Coronary artery disease risk reclassification by a new acoustic-based score.

To determine the potential of a non-invasive acoustic device (CADScor®System) to reclassify patients with intermediate pre-test probability (PTP) and clinically suspected stable coronary artery disease (CAD) into a low probability group thereby ruling out significant CAD. Audio recordings and clinical data from three studies were collected in a single database. In all studies, patients with a coronary CT angiography indicating CAD were referred to coronary angiography. Audio recordings of heart sounds were processed to construct a CAD-score. PTP was calculated using the updated Diamond-Forrester score and patients were classified according to the current ESC guidelines for stable CAD: low < 15%, intermediate 15-85% and high > 85% PTP. Intermediate PTP patients were re-classified to low probability if the CAD-score was ≤ 20. Of 2245 patients, 212 (9.4%) had significant CAD confirmed by coronary angiography ( ≥ 50% diameter stenosis). The average CAD-score was higher in patients with significant CAD (38.4 ± 13.9) compared to the remaining patients (25.1 ± 13.8; p < 0.001). The reclassification increased the proportion of low PTP patients from 13.6% to 41.8%, reducing the proportion of intermediate PTP patients from 83.4% to 55.2%. Before reclassification 7 (3.1%) low PTP patients had CAD, whereas post-reclassification this number increased to 28 (4.0%) (p = 0.52). The net reclassification index was 0.209. Utilization of a low-cost acoustic device in patients with intermediate PTP could potentially reduce the number of patients referred for further testing, without a significant increase in the false negative rate, and thus improve the cost-effectiveness for patients with suspected stable CAD.

Influence of Cardiac CT based disease severity and clinical symptoms on the diagnostic performance of myocardial perfusion.

We aimed to identify factors influencing the sensitivity of perfusion imaging after an initial positive coronary computed tomography angiography (CCTA) using invasive coronary angiography (ICA) with conditional fractional flow reserve (FFR) as reference. Secondly we aimed to identify factors associated with revascularisation and to evaluate treatment outcome after ICA. We analysed 292 consecutive patients with suspected significant coronary artery disease (CAD) at CCTA, who underwent perfusion imaging with either cardiac magnetic resonance (CMR) or myocardial perfusion scintigraphy (MPS) followed by ICA with conditional FFR. Stratified analysis and uni- and multiple logistic regression analyses were performed to identify predictors of diagnostic agreement between perfusion scans and ICA and predictors of revascularisation. Myocardial ischemia evaluated with perfusion scans was present in 65/292 (22%) while 117/292 (40%) had obstructive CAD evaluated by ICA. Revascularisation rate was 90/292 (31%). The overall sensitivity for perfusion scans was 39% (30-48), specificity 89% (83-93), PPV 69% (57-80) and NPV 68% (62-74). Stratified analysis showed higher sensitivities in patients with multi-vessel disease at CCTA 49% (37-60) and typical chest pain 50% (37-60). Predictors of revascularisation were multi-vessel disease by CCTA (OR 3.51 [1.91-6.48]) and a positive perfusion scan (OR 4.69 [2.49-8.83]). The sensitivity for perfusion scans after CCTA was highest in patients with typical angina and multiple lesions at CCTA and predicted diagnostic agreement between perfusion scans and ICA. Abnormal perfusion and multi vessel disease at CCTA predicted revascularisation.

Diagnosing coronary artery disease after a positive coronary computed tomography angiography: the Dan-NICAD open label, parallel, head to head, randomized controlled diagnostic accuracy trial of cardiovascular magnetic resonance and myocardial perfusion scintigraphy.

Aims: Perfusion scans after coronary computed tomography angiography (CCTA) in patients with suspected coronary artery disease (CAD) may reduce unnecessary invasive coronary angiographies (ICAs). However, the diagnostic accuracy of perfusion scans after primary CCTA is unknown. The aim of this study was to determine the diagnostic accuracy of cardiac magnetic resonance (CMR) and myocardial perfusion scintigraphy (MPS) against ICA with fractional flow reserve (FFR) in patients suspected of CAD by CCTA. Methods and results: Included were consecutive patients (1675) referred to CCTA with symptoms of CAD and low/intermediate risk profile. Patients with suspected CAD based on CCTA were randomized 1:1 to CMR or MPS followed by ICA with FFR. Obstructive CAD was defined as FFR ≤ 0.80 or > 90% diameter stenosis by visual assessment. After initial CCTA, 392 patients (23%) were randomized; 197 to CMR and 195 to MPS. Perfusion scans and ICA were completed in 292 patients (CMR 148, MPS 144). Based on the ICA, 117/292 (40%) patients were classified with CAD. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for CMR were 41%, 95% CI [28-54], 84% [75-91], 62% [45-78], and 68% [58-76], respectively. For the MPS group 36% [24-50], 94% [87-98], 81% [61-93], and 68% [59-76], respectively. Conclusion: Patients with low/intermediate CAD risk and a positive CCTA scan represent a challenge to perfusion techniques indicated by the low sensitivity of both CMR and MPS with FFR as a reference. The mechanisms underlying this discrepancy need further investigation.

Chronic pain and the development of a symptom checklist: a pilot study.

BACKGROUND: There is currently no instrument to systematically assess the range of symptoms/problems and their bothersomeness in patients with chronic non-cancer pain (CNPN). Systematic assessment and prioritizing may target treatments and improve outcomes. METHODS: The authors developed a checklist of symptoms and problems, the Copenhagen Symptom Checklist (CSC), presented clinically by patients. Fifty-three items representing biological, psychological and social areas were selected. Symptom/problem severity was rated on a 5-point scale anchored at 0 = 'not at all' and 4 = 'severe'. Patients ranked the five most bothersome symptoms/problems and could add five open-ended items. Patients completed the CSC after the first visit at the multidisciplinary pain centre. RESULTS: One hundred and twelve consecutive patients completed the CSC. Eighty-nine percent scored pain as rather severe or very severe (score = 3 plus score = 4), followed by reduction in physical activity (67%), fatigue (66%) and sleep disturbance (53%). Pain and fatigue, but not reduction in physical activity, were given highest priority. Cognitive problems were important to a third of the patients. Depressive symptoms, cognitive problems and worry explained 17.5% of the total variance. Patients filled in the CSC without important loss of information, but a minority prioritized more than three areas or used the free text alternative. CONCLUSIONS: Patients prioritized pain and fatigue as the most burdensome symptoms, but reduction in physical activity and sleep problems were also highly ranked. Patients were positive to the idea of symptom reporting; however, the 53-item number in this version of CSC is larger than may be necessary.

Late coronary stent thrombosis.

Coronary stent thromboses are characterized as early, if they occur within one month of the index PCI. Late stent thromboses (LST) have an occurrence after one month. Both early and late stent thromboses are a major concern in PCI, because of their clinical presentation as acute myocardial infarction and sudden cardiac death. Early stent thromboses are seen following implantation with bare metal (BMS) and drug eluting (DES) stents. Late occurring stent thromboses (LST) are rare but usually severe events and primarily seen after DES implantation. A number of pathogenetic mechanisms seem to be operating and there will probably be major differences between different types DES and the risk of LST. While early stent thrombosis is primarily related to stent implantation techniques, lesion characteristics and the effect of double platelet therapy, there is emerging evidence that very late stent thrombosis, occurring more than one year after the implantation may be caused by local tissue reaction to the polymers of sirolimus and paclitaxel eluting stents. It is likely that the use of new generations DES with tissue friendly polymers or bioabsorbable polymers will reduce the risk of late stent thrombosis.

Intra- and inter-investigator variation in the analysis of pressure-flow studies in men with lower urinary tract symptoms.

The objective of this study was to assess the intra- and inter-investigator variation in the analysis of pressure-flow studies that were performed in men with lower urinary tract symptoms. Two hospitals were involved in this study. In each hospital 100 PFS were selected. Photocopies of printouts of all PFS were analyzed manually by six experienced investigators, including determination of P(detQmax) and Q(max). Afterward, all 200 PFS were analyzed again in a different order. For each P(detQmax) and accompanying Q(max) the AG-number was calculated. With these AG numbers, the intra-investigator SD, the inter-investigator SD and the intra- and inter-investigator SD combined were calculated. The intra- and inter-investigator SD combined was 10.7. This implies that if one investigator analyzes a PFS once and determines an AG number of 40, another investigator may determine an AG number between 40 +/- 2. 77*10.7 = 10-70, using a 95% confidence interval. The inter-investigator SD was 10.0 and the intra-investigator SD was 3.7. The reproducibility of the manual analysis of urodynamic studies is moderate owing to a considerable intra- and inter- investigator variation. This is mostly caused by the substantial intra-investigator variation.

Interstitial cystitis. Ultrastructural observations on detrusor smooth muscle cells.

Ultrastructural investigation of detrusor muscle cells in biopsies from 13 patients (8 interstitial cystitis (IC) and 5 controls) was performed. In all IC-patients and in one control a varying number of smooth muscle cells revealed a characteristic oak leaf pattern with protrusions of the sarcolemma. The alterations may express degeneration of smooth muscle cells. Although most probably non-specific yet highly characteristic, the ultrastructural detrusor changes may be important in diagnosing IC.

Activation of calcium-dependent potassium channels in mouse [correction of rat] brain neurons by neurotrophin-3 and nerve growth factor.

The neurotrophins are signaling factors that are essential for survival and differentiation of distinct neuronal populations during the development and regeneration of the nervous system. The long-term effects of neurotrophins have been studied in detail, but little is known about their acute effects on neuronal activity. Here we use permeabilized whole-cell patch clamp to demonstrate that neurotrophin-3 (NT-3) and nerve growth factor activate calcium-dependent, paxilline-sensitive potassium channels (BK channels) in cortical neurons. Application of NT-3 or nerve growth factor produced a rapid and gradual rise in BK current that was sustained for 30-50 min; brain-derived neurotrophic factor, ciliary neurotrophic factor, and insulin-like growth factor-1 had no significant effect. The response to NT-3 was blocked by inhibitors of protein kinases, phospholipase C, and serine/threonine protein phosphatase 1 and 2a. Omission of Ca2+ from the extracellular medium prevented the NT-3 effect. Our results indicate that NT-3 stimulates BK channel activity in cortical neurons through a signaling pathway that involves Trk tyrosine kinase, phospholipase C, and protein dephosphorylation and is calcium-dependent. Activation of BK channels may be a major mechanism by which neurotrophins acutely regulate neuronal activity.

Fixation of human detrusor smooth muscle cells: role of osmolarity and magnesium ions on the ultrastructural morphology.

Magnesium ions added to fixatives for processing to Transmission Electron Microscopy (TEM) have been claimed to cause relaxation of detrusor smooth muscle cells [1]. This should facilitate the morphologic evaluation of the tissue. However, magnesium ions are osmotically active and their addition may cause the fixative to become hypertonic to the tissue. To ascertain whether the presence of magnesium ions causes significant changes compared to those found where the osmolarity is raised without the presence of magnesium, human detrusor specimens were fixed in glutaraldehyde to which increasing amounts of MgCl2 or NaCl were added in different concentrations. With the addition of increasing amounts of MgCl2 and NaCl, the osmolarity of the fixative increased, causing significant changes in the morphology and morphometry of the tissue. The intercellular distances increased, the cells shrank and the shape of the cells changed from smooth and rounded to spiky and angulated. With regard to its muscle-relaxing effect, it was not possible to distinguish the specimens fixed in magnesium-containing fixatives from those without. In this study it was not possible to prove any relaxing effect of magnesium ions added to the fixative. On the contrary the magnesium ions caused an increase in the osmolarity, with significant changes in both the morphometry and the morphology of the human detrusor smooth muscle cells.

A new technique for detrusor biopsy and its applicability in the ultrastructural study and diagnosis of voiding dysfunction.

OBJECTIVE: To determine the clinical applicability of ultrasound-guided detrusor biopsy from the anterior bladder wall and to assess whether it is as representative and as sufficient for determining detrusor ultrastructure as the traditional transurethral biopsy from the lateral bladder wall. MATERIALS AND METHODS: The detrusor structure in 22 biopsies. 11 obtained transabdominally and 11 transurethrally from 11 patients, was evaluated without knowledge of the biopsy method by light and electron microscopy, including morphometric analysis. In addition, several specimens from each of three bladders were evaluated, also 'blindly', for ultrastructural diagnosis of the detrusor in an independent current study of voiding dysfunction in geriatric patients. RESULTS: There were no differences in intercellular distances and cell: nucleus ratios between transabdominal and transurethral biopsies in eight of the 11 patients. Furthermore, ultrasound-guided transabdominal biopsies were as representative of the detrusor as were transurethral biopsies. CONCLUSION: The transabdominal approach is recommended as an easy, relatively inexpensive and efficient method of obtaining biopsies of the detrusor for study of its structure in voiding dysfunction. On the other hand, the observations and diagnoses made by 'blind' qualitative study of several specimens from the same bladder were identical. This, together with the similarity of detrusor structure in the transabdominal and transurethral biopsies, strongly supports the idea that such structure is relatively uniform throughout the entire bladder wall.

The symptomatic outcome of transurethral prostatectomy evaluated with the DAN-PSS-1 score system.

We assessed the symptomatic outcome of transurethral prostatectomy with the newly developed self-administered questionnaire, Danish Prostate Symptom Score (DAN-PSS-1), in men suffering from uncomplicated benign prostatic hyperplasia (BPH). The questionnaire was filled in adequately by 53 men, median age 69 (range 52-82), preoperatively and 2, 4 and 6 months after transurethral prostatectomy (TUR-P). The DAN-PSS-1 symptom score showed a high degree of sensitivity as the preoperative total score was median 20 (quartiles 14-36) and decreased to 4, 0 and 1 (quartiles from 0-4) at the 2, 4, and 6-month control respectively. The symptoms related to voiding were relieved totally after 2 months while symptoms related to storage were first relieved completely at 4-month control. Bother from symptoms was relieved after 2 months, although some symptoms still remained. The questionnaire was internally consistent with a reliability coefficient, Cronbach's alpha (alphaCr), of 0.73. We conclude that the DAN-PSS-1 questionnaire is an efficient tool among others in the indication and evaluation of treatment of uncomplicated BPH.

Sexual function in patients with symptomatic benign prostatic hyperplasia.

This study evaluated the sexual function in an unselected population referred to hospital for treatment of clinical BPH. 401 patients filled in the DAN-PSS questionnaire including 3 questions concerning sexuality (erection, ejaculation volume and pain/discomfort during eja culation). The patients were divided into four age groups (< 50; 50-59; 60-69 and > 69 years). The answers were analyzed for severity of symptoms and the related bothersomeness. The proportion of patients with erectile dysfunction increased with increasing age, and the related bother was much higher in the young males. Fiftyfour percent noticed that the amount of semen had decreased, and a correlation between increasing age and smaller ejaculation volume was observed. However, the related botherfactor was low. There was an age independent occurrence of about 15% of patients experiencing pain/discomfort during ejaculation and the bother factor is high. This study shows that the questions concerning sexuality in the DAN-PSS score system are formulated in a way that most patients can understand, and are willing to fill in the form.

Modulation of the Ca(2+)-dependent K+ channel, hslo, by the substituted diphenylurea NS 1608, paxilline and internal Ca2+.

The high-conductance Ca(2+)-activated K channel (BK channel) is not only regulated by a number of physiological stimuli, but it is also sensitive to pharmacological modulation. We have stably expressed the alpha-subunit of the human BK channel, hslo, in HEK 293 cells and studied by patch-clamp technique how its gating is modulated by the channel activator NS 1608, by the selective channel blocker paxilline, as well as by changes in [Ca2+]i and Vm. The cells expressed 200-800 hslo channels per patch. The channel activity was determined by tail current analysis, and the activation curves were fitted to single Boltzmann functions, from which a gating charge for the hslo channel of 1.2 elementary charges was deduced. The hslo channel was very sensitive to changes in [Ca2+]i within the physiological range, whereas Ca(2+)-independent openings were seen at Ca2+ concentrations of 15 nM or below. NS 1608 shifted the hslo channel activation curve towards negative membrane potentials with an EC50 of 2.1 microM and a maximal shift of -74 mV. The channels activated by NS 1608 were sensitive to block by paxilline, but the two molecules apparently did not interact within the same site, since paxilline reduced the size of the tail current at all voltages, whereas NS 1608 shifted the activation curve along the voltage axis. Further, the effect of paxilline was Ca(2+)-sensitive, whereas NS 1608 elicited identical effects in the presence of either < 0.5 nM or 500 nM [Ca2+]i. NS 1608 hyperpolarized the cells by -50 to -70 mV, and paxilline depolarized them towards 0 mV. In addition to the effects on the steady state current NS 1608 also significantly influenced the non-stationary channel kinetics. In the presence of NS 1608 the time constants for deactivation of tail currents were more than tripled at all potentials. We have shown, that NS 1608 modulates steady-state BK currents and channel gating kinetics through a Ca(2+)-independent interaction with the alpha-subunit of the channel.

Detrusor in ageing and obstruction.

It is disputed whether fibrosis of the detrusor is a consequence of obstruction or ageing. In the present study, bladder wall morphology was analyzed semiquantitatively in biopsies from "normal" young persons, infravesically obstructed and non-obstructed elderly persons. Fibrosis occurring around and inside muscle fascicles was demonstrated to the same degree with obstruction as well as ageing. Our results give rise to the question whether "prostatism" is related to obstruction per se or to ageing or both.

Gene expression and secretion of insulin-like growth factor-II and insulin-like growth factor binding protein-2 from cultured sheep choroid plexus epithelial cells.

The gene expression of insulin-like growth factor II (IGF-II) and insulin-like growth factor binding protein-2 (IGFBP-2) has previously been demonstrated in rat and human choroid plexus by in situ hybridization analysis. In the present study we have characterized IGF-II and IGFBP-2 transcripts and proteins in primary cultures of epithelial cells from lateral choroid plexus of sheep brain. Northern blot analysis of total RNA showed one major IGF-II mRNA of 4.8 kb and four minor IGF-II transcripts of 1.5, 2.0, 3.0 and 6.0 kb as well as one IGFBP-2 transcript of 1.7 kb. Radioreceptor assay of conditioned medium from the cultured choroid plexus epithelial cells showed inhibition of [125I]IGF-I and [125I]IGF-II binding to mouse NIH 3T3 fibroblasts, the displacement curves being identical to that of unlabelled IGF-II. The conditioned medium was fractionated by gel filtration on a Bio-Gel P-60 column, and analysis by IGF-II radioreceptor assay showed two peaks of IGF-II-binding inhibitory activity of M(r) 7.5-10 and 25 kDa, suggesting the presence of both IGF-II, and an IGFBP. Western immunoblot analysis of conditioned medium with antibodies toward IGF-II and IGFBP-2 demonstrated proteins with M(r) 6 kDa and 32 kDa, respectively. Protein binding assays of the conditioned medium with [125I]IGF-I or [125]IGF-II demonstrated that the IGFBP present in the conditioned medium preferentially binds IGF-II. In conclusion, cultured sheep choroid plexus epithelial cells synthesize and secrete IGF-II and IGFBP-2, suggesting that the choroid plexus epithelium is the main source of these polypeptides in the cerebrospinal fluid.

[Is the clinical diagnosis of acute appendicitis good enough?]. / Er den kliniske diagnose god nok ved appendicitis acuta?

In order to estimate the specificity of the clinical diagnosis of acute appendicitis, case records of 148 patients, who underwent appendectomy or who were diagnosed as having periappendicular abscess during one year at a regional hospital in Denmark were analyzed. Operations without finding acute appendicitis occurred in 25.4 per cent of the patients. The group of women in the fertile age (12-50 years) was prone to unnecessary surgery (51.9 per cent in this group had a normal appendix). In children, men and non-fertile women only a few patients had unnecessary surgery. Belated diagnoses (perforation and/or abscess) were found truly in 10.7 per cent of the cases, and, with a significant higher incidence, in elderly patients (age greater than 50 years). The possibilities of diminishing the incidence of unnecessary surgery and belated diagnoses are discussed.