Multiple myeloma and paget disease with abnormal skull lesions and intracranial hypertension.

We report a 73 years old man with a diagnosis of Paget Disease (PD) and symptomatic Multiple Myeloma (MM). Coexistence of MM and PD has rarely been described. PD mimics many of the features of bone destructive process in MM, making differential diagnosis more complicated. In addition, the presence of serious muscolo-skeletal and metabolic complications in both diseases makes management of patients difficult, worsening the prognosis.The comparison of these two diseases has led to the characterization of a common molecular mechanism represented by the receptor activator of nuclear factor-kB ligand (RANKL)/Osteoprotegerin signaling pathway. The improved comprehension of these mechanisms led to the development of new pharmacologic agents (bisphosphonates, cytokines inhibitors) effective for the treatment of these bone diseases.

Combined analysis of three crossover clinical pharmacology studies of effects of rabeprazole and esomeprazole on 24-h intragastric pH in healthy volunteers.

AIM: To compare antisecretory effects of rabeprazole and esomeprazole after single and repeat dosing in Helicobacter pylori-negative healthy volunteers. METHODS: Results were pooled from three smaller, open, crossover, randomized studies to obtain data from 80 subjects. The studies compared: (a) 5 days' dosing of 20 mg rabeprazole and esomeprazole (n = 24); (b) single doses of rabeprazole 20 mg and esomeprazole 40 mg (n = 27) and (c) 5 days' dosing of rabeprazole 10 mg and esomeprazole 20 mg (n = 29). Washout periods were > or =14 days. Intragastric pH was recorded continuously for 24 h on days 0, 1 and 5. RESULTS: Single doses of rabeprazole 20 mg maintained 24-h intragastric pH >4 for longer than esomeprazole 20 mg (45% vs. 32%; P < 0.001); rabeprazole 20 mg and esomeprazole 40 mg were equivalent in their effects. After 5 days' dosing, rabeprazole 20 mg maintained pH >4 for longer than esomeprazole 20 mg (62% vs. 56%; P = 0.046); the reverse was true for esomeprazole 20 mg vs. rabeprazole 10 mg (56% vs. 48%; P = 0.035). In general, intragastric pH AUC during 0-5 h after dosing was higher after esomeprazole than rabeprazole, whereas the reverse was true during the night. CONCLUSIONS: The order of effects on 24-h pH was: rabeprazole 10 mg < or = esomeprazole 20 mg < rabeprazole 20 mg = esomeprazole 40 mg. Esomeprazole acts faster, whereas rabeprazole's effect lasts longer.

Pharmacodynamic effects of single doses of rabeprazole 20 mg and pantoprazole 40 mg in patients with GERD and nocturnal heartburn.

BACKGROUND: Rabeprazole and pantoprazole are both used for symptomatic treatment of gastro-oesophageal reflux disease (GERD). Speed and duration of acid suppression and intensity of effect after a single dose may be important pharmacodynamic properties in clinical use. AIM: To compare antisecretory effects of single doses of rabeprazole and pantoprazole in patients with GERD and a history of nocturnal heartburn. METHODS: An open-label, randomized, two-way crossover, clinical pharmacology study was conducted. Twenty-nine Helicobacter pylori-negative GERD patients (17 men, mean age 44 years), with a history of nocturnal heartburn (mean frequency 4.7 episodes/week), received a single dose of rabeprazole 20 mg or pantoprazole 40 mg, with a 14-day 'washout'. Intragastric pH was recorded continuously from 24 h before to 24 h after dosing. RESULTS: Mean area under the intragastric pH-time curve (AUC) was significantly higher after dosing with rabeprazole 20 mg than with pantoprazole 40 mg in all time intervals analysed, including night (P 3 and >4 was significantly greater after rabeprazole than pantoprazole in all time intervals (P

An open-label study of rabeprazole in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion.

BACKGROUND: Omeprazole and lansoprazole are both of proven efficacy in the treatment of Zollinger-Ellison syndrome and idiopathic gastric acid hypersecretion. Rabeprazole, which has a similar mechanism of action, has not previously been studied in these diseases. AIM: To determine the dose of rabeprazole that decreased basal acid output to safe levels in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion. METHODS: Patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion were given rabeprazole 60 mg once daily for uncomplicated disease or 40 mg twice daily for complicated disease. Doses were titrated according to response and continued for 2 years. Efficacy was assessed primarily by measuring basal acid output. RESULTS: All patients had basal acid output before the next dose controlled to <10 mmol/h either at the starting dose or after minor dose titration. Control of acid output was maintained for 2 years. Consistent with this, most patients reported few gastrointestinal symptoms. Gastric biopsy showed no enterochromaffin-like cell dysplasia or neoplasia. CONCLUSIONS: Rabeprazole was an effective and well-tolerated treatment for Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion, which reliably reduced gastric acid output to safe levels. Although a dose of 60 mg once daily was appropriate for most patients in this study, doses may need adjustment according to individual response.

Anoxic brain injury following near-drowning in children. Rehabilitation outcome: three case reports.

PRIMARY OBJECTIVE: To describe the outcome of near-drowning and rehabilitation contexts for recovery. METHODS AND PROCEDURES: Standardized measures were used to emphasize the functional impact of deficits over the first year post-injury in three children <2 years. Multimodal contexts for meaningful interplay were early adapted to the three cases. MAIN OUTCOMES AND RESULTS: The clinical pathways of recovery are identified. Initially all three cases manifested a generalized dystonia. Case 1 exhibited a good outcome with transient dyskinetic-dystonic syndrome; subsequently Bálint's syndrome emerged. In this case, the rehabilitation approach was organized on the pickup of direct perception of task-specific affordances. Cases 2 and 3 had poor outcomes presenting the worsening of torsion dystonia (status dystonicus) that hindered rehabilitation intervention. CONCLUSIONS: The dynamic reaggregation of spatial organization through meaningful interaction in specific ecological contexts is the principal goal of rehabilitation intervention. Status dystonicus represents the worst feature for recovery.

A randomized, double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years.

BACKGROUND: Gastro-oesophageal reflux disease has a chronic course, and often requires long-term treatment. Proton pump inhibitors are the treatment of choice for both acute and maintenance treatment, but little is known from randomized controlled trials of their effects beyond 1 year. AIM: To compare the efficacy and safety of two doses of rabeprazole with 20 mg omeprazole in the maintenance treatment of erosive gastro-oesophageal reflux disease over 5 years. METHODS: Two hundred and forty-three patients who had previously responded to acute treatment for erosive gastro-oesophageal reflux disease were prospectively randomized to receive 5 years of treatment with rabeprazole (10 or 20 mg daily) or omeprazole (20 mg daily). The primary outcome measure was endoscopically confirmed relapse of erosive gastro-oesophageal reflux disease. RESULTS: One hundred and twenty-three patients (51%) completed all 5 years of the study, with similar completion rates in the three groups. Relapses occurred in nine of 78 (11.5%), eight of 82 (9.8%) and 11 of 83 (13.3%) patients in the rabeprazole 20 mg, rabeprazole 10 mg and omeprazole 20 mg groups, respectively. Gastric biopsy showed no evidence of any harmful effects. All treatments were well tolerated. CONCLUSIONS: Rabeprazole 10 mg, rabeprazole 20 mg and omeprazole 20 mg all had similar efficacy in the maintenance treatment of gastro-oesophageal reflux disease. All three were safe and well tolerated during 5 years of treatment.

Effects of rabeprazole, 20 mg, or esomeprazole, 20 mg, on 24-h intragastric pH and serum gastrin in healthy subjects.

AIM: To compare the antisecretory effects of rabeprazole and esomeprazole in an open, randomized, two-way crossover, clinical pharmacology study. METHODS: Twenty-four healthy subjects (14 men, 10 women; mean age 26.8 years) received rabeprazole 20 mg or esomeprazole 20 mg daily on days 1-5, with a 14-day 'wash-out'. Intragastric pH was recorded continuously, and serum gastrin measured, on days 0, 1 and 5. RESULTS: On day 0, mean intragastric pH AUC was significantly higher before the esomeprazole than before the rabeprazole treatment in four of the five time intervals analysed. On days 1 and 5, mean intragastric pH AUC was higher after rabeprazole than esomeprazole during 5-11, 14-24 and 0-24 h after dosing. Mean pH AUC in the first 5 h after dosing on day 5 was higher after esomeprazole than rabeprazole (P=0.012). On day 1, mean per cent times pH > 3 and > 4 were significantly greater after rabeprazole than esomeprazole during 0-14, 14-24 and 0-24 h. On day 5, mean serum gastrin AUC0-4 was higher (P = 0.017) after rabeprazole than esomeprazole (335 vs. 316 pg/mL.h). CONCLUSION: In this clinical pharmacology study, rabeprazole 20 mg daily was more effective than esomeprazole 20 mg daily in increasing intragastric pH and maintaining pH > 3 and > 4. On day 5, mean pH AUC was higher after esomeprazole than rabeprazole.

L-dopa effects on preprogramming and control activity in a skilled motor act in Parkinson's disease.

OBJECTIVES: The authors investigated whether preprogramming (Bereitschaftspotential, BP) and control activity (skilled performance positivity, SPP) in a bimanual, sequential skilled performance task (SPT) is sensitive to L-dopa administration in non-demented Parkinson's disease (PD) patients. METHODS: Movement related potentials (MRPs) were recorded in 12 non-demented parkinsonian patients before and after acute L-dopa administration, and in 17 control subjects, all of whom were performing SPT for the first time. BP, SPP and correct performances were evaluated both as a grand average and in sequential blocks in order to verify the learning effect. RESULTS: After L-dopa administration the PD patients scored a significantly higher percentage of correct performances (P<0.05), linked to a decreased BP amplitude (P<0.001) and an increased SPP amplitude (P<0.005), than before therapy. Dynamic evaluation through the block analysis did not show any learning effect in off-therapy patients but showed that L-dopa intake improved learning, linked to a BP amplitude decrease (P<0.005) and a SPP amplitude increase (P<0.05). Furthermore, L-dopa minimized differences in the learning trend between off-therapy PD patients and controls. CONCLUSIONS: Our findings suggest that skilled motor learning is impaired in non-demented untreated PD patients. Dopaminergic drug administration seems to restore the ability of PD patients to use more automatic motor strategies, as demonstrated by the electrophysiological and behavioural pattern, which became more similar to that of normal subjects.

Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy.

There is an individual susceptibility to diabetic nephropathy, and oxidative stress is believed to play an important role in the pathogenesis of diabetic complications. Active oxygen species induce antioxidant enzyme expression in tissues, an effect considered to be a defensive mechanism. To test whether altered intracellular antioxidant enzyme production might explain the predisposition to diabetic nephropathy, we studied the effect of long-term (12 weeks) exposure to normal (5 mmol/l) or high (22 mmol/l) glucose concentrations on fibroblast antioxidant enzyme gene expression and protein activity in type 1 diabetic patients with and without nephropathy, nondiabetic nephropathic patients, and nondiabetic control subjects. Under conditions of normal glucose concentration in the culture media, CuZnSuperoxide-dismutase, MnSuperoxide-dismutase, catalase, and glutathione-peroxidase activity and mRNA expression were not different among the four groups. Under high-glucose conditions, CuZnSuperoxide-dismutase mRNA and activity increased similarly in all groups (P < 0.001 vs. basal), whereas MnSuperoxide-dismutase did not change. In contrast, catalase mRNA and activity as well as glutathione-peroxidase mRNA and activity increased in fibroblasts from type 1 diabetic patients without nephropathy (P < 0.001), in fibroblasts from nondiabetic nephropathic patients (P < 0.001), and in fibroblasts from nondiabetic control subjects (P < 0.001), but not in fibroblasts from type 1 diabetic patients with nephropathy. Exposure to high glucose concentrations significantly increased lipid peroxidation in cells, higher levels being found in cells from diabetic patients with nephropathy (P < 0.001). These data, while confirming that exposure to high glucose concentrations induces an antioxidant defense in skin fibroblasts from normal subjects, demonstrate a failure of this defensive mechanism in cells from type 1 diabetic patients with nephropathy, whereas skin fibroblasts from diabetic patients without complications or from nondiabetic nephropathic patients have an intact antioxidant response to glucose-induced oxidative stress.

QT dispersion in microalbuminuric Type 1 diabetic patients without myocardial ischemia.

Microalbuminuria is associated with an increased risk of cardiac death. We assessed whether urinary albumin excretion is related to abnormalities of the QT interval independently of myocardial ischemia. Thirty-four patients with type 1 diabetes who were free from ischemic heart disease on the basis of normal stress electrocardiography and echocardiography were studied. Maximal QT interval and dispersion were significantly greater in the group with microalbuminuria (n=17) compared to controls (n=17) with normal urinary albumin excretion (394 [26.1] vs. 373.8 [27.8] ms; P=.044 and 62.4 [21.8] vs. 42.7[11.6] arbitrary units; P=.009). Autonomic function was similar between the groups. Urinary albumin excretion correlated positively with QT dispersion (P=.023). These data suggest that in type 1 diabetic patients, QT abnormalities can occur independently of autonomic dysfunction or myocardial ischemia and may be related to the processes which increase urinary albumin leakage.

Glutathione reverses the growth abnormalities of skin fibroblasts from insulin-dependent diabetic patients with nephropathy.

Oxidative stress has been proposed as a possible pathogenic factor for diabetic complications. It is relevant in determining cell replicative capacity and life span, and in vitro antioxidant treatment is able to reverse the impaired proliferative activity of different cell types. It was recently demonstrated that cultured skin fibroblasts from insulin-dependent diabetic patients with nephropathy age prematurely and have a shorter life cell cycle. To test whether the growth phenotype of cells from patients with diabetic nephropathy was related to a lack of protection from oxidative stress, the effect of reduced glutathione (GSH) on cultured skin fibroblasts from 13 insulin-dependent diabetes mellitus (IDDM) patients with nephropathy (DN), 10 IDDM patients without kidney disease (D), and 10 nondiabetic control subjects (C), in normal (5 mM) glucose (NG) and high (22 mM) glucose (HG) medium was studied. After 6 to 8 passages, fibroblasts from DN showed impaired growth both in NG (mean +/- SD fold increase over baseline counts in DN 1.17 +/- 0.6 versus D 1.7 +/- 0.5 versus C 1.95 +/- 0.8; P = 0.04 by ANOVA) and in HG (mean +/- SD fold increase over baseline counts DN 1.16 +/- 0.41 versus D 1.89 +/- 0.66 versus C 2.24 +/- 0.9; P = 0.003 by ANOVA). GSH prevented the growth abnormalities of cells from DN restoring it to values similar to that of the other two groups (mean +/- SD fold increase over baseline counts NG +/- GSH: DN 1.68 +/- 0.9 versus D 1.78 +/- 0.49 versus C 1.99 +/- 0.7, P = 0.6; and in HG + GSH: DN 1.66 +/- 0.69 versus D 1.87 +/- 0.75 versus C 2.2 +/- 0.9, P = 0.3). Growth rates were not affected by the addition of GSH in fibroblasts from D and C. The treatment of fibroblasts from D and C with the inhibitor of the gamma-glutamylcysteine synthetase activity, L-buthionine-S,R-sulfoximine, resulted in growth impairment, and the addition to the culture medium of another antioxidant, superoxide dismutase, corrected the growth abnormalities in fibroblasts from DN. The impaired growth of cultured fibroblasts from IDDM patients with nephropathy is prevented by GSH and superoxide dismutase and is independent of prevailing glucose concentrations. This suggests that oxidative stress is an important mechanism of intrinsic cell dysfunction in these patients.

Elevated sodium-lithium countertransport activity in erythrocytes is predictive of the development of microalbuminuria in IDDM.

Pathogenetic mechanisms other than the quality of metabolic control may play a role in the development of diabetic nephropathy. Some cross-sectional studies have shown that elevated erythrocyte sodium-lithium countertransport (Na+/Li+ CT) activity may be linked to incipient or overt nephropathy in insulin-dependent diabetic (IDDM) patients. The aim of the present work was to ascertain if high erythrocyte Na+/Li+ CT activity anticipates the development of microalbuminuria in IDDM patients. Evaluation of this cation transport system was carried out in 159 normotensive, normoalbuminuric IDDM patients, who were divided into two groups: those with values above (Group A) and those with values below (Group B) the median level in the overall population (300 mumol/erythrocytes x h). A total of 79 patients in Group A and 80 in Group B underwent periodic examinations over a similar time period (5.2 years, range 3.3-7.4 years and 5.4 years, range 3.4-7.5 years, respectively). Median sodium-lithium countertransport activity was stable when evaluated after 2 and 4 years of follow-up. Only seven patients were excluded from the protocol because changes in their sodium-lithium countertransport activity placed them on the other side of the median value with respect to their baseline measurement. Thus, 152 patients completed the study (76 in Group A and 76 in Group B). Of the 76 patients in Group A, 17 developed persistent microalbuminuria (22.3%). The number of patients in Group B showing persistent microalbuminuria was significantly lower (4 of 76; 5.2%; p < 0.01). The sensitivity of erythrocyte Na+/Li+ CT in predicting the development of microalbuminuria was 85% and its specificity was 55%. Seven patients of Group A and five of Group B developed arterial hypertension. Subjects in Group A had significantly higher mean HbA1c values of twice yearly measurements than those in Group B (9.6 +/- 1.7 vs 8.3 +/- 1.7%, p < 0.002, mean +/- SD) despite similar daily insulin requirements. Systolic and diastolic blood pressure levels were also evaluated every 6 months and were significantly higher in the Group A than in the Group B patients, although on average within the normal range. The odds ratio for developing persistent microalbuminuria in IDDM with elevated baseline erythrocyte Na+/Li+ CT activity after adjustment for gender and baseline albumin excretion rate, and mean 6 monthly plasma creatinine, HbA1c and systolic and diastolic blood pressure levels was 4.2 (95% confidence intervals 2.0-11.1). It was also found that the percentage of offspring having both parents with Na+/Li+ CT activity above the median value was significantly higher in Group A than in Group B (Group A vs Group B: 35 vs 19%; p < 0.01). On the contrary the percentage of offspring whose erythrocyte Na+/Li+ CT was lower in both parents was lower in Group A than in Group B: 10 vs 38%, p < 0.01). Parents of Group A offspring had arterial hypertension more frequently than those of Group B. These results indicate that erythrocyte Na+/Li+ CT activity is a useful diagnostic tool in identifying normotensive, normoalbuminuric patients who may be predisposed to develop persistent microalbuminuria. This disorder in the cation transport system is associated with poor metabolic control, higher blood pressure, and male sex; it also appears to be, at least partly, genetically transmitted.

Permissive role of hypertension in the development of proteinuria and progression of renal disease in insulin-dependent diabetic patients.

BACKGROUND: In insulin-dependent diabetic subjects, heritable factors related to hypertension and cardiovascular disease are associated with nephropathy. OBJECTIVE: To determine the relationship of blood pressure, glycaemic control, family history of cardiovascular disease and sodium-lithium countertransport activity to the onset of proteinuria and decline in glomerular filtration. DESIGN: A retrospective analysis of the rate of onset of proteinuria and a longitudinal study of the progression of established renal disease. SETTING: Guy's Hospital Diabetes Renal Clinic, a secondary referral centre. PATIENTS: Fifty-four insulin-dependent diabetic patients with nephropathy, persistent total protein excretion rate > 500 mg/24 h, enrolled between 1978 and 1992. MAIN OUTCOME MEASURES: Rate of decline in glomerular filtration rate. Duration of diabetes at onset of nephropathy (time to proteinuria). Blood pressure and glycosylated haemoglobin at the time of diagnosis of nephropathy (baseline). Family history of cardiovascular disease and hypertension. Erythrocyte sodium-lithium countertransport activity in a subset of patients (n = 41) not being administered renal replacement therapy in 1992. RESULTS: The estimated (95% confidence interval) time to proteinuria was shortened in relation to increments in diastolic blood pressure at baseline and to a family history of cardiovascular disease in both parents [1.9 (0.2-3.2) years/10 mmHg, P < 0.05 and 6.7 (-0.3-13.7) years, P < 0.07, respectively]. During follow-up 15% (n = 8) of the patients who did not require antihypertensive therapy had slower rates of decline in glomerular filtration and lower rates of sodium-lithium countertransport activity than did those who had been administered treatment [median (range): 2.88 (0.2 to -11.28) versus 7.8 (0.1 to -20.4) ml/min per 1.73 m2/year, P < 0.05 and 0.28 (0.14-0.54) versus 0.43 (0.18-0.88) mmol/l per erythrocyte/h, P < 0.03, respectively]. In this group there was an inverse relationship between the time to proteinuria and glycosylated haemoglobin (r = -0.79, P = 0.018). For the whole group a multivariate analysis showed hypertension and initial glomerular filtration rate to be related independently to the rate of decline in renal function; glycaemic control just failed to attain statistical significance (P < 0.06). CONCLUSION: Elevation of blood pressure accelerates the onset of nephropathy and its progression; its absence, a reduced familial predisposition to cardiovascular disease, low sodium-lithium countertransport activity and good blood glucose control favour a more benign prognosis.

Premature cell ageing and evolution of diabetic nephropathy.

The rate of development and progression of renal disease varies greatly in insulin-dependent diabetic (IDDM) patients. The cellular and molecular reasons for this difference are largely unknown but could be related to early cell differentiation, a phenomenon recently reported in IDDM patients with nephropathy. In this study we compared cell differentiation and cell volume between IDDM patients with and without nephropathy and investigated the cell ageing characteristics in relation to the rate of evolution of renal disease in the IDDM patients with diabetic nephropathy. Cell volume was larger and the percentage of post-mitotic fibrocytes was higher in skin fibroblasts derived from IDDM patients with diabetic nephropathy compared to those from IDDM patients without kidney disease (mean +/- SD in arbitrary units 817.3 +/- 25.7 vs 760 +/- 32.8; p = 0.005; and mean +/- SD % 33.6 +/- 11.8 vs 20.8 +/- 10; p = 0.02 respectively). Analysis of the interaction of the time to proteinuria (TTP) and the rate of change of glomerular filtration rate (GFR) with glycaemic control, arterial blood pressure and cell volume and the state of cell differentiation showed that glycated haemoglobin and the percentage of post-mitotic fibrocytes were negatively correlated to TTP (r = -0.68; p = 0.008; r = 0.52; p = 0.05 respectively) and positively associated with the rate of change of GFR (r = 0.76; p = 0.03; r = 0.56; p = 0.037 respectively). Cell volume was negatively correlated to TTP (r = -0.53; p = 0.05). Diastolic blood pressure was also related to the rate of GFR change (r = 0.56; p = 0.039). In a multiple linear regression analysis glycated haemoglobin maintained its significance independent relationship with TTP at the 1% level, while the strength of the association between the percentage of post-mitotic cells and cell volume was reduced to the 11 and 9% level, respectively. Cultured skin fibroblasts from IDDM patients with nephropathy show signs of early differentiation. Glycaemic control is a key factor in the rate of onset of proteinuria and different rates of cell ageing appear to contribute to the rate of development and progression of diabetic nephropathy. Their interaction may be responsible for the severity of renal involvement in susceptible IDDM patients.

Premature senescence of skin fibroblasts from insulin-dependent diabetic patients with kidney disease.

Diabetic glomerulopathy develops in a subset only of patients with insulin-dependent diabetes (IDDM) and early, in its course, is characterized by cell hypertrophy and by excessive extracellular matrix production. These observations suggest that an alteration in the control of cell growth processes may contribute to its pathogenesis and be related to the susceptibility to kidney disease. We therefore investigated whether the development of diabetic nephropathy is associated with abnormalities of cell growth and morphology. Cultured skin fibroblasts from 14 IDDM patients with nephropathy (DN) were compared with those of 10 IDDM patients without nephropathy (D) and of 14 control non-diabetic subjects (C). Cell volume (in arbitrary units) and total protein content (microgram/10, 000 cells) were increased in serially passaged skin fibroblasts of IDDM patients with nephropathy (DN = 809.5 +/- 33.1 and 1.93 +/- 0.38 vs. D = 764.4 +/- 31.5 and 1.5 +/- 0.37, P = 0.005 and P = 0.03, respectively; vs. C = 756.2 +/- 36.3 and 1.5 +/- 0.38, P = 0.0006 and P = 0.03, respectively). These hypertrophic cells had a tendency to a slower duplication rate and exhibited a dissociation of the DNA and cytoplasmic cell-cycles, resulting in a higher proportion of tetraploid cells (DN = 25 +/- 15% vs. D = 6 +/- 4%, P = 0.005; and vs. C = 10 +/- 8%, P = 0.04). The frequency of terminally differentiated post-mitotic fibrocytes, cells specialized for extracellular matrix production, was higher in patients with nephropathy compared to that of patients without nephropathy and normal controls (DN = 34 +/- 14% vs. D = 21 +/- 10%, P = 0.02; and vs. C = 19 +/- 12%, P = 0.008). That early differentiation was a specific feature of cells derived from patients with diabetic nephropathy was confirmed by the study of cell life-span which demonstrated that these cells aged prematurely (log rank test, chi 2 = 10,012; P = 0.0067). We conclude that an acceleration of cell aging is a peculiar feature of diabetic kidney disease and may contribute to its pathological tissue changes.

Microalbuminuria as a marker of silent myocardial ischaemia in IDDM patients.

Insulin-dependent diabetic (IDDM) subjects with microalbuminuria have an increased long-term risk of overt cardiovascular disease; however, the early exposure to cardiovascular risk factors may increase their predisposition to current silent myocardial ischaemia. The frequency of silent myocardial ischaemia detected by stress echocardiography and electrocardiography was significantly greater in 32 asymptomatic IDDM patients with microalbuminuria compared to 32 normoalbuminuric IDDM patients (25% [n = 8] vs 6.3% [n = 2]; p = 0.03, odds ratio [95% CI] 6.3 [1.2, 37.8]). Elective coronary artery bypass grafting was required in 1 patient with microalbuminuria and silent myocardial disease. Microalbuminuria and poorer autonomic function were independently associated with silent myocardial ischaemia in multivariate analysis (p = 0.03 and p = 0.02, respectively). Screening for silent myocardial ischaemia using these non-invasive tests may be warranted in microalbuminuric IDDM which patients could be of considerable clinical importance.

Signal-averaged electrocardiography and Doppler echocardiographic study in predicting acute rejection in heart transplantation.

BACKGROUND AND METHODS: In a prospective protocol for noninvasive diagnosis of acute cardiac rejection, 83 routine endomyocardial biopsies, followed each time by the analysis of signal-averaged electrocardiography and by a cardiac Doppler echocardiographic study, were performed in 18 heart transplant recipients. The follow-up time was 5 +/- 3.6 months. To detect noninvasively acute cardiac rejection, we compared biopsy findings with the presence of late potentials at signal-averaged electrocardiography and with two diastolic indexes, pressure half-time, and isovolumic relaxation time obtained from Doppler echocardiographic study. RESULTS: Thirteen acute rejection crises requiring modification of immunosuppression were diagnosed by means of endomyocardial biopsy. This clinically relevant acute cardiac rejection was associated with the presence of late potentials in 69% of cases and with the presence of pressure half-time < or = 55 msec and isovolumic relaxation time < or = 60 msec in 69% and 62% of cases, respectively. Sensitivity and specificity were as follows: for late potentials, 69% and 71%; for pressure half-time < or = 55 msec, 69% and 76%; for isovolumic relaxation time < or = 60 msec, 62% and 83%, respectively. The presence in a single patient of at least one abnormal parameter showed a sensitivity of 100% and a specificity of 60% in detecting important rejection. CONCLUSIONS: These data support the use of combined signal-averaged electrocardiography and Doppler echocardiographic study of the left ventricular diastolic function in the screening of acute cardiac rejection. Such results can suggest when endomyocardial biopsy should be performed, with the reliance that a normal noninvasive study highly excludes the presence of acute cardiac rejection requiring intensified immunosuppression.

Serum sialic acid, a risk factor for cardiovascular disease, is increased in IDDM patients with microalbuminuria and clinical proteinuria.

OBJECTIVE: An elevated serum sialic acid concentration has recently been shown to be a potent cardiovascular risk factor in the general population. Because clinical proteinuria is associated with a high frequency of cardiovascular disease, and because microalbuminuria predicts the development of renal and cardiovascular disease in diabetes, we investigated whether serum sialic acid levels are increased in insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria or clinical proteinuria. RESEARCH DESIGN AND METHODS: We studied 23 patients with IDDM who had a normal urinary albumin excretion rate, 23 patients who had microalbuminuria, and 23 patients with clinical proteinuria. The patients were matched for age, sex, duration of diabetes, GHb levels, and body mass index (BMI). Fasting blood samples were taken for measurement of sialic acid, cholesterol, triglyceride, creatinine, and GHb. RESULTS: Serum sialic acid was significantly higher in the microalbuminuric patients compared with the normoalbuminuric group (mean +/- SD: 1.93 +/- 0.26 vs. 1.76 +/- 0.27 mM, P < 0.01). Moreover, serum sialic acid was also significantly higher in the group with clinical proteinuria compared with the microalbuminuric patients (2.34 +/- 0.24 vs. 1.93 +/- 0.26 mM, P < 0.001). Serum sialic acid was not related independently to age, BMI, diabetes duration, GHb, blood pressure, serum cholesterol, triglyceride, or creatinine concentration in any of the diabetic groups. CONCLUSIONS: These observations suggest that the serum sialic acid concentration is raised in IDDM patients with both microalbuminuria and clinical proteinuria and may play a role as a cardiovascular risk factor or disease marker in these conditions.