Relationship of Reverse Anatomical Remodeling and Ventricular Arrhythmias After Cardiac Resynchronization

Introduction: Cardiac resynchronization (CRT) affects reverse anatomical remodeling in patients with heart failure. CRT has also been associated with fewer ventricular arrhythmias and reduced sudden death in some clinical trials, but the predictors and mechanism of the antiarrhythmic actions of CRT have not been well defined. The purpose of this study is to investigate the relationship of reverse anatomical remodeling to ventricular arrhythmias in CRT patients.
Methods and Results: A retrospective analysis was performed of the InSync III Marquis study, a prospective, randomized, multicenter CRT trial. Echocardiographic data from 198 patients were obtained at baseline and after 6 months of CRT, and anatomical responders were defined as a reduction in left ventricular end systolic volume (LVESV) of ≥15%. Anatomical responders (n = 71, 36%) demonstrated 29% fewer single premature ventricular contractions beats (PVCs) (P = 0.0001), 48% fewer PVC runs (p = 0.0096), and fewer treated episodes of ventricular tachycardia or fibrillation (VT/VF) (P = 0.050) than nonresponders. Multiple regression analysis demonstrated that responder status significantly predicted single PVCs and PVC runs. Gender was the most important predictor of treated VT/VF with females having no episodes over 6 months of follow-up.
Conclusions: Anatomic responders to CRT demonstrate significantly fewer single PVCs and runs of PVCs. The implication of these observations is that anatomic remodeling is linked to electrical remodeling.     

AN APPROACH FOR HIGH SENSITIVITY DETECTION OF PROSTATE CANCER BY ANALYSIS OF CHANGES IN STRUCTUREDNESS OF THE CYTOPLASMIC MATRIX OF LYMPHOCYTES SPECIFICALLY INDUCED BY PSA-ACT

PURPOSE: An alternative procedure for detection of prostate cancer was examined based on the observation that cells reexposed in vitro to antigenic or mitogenic stimulation will change their intracellular structuredness as measured by polarization of fluorescent light emitted by labeled cells (SCM test). MATERIALS AND METHODS: Lymphocytes derived from patients bearing a nonmalignant prostate tumor and healthy individuals were exposed to PSA-ACT, PHA, and MUC-1. RESULTS: Of sixty-five patients with prostate carcinoma (CaP), sixty-two were correctly diagnosed by the test. Of the eighty males in the control group, five were incorrectly diagnosed as having the disease and seventy-five were correctly diagnosed as healthy subjects. The sensitivity of the test was 96.8%. The specificity was 91.1%. The BPH (Benign Prostatic Hyperplasia) control group exhibited a sensitivity of 9.38%, but the specificity was 91.1%. Similar percentages for specificity and sensitivity were observed in the NRT (Non-Relevant Tumor) control group. CONCLUSIONS: The results shown here indicate the possibility of a different use of PSA-ACT for detection of prostate cancer with high specificity and sensitivity.     

Low HL—A2 Frequency and Periodontitis1

The frequency of HL-A2 was significantly low (21%) in patients with periodontitis when compared to controls who were free of periodontal disease (61%). The effect was most pronounced in females in whom HL-A2 was present in 12.5% (2 out of 16). This finding suggests that genes controlling susceptibility to microbial agents may be linked to the HL-A LOCUS.     

A TREE-BASED METHOD OF ANALYSIS FOR PROSPECTIVE STUDIES

Prospective studies often involve rare events as study outcomes, and a primary concern is to identify risk factors and risk groups associated with the outcomes. We discuss practical solutions to risk factor analyses in prospective studies and address strategies to determine tree structures, to estimate relative risks, and to manage missing data in connection with some important epidemiologic problems. Some of the basic ideas for our strategies follow from work of Breiman, Friedman, Olshen, and Stone, although we propose extensions to their methods to resolve some practical problems that arise in implementation of these methods in epidemiologic studies. To illustrate these ideas, we analyse low birthweight associated risk factors with use of a data set from the Yale Pregnancy Outcome Study.     

CONFIDENCE INTERVALS FOR MEDIAN SURVIVAL TIMES UNDER A PIECEWISE EXPONENTIAL MODEL WITH PROPORTIONAL HAZARDS COVARIATE EFFECTS

Brookmeyer and Crowley derived a non-parametric confidence interval for the median survival time of a homogeneous population by inverting a generalization of the sign test for censored data. The 1−α confidence interval for the median is essentially the set of all values t such that the Kaplan–Meier estimate of the survival function at time t does not differ significantly from one-half at significance level α. Here I extend the method to incorporate covariates into the analysis by assuming an underlying piecewise exponential model with proportional hazards covariate effects. Maximum likelihood estimates of the model parameters are obtained via iterative techniques, from which the estimated (log) survival curve is easily constructed. The delta method provides asymptotic standard errors. Following Brookmeyer and Crowley, I find the confidence interval for the median survival time at a specified value of the covariate vector by inverting the sign test. I illustrate the methods using data from a clinical trial conducted by the Radiation Therapy Oncology Group in cancer of the mouth and throat. It is seen that the piecewise exponential model provides considerable flexibility in accommodating to the shape of the underlying survival curve and thus offers advantages to other, more restrictive, parametric models. Simulation studies indicate that the method provides reasonably accurate coverage probabilities.     

Synthesis and biological activity of analogues of the C-terminal hexapeptide of substance P with modifications at glutaminyl and methioninyl residues

Analogues of [Orn⁶]-SP_6-11 have been synthesized in which the methionyl residue is replaced by glutamine γ-carboxamide substituted derivatives. These analogues where tested in three in vitro preparations representative of NK-1, NK-2 and NK-3 receptor types. Substitution of the SCH₃ group of the Met¹¹ side chain by CONHCH₃, CON(CH₃)₂, CONHPh and CONCH₃Ph groups results in analogues which are full agonists in NK-1 and NK-2 preparations with the exception of the Glu[N(CH₃)₂]¹¹ and the Glu(NHCH₃)¹¹ analogues, which are partial agonists at NK-1 and NK-2 receptors respectively. The Glu(NHCH₃)¹¹ analogue shows selectivity for the NK-1 receptor type and is equipotent to the Glu(NCH₃Ph)¹¹ analogue in the same receptor type. The latter analogue is 2.84 times more potent than the parent hexapeptide in the NK-2 preparation. The Glu(NHPh)¹¹ analogue is a full agonist in the NK-3 preparation and equipotent to the parent hexapeptide, in contrast to the other analogues in which Met has been replaced by glutamine γ-carboxamide substituted residues. It is concluded that for NK-1 receptor type the lipophilic character of Met¹¹ side chain is not a determining factor for activity but it is an important factor for activity in the NK-2 receptor type and has a stronger effect when a phenyl group is present, thus leading to analogues which are full agonists and more potent than the parent hexapeptide.     

Solvent use and psychiatric comorbidity

From a family study of 286 alcoholics, 157 felons, 60 control subjects, and 1640 of their relatives, 130 solvent users were retrospectively identified. Risk for diagnosis of antisocial personality disorder was significantly elevated for all solvent users. Relatives, though not probands, were more likely to receive diagnoses of alcoholism and secondary depression, but this relationship appeared to be mediated by the presence of antisocial personality disorder. Solvent users were not at increased risk for primary depression or other psychiatric illnesses. Subjects reporting any solvent use also had significantly increased risk of suicidal ideation and suicide attempt compared to non-users, with half of the solvent users reporting suicidal ideation and 30% reporting a history of suicide attempt. However, risk for suicidal ideation and suicide attempt among solvent users appeared to covary with presence of antisocial personality disorder, alcoholism, and secondary depression rather than being specifically associated with solvent use.     

The MoAb-VκIIIb Cross-Reactive Idiotope on A27a (Humkv325) Encoded Kappa Chains Maps to Framework Region 3

The monoclonal antibody MoAb-VκIIIb binds a cross-reactive idiotopic (CRI) determinant on light (L) chains encoded by the VκIIIb subgroup A27a (Humkv325) gene segment. The aim of this study was to localize the MoAb-VκIIIb CRI. Mutational analyses involving region exchanges between a CRI-positive VκIIIb chain and a CRI-negative Vκ1 chain indicate that the MoAb-VκIIIb CRI is located in framework region (FR) 3 of A27a (Humkv325) encoded L chains. CRI-positive kappa chains unpaired with a heavy (H) chain are reactive with MoAb-VκIIIb, indicating that the CRI is located on the kappa chain alone without involvement of H chain residues. Combinatorial antibodies composed of non-parental L and H chain pairings are reactive with MoAb-VκIIIb only when the L chain is A27a (Humkv325) encoded. The CRI, therefore, is not readily perturbed by H chain interactions. When the FR3 from a CRI-positive kappa chain replaced the FR3 in a CRI-negative lambda chain, the determinant was no longer detectable with MoAb-VκIIIb. It is possible, therefore, to exchange regions between kappa chains from different families and retain the CRI structure, however the determinant is lost when placed in a more foreign background such as a lambda chain. These data more precisely define the interaction between MoAb-VκIIIb and its CRI, and indicate that there are limits within which antibody FRs can be shuffled and still retain their native structural features.     

Synthesis and biological evaluation of mouse growth hormone-releasing factor

The recently described mouse growth hormone-releasing factor (mGRF) was synthesized by the solid phase procedure, purified by 2 stages of preparative high performance liquid chromatography and fully characterized. The biologic activity of the 42-amino acid peptide (H-His-Val-Asp-Ala-Ile-Phe-Thr-Thr-Asn-Tyr-Arg-Lys-Leu-Leu-Ser-Gln-Leu-Tyr-Ala-Arg-Lys-Val-Ile-Gln-Asp-Ile-Met-Asn-Lys-Gln-Gly-Glu-Arg-Ile-Gln-Glu-Gln-Arg-Ala-Arg-Leu-Ser-OH) was assessed in primary cultures of both mouse and rat anterior pituitary cells and compared to synthetic rat (rGRF) and human (hGRF) growth hormone-releasing factors. mGRF was equipotent to rGRF in mouse somatotrophs but slightly less potent in rat somatotrophs, while hGRF was 3-5 times less potent in both rodent species.