Prognostic value of adenosine stress cardiovascular magnetic resonance in patients with low-risk chest pain

Background

Approximately 5% of patients with an acute coronary syndrome are discharged from the emergency room with an erroneous diagnosis of non-cardiac chest pain. Highly accurate non-invasive stress imaging is valuable for assessment of low-risk chest pain patients to prevent these errors. Adenosine stress cardiovascular magnetic resonance (AS-CMR) is an imaging modality with increasing application. The goal of this study was to evaluate the negative prognostic value of AS-CMR among low-risk acute chest pain patients.

Methods

We studied 103 patients, mean 56.7 ± 12.3 years of age, with chest pain and no electrocardiographic evidence of ischemia and negative cardiac biomarkers of necrosis, who were admitted to the Cardiac Decision Unit of our institution. All patients underwent AS-CMR. A negative AS-CMR was defined as absence of all the following: regional wall motion abnormalities at rest; perfusion defects during stress (adenosine) and rest; and myocardial scar on late gadolinium enhancement images. The patients were followed for a mean of 277 (range 161-462) days. The primary end point was defined as the combination of cardiac death, nonfatal acute myocardial infarction, re-hospitalization for chest pain, obstructive coronary artery disease (>50% coronary stenosis on invasive angiography) and coronary revascularization.

Results

In 14 patients (13.6%), AS-CMR was positive. The remaining 89 patients (86.4%), who had negative AS-CMR, were discharged. No patient with negative AS-CMR reached the primary end-point during follow-up. The negative predictive value of AS-CMR was 100%.

Conclusion

AS-CMR holds promise as a useful tool to rule out significant coronary artery disease in patients with low-risk chest pain. Patients with negative AS-CMR have an excellent short and mid-term prognosis.     

Effects of Various Parameters on Lateral Displacement Estimation in Ultrasound Elastography

Complementary to axial, lateral displacement and strain can provide important information on the biological soft tissues. In this paper, the effects of key parameters (i.e., lateral displacement, pitch, beamwidth, beam overlap and interpolation) on lateral displacement estimation were investigated, in simulations and homogeneous phantom experiments, using lateral rigid motion only to study its fundamentals separately from the effects of axial motion and 2-D deformation on lateral displacement estimation. The performance of the lateral motion estimator was evaluated by measuring its associated bias, jitter and correlation coefficient. Simulation results showed that the bias and jitter of the lateral displacement estimation and correlation coefficient of RF signals undergo periodic variations depending on the lateral displacement, with a period equal to the pitch. The performance of the lateral estimation was improved when a smaller pitch or a larger beamwidth, was used. The effect of the pitch on the lateral estimation on lateral displacement estimation was found to be greater than the beamwidth effect. Therefore, a smaller pitch is preferred when the beam overlap remains the same. The use of cubic spline, instead of linear interpolation, increases the correlation coefficient, and decreases the jitter, with the trade-off of increased bias. The results of the phantom experiments were shown in good agreement with the simulation findings, including the periodic variation of the performance with lateral displacement and effects of pitch, beamwidth and interpolation method on lateral displacement estimation. In conclusion, smaller pitch, wider beamwidth and spline interpolation were shown to be key in reducing the jitter error in the lateral displacement estimation. (E-mail: ek2191@columbia.edu)     

Deletion mapping of chromosome 17 in benign and malignant adrenocortical tumors associated with the Arg337His mutation of the p53 tumor suppressor protein

The human p53 tumor suppressor gene is located at the short arm of chromosome 17. A germinative mutation (Arg337His) in the tetramerization domain of p53 has been frequently identified in Brazilian children with sporadic adrenocortical tumors. Loss of heterozygosity at this region was demonstrated in the majority of the cases. In the present study, we performed deletion mapping of chromosome 17 in 30 adrenocortical tumors from 29 Brazilian patients (15 children and 14 adults). One boy had bilateral adrenocortical tumor. Sixteen patients had the germinative Arg337His mutation. Loss of heterozygosity analysis using six polymorphic microsatellite markers disclosed loss of the entire chromosome 17 in 18 tumors (10 adenomas and eight carcinomas) from 17 patients. The Arg337His mutation was present in 13 of them. Chromosomal instability involving chromosomes 2, 9, and 11 was also found in 47, 47, and 70% of the 17 patients who exhibited chromosome 17 losses, respectively. The concomitant loss of chromosomes 2, 9, 11, and 17 was evidenced exclusively in malignant tumors. Therefore, chromosomal instability involving three or more chromosomes may contribute to define the malignant adrenocortical lesions. In conclusion, we demonstrated a high frequency of biallelic inactivation of p53 derived from two distinct events, the germinative Arg337His mutation and the acquired loss of the entire chromosome 17. In addition, the isolated loss of the entire chromosome 17 did not correlate with aggressive tumor behavior in these patients with adrenocortical tumors.     

Progress in chemoprevention of breast cancer

Primary prevention trials have shown that tamoxifen lowers breast cancer incidence by 30-40%. Because of the endometrial risk of tamoxifen and the pro-thrombotic effects of tamoxifen and raloxifene, different strategies are being pursued to improve the risk:benefit ratio of breast cancer chemoprevention. Thus, raloxifene is being compared with tamoxifen in a phase III trial, while the minimal active dose of tamoxifen is being assessed in phase I-II trials. Also, the combination of hormone replacement therapy (HRT) and tamoxifen may reduce the risks while retaining the benefits of either agent. Anastrozole holds promise as a preventive agent based on preliminary results on contralateral breast cancer. The identification of women at increased risk for estrogen receptor (ER)-positive breast cancer due to hormonal and reproductive factors may maximize the therapeutic index of hormonal agents. Finally, new targets that interfere with ER-negative breast carcinogenesis are being sought as one-third of breast cancers will not be preventable by hormonal interventions.     

Outcome of surgical treatment for acromegaly performed by a single neurosurgeon and cumulative meta-analysis

The aim of this retrospective study was to evaluate the results of transsphenoidal surgery in a group of patients with acromegaly who were operated by the same neurosurgeon. Our results were compared to those from a cumulative meta-analysis of 10 series (1,632 patients) published between 1992 and 2005. We followed 28 patients (17M/11F; 44.1 +/- 12.7 yr; 27 with macroadenomas; 86% being invasive) during 21.4 +/- 17.6 months after treatment. Patients were classified according to disease activity as follows: 1) controlled (CD): basal or mean GH < 2.5 ng/ml or nadir GH (OGTT) < 1 ng/ml and normal IGF-1; 2) uncontrolled (UCD): basal or mean GH > 2.5 ng/ml or nadir GH > 1 ng/ml and elevated IGF-1; 3) inadequately controlled (ICD): normal GH and elevated IGF-1 or elevated GH and normal IGF-1. After surgery, GH levels decreased from 61.7 +/- 101.1 ng/ml to 7.2 +/- 13.7 ng/ml (p< 0.001) and mean IGF-1 from 673.1 +/- 257.7 ng/ml to 471.2 +/- 285 ng/ml (p= 0.01). Biochemical remission rate was 57% [10 (35.5%) patients with CD and 6 (21.5%) with ICD], similar to the mean remission rate observed in the meta-analysis of surgical outcome of macroadenomas. Seven of 28 patients were submitted to surgical re-intervention (4 had been previously operated elsewhere and 3 by our neurosurgeon), with CD observed in 5 (71.5%) on follow-up. Cavernous sinuses invasion was more prevalent in UCD and ICD, whereas infundibular stalk deviation occurred only in patients with UCD. Remission rate was significantly higher in series where all surgical procedures were performed by the same surgeon (66% vs. 49%; p< 0.05). Thus, the surgeon's experience significantly improves the surgical outcome in acromegaly, especially in patients harboring large and invasive tumors, and re-intervention performed by an experienced surgeon should be considered in the algorithms for clinical management of this disease.     

Main factors influencing long-term outcomes of liver transplantation in 2022

Liver transplant(LT) outcomes have markedly improved in the recent decades,even if long-term morbidity and mortality are still considerable.Most of late deaths are independent from graft function and different comorbidities,including complications of metabolic syndrome and de novo neoplasms,seem to play a key role in determining long-term outcomes in LT recipients.This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term managemen...     

Red cell pyruvate kinase deficiency: molecular and clinical aspects

Red cell pyruvate kinase (PK) deficiency is the most frequent enzyme abnormality of the glycolytic pathway causing hereditary non-spherocytic haemolytic anaemia. The degree of haemolysis varies widely, ranging from very mild or fully compensated forms, to life-threatening neonatal anaemia and jaundice necessitating exchange transfusions. Erythrocyte PK is synthesized under the control of the PK-LR gene located on chromosome 1. To date, more than 150 different mutations in the PK-LR gene have been associated with PK deficiency. First attempts to delineate the biochemical and clinical consequences of the molecular defect were mainly based on the observation of the few homozygous patients and on the analysis of the three-dimensional structure of the enzyme. More recently, the comparison of the recombinant mutants of human red cell PK with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined and help to correlate genotype to clinical phenotype.     

ROMK1 channel activity is regulated by monoubiquitination

The ubiquitination of proteins can signal their degradation, modify their activity or target them to specific membranes or cellular organelles. Here, we show that monoubiquitination regulates the plasma membrane abundance and function of the potassium channel, ROMK. Immunoprecipitation of proteins obtained from renal cortex and outer medulla with ROMK antibody revealed that this channel was monoubiquitinated. To determine the ubiquitin binding site on ROMK1, all intracellular lysine (Lys) residues of ROMK1 were individually mutated to arginine (Arg), and a two-electrode voltage clamp was used to measure the ROMK1 channel activity in Xenopus oocytes. ROMK1 channel activity increased from 8.1 to 27.2 microA only when Lys-22 was mutated to Arg. Furthermore, Western blotting failed to detect the ubiquitinated ROMK1 in oocytes injected with R1K22R. Patch-clamp experiments showed that biophysical properties of R1K22R were identical to those of wild-type ROMK1. Although total protein expression levels of GFP-ROMK1 and GFP-R1K22R in oocytes were similar, confocal microscopy showed that the surface fluorescence intensity in oocytes injected with GFP-R1K22R was higher than that of GFP-ROMK1. In addition, biotin labeling of ROMK1 and R1K22R proteins expressed in HEK293 cells showed increased surface expression of the Lys-22 mutant channel. Finally, expression of R1K22R in COS7 cells significantly stimulated the surface expression of ROMK1. We conclude that ROMK1 can be monoubiquitinated and that Lys-22 is an ubiquitin-binding site. Thus, monoubiquitination of ROMK1 regulates channel activity by reducing the surface expression of channel protein. This finding implicates the linking of a single ubiquitin molecule to channels as an important posttranslational regulatory signal.     

Physiological response to intrapulmonary percussive ventilation in stable COPD patients

Intrapulmonary percussive ventilation (IPV) is a ventilatory technique that delivers bursts of high-flow respiratory gas into the lung at high rates, intended for treating acute respiratory failure and for mobilization of secretions. We performed a study, aimed at assessing the physiological response to IPV, on patients' breathing pattern, inspiratory effort, lung mechanics and tolerance to ventilation. Ten COPD patients underwent randomized trials of IPV through a face mask at different pressure/frequency combinations (1.2 bar/250 cycles/min; 1.8/250; 1.2/350; 1.8/350), separated by return to baseline (SB), using the IMP2 ventilator. In 5 patients we have also compared the physiological changes of IPV with those obtained during pressure support ventilation (PSV). Minute ventilation did not vary among the trials, but tidal volumes (VT) were significantly greater during 1.2/250, 1.2/350 and 1.8/350 compared to SB. The pressure time product of the diaphragm per minute (PTPdi/min) estimate of the diaphragm oxygen expenditure was also significantly reduced during 1.2/250 and 1.8/250 (209 cmH2O x s/min for SB vs. 143 and 125 for 1.2/250 and 1.8/250, respectively P < 0.05), as well as dynamic intrinsic end-expiratory pressure (PEEPi,dyn). Similar reduction in PTPdi/min were obtained also during PSV. Tolerance to ventilation and oxygen saturation were satisfactory and did not change during the different trials. In 5 normal subjects a prolonged apnea trial lasting > 2 min was also performed, without any significant decrease in SaO2 or subjective discomfort. In conclusion, IPV was able to guarantee an adequate ventilation, while inducing a significant unloading of the diaphragm during the "low-frequency" trials.