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.

[Renal atheroembolic disease: evaluation of the efficacy of corticosteroid therapy]. / Malattia ateroembolica: valutazione dell'efficacia della terapia steroidea.

BACKGROUND: Even though many organs may be involved and clinical manifestations are extremely variable, a sudden worsening of renal function after vascular surgery or invasive angiographic manoeuvres is a clue for the diagnosis of renal cholesterol crystal embolization. In rare cases the disease may also occur spontaneously during anticoagulant or thrombolytic therapy. Renal atheroembolism is becoming increasingly recognized as an important cause of renal failure particularly in elderly men, and is often associated with a bad outcome. To date there is no specific and proven useful treatment apart from a few anecdotal reports on the benefits of corticosteroids. PATIENTS AND METHODS: We report a group of seven patients with cholesterol atheroembolic disease presenting acute renal failure; in six patients the disease appeared after coronary arteriography and PTCA performed in the last four months, and in one patient in an apparently spontaneous form. All the patients presented cutaneous lesions, livedo reticularis, purpuric rush, necrosis of the toes; laboratory data showed an increase of acute phase proteins and eosinophilia. Results. Treatment with prednisolone was begun at a dose of 40 mg/day i.v. for four days; the dose was reduced to prednisone 0.4-0.5 mg/kg/day for 1 week, than gradually reduced further and stopped within a month. Following therapy renal function rapidly improved; clinical symptoms of malaise and abdominal discomfort subsided, with amelioration of skin lesions and cyanosis of toes. CONCLUSIONS: Despite the small number of patients studied, our experience suggests that corticosteroid treatment is an effective therapeutic option in cholesterol renal atheroembolic disease, especially in the more severe cases of acute renal failure.

[The institutional accreditation process in the Italian Regions of Emilia Romagna and Lazio: professional contents]. / L'accreditamento istituzionale in Emilia Romagna e Lazio: i contenuti professionali.

The problems related to the institutional accreditation of the structures of Nephrology, Dialysis and Transplantation has been dealt with in various documents of the Regional Scientific Societies and in Regional Legislative Decrees. Two of these documents are particularly important, one is a special experimental project by the city councillor office for Health Policies issued by the region of Lazio and the other drafted by the Regional Health Agency for the region of Emilia Romagna. What is special about these documents is the fact that nephrologists have actually participated in the drafting process and consequently great attention was given to the professional aspects of the specialised activity. The document issued by the region of Lazio tends to monitor - through criteria, indicators and standards - the various phases of health intervention in Nephrology, by following the different sectors of the process and health care areas identified by the Manual of Accreditation of the Italian Nephrology Society. The document of the region of Emilia Romagna, more complex and articulated, deals systematically with specific requirements (structural, technological, organisational), services, clinical competence and teaching, qualification of diagnostic and therapeutic processes and health care. The Italian Society of Nephrology has been asked to give an official evaluation of both documents. At this particularly uncertain stage, this approach is to be considered as being essential in maintaining consistent performance in the protection of the professional quality of the specialisation in Nephrology.

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.

Associations of squaric acid and its anions as multiform building blocks of hydrogen-bonded molecular crystals.

Squaric acid, H(2)C(4)O(4) (H(2)SQ), is a completely flat diprotic acid that can crystallize as such, as well as in three different anionic forms, i.e. H(2)SQ.HSQ(-), HSQ(-) and SQ(2-). Its interest for crystal engineering studies arises from three notable factors: (i) its ability of donating and accepting hydrogen bonds strictly confined to the molecular plane; (ii) the remarkable strength of the O-H...O bonds it may form with itself which are either of resonance-assisted (RAHB) or negative-charge-assisted [(-)CAHB] types; (iii) the ease with which it may donate a proton to an aromatic base which, in turn, back-links to the anion by strong low-barrier N-H+...O(1/2-) charge-assisted hydrogen bonds. Analysis of all the structures so far known shows that, while H(2)SQ can only crystallize in an extended RAHB-linked planar arrangement and SQ(2-) tends to behave much as a monomeric dianion, the monoanion HSQ(-) displays a number of different supramolecular patterns that are classifiable as beta-chains, alpha-chains, alpha-dimers and alpha-tetramers. Partial protonation of these motifs leads to H(2)SQ.HSQ(-) anions whose supramolecular patterns include ribbons of dimerized beta-chains and chains of emiprotonated alpha-dimers. The topological similarities between the three-dimensional crystal chemistry of orthosilicic acid, H(4)SiO(4), and the two-dimensional one of squaric acid, H(2)C(4)O(4), are finally stressed.

Erythropoietin and cardiocirculatory condition in aged patients with chronic renal failure.

BACKGROUND/AIM: The clearest benefit of recombinant human erythropoietin (rHuEPO) in end-stage renal disease is a substantial reduction in transfusion dependency and an improved quality of life. In this report, we describe the efficacy of weekly subcutaneous administration of rHuEPO in 11 elderly patients with anemia secondary to chronic renal failure. METHODS: The role of rHuEPO therapy in increasing the patient's quality of life and in decreasing the hospitalization rates secondary to cardiac morbidity was verified in 11 elderly patients (age range between 66 and 85 years) with anemia due to chronic renal failure. The mean hemoglobin level at the beginning of the study was 8.2 +/- (SD) 0.7 g/dl, and the serum creatinine concentration was 4.8 +/- 1.36 mg/dl. The patients underwent baseline and annual echocardiography, in addition to an electrocardiogram. RESULTS: Most patients experienced a partial regression of left ventricular hypertrophy, and no congestive heart failure was documented. The mean hemoglobin level during rHuEPO therapy increased to 11.3 +/- 1.2 g/dl, while the mean serum creatinine concentration did not change significantly. CONCLUSIONS: Our results confirm that early anemia correction in aged chronic renal failure patients permits improvement of the quality of life, of exercise performance, and of cognitive functions. Reduced transfusion need and regression of left ventricular hypertrophy favor a minor incidence of cardiac morbidity and contribute to reduce health costs.

General rules for the packing of hydrogen-bonded crystals as derived from the analysis of squaric acid anions: aminoaromatic nitrogen base co-crystals.

Preparation and single-crystal X-ray structure determination of three co-crystals of hydrogen squarate, HSQ(-), with 2-aminopyrimidine, 3-aminopyridine and 4-aminopyridine, and one of squarate, SQ(2-), with 8-aminoquinoline are reported. Their crystal packings are analyzed and discussed in terms of the intermolecular O--H...O, N--H...O/N and C--H...O hydrogen bonds formed. Although the fine details of the supramolecular architecture are barely rationalizable, the comparative analysis of the data makes it possible to suggest some simple rules that may be of general application for the packing of hydrogen-bonded crystals, i.e. Rule 1: 'All hydrogen-bond acceptors available in a molecule will be engaged in hydrogen bonding as far as there are available donors'; Rule 2: 'The hydrogen-bond acceptors will be saturated in order of decreasing strength of the hydrogen bonds formed'.

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.

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.

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.

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.

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.

[Causes and risks of hyperlipidemia during dialysis and after renal transplantation]. / Cause e rischi dell'iperlipidemia durante trattamento dialitico e dopo trapianto renale.

The most widely studied hyperlipidemies in patients affected by renal insufficiency or subsequent to kidney transplant present phenotype IIa, IIb or IV. The lipidic alteration most frequently observed in chronic renal insufficiency and/or dialytic treatment is represented by hypertrigliceridemia as a result of: 1) altered VLDL metabolism; 2) reduced activity of lecithin cholesterol acyltransferase (LCAT); 3) decrease in Apo-A1 and HDL3. Furthermore, marked anomalies in lipoprotein Lp (a) have been reported in hemodialysis. In patients undergoing peritoneal dialysis, hyperlipidemia arises from both an anomalous retrograde absorption of glucose and protein dispersion. Following kidney transplant the most frequent hyperlipidemia is hypercholesterolemia, consequent to immunosuppressive treatment (mainly steroids and cyclosporin). The documented significant increase of cardiovascular risk in the presence of hyperlipidemia points to the need for a clearer etiopathogenic definition of this anomaly, as well as the necessity to find an efficacious pharmacological treatment.

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.