Patient classification and outcome prediction in IgA nephropathy.

OBJECTIVE: IgA Nephropathy (IgAN) is a common kidney disease which may entail renal failure, known as End Stage Kidney Disease (ESKD). One of the major difficulties dealing with this disease is to predict the time of the long-term prognosis for a patient at the time of diagnosis. In fact, the progression of IgAN to ESKD depends on an intricate interrelationship between clinical and laboratory findings. Therefore, the objective of this work has been the selection of the best data mining tool to build a model able to predict (I) if a patient with a biopsy proven IgAN will reach ESKD and (II) if a patient will reach the ESKD before or after 5 years. MATERIAL AND METHODS: The largest available cohort study worldwide on IgAN has been used to design and compare several data-driven models. The complete dataset was composed of 1174 records collected from Italian, Norwegian, and Japanese IgAN patients, in the last 30 years. The data mining tools considered in this work were artificial neural networks (ANNs), neuro fuzzy systems (NFSs), support vector machines (SVMs), and decision trees (DTs). A 10-fold cross validation was used to evaluate unbiased performances for all the models. RESULTS: An extensive model comparison based on accuracy, precision, recall, and f-measure was provided. Overall, the results indicate that ANNs can provide superior performance compared to the other models. The ANN for time-to-ESKD prediction is characterized by accuracy, precision, recall, and f-measure greater than 90%. The ANN for ESKD prediction has accuracy greater than 90% as well as precision, recall, and f-measure for the class of patients not reaching ESKD, while precision, recall, and f-measure for the class of patients reaching ESKD are slightly lower. The obtained model has been implemented in a Web-based decision support system (DSS). CONCLUSIONS: The extraction of novel knowledge from clinical data and the definition of predictive models to support diagnosis, prognosis, and therapy is becoming an essential tool for researchers and clinical practitioners in medicine. The proposed comparative study of several data mining models for the outcome prediction in IgAN patients, using a large dataset of clinical records from three different countries, provides an insight into the relative prediction ability of the considered methods applied to such a disease.

The CST3 B haplotype is associated with frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementia. Given the role of cystatin C in brain neurodegeneration and neuroregeneration, the aim of this study was to determine whether the cystatin C gene (CST3) was genetically associated with FTLD. METHODS: Hundred and eighty-six FTLD patients and 457 controls underwent CST3 analysis by PCR and KspI enzyme digestion. RESULTS: In FTLD patients negative for the presence of PGRN mutations, we found an over-representation of the CST3 haplotype B [odds ratio (OR = 1.619, P = 0.002)] and of AB/BB genotypes (OR = 1.704, P = 0.008) in FTLD patients. CONCLUSIONS: The present study indicated the CST3 B haplotype as a putative risk factor for FTLD in PGRN mutations negative patients. The reduced level of cystatin C, previously associated with the B haplotype, might represent the molecular factor responsible for the increased risk. Long-term depletion of neurotrophic factors, such as cystatin C and progranulin proteins, seem to be a common theme in FTLD: boosting the expression of such proteins might be a promising therapeutic strategy for FTLD.

DCUN1D1 is a risk factor for frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is considered as a proteinopathy; therefore, it is conceivable that genes encoding for factors involved in protein misfolding and/or degradation could play a role in its pathogenesis. METHODS: An association study of defective in cullin neddylation 1 (DCN-1)-domain containing 1 (DCUN1D1), which is involved in protein degradation, was carried out in a population of 220 patients with FTLD as compared with 229 age-matched controls. RESULTS: A statistically significant increased frequency of the GG genotype of the DCUN1D1 rs4859146 single nucleotide polymorphism (SNP) was observed in patients compared with controls (6.9 vs. 1.7%, P = 0.011, adjusted OR: 4.39, 95% CI: 1.40-13.78). Stratifying according to the clinical syndrome, significant differences were observed between the behavioral variant of frontotemporal dementia and controls (GG frequency: 6.3 vs. 1.7%, P = 0.02, OR:4.0, 95%, CI = 1.24-12.92), as well as between patients with progressive aphasia compared with controls (15.4 vs. 1.7%, P = 0.014, OR = 11.30, 95%, CI = 1.63-78.45), but not in patients with SD versus controls (8.3 vs. 1.7%, P = 0.18, OR = 5.24, 95% C.I. = 0.45-60.63). No significant differences in allelic and genotypic frequencies of the DCUN1D1 rs4859147 SNP were found. CONCLUSIONS: The GG genotype of the DCUN1D1 rs4859147 SNP represents a risk factor for the development of FTLD, increasing the risk of about fourfold.

Dementia, delusions and seizures: storage disease or genetic AD?

We describe a case of a young patient suffering from a rapidly progressive cognitive decline, associated with delusions, myoclonus and seizures and with no family history for dementia. Clinical features, along with skin biopsy findings were overlapping storage disease; the genetic analysis, however, demonstrated a de novo presenilin 1 mutation. The present report suggests the usefulness of genetic determinations in early-onset cases of dementia, even without an autosomal dominant trait of inheritance; for these cases and their relatives an extensive genetic counselling should be recommended.

Inhibition of energy metabolism down-regulates the Alzheimer related presenilin 2 gene.

Defects in energy metabolism and oxidative stress play an important role in the pathogenesis of Alzheimer's Disease (AD). In sporadic AD cases, presenilin 2 (PS2) mRNA levels are decreased in brain areas affected by the disease. The aim of the present study was to investigate whether mitochondrial dysfunction might influence PS2 gene expression. We demonstrated that the inhibition of energy metabolism by sodium azide down-regulates PS2 gene expression through modification of promoter activity. No one of the analyzed transcription factors, sensitive to redox status of the cell, could explain this effect. Azide effect on PS2 expression was completely inhibited by the addition of an antioxidant suggesting that the imbalance of the cellular redox homeostasis modulates the expression of this gene.

Detection of the presenilin 1 COOH-terminal fragment in the extracellular compartment: a release enhanced by apoptosis.

Mutations in gene encoding presenilin 1 (PS1) are responsible for the majority of familial Alzheimer's disease (FAD) cases. We studied PS1 localization in HEK293 cells and in primary neurons obtained from rat cortex and hippocampus. We first demonstrated that PS1-CTF, but neither PS1-FL nor PS1-NTF, is released into the medium as a soluble and membrane-associated form. After induction of apoptosis with staurosporine (Sts), we observed a dramatic increase in the level of PS1-CTF in the medium, both in HEK293 and in primary neurons. Immunocytochemical analysis suggested that the release of PS1-CTF might occur via membrane shedding. Abeta(1-42) treatment reduced PS1-CTF extracellular levels. This decrease was strongly associated to an impaired secretion of sAPP fragments, thus suggesting a role of PS1-CTF in the control of trafficking and generation of APP fragments.

Genetic association of a cystatin C gene polymorphism with late-onset Alzheimer disease.

OBJECTIVE: To determine whether the cystatin C gene (CST3) is genetically associated with late-onset Alzheimer disease (AD). DESIGN: A case-control study with 2 independent study populations of patients with AD and age-matched, cognitively normal control subjects. SETTING: The Alzheimer's Disease Research Unit at the University Hospital Hamburg-Eppendorf, Hamburg, Germany, for the initial study (n = 260). For the independent multicenter study (n = 647), an international consortium that included the Massachusetts Alzheimer's Disease Research Center at the Massachusetts General Hospital, Boston; the Scientific Institute for Research and Patient Care, Brescia, Italy; and Alzheimer's research units at the Universities of Basel and Zurich, Switzerland, and Bonn, Goettingen, and Hamburg, Germany. PARTICIPANTS: Five hundred seventeen patients with AD and 390 control subjects. MEASURES: Molecular testing of the KspI polymorphisms in the 5' flanking region and exon 1 of CST3 and the apolipoprotein E (APOE) genotype. Mini-Mental State Examination scores for both patients with AD and control subjects. RESULTS: Homozygosity for haplotype B of CST3 was significantly associated with late-onset AD in both study populations, with an odds ratio of 3.8 (95% confidence interval, 1.56-9.25) in the combined data set; heterozygosity was not associated with an increased risk. The odds ratios for CST3 B/B increased from 2.6 in those younger than 75 years to 8.8 for those aged 75 years and older. The association of CST3 B/B with AD was independent of APOE epsilon4; both genotypes independently reduced disease-free survival. CONCLUSIONS: CST3 is a susceptibility gene for late-onset AD, especially in patients aged 75 years and older. To our knowledge, CST3 B is the first autosomal recessive risk allele in late-onset AD.

Presenilin 1 protein directly interacts with Bcl-2.

Presenilin proteins are involved in familial Alzheimer's disease, a neurodegenerative disorder characterized by massive death of neurons. We describe a direct interaction between presenilin 1 (PS1) and Bcl-2, a key factor in the regulation of apoptosis, by yeast two-hybrid interaction system, by co-immunoprecipitation, and by cross-linking experiments. Our data show that PS1 and Bcl-2 assemble into a macromolecular complex, and that they are released from this complex in response to an apoptotic stimulus induced by staurosporine. The results support the idea of cross-talk between these two proteins during apoptosis.

Energy metabolism inhibition impairs amyloid precursor protein secretion from Alzheimer's fibroblasts.

The present study investigates the influence of aglycemia and sodium azide (a Cytochrome c Oxidase inhibitor) on sAPP secretion from skin fibroblasts derived from sporadic AD patients and control subjects. Aglycemia reduced sAPP release in the medium of both AD and control fibroblasts to a similar extent after 2 h incubation. Treatment for 2 h with increasing azide concentrations (1 microM-100 mM) under glucose deprivation did not significantly affect sAPP secretion from control fibroblasts, but was able to significantly inhibit sAPP secretion from AD fibroblasts (maximal inhibition 51%). The failure of antioxidants like glutathione (GSH) or N-acetylcysteine (NAC) to antagonize the azide effect on AD fibroblasts and lipoperoxidation data seemed to rule out the possibility that oxidative stress could mediate the sodium azide effect on sAPP release from AD fibroblasts.

Specific role for protein kinase C alpha in the constitutive and regulated secretion of amyloid precursor protein in human skin fibroblasts.

Reduced levels of protein kinase C alpha (PKC alpha) seems to be related to an altered amyloid precursor protein (APP) secretion in fibroblasts from Alzheimer's disease (AD) patients. In this report we used a specific inhibitor of PKC alpha (Gö-6976), to investigate the role of PKC alpha in the basal and phorbol esters regulated secretion of soluble APP (sAPP) in human fibroblasts derived from healthy aged volunteers. Treatment with Gö-6976 alone reduced basal secretion by a maximum of 39%, compared to untreated cells, suggesting the partial dependence of constitutive APP secretory pathway on PKC alpha enzyme. Moreover Gö-6976 treatment completely abolished the effect of phorbol-esters mediated PKC stimulation on sAPP release, suggesting that PKC alpha is the only PKC isoform involved in controlling the secretion of sAPP in human fibroblasts.

Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease.

Alterations in amyloid precursor protein (APP) metabolism, calcium regulation, oxidative metabolism, and transduction systems have been implicated in Alzheimer's disease (AD). Limitations to the use of postmortem brain for examining molecular mechanisms underscore the need to develop a human tissue model representative of the pathophysiological processes that characterize AD. The use of peripheral tissues, particularly of cultured skin fibroblasts derived from AD patients, could complement studies of autopsy samples and provide a useful tool with which to investigate such dynamic processes as signal transduction systems, ionic homeostasis, oxidative metabolism, and APP processing. Peripheral cells as well as body fluids (i.e., plasma and CSF) could also provide peripheral biological markers for the diagnosis of AD. The criteria required for a definite diagnosis of AD presently include clinical criteria in association with histopathologic evidence obtained from biopsy or autopsy. Thus, the use of peripheral markers as a diagnostic tool, either to predict or at least to confirm a diagnosis, may be of great importance.

The gain of apolipoprotein E genotyping to separate patients with Alzheimer's disease from normal individuals: relevance to community studies.

Neuropsychological screening tests such as the Mini Mental State Examination (MMSE) are commonly used for case finding in community studies on dementia or Alzheimer's disease (AD). However, the high proportion of false-positives is an important limitation to the feasibility of such studies. The aim of this study was to evaluate whether adding apoliporotein E (apoE) genotyping to the MMSE is followed by a significant reduction of the false-positive rate. Subjects were 70 AD patients (MMSE 13-28) and 70 normal controls (MMSE 25-30). Multivariable discriminant analysis was used to classify subjects on the basis of age, gender, MMSE score and the presence of the epsilon 4 allele of apoE. When sensitivity was set at 99%, the model including age, gender and MMSE had a false-positive rate of 13.5%, while adding epsilon 4 to the previous variables decreased this figure to 6.7%. In a hypothetical community study screening for AD in a population of 1,000,000, this would turn in a decrease of false-positives from about 19,000 to about 9,500. We conclude that the use of apoE genotyping in community case-finding studies is promising and should deserve further consideration.

Severe postcardiac-transplant rejection associated with recurrence of giant cell myocarditis.

Giant cell myocarditis is a disease of unknown etiology with several controversial aspects: clinical course, therapeutic management, recurring risk after heart transplantation, and histopathological factors. We report a case of giant cell myocarditis that recurred after orthotopic heart transplantation and an uneventful postoperative period. The myocardial inflammatory process in this patient showed various evolutive phases: an acute onset of diffuse giant cell myocarditis, an evolution into a granulomatous form of inflammation within the explanted heart, and a recurrence with multiple giant cell inflammatory infiltrates in the transplanted heart. Moreover, the patient presented a severe clinical course after surgery with precocious and continuous acute rejections despite the repeated immunosuppressive treatments. In this article we discuss the morphological aspects of the disease and the postoperative course of this case in relation to the possible immune dysregulation of patients affected by myocarditis before heart transplantation.

Prognostic significance of basement membrane antigens and of soluble interleukin 2 receptor serum concentrations in heart transplant rejection.

Endomyocardial biopsy is still considered the only reliable method for diagnosing acute rejection. However, because of its invasive nature, this procedure cannot be performed on a daily basis. Therefore, for the noninvasive monitoring of transplanted patients, we tested the sensitivity of serum levels of basement membrane antigens, type IV collagen fragment NC1 and laminin fragment P1 (LP1), of antibodies against laminin and type IV collagen, and of soluble interleukin 2 receptor (sIL2R). In 17 patients who underwent heart transplantation no correlation was found between the degree of rejection and the levels of antibodies to type IV collagen and laminin. Serum laminin P1 and sIL2-R values were found increased in all the study groups even in absence of rejection; however, sIL2R levels were higher in patients with more severe rejection. NC1 levels were found significantly higher in patients with mild or moderate rejection than in those with no rejection or in controls. These preliminary data suggest a possible predictive role of basement membrane antigens in cardiac rejection, but further studies in a larger group of transplanted patients are needed.

[A case of oxalosis with heart and lung involvement]. / Un caso di ossalosi con interessamento cardiaco e polmonare.

We report the case of a 37-year-old woman with oxalosis, and cardiopulmonary involvement. Two-dimensional and Doppler echocardiography disclosed intracardiac calcifications compatible with deposition of calcium oxalate, and severe chronic pulmonary hypertension. Endomyocardial biopsy showed interstitial deposition of calcium oxalate. The absence of severe cardiac disease strengthened a deposition of calcium oxalate even in the arteries of the lungs, with secondary chronic pulmonary hypertension.

Idiopathic restrictive cardiomyopathy in the young: report of two cases.

Two cases of idiopathic restrictive cardiomyopathy in young age are reported. This rare kind of restrictive cardiomyopathy is characterized by the absence of specific histologic features of myocardial abnormalities. In both cases (aged 12 and 9 years at diagnosis), the clinical picture was characterized by severe and slowly progressive congestive heart failure. The electrocardiogram showed biventricular hypertrophy, right bundle branch block and pseudoinfarctional Q waves. Echocardiography revealed moderate pericardial effusion, biatrial enlargement, and normal or nearly normal biventricular dimensions and systolic function. Cardiac catheterization disclosed the typically restrictive filling pattern. Right ventricular endomyocardial biopsy demonstrated moderate interstitial fibrosis and cellular hypertrophy without any evidence of infiltrative or storage myocardial disease or endocardial pathology. One patient underwent cardiac transplantation, whereas in the other, transplantation was contraindicated because of longstanding pulmonary hypertension and liver cirrhosis. The knowledge of this rare entity may correctly orient the diagnostic process in children suspected of having restrictive myocardial disease. Heart, or even heart-lung, transplantation must be considered in cases with congestive heart failure before irreversible damage occurs in many organs.

Human immunodeficiency virus type 1 antigen detection in endomyocardial biopsy: an immunomorphological study.

A virological and immunomorphological study has been performed on endomyocardial biopsy from an AIDS patient. Some data suggest the possible involvement of HIV in the pathogenesis of the cardiomyopathy.

[Idiopathic restrictive cardiomyopathy: clinical, hemodynamic, histologic and prognostic profile]. / Cardiomiopatia restrittiva idiopatica: profilo clinico, emodinamico, istologico e prognostico.

Idiopathic restrictive cardiomyopathy is a rare myocardial disease characterized by restrictive physiology without a specific histologic basis. To assess its clinical, hemodynamic, morphologic and prognostic details we retrospectively evaluated all the patients hospitalized in our Institute from 1974 to 1988. Nine patients, aged 42 +/- 16 years, M/F ratio = 0.29, who represent 64% of all the restrictive myocardial diseases biopsied were identified. Severe cardiac heart failure (3-4 NYHA) and arrhythmias (ventricular and supraventricular) were extremely common. The electrocardiogram showed several non specific signs: low voltage of QRS in peripheral leads (4/7), pseudo-infarctional aspects (3/7), mono or biventricular hypertrophy (3/7) disturbance of ventricular conduction (3/7), aspecific abnormalities of ventricular repolarization (3/7). All patients showed a prolonged QTc. M-mode and 2-dimensional echocardiography demonstrated in 6 cases biatrial enlargement, normal or slightly enlarged ventricles, normal or moderately depressed fractional shortening; biventricular concentric hypertrophy was detected in 3 cases, asymmetrical septal hypertrophy in 1. Five patients showed pericardial effusion. Cardiac catheterization disclosed an increase of left and right ventricular end-diastolic pressures (8/8) with a dip-plateau pattern and/or characteristic W waveform in the atrial pressure tracing (9/9). Passive pulmonary hypertension was detected in 6/9 cases. The cardiac index was decreased in 4/8 cases. Left ventricular angiography showed mitral regurgitation in 5/8 patients, tricuspidal in 5/8. Ejection fraction was decreased in 3/8 cases. Endomyocardial biopsy showed interstitial fibrosis (8/9), cellular hypertrophy and/or nuclear alterations (7/9), slight endocardial thickening (2/9). At a mean follow-up of 22 +/- 15 months 3 patients died and 2 underwent heart transplantation. In conclusion idiopathic restrictive cardiomyopathy is one of the most frequent forms of restrictive myocardial diseases in our geographic area. Severe congestive heart failure and arrhythmias are extremely common. The disease can be suspected by clinical, electrocardiographic and echocardiographic features, but the final diagnosis requires cardiac catheterization and endomyocardial biopsy. Prognosis is severe and heart transplantation must be considered in the cases with severe heart failure.

[Clinical and hemodynamic results after aneurysmectomy and coronary revascularization]. / Risultati clinici ed emodinamici dopo aneurismectomia e rivascolarizzazione coronarica.

To assess the effects of left ventricular aneurysmectomy (l.v.a.) on left ventricular function (l.v.f.), a prospective clinical and hemodynamic study has been performed in nineteen patients (pts) operated on from 1979 to 1983. There where no operative deaths and only one late death during follow-up. A significant improvement in NYHA class was observed in 68% of the pts, 16% worsened, and the clinical status in the remaining 16% was unchanged. Hemodynamic data showed an increase in e.f. (33 +/- 12% to 43 +/- 10%; p less than 0.001), a reduction of the percentage of the abnormally contracting left ventricular segments (66 +/- 23% to 57 +/- 23%; p less than 0.05) and no significant changes of left ventricular end diastolic pressure. Revascularization index (nr. of bypassed vessels/nr. of stenotic vessels) and graft patency rate were low (0.57 and 0.72 respectively). No significant relation was noted between clinical and hemodynamic findings in the postoperative study. We conclude that l.v.a. is associated with an improvement of l.v.f. (mainly in e.f. and segmental wall contractility) and of clinical status of the pts but without a direct relation between these two parameters.