Canine and human sinoatrial node: differences and similarities in the structure, function, molecular profiles, and arrhythmia.

The sinoatrial node (SAN) is the primary pacemaker in canine and human hearts. The SAN in both species has a unique three-dimensional heterogeneous structure characterized by small pacemaker myocytes enmeshed within fibrotic strands, which partially insulate the cells from aberrant atrial activation. The SAN pacemaker tissue expresses a unique signature of proteins and receptors that mediate SAN automaticity, ion channel currents, and cell-to-cell communication, which are predominantly similar in both species. Recent intramural optical mapping, integrated with structural and molecular studies, has revealed the existence of up to five specialized SAN conduction pathways that preferentially conduct electrical activation to atrial tissues. The intrinsic heart rate, intranodal leading pacemaker shifts, and changes in conduction in response to physiological and pathophysiological stimuli are similar. Structural and/or functional impairments due to cardiac diseases including heart failure cause SAN dysfunctions (SNDs) in both species. These dysfunctions are usually manifested as severe bradycardia, tachy-brady arrhythmias, and conduction abnormalities including exit block and SAN reentry, which could lead to atrial tachycardia and fibrillation, cardiac arrest, and heart failure. Pharmaceutical drugs and implantable pacemakers are only partially successful in managing SNDs, emphasizing a critical need to develop targeted mechanism-based therapies to treat SNDs. Because several structural and functional characteristics are similar between the canine and human SAN, research in these species may be mutually beneficial for developing novel treatment approaches. This review describes structural, functional, and molecular similarities and differences between the canine and human SAN, with special emphasis on arrhythmias and unique causal mechanisms of SND in diseased hearts.

On the role of TRPC1 in control of Ca2+ influx, cell volume, and cell cycle.

Ca(+) signaling plays a crucial role in control of cell cycle progression, but the understanding of the dynamics of Ca(2+) influx and release of Ca(2+) from intracellular stores during the cell cycle is far from complete. The aim of the present study was to investigate the role of the free extracellular Ca(2+) concentration ([Ca(2+)](o)) in cell proliferation, the pattern of changes in the free intracellular Ca(2+) concentration ([Ca(2+)](i)) during cell cycle progression, and the role of the transient receptor potential (TRP)C1 in these changes as well as in cell cycle progression and cell volume regulation. In Ehrlich Lettré Ascites (ELA) cells, [Ca(2+)](i) decreased significantly, and the thapsigargin-releasable Ca(2+) pool in the intracellular stores increased in G(1) as compared with G(0). Store-depletion-operated Ca(2+) entry (SOCE) and TRPC1 protein expression level were both higher in G(1) than in G(0) and S phase, in parallel with a more effective volume regulation after swelling [regulatory volume decrease (RVD)] in G(1) as compared with S phase. Furthermore, reduction of [Ca(2+)](o), as well as two unspecific SOCE inhibitors, 2-APB (2-aminoethyldiphenyl borinate) and SKF96365 (1-(ß-[3-(4-methoxy-phenyl)propoxyl-4-methoxyphenethyl)1H-imidazole-hydrochloride), inhibited ELA cell proliferation. Finally, Madin-Darby canine kidney cells in which TRPC1 was stably silenced [TRPC1 knockdown (TRPC1-KD) MDCK] exhibited reduced SOCE, slower RVD, and reduced cell proliferation compared with mock controls. In conclusion, in ELA cells, SOCE and TRPC1 both seem to be upregulated in G(1) as compared with S phase, concomitant with an increased rate of RVD. Furthermore, TRPC1-KD MDCK cells exhibit decreased SOCE, decreased RVD, and decreased proliferation, suggesting that, at least in certain cell types, TRPC1 is regulated during cell cycle progression and is involved in SOCE, RVD, and cell proliferation.

Myocardial infarction and percent arteriographic stenosis of culprit lesion: report from the Program on the Surgical Control of the Hyperlipidemias (POSCH).

The objective of this study was to assess the percent stenosis of the culprit lesion responsible for subsequent myocardial infarction in the Program on the Surgical Control of the Hyperlipidemias (POSCH). It is unknown if the susceptible coronary artery culprit lesion responsible for an acute myocardial infarction is relatively large ( > or = 50% arteriographic stenosis) and hemodynamically significant ( > or = 70% stenosis), or small ( < 50%, stenosis) and asymptomatic. Certain necropsy and arteriography studies support the large progenitor lesion concept, and other arteriography studies support the small lesion hypothesis. We analyzed the coronary arteriogram immediately preceding a Q wave (transmural) myocardial infarction for the degree of stenosis of the suspected culprit lesion, which was selected by visual inspection of the coronary circulation supplying the electrocardiogram-defined area of myocardial infarction. There was no perceptible difference with respect to vessel segment distribution of culprit lesions or time to infarction between the 52 control-group patients and the 27 intervention-group patients. For the two groups combined (n=79), the predominantly involved segments were the middle right coronary artery and the proximal left anterior descending coronary artery. The time interval from the preceding coronary arteriogram closest to the index myocardial infarction ranged from 0 days to 10 years; however, 64.6% of the arteriograms were performed 2 years or less prior to the myocardial infarction. Only 5.1% of the patients in both groups combined had a culprit lesion stenosis < 50%, while 88.6% of the patients in both groups combined had a culprit lesion stenosis > or = 70%. The results strongly favor the large lesion hypothesis of causation for myocardial infarction. It is premature, however, to state that the relative size of the culprit lesion has been indisputably determined. The resolution of this problem has exceedingly important practical implications for the management of patients with known atherosclerotic coronary heart disease and for those asymptomatic individuals with silent atherosclerotic coronary heart disease.

Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias.

BACKGROUND: In 1990, when the Program on the Surgical Control of the Hyperlipidemias (POSCH) reported its in-trial results strongly supporting the conclusion that effective lipid modification reduces progression of atherosclerosis, the differences for the end points of overall mortality and mortality from atherosclerotic coronary heart disease (ACHD) did not reach statistical significance. METHODS: The Program on the Surgical Control of the Hyperlipidemias recruited men and women with a single documented myocardial infarction between the ages of 30 and 64 years who had a plasma cholesterol level higher than 5.69 mmol/L (220 mg/dL) or higher than 5.17 mmol/L (200 mg/dL) if the low-density lipoprotein cholesterol level was in excess of 3.62 mmol/L (140 mg/dL). Between 1975 and 1983, 838 patients were randomized: 417 to the diet control group and 421 to the diet plus partial ileal bypass intervention group. Mean patient follow-up for this 5-year posttrial report was 14.7 years (range, 12.2-20 years). RESULTS: At 5 years after the trial, statistical significance was obtained for differences in overall mortality (P = .049) and mortality from ACHD (P = .03). Other POSCH end points included overall mortality (left ventricular ejection fraction > or =50%) (P = .01), mortality from ACHD (left ventricular ejection fraction > or =50%) (P = .05), mortality from ACHD and confirmed nonfatal myocardial infarction (P<.001), confirmed nonfatal myocardial infarction (P<.001), mortality from ACHD, confirmed and suspected myocardial infarction and unstable angina (P<.001), incidence of coronary artery bypass grafting or percutaneous transluminal coronary angioplasty (P<.001), and onset of clinical peripheral vascular disease (P = .02). There were no statistically significant differences between groups for cerebrovascular events, mortality from non-ACHD, and cancer. All POSCH patients have been available for follow-up. CONCLUSION: At 5 years after the trial, all POSCH mortality and atherosclerosis end points, including overall mortality and mortality from ACHD, demonstrated statistically significant differences between the study groups.

Comparison of the Danish Prostatic Symptom Score with the International Prostatic Symptom Score, the Madsen-Iversen and Boyarsky symptom indexes. ALFECH Study Group.

OBJECTIVE: To compare the Danish Prostatic Symptom Score (DAN-PSS) with the International Prostatic Symptom Score (IPSS). Madsen-Iversen and Boyarsky symptom indexes in a clinical setting, and to evaluate the potential significance of any differences in information obtained from these questionnaires. PATIENTS AND METHODS: The study comprised two substudies: in the first, 205 patients with lower urinary tract symptoms (LUTS) suggestive of bladder outlet obstruction (BOO), a Madsen-Iversen score > 6 and a maximum flow rate of < 10 mL/s were randomized to receive either placebo or alfuzosin in a double-blind study of 16 weeks. The symptoms were assessed using the Madsen-Iversen, DAN-PSS and the IPSS questionnaires. In the second, 138 patients with LUTS suggestive of BOO were selected for treatment with transurethral microwave thermotherapy (TUMT, 52 degrees C for 60 min, microwave energy 200 kJ) and their symptoms assessed using the Boyarsky and the DAN-PSS questionnaires. Patients were then followed for one year. Rank correlation coefficients and regression lines were calculated using Spearman's non-parametric test. The relative changes, i.e. responsiveness, calculated for the DAN-PSS, IPSS and Boyarsky indexes were compared pairwise using the Wilcoxon-Pratt test. RESULTS: The DAN-PSS, IPSS and Madsen-Iversen indexes were correlated on a pairwise basis. The DAN-PSS and IPSS indexes have significant construct validity in terms of correlation with the Madsen-Iversen system (Spearman's correlation coefficient, rs = 0.51 and rs = 0.45, respectively). The DAN-PSS and the IPSS indexes were correlated (rs = 0.61). The DAN-PSS was more sensitive than the IPSS to changes after pharmacological treatment, with scores decreasing 70% and 29% (P < 0.05), respectively, after treatment with an alpha-blocker for 4 months, and 50% and 29% (P < 0.05), respectively, after 4 months on placebo treatment. Finally, the responsiveness of the Boyarsky and DAN-PSS indexes to TUMT showed that the DAN-PSS system was significantly more responsive than the Boyarsky index, with scores decreasing 57% and 15% (P < 0.05), respectively, after one year. CONCLUSIONS: The DAN-PSS index is more sensitive than the IPSS, Madsen-Iversen and Boyarsky symptom indexes, incorporates important outcome events, includes a patient-weighting of each symptom, thereby reflecting better the patients' global assessment of outcome.

[Validation of the patient-administered Danish Prostate Symptom Score Schedule]. / Validering af det patientadministrerede Danske Prostate Symptom Scoringsskema.

The DAN-PSS-1 system, a self-administered quality-of-life questionnaire comprising 12 questions related to voiding problems and the perceived bother of each individual symptom, was compared to other extensively used score systems and furthermore included in different clinical situations so as to validate the system. The system was internally consistent (alpha cr = 0.73), the median test-retest reliability of answers to each question was 83.5% (range 0-99.7%). A high degree of construct validity demonstrated in the correlation with the Madsen-Iversen score system (rs = 0.51) and with the patients' answers to questions about how bothersome their symptoms were (rs = 0.71). The discriminant validity of the DAN-PSS-1 was excellent with an area under the ROC curve of 0.94. Finally, the DAN-PSS-1 was sensitive to changes following intervention, with scores decreasing 100% after transurethral prostatectomy and 65% after four months of treatment with an alpha-blocker. The DAN-PSS-1 is reliable, valid and responsive, and therefore can be recommended for assessing the severity of symptoms among patients presenting with lower urinary tract complaints suggestive of BPH and during follow-up.

Placebo effects in the pharmacological treatment of uncomplicated benign prostatic hyperplasia. The ALFECH Study Group.

In order to establish accurately the exact effect of any drug therapy for symptomatic benign prostatic hyperplasia (BPH) it is important to define the effect of placebo treatment. This effect was assessed by throughly analyzing the placebo arm, which included 101 patients, from a randomized, double-blind, placebo-controlled trial of the selective alpha-blocker alfuzosin and comparing the data with those of a variety of independent studies which followed a placebo group of patients with clinical BPH. Following 16 weeks of placebo treatment a decrease of 24% (p < 0.05) in Madsen-Iversen score and an increase of 14% (p < 0.05) in peak flow rate was demonstrated. The percentages of patients who reported worsening, improvement or no change in symptoms were 9.2%, 73.6% and 17.2% respectively. The maximal effect of placebo, approximately 40% reduction in symptom scores, is likely to be achieved within the first four to six months. After this, the placebo effect stabilizes and gradually wears off but is still present following 12 months of treatment. The duration of the placebo effect and the time until it has totally worn off, if ever, remains to be studied in long-term, placebo-controlled trials, including an untreated cohort. The present study emphasizes the importance of properly designed, double-blind, placebo-controlled studies in evaluating any pharmacological intervention in clinical BPH.

Symptomatic outcome of transurethral prostatectomy, alpha-blockade and placebo in the treatment of benign prostatic hyperplasia. Evaluation of treatment with the Danish Prostatic Symptom Score (DAN-PSS-1) system. The ALFECH Study Group.

To assess the symptomatic outcome following transurethral prostatectomy (TURP), alpha-blockade and placebo treatment in uncomplicated benign prostatic hyperplasia (BPH), 260 patients were evaluated with the recently formulated Danish Prostatic Symptom Score (DAN-PSS-1) system: 205 were randomized to either the selective alpha-blocker alfuzosin or placebo and 55 underwent TURP. Following TURP, the DAN-PSS-1 score was reduced by 80% after 6-10 weeks (visit 2) and by 100% after 12-16 weeks (visit 3). In the alfuzosin group the corresponding reductions were 40% and 65% (p < 0.02 vs. placebo). In the placebo group the reduction was 25% at visit 2, with no further fall demonstrated thereafter. During alfuzosin treatment the bother score (impact of symptoms on quality of life) fell more than the symptom score. During placebo treatment there was no reduction in symptom score. We conclude that the DAN-PSS-1 questionnaire sensitively identifies clinically important responses to treatment of BPH.

Validation of the self-administered Danish Prostatic Symptom Score (DAN-PSS-1) system for use in benign prostatic hyperplasia.

OBJECTIVE: To validate the Danish Prostatic Symptom Score (DAN-PSS-1), a self-administered quality-of-life questionnaire comprising 12 questions related to voiding problems and the perceived bother of each individual symptom. METHODS: Using published results from several comparisons of other symptom scoring systems with DAN-PSS-1, the test-retest reliability, internal consistency, construct and content validity, and responsiveness of the DAN-PSS-1 system were assessed. RESULTS: The system was internally consistent (Cronbach's alpha = 0.73), the median test-retest reliability of answers to each question was 83.5% (range 0-99.7%) and the questionnaire was well understood by the patients. The DAN-PSS-1 system demonstrated a high degree of construct validity, correlating with the extensively used Madsen-Iversen score system (Spearman's correlation coefficient, rs = 0.51) and with the patients' answers to questions about how bothersome their symptoms were (rs = 0.71). The DAN-PSS-1 system discriminated clearly between patients with benign prostatic hyperplasia (BPH) and control subjects (an area under the receiver operating characteristic curve of 0.94). Finally, the DAN-PSS-1 was sensitive to changes following intervention, with scores decreasing from a median of 20 to zero 4 months after patients underwent transurethral prostatectomy and from a median of 11.5 to 7.5 (65%) after patients had received 4 months treatment with an alpha-blocker. CONCLUSIONS: The DAN-PSS-1 system is reliable, valid and responsive, and therefore can be recommended for assessing the severity of symptoms among patients presenting with lower urinary tract complaints suggestive of BPH and in the follow-up after intervention.

[Giant fecaloma]. / Gigantisk faekalom.

A case of a giant faecaloma of the sigmoid colon secondary to surgery is reported. The predisposing factors, the diagnostic and therapeutic approaches are discussed.

Alfuzosin in the treatment of benign prostatic hyperplasia: effects on symptom scores, urinary flow rates and residual volume. A multicentre, double-blind, placebo-controlled trial. ALFECH Study Group.

In order to assess the efficacy and safety of alfuzosin, a selective alpha-1 receptor antagonist, 205 patients with Benign Prostatic Hyperplasia (BPH) were randomly assigned in a double-blind, placebo-controlled manner, to receive either alfuzosin 2.5 mg TID or placebo TID during 12 weeks. After 12 weeks symptom scores-assessed according to the Madsen-Iversen scale were significantly reduced in the alfuzosin group and peak flow rate significantly increased compared to the placebo group. There were no significant differences concerning adverse events or withdrawals. Alfuzosin proved to have a beneficial effect in patients with symptomatic BPH with few and minor adverse events.

Perception of quality of life before and after disclosure of trial results: a report from the Program on the Surgical Control of the Hyperlipidemias (POSCH).

The Program on the Surgical Control of the Hyperlipidemias (POSCH) was a randomized controlled clinical trial designed to ascertain whether cholesterol lowering induced by the partial ileal bypass operation would favorably affect overall mortality and the mortality and morbidity due to coronary heart disease. The trial results provided strong clinical and coronary arteriographic support for the beneficial effects of lipid modification for the reduction of atherosclerosis progression. At the same time, the surgery-assigned group experienced diarrhea and an increased incidence of kidney stones and gallstones compared to the control-assigned group. Identical quality of life determinations were performed in the POSCH study population shortly before disclosure of the trial results to the patients and shortly thereafter. The purpose of this dual assessment was to evaluate the effect of knowledge of outcomes on the patients' subjective evaluation of quality of life. The primary instrument utilized for analysis of the perception of quality of life in POSCH was the McMasters Health Index Questionnaire (MHIQ). In addition, four study-specific questions were asked of the trial patients. The results for the MHIQ before disclosure of trial results showed a difference (p = 0.07) favoring the control-assigned group (diet-treated), for the social function index of the MHIQ. After disclosure of the trial results, the difference was larger (p < 0.05). For the four study-specific questions, all differences favored the control-assigned group (p < 0.01) before and after disclosure of the trial results, with the exception of satisfaction with randomization allocation in the surgery-assigned group (p = 0.08). The intragroup MHIQ indices before and after disclosure of the trial results showed no suggestive significant differences, except in the surgery-assigned group, in which there was an improvement in the emotional function index after disclosure of the trial results (p = 0.03). The intragroup responses to the study-specific questions before and after disclosure of the trial results again showed no significant differences, except in the surgery-assigned group, in which there was an improvement in patient satisfaction with randomization allocation after disclosure of the trial results (p = 0.04).(ABSTRACT TRUNCATED AT 400 WORDS)

Persistent postoperative hiccups: a review.

The pathogenesis of persistent postoperative hiccups is not known. Hiccups can present as a symptom of a subphrenic abscess of gastric distention, and metabolic alterations may also cause hiccups. The hiccups may develop because of increased activity in neural reflex pathways not yet fully defined. Numerous treatment modalities have been tried but with questionable success. Valproate has proven effective in two trials investigating persistent non-surgical hiccups. The simple application of a nasogastric tube may successfully treat the hiccups, possibly because of an alteration of the activity in the reflex neural pathways involved. The available literature on the treatment of persistent hiccups is reviewed, and a treatment protocol for persistent postoperative hiccups is provided.