-308(G/A) TNF-alpha gene polymorphism and risk of depression late in the life.

The relationship between major depression (MD) and dementia in the elderly is still not clear, but it is certain that the immune system and in particular, pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, play a key role in the mechanisms underlying the two neuro-psychiatric disorders. In our experience, the -308(G/A) single nucleotide polymorphism (SNP) in the TNF-alpha gene is associated with earlier age at onset in patients affected by Alzheimer's disease (AD). The aim of this study was to investigate the association between the -308(G/A) SNP and late-life MD in elderly people without dementia. Blood samples were obtained from 50 subjects, after screening with the geriatric depression scale (GDS>or=15) and mini-mental state examination (MMSE>or=24). The -308 (G/A) SNP was genotyped by SSP-PCR amplification. Two-hundred-fourty age-matched healthy volunteers were taken as the control group. We identified different genotype and allele distributions of the SNP in old depressed patients and healthy controls (HC). Our results evidenced a significantly higher percentage of the GG genotype in depressed subjects (84.0% vs. 68.3%; p=0.007) and consequently of the G allele (92.0% vs. 81.9%; p=0.05). The presence of the GG genotype raised the risk of developing MD (odds ratio=OR=2.433, confidence interval=Cl=1.09-5.43). Our findings suggested that the investigated TNF-alpha SNP may: (1) affect MD susceptibility; (2) be involved both in AD and MD development, but probably with a distinct role in the two pathologies.

Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia.

Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and alpha(1)-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer's disease (AD, n = 121) or vascular dementia (VD, n = 68) in comparison with elderly controls (n = 125). The frequency of the ApoE epsilon 4 allele was significantly increased both in late-onset AD (0.35) and in VD (0.17); the frequency of ApoE epsilon 2 was significantly reduced in AD, but it was similar in VD and controls. The presence of the allele 1 of PS-1 intronic polymorphism was not associated with AD or VD and was not influenced by the ApoE genotypes. Also, the frequency of allele A of the intronic polymorphism of ACT was similar in AD, VD and controls and it was not altered by ApoE or PS-1 genotypes. The results confirm the association between ApoE epsilon 4 and AD and indicate an increase in ApoE epsilon 4 in Vd, too. A potential protective role of ApoE epsilon 2 is also suggested for late-onset AD but not for VD. No association was shown between ACT allele A and PS-1 allele 1 in AD or VD.

Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis.

We report the clinical outcome of 105 essential mixed cryoglobulinemia (EMC) patients with renal involvement collected throughout 25 years in three renal Units of Milan. The median follow-up was 72 months since renal biopsy and 131 months since the clinical onset of EMC. Patient survival was 49% at 10 years after renal biopsy. Forty-two patients died primarily from cardiovascular and liver disease or infection, whereas 15 patients developed chronic renal failure. Two patients had a complete remission of the disease while 15 had a remission only of renal signs. Thirty-one patients are alive with persistent renal and extrarenal manifestations. Anti-HCV antibodies were retrospectively detected in 34 patients and were present in 85% of them. This variable was not included in the statistical evaluation. At multivariate analysis, age older than 50 years, purpura, splenomegaly, cryocrit levels higher than 10%, C3 plasma levels lower than 54 mg/dl, and serum creatinine higher than 1.5 mg/dl were independent risk factors for death or dialysis. In conclusion, several factors may influence the outcome of patients with EMC nephritis. Markers of disease activity and an impaired renal function can herald a bad prognosis. It should be stressed, however, that only a minority of patients eventually develop renal failure, probably because in the most severe cases patients die earlier.

Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: a multicentre randomized controlled trial.

OBJECTIVE: To compare the efficacy (maintenance of remission), safety and tolerability of cyclosporin (CsA) with those of cyclophosphamide in patients with steroid-dependent or frequently relapsing nephrotic syndrome (NS). DESIGN: Open, prospective, randomized, multicentre, controlled study for parallel groups, stratified for adults and children. The setting was in nephrological departments in Italy. SUBJECTS AND INTERVENTIONS: Seventy-three patients with steroid-sensitive idiopathic NS admitted to the study were randomly assigned to cyclophosphamide (2.5 mg/kg/day) for 8 weeks or CsA (5 mg/kg/day in adults, 6 mg/kg/day in children) for 9 months, tapered off by 25% every month until complete discontinuation at month 12. Seven patients lost to follow up were not considered in the analysis. The remaining 66 patients were followed up for 3-24 months after randomization. MAIN OUTCOME MEASURES: Relapse-free survival; number of N.S. relapses/patient/year; cumulative dose of prednisone/patient; laboratory investigations (kidney and liver functions, haematological parameters); incidence of adverse events. RESULTS: At month 9, 26 of 35 CsA-treated patients were still in complete remission and a further five patients were in partial remission; 18 of 28 cyclophosphamide-treated patients were in complete remission, and one in partial remission (P = NS). No difference between adults and children was seen with either treatment. The risk of relapse was similar between frequent relapsers (19 of 22) and steroid-dependent patients (8 of 14) given CsA, and those given cyclophosphamide (5 of 15 and 6 of 15). The mean number of relapses per year and the mean dose of prednisone per year were significantly less (P < 0.001) in both groups for the experimental year than for the year before randomization. At 2 years, 25% of the patients given CsA (50% adults and 20% children) and 63% of those given cyclophosphamide (40% adults and 68% children) had not had any relapse of NS. Tolerance to the two drugs was generally good. The CsA-related side-effects were mild and disappeared after drug discontinuation. CONCLUSIONS: This study shows that both treatments are effective and well tolerated; more patients given cyclophosphamide had stable remissions.

Interstitial leucocyte infiltration in primary glomerulonephritis: extent and composition analysis.

In the interstitial cell infiltrates associated with primary glomerulonephritis, approximately the same cellular composition has been found, T cells being predominant, monocytes fewer, and B cells least. Cell composition did not seem to be related to the cell density; the lowest percentages of monocytes have been observed with either very high (FSGS) or very low (MGN) cell densities; and the highest percentages of T cells, with either the highest (FSGS) or the lowest (MGN) cell densities. On the other hand, some relationship seemed to exist with the cell distribution in the interstitium. The cell composition was nearly the same in diffuse and disseminated patterns, but was markedly different in nodular (focal) cell infiltrates; T cells were always in first place, but B cells instead of monocytes were in second place. Furthermore, IL2-receptor-presenting cells have been more often observed in nodular (focal) than in both diffuse and disseminated patterns, and more markedly in nonjuxtaglomerular than in juxtaglomerular noduli (foci). In conclusion, cell composition of interstitial infiltrates seems to reflect a cell-mediated immune reaction, leading to all interstitial cell infiltrates associated with primary glomerulonephritis. It is conceivable that the nodular (focal) pattern of distribution might correspond to a discrete mechanism and have a different meaning.

Pattern of double glomerulopathies. A clinicopathologic study in nine nondiabetic patients.

Nine new cases of double glomerulopathies (GP) were found among 1,715 renal biopsies. Immunofluorescence and electron microscopy were needed to achieve a correct diagnosis and the prevailing relevance of these techniques in single cases was stressed. IgA nephropathy was the most commonly found GP, being associated with membranous glomerulonephritis (GN) (2 patients), minimal change disease (3 patients), and focal segmental glomerulosclerosis (1 patient). In addition, single cases of membranous GN plus crescentic GN and acute GN plus cryoglobulinemic GN were recorded. Possible factors involved in the pathogenesis and clinical significance of double glomerulopathies are discussed.

[Evolution of pregnancy in 14 patients with lupus nephropathy]. / Evoluzione della gravidanza in 14 pazienti con nefropatia lupica.

Authors have examined 14 pregnant patients with renal involvement by systemic lupus erythematosus. Variations in blood creatinine, proteinuria and blood pressure were considered in the prepregnancy, pregnancy and postpartum periods in relation to the histologic results of renal biopsy and obstetric outcome.

Pattern of double glomerulopathies: a clinicopathologic study of superimposed glomerulonephritis on diabetic glomerulosclerosis.

Among 1715 renal biopsies investigated by means of light microscopy, immunofluorescence, and/or electron microscopy, 20 cases of various glomerulopathies (GP) were found to be superimposed on diabetic glomerulosclerosis (DGS). The most frequently superimposed GPs were acute GN (nine cases) and cryoglobulinemic GN (six cases). Although the former association is known to occur, the latter has not so far been reported. In the other patients DGS was associated with crescentic GN (two cases), membranoproliferative GN, membranous GN, and IgA nephropathy (one case each). Morphologic clues allowing the identification of the superimposed GP and the diagnostic relevance of the available morphologic methods were stressed. In particular, light microscopy was sufficient to identify the superimposed crescentic GN, whereas immunofluorescence and/or electron microscopy were needed in the other cases in order to show the composition and the seat of the deposits, respectively. In addition, electron microscopy was useful in identifying some peculiar features such as humps, mesangial cell interposition, and organized deposits in cryoglobulinemic GN. The actual frequency of superimposed GPs is difficult to assess: either under or overestimation is possible. Pathologists must be aware that this miscalculation is not an episodic event and that the estimation must be carefully sought whenever clinical data are equivocal and not fully fitting with DGS alone. The duration of the diabetes seems to favor the superimposition of GN on DGS. In these patients the prognosis is poor, not only when it could be expected to be, as in the cases with superimposition of crescentic or membranoproliferative GN, but also when DGS is associated with acute GN, whose prognosis is generally favorable.

Light chain nephropathy: histological and clinical aspects in 15 cases.

Fifteen patients aged 31-74 years (five male, ten female) on renal biopsy showed intense linear deposits of light chains along tubular basement membranes (TBM) by immunofluorescence, and/or granular dense deposits on electronmicroscopy. Multiple myeloma was diagnosed in ten patients. The onset of myeloma and nephropathy was simultaneous in six patients; nephropathy preceded or followed the diagnosis of myeloma in three and one patients respectively. The mode of onset of nephropathy was acute or rapidly progressive renal failure in five cases, chronic renal failure in seven, and heavy proteinuria in three. Only two patients had normal renal function at biopsy. Serum monoclonal component was kappa in five patients, IgG kappa in three, IgD kappa in one, IgG lambda in one, IgA lambda in one, absent in three, and not detected in one. On light microscopy eight cases had nodular glomerulosclerosis, three cast nephropathy and 14 TBM thickening. Immunofluorescence for monoclonal light chain(s) was positive in 11 of 13 cases. Electron microscopy showed finely granular deposits in the inner side of glomerular basement membranes (GBM) and the outer side of TBM in 11 of 11 tested cases. The evolution was towards chronic renal failure in 12 patients (six of whom required dialysis), death in two, unknown in one. Four patients died after a period of dialysis, from infections or cardiovascular complications.

Renal histological lesions and clinical syndromes in multiple myeloma. Renal Immunopathology Group.

This retrospective multicenter study, based on 42 patients affected by renal damage due to multiple myeloma, analyzes the renal biopsy results, the clinical data at the time of biopsy and the subsequent renal outcome in order to clarify the correlations existing between clinical and histological changes. Plasmocytoma components were Bence Jones alone in 55% of the patients and light-chain excretion was present in over 90%. Rapidly progressive renal failure was the most frequent clinical presentation (27 cases). The histological lesions directly attributable to multiple myeloma were subdivided into 3 basic categories: related to light-chains, direct tumor involvement of renal parenchyma and attributable to systemic effects of neoplastic disease. Light-chains seemed to cause renal lesions in 59.4% of the cases. Myeloma cast nephropathy was the prominent bioptic diagnosis established (20 cases). Among the clinical, laboratory and histological parameters studied, only the degree of tubular-interstitial damage was significantly correlated to the renal outcome in the 32 patients who had an adequately documented follow-up period.

Ultrastructural glomerular findings in cryoglobulinemic glomerulonephritis.

Thirty-three renal biopsies of patients affected by cryoglobulinemic glomerulonephritis (CRYGN) were investigated by electron microscopy, paying particular attention to the nature of cells responsible of glomerular hypercellularity, the presence and site of electron-dense deposits and their ultrastructural characteristics. Personal as well as literature data suggest (a) diffuse glomerular hypercellularity found in most cases of CRYGN is mainly due to polymorphonuclear leukocytes and even more to monocyte exudation; (b) the interposition of the latter cell type in the glomerular capillary wall is the main responsible cause of the frequent occurrence of the membranoproliferative pattern in CRYGN, and (c) peculiar structures found in the electron dense deposits are characteristic of CRYGN and related to cryoglobulin composition. Electron microscopy therefore seems to be a valuable diagnostic procedure for this type of glomerulonephritis.

Immunophenotyping of mononuclear cell infiltrates associated with renal disease.

Twenty-eight frozen renal biopsy specimens with a marked mononuclear cell interstitial infiltrate (MCI) were analyzed with monoclonal antibodies and a biotin-avidin peroxidase technique to define the surface phenotype distribution of the infiltrating cells. Twelve cases were diagnosed as tubulointerstitial nephritis of acute and chronic presentation, of unknown cause in 5 cases or secondary to multiple myeloma or drug reactions. Sixteen cases occurred in primary and secondary glomerulonephritis, 3 cases being associated with lymphoproliferative disorders. The results showed a remarkable heterogeneity of the MCI composition, even in cases with similar clinical and pathological findings. Namely, the T cells accounted for the majority of the infiltrating cells in most cases but a variable predominance of the T cell subsets Leu3 and Leu2 was observed. B cells and monocytes were also prominent in some cases. Such differences in the MCI composition may indicate the activation of different mechanisms of tissue damage, or a different phase of the renal disease. In the three cases of glomerulonephritis associated with lymphoproliferative disorders, the malignant origin of the MCI was demonstrated in one case, while in the remaining cases it was excluded.

Morphological parameters in lupus nephritis: their relevance for classification and relationship with clinical and histological findings and outcome.

One hundred and sixty-seven renal biopsies from 147 patients with lupus nephritis were studied retrospectively to assess the contribution to morphological classification by features assessed with immunofluorescence and electron microscopy, together with pathological indices obtained by scoring specific histologic changes. The prognostic relevance of the histologic scoring was also evaluated. The biopsies were assigned to the following classes: I, absence of glomerular lesions; II, mesangial proliferation; III, focal segmental proliferation; IVa, diffuse (more than 50 per cent of the glomeruli) but segmentally distributed proliferation; IVb, diffuse and generalised proliferation; IVc, extracapillary proliferation; Va, pure membranous changes; Vb, membranous changes with slight mesangial proliferation; VI, association of class V and class III or IV. The incidence and degree of some glomerular and non-glomerular 'active' and 'sclerotic' changes as assessed by light microscopy were evaluated in the different classes. Both the activity and sclerosis indices obtained by scoring these lesions were found to be significantly higher in classes with glomerular proliferative changes. Eighteen patients had a second biopsy and two of these had a third; more severe changes were observed in nine and improvement in four. In 146 biopsies light microscopy findings were compared with immunofluorescence patterns (negative, mesangial, mesangial and peripheral, peripheral, membranous). The mesangial pattern was mainly present in class II with a few examples in classes I and III; in the last two the mesangial-peripheral pattern was most common; the peripheral pattern was by far the most common in class IV (a, b and c) and frequent in class VI; a membranous pattern was the rule in class V and occasionally found in class VI. Immunoglobulins (Igs) and complement (C) fractions were simultaneously present in most cases, IgG, C3 and C1q being the commonest in all classes. Except for IgM and fibrinogen, the differences in distribution of Igs and C fractions among the various classes were statistically significant. The deposits most commonly found by electron microscopy in all biopsies were mesangial; subendothelial deposits were mainly found in classes with active glomerular changes, frequently associated with deposits at the other sites in the most severe cases. A highly significant correlation was found between the activity index and the sclerosis index and severity of the clinical picture at biopsy. An unfavourable progress was confined mainly to classes with extensive intracapillary proliferation and correlated significantly with the highest activity and sclerosis indices.(ABSTRACT TRUNCATED AT 400 WORDS)