Dual vs. triple antithrombotic treatment after percutaneous coronary intervention in patients with non-valvular atrial fibrillation: a meta-analysis on current evidence.

OBJECTIVE: Combination and duration of antithrombotic therapy in order to prevent both stent thrombosis and thromboembolic complications after coronary artery stenting (PCI) in non-valvular atrial fibrillation (AF) is still debated. This uncertainty can be attributed mainly to the fact that the reference trials were open-label and not adequately powered in order to reach a definitive conclusion on ischemic endpoints (i.e., stent thrombosis). On these grounds, data from real-life studies could support evidence on dual antithrombotic treatment (DAT) safety (bleeding risk) and efficacy (stent thrombosis prevention). The aim of the meta-analysis is to investigate in both randomized controlled trials (RCTs) and observational studies (Obs) the risks and/or benefits related to DAT vs. triple antithrombotic treatment (TAT) regimens in patients affected by AF undergoing PCI. MATERIALS AND METHODS: RCTs and Obs were retrieved through PubMed database. The risk ratio with 95% confidence interval was used to compare the primary and the safety endpoints. RESULTS: Meta-analysis demonstrated no significant differences between DAT vs. TAT for mortality. However, a two-fold higher mortality rate was registered in Obs than in RCTs. The Obs did not confirm the expected significant reduction in bleeding risk shown by the RCTs; however, the bleeding rates in Obs were more than three-fold those of RCTs. In Obs, a significant greater risk for stent thrombosis was observed in DAT than in TAT. CONCLUSIONS: The safety and efficacy outcomes observed in RCTs are unrealistic with respect to the current clinical practice. So, more evidence is needed to have more exhaustive guidelines based on RCTs with homogeneous designs and protocols that should mimic real-life population and practice.

Takotsubo cardiomyopathy and flecainide toxicity: a case report and brief literature review.

OBJECTIVE: Takotsubo syndrome, also known as stress cardiomyopathy, is predominantly reported in postmenopausal women and it is often triggered by a physical or emotional stressor. CASE REPORT: We present the case of a 44-year-old Caucasian woman admitted to the emergency department after voluntary intake of 20 tablets of flecainide 150 mg to commit suicide. During the in-hospital stay in the Cardiac Intensive Care Unit, the patient developed Takotsubo syndrome. CONCLUSIONS: The relative role of flecainide as a possible trigger of the syndrome is discussed in the context of the current literature evidence.

Improving performance of 3D speckle tracking in arterial hypertension and paroxysmal atrial fibrillation by using novel strain parameters.

The function of left atrium (LA) is closely related to LA remodeling and one of the most important mechanisms is an increased deposition of fibrous tissue that often is the basis for LA electro-mechanical changes before the onset of atrial fibrillation (AF). This study evaluated LA shape and function, by investigating standard and novel strain parameters calculated by a new approach based on homologous times derived from 3D speckle tracking echocardiography (3DSTE) in hypertensive (HT) and paroxysmal atrial fibrillation (PAF) patients with or without left ventricular hypertrophy (LVH), compared to control (C) subjects. LA function was assessed using homologous times to compare strain variables among different individuals, acquired at different physiological time periods. Standard global longitudinal (GLS) and circumferential (GCS) strains were measured at peak of atrial diastole, while longitudinal and circumferential strains (GLSh, GCSh), strain rate (GLSr, GCSr), volume (Vh) and volume rate (Vr) were measured during the atrial telediastolic phase (fifth homologous time) and atrial pre-active phase (tenth homologous time). Using ANOVA, we found an impaired LA deformation detected by standard, interpolated strains and strain rates in both HT and PAF groups compared to C. We also performed ROC analysis to identify different performances of each parameter to discriminate groups (GLSr10 + GCSr10: C vs PAF 0.935; C vs PAF_LVH 0.924; C vs HT_LVH 0.844; C vs HT 0.756). Our study showed anatomical and functional LA remodeling in patients with PAF and HT. 3D strains and strain rates derived from the homologous times approach provide more functional information with improved performance to identify among the explored groups, in particular PAF patients.

The natural history of prehypertension. A 20-year follow-up.

OBJECTIVE: According to the JNC7 report, prehypertension category includes subjects with systolic blood pressure between 120 and 139 mmHg and/or diastolic blood pressure between 80 and 89 mmHg that would be at risk for developing hypertension and its untoward sequelae as myocardial infarction and cerebrovascular disease. Moreover, ambulatory blood pressure monitoring made it possible to detect subjects with masked hypertension, who are at risk of greater target organ damage than those with normal ambulatory or home blood pressure. The aim of this study was to evaluate the risk of cardiac, cerebral and vascular events in a group of prehypertensive subjects, with and without masked hypertension. PATIENTS AND METHODS: We studied 204 consecutive asymptomatic prehypertensive subjects without history and signs of cardiovascular disease or diabetes. All the subjects underwent clinical evaluation, electrocardiogram, routine laboratory tests and ambulatory blood pressure monitoring. They were followed-up for a maximum of 237 months or until a cardiovascular event occurred. RESULTS: Twenty-seven cardiovascular events (13.2%) occurred, including 4 abdominal aortic aneurysms. Age (p<0.0001), total cholesterol (p=0.004), smoking (p=0.03) and clinically overt hypertension development (p=0.011) were related to cardiovascular events. Prognosis was not related to masked hypertension. CONCLUSIONS: The results of this study suggest that, in subjects with prehypertension, followed for 20 years, traditional cardiovascular risk factors and development of clinically overt hypertension could be more relevant than ambulatory hypertension in the prediction of an adverse outcome.

Randomised, double-blind, placebo-controlled, assessment of the efficacy and safety of dietary supplements in prehypertension.

We aimed to evaluate efficacy and tolerability of a protocol including lifestyle modifications and a novel combination of dietary supplements in prehypertension. A prospective, double-blind, randomised, placebo-controlled trial was conducted in 176 subjects (103 men, aged 52±10 years), with blood pressure (BP) of 130-139 mm Hg systolic and/or 85-89 mm Hg diastolic entered. After a single-blind run-in period, participants were randomised to twice daily placebo (n=88) or a commercially available combination pill (n=88). Primary endpoints were the differences in clinic BP between the two groups at the end of the trial. Secondary endpoints included intragroup differences in clinic BP during the study period and response rates (that is, BP <130/85 mm Hg or a BP reduction >5 mm Hg on week 12). Baseline characteristics were similar among the treatment groups. At 12 weeks, the supplement group had lower systolic BP (124±9 versus 132±7 mm Hg, P<0.0001) and similar diastolic BP (81±8 versus 82±7 mm Hg, P=0.382) compared to the placebo group. With respect to baseline measures, changes in BP with supplements were statistically significant for systolic (-9.3±4.2 mm Hg, P<0.0001) and diastolic values (-4.2±3.6 mm Hg, P<0.0001). Changes versus baseline in systolic and diastolic BP, conversely, were not different on placebo. The overall response rate at week 12 was significantly greater with supplements than placebo (58% (51 of 88) and 25% (22 of 88), respectively, P<0.0001). This randomised trial shows that combination of supplements with BP-lowering effect is an effective additional treatment to conventional lifestyle modifications for a better control of systolic BP in prehypertension.

Is it possible a new definition of metabolic syndrome in childhood?

OBJECTIVE: To investigate whether a group of Italian children and adolescents who were diagnosed to have metabolic syndrome (MS) according to a new ethnic age and gender specific definition had, in comparison with a control group, other signs and metabolic risk factors which are commonly associated with MS. PATIENTS AND METHODS: The cross-sectional study population included 300 subjects (51% boys, age range 6-14 years), who were divided into 2 groups according to the presence of MS, diagnosed on the basis of 3/5 factors derived from the age and gender specific quantile distribution of MS components in a large regional Italian population survey (Calabrian Sierras Community Study, CSCS). In all subjects the following data were collected: anthropometric measures, blood pressure, liver function, C-reactive protein (hsCRP), uric acid blood levels, lipid and glucose profile. Triglycerides/HDL-cholesterol (TG/HDL-C) ratio was calculated. RESULTS: There were 38 subjects (13%) with MS, who had higher indices of growth and fat distribution and higher blood levels of uric acid, alanine aminotransferase and gamma-glutamyltransferase. TG/HDL ratio was higher (median 3.11 vs. 1.14, p = 0.00001) in MS subjects who had lower apolipoprotein A and higher apolipoprotein B and non-HDL-C levels. hsCRP was not different between groups. CONCLUSIONS: Our ethnic age and gender specific definition of MS in Italian children and adolescents was able to identify in a youth group different cardiometabolic risk factors related to insulin resistance, endothelial damage and nonalcoholic fatty liver disease, which are commonly associated with MS diagnosis.

Blood pressure control and clustering of cardiovascular risk factors in Mediterranean post-menopausal hypertensive women.

BACKGROUND: Control of hypertension is unsatisfactory among older women. Data about Mediterranean countries are not currently reported. AIM: The aim of the present study was to describe the features of blood pressure (BP) control and the clustering of other cardiovascular (CV) risk factors in Mediterranean post-menopausal hypertensive women. PATIENTS AND METHODS: We consecutively selected 516 post-menopausal female patients (mean age 69±11 years) with drug-treated essential hypertension (ESH/ESC grade 1 and 2) for this cross-sectional study. All patients were divided in 4 groups: < 60 years; 60-69 years; 70-79 years; ≥ 80 years. RESULTS: The Kruskal-Wallis analysis of variance showed a significant difference among the 4 age groups both for systolic BP (p < 0.001) and diastolic BP (p < 0.01). Mann-Whitney test for multiple comparisons of each age group vs. octogenarians demonstrated that there is a significant incremental trend of SBP through the age decades. Mean diastolic BP values were significantly higher in younger patients (age decades < 60 and 60-69 years, p < 0.01 and p < 0.05 respectively), while in patients aged 70-79 years there was no difference vs. octogenarians. Dyslipidemia was the more prevalent clustered risk factor with a peak rate of 49% in patients aged 60-69 years, statistically different (p < 0.05) from octogenarians. Global BP control (i.e. treated BP < 140/90 mmHg) was low (33.5% in the whole population) and there was no trend through age decades. CONCLUSIONS: BP control varied across age groups, but was poor. Nevertheless, the studied population appeared to be at low cardiovascular risk, due to a modest clustering of traditional risk factors.

Cigarette smoking and ambulatory blood pressure: a case-control study in normotensives.

The aim of our study was the evaluation of the effects of cigarette smoking on ambulatory blood pressure (ABP) in normotensive subjects participating to a cardiovascular prevention program. All subjects were followed up for an average time of 97+/-42 months to assess the event of hypertension development. Prevalence of hypertension development was higher in smokers even if regression logistic analysis was not able to predict hypertension development.

Evaluation of systolic blood pressure control in elderly patients with isolated systolic hypertension.

The aim of this retrospective study was the evaluation of systolic blood pressure (SBP) control in elderly patients (pts) with isolated systolic hypertension (ISH). We assessed SBP control (i.e. average of 2 clinic BP measurements < 140 mmHg) in 152 pts (44 M, 108 F, 75 +/- 6 years) with ISH (149/84 +/- 17/6 mmHg), treated for at least 3 months by general practitioners or specialists with treatments of their choice. Most antihypertensive drugs were used at starting doses in monotherapy or combination treatment, as usual in clinical practice. ECG was abnormal in 82/152 pts (54.0%). All pts were divided in 2 groups according to SBP control. The 2 groups were compared by chi-square test for categorical variables and by Mann-Whitney test for quantitative variables. A p value < 0.05 was considered statistically significant. The global SBP control rate was 41.4% (63/152 pts). BP was higher in pts with poor SBP control, as expected, but the 2 groups were similar for sex distribution, age, prevalence of other cardiovascular risk factors and type of care (general practitioner or specialist). Pts with poor SBP control had a higher prevalence of abnormal ECG tracings (p = 0.003), a lower prevalence of combination regimes (p = 0.007) and prescriptions of dihydropyridine calcium antagonists or thiazide diuretics (p = 0.006). Global SBP control rate in our retrospective study in pts with ISH was unsatisfactory. Use of dihydropyridines or thiazides, drugs of choice in the management of ISH according to ESH/ESC and JNCVII guidelines, as single drugs or in combination regimes, can improve BP control and prevent cardiac damage.

Kidney disease associated with primary antiphospholipid syndrome: clinical signs and histopathological features in an case experience of five cases.

BACKGROUND: The primary antiphospholipid syndrome (PAPS) is characterized by the presence of circulating antiphospholipid antibodies, clinically associated with blood hypercoagulability. Renal involvement in course of PAPS is very frequent, although the true prevalence of PAPS-correlated kidney disease is difficult to estimate. MATERIALS AND METHODS: We reviewed 270 consecutive renal biopsies examined in our Nephrology Division of Bari University Hospital between 1998 and 2004 to identify those performed in patients with PAPS. RESULTS: We identified five biopsies performed in patients with PAPS. In three patients the diagnosis of PAPS was made at onset of the kidney disorder, while in the other two cases the initial diagnosis was primary focal segmental glomerulosclerosis (FSGS). In these cases the subsequent finding of positive antiphospholipid antibodies reoriented the diagnosis toward PAPS-correlated nephropathy. The clinical onset of kidney disease consisted of acute renal failure in three patients and urinary abnormalities in the other two. Histological examination of renal biopsies showed vascular lesions (intimal fibrous hyperplasia, arteriolar hyalinosis, double outline of the capillary walls) in four patients. Focal segmental glomerulosclerosis was present in four patients, two of whom showed double outline of the capillary walls. All patients had tubulo-interstitial lesions, while immunofluorescence was positive in only two patients. All patients preserved stable renal function throughout follow-up (mean value: 10.6 years, range 4 months-24 years). The prevalence of PAPS-correlated nephropathy in our population was 1.85% CONCLUSION: Our data confirm that PAPS-associated nephropathy has slow progression and rarely leads to end-stage renal failure. The prevalence of PAPS-correlated nephropathy is likely underestimated because some patients with a diagnosis of primary focal sclerosis may actually be affected by PAPS.

Noninvasive assessment of coronary artery stenoses by multidetector-row spiral computed tomography: comparison with conventional angiography.

BACKGROUND: Coronary artery disease (CAD) is the most common cause of hospitalization and mortality in many industrialized countries. We analysed the diagnostic accuracy of multi-detector row spiral computed tomography (MDCT) in determining mid- to high-grade coronary artery stenoses (> 50%). METHODS: Sixty-nine patients with suspected CAD were referred to MDCT coronary angiography. Patients with a heart rate above 60 bpm received 20-40 mg propranol before the scan. The left main (LM), the left anterior descending artery (LAD), the first diagonal branch (D1), the right coronary artery (RCA) and the proximal tract of the circumflex artery (LCX) were independently evaluated by two blinded observers and screened for > 50% stenoses. The mean values of MDCT coronary narrowings assessed by two observers were compared to quantitative coronary angiography. RESULTS: MDCT correctly detected 95 of 123 coronary lesions (sensitivity 77.2%) and absence of stenoses was correctly identified in 388 of 426 segments (specificity 91%). The sensitivity for the LM, LAD, RCA and the proximal tract of LCX was 100%, 86.5%, 69.8% and 80% respectively. Classification of patients as having 1-vessel, 2-vessels, 3-vessels or left main disease was accurate in 75.4% (46/61) of patients. CONCLUSIONS: MDCT technology, combined with heart rate control, allows reliable noninvasive detection of hemodynamically significant CAD.

Up-regulation of IL-18 and predominance of a Th1 immune response is a hallmark of lupus nephritis.

There is evidence that nephritis is dominated by a Th1 immune response in systemic lupus erythematosus. Since IL-18 promotes polarization of the immune response toward Th1, we investigated the role of this cytokine in lupus nephritis (LN). A total of 133 lupus patients and 44 healthy subjects were enrolled. Demographic and clinical characteristics with renal biopsy data were recorded. IL-18 along with IFN-gamma and IL-4, two prototypical of Th1 and Th2 cytokines, were measured in serum by ELISA. Peripheral blood lymphocytes were analysed by flow cytometry for IFN-gamma and IL-4. IL-18 expression was determined by immunohistochemistry in 13 renal biopsy specimens from patients with LN and 2 controls. Serum IL-18 was higher in lupus patients than in controls. Levels of IL-18 correlated with urinary microalbumin and were increased in patients with LN when compared to those without LN. IL-18 expression was also increased within the glomeruli of nephritic patients and was primarily detected within the mesangial matrix and in infiltrating mononuclear cells. Measurement of IFN-gamma and IL-4 in either sera or peripheral blood lymphocytes showed high IFN-gamma along with low IL-4 expression in LN patients compared to patients without nephritis. A positive correlation between serum IL-18 and IFN-gamma levels was found. IL-18 may play a prominent role in the pathogenesis of LN by promoting a cytokine imbalance towards a Th1 immune response. Measurement of IL-18 may be helpful for the early identification of lupus patients with LN and may help gauge the response to treatment in patients with active LN undergoing treatment.

Prominent crista terminalis mimicking a right atrial mixoma: cardiac magnetic resonance aspects.

A 68-year-old woman came to our observation with a clinical history of isolated systolic hypertension poorly controlled by the combination of ramipril 5 mg and hydrochlorothiazide 12.5 mg o.d. The ECG showed sinus rhythm with heart rate of 68 beats per minute and signs of left ventricular hypertrophy without strain. Further investigation included an echocardiogram that showed normal left and right cavities and normal cardiac valves. At the level of the posterior wall of the right atrial (RA) an apparent smooth, bean-like tumor, having a thin pedicle, was identified as a RA mixoma. Cardiac MRI was requested and showed in two sequential slices a muscular ridge, identified as a prominent crista terminalis. Some para-physiological structures sited in the RA may have the appearance of tumors, as crista terminalis, Eustachian valve extending into the RA chambers and Chiari network. The multiplain projections of MRI allow the cardiologist to identify the presence of intracardiac masses and to make a differential diagnosis between neoplasms and variant anatomic structures.

Primary renal lymphoma does exist: case report and review of the literature.

Primary renal lymphoma (PRL) is a controversial and rare disease and there is still no agreement on its existence. Many cases have been reported in the literature, but clear diagnostic criteria have not yet been established. Most of the reported cases are questionable because of incomplete staging or the presence of extrarenal disease. Here we report a new case and a review of the literature based on a critical examination of the diagnostic procedure. Thus, probably only 29 cases, ours included, should be recognized as PRL, because only these cases fulfil the three diagnostic criteria and underwent complete diagnostic screening, including renal biopsy, bone marrow biopsy and thoraco-abdominal computerised tomography (CT).

Results of antihypertensive treatment by primary and secondary care physicians as assessed by ambulatory blood pressure monitoring.

BACKGROUND: We present data from a cross-sectional study on consecutive non-randomized drug-treated mild-to-moderate essential hypertensives, whose blood pressure was ambulatorily monitored for 24 h to evaluate the presence of adequate control. DESIGN: Primary and secondary care physicians were invited to send to our clinic drug-treated patients with essential hypertension (JNC VI stages 1-2) to undergo 24-h ambulatory blood pressure monitoring (ABPM) while continuing their prescribed medications. METHODS: The 436 enrolled patients (255 males, 181 females, age 61+/-11 years) were left on their therapeutic regime: monotherapy in 208 patients (47. 7%) and combination therapy in 228 patients (52.3%). All the patients were divided into two care groups: primary care, 238 patients (54.6%) and secondary care, 198 patients (45.4%). A mean daytime blood pressure < or =135/85 mmHg was chosen as a definition of adequate blood pressure control. RESULTS: Adequate blood pressure control was found in 196/436 total patients (45%); 112/238 patients in primary care (47%) and 84/198 patients in secondary care (42.4%) (P=NS); 94/208 patients (45.2%) in monotherapy and 102/228 patients (44.7%) in combination therapy (P=NS); 125/255 male patients (49%) and 71/181 female patients (39.2%) (P=0.0428). In the logistic regression model, female sex was associated with a higher risk of inadequate blood pressure control of about 50%. CONCLUSIONS: Adequate blood pressure control, as assessed by ABPM, is not different in the two settings of family doctor's office and specialist's clinic and is predicted by male gender. The figures of adequate blood pressure control remind us of the rule of halves, regardless of treatment regimes and medications.

Therapeutic assessment of adult patients with isolated corrected transposition of the great arteries.

Corrected transposition of the great arteries is a rare congenital heart disease, affecting 1% of children with cardiac malformation. Patients with transposition of the great arteries and without associated cardiovascular anomalies are very infrequent and may remain undiagnosed until adult life, because they usually are asymptomatic until the fourth or fifth decades. At this time, most symptoms occur in close connection with deterioration in systemic (right) ventricle performance and with an increase in left atrial pressure. In this report, we describe two new adult cases of isolated, corrected transposition of the great arteries, offering several considerations on their clinical profile and therapeutic assessment.

Blood pressure circadian rhythm and variability in subjects with severe heart failure.

To explore whether a condition of severe heart failure results in alteration of the 24-h-blood pressure (BP) profile and BP circadian rhythm, 19 patients with severe heart failure (NYHA class III-IV, 17M, 2F, mean age 57+/-8 years) were considered and compared to a control group of age- and sex-matched normal subjects. All subjects were submitted to non-invasive 24-h ambulatory blood pressure monitoring using a SpaceLabs 90207 unit (recording interval 15 min). Both systolic and diastolic BP profiles were evaluated using the two-step method of analysis reported by Staessen: the existence of a BP circadian rhythm was first tested using Siegel's runs test, then a Fourier multiple harmonic analysis allowed us to obtain the BP profile parameters Acrophases (Acro, hh:mm) and Amplitudes (Ampl, mm Hg). The same methods were used for pulse rate. Our results showed the presence of a BP circadian rhythm in severe heart failure subjects, as well as in control subjects. Furthermore, no significant difference was found between the two groups when considering the BP profile parameters Acro and Ampl. In conclusion, in contrast with previous reports, our results show that both BP circadian rhythm and BP profile parameters are preserved in patients with severe heart failure.

[Echography in the diagnosis and follow-up of renal biopsy complications]. / Ruolo dell'ecografia nella diagnosi e nel follow-up delle complicanze della biopsia renale.

The introduction of echography represented a focal step in the management of renal biopsy, resulting in easier and faster procedures. Chiefly, echography allows the diagnosis and monitoring of complications of bioptic procedure. Here we present a series of 722 consecutive echo-guided renal biopsies, carried out from 1990 to 1995, 97 of which on kidney allografts. Echographic examination, performed 24 to 48 hours after renal biopsy, enable to diagnose the presence of perirenal hematoma in 30% of patients. Of these, only 10% presented with clinical symptoms and/or signs (reduction of Hct and arterial pressure, local pain). Our protocol comprises an echographic follow-up to control the evolution of hematoma, that usually resolves within 15-40 days, according to the initial size of the lesion. One time we observed an intra-parenchimal hematoma, which resulted in kidney rupture and consequent nephrectomy. 14% of all patients complained with macrohematuria: in 10% of these cases, echography showed the presence of coaguli in the urinary tract, which was associated with the clinical features of renal colic pain. Only in two cases of persistent macrohematuria, the echography together with echo- and color-doppler, allowed the diagnosis of the arterio-venous fistula. In conclusion, our experience demonstrates that the echographic examination allows not only to simplify the bioptic procedure, but also to early diagnose the complications due to this invasive manouvre.

Expression of epidermal growth factor and its receptor in normal and diseased human kidney: an immunohistochemical and in situ hybridization study.

The kidney is one of the major sites of EGF production and there it seems to play several biological functions, such as modulation of cell growth, renal repair following injury, regulation of cellular metabolism and glomerular haemodinamics. The present study was first aimed at localizing EGF and its receptor (R) in normal human kidney by immunohistochemical and in situ hybridization techniques. Then, the distribution of the growth factor and its R was explored in biopsy specimens from eight patients with acute tubulointerstitial damage. In the normal human kidney, both EGF immunoreactivity and EGF mRNA were localized in tubular profiles corresponding to Henle's loop and, although to a lesser intensity, to distal convoluted tubule. EGF immunostaining was remarkable mainly at the apical surface of tubular cells. EGF-R protein expression was detected in glomerular endothelial cells, in peritubular capillaries and arteriolar walls, as well as along the thick ascending limb of Henle's lop and distal convoluted tubule, where it colocalized with Tamm-Horsfall protein. Immunohistochemical analysis of tubular profiles revealed that EGF-R was located especially along the basolateral membrane of tubular cells and within the basal part of cytoplasm. Endogenous alkaline phosphatase and CHIP28 positive tubules did not show any signal for EGF and its receptor. Kidneys with acute tubulointerstitial injury exhibited a dramatic decrease of EGF expression, whereas EGF-R showed only minor modifications. Interestingly, EGF-R was localized to both apical and antiluminal membranes of positive tubular cells. It is concluded that EGF-EGF receptor loop may be relevant in the pathogenesis of acute tubulointerstitial damage and recovery from tubular injury, while its role in the physiological renewal of the urothelium remains speculative.