Managing data for the international, multicentre INTERGROWTH-21st Project.

The INTERGROWTH-21(st) Project data management was structured incorporating both a centralised and decentralised system for the eight study centres, which all used the same database and standardised data collection instruments, manuals and processes. Each centre was responsible for the entry and validation of their country-specific data, which were entered onto a centralised system maintained by the Data Coordinating Unit in Oxford. A comprehensive data management system was designed to handle the very large volumes of data. It contained internal validations to prevent incorrect and inconsistent values being captured, and allowed online data entry by local Data Management Units, as well as real-time management of recruitment and data collection by the Data Coordinating Unit in Oxford. To maintain data integrity, only the Data Coordinating Unit in Oxford had access to all the eight centres' data, which were continually monitored. All queries identified were raised with the relevant local data manager for verification and correction, if necessary. The system automatically logged an audit trail of all updates to the database with the date and name of the person who made the changes. These rigorous processes ensured that the data collected in the INTERGROWTH-21(st) Project were of exceptionally high quality.

Prevalence of infected patients and understaffing have a role in hepatitis C virus transmission in dialysis.

To assess hepatitis C virus (HCV) incidence rates and identify determinants of infection among hemodialysis patients, a multicenter study was conducted in 58 units in ITALY: An initial seroprevalence survey was conducted among 3,492 patients already on hemodialysis therapy as of January 1997 and among an additional 434 patients who began dialysis up to January 1998. HCV antibodies were assessed by third-generation enzyme immunoassays. Patients testing seronegative at baseline were enrolled into a 1-year incidence study with serological follow-up at 6 and 12 months. For patients who seroconverted, an HCV RNA assay was performed on stored baseline samples to confirm new infection. A nested case-control study was subsequently performed to investigate potential risk factors. For each incident case, three controls negative for both HCV antibodies and HCV RNA were randomly selected. At enrollment, HCV seroprevalence was 30.0%. During follow-up, 23 new HCV cases were documented, with a cumulative incidence of 9.5 cases/1,000 patient-years. By logistic regression analysis, an increased risk for HCV infection emerged for patients attending the dialysis units with a high prevalence of HCV-infected patients at baseline (odds ratio [OR], 4.6) and for those attending units with a low personnel-patient ratio (OR, 5.4). Among extradialysis factors, a history of surgical intervention in the previous 6 months (OR, 16.7) significantly increased HCV risk. These findings suggest that the combination of understaffing and a high level of infected patients in the dialysis setting increases the risk for HCV nosocomial transmission. This is likely related to an increased likelihood for breaks in infection control measures.

Can thermodynamic measurements of receptor binding yield information on drug affinity and efficacy?

The present commentary surveys the methods for obtaining the thermodynamic parameters of the drug-receptor binding equilibrium, DeltaG degrees, DeltaH degrees, DeltaS degrees, and DeltaC degrees (p) (standard free energy, enthalpy, entropy, and heat capacity, respectively). Moreover, it reviews the available thermodynamic data for the binding of agonists and antagonists to several G-protein coupled receptors (GPCRs) and ligand-gated ion channel receptors (LGICRs). In particular, thermodynamic data for five GPCRs (beta-adrenergic, adenosine A(1), adenosine A(2A), dopamine D(2), and 5-HT(1A)) and four LGICRs (glycine, GABA(A), 5-HT(3), and nicotinic) have been collected and analyzed. Among these receptor systems, seven (three GPCRs and all LGICRs) show "thermodynamic agonist-antagonist discrimination": when the agonist binding to a given receptor is entropy-driven, the binding of its antagonist is enthalpy-driven, or vice versa. A scatter plot of all entropy versus enthalpy values of the database gives a regression line with the equation TDeltaS degrees (kJ mol(-1); T = 298.15 K) = 40.3 (+/- 0.7) + 1.00 (+/-0.01) DeltaH degrees (kJ mol(-1)); N = 184; r = 0.981; P < 0.0001 - which is of the form DeltaH degrees = beta. DeltaS degrees, revealing the presence of the "enthalpy-entropy compensation" phenomenon. This means that any decrease of binding enthalpy is compensated for by a parallel decrease of binding entropy, and vice versa, in such a manner that affinity constant values (K(A)) of drug-receptor equilibrium (DeltaG degrees = -RT ln K(A) = DeltaH degrees - TDeltaS degrees ) cannot be greater than 10(11) M(-1). According to the most recent hypotheses concerning drug-receptor interaction mechanisms, these thermodynamic phenomena appear to be a consequence of the rearrangement of solvent molecules that occurs during the binding.

Binding thermodynamics at the human neuronal nicotine receptor.

The thermodynamic parameters deltaGo (standard free energy), deltaHo (standard enthalpy) and deltaSo (standard entropy) of the binding equilibrium of eleven ligands (six agonists and five antagonists) to the neuronal nicotinic receptor were determined by affinity measurements carried out on human thalamus membranes at six different temperatures (0, 10, 20, 25, 30, 35 degrees) and deltaG vs. T plot analysis. Affinity constants were obtained by saturation experiments for [3H]-cytisine, a ganglionic nicotinic agonist, or its displacement in inhibition assays for the other compounds. The deltaG vs T plots appeared to be reasonably linear in the full temperature range for most of the compounds investigated (equilibrium heat capacity change,deltaCo(p) approximately 0), with the exception of the three agonists cytisine, nicotine and methylcarbachol (deltaCo(p) of the order of -720 / -1610 J mol(-1) K(-1)). Thermodynamic parameters were in the range -53.3 < or =deltaHo < or = -28.9 kJ mol(-1) and -41 < or = deltaSo < or = 69 J mol(-1) K(-1) for agonists, and 8.7 < or = deltaHo < or = 68.2 kJ mol(-1) and 99 < or = deltaSo < or = 311 J mol(-1) K(-1) for antagonists, indicating that agonistic binding was both enthalpy- and entropy-driven, while antagonistic binding was totally entropy-driven. Agonists and antagonists were, therefore, thermodynamically discriminated. Experimental results were discussed with particular regard to the following points: 1) reasons why membrane receptors displayed unusually low values of deltaCo(p); 2) possible reasons for the phenomenon of thermodynamic discrimination between agonists and antagonists particularly in connection with ligand-gated ion channel receptors; and 3) the origin of the recurrent phenomenon of enthalpy-entropy compensation which has been observed for neuronal nicotinic receptor ligands as well as for all membrane receptors studied thus far.

Oral aluminum and neuropsychological functioning. A study of dialysis patients receiving aluminum hydroxide gels.

Nine dialysis patients with significantly increased serum-aluminum levels due to chronic ingestion of aluminum hydroxide gels and eleven dialysis patients with normal serum-aluminum levels were tested neuropsychologically for generalized functions (intelligence, reasoning, memory) and for more specific abilities (visual memory, verbal and reading fluency, manual dexterity). All tests did not reveal any significant difference in neurophyscholigical functioning between the two groups. This finding seems to indicate that oral aluminum is not neurotoxic for man, even under circumstances of renal failure. This contradicts the idea that oral aluminum plays a role in etiology of dialysis dementia. However, the possibility cannot be excluded that aluminum overload in the present sample was not sufficient to induce changes in CNS functioning. Thus, until the importance of oral aluminum has been decided, it seems wise to keep all sorces of aluminum overload as low as possible.

Urinary glycosaminoglycans in recurrent urinary tract infections in kidney transplant patients.

Glycosaminoglycans have generalized antibacterial anti-adherent activity, and cooperate with secretory immunoglobulin-A in anti-infection defense mechanisms of the urinary tract. Cyclosporin A modulates T-lymphocytes and fibroblast functions. In this report we analyze urinary glycosaminoglycans and secretory immunoglobulin-A in renal transplant patients with recurrent urinary tract infections treated with cyclosporin. The results show a significant decrease of total glycosaminoglycans and secretory immunoglobulin-A in recurrent urinary tract infections which is unrelated to cyclosporin treatment. The data support the hypothesis that recurrent urinary tract infections may be the consequence of a genetic pathology rather than cyclosporin-induced alterations.

Effects of the recombinant human erythropoietin (rHuEPO) administration on hematologic parameters, red cell creatine and 2,3-diphosphoglycerate contents, in patients affected by end-stage renal disease.

Twenty patients with renal failure and severe anemia (hemoglobin range 6.6-8.7 g/dl) on thrice-weekly maintenance hemodialysis were treated with recombinant human erythropoietin (rHuEPO). After three months of intravenous (iv) therapy the hemoglobin increase averaged 2 g/dl, and was steadily maintained even after two months of subcutaneous (sc) therapy. The significant increase of macrocyte counts, determined by an automated red blood cell counter after both steps of therapy, suggested the release of young red cells (large cells) into blood circulation. This assumption may be supported by the significant increase of the red cell creatine contents. 2,3-diphosphoglycerate (2,3-DPG) levels of the erythrocytes did not significantly change after rHuEPO administration.

HBV-related cutaneous periarteritis nodosa in a patient 16 years after renal transplantation: efficacy of lamivudine.

Cutaneous periarteritis nodosa (PAN) is a clinical feature characterized by chronic, benign course; its pathogenesis is unknown. In patients submitted to renal transplantation cutaneous PAN is a rare complication. We report a case of cutaneous PAN associated with the reappearance of hepatitis B antigen 16 years after kidney transplantation. A 44-year-old man underwent successful renal transplantation in June 1980. In December 1996 he presented multiple painful erythematous subcutaneous nodules on both legs. Skin lesion biopsy showed the presence of cutaneous PAN. Six months later laboratory data demonstrated the presence of HbsAg. HBeAg, HBcAb and detectable HBV-DNA serum by polymerase-chain-reaction (PCR) assay. Anti-HBs and anti-HBe proved negative. In July 1998 the laboratory tests showed an important increase of HBV-DNA (5.1 billion by Branched DNA), and so lamivudine (100 mg/day) was introduced. HBV-DNA became undetectable by PCR after 3 months of therapy. Seven months later a new skin biopsy was performed. The typical signs of PAN were no longer evident. As HBV infecion was demonstrated six months after the clinical appearance of the PAN, in a patient who was believed to be immune to the virus, it is possible that, in the early stages, the hepatitis B antigen title was methodologically indeterminable, but sufficient to form circulating immune complexes responsible for vasculitis primer. Lamivudine therapy resulted efficacious in favouring the regression of cutaneous PAN, but its long-term efficacy requires further evaluation as regards potential selection of drug resistant hepatitis B virus (HBV) mutants during treatment.

Kaposi's sarcoma in renal transplant recipients: pathogenetic relation between the reduced density of Langerhans cells and cyclosporin-A therapy.

Patients treated with immunosuppressive drugs can develop cancers. The authors present two cases of Kaposi's sarcoma in kidney transplant patients who had been treated with azathioprine, steroids and cyclosporin-A; during this treatment the Langerhans cells decreased and Kaposi's sarcoma appeared. Discontinuation or reduction of the dosage of cyclosporin-A led to complete regression of the illness, and the Langerhans cells reappeared. We suggest that cyclosporin-A damages the immunological function of the epidermal Langerhans cells, and that this is the primary factor in the development of Kaposi's sarcoma.

Cognitive function and regular dialysis treatment.

The purpose of this investigation was to assess the intellectual function of patients on regular dialysis treatment by using neuropsychological tests such as the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scale (WMS). Studies were performed on 54 patients; 21 patients were retested after at least 12 months. We found no relationship between the neuropsychological scores and the blood levels of small molecules, the hemoglobin concentrations, the serum aluminium levels, and the levels of formal education. We found, however, an impairment of neuropsychological performance, mainly for memory function, related to the duration of dialysis and, possibly, to parathormone levels. We conclude that standard hemodialysis strategies are not able to prevent the development of intellectual impairment in uremic patients and that the WMS could be used as a sensitive objective measure of the comparative adequacy of various long-term dialysis treatments.

Clinical characteristics associated to atrial fibrillation in chronic hemodialysis patients.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia diagnosed in non-uremic patients and its prevalence increases in older subjects, however, information concerning AF in dialysis patients is scarce. Therefore, we carried out a prospective cross-sectional study from September 1996 to December 1996 in order to evaluate the prevalence and some of the clinical characteristics associated to AF in hemodialysis (HD) patients. SUBJECTS AND METHODS: 316 HD patients (age 63 +/- 12 years, dialysis duration 69 +/- 71 months) treated in three different hospital-based units were studied. Standard 12-lead electrocardiograms (ECGs) carried out in the interdialytic day during the study period were reviewed. Data concerning age, history of ischemic heart disease (IHD), cerebrovascular disease (CVD), peripheral vascular disease (PVD), presence of diabetes, smoking history and antihypertensive therapy were collected. Systolic and diastolic blood pressure, fasting cholesterol and triglycerides, albumin and hemoglobin were also derived from the clinical records. Performance status was assessed by Karnofsky index (Ki). RESULTS: 74 patients (23.4%) had persistent AF, i.e. presence of AF in all (at least two) ECGs performed in the study time. Patients with AF were older (age 69 +/- 10 vs 62 +/- 12 years, p < 0.001), had lower Ki (54 +/- 20 vs 68 +/- 17, p < 0.01), cholesterol (182 +/- 46 vs 198 +/- 52 mg/dl, p < 0.01) and albumin (3.9 +/- 0.5 vs 4.1 +/- 0.5 g/dl, p < 0.001) compared to those with no AF. Prevalence of IHD (44.5% vs 19%, p < 0.05) and PVD (23% vs 11%, p < 0.05) was higher among AF patients. Logistic regression analysis showed that IHD (p < 0.001) and Ki (p < 0.01) were independently associated to AF. CONCLUSION: We conclude that AF is a frequent arrhythmia in HD patients treated in hospital-based dialysis units, especially in those with low performance status. It appears to be associated to the atherosclerotic damage of coronary arterial tree. Prospective studies are necessary to assess whether it could contribute to cardiovascular morbidity and mortality in end-stage renal disease.

Altered circadian rhythms of blood pressure and heart rate in non-hemodialysis chronic renal failure.

The extended use of ambulatory monitoring has permitted the identification of many conditions in which the circadian rhythm of blood pressure is altered. The common denominator seems to be an impairment of the autonomic nervous system function. We examined whether the circadian blood pressure rhythm is altered in chronic renal failure (where autonomic dysfunction is usually present) by using a standardized chronobiological inferential statistical method in hospitalized subjects. For this purpose, a group of 30 non-hemodialysis hypertensive patients with chronic renal failure was compared with a second group of 30 patients affected by uncomplicated mild-to-moderate essential hypertension. The two groups were matched by age, sex and circadian mesors of blood pressure. Diet, meal times, sleep, and activity logs were standardized. Blood pressure and heart rate recordings were obtained by using an automatic oscillometric recorder and subsequently analyzed according to the cosinor method. A mean circadian rhythm of blood pressure was documented in both groups, but while the mean acrophases occurred between 2 and 3 p.m. in essential hypertension, in renal failure they were between 11 p.m. and midnight for blood pressure and around 7 p.m. for heart rate. In addition, the mean circadian amplitudes were significantly lower in renal failure, while the mean circadian mesor of heart rate was significantly higher. Our data demonstrate that the circadian rhythms of blood pressure and heart rate are altered also in hypertension due to chronic renal failure.

Self-assembly of NH-pyrazoles via intermolecular N-H.N hydrogen bonds.

The crystal structures of two NH-pyrazole derivatives forming intermolecular N-H.N hydrogen bonds are reported: 5-methyl-4-(3-methylpyrazol-5-yl)pyrazol-3-ol, C(8)H(10)N(4)O (P1), and 3-methyl-5-dihydro-1H-naphtho[1,2-d]pyrazole hemihydrochloride, C(12)H(12)N(2).-C(12)H(13)N(2)(+).Cl(-) (P2). 26 other structures are surveyed in order to obtain a deeper insight into the ways NH-pyrazoles self-assemble by means of intermolecular N-H.N hydrogen bonds in molecular crystals. A limited number of compounds form chains or dimers via homonuclear N(+)-H.N positive-charge-assisted hydrogen bonds, typical of proton sponges, which can be remarkably short [e.g. N.N 2.714 (3), N-H 1.09 (3), H.N 1.63 (3) Å, N-H.N 169 (3) degrees in (P2)]. Most pyrazoles, however, pack via neutral N-H.N bonds which are formally assisted by resonance (resonance-assisted hydrogen bond, RAHB) through the.N=C-C=C-NH. iminoenamine fragment, contained in the ring, giving rise to dimers, trimers, tetramers and infinite chains of pyrazole molecules. Surprisingly, the resonance does not appear to shorten the N-H.N bond with respect to the accepted mean value N.N 2.97 (10) Å for non-resonant N-H.N bonds. It is shown that this is due to the internal pi-delocalization of the pyrazole ring, which can be hardly increased by the hydrogen-bond interaction, except in symmetrically 3,5-substituted pyrazoles which display N.N distances as short as 2.82 Å, identical C-C and C-N distances in the two halves of the pyrazole molecule, and typical phenomena of N-H.N dynamical proton disorder, detectable by (15)N-CP/MAS solid-state NMR.

Interplay of hydrogen bonding and other molecular interactions in determining the crystal packing of a series of anti-beta-ketoarylhydrazones.

The crystal structures of six anti-beta-ketoarylhydrazones are reported: (a1) (E)-2-(4-cyanophenylhydrazono)-3-oxobutanenitrile; (a2) (E)-2-(4-methylphenylhydrazono)-3-oxobutanenitrile; (a3) (E)-2-(4-acetylphenylhydrazono)-3-oxobutanenitrile; (a4) (E)-2-(2-methoxy-phenylhydrazono)-3-oxobutanenitrile; (a5) (E)-2-(2-acetylphenylhydrazono)-3-oxobutanenitrile; (a6) (E)-2-(2-nitrophenylhydrazono)-3-oxobutanenitrile. All compounds contain the pi-conjugated heterodienic group HN-N=C-C=O and could form, at least in principle, chains of intermolecular N-H.O hydrogen bonds assisted by resonance (RAHB-inter). Compounds (a1) and (a2) form this kind of hydrogen bond though with rather long N.O distances of 2.948 (3) and 2.980 (2) Å, and compound (a6) undergoes the same interaction but even more weakened [N.O 3.150 (1) Å] by the intramolecular bifurcation of the hydrogen bond donated by the N-H group. The intrinsic weakness of the intermolecular RAHB makes possible the setting up of alternative packing arrangements that are controlled by an antiparallel dipole-dipole (DD) interaction between two C=O groups of the beta-ketohydrazone moiety [compounds (a4) and (a5)]. The critical factors that cause the switching between the different packings turn out to be the presence of hydrogen bonding accepting substituents on the phenyl and, most frequently, the intramolecular N-H.O bond with the O atom of the phenyl o-substituent. The crystal packing is widely determined by RAHB-inter (three cases) or DD (two cases) interactions. Only compound (a3) displays a different packing arrangement, where the DD interaction is complemented by a non-resonant hydro-gen bond between a p-acetyl phenyl substituent and the hydrazone N-H group [N.O 2.907 (2) Å]. Crystal densities range from 1.24 to 1.44 Mg m(-3) and are shown to increase with the number of intermolecular hydrogen bonds and other non-van der Waals interactions.

Favorable clinical effects of iloprost infusion in 4 uremic patients with critical limb ischemia.

Four uremic patients with advanced peripheral arterial occlusive disease (PAOD) of lower limbs causing rest pain and ischemic-necrotic lesions were treated with a four-hour intravenous infusion of iloprost at doses of 0.75-2.5 ng/kg/min for twenty-eight days. After a week of the therapy all patients experienced disappearance of rest pain and prolonged walking distance. At the end of the trial a diabetic patient showed a complete regression of the necrotic areas of two toes while the other patients still showed ischemic-necrotic foot lesions that were well demarcated. Iloprost therapy can be effective in uremic patients with severe PAOD.

Early skeletal changes of the hand phalanges in patients with chronic renal failure.

Appearance time and the severity of skeletal changes in patients with chronic renal failure are still not well defined. In 61 patients with incipient to advanced renal insufficiency (glomerular filtration rate 70 to 5 ml/min X 1.73 m2), bone alterations (acro-osteolysis, subeperiosteal and intracortical resorption) were mammographically studied in hand phalanges. A high correlation (p less than 0.001) was found between the radiological score and the severity of the renal insufficiency. The earliest changes of renal osteodystrophy occurred in the tufts. Biopsy specimens were taken from the iliac crest in 22 patients. Qualitative bone histology correlated significantly (p less than 0.001) with the total radiological score. Mammography offers an effective and non-invasive means of studying early skeletal changes in patients with chronic renal failure.

Clinical and radiological features of bone disease in long-term (15 or more years) hemodialysis patients.

Fifteen patients on regular dialytic treatment for more than 15 years were given X-rays of the skull, spine, shoulders, wrists, pelvis and knees with the purpose of studying the principal skeletal and articular alterations due or not due to the uraemic status. Serum calcium, phosphorus, parathyroid hormone, alkaline phosphatase and basal aluminium were recorded. Osteopenia was evident in all the patients. Ten of whom (67%) showed alterations due to hyperparathyroidism. Nine patients presented the marks of dialysis spondyloarthropathy; in 14/15 cases geodes were present in the wrists, humeral heads or hip-joints; in ten patients there were multiple amyloid lesions. Two patients with serum basal aluminum above 100 micrograms/L showed the typical radiographic marks of osteomalacia. The majority of the long-term survivors showed multifactorial osteo-articular alterations resulting mainly from the combination of hyperparathyroidism and dialysis-related amyloidosis. The less frequent joint alterations were represented by arthrosis, enthesopathy and chondrocalcinosis. Disability and decreased articular mobility resulted in being mainly due to amyloid osteo-arthropathy.

Red blood cell volume distribution width (RDW) in uraemic patients on chronic haemodialysis.

Red blood cell volume distribution width (RDW) was obtained with the Coulter counter in 60 haemodialysis patients and 55 normal individuals. RDW tended to be higher in the former and the degree of increase was to some extent correlated with the underlying nephropathy. Although RDW failed to correlate with conventional tests of iron status, it was observed that iron administration could produce a decrease toward normal in RDW and a parallel increase in haemoglobin when the initial RDW was increased. In contrast, the response to iron was negligible in the patients with normal RDW basally. It was concluded that high RDW is an acceptable indicator of iron deficiency in haemodialysis patients.

Non-A, non-B hepatitis and anti-HCV antibodies in dialysis patients.

To define the prevalence of non-A, non-B hepatitis, antibodies to HCV were detected in 193 patients on renal replacement therapy (52 transplant and 141 hemodialysis patients) and in 50 staff members of a Nephrology Department. Unequivocal seroconversion was documented in 5 transplant (9.6%) and in 26 dialysis patients (18.4%). In the dialysis population, the prevalence of anti-HCV antibodies was evaluated in patients grouped according to the number of blood transfusions and to the different sections of dialytic treatment. The most striking findings were the marked differences in the prevalence of anti-HCV antibodies among patients treated in different sections (from 0% to 70%), and the presence of a significant increase in alanine-amino-transferase (ALT) concentrations in 14 anti-HCV negative patients. The results suggest that the diffusion of non-A, non-B hepatitis is mainly transfusion-related, with the possibility of significant environmental diffusion related to the violation of infection-control measures. The current immunoassay is probably unable to detect the actual frequency of the infection.

Serum aluminum levels and peritoneal dialysis.

Serum aluminum levels, significantly higher in dialysis patients than in normal subjects, were also found to be significantly higher in patients on PD than in those on HD. This could be related to a higher AI transport rate across membrane during PD than during HD. The easier contamination of PD dialysates and their acidic pH could account for this trend to a positive AI balance in PD. On the basis of our observations, however, the significance of the serum aluminum level could be very low, since aluminemia does not seem to reflect the cumulative amount of AI ingested and might not readily help predict the risk of AI intoxication.