in reduced amounts. A competitive hybridization experiment showed the presence of the same plastid mRNA species in mutant and wild-type plants except for slightly lower levels of some transcripts in the mutant. Northern hybridization and dot blot hybridization experiments showed the features of transcripts for alpha and beta subunits of CF(1) in the mutant to be similar to those in the wild-type maize although their levels are somewhat lower in the mutant. In vivo and in organello protein labeling experiments with L-[(35)S]Met have shown that alpha and beta subunits of CF(1) are synthesized, assembled into CF(1), and probably associated with thylakoid membranes in mutant plants. It is concluded that they are subsequently degraded.

Effect of nuclear mutation in maize on photosynthetic activity and content of chlorophyll-protein complexes.

A number of new nuclear mutants have been isolated from maize by selection for high chlorophyll (Chl) fluorescence. These mutants show reduced rates of photosynthesis and/or are deficient in Chl. Electrophoretic examination of wild type thylakoid membranes revealed five Chl-protein complexes, two containing only Chl a and three containing Chl a and Chl b. A class of nonviable, photosystem I-deficient mutants was found to be lacking one (A-1) of the two Chl a-protein complexes. A second class of nonviable, photosystem I-lacking mutants was found to be missing not only this A-1 complex but also one or more of the three Chl a and b-containing, light-harvesting Chl-protein complexes. Viable mutants were obtained which appeared to have lost just one of the Chl b-containing complexes, whereas a second class of viable mutants was missing all three of the Chl b-complexes. The results confirm that the A-1 band is associated with the P700-Chl a-protein complex characterized previously. The data also indicate the existence of structurally different forms of the light-harvesting Chl a- and b-containing complexes. The results also show a lower molecular weight band (A-2) containing primarily Chl a and which appears to be required for viability.

Inhibition of Photosystem II in Isolated Chloroplasts by Lead.

Inhibition of photosynthetic electron transport in isolated chloroplasts by lead salts has been demonstrated. Photosystem I activity, as measured by electron transfer from dichlorophenol indophenol to methylviologen, was not reduced by such treatment. However, photosystem II was inhibited by lead salts when electron flow was measured from water to methylviologen and Hill reaction or by chlorophyll fluorescence. Fluorescence induction curves indicated the primary site of inhibition was on the oxidizing side of photosystem II. That this site was between the primary electron donor of photosystem II and the site of water oxidation could be demonstrated by hydroxylamine restoration of normal fluorescence following lead inhibition.