Limits of detection of regional differences in vasodilated flow in viable myocardium by first-pass magnetic resonance perfusion imaging.

BACKGROUND: Perfusion imaging techniques intended to identify regional limitations in coronary flow reserve in viable myocardium need to identify 2-fold differences in regional flow during coronary vasodilation consistently. This study evaluated the suitability of current first-pass magnetic resonance approaches for evaluating such differences, which are 1 to 2 orders of magnitude less than in myocardial infarction. METHODS AND RESULTS: Graded regional differences in vasodilated flow were produced in chronically instrumented dogs with either left circumflex (LCx) infusion of adenosine or partial LCx occlusion during global coronary vasodilation. First-pass myocardial signal intensity-time curves were obtained after right atrial injection of gadoteridol (0.025 mmol/kg) with an MRI inversion recovery true-FISP sequence. The area under the initial portion of the LCx curve was compared with that of a curve from a remote area of the ventricle. Relative LCx and remote flows were assessed simultaneously with microspheres. The ratio of LCx and remote MRI curve areas and the ratio of LCx and remote microsphere concentrations were highly correlated and linearly related over a 5-fold range of flow differences (y=0.96 x+/-0.07, P<0.0001, r(2)=0.87). The 95% confidence limits for individual MRI measurements were +/-35%. Regional differences of >/=2-fold were consistently apparent in unprocessed MR images. CONCLUSIONS: Clinically relevant regional reductions in vasodilated flow in viable myocardium can be detected with 95% confidence over the range of 1 to 5 times resting flow. This suggests that MRI can identify and quantify limitations in perfusion reserve that are expected to be produced by stenoses of >/=70%.

Endothelium-derived relaxing factor (nitric oxide) has a tonic vasodilating action on coronary collateral vessels.

OBJECTIVES: We sought to determine whether endothelium-derived relaxing factor (nitric oxide) exerts a tonic vasodilating effect on coronary collateral channels developed in response to myocardial ischemia. BACKGROUND: Although the coronary collateral circulation is known to react to several vasoactive agents, the role of endogenously produced nitric oxide is unclear. METHODS: Coronary collateral channels were induced in the left circumflex artery bed of 12 chronically instrumented dogs by either ameroid implantation or repeated occlusion of the left circumflex coronary artery. With the native circumflex artery occluded, aortic and circumflex pressures and microsphere flows were measured before and after systemic administration of NG-nitro-L-arginine methyl ester, an arginine analogue known to block the synthesis of nitric oxide. RESULTS: NG-nitro-L-arginine methyl ester increased mean aortic pressure from a mean +/- SEM of 92 +/- 4 to 114 +/- 4 mm Hg, whereas pressure in the occluded circumflex artery decreased from 61 +/- 4 to 55 +/- 4 mm Hg. The increase in aortic-circumflex pressure gradient (from 31 +/- 4 to 59 +/- 5 mm Hg) was accompanied by a decrease in flow in the circumflex bed (from 1.31 to +/- 0.14 to 1.09 +/- 0.15 ml/min per g), resulting in an increase in coronary collateral resistance averaging 173 +/- 37% (from 26 +/- 4 to 64 +/- 9 mm Hg/ml per min per g, p < 0.01). The increase in collateral resistance could be partially reversed by administration of L-arginine. CONCLUSIONS: We conclude that nitric oxide normally exerts a substantial tonic dilating effect in coronary collateral vessels. Disease-induced alterations in endothelial function may limit collateral perfusion importantly.

Proportionate reversible decreases in systolic function and myocardial oxygen consumption after modest reductions in coronary flow: hibernation versus stunning.

OBJECTIVES: This study sought to determine whether modest short-term reductions in coronary flow can produce subsequent proportionate reductions in myocardial function and O2 consumption compatible with myocardial hibernation. BACKGROUND: Acute studies indicate that myocardial energy utilization can be downregulated during moderate flow reduction. Whether this apparently beneficial adjustment persists into the reperfusion period is unsettled because most postischemic contractile dysfunction has been presumed to represent stunned or irreversibly injured myocardium. METHODS: Responses of regional myocardial function and O2 consumption were assessed in chronically instrumented dogs after approximately 50% reductions in flow for 2 h (n = 8) or repeated 2-min total coronary occlusions (n = 6). RESULTS: When unrestricted perfusion was restored after sustained partial occlusions, regional function and O2 consumption stabilized at proportionate, systematically decreased levels ([mean +/- SEM] 80 +/- 3.1% and 81 +/- 5.1% of control values, both p < 0.05) and then returned to control values within 24 h. Similar proportionate reductions occurred after as few as five cycles of brief total occlusion (79 +/- 5.1% and 83 +/- 1.6% of control values, both again p < 0.05); these persisted with additional occlusions and then returned to baseline values within 3 h. The absence of irreversible injury was documented histologically in both series. Sham animals (n = 5) showed no changes in regional function or O2 consumption throughout similar experimental periods. CONCLUSIONS: Moderate decreases in coronary flow or repeated brief coronary occlusions can be followed by proportionate reversible reductions in regional systolic function and O2 consumption compatible with the traditional definition of myocardial hibernation. These findings emphasize the complexity of myocardial responses to flow restriction and call attention to limitations in characterizing reversibly hypocontractile myocardium as simply hibernating or stunned.

Coronary vascular responsiveness to adenosine is impaired additively by blockade of nitric oxide synthesis and a sulfonylurea.

OBJECTIVES: We sought to define effects of glibenclamide, a sulfonylurea known to block ATP-dependent potassium (KATP) channels, and Nomega-nitro-L-arginine methyl ester (L-NAME), an L-arginine analog known to block nitric oxide (NO) synthesis, on coronary vascular responsiveness to adenosine. BACKGROUND: The role of adenosine in coronary flow regulation becomes increasingly important when KATP channel function or NO synthesis is impaired. Both variables are potentially altered in patients with coronary artery disease taking a sulfonylurea. METHODS: Dose-response curves relating coronary conductance to plasma adenosine concentration were obtained by using intracoronary infusions of adenosine (10 to 1,000 microg/min) in chronically instrumented dogs. RESULTS: ED50, the plasma concentration of adenosine needed to produce 50% of the maximal increase in conductance under baseline conditions, increased threefold after either 1 or 10 mg/kg of L-NAME. ED50 also increased in response to glibenclamide in a dose-related fashion (5.7-fold increase per 1 mg/kg body weight of glibenclamide). Effects of combined blockade of KATP channels and NO synthesis were additive, with increases in ED50 as high as 15-fold. Both L-NAME and glibenclamide increased systemic pressure and reduced coronary conductance, confirming the roles of NO and KATP channels in regulating coronary and systemic vascular tone under rest conditions as well as during stress. CONCLUSIONS: Coronary vascular responsiveness to adenosine is blunted in vivo by both L-NAME and glibenclamide. Effects of the sulfonylurea and blockade of NO synthesis are additive and can limit coronary vasodilation as well as other responses involving KATP channels and NO.

Serum C-reactive protein. A useful and economical marker of immune activation in renal transplantation.

This study investigated whether serial daily measurements of serum C-reactive protein (sCRP) in 187 renal allograft recipients could help discriminate episodes of renal dysfunction due to rejection or cyclosporine (CsA) nephrotoxicity and help adjust immunosuppression in the early posttransplant period. Excellent primary graft function was associated with an initial peak of sCRP on day 2 after transplant (median, 29 microg/ml; range, 4 to >200 microg/ml) with a return to <20 microg/ml in all patients by day 5 (median, 7 microg/ml; range, 2-19 microg/ml). Stable graft function (mean creatinine, 155 microg/ml) was accompanied by a median sCRP of 4 microg/ml (range, 1-19 microg/ml). In 30 episodes of rejection responsive to methylprednisolone, sCRP was initially significantly raised to a median of 49 microg/ml (P<0.001) but fell rapidly in response to treatment to a median of 11 microg/ml and continued to fall. In 19 episodes of rejection unresponsive to methylprednisolone, median initial sCRP levels were significantly higher (P<0.001) at 119 microg/ml and were still at a median of 77 microg/ml at the end of the treatment. Twenty-four patients in whom renal dysfunction was associated with CsA nephrotoxicity showed no increase in sCRP concentrations; median sCRP concentrations remained at <5 microg/ml throughout the episodes. A similar pattern was seen in patients with acute tubular necrosis. Serial sCRP measurements provide economical and reproducible evidence of immune activation, help discriminate renal dysfunction due to CsA nephrotoxicity or rejection, and allow appropriate modification of immunosuppressive therapy.

Immunoexpression of villin in neuroendocrine tumors and its diagnostic implications.

BACKGROUND: Villin, a 95-kd cytoskeletal protein associated with axial microfilament bundles of brush border microvilli, is mostly restricted to intestinal glandular tumors. Villin immunoexpression was recently observed in a small number of carcinoids of the intestinal tract and lung, but its significance in a broad category of neuroendocrine tumors has not been evaluated. DESIGN: A total of 114 neuroendocrine tumors of different origins were tested for villin expression. They included gastrointestinal carcinoids (n = 30), lung carcinoids (n = 15), small cell carcinomas of the lung (n = 24), small cell carcinomas of other sites (n = 15), islet cell tumors (n = 8), Merkel cell carcinomas (n = 6), paragangliomas (n = 6), and others (n = 10). Nine round cell sarcomas were tested as well. RESULTS: Villin immunoreactivity was present in 85% of gastrointestinal carcinoids and small cell carcinomas, but was found in only 40% of lung carcinoids. Other tumors tested were virtually negative for villin. In general, while cytoplasmic reactivity was most common, a characteristic apical membranous pattern simulating brush border was seen in 76% of the gastrointestinal carcinoids and in 50% of the lung carcinoids. CONCLUSIONS: We found that villin was predominantly restricted to gastrointestinal neuroendocrine tumors (excluding islet cell tumors), although a small number of bronchial carcinoids may be positive as well. These results suggest a role for villin in the differential diagnosis of neuroendocrine tumors.

Conceptual, methodological, and clinical issues in cognitive-behavioral assessment.

This article reviews cognitive-behavioral assessment principles and procedures. The functions of such assessments are noted, and issues and advances in cognitive assessment are discussed. The need for integrated cognitive, behavioral, and affective assessments is then explored. Finally, conceptual methodological, and clinical issues in the integration of assessments and study of reciprocal determinants are presented.

The effects of cognitive-behavior modification on private speech and task performance during problem solving among learning-disabled and normally achieving children.

Recent research has supported the hypothesis that poor performance among learning-disabled (LD) children is frequently the result of deficits in self-regulation of strategic behaviors, rather than structural or ability deficits. As a result, cognitive-behavior modification (CBM) techniques that emphasize development of self-regulation through self-verbalizations (private speech) have been strongly recommended. The present study examined the natural occurrence of regulatory private speech among LD and normally achieving children during problem solving, as well as the effects of CBM training on private speech and task performance. Results indicated significant deficiencies in private speech and task performance among LD children; CBM training resulted in significant improvements. These results provide further verification of deficits in self-regulation of cognitive activity among LD children and import implications for intervention.

The effects of goal setting and self-instruction on learning a reading comprehension strategy: a study of students with learning disabilities.

This study examined the contributions of instruction in goal setting and self-instruction, separately and combined, on the acquisition, maintenance, and generalization of a reading comprehension strategy by fourth-through sixth-grade students with learning disabilities. A previously validated strategy involving the use of story structure to analyze and remember story content was taught to 47 students with learning disabilities using the self-regulated strategy development (SRSD) model. Comparisons were made among students with learning disabilities in four conditions (strategy instruction, strategy instruction plus goal setting, strategy instruction plus self-instruction, and strategy instruction plus goal setting and self-instruction). Result indicated that instruction in the reading strategy produced meaningful, lasting, and generalizable effects on students' story comprehension skills. Furthermore, the comprehension performance of the students with learning disabilities after strategy instruction was indistinguishable from that of a social comparison group of normally achieving students. Explicit instruction in goal setting and self-instruction, however, did not augment the comprehension performance of students with learning disabilities.

The spelling for writing list.

Four different vocabulary lists based on the study of children's writing were used to generate a basic spelling list for students with learning disabilities and other poor spellers. For each vocabulary list, the smallest number of different words that accounted for 80% of the words children used in their writing were identified. Words that were common to only one or two of the lists or not normally used by children until fourth grade or later were eliminated. Each word was assigned a grade placement based on difficulty, pattern of occurrence in children's writing, and placement on current vocabulary lists and spelling materials. The resulting spelling list of 335 words is provided.

Improving learning disabled students' skills at composing essays: self-instructional strategy training.

This study was conducted to determine if self-instructional strategy training would improve learning disabled students' writing. Students were taught a strategy designed to facilitate the generation, framing, and planning of argumentative essays. Training effects were investigated using a multiple-baseline across-subjects design, with multiple probes in baseline. Strategy instruction had a positive effect on students' writing performance and self-efficacy. Effects were maintained over time and transferred to a new setting and teacher. Evidence for generalization to a second genre, story writing, was also obtained. The students and their special education teacher recommended the use of the strategy with other students.

Self-monitoring of attentional behavior versus self-monitoring of productivity: effects on on-task behavior and academic response rate among learning disabled children.

I investigated the differential effects of self-monitoring of attentional behavior and self-monitoring of productivity on on-task behavior and academic response rate. Subjects were four learning disabled children with significant attentional problems. Results indicated relatively equivalent increases in on-task behavior over baseline during all treatment phases. Academic response rate also improved under both interventions, with self-monitoring of productivity showing a superior effect for one subject, an equivalent effect for one subject, and less clear results for two subjects.