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The identification of dysfunctional human apolipoprotein A-I (apoA-I) in atherosclerotic plaques suggests that protein structure and function may be hampered under a chronic pro inflammatory scenario. Moreover, the fact that natural mutants of this protein elicit severe cardiovascular diseases (CVD) strongly indicates that the native folding could shift due to the mutation, yielding a structure more prone to misfold or misfunction. To understand the events that determine the failure of apoA-I structural flexibility to fulfill its protective role, we took advantage of the study of a natural variant with a deletion of the residue lysine 107 (K107del) associated with atherosclerosis. Biophysical approaches, such as electrophoresis, fluorescence and spectroscopy were used to characterize proteins structure and function, either in native conformation or under oxidation or intramolecular crosslinking. K107del structure was more flexible than the protein with the native sequence (Wt) but interactions with artificial membranes were preserved. Instead, structural restrictions by intramolecular crosslinking impaired the Wt and K107del lipid solubilization function. In addition, controlled oxidation decreased the yield of the native dimer conformation for both variants. We conclude that even though mutations may alter protein structure and spatial arrangement, the highly flexible conformation compensates the mild shift from the native folding. Instead, post translational apoA-I modifications (probably chronic and progressive) are required to raise a protein conformation with significant loss of function and increased aggregation tendency. The results learnt from this variant strength a close association between amyloidosis and atherosclerosis. Unlabelled Image • Oxidation is clue to induce protein misfolding. • Natural mutation does not seem critical as a sole reason to determine pathogenicity. • Atherosclerosis and amyloidosis are closely related. • Intramolecular crosslinking restrains protein flexibility and function. [ABSTRACT FROM AUTHOR]

The reason that determines the pathological deposition of human apolipoprotein A-I variants inducing organ failure has been under research since the early description of natural mutations in patients. To shed light into the events associated with protein aggregation, we studied the structural perturbations that may occur in the natural variant that shows a substitution of a Leucine by an Arginine in position 60 (L60R). Circular dichroism, intrinsic fluorescence measurements, and proteolysis analysis indicated that L60R was more unstable, more sensitive to cleavage and the N-terminus was more disorganized than the protein with the native sequence (Wt). A higher tendency to aggregate was also detected when L60R was incubated at physiological pH. In addition, the small structural rearrangement observed for the freshly folded variant led to the release of tumor necrosis factor-α and interleukin-1β from a model of macrophages. However, the mutant preserved both its dimeric conformation and its lipid-binding capacity. Our results strongly suggest that the chronic disease may be a consequence of the native conformation loss which elicits the release of protein conformations that could be either cytotoxic or precursors of amyloid conformations. Image 1 •) L60R is more unstable, more sensitive to cleavage and the N-Terminus of this variant is more disorganized than the Wt. • A small conformational rearrangement in the L60R variant induces release of cytoquines from a model of macrophages. • L60R preserves Lipid binding eficiency. • The mutation mentioned above may stabilize the dimer conformation. [ABSTRACT FROM AUTHOR]

Different protein conformations may be involved in the development of clinical manifestations associated with human amyloidosis. Although a fibrillar conformation is usually the signature of damage in the tissues of patients, it is not clear whether this species is per se the cause or the consequence of the disease. Hereditary amyloidosis due to variants of apolipoprotein A-I (apoA-I) with a substitution of a single amino acid is characterized by the presence of fibrillar protein within the lesions. Thus mutations result in increased protein aggregation. Here we set up to characterize the folding of a natural variant with a mutation leading to a deletion at position 107 (apoA-I Lys107–0). Patients carrying this variant show amyloidosis and severe atherosclerosis. We oxidized this variant under controlled concentrations of hydrogen peroxide and analyzed the structure obtained after 30-day incubation by fluorescence, circular dichroism and microscopy approaches. Neutrophils activation was characterized by confocal microscopy. We obtained a high yield of well-defined stable fibrillar structures of apoA-I Lys107–0. In an in vitro neutrophils system, we were able to detect the induction of Neutrophils Extracellular Traps (NETs) when we incubated with oxidized apoA-I variants. This effect was exacerbated by the fibrillar structure of oxidized Lys 107–0. We conclude that a pro-inflammatory microenvironment could result in the formation of aggregation-prone species, which, in addition may induce a positive feed-back in the activation of an inflammatory response. These events may explain a close association between amyloidosis due to apoA-I Lys107–0 and atherosclerosis. • We characterized the soluble structure of a natural apoA-I mutant associated with atherosclerosis and amyloidosis (Lys1070). • We determined that this variant has strong tendency to aggregate into amlyoid-like structures • We obtained high yield and deeply characterized well-defined fibrillar structures of Lys1070 obtained by oxidation. • We demonstrated that this fibrillar conformation promoted the induction of NETs (Neutrophils Extracellular Traps) • Fibrillar Lys1070 induce a positive feedback in the activation of an inflammatory response. [ABSTRACT FROM AUTHOR]

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) primarily affects small- and medium-sized arteries, including kidney vessels, thus causing rapidly progressive glomerulonephritis. The pathogenesis of AAV is intricate and several factors, including infections, are known to possibly trigger the autoimmune process. Numerous studies have reported that SARS-CoV-2 might cause acute kidney injury (AKI). To date, a modest number of AAV with COVID-19 cases has been reported. Herein, we discuss the case of a 61-year-old man with new-onset of diffuse proliferative ANCA-associated glomerulonephritis after COVID-19., (Copyright by Società Italiana di Nefrologia SIN, Rome,Italy.)

Introduction: In this paper we investigated whether cholecalciferol supplementation, prescribed to treat vitamin D deficiency in patients with nephrolithiasis, increased the risk of stone recurrence., Methods: Calcium excretion and urine supersaturation with calcium oxalate (βCaOx) and brushite (βbsh) were evaluated in 33 kidney stone formers (aged 56±17; 12 males), both before and after therapy with cholecalciferol, prescribed as oral bolus of 100.000-200.000 UI, followed by maintenance doses, repeated every week (5.000-10.000 UI) or month (25.000-50.000 UI). During the study, patients followed a dietary regimen which included a daily calcium intake of about 800-1000 mg., Results: Urinary nitrogen, sodium and ash-acid excretion did not significantly change during the study. After cholecalciferol supplementation, the main results were as follows: both serum calcium and phosphate did not vary significantly; 25(OH)VitD₃ increased from 11,8±5,5 to 40,2±12,2 ng/mL (p<0,01); 1,25(OH) ₂ VitD₃ increased from 41,6±17,6 to 54,0±16,0 pg/mL (p<0,01); PTH decreased from 75,0±27,2 to 56,7±21,1 pg/mL (p<0,01); daily urinary calcium increased from 2,7±1,5 to 3,6±1,6 mg/Kg b.w. (p<0,01), whereas fasting urinary calcium did not change significantly. After therapy, βbsh increased from 0,9±0,7 to 1,3±1,3 (p=0,02) and βCaOx did not vary significantly. Before cholecalciferol supplementation, 6/33 patients (18.2%) were hypercalciuric, whereas 13/33 patients (39,4%) showed hypercalciuria after supplementation (pX²=0,03)., Conclusions: Cholecalciferol supplementation for vitamin D deficiency may increase both urinary calcium and urine supersaturation in stone formers. If vitamin D supplements are needed in these patients, a careful monitoring of urine metabolic profile is warranted, in order to customize the metaphylaxis accordingly (hydration, potassium citrate, thiazides)., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Primary hyperparathyroidism (PHPT) may favor nephrolithiasis mainly through an increase in calcium and phosphate urinary excretion. Cinacalcet exhibits good efficacy to control hypercalcemia in PHPT, but it is not so far known whether it might be a useful tool to prevent stone recurrences. Of 67 patients with PHPT and recurrent nephrolithiasis, 55 underwent parathyroidectomy (PTX) and 12, not eligible to PTX, were prescribed Cinacalcet. All the patients were evaluated for mineral metabolism, including estimation of state of saturation for calcium oxalate (CaOx) and brushite (bsh), both at baseline and after either PTX or Cinacalcet. PTX compared to baseline reduced PTH (4617 vs 15786 pg/mL, p<0.01), calcemia (9.40.5 vs 11.30.9 mg/dL, p<0.01), calciuria (3.62.3 vs 9.24.5 mmol/24h, p<0.01), phosphaturia (18.47.1 vs 21.99.9 mmol/24h, p<0.05), CaOx (4.73.9 vs 9.86.8, p<0.01) and bsh (1.10.9 vs 3.22.2, p<0.01). Cinacalcet decreased both PTH (13379 vs 17187 pg/mL, p<0.05) and calcemia (9.70.6 vs 11.20.8 mg/dL, p<0.001), whereas no change was seen in calciuria (7.42.2 vs 7.42.4 mmol/24h, p=ns), phosphaturia (21.97.3 vs 23.06.5 mmol/24h, p=ns), CaOx (6.92.7 vs 5.42.5, p=ns) and bsh (1.71.1 vs 1.31.3, p=ns). We conclude that in patients with PHPT, PTX is able to decrease the risk for crystallization of calcium salts, whereas calcimimetic Cinacalcet did not. Therefore, in patients with PHPT complicated with nephrolithiasis only PTX can improve urine biochemistries thereby reducing the risk for recurrent calcium stone disease.

Renal stone disease often begins by renal colic. In order to manage this event adequately, several goals should be pursued: first, attenuate pain; second, favour progression and spontaneous expulsion of stones; third, prevent from obstructive and infectious complications. All of the aforementioned points pertain to medical management of this disease. Concerning prevention, it is widely agreed that pathogenesis of kidney stones is a consequence of abnormalities in urine environment, leading to a disequilibrium between promoters and inhibitors of crystallization. Therefore, the rationale for therapy is to make urine less conductive to stone formation, by both decreasing state of saturation and increasing inhibitory potential. In only some types of stone-forming salts it is possible to obtain undersaturation with the solid phase. Indeed, uric acid stones can be chemically dissolved by using alkali and allopurinol. To a lesser extent, this also applies to cystine stones, with the use of thiols and alkali. In these subsets, the aforementioned tools are also effective to prevent new stone formation. Much more challenging appears the treatment of calcium containing stones. About 10% of such stones is caused by systemic disorders and, in these cases, the prevention of new stones is successfully accomplished by curing the underlying disease. For instance, parathyroidectomy cures calcium nephrolithiasis in case of hyperparathyroidism. However, the majority of patients with calcium stones are idiopathic stone-formers, in whom metabolic abnormalities often occur, namely, hypercalciuria, hyperoxaluria, hypocitraturia. The correction of these abnormalities by using thiazide diuretics, alkaline citrates, potassium phosphate and bisphosphonates is based on the prevailing metabolic defect. Among the most recent available tools, Oxalobacter Formigenes and probiotics have been proposed to treat primary or secondary hyperoxalurias. In general, the treatment of stone disease reduces its recurrence rate, but only seldom results in stable remission. Anyway, less stones mean reduction of the need for urological procedures and the associated infective or obstructive complications. Of course, medical prevention implies financial efforts, but a careful cost to benefit analysis demonstrates that these are well justified.

The treatment with infliximab is employed successfully in Crohn's disease (CD) but predictors of efficacy are lacking. Activation of the transcription factor NF-kB has been demonstrated in CD and its inhibition is one of the mechanisms by which anti-inflammatory agents exert their effects. We evaluated the production of TNFalpha by peripheral blood mononuclear cells (PBMC) and the levels of NF-kappaB family molecules in the intestinal mucosa during infliximab therapy in 12 patients. TNFalpha was assayed on supernatants of PBMC culture stimulated with PHA or LPS. Immunohistochemistry was also done on intestinal biopsies. In six patients, Western blot analysis of the NF-kappaB subunit Rel-A, and its inhibitors IkappaBalpha and IkappaBgamma was performed on intestinal biopsies and PBMC. The TNFalpha production by LPS stimulated PBMC showed mild changes, while it was increased by PHA-stimulated PBMC after treatment. The number of inflammatory cells in the intestinal mucosa was reduced (p<0.002) by the treatment. In five out of six cases we detected an increase of the IkappaBalpha and IkappaBgamma)inhibitor levels in intestinal biopsies after treatment. An increase of IkappaB inhibitors levels could be one of the mechanisms by which infliximab decreases NF-kappaB activity and exerts its anti-inflammatory effects.

Background: In this paper, the clinical and metabolic patterns of nephrolithiasis in different ages of adulthood are studied., Methods: Eight-hundred patients observed at the Mauriziano Hospital between 1990 and 1995, were classified into 3 groups, on the basis of age at the onset of disease: A: 20 through 39 years; B: 40 through 59; C: 60 years and over., Results: Calcium-oxalate stones had a lower recurrence in C (19.1%) and B (31.5%) than in A (41.7%). Pure uric acid stones recurred in 18.9% of C, 16.7% of B and 4.3% of A. The prevalence of hypercalciuria was higher in A (50.3%) than in B (35.9%) and C (36%); so did hypocitraturia. Hyperuricuria was lower in A (5%, p < 0.05) than in B (9.4%) and C (10%). Low urine pH (< 5.5) was 13% in A, 21.3% in B, 38% in C. Prevalence of hyperoxaluria was about 14% in all groups. The whole prevalence of secondary forms of stone disease was 13% in A, 12% in B and 30% in C. Differences among groups were mainly due to prevalence of urological abnormalities and urinary tract infection. In patients without metabolic disturbances. urological abnormalities or urinary tract infections altogether, were 4.6% in A; 5.2% in B; 33% in C. Urological approach removed 8% of stones in A, 5.6% in B and 10.2% in C., Conclusions: Higher morbidity in younger patients could be due to a lower prevalence of easier-passing uric acid stones. The higher occurrence of urological disturbances and struvite stones in the elderly could explain the higher morbidity in this group.

The increased survival of patients in dialysis and the gradual increase in the age of uremic patients commencing chronic dialysis raises serious problems for the creation and maintenance of efficient vascular access. In cases in which it is extremely difficult to create arteriovenous fistulas (AVF) using existing upper limb veins, it is possible to resort to vascular grafts, lower limb AVF, central venous catheters or refer the patients for peritoneal dialysis if this method is technically possible. In order to evaluate the incidence of these phenomena in quantitative terms, the authors have made a retrospective analysis of patients undergoing vascular access surgery since the opening of the Dialysis Centre on 1/9/1973 to 30/9/1996. During this period (277 months) a total of 1,037 AVF implant operations were performed (in addition to 65 arteriovenous shunts in the earlier period and 28 permanent central venous catheters in the last 10 years). The survival of AVF grafts was lower than that in natural vessels in 384 patients without clinical risk. In diabetic subjects, those suffering from vascular pathologies, systemic diseases, or aged over 70, the survival of AVF was distinctly lower compared to the group without these risk factors. However, the higher risk group did not show any marked difference in survival between AVF in the patient's own veins and grafts. In only 4 out of 1,037 operations it was impossible to obtain vascular access in the upper limbs (2 patients were referred for peritoneal dialysis and AVF were executed in the thigh in 2 patients). In conclusion, the retrospective analysis of this series leads the authors to affirm that the rational use of natural vascular accesses normally allows a sufficient operating margin; however, in special cases suitable techniques (such as permanent central venous catheter or AVF in the thigh) can enable difficult situations to be resolved as an alternative to peritoneal dialysis.

Previous studies on DNA repair in ageing have demonstrated increased frequencies of single and double strand breaks in lymphocytes from elderly subjects and, as a consequence, decreased efficiency in DNA replication. We have investigated the relationship between cell proliferation and the nuclear expression of ku protein in a human population of 43 subjects of different ages. Ku is an heterodimeric protein composed of two subunits of 70 and 80 kDa, which is involved in the early steps of DNA damage recognition. In the present study, PBL from subjects of different ages were PHA-activated to evaluate the stimulation index and the production of Th1- and Th2-type cytokines. Moreover, nuclear extracts were obtained from activated lymphocytes to evaluate by a gel retardation assay the presence and the functional activity of the heterodimer ku 70/80. Our results indicate that ageing affects the mitotic responsiveness and cytokine production to a significant extent, but only marginally the expression of ku 70/80. These findings suggest that the age-related impairment in DNA repair mechanisms are only in part related to the reduced expression of ku protein able to recognize DNA damage.

Objective: To determine if either supplemental vitamin A, zinc, or both increases cell-mediated immune response in an older population., Design: A double-blind, randomized, controlled trial of supplementation with vitamin A and zinc., Setting: Casa Di Riposo Roma III, a public home for older people in Rome, Italy., Subjects: The health and nutritional status of 178 residents were evaluated. One hundred thirty-six residents agreed to participate in the trial and were randomized into four treatment groups, and 118 of these residents completed the trial., Intervention: The four treatments consisted of: (1) Vitamin A (800 micrograms retinol palmitate); (2) Zinc (25 mg as zinc sulfate); (3) Vitamin A and Zinc (800 micrograms retinol palmitate and 25 mg as zinc sulfate); (4) Placebo capsules containing starch., Main Outcome Measurements: Immune tests-counts of leucocytes, lymphocytes, T-cell subsets, and lymphocyte proliferative response to mitogens-were measured before and after supplementation., Results: Zinc increased the number of CD4 + DR + T-cells (P = .016) and cytotoxic T-lymphocytes (P = .005). Subjects treated with vitamin A experienced a reduction in the number of CD3 + T-cells (P = .012) and CD4 + T-cells (P = .012)., Conclusions: These data indicate that zinc supplementation improved cell-mediated immune response, whereas vitamin A had a deleterious effect in this older population. Further research is needed to clarify the clinical significance of these findings.

Background: The senescence of the immune system is a complex phenomenon, characterized by impairment of several lymphocyte activities and generally considered a state of immune dysregulation. Aging is a condition associated with many social changes likely to induce psychological stress, which is often perceived as uncontrollable and can lead, in some cases, to clinically relevant depression. In the recent years a growing interest has been raised for the study of bidirectional interactions between the central nervous system and the immunological network (psychoneuroimmunology)., Objective and Methods: We analyzed the possibility that chronic psychological distress and depression could worsen some immune functions in the aged. We postulate the neuroendocrine mechanisms of psychoimmune interaction, analyzing both the human and animal studies focused on aging., Results: The data from the literature reviewed suggest a significant impact of affective disorders on immune functions in the elderly subjects. This psychoimmune imbalance appears particularly important when the studies are carried out in otherwise healthy aged people., Conclusions: Here we reviewed the relationships between psychological stress and depression and immunological functions, with particular regard to those aspects pertinent to the aging process. The clinical relevance of these interactions remains to be elucidated, but the high frequency in the aged of autoimmune, infectious, and neoplastic diseases suggests to focus on the psychoneuroimmune interactions in the old age. We also propose some outlines for future studies concerning psychoneuroimmunology and aging.

Rifampin is a drug able to induce adverse reactions involving both the kidney and the hematological system. We observed a case, throughly studied and we deemed worth-while to report it, for some important features that were evident. Transient hemolytic anemia, recoverable acute renal failure, persistent increased titer of anti-platelet antibody lasting also after 3 weeks from the withdrawal of the drug and in spite of corticosteroid therapy, could be explained by the immune mechanisms that are, therefore, postulated.

To investigate patterns of monolateral and bilateral nephrolithiasis, we enrolled 196 patients with idiopathic calcium stone disease (ICaSD) and 36 with proven primary hyperparathyroidism (PHP). Monolateral disease occurred in 45 subjects with ICaSD and 3 with PHP. All had had three or more stone events. They were studied for a number of clinical and biochemical parameters. The expected prevalence of monolateral stone disease was calculated according to the binomial distribution of random events. Whereas the observed and expected prevalence of monolateral nephrolithiasis did not differ in PHP, the distribution did not follow a chance pattern in ICaSD, since monolateral disease was still frequent among patient with more than 6 episodes. To find out whether monolateral and bilateral ICaSD had distinct pathogenic mechanisms the two groups were compared for clinical and biochemical patterns: no differences emerged concerning metabolic derangements, urine saturation and diet-related biochemistries. Bilateral stone-formers had a higher recurrence rate, but a similar number of stone-operations or ESWL. In 81 of 151 bilateral idiopathic stone-formers in which we were able to assess the exact number of stone events in left and right kidney, the distribution of stones between kidneys did not differ from the binomial distribution. In conclusion, while PHP-associated nephrolithiasis presents predictable patterns, ICaSD comprises a subset in which the disease occurs monolaterally. These forms cannot be distinguished from bilateral forms with common clinical features or routine biochemistries.

In patients affected with different tumours, disorders concerning clotting are frequently observed. The biological processes leading to coagulation are probably involved in the mechanisms of metastasis. We studied plasma levels of thrombin-antithrombin III complexes (TAT) in 90 patients affected with lung tumours subgrouped in small cell and non-small cell (NSC) lung cancer: 17 patients had no evidence of disease after surgery (NE); the remaining 73 patients were divided according to the absence (LOC) or the presence (META) of metastases. All the patients were followed up for several months. In all the lung cancer patient groups, at the beginning of the study we detected TAT levels that were higher than in controls. During the follow-up period, the NSC-NE patients with no recurrence of the disease as well as the NSC-LOC patients responding to the treatment had a decrease in TAT levels (p < 0.01 and p < 0.05, respectively). The NSC-META patients with progression of their disease had, in contrast, an increase in TAT levels (p < 0.01). Our data reveal the presence of 'latent coagulation disorders' as assessed by the presence of high TAT levels in the majority of lung cancer patients. The follow-up study indicates that in the NSC group, a relation exists between coagulation activation and rate of tumour progression and/or response to treatment. In cancer patients the early detection of coagulation disorders could also allow, therefore, the prevention of thromboembolism and/or haemorrhage by administration of appropriate treatment.

Wegener's granulomatosis (WG) is a rare small vessels necrotizing and granulomatous systemic vasculitis which usually affects the respiratory-tract and the kidneys. Diagnosis is often difficult, but has become easier with antineutrophil cytoplasmic antibodies (ANCA) detection that may justify a more aggressive biopsy policy also in the elderly. Classic treatment with steroids and oral cyclophosphamide (CY) has proven to be of benefit, but side-effects are severe and frequent and the search for less toxic therapeutic schemes should be encouraged. We treated with intravenous pulses of CY (1 g/m2 monthly for 6 months, every two months for the following 6 and quarterly for another year) 5 of 7 patients with WG recently admitted to our institution. We obtained a quick, complete response in 4 of these patients, with no side effects, nor relapses, after a mean follow-up of 17 months. The only patient who did not respond was identified soon after the beginning of the treatment because of a poor reduction of ESR and could be shifted to oral administration of CY successfully. From our still limited experience CY intravenous pulses have proven to be safe and effective enough to advice its use as the first-choice treatment for WG.

Oxalate retention occurs in end-stage renal failure. Regular dialysis treatment does not prevent progressive accumulation of oxalate in cases of ESRF due to primary hyperoxaluria (PH), whereas such accumulation seldom seems to occur in oxalosis-unrelated ESRF. To elucidate this issue we have measured the bony content of oxalate on biopsies of the iliac crest taken from 32 uremic patients, 7 of them with ESRF associated with PH1 (6 cases) or PH2 (1 case). Ten subjects with normal renal function and no evidence of metabolic bone disease were taken as controls. Only trace amounts levels of oxalate were detected in normal subjects and oxalate to phosphate ratio was below 3:10,000. Non-PH dialyzed patients exhibited fivefold increases in oxalate levels, which rose to 5.1 +/- 3.6 mumol/g bony tissue. Calcium oxalate was estimated to represent 0.18% of the hydroxyapatite content of bone. Oxalate amounts were neither related to pre-dialysis plasma levels of oxalate, nor with duration of dialysis treatment, suggesting that accumulation was not progressive disorder. Oxalate levels were slightly higher in patients with a low turnover osteodystrophy compared to those with a high turnover pattern. Dialyzed patients with PH had remarkable increases in oxalate levels, which ranged between 14.8 and 907 mumol/g bony tissue. Oxalate deposition appeared to be progressive in that oxalate levels were significantly related to time on dialysis. In three patients calcium oxalate was a significant fraction of the mineralized bone. The occurrence of calcium oxalate crystals affected the histomorphometric patterns, that were featured by an increase in resorptive areas and a decrease in bone formation rate.(ABSTRACT TRUNCATED AT 250 WORDS)

In recent years the relationships among immune, endocrine and nervous systems have been extensively studied, and grouped in a new research field: psychoneuro-immunoendocrinology. Since ancient times its has been known that, in humans, mood as well as environmental influences could affect health. In the late '70s, only, evidence of bi-directional pathways has been achieved, first in animal models and, later on, in humans. We reviewed current knowledge on neuroimmunomodulation, concerning the influence of stress and psychological status on immunity as well as neuroendocrine modulation by the immune system, reporting some data obtained from our studies. Particularly, having detected a relevant impairment concerning most of the parameters studied, we emphasized the effects of depressive disorders on immune function in the elderly.

Six patients (3 children and 3 adults) with the clinical and biochemical features of Bartter's syndrome are presented. Pediatric cases included a more severe form, in one patient, with physical and mental retardation, hypercalciuria and nephrocalcinosis, and a less severe one, including two patients, with milder clinical features, low calcium and high magnesium excretion and hypomagnesiemia. Adult patients were affected by either the mild congenital form (case n. 4) or the acquired variety (cases n.5 and 6). Tubular function was investigated in the 3 adults by assessing clearance measurements during maximal diuresis. There was a defective fractional distal solute reabsorption (FDR) ranging between 0.52 and 0.60. This was well below the results obtained in one patient with psychogenous vomiting (FDR 0.94) and comparable to those in two patients with interstitial nephropathies caused by vesico-ureteral reflux (FDR 0.63 and 0.67 respectively). We concluded that: 1) the etiopathogenetic spectrum of Bartter's syndrome corresponds to different clinical presentation (mild, heavy, congenital or acquired varieties), and alterations in mineral and electrolyte renal handling; 2) reduction in FDR is a feature neither essential nor exclusive of this syndrome.

Circulating immune complexes (CIC) have been detected in several autoimmune diseases, and studies have also suggested that CIC provide a useful tool as tumor markers. In order to identify differences or similarities in antigenic composition, CIC from 23 patients with gastrointestinal (GI) tumors, from 20 patients with stage III and IV melanoma and from 6 patients with inflammatory bowel disease (IBD) were studied. Serum from all GI, melanoma and IBD patients showed higher levels of CIC than controls. SDS/PAGE electrophoresis under reducing conditions revealed some differences between cancer and IBD patients as far as the CIC protein composition was concerned. In melanoma patients, two fast-migrating bands, in the regions of 71-74 and 30-49 kD, were found, consistent with previously isolated and characterized antigens described in the literature.

Sixty patients with Echinococcus granulosus infection of the liver, lungs, bone and/or soft tissues were treated for several months with oral mebendazole (50-60 mg kg-1 day-1), in divided doses after fat-rich meals, either without surgery (WS), post-surgery (PS) or pre- and post-surgery (PPS). Long-term follow-up, possible for 52 of the patients, showed that WS, PS and PPS patients have so far remained disease-free following treatment for (means +/- standard deviations) 65.5 +/- 37.7, 82.5 +/- 37.0 and 84.1 +/- 28.3 months, respectively. Ultrasound and computed tomography scans were similar in WS and PPS patients post-treatment. Blood eosinophil levels, which were sometimes elevated initially, returned to normal in all patients and this decrease indicated cyst degeneration before this was evident on the scans. Treatment of patients with cystic echinococcosis may no longer require surgery.

Coagulation disorders are frequently detected in patients affected by different tumours even though clinical symptoms occur in a very small percentage of such subjects. Coagulation processes are probably involved in the mechanism of metastatic spread. We assayed the plasma levels of thrombin-antithrombin III (TAT) complexes in a group of 276 patients with several tumours in different stages in order to achieve a better understanding of the complex interactions between coagulation disorders and either tumour growth or metastatic spread. High levels of TAT complexes were found in 51% of localized, 66.3% of metastatic and 58.3% of patients with no evidence of disease; a statistically significant difference was observed comparing metastatic cancer either with localized (p < 0.00015) or with free-of-disease (p < 0.004) groups. Gastrointestinal tract neoplasms showed higher levels of TAT complexes in the metastatic than in the localized group. No difference was seen between small-cell and non-small-cell lung-localized cancer. Our results confirm the frequent coexistence of cancer and subclinical blood coagulation disorders. The evidence of higher levels of TAT complexes in metastatic cancer than in the other groups could be related to the mechanisms involved in tumour spread.

In the elderly, an impairment of the immune system could lead to increased incidence of infectious, neoplastic and autoimmune diseases; on the other hand, depression, which is the most common psychiatric problem in aged people, seems to be linked with alterations in immunological function. Thirteen institutionalized elderly subjects were studied to investigate the relationship between depression and immunological parameters. These subjects were selected as "healthy" according to the SENIEUR-EURAGE protocol and they belonged to a population already evaluated by our group--one year before--for psychological, endocrinological and immunological parameters. The lymphocyte mitotic response to PHA was greatly diminished in aged subjects, when compared to the adult controls. Depressed elderly showed impaired immunological function as compared with nondepressed ones, either "in vitro" or "in vivo". Lymphocyte stimulation with phytohemagglutinin (PHA), T cell growth factor (TCGF) production (induced by stimulation with PHA) and cutaneous delayed hypersensitivity (CDH) were reduced in depressed aged subjects. As far as lymphocyte proliferation with PHA in the whole group were concerned, no differences were found comparing the present results with those obtained in a former study. Although it is difficult to understand the significance of the immune imbalance associated with depression in the elderly, our results suggest that psychological status could influence the immunological functions in old people.

The relationship between cancer and coagulation disorders is widely accepted. Such disorders can contribute to the metastatic spreading of the primary tumor. Aim of our study was to evaluate the alterations of thrombin-antithrombin III complex (TAT) measured by an ELISA plasma assay in a population of 78 patients suffering from various gastrointestinal tumors. We found high levels of TAT in 68.6% of the patients. Our data show that assay of TAT plasma levels may be a useful test in detecting early coagulation disorders in cancer patients.

To investigate the presence of reduced bone mineral density (BMD) and to assess determinants of bone loss in rheumatoid arthritis, 45 female patients suffering from non-steroid treated rheumatoid arthritis were submitted to dual photon absorptiometry of the lumbar spine and to laboratory tests for calcium metabolism. The rheumatoid arthritis patients were divided into two groups according to anatomic grade and functional class; no abnormalities in calcium metabolism were detected whereas BMD was significantly lower in the third and fourth grade and in the third and fourth class patients (P less than 0.005 versus controls, versus grades I and II and versus classes 1 and 2). BMD was significantly correlated with age (P less than 0.001) and years postmenopausal (P less than 0.01), but not with duration of disease. By multiple linear regression we derived an equation predictive of BMD. Osteoporosis in rheumatoid arthritis is observed even in non-corticosteroid treated patients; articular lesions with subsequent reduction in physical activity appear to play an important role in axial bone loss in rheumatoid arthritis.

Circulating immune complexes (CIC) were previously reported to be higher in extended cancer rather than in localized one, by a few groups of investigators as well as by ourselves. The techniques employed were quite different in each study. We described a "direct" laser nephelometric assay. At the same time we determined the serum levels of 4 acute phase proteins (AFP)--alpha 2 macroglobulin, C reactive protein, haptoglobin, alpha 1 acid glycoprotein--by conventional light scattering method, in order to investigate on other possible "immune-modulating" factors. The possible correlations either with prognosis or clinical stage are looked for; the hypothetical behaviour of CIC as one of the serum "blocking factors" and of acute phase reactant as "immune modulating" proteins are discussed. The data concerning the techniques able to remove CIC from the blood stream of the cancer patients were also showed (plasmapheresis and immunoadsorption).

Keeping calcium (Ca) balance in equilibrium is one of the main goals in dialysis patients, and the dialysis schedule by itself can affect mineral metabolism. The aim of this paper is to evaluate Ca and magnesium (Mg) balances on different Quf in patients on RDT. Twenty-one patients [7 on hemodialysis (HD), 14 on hemodiafiltration (HDF)] were studied. Ca and Mg balances were assessed by measuring Ca and Mg in whole dialysis fluid. One patients on HDF was observed for three dialysis sessions, on different Quf, and negative values were observed for Quf above 70 ml/min. Mg balance was always negative. We conclude that an accurate survey of Ca balance is mandatory in high-efficiency dialysis, when high fluxes may produce adverse effects on mineral metabolism.

The occurrence of chronic renal insufficiency was investigated in 171 patients with severe idiopathic calcium stone disease. Ninety healthy subjects matched for age and sex were used as controls. The patients were thereafter subclassified into two subgroups, assuming a GFR of 80 ml/min/1.73 m2 body surface area as a cut-off value: the normal GFR, 141 patients, and the impaired GFR, 30 patients. The normal GFR group included more males and the patients were younger both at onset and at presentation. In the impaired GFR group the disease lasted longer, but the overall stones and the stone recurrence rate were as high as those of the normal GFR patients. The single stone episodes were more severe in the former group as suggested by the occurrence of more surgery and complications. The GFR level was in part predicted by the age of patients; however, stone disease was shown to induce a clear-cut influence in accelerating the natural worsening of GFR with age. The onset of renal insufficiency causes multiple changes in renal pathophysiology, which result in a sharp decrease in the urine saturation with respect to calcium salts. These changes account for the decrease in the stone recurrence rate in the impaired GFR group. Thus, unless factors independent of or complicating the calcium stone disease supervene, the renal insufficiency of treated patients remains mild and relently progressive.

Hemodialysis treatments with large surface area dialyzers were introduced in our dialysis unit since 1974. 129 uremic subjects were treated between September 1974 and August 1988. Age at start of high efficiency therapy ranged between 16 and 72 years; patients survival was: 95.3% at 1 year, 78.3% at 5 years, 65.8% at 10 years. At present 48 subjects are treated with this schedule. The key technical elements for implementation of such program include: high blood flow rates (greater than 300 ml/min), high surface area dialyzers (greater than 1.8 m2), bicarbonate as the buffer source. Traditionally, the rate of ultrafiltration was controlled by monitoring the TMP and the patients body weight, but in some case a preferred approach is the use of an automatic ultrafiltration control system. We conclude that, in a quite large dialysis population, an individualized short dialysis schedule may be safely applied for long time periods.

The results are presented of the dietary management, alone or in association with thiazides and/or allopurinol, evaluated in 143 idiopathic calcium stone formers after a mean follow-up of 18 months. Diet alone proved to be effective in the prevention of stone relapses. The addition of thiazide and/or allopurinol provided mild improvements of urine environment but seemed to give no further clinical benefits irrespective of underlying metabolic abnormalities.

It is becoming more apparent that the common gastritis and ulcer complications associated with non steroidal anti-inflammatory drugs (NSAID's) are distinct from classic peptic ulcer disease. To assess the incidence of gastrointestinal lesions and the existence of correlation with gastrointestinal symptoms, patients affected by rheumatic diseases treated with NSAIDs were carefully questioned to evaluate gastrointestinal symptoms and then underwent an esophagogastroduodenoscopic examination. The study demonstrates a relevant absence of gastrointestinal symptoms with an high incidence of gastric mucosal lesions in this patients. Asymptomatic lesions seem to be a characteristic feature of NSAID gastropathy. The blockade of synthesis of prostaglandins, due to the inhibition of cyclooxygenase by NSAIDs, may create an environment conducive to gastritis or ulcer disease and may be responsible of the absence of gastrointestinal symptoms.

Some nonspecific components (IgG, C3c, C4,) of circulating immune complexes (IC) precipitable by 3.5% PEG were assayed by laser nephelometry in the sera of 71 patients with solid tumours, and of 39 patients with autoimmune diseases. PEG-IgG, PEG-C3c, and PEG-C4 were higher in cancer and in autoimmune diseases than in controls. In cancer patients, PEG-C4 levels and PEG-C4 positivity rate correlated well with tumour burden. PEG-C3c and PEG-IgG were present at higher levels and PEG-C4 was present at lower concentration in cancer than in autoimmune diseases. The results of the present study, performed on a large population of patients with cancer and autoimmune diseases, indicate a different composition of circulating IC in these diseases. Particularly, these data suggest a preferential involvement of the alternative pathway of complement activation in cancer, as already described by other authors. The aggregation of C3c to IC, mediated by the alternative pathway, seems to be the "key" event in the process of IC solubilization. In cancer patients' sera, the presence of "solubilized" IC could partly explain their peculiar biological behaviour as well as the disagreement observed among the different assay methods based upon the binding with complement factors.

Juxtaarticular osteoporosis is a recognized clinical feature in both rheumatoid arthritis (RA) and psoriatic arthritis (PA), while generalised osteopenia seems to be characteristic of RA only. To assess differences in bone turnover in the two forms of disease, we measured serum osteocalcin levels and other parameters of bone metabolism in two groups of female, ambulant, age-matched patients suffering from active RA or active PA and never treated with steroid therapy. Serum osteocalcin levels were significantly higher in RA patients than in PA patients (13.05 +/- 1.27 ng/ml vs 4.83 +/- 0.88 ng/ml; p less than 0.001), with a significant positive correlation between osteocalcin and serum alkaline phosphatase in both groups. These data suggest that bone turnover is higher in active RA than in active PA. Juxtaarticular osteoporosis could be mediated by local disease mechanisms both in RA and in PA, while factors specifically related to active RA seem to determine a more generalized impairment of bone turnover.

C-reactive protein and rheumatoid factor assays are relevant laboratory parameters, among the most used in the clinical practice, being very useful in diagnosing and "monitoring" rheumatic diseases. A quantitative test to detect these two serum proteins is an important, more specific, new tool for clinical medicine. In our study we evaluated two new laser nephelometric assays, both quantitative, based on the agglutination of polystyrene latex particles, able to show serum concentration of CRP and RF. With a similar technique we tested the presence of circulating immune complexes. We performed our tests in a group of patients with rheumatoid arthritis, other autoimmune diseases, and healthy blood bank donors assaying simultaneously, whenever possible, the "classic" Rose-Waaler and RA tests. We found both methods easy to perform, well correlating with the semi-quantitative techniques and highly reproducible.

Association between diabetes and some rheumatic diseases have been proposed. The aim of our work is the evaluation of the prevalence of diabetes mellitus (DM) in a population of patients affected by some common rheumatic disease. We evaluated 356 consecutive out-patients [205 (71.66%) women and 101 (28.34%) men] attending the Rheumatology Unit of the Dept. of Internal Medicine of the Catholic University of Rome. The control group consisted of 200 out-patients, age and sex matched, who were examined in the Dept. of Surgery. The diagnosis of rheumatic patients were osteoarthritis (OA) (45.5%), rheumatoid arthritis (RA) (34%) and periarthritis (PA) (20.5%). The prevalence of diabetes mellitus in our rheumatic population was 5.78% in RA, 6.17% in OA, 10.9% in PA. The prevalence of DM in the control group was 4%. Our data suggest that the prevalence of DM in OA and RA patients is similar to that of general population, while it is significantly higher in PA patients probably for an active role of microangiopathy and hyperglycemia in the genesis of such disease.