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Biomedical subjects

P Ferrari

Publications and source records attributed to P Ferrari.

At least 73 records · Page 4Linked to original sources
PubMed2001

Circulating insulin-like growth factor-I and benign prostatic hyperplasia--a prospective study.

OBJECTIVE: The aim of this study was to investigate the role of insulin-like growth factor-I (IGF-I), a strongly mitogenic and anti-apoptotic factor, in the development of benign prostatic hyperplasia (BPH). The bioactivity of IGF-I within tissues depends on circulating levels, as well as on the local production of IGF-I and the presence of IGF-binding proteins (IGFBPs). The IGFBPs regulate the efflux of IGF-I to the extravascular space and the bioavailability of IGF-I within tissues. MATERIAL AND METHODS: Within the Northern Sweden Health and Disease Study, 60 cases of BPH defined by a history of prostate resection were identified, and two controls per case were selected. IGF-I, IGFBP-1, IGFBP-3 and insulin were measured by immuno-radiometric assays in stored plasma samples drawn a mean of 3.2 years before surgery. RESULTS: The risk of BPH increased with increasing quartile levels of IGF-I adjusted for IGFBP-3 (p(trend) = 0.10) up to a relative risk of 2.16 (95% confidence interval 0.83-5.64) for the highest quartile. The risk decreased with increasing levels of IGFBP-1 (p(trend) = 0.10). CONCLUSIONS: Our results suggest that elevated IGF-I bioactivity may stimulate the development of BPH; however, they were not statistically significant and require confirmation from larger studies.

Humans↗
PubMed2001

The ablative effect of quarter dose bacillus Calmette-Guerin on a papillary marker lesion of the bladder.

PURPOSE: Low dose bacillus Calmette-Guerin (BCG) for stage TaT1 transitional cell carcinoma of the bladder has been given in various studies with the aim of decreasing side effects while maintaining the same efficacy as full dose bacillus Calmette-Guerin. However, its application in clinical practice remains controversial. We examined the ablative activity and incidence of side effects of intravesical quarter dose BCG given for a papillary marker lesion of the bladder. MATERIALS AND METHODS: Included in our study were 44 patients with primary or recurrent, multiple but no more than 10 lesions of stage pTaT1, grades 1 to 2 transitional cell carcinoma of the bladder. Intravesical treatment begun 14 days after the complete transurethral resection of all visible tumors except 1 marker lesion no larger than 1 cm. consisted of instillations of 30 mg. Connaught strain BCG diluted in 50 ml. saline once weekly for 6 consecutive weeks. Two weeks after the last instillation any residual tumor was completely resected. In cases of complete disappearance of the marker lesion deep biopsy of the tumor area was done. Urine cytology was also performed. RESULTS: There was a complete response in 27 of the 44 patients (61%), no response in 12 (27%) and progression to carcinoma in situ in 1 (2%), while the response was not evaluable in 4. Local side effects included dysuria in 54% of cases and macroscopic hematuria in 39%. Neither BCG induced infection nor BCG sepsis was observed. CONCLUSIONS: Quarter dose BCG has a clear ablative effect on superficial bladder cancer with a 61% response rate. Phase III trials are now required to compare its efficacy and toxicity to those of full dose BCG.

Adjuvants, Immunologic↗
PubMed2001

Functional activity within brain tumors: a magnetic source imaging study.

OBJECTIVE: To determine whether low-grade gliomas contain functional cortical activity more often than high-grade gliomas within radiologically defined abnormal tissue. METHODS: Patients with intra-axial cerebral lesions located in the vicinity of eloquent brain cortex preoperatively underwent magnetic source imaging. A dual 37-channel biomagnetometer was used to perform the imaging. Evoked magnetic fields were analyzed using the single-equivalent dipole representation to ascertain the neuronal source. Stimuli included painless tactile somatosensory stimulation of fingers, toes, and lips and auditory presentation of pure sinusoidal tones. RESULTS: A retrospective analysis of 106 nonconsecutively treated patients, who had undergone preoperative magnetic source imaging between February 1996 and December 1999, revealed that 24.5% of the patients had been at risk for neurological deficits, because functionally active tissue was located within or at the border of the tumor. Functional activity was found within the radiologically defined lesion in 18% of Grade 2 tumors, in 17% of Grade 3 tumors, and in 8% of Grade 4 tumors. CONCLUSION: The results confirm that, regardless of tumor grade, intra-axial brain tumors may involve or directly border on functional cortex. The degree of involvement of functionally viable cortex appeared greater for low-grade tumors than for high-grade lesions. On the other hand, high-grade lesions were more likely to be associated with functional cortex at their margins or within peritumoral edema. To safely maximize tumor resection, preoperative functional imaging and intraoperative electrophysiological mapping of the cerebral cortex and the white matter tracts are deemed necessary.

Brain Mapping↗
PubMed2001

Rheumatic disorders and primary biliary cirrhosis: an appraisal of 170 Italian patients.

OBJECTIVE: To establish the frequency of connective tissue diseases (CTD) in a cohort of Italian patients with primary biliary cirrhosis (PBC) and to evaluate the availability of a marker for the early identification of the more common associated CTD. METHODS: One hundred and seventy consecutive patients with histologically diagnosed PBC were screened for the presence of a CTD and/or Raynaud's phenomenon (RP). Patients were classified as having a CTD only if they fulfilled standardised criteria. RESULTS: Forty seven patients had a CTD. The most common CTD was systemic sclerosis (SSc), found in 21 patients. RP was present in 54 patients, most of whom (n=39) had an associated CTD. The most prevalent autoantibodies included antinuclear antibodies (ANA) with anticentromere (ACA) and speckled patterns (34 and 33 patients, respectively) and extractable nuclear antigens (ENA, 27 patients). However, while the frequencies of ACA and ENA were significantly higher in patients with an associated CTD (p<0.0001 and p<0.005, respectively), no relationship was found for speckled ANA. ACA was the best predictor of a CTD in patients with PBC (odds ratio (OR) 24.5, 95% CI 5.5 to 108.8), followed by the presence of ENA (OR 23.9, 95% CI 5.6 to 101.0) and RP (OR 20.2, 95% CI 5.7 to 71.2). CONCLUSIONS: Using strict standardised classification criteria we have found that SSc is the most common CTD associated with PBC and that ACA and ENA are strong markers for an associated CTD in patients with PBC.

Adult↗
PubMed2001

Juvenile hypertension, the role of genetically altered steroid metabolism.

The importance of hypertension in the pediatric population is not as well appreciated as in adults. This might be related in part to the lower prevalence of high blood pressure in this age group. As with height and weight, blood pressure increases with age during childhood. The underlying causes of significant hypertension in children differ considerably from those in adults: while the prevalence of hypertension in pediatrics is lower than in adults, clinically identifiable causes of hypertension are common. Abnormalities in steroid biosynthesis have been known for years to cause hypertension in some cases of congenital adrenal hyperplasia. In these patients, hypertension usually accompanies a characteristic phenotype with abnormal sexual differentiation. Recently, the molecular basis of four forms of severe hypertension transmitted on an autosomal basis has been elucidated: (a) the glucocorticoid-remediable aldosteronism (GRA), (b) the syndrome of apparent mineralocorticoid excess (AME), (c) activating mutation of the mineralocorticoid receptor and (d) Liddle's syndrome. All these conditions are characterized primarily by low or low-normal plasma renin, normal or low serum potassium and salt-sensitive hypertension, indicating an increased mineralocorticoid effect. These forms of juvenile hypertension are a consequence of abnormal biosynthesis, metabolism or action of steroid hormones: (a) GRA is due to expression of a chimeric gene produced by fusion of 11beta-hydroxylase aldosterone-synthase genes. Expression of the chimeric enzyme occurs in the zona fasciculata of the adrenal cortex under the control of ACTH and can be suppressed by administration of glucocorticoids. (b) AME is caused by mutations of the 11beta-hydroxysteroid dehydrogenase type 2 enzyme, an enzyme that metabolizes cortisol into its receptor inactive keto-form cortisone, thus protecting the mineralocorticoid receptor (MR) from occupation by glucocorticoids. (c) The activating mutation of the MR results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups becoming potent agonists. (d) Liddle's syndrome is due to mutations in the beta or gamma chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption. With the advent of molecular biology in clinical practice it has become evident that some genetic defect may present with a more discrete phenotype, with only moderate hypertension with or without hypokalemia as presenting feature. Considering that hypertension in children and adolescents is often 'nonessential', a search for disorders should be integral part of the diagnostic work-up in young patients with hypertension.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

A mutation in the cofactor-binding domain of 11beta-hydroxysteroid dehydrogenase type 2 associated with mineralocorticoid hypertension.

Renal 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is an enzyme responsible for the peripheral inactivation of cortisol to cortisone in mineralocorticoid target tissues. Mutations in the gene encoding 11betaHSD2 cause the syndrome of apparent mineralocorticoid excess (AME), an autosomal recessive form of inherited hypertension, in which cortisol acts as a potent mineralocorticoid. The mutations reported to date have been confined to exons 3-5. Here, we describe two siblings, 1 and 2 yr old, who were diagnosed with hypokalemic hypertension and low plasma aldosterone and renin levels, indicating mineralocorticoid hypertension. Analysis of urinary steroid metabolites showed a markedly impaired metabolism of cortisol, with (tetrahydrocortisol + 5alpha-tetrahydrocortisol)/tetrahydrocortisone ratios of 40-60, and nearly absent urinary free cortisone. Although phenotypically normal, the heterozygous parents showed a disturbed cortisol metabolism. Genetic analysis of the HSD11B2 gene from the AME patients revealed the homozygous deletion of six nucleotides in exon 2 with the resultant loss of amino acids Leu(114) and Glu(115), representing the first alteration found in the cofactor-binding domain. The deletion mutant, expressed in HEK-293 cells, showed an approximately 20-fold lower maximum velocity but increased apparent affinity for cortisol and corticosterone. In contrast, two additionally constructed substitutions, Glu(115) to Gln or Lys, showed increased maximal velocity and apparent affinity for 11beta-hydroxyglucocorticoids. Functional analysis of wild-type and mutant proteins indicated that a disturbed conformation of the cofactor-binding domain, but not the missing negative charge of Glu(115), led to the observed decreased activity of the deletion mutant. Considered together, these findings provide evidence for a role of Glu(115) in determining cofactor-binding specificity of 11betaHSD2 and emphasize the importance of structure-function analysis to elucidate the molecular mechanism of AME.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

Antiplatelet and antithrombotic activity of SL65.0472, a mixed 5-HT1B/5-HT2A receptor antagonist.

The antiplatelet and antithrombotic activity of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno [3,2-c]pyrin-4-yl) piperazin-1-yl]ethyl]-1,2-di-hydroquinoline-acetamide), a mixed 5-HT1B/5-HT2A receptor antagonist was investigated on 5HT-induced human platelet activation in vitro, and in rat, rabbit and canine platelet dependent thrombosis models. SL65.0472 inhibited 5-HT-induced platelet shape change in the presence of EDTA (IC50 values = 35, 69 and 225 nM in rabbit, rat and human platelet rich plasma (PRP)), and also inhibited aggregation induced in human PRP by 3-5 microM 5-HT + threshold concentrations of ADP (0.5-1 microM) or collagen (0.3 microg/ml) with mean IC50 values of 49 +/- 13 and 48 +/- 6 nM respectively. SL65.0472 inhibited thrombus formation when given both intravenously 5 min and orally 2 h prior to assembly of an arterio-venous (A-V) shunt in rats as from 0.1 and 0.3 mg/kg respectively. It was active in a rabbit A-V shunt model with significant decreases in thrombus weight as from 0.1 mg/kg i. v. and at 10 mg/kg p.o. The delay to occlusion in an electric current-induced rabbit femoral artery thrombosis model was increased by 251% (p <0.05) after 20 mg/kg p.o. SL65.0472 (30 microg/kg i.v.) virtually abolished coronary cyclic flow variations (7.2 +/- 1.0/h to 0.6 +/- 0.6/h, p <0.05) and increased minimum coronary blood flow (1.2 +/- 0.8 ml/min to 31.8 +/- 8.4 ml/min, p <0.05) in a coronary artery thrombosis model in the anaesthetised dog. Finally, SL65.0472 significantly increased the amount of blood lost after rat tail transection at 3 mg/kg p.o. Thus the anti-5-HT2A component of SL65.0472 is reflected by its ability to inhibit 5-HT-induced platelet activation, and platelet-rich thrombus formation.

Animals↗
PubMed2001

Effects of strength exercise and training on the natural killer cell counts in elderly humans.

BACKGROUND: To investigate the effects of strength exercise and training on the natural killer cell counts in elderly humans. METHODS: The study examined strength exercise-induced changes in the number of NK cells and changes in stress hormones in 16 sedentary elderly subjects before and after a 8-week strength training intervention. Blood samples were obtained before, immediately and 6 hours after a standardized strength test. Blood samples were also obtained from ten sedentary young subjects, under the same conditions and from ten resting elderly subjects serving as time controls. RESULTS: Prior to training, older adults immediately decreased (from 165.4+/-19.5 microL to 110.6+/-14.3 microL; mean+/-SEM) their NK cell count in response to the standardized strength test, whereas young controls increased their count (from 157.6+/-28.8 microL(-1) to 241.4+/-39.8 microL(-1)). After strength training, the same old subjects slightly increased (from 159+/-19.8 microL(-1) to 166.6+/-19.7 microL(-1)) their NK cell counts in response to the standardized strength test. In elderly subjects, no increase in stress hormone was observed following the strength test either before or after the strength training programme. CONCLUSIONS: The results suggest that in sedentary older adults, unlike young subjects, strength exercises can induce a transient decrease in NK cell count which can be cancelled by a short-term strength conditioning. Therefore, caution should be taken regarding immunocompetence of older adults when initiating a rehabilitation programme based on strength.

Adult↗
PubMed2000

[Dangerous hyperkalemia as sequelae of new treatment strategies of heart failure].

This case report presents a patient who developed severe life-threatening hyperkalemia following combined treatment with an ACE-inhibitor and the aldosterone-antagonist spironolactone for his congestive heart failure and who also suffered from pre-existing moderate renal failure. The pathophysiological reasons and the clinical evidence for the treatment of congestive heart failure with a combination of ACE-inhibitors and aldosterone-antagonists are discussed in details. The reasons for the occurrence of hyperkalemia in this patient and how spironolactone should be prescribed in patients with congestive heart failure are also elucidated.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

17beta-O-Aminoalkyloximes of 5beta-androstane-3beta,14beta-diol with digitalis-like activity: synthesis, cardiotonic activity, structure-activity relationships, and molecular modeling of the Na(+),K(+)-ATPase receptor.

A series of digitalis-like compounds with a 17-aminoalkoxyiminoalkyl or -alkenyl substituent was synthesized and evaluated for inhibition of Na(+),K(+)-ATPase and for inotropic activity. The highest inhibition was found with compounds having the substituent in configuration 17beta and the amino group at a distance of 6 or 7 bonds from C(17) of the digitoxigenin skeleton. The presence of the oxime function strengthens the interaction with the receptor, more if alpha,beta-unsaturated, thus mimicking the electronic situation of the unsaturated lactone in natural digitalis compounds. The most active compounds showed Na(+),K(+)-ATPase inhibitory potencies (IC(50)) 17-25 times higher than the standards digitoxigenin and digoxin and 3-11 times higher inotropic potencies (EC(50)) in isolated guinea pig left atria. These features are supported by a molecular model suggesting the possible interactions of the groups described above with particular amino acid residues in the H1-H2 domains of Na(+),K(+)-ATPase. Some interactions are the classical ones already described in the literature; a new, very strong interaction of the basic group with the Cys138 was found and adds new possibilities to design compounds interacting with this region of the receptor. The most interesting compounds were also studied in vivo in the anesthetized guinea pig for evaluating their inotropic effect versus the lethal dose. Compounds 9 and 12 showed a slightly higher safety ratio than digoxin and deserve further evaluation.

Androstanes↗
PubMed2000

[How relevant is the trough-to peak ratio?].

A marked blood pressure rise in the early morning hours is associated with an increased prevalence of cardiovascular events. Moreover, it has been reported that the blood pressure fall during the night is inversely correlated with left ventricular mass, peripheral vascular resistance and cerebrovascular insults. Recently, assessment of the so called "trough-to-peak ratio" has been increasingly used in order to evaluate the duration of action of antihypertensive agents. In this review some aspects of this arithmetical index are highlighted, and specifically the fact that this ratio as a surrogate endpoint may in some circumstances influence the choice of an antihypertensive agent but nevertheless does not serve to predict the clinical efficacy of blood pressure lowering drugs. To date the trough-to-peak ratio remains a problematic parameter because of the lack of defined optimal values and the lack of general and standardised methods for its determination. It is thus a purely arithmetical index without major clinical relevance. Evaluation of the clinical efficacy of antihypertensive drugs should rather be based on 24-hour measurements, as a more reproducible parameter.

Antihypertensive Agents↗
PubMed2000

Multi gram synthesis of UDP-N-acetylmuramic acid.

As part of an effort to discover novel antibacterial agents, a new and efficient synthesis was established in order to provide a large amount of UDP-N-acetylmuramic acid (UDP-MurNAc).

Molecular Structure↗
PubMed2000

Presurgical mapping with magnetic source imaging: comparisons with intraoperative findings.

We compare noninvasive preoperative mapping with magnetic source imaging to intraoperative cortical stimulation mapping. These techniques were directly compared in 17 patients who underwent preoperative and postoperative somatosensory mapping of a total of 22 comparable anatomic sites (digits, face). Our findings are presented in the context of previous studies that used magnetic source imaging and functional magnetic resonance imaging as noninvasive surrogates of intraoperative mapping for the identification of sensorimotor and language-specific brain functional centers in patients with brain tumors. We found that magnetic source imaging results were reasonably concordant with intraoperative mapping findings in over 90% of cases, and that concordance could be defined as "good" in 77% of cases. Magnetic source imaging therefore provides a viable, if coarse, identification of somatosensory areas and, consequently, can guide and reduce the time taken for intraoperative mapping procedures.

Brain Mapping↗
PubMed2000

Fatal cardiac arrhythmia after infusion of dimethyl sulfoxide-cryopreserved hematopoietic stem cells in a patient with severe primary cardiac amyloidosis and end-stage renal failure.

Amyloidosis (AL) is a rapidly fatal plasma cell dyscrasia causing progressive multiorgan failure. Recently, substantial improvement of survival was reported following high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue. We describe a patient with AL with severe cardiac and renal involvement who received high-dose melphalan followed by fractioned autologous PBSC transplantation (455 ml on day 1 and 350 ml on day 2). Immediately after the second infusion of the PBSCs, life-threatening cardiac arrhythmias occurred and, despite intensive treatment, the patient died less than 24 h later. The infusion of cryopreserved PBSCs may be associated with complications, including cardiac toxicity. Dimethyl sulfoxide (DMSO) is the most frequently used cryopreservation agent. In the present case, we suggest that DMSO could have played an important role in causing the fatal cardiac arrhythmias. The mechanisms of the cardiovascular effects of DMSO and the possible preventive measures are discussed. Given the poor prognosis of AL and the promising results of dose-intensive chemotherapy with autologous PBSC transplantation, careful patient selection and intensive monitoring are mandatory in order to further pursue this therapeutic approach.

Amyloidosis↗
PubMed2000

Parkinsonian syndrome in a patient with a pterional meningioma: case report and review of the literature.

The onset of a Parkinsonism in a patient with intracranial meningioma is definitely rare. The authors described the case of a patient suffering from a Parkinsonian syndrome for 10 years with no evidence of clinical improvement after medical treatment. A CT-scan of the brain evidenced a right pterional intracranial meningioma. The complete surgical removal of the neoplasm succeeded in resolving the Parkinsonian syndrome. The extension of the neoplasm and of the peritumoral edema may play an important role in compressing and consequently impairing perfusion of the basal ganglia region.

Basal Ganglia↗
PubMed2000

Genetic mapping and tailored antihypertensive therapy.

A tailored or individualized antihypertensive therapy represents the new frontier for the treatment of essential hypertension and its organ complications. Indeed, individual variation in the efficacy and tolerability of antihypertensive drugs in human essential hypertension is currently experienced by all physicians and is linked to the genetic heterogeneity of this multifactorial disease. Different approaches have been pursued in the attempt to correlate specific responsiveness to the therapy with phenotypic traits of the patients, but with poor results. More recently, the genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure both in animal models and in patients. But the relevance of these polymorphisms for defining and classifying patients in terms of therapy responsiveness must be analyzed in a more complex context that takes into account the crucial aspects of environmental influences, stage of disease, previous treatments, efficacy, tolerance, and duration of the treatment. Only a few examples of a pharmacogenomic approach to hypertension therapy are now available. In particular, the association of different variants of ACE, angiotensinogen, and G-protein genes with the blood pressure response to drugs interfering with RAS or beta-adrenergic receptor has been studied. However, the results of these studies cannot be considered conclusive, since not all the criteria have been fully applied for proper assessment of an association between genetic polymorphism and drug response. Our group has identified a polymorphism of the genes coding for the cytoskeletal protein, adducin, which is associated with both rat and human hypertension, sodium sensitivity, and the antihypertensive effects of diuretics. A modification of the renal Na-KATPase leading to an increase of tubular sodium reabsorption seems to be the most likely underlying mechanism. A new antihypertensive compound has been developed that can correct the abnormality of the renal Na-KATPase and the blood pressure increase associated with adducin polymorphism in the rat. At present, the antihypertensive activity of this compound is under evaluation in patients with different adducin genotypes.

Animals↗