The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

Evaluation of clinical outcomes in anterior cruciate ligament surgery

Clinical outcomes data can be used to facilitate patient management decisions, assess clinician and organizational performance, and to provide evidence for the effectiveness of surgery and rehabilitation. The validity of the inferences made from outcomes data are dependent on the validity of the outcomes measures themselves and the circumstances under which the data were collected, analyzed, and interpreted. Clinical outcomes may include measures of impairment of body structure and function, activity limitation, and participation restriction. However, because the relationship between impairment and the resulting activity limitation and participation restriction is not direct, and because activity limitations and participation restrictions are of the utmost concern to the athlete, the primary clinical outcome should be measures of activity limitation and participation restriction. Activity limitation and participation restriction may be measured either through direct observation of performance or by general or specific measures of health related quality of life. Clinical outcomes data must be collected systematically to ensure valid inferences from the data.     

Presurgical electroencephalographic patterns and outcome from anterior temporal lobectomy.

We reviewed data from 48 patients after anterior temporal lobe resection for medically intractable epilepsy. All had ictal electro-encephalographic (EEG) evidence of unilateral temporal lobe onset. Depth electrodes were used in 19 patients. Successful surgical outcome correlated significantly with factors that suggested a temporal lobe focus, particularly in the interictal scalp EEG. The most successful outcome occurred in patients with well-localized unilateral interictal temporal spikes (100% improved). The group with well-localized bilateral temporal spikes also did well (76% improved). Patients with extratemporal spread of the interictal spike on scalp EEG, either unilaterally or bilaterally, did less well. Only one third improved, despite extensive extracranial and intracranial monitoring, when indicated. The interictal scalp EEG may be the only EEG necessary for the presurgical evaluation of selected patients with intractable temporal lobe epilepsy.     

LIPOPROTEIN(α) IN HEALTH AND DISEASE

SUMMARY Elevated plasma levels of Lp(a) do seem to influence the progression of atherosclerosis. Evidence is emerging that certain apo(a) isoforms may be more atherogenic than others, and in transgenic mice free apo(a) has been shown to be associated with accelerated atherosclerosis. Currently it is not known whether treating elevated Lp(a) levels will reduce progression of atherosclerosis and, as therapeutic options are limited, mass screening of Lp(a) levels in populations is not indicated. The presence of raised Lp(a) levels, however, warrants aggressive treatment to reduce other cardiovascular risk factors. Continuing research to investigate the relationship of the apo(a) gene to other genes, including the plasminogen gene and apo(a)-related genes, will add further information pertaining to the evolution, function, regulation and clinical implications of Lp(a).     

Evidence for effector independent and dependent representations and their differential time course of acquisition during motor sequence learning

To investigate the representation of motor sequence, we tested transfer effects in a motor sequence learning paradigm. We hypothesize that there are two sequence representations, effector independent and dependent. Further, we postulate that the effector independent representation is in visual/spatial coordinates, that the effector dependent representation is in motor coordinates, and that their time courses of acquisition during learning are different. Twelve subjects were tested in a modified 2x10 task. Subjects learned to press two keys (called a set) successively on a keypad in response to two lighted squares on a 3x3 display. The complete sequence to be learned was composed of ten such sets, called a hyperset. Training was given in the normal condition and sequence recall was assessed in the early, intermediate, and late stages in three conditions, normal, visual, and motor. In the visual condition, finger-keypad mapping was rotated 90 degrees while the keypad-display mapping was kept identical to normal. In the motor condition, the keypad-display mapping was also rotated 90 degrees, resulting in an identical finger-display mapping as in normal. Subjects formed two groups with each group using a different normal condition. One group learned the sequence in a standard keypad-hand setting and subsequently recalled the sequence using a rotated keypad-hand setting in the test conditions. The second group learned the sequence with a rotated keypad-hand setting and subsequently recalled the sequence with a standard keypad-hand setting in the test conditions. Response time (RT) and sequencing errors during recall were recorded. Although subjects committed more sequencing errors in both testing conditions, visual and motor, as compared to the normal condition, the errors were below chance level. Sequencing errors did not differ significantly between visual and motor conditions. Further, the sequence recall accuracy was over 70% even by the early stage when the subjects performed the sequence for the first time with the altered conditions, visual and motor. There were parallel improvements thereafter in all the conditions. These results of positive transfer of sequence knowledge across conditions that use dissimilar finger movements point to an effector independent sequence representation, possibly in visual/spatial coordinates. Initially the RTs were similar in the visual and the motor conditions, but with training RTs in the motor condition became significantly shorter than in the visual condition, as revealed by significant interaction for the testing stage and condition term in the repeated measures ANOVA. Moreover, using RTs for single key pressing in the three conditions as baseline indices, it was again observed that RTs in the visual and motor conditions were not significantly different in the early stage, but motor RTs became significantly shorter by the late testing stage. These results support the hypothesis that the motor condition benefits more than the visual because it uses identical effector movements to the normal condition. Further, these results argue for the existence of effector dependent sequence representation, in motor coordinates, which is acquired relatively slowly. The difference in the time course of learning of these two representations may account for the differential involvement of brain areas in early and late learning phases found in lesion and imaging studies.     

Expression of P-cadherin identifies prostate-specific-antigen-negative cells in epithelial tissues of male sexual accessory organs and in prostatic carcinomas. Implications for prostate cancer biology.

Cadherins constitute a family of calcium-dependent cell-cell adhesion molecules the individual members of which are essential for the sorting of cells into tissues during development. In this study, we examined the expression of E-cadherin, N-cadherin, and P-cadherin in tissues obtained from radical prostatectomies. Epithelial cells of prostatic glands, ejaculatory ducts, and seminal vesicles expressed E-cadherin but not N-cadherin. P-cadherin was expressed in epithelial cells of the seminal vesicles and ejaculatory ducts. In the prostate it was limited to the basal cells of prostatic acini, glands with basal cell hyperplasia, and atrophic glands denuded of the luminal cells. All P-cadherin-positive cells were negative for prostatic-specific antigen. Prostatic cancers were mostly P-cadherin negative, but some tumors had P-cadherin-positive areas frequently located close to ejaculatory ducts and negative for prostatic-specific antigen. The mutually exclusive expression of P-cadherin and prostatic-specific antigen suggests that these proteins are involved in differential mechanisms of cell regulation in prostate cancer. P-cadherin may become a useful marker in the diagnosis and management of patients with prostate cancer and low levels of prostatic-specific antigen.     

Detection of chromosomes and estimation of aneuploidy in human spermatozoa using fluorescence in-situ hybridization

The development and application of fluorescence in-situ hybridization (FISH) has opened the way for comprehensive studies on numerical chromosome abnormalities in human spermatozoa. FISH can be rapidly applied to large numbers of spermatozoa and thus overcomes the major limitation of karyotyping spermatozoa after penetration of zona-free hamster oocytes. The simultaneous hybridization of two or more chromosome-specific probes to spermatozoa and subsequent detection of the bound probes using different fluorescent detection systems enables two or more chromosomes to be localized simultaneously in the same spermatozoon and provides a technique for undertaking reasonable estimates of aneuploidy. The most commonly used probes are those which bind to the centromeric region of specific chromosomes. Most studies to date have concentrated on estimating aneuploidy in spermatozoa from normospermic men, although reports are beginning to appear on aneuploidy in spermatozoa from subfertile and infertile men. Multi- probe FISH studies have generally reported disomy (hyperhaploidy) estimates of 0.05-0.2% per chromosome. There is preliminary evidence that some chromosomes such as X, Y and 21 are predisposed towards higher rates of non-disjunction during spermatogenesis. There are also suggestions of inter-donor variability in aneuploidy frequencies for specific chromosomes, although this requires confirmation in larger studies. While FISH is clearly a powerful technique that has many applications in reproductive medicine, it must also be realized that it does have limitations and the technology itself is still evolving and has yet to be fully validated on spermatozoa.      

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.