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Biomedical subjects

C Manzoni

Publications and source records attributed to C Manzoni.

At least 55 records · Page 3Linked to original sources
PubMed1998

Tumor necrosis factor is increased in the spinal cord of an animal model of motor neuron degeneration.

Autoimmunity and oxidative/excitotoxic damage are considered as possible pathogenetic mechanisms in amyotrophic lateral sclerosis (ALS). As tumor necrosis factor (TNF) is implicated in autoimmune diseases, including experimental autoimmune encephalomyelitis, and can be neurotoxic, we studied TNF production in a proposed animal model of ALS, the mnd mouse. These mice develop symptoms (progressive weakness of the limbs) as late as at 7 months of age. We measured TNF in serum, brain and spinal cord of mnd mice at 3 and 7 months of age. TNF was detectable in the brain and spinal cord (but not in the serum) at 7 months, while no TNF was detected in mnd mice at 3 months (asymptomatic) or in control mice of the same genetic background and the same age. Immunohistochemistry confirmed localization of TNF-alpha in motor neurons situated in the ventral horn of the spinal cord of 7-month old mnd mice. These results suggest the possibility of testing inhibitors of TNF production in this disease.

Amyotrophic Lateral Sclerosis↗
PubMed1998

Chronic hemodialysis: Kt/V or solute removal index to evaluate the effective delivered dose?

A standard for quantifying the hemodialysis dose has not yet been defined. Many authors suggest the use of an alternative method to Kt/V: the solute removal index (SRI). We compared three methods based on blood-side urea determinations with the direct quantification method (DDQ) for estimating the delivered dialysis dose, expressed as SRI as well as Kt/V. Eight patients underwent three consecutive dialysis sessions, with the same dialytic efficiency. For each patient and each dialytic session the SRI and Kt/V were determined using the DDQ method and the single pool variable volume kinetic model, in its classical version (SPVV) as well by using the postdialysis urea value determined 30 min after the end of the session (eqSPVV). Double pool Kt/V was also estimated by the Daugirdas-Schneditz rate equation. Our results showed that the SPVV kinetic model significantly overestimated the delivered dialysis dose, the mean value of SRI and Kt/V were respectively 8.9% and 17% higher than those obtained by DDQ. The eqSPVV allowed the SRI to be estimated with a difference of -0.3% and Kt/V with a difference of -2% in comparison with DDQ. By using the Daugirdas-Schneditz rate of equation, which does not require blood samples to be drawn after the end of the session, the difference in Kt/V value was 3%. Therefore, both the eqSPVV kinetic model and the Daugirdas method allow quantification of the delivered dialysis dose with results similar to those determined by DDQ, which cannot be routinely applied. Kt/V seems the best marker for dialytic doses quantification.

Hemodialysis Solutions↗
PubMed1998

Conductivity: on-line monitoring of dialysis adequacy.

Cardiovascular disease and the inadequacy of delivered dialysis are the main factors determining morbidity and mortality in dialysis patients. We have already demonstrated that a conductivity kinetic model makes it possible to match interdialytic sodium loading and intradialytic sodium removal (the main factor determining cardiovascular morbidity) without the need for blood samples and, thus, in routine clinical practice. The aim of the present study was to test the possibility of using the conductivity method also to determine Kt/v without blood or dialysate sampling. In 18 steady-state patients, the urea distribution volume (V) was kinetically determined once using ionic dialysance (D) values instead of those of effective urea clearance. One month later, the Kt/V was determined by using the current D and T values and the predetermined V (Dt/V), then compared with the equilibrated Kt/V computed by means of the SPVV kinetic model (eqKt/V). The mean value of Dt/V was 1.18+/-0.15; while of eqKt/V it was 1.18+/-0.16, with a mean difference of 0.00+/-0.07. The conductivity method therefore seems to be very promising not only for monitoring the sodium balance, but also for quantifying delivered dialysis. Since its simplicity and low-cost make it suitable for use at each dialysis session, the conductivity method could therefore lead to significant progress in dialytic practice by contributing to the elimination of the two main causes of morbidity and mortality in dialysis patients.

Anuria↗
PubMed1997

Mapping the peripheral benzodiazepine receptor binding site by conformationally restrained derivatives of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3- isoquinolinecarboxamide (PK11195).

A synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK11195, 1) within their receptor has been developed. A wide series of conformationally restrained derivatives of 1 has been designed with the aim of probing the PBR binding site systematically. The synthesis of these compounds involves palladium-catalyzed coupling and amidation as the key steps. Twenty-nine rigid and semirigid derivatives of 1 were tested in binding studies using [3H]-1, and most of these showed PBR affinities in the nanomolar range. The essential role of the carbonyl moiety as a primary pharmacophoric element in the recognition by and the binding to PBR has been confirmed, and the restricted range of the carbonyl orientations, which characterizes the most potent ligands, points to a specific hydrogen-bonding interaction, mainly directed by the geometrical factors, when the electronic ones are fulfilled. Moreover, the fundamental importance of the short-range dispersive interactions in the modulation of the binding affinity and, hence, in the stabilization of the ligand-receptor complex, emerged from the QSAR models reported.

Animals↗
PubMed1997

Arachidonic acid inhibits 3H-glutamate uptake with different potencies in rodent central nervous system regions expressing different transporter subtypes.

High-affinity glutamate reuptake in neurons and glial cells, a mechanism involved in the maintenance of physiological excitatory amino acid neurotransmission, can be inhibited by arachidonic acid (AA). We studied the effect of different doses (from 10 to 500 microM) of AA on L-[3H]glutamate uptake in synaptosomes from rat cortex, rat cerebellum and mouse spinal cord. We found that AA inhibition was dose-dependent, but the IC50 in the cortex differed significantly from those in the cerebellum and spinal cord (170+/-7.9 microM vs 42.5+/-5.4 microM and 34.7+/-2.2 microM respectively). We therefore suggest that arachidonic acid modulates uptake differently in relation to the regional expression of the glutamate transporter subtypes.

ATP-Binding Cassette Transporters↗
PubMed1997

Biocompatibility in haemodialysis: fact and fiction.

Several of the pro-inflammatory pathways that are activated in patients during dialysis have the potential of producing many side effects. These occur three times a week, accompanying dialysis, and are particularly intense in patients dialysed with so-called 'bioincompatible' membranes. Despite the proven biological superiority of biocompatible membranes, we lack definitive evidence that complement and cell activation three times a week over a period of years is detrimental to patients, because the results of prospective randomized studies are conflicting. Although they do not lead to a decrease in acute clinical symptoms, epidemiological studies suggest that semi-synthetic and synthetic membranes may reduce morbidity and mortality in dialysis patients. Further large scale, prospective and randomized trials with a long follow-up are needed in order to clarify the clinical effects of biocompatibility per se, the increasingly recognized clinical importance of high-flux treatments and the possible interaction between biocompatibility and membrane flux.

Biocompatible Materials↗
PubMed1997

Optimization of sodium removal in paired filtration dialysis by single pool sodium and conductivity kinetic models.

Sodium removal is one of the main factors affecting intradialytic cardiovascular stability and interdialytic hypertension, and its removal should therefore be individualized. The aims of this study were: (1) to test the ability of a single-pool variable volume (SPVV) sodium kinetic model (NaKM) to optimize sodium removal in paired filtration dialysis (PFD), and (2) to test a SPVV conductivity kinetic model (CKM) in order to verify whether CKM can be used as an alternative for NaKM in estimating sodium balance. The mean difference between the NaKM-predicted and measured end-PFD plasma water ionized sodium concentrations was 0.00 +/- 0.55 mEq/l, which means that the model has an imprecision of < or = 1.1 mEq/ l. The mean difference between predicted and measured sodium removal was 0.21 +/- 16.86 mEq/session, which means a model overestimate of 0.21 mEq/session. The mean difference between the CKM-predicted and measured end-PFD ultrafiltrate conductivity was 0.01 +/- 0.05 mS/cm, which means an inaccuracy of the model of 0.01 mS/cm and an imprecision of < or = 0.1 mS/cm. The regression in the ionized sodium concentration measured in plasma or blood on the conductive values of the ultrafiltrate shows an error of < or = 2 mEq/l in the prediction of the ionized sodium concentration in blood by means of ultrafiltrate conductivity measurements. These results demonstrate that both models make it possible to obtain a level of dialytic sodium removal that is almost equivalent to interdialytic sodium loading. Moreover, given that it does not require blood sampling and the possibility of making repeated and inexpensive ultrafiltrate conductivity measurements, the CKM allows online monitoring of programmed sodium removal.

Convection↗
PubMed1997

Factors affecting progression of renal insufficiency.

The aim of this study was to analyze the factors affecting chronic renal insufficiency (CRI) progression at diagnosis (markers of progression), their spontaneous or therapy-induced behavior, and their relationship to CRI progression during follow-up. The underlying disease is the 'determinant factor' of progression and although clinical trials usually report crude cumulative renal survival without taking into account concomitant risk factors, it is known that diabetic nephropathy, polycystic kidney disease, and glomerulonephritis are more progressive than nephroangiosclerosis and interstitial nephropathy. Among the 'effect modifiers,' the baseline level of renal function, hypertension, and proteinuria are the most important. The adverse synergistic effects of proteinuria and high blood pressure have been confirmed, and the importance of correcting hypertension (systemic and glomerular) and proteinuria for slowing disease progression has also been demonstrated. The potential adverse role of a high-protein intake, strongly suggested by experimental studies and the clinical data of uncontrolled trials, has been challenged by the data coming from large controlled trials. The role of lipids needs to be clarified by prospective randomized trials, but the effects of therapeutic interventions aimed at correcting lipid abnormalities seem very promising. The association between the DD genotype of the gene encoding the angiotensin-converting enzyme (ACE) and an increased risk of renal function loss is under evaluation with the aim of identifying the patients who may most benefit from ACE inhibition.

Biomarkers↗
PubMed1996

Synthesis, biological activity, and SARs of pyrrolobenzoxazepine derivatives, a new class of specific "peripheral-type" benzodiazepine receptor ligands.

The "peripheral-type" benzodiazepine receptor (PBR) has been reported to play a role in many biological processes. We have synthesized and tested a novel series of PBR ligands based on a pyrrolobenzoxazepine skeleton, in order to provide new receptor ligands. Several of these new compounds proved to be high affinity and selective ligands for PBR, and benzoxazepines 17f and 17j were found to be the most potent ligands for this receptor to have been identified to date. The SAR and the molecular modeling studies detailed herein delineated a number of structural features required for improving affinity. Some of the ligands were employed as "molecular yardsticks" to probe the spatial dimensions of the lipophilic pockets L1 and L3 in the PBR cleft and to determine the effect of occupation of L1 and L3 with respect to affinity, while other C-7 modified analogues provided information specifically on the hydrogen bonding with a putative receptor site H1. The new pyrrolobenzoxazepines were tested in rat cortex, a tissue expressing high density of mitochondrial PBR, and exhibited IC50 and Ki values in the low nanomolar or subnanomolar range, as measured by the displacement of [3H]PK 11195 binding. A subset of the highest affinity ligands was also found to have high affinities for [3H]PK 11195 and [3H]Ro 5-4864 binding in rat adrenal mitochondria. All the ligands in this subset are stimulators of steroidogenesis having similar potency and extent of stimulation as PK 11195 and Ro 5-4864 of steroidogenesis in the mouse Y-1 adrenocortical cell line.

Animals↗
PubMed1996

Cardiovascular characterization of pyrrolo[2,1-d][1,5]benzothiazepine derivatives binding selectively to the peripheral-type benzodiazepine receptor (PBR): from dual PBR affinity and calcium antagonist activity to novel and selective calcium entry blockers.

The synthesis and cardiovascular characterization of a series of novel pyrrolo[2,1-d][1,5]-benzothiazepine derivatives (54-68) are described. Selective peripheral-type benzodiazepine receptor (PBR) ligands, such as PK 11195 and Ro 5-4864, have recently been found to possess low but significant inhibitory activity of L-type calcium channels, and this property is implicated in the cardiovascular effects observed with these compounds. In functional studies both PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide) and Ro 5-4864 (4'-chlorodiazepam) did not display selectivity between cardiac and vascular tissue. Therefore, several 7-(acyloxy)-6-arylpyrrolo[2,1-d][1,5]benzothiazepines, potent and selective peripheral-type benzodiazepine receptor ligands recently developed by us (3, 7-20), were subjected to calcium channel receptor binding assay. Some of these compounds showed an unexpected potency in displacing the binding of [3H]nitrendipine from L-type calcium channels, much higher than that reported for PK 11195 and Ro 5-4864 and equal to or higher than that of reference calcium antagonists such as verapamil and (+)-cis-diltiazem. Specifically, in rat cortex homogenate, our prototypic PBR ligand 7-acetoxy-6-(p-methoxyphenyl)pyrrolo[2,1-d][1,5]benzothiazepine (3) showed an IC50 equal to 0.13 nM for inhibition of [3H]nitrendipine binding. Furthermore, in functional studies this compound displayed a clear-cut selectivity for cardiac over vascular tissue. Comparison of calcium antagonist activity on guinea pig aorta strips with the negative inotropic activity, determined by using isolated guinea pig left atria, revealed that 3 displayed higher selectivity than the reference (+)-cis-diltiazem. Thus, the pyrrolobenzothiazepine 3 might represent a new tool for characterizing the relationship between the PBR and cardiac function. Furthermore, we have also investigated the structural dependence of binding to PBR and L-type calcium channels, and this study allowed us to identify a new class of potent calcium channel blockers selective for cardiac over vascular tissue, with no affinity for PBR. A number of structure-activity relationship trends have been identified, and a possible explanation is advanced in order to account for the observed differences in selectivity. Three structural features, namely, (i) the saturation of the C(6)-C(7) double bond, with a consequent higher molecular flexibility, (ii) the presence of a substituent in the benzofused ring, and (iii) a basic side chain at C-10 of the pyrrolobenzothiazepine ring system, were found to be responsible for potent L-type calcium channel antagonism and clear-cut selectivity for cardiac over vascular tissue. Among the synthesized compounds the pyrrolobenzothiazepine 62 was found to be the most promising selective calcium channel blocker. Additionally, the molecular structure determination of the key intermediate 48 by X-ray diffraction, molecular modeling, and NMR analysis is reported.

Animals↗
PubMed1996

Endocytosis inhibitors abolish the active transport of polypeptides in the mucosa of the nasal upper concha of the rabbit.

An active absorption of polypeptides (elcatonin = CCT; adrenocorticotropic hormone) had been previously observed in the nasal respiratory mucosa of the rabbit. Its saturation kinetics and the parallel absence of a net transfer of other non-polypeptidic organic markers excluded the involvement of a simple pinocytosis. This absorption has been now better localized and further characterized. Unidirectional CCT fluxes (determined with radioimmunoassay) have been concomitantly monitored with transepithelial electric potential difference (Vms). Although the mucosae covering the ectoturbinal A and the lower and upper conchae displayed similar Vms, the active CCT transport was only evidenced in the upper concha. In this region cytochalasin B (which by disassembling actin microfilaments prevents the apical formation of vesicles in epithelial cells) and monensin (which prevents the split of the ligand-receptor complex in the endosomes) both eliminated the net CCT absorption, however, also permanently increasing the passive CCT junctional permeability. Aluminum fluoride (which prevents the fusion of endocytic vesicles into endosomes) and colchicine (which disrupts microtubules along which vesicles move in the cytoplasm) also permanently abolished net CCT transport, without affecting, or shortly and transiently affecting, passive permeability. On the whole these results are in favor of an active CCT transport supported by a specific vesicular transport.

Aluminum Compounds↗
PubMed1996

Effects of sub-chronic exposure to SO2 on lipid and carbohydrate metabolism in rats.

Sulfur dioxide (SO2) is a ubiquitous air pollutant, present in low concentrations in the urban air, and in higher concentrations in the working environment. While toxicological reports on SO2 have extensively dealt with the pulmonary system, essentially no data are available on the effects of chronic exposure to this pollutant on intermediary metabolism, although some biochemical changes in lipid metabolism have been detected. The present investigation was aimed at evaluating the effects of sub-chronic exposure to SO2 on concentrations of serum lipids/lipoproteins and on glucose metabolism, in animal models of hypercholesterolemia and diabetes. A specially designed control-inert atmosphere chamber was used, where male Sprague-Dawley rats fed on either standard or cholesterol enriched (HC) diets, as well as streptozotocin diabetics, were exposed to SO2 at 5 and 10 ppm, 24 h per day for 14 days. In rats, both on a standard diet and on a HC regimen, SO2 exposure determined a significant dose-dependent increase in plasma triglycerides, up to +363% in the 10 ppm HC exposed animals. This same gas concentration significantly reduced HDL cholesterol levels. In contrast, exposure of diabetic animals to 10 ppm SO2 resulted in a fall (-41%) of plasma and liver triglycerides and in a concomitant increase (+62%) of plasma HDL cholesterol. This discrepancy could apparently be related to diverging effects of SO2 exposure on plasma insulin levels in the different animal groups. Kinetic analyses of triglyceride synthesis carried out in rats on a standard diet revealed, in exposed animals, a significant reduction in the secretory rate, in spite of the concomitant hypertriglyceridemia. These findings suggest that SO2 exposure can markedly modify major lipid and glycemic indices, also indicating a differential response in normo/hyperlipidemic versus diabetic animals.

Animals↗
PubMed1996

7S globulin from soybean is metabolized in human cell cultures by a specific uptake and degradation system.

We examined the biological fate of 7S globulin from soybean in a hepatoma cell line (Hep G2) and in human skin fibroblasts (HSF) to gain new insights into the 7S globulin cell process, the final effect of which is an enhanced expression of the LDL-receptor. The ability of 7S globulin to bind and to be internalized and degraded by both cell types was investigated under different experimental conditions. In all cases, specific uptake (binding + internalization) and degradation of 125I-7S globulin were curvilinear functions of substrate concentration at 37 degrees C. The two processes were saturated at around 80 mg/L, a concentration at which an up-regulation of LDL-receptor was previously reported. The specific uptake of 125I-7S globulin at 37 degrees C was a curvilinear function of time, and achieved equilibrium after 6 and 12 h in HSF and Hep G2 cells, respectively. Binding experiments, conducted at 4 degrees C in Hep G2 cells, showed a specific and saturable association of 7S globulin to the cell membrane. Linear Scatchard analysis demonstrated a single population of binding sites. The amount of 7S globulin bound at saturation (Bmax) was about 2.73 mg/L, with an apparent Kd of 21 micromol/L, assuming 175 kDa as the 7S globulin molecular weight. SDS-PAGE of Hep G2 membrane proteins incubated with 125I-7S globulin revealed a specific interaction of 7S globulin with a cell protein component with molecular weight between 14 and 21 kDa. Further studies are needed to ascertain whether this interaction is directly or indirectly related to the observed stimulation of the LDL-receptor.

Carcinoma, Hepatocellular↗
PubMed1996

Ionic dialysance as a method for the on-line monitoring of delivered dialysis without blood sampling.

BACKGROUND: It is well known that the difference between prescribed and delivered dialysis doses greatly affects the morbidity and mortality of dialysed patients. The on-line monitoring of delivered dialysis is therefore of paramount importance. Recently, a conductivity-based method for determining Kt/V on routine basis has been proposed. METHODS: The study was performed using a specially designed module (Biofeedback Module, COT, Hospal) which, when connected to a dialysis monitor, automatically determines effective ionic dialysance (ID). During three consecutive dialysis sessions, administered to each of eight patients at the same depurative efficiency, we determined Kt/V by using mean effective ionic dialysance and by assuming, as suggested, that urea distribution volume corresponded to 55% of body weight. This method was compared with the gold standard of the direct quantification method. The Kt/V was also calculated by using mean effective ionic dialysance and the volume of urea distribution derived from anthropometric parameters. RESULTS: The Kt/V determined by using mean effective ionic dialysance and by assuming that urea distribution volume corresponded to 55% of body weight was heavily underestimated (-22%). This difference was due to both the overestimate of urea distribution volume (+17%) and underestimate of effective urea clearance (KUeff) (-11%). The mean Kt/V calculated on the basis of ionic dialysance and anthropometric volume was also underestimated (-23%) since this volume was overestimated (+17%). Nevertheless, ionic dialysance and urea clearance proved to be closely correlated (r2 = 0.89) so that effective urea clearance can be derived according to: Kueff = ID x 0.865 + 39.89. CONCLUSIONS: In steady-state patients, once urea distribution volume has been correctly determined by means of direct quantification, effective urea clearance can be easily derived from ionic dialysance and Kt/V calculated on-line at each session, without blood sampling or any additional costs.

Evaluation Studies as Topic↗
PubMed1996

Determining the adequacy of sodium balance in hemodialysis using a kinetic model.

The importance of sodium balance avoiding intradialytic cardiovascular instability and interdialytic hypertension and pulmonary edema is well known. An early analytical single-pool kinetic model created to evaluate sodium balance in hemodialysis, using flame photometry to determine plasma and dialysate sodium concentrations, has been shown to have a level of imprecision of +/- 2.8 mEq/l in predicting end-dialysis sodium plasma water concentrations (NaPWt). The ionometric determination of sodium concentrations seems to be more accurate and refers to the activity of the sodium capable of crossing dialysis membranes. On the basis of the theoretical premises of the model mentioned above, we developed a computerized single-pool kinetic model which makes it possible to calculate the ionized dialysate sodium activity (NaDI) required to reach a pre-established target of end-dialysis blood sodium activity (NaBI). Thirty-seven non-diabetic and anuric patients undergoing regular thrice-weekly hemodialysis were given their usual dialysis treatment, with NaDI at the usual value for each patient (range 137-147 mEq/l) and kept constant throughout dialysis. At the beginning and end of the session, NaDI and NaBI were measured in quadruplicate by means of a Nova-1 device (Direct Potentiometry, Pabisch Instruments). The validity of this kinetic model was tested by considering the difference between predicted and observed (P-O) NaBI at the end of dialysis [(t)]. P-O NaBI(t) was -0.37 +/- 0.42 mEq/l, which was statistically different from 0 (p < 0.001). When P-O NaBI(t) was plotted against ONaBI(t), it was more negative at the higher values of ONaBI(t). P-O intradialytic sodium removal (Nag) was -12.5 +/- 17.8 mEq/session, which was also statistically different from 0 (p < 0.001). The imprecision of this kinetic model was less than 0.84 mEq/l, as estimated by doubling the SD of P-O NaBI(t) (0.42 = 0.84 mEq/l). Although the reasons for its inaccuracy especially at higher ONaBI(t) values remain to be clarified, these data are the expression of a satisfactory clinical model.

Aged↗