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The chondroitin sulfate proteoglycan (PG) PG-M/versican is known to be a primary component of the vertebrate embryonic extracellular matrix and, in the mouse, functional abrogation of the versican gene leads to severe cardiovascular malformations and embryonic lethality. In order to provide a means for approaching the study of the role of versican during embryogenesis, we have cloned the Xenopus versican cDNA and we have performed in situ hybridization on embryos at different stages of development. We showed maternal Xversican transcription, as well as a previously undocumented early expression of the PG during gastrulation and neurulation. At later stages of development, spatial transcription of Xversican correlates with the patterns of migrating neural crest cells (NCC) and it is expressed in embryonic regions representing the final sites of arrest of NCC. Xversican mRNA was also detected in a subpopulation of trunk NCC migrating into the fin, in tissues flanking the trunk NCC ventral migratory pathway and in post-migratory cranial skeletogenic NCC. Further embryonic sites expressing Xversican were the pronephros, pronephric ducts, heart anlage and branchial pouches. These findings constitute the basis for future studies aimed at clarifying unresolved aspects of versican function during embryogenesis.

Objective: To precisely characterize the chronology of testicular endocrine function impairment during childhood and adolescence in patients with Klinefelter syndrome. Design Retrospective chart review. Patients A total of 29 boys with Klinefelter syndrome with up to 12.3 years follow-up., Measurements: Clinical features and serum hormone levels were analysed during follow-up., Results: Of the 29 patients, 16 were prepubertal and 13 had already entered puberty at their first visit. Fifteen patients were followed up through late puberty. Before puberty, LH, FSH, testosterone, anti-Müllerian hormone (AMH) and inhibin B were within the expected range in almost all cases. However, levels of the inhibin alpha-subunit precursor Pro-alphaC were in the lowest levels of the normal range in most cases. During puberty, FSH levels increased earlier and more markedly than LH. Inhibin B and AMH declined to abnormally low or undetectable levels in advanced pubertal stages. Although testosterone and Pro-alphaC levels were within the reference ranges in most cases, they were abnormally low for the observed LH values., Conclusions: In Klinefelter syndrome, a mild Leydig cell dysfunction is present from early childhood in most cases and persists throughout puberty. Sertoli cell function is normal until mid puberty, when a dramatic impairment is observed.

MyD88 is an adaptor protein, which plays an essential role in the intracellular signaling elicited by IL-1R and several TLRs. Central to its function is the ability of its Toll/IL-1R translation initiation region (TIR) domain to heterodimerize with the receptor and to homodimerize with another MyD88 molecule to favor the recruitment of downstream signaling molecules such as the serine/threonine kinases IL-1R-associated kinase 1 (IRAK1) and IRAK4. Herein, we have synthesized and tested the activity of a synthetic peptido-mimetic compound (ST2825) modeled after the structure of a heptapeptide in the BB-loop of the MyD88-TIR domain, which interferes with MyD88 signaling. ST2825 inhibited MyD88 dimerization in coimmunoprecipitation experiments. This effect was specific for homodimerization of the TIR domains and did not affect homodimerization of the death domains. Moreover, ST2825 interfered with recruitment of IRAK1 and IRAK4 by MyD88, causing inhibition of IL-1beta-mediated activation of NF-kappaB transcriptional activity. After oral administration, ST2825 dose-dependently inhibited IL-1beta-induced production of IL-6 in treated mice. Finally, we observed that ST2825 suppressed B cell proliferation and differentiation into plasma cells in response to CpG-induced activation of TLR9, a receptor that requires MyD88 for intracellular signaling. Our results indicate that ST2825 blocks IL-1R/TLR signaling by interfering with MyD88 homodimerization and suggest that it may have therapeutic potential in treatment of chronic inflammatory diseases.

Endometriosis is a chronic estrogen-dependent gynecological disease, characterized by pelvic pain and infertility, defined as the presence of endometrial glands and stroma within the pelvic peritoneum and other extrauterine sites. In the peritoneal cavity endometrial cells adhere, proliferate and induce an inflammatory response. Despite a long history of clinical and experimental research, the pathogenesis of endometriosis is still controversial. Abnormal immunological activation, the endocrine milieu and the peritoneal environment all dramatically affect endometriotic tissue function. Recent studies suggest that the peritoneal fluid of women with endometriosis contains an increased number of activated macrophages and other immune cells that secrete various local products, such as growth factors and cytokines, which exert a paracrine action on endometriotic cells. Since the peculiar biological characteristics of eutopic endometrium from women with endometriosis differ from endometrium of normal subjects, an important role in the pathogenesis of this complex disease has been suggested. All of these factors contribute to enhanced proliferative and angiogenic activity and a number of functional and structural changes, resulting in the particular behavior of this tissue.

The aim of this study was to evaluate how growth factors (PDGF-BB, EGF, and TGF-1beta) modulate hyaluronan synthase (HAS) activities in normal or stressed cultured human skin fibroblasts. The effects of concomitant treatment with cytokines and FeSO4 plus ascorbate on HAS mRNA expression, protein synthesis, and hyaluronic acid (HA) concentrations were also studied. Treatment of fibroblasts with growth factors up-regulated HAS gene expression and increased HAS enzymes and HA production. PDGF-BB induced HAS mRNA expression, protein synthesis, and HA production more efficiently than EGF and TGF-1beta. EGF was less effective than TGF-1beta. In addition, TGF-1beta reduced the expression and synthesis of HAS3, while PDGF-BB and EGF had the opposite effect. Concomitant treatment with growth factors and the oxidant was able to further increase HAS mRNA expression, once again with the exception of HAS3 with TGF-1beta. HAS protein synthesis was reduced, while HA levels were unaffected in comparison to those obtained from exposure to FeSO4 plus ascorbate alone. In conclusion, although growth factors plus the oxidant synergistically induced HAS mRNA expression in part, enzyme production was not correlated with this increase. Moreover, the increase in HAS mRNA levels was not translated into a consequent rise in HA concentration.

Aquaretic drugs, by definition, can induce an increase in urinary volume and urinary free water associated with a decreased urinary osmolarity with a consequent increase in plasma sodium. This enhanced diuresis is not accompanied by an increased loss of electrolytes, whereas traditional diuretics have the opposite, so-called saluretic effect. Aquaretics belong to a family of vasopressin receptor antagonists, V2 in particular, that regulate tubular water reabsorption. Several studies have confirmed their utility in the treatment of hyponatremic states associated with water retention such as heart failure, cirrhosis related ascites and SIADH. Furthermore, new applications may include the treatment of arterial hypertension, polycystic kidney disease, glaucoma and Meniere's syndrome.

Background: The aim of our study was to determine whether intermittent hemodiafiltration (HDF) leads to an alteration in monocyte antiviral activity as well as in the in vitro release of cytokines such as interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-alpha) and interferon-alpha (IFN-alpha) by the same cells., Methods: We enrolled 25 patients undergoing HDF for 3.5-4 hours 3 times a week (12 men, 13 women; mean age 58 +/- 6.7 years) and 25 healthy donors (ND) (12 men, 13 women; mean age 57 +/- 8 years). Monocytes from peripheral blood mononuclear cells were isolated with a Monocyte Isolation Kit II. Monocytic cells were infected with herpes simplex virus type 2 (HSV-2). Cytokines were assayed in supernatants., Results: The in vitro antiviral activity of monocytes from HDF patients was significantly impaired with respect to ND. Furthermore, monocytes from post-HDF patients were more prone to viral infection. Lipopolysaccharide (LPS) stimulation induced significant viral inhibition only in monocytes from NDs (p<0.05). The cytokine pattern (TNF-alpha, IFN-alpha and IL-12) in monocytes stimulated with LPS was markedly inhibited in HDF patients compared with ND (p<0.05). A basal production of TNF-alpha was found in monocytes from pre-HDF and post-HDF patients. No IFN-alpha production was found in LPS-stimulated and HSV-2-infected monocytes from pre-HDF and post-HDF patients. IL-12 production appeared significantly decreased after HDF in all experimental conditions (p<0.05)., Conclusions: The significant increase of viral replication in monocytes from HDF patients compared with healthy donors could be related to a significant reduction of cytokine production. Moreover, the dialytic session influenced the intrinsic antiviral activity of monocytes, favoring viral replication.

Cigarette smoking in college is often described as social smoking, but the term lacks definition and implicitly discounts dependence. We report on college students' use of the terms social smoker and smoker. Students who currently smoked cigarettes were asked whether they considered themselves smokers, and whether they smoked because they were social smokers. The survey was conducted during 1999-2004 at eight colleges; analysis was limited to 1,401 students aged 18-24 years. More than half of students (56.3%) denied being smokers ("deniers") despite current smoking behavior. Half of deniers, and fewer than half of admitters, called themselves social smokers. Deniers were highly likely to smoke infrequently, to say they were not addicted to cigarettes, to have mostly nonsmokers as close friends, to prefer dating nonsmokers, and to smoke for reasons other than stress relief. In contrast, social-smoker identity was associated only weakly with any attitude, behavior, or belief. Smoker and social-smoker identities were not significantly correlated with each other. Regardless of identity, more than half of the respondents wanted to quit smoking by graduation. Results suggest that denying being a smoker may be a widespread dissonance among college students who smoke. The possibility should be evaluated using population-level research, because it has potentially undermining implications for smoking cessation campaigns. Campus health centers should avoid using "smoker" self-assessment items on pre-exam questionnaires. Further research is needed to explore the psychosocial mechanisms involved with denier identity, to clarify the implications for public health communications, and to develop appropriate intervention strategies.

With this study, possible complications of diagnostic and surgical hysteroscopy were identified in order to define minimum safety requirements for the technique in three different healthcare settings: the physician's office, the outpatient clinic and the operating room. A literature review was conducted to compare the results in terms of feasibility and simplicity, as well as complications associated with the use of various instruments and techniques. Thanks to advances in technologies and procedures, diagnostic hysteroscopy has an excellent safety profile and is widely accepted. With the aid of minioptics (lens or fiber <4 mm in diameter), success rates have increased and hysteroscopy-associated pain has been considerably reduced. Published studies report low complication rates with minioptic hysterectomy. Surgical interventions conventionally performed on an inpatient basis (polypectomy, myoma removal) can be carried out under an outpatient or day surgery regime without the need for cervical canal dilation or anesthesia. The complications rate following hysteroscopy depends on the diameter and type of the instrument, the duration of the intervention, the extent and type of the disorder and the patient's clinical condition. Based on the study findings, the following recommendations for procedures and services can be made: diagnostic hysteroscopy with or without anesthesia performed as a simple ambulatory or gynaecologist's office procedure; surgical hysteroscopy for polypectomy, removal of myomas G0 <1 cm, synechiae and metroplasty as an ambulatory surgical procedure; surgical hysteroscopy for polypectomy, removal of myomas G0 <1 cm, synechiae and metroplasty as a safe ambulatory surgical procedure (in at-risk patients); surgical hysterectomy for myomectomy, voluminous polyps, metroplasty as a surgical procedure in day surgery.

Expression of pathogenesis-related (PR) genes is part of the plant's natural defense response against pathogen attack. The PRms gene encodes a fungal-inducible PR protein from maize. Here, we demonstrate that expression of PRms in transgenic rice confers broad-spectrum protection against pathogens, including fungal (Magnaporthe oryzae, Fusarium verticillioides, and Helminthosporium oryzae) and bacterial (Erwinia chrysanthemi) pathogens. The PRms-mediated disease resistance in rice plants is associated with an enhanced capacity to express and activate the natural plant defense mechanisms. Thus, PRms rice plants display a basal level of expression of endogenous defense genes in the absence of the pathogen. PRms plants also exhibit stronger and quicker defense responses during pathogen infection. We also have found that sucrose accumulates at higher levels in leaves of PRms plants. Sucrose responsiveness of rice defense genes correlates with the pathogen-responsive priming of their expression in PRms rice plants. Moreover, pretreatment of rice plants with sucrose enhances resistance to M. oryzae infection. Together, these results support a sucrose-mediated priming of defense responses in PRms rice plants which results in broad-spectrum disease resistance.

Intravenous high-dose immunoglobulin (IVIG) therapy is used in several antibody-mediated diseases including Guillain-Barré syndrome, idiopathic thrombocytopenic purpura, and autoimmune neuropathies. In the last decade, numerous studies have evaluated the application of IVIG therapy in autoimmune glomerulopathies such as lupus nephritis, membranous glomerulonephritis, and transplant-related chronic nephropathy. These studies were conducted on small numbers of patients and varied with respect to IVIG doses and duration of therapy cycles. Furthermore, many of the patients included in the studies did not respond to conventional therapies, were affected by complications, and had impaired renal function. IVIG therapy was able to reduce proteinuria and inflammation and improve renal function in some forms of glomerulonephritis, particularly LES-related forms. IVIG therapy was also tested in patients awaiting kidney transplantation and in patients affected by transplant-related chronic nephropathy: in both groups the results were controversial. Seventy-eight cases of IVIG-related nephrotoxicity have been reported in the literature. In most cases the toxic effect was reversible and observed in patients with pre-existing renal failure treated with IVIG formulations containing saccharose. IVIG could have beneficial effects in many glomerulopathies. Nevertheless, further trials are needed to clarify the potential and the limitations of this therapeutic approach.

Caffeine, or 1, 3, 7-trimethylxanthine, is one of the most frequently consumed active drugs worldwide. Its main mechanisms of action include inhibiting the phosphodiesteratic enzyme and adenosine receptors and activating the ryanodine receptors with several actions on all organs. What effect does caffeine have on the kidney? Is caffeine beneficial or dangerous? A review of the current literature reveals conflicting opinions regarding the prolithiasic effect of this substance, whereas its diuretic action is least disputed and more easily observed. Caffeine may have a toxic or preventive effect in some physiologic or pathologic conditions. Some of these incongruences may depend on several factors, such as dosage, prior chronic exposure, genetic-enzymatic axes, and concomitant drug consumption. While awaiting further insight from forthcoming studies on the issue, we may reach a preliminary conclusion that, as yet, there is no evidence contraindicating the consumption of the equivalent of 3 to 4 cups of coffee per day in healthy or nephropathic subjects. However, particular attention should be paid to the elderly, children, and patients on concomitant treatment with analgesics or diuretics, whereas in subjects with a family or clinical history of calcium lithiasis a moderate caffeine consumption should be associated with an adequate fluid intake. Further in-depth studies are required to investigate whether this beverage is beneficial to patients on hemodialysis.

Caffeine is one of the most frequently consumed substances worldwide. It is present in some common beverages such as tea and coffee and in a variety of drugs, particularly analgesics. Its main mechanisms of action include inhibition of phosphodiesterase enzyme and adenosine receptors; its effects involve the whole body. In recent years there has been a debate in the scientific literature over the relationship between caffeine and the kidney and its possible toxicity. Several experimental studies have demonstrated that caffeine may exacerbate some pathological conditions such as polycystic disease and proteinuria, while others have underlined its protective effects in specific situations. While awaiting new, in-depth studies that will help to solve the debate, we can conclude that there is currently no evidence contraindicating the consumption of moderate quantities of caffeine by healthy subjects or kidney patients.

A combined application of high resolution (1)H NMR spectroscopy and multivariate statistical techniques focused on establishing a consistent statistical approach to metabonomic studies was tested. The data reduction, which is preliminary to the application of multivariate analysis to NMR spectra, was carried out by means of two complementary methods: pure Pattern Recognition (PR) and Assigned Signal Analysis (ASA). The simultaneous use of both approaches allowed us to obtain additional information in the analysis of metabonomic data, compared to the use of PR alone. This additional information consists in the possibility of a biochemical interpretation of the effects induced by treatment with xenobiotics, such as drugs or drug vehicles, on the metabolic networks of the systems under investigation. This approach allowed us to ascertain that a single-dose treatment with ST1959 vehicled by Sesame oil affects the production of hepatic glucose associated to an increment of the amino acid ketogenic process.

HMG-CoA reductase inhibitors (statins) are among the most widely used hypolypemizing drugs with a pleiotropic activity. Numerous clinical trials have demonstrated that statins can have a significant effect in the prevention of cardiovascular diseases in the general population. In patients with renal failure, this drug preserves the hypolypemizing efficacy found in the general population without increasing their unwanted side-effects. The re-analysis of data from epidemiological studies conducted on the general population has confirmed that statins provide cardiovascular protection also in subjects with renal failure. These data have been partly confirmed by the findings made by 4D (Die Deutsche Diabetes Dialyse Studie) and Alert studies, conducted on diabetic patients on dialysis and patients with renal transplants, respectively. The results of other studies, such as AURORA, SHARP, REnal and Vascular End stage Disease, and ESPLANADE, clearly indicate that statins prevent cardiovascular disease in patients with renal insufficiency, just as they do in the general population.

Background: Endometrial ossification is a rare disease. More than 80% of cases occur after pregnancy, but it has been observed in patients with a history of endometritis, dilation and curettage, and metabolic disorders., Case: A 42-year-old woman presented with osseous metaplasia of both the endometrium and ovaries. At laparoscopy both adnexa were covered with adhesions and were adherent to the posterior wall of the uterus. Following adhesiolysis, calcified nodules were removed from both ovaries with biopsy forceps. Endometrial bone tissue was removed by hysteroscopic resection., Conclusion: To our knowledge, this is the first reported case of osseous metaplasia of both the endometrium and ovaries since all cases described to date in the literature involved only the uterine cavity. Conservative management with endoscopic surgery is effective.

FSH is synthesized and secreted in multiple molecular forms with different oligosaccharide structures which are needed for full expression of biological activity. GnRH and sex steroids modulate oligosaccharide structure and composition. In the present study we have assessed the carbohydrate complexity and proportion of circulating FSH isoforms during puberty, aging and after androgen administration to pubertal anorchid boys. Preparative isoelectrofocusing and lectin chromatography were used to isolate FSH isoforms on the basis of charge and internal carbohydrate complexity. Differences in sialic acid content and a progressive increase of isoforms bearing highly branched oligosaccharides were found during puberty. Less acidic, more bioactive FSH isoforms, secreted at mid-puberty may modulate important maturational events in the Sertoli cell population. Androgen administration to pubertal anorchid boys favoured the secretion of this type of isoforms. In adult men, the predominance of FSH isoforms bearing complex type oligosaccharides remained unchanged until very advanced age. These results show that the predominance of FSH isoforms bearing fully processed oligosaccharides in circulation may contribute to the development and maintenance of seminiferous epithelium function in men.

Numerous uremic patients on hemodialysis have pulmonary hypertension attributable to the presence of arteriovenous fistulas, vascular calcification, and endothelial dysfunction due to alterations in the balance between vasoconstrictive and vasodilatory substances. For these reasons, the effects of recombinant human erythropoietin, a drug widely used in patients on dialysis, on the pulmonary circulation were studied. Some authors maintain that recombinant human erythropoietin has an antihypertensive effect, while others have observed that this hormone induces a reduction in pulmonary arterial pressure due to its vasoactive and stimulatory effects on endothelial and smooth muscle cell precursors., (Copyright 2007 S. Karger AG, Basel.)

The aquaporin-2 (AQP2) plays a key role in AVP-induced absorption of water, and its urinary excretion is related to its function. We aimed to test if the assumption of water with different mineral content can modify the expression of AQP2, leading to a change in AQP2 urinary concentration, in 20 healthy young subjects. Each subject received an oral water load (LM or HM) of 250 mL/hour for four hours, and several variables were measured. Plasmatic osmolality after water assumption was significantly reduced with no differences after the low (LM) or the high mineral (HM) water load. Urinary osmolality and plasmatic vasopressin concentration were significantly reduced after an assumption of both kinds of water. However, serum vasopressin was lower after HM water assumption than after LM. AQP2 urinary excretion was significantly reduced after water assumption with respect to the basal level and it was lower after LM than after HM water assumption. The different mineral content of water was investigated as a factor contributing to the development of hypertension. Considering that AQP2 can play a role in pathogenesis of hypertension, our demonstration that AVP-mediated AQP2 urinary excretion is strictly influenced by the consumption of water with different mineral content suggests a new, interesting field of investigation related to the link between blood pressure alterations and nutritional habits.

The kidney can achieve a structural and functional recovery after the damage induced by ischemia and reperfusion. This is due to the regeneration of epithelial tubular cells, the intervention of immature cells mainly localized in the medulla, and a small number of bone marrow-derived stem cells. In many instances, however, recovery is delayed or does not occur at all. The mechanisms allowing the renal cells to de-differentiate still need to be clarified in order to find a therapeutic approach that can amplify this ability and then stop the fibroid involution and the progression toward renal failure. Several authors have hypothesized a protective effect of EPO against ischemic and cytotoxic renal damage and observed that patients precociously treated with EPO showed a slower progression of renal failure. EPO has been demonstrated to have proliferative and anti-apoptotic effects in ischemia-reperfusion models in the brain and cell cultures. Moreover, EPO can mobilize stem cells and increase the plasmatic levels and the renal expression of VEGF. These effects seem to be dose-dependent and could be due to the activation of signal transduction systems, like Jak and STAT. In the presence of high doses of exogenous EPO or during the treatment with long-acting EPO-like molecules, non-specific receptors may be activated through a low-affinity link. Further investigations are needed to determine new therapeutic applications for EPO and other analogous hormones. Very long-acting molecules or molecules with cyto-protective but no erythropoietic effect may represent useful tools in the study of the molecular mechanisms underlying EPO's action and may have a rapid and safe therapeutic application.

During haemodialysis (HD) the endothelium is the first organ to sense and to be impaired by mechanical and immunological stimuli. We hypothesized that a single HD session induces mobilization of endothelial progenitor cells (EPCs) and that cardiovascular risk factors may influence this process. We quantified EPCs at different maturational stages (CD34+, CD133+/VEGFR2+) in blood samples from 30 patients, during HD and on the interdialytic day, and in 10 healthy volunteers. Samples were drawn at the start of HD, 1, 2 and 3 h after, at the end of HD and at 24 h on the interdialytic day. Patients were divided into two groups based on a recent risk scoring system (SCORE project): low-risk (LR) and high-risk groups (HR). HD patients showed a significantly reduced basal number of EPCs with respect to healthy volunteers. In contrast, we observed increasing EPCs during HD whereas they diminished on the interdialytic day. The EPC number was directly correlated with HD time progression. The EPC number during HD was increased in the HR group with respect to the LR group. We had a direct correlation between risk score and number of EPCs. Cardiovascular risk factors influenced the mobilization of stem cells from the bone marrow. This feature could be the direct consequence of an augmented request of stem cells to respond to the most important endothelial impairment but could also show a defective capacity of EPCs to home in and repair the sites of vascular injury., (Copyright 2007 S. Karger AG, Basel.)

Background: Healthy subjects and patients after successful kidney transplantation show a circadian rhythm for glomerular filtration rate and for the glomerular transport of macromolecules. We aimed to evaluate by bioelectrical impedance analysis (BIA) whether body hydration status also follows a circadian rhythm in patients with impaired renal function., Methods: The study was conducted on 28 subjects divided into 3 groups: 8 healthy volunteers, 8 patients affected by chronic kidney disease and 12 end-stage renal disease (ESRD) patients on hemodialysis. During 24 h, 9 BIA measurements were taken in every subject every 180 min., Results: BIA findings demonstrate that normal subjects have a circadian rhythm in hydration status that reaches maximum body water content at night, between 21.00 and 23.00 h. In patients with chronic kidney disease, this rhythm, with maximum at night, is maintained. The rhythm is also present in ESRD patients, if the residual diuresis is at least 500 ml/day, while there is no rhythm when residual diuresis is <300 ml/day., Conclusions: In normal subjects, body hydration status shows a circadian rhythm, which is weakened or lost in oligoanuric patients on dialysis, but partially maintained in subjects with preterminal uremia and in hemodialyzed patients with residual diuresis >500 ml/day., (Copyright 2007 S. Karger AG, Basel.)

It is known that many tubular proteins are involved in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which causes 8-10% of the cases of end-stage renal disease (ESRD) worldwide. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein expressed on tubular cells of which the production is markedly increased in response to harmful stimuli such as ischemia or toxicity. In the present study, serum and urinary NGAL levels were evaluated in 26 ADPKD subjects. Both levels were significantly higher in patients than in controls (sNGAL 174 +/- 52 vs. 50 +/- 27 ng/ml, p < 0.05; uNGAL 119 +/- 42 vs. 7 +/- 6 ng/ml, p < 0.005) and a close correlation was also found between these parameters and the residual renal function (sNGAL/GFR: r = -0.8, p = 0.006; sNGAL/Creatinine: r = 0.9, p = 0.007; uNGAL/GFR: r = -0.49, p < 0.05; uNGAL/Creatinine: r = 0.84, p < 0.001). Patients were further divided into two groups according to the cystic development assessed with echotomography; subjects with higher cystic growth (HCG) presented higher sNGAL and uNGAL levels with respect to others (sNGAL: 242 +/- 89 vs. 88 +/- 34 ng/ml, p < 0.05; uNGAL: 158 +/- 45 vs. 73 +/- 27 ng/ml, p < 0.05). The strict correlation between NGAL levels and residual renal function is perfectly in accord with recent studies on patients with other ESRD-associated diseases. We can hypothesize that tubular cells produce big quantities of NGAL as a consequence of increased apoptosis following chronic damage or as a compensatory response, similar to that observed in acute stress conditions (ischemia, toxicity ...). Finally, our last finding that patients with HCG showed higher levels of NGAL suggests that this protein could be also involved in the cyst growth process, as previously reported about epithelial and tumoral expansion., (Copyright 2007 S. Karger AG, Basel.)

Unlike the more commonly used diuretics, aquaretic agents can induce an increase in urinary volume without incurring a loss of electrolytes. These molecules belong to a family of vasopressin receptor antagonists, V2 in particular, that regulate optional renal water re-absorption via the synthesis and expression of aquaporin-2. In view of their properties, they have become the agent of choice in the treatment of hyponatremic states with water retention, and different studies have demonstrated that they are more effective and practical to use than other traditional approaches in the treatment of diseases such as cirrhosis-related ascites, SIADH and, above all, heart failure. However, the future probably holds the promise of new and unexpected applications for this type of drug in the treatment of several conditions, including polycystic kidney and glomerular disease, glaucoma and Meniere's syndrome.

One third of all U.S. adult women, and more than 75% of African American women, are overweight or obese. This study examined overweight and obesity editorial content (N=406) in three mainstream and three African American women's magazines between 1984 and 2004. Content analysis was used to determine which strategies were suggested regarding diet, overweight, and obesity, which components of social cognitive theory were offered (behavior, person, or environment), and whether or not there were differences in the genres. The results suggest that although a wide range of strategies were being offered, the vast majority were behavioral changes with an individual solution focus. Although African American and mainstream magazines suggested many of the same strategies, nearly half more frequently appeared in one or the other genre. Mainstream magazines were twice as likely to offer the limiting or eliminating of fast food or junk food, eating more protein, eating lower-fat foods, and eating smaller portions. African American magazines were much more likely to cover fad diets and to suggest readers rely on God or faith in their diet plans. The average number of strategies offered per article was significantly higher in mainstream than in African American magazines.

Most biological molecules exhibit more than one function. In particular, many molecules have the ability to directly/indirectly scavenge free radicals and thus act in living organisms as antioxidant. During oxidative stress, the increase of these molecules levels seems to be a biological response that in synergism with the other antioxidant defence systems may protect cells from oxidation. Among these structures, chondroitin sulphate is a biomolecule which has increasingly focused the interest of many research groups due to its antioxidant activity. This review briefly summarises the action of chondroitin sulphate in reducing molecular damage caused by free radicals and associated oxygen reactants.

mRNA/cDNA gene expression of both small leucine-rich proteoglycans decorin and biglycan was evaluated by PCR real time in lymphocytes collected from patients with chronic lymphocytic leukaemia (CLL) at different stages of disease and from healthy controls. Lymphocytes obtained from healthy controls showed no or very low levels of mRNA expression of both decorin and biglycan. Biglycan expression was very low in CLL patients, values being close to those of controls. On the contrary, decorin mRNA was clearly expressed in patients with early B-cell CLL, while a low expression was found in advanced clinical stages. Furthermore, a significant higher decorin expression was found in patients with non-progressive CLL type in comparison with patients with aggressive type of the disease. Decorin expression resulted especially high in the low-progressive low-risk patients. The synthesis of decorin was also assessed by Western blot analysis. The peculiar occurrence of decorin in the non-aggressive type of CLL is consistent with its suggested anti-oncogenic role. Intracellular Bcl-2 level does not correlate with decorin mRNA transcription, suggesting that a Bcl-2 independent anti-cancer mechanism may occur. The measurement of galactosamine-containing proteoglycans concentration in plasma confirmed decorin expression results, with significant differences between CLL patients and controls. Significant changes were also seen between groups of patients of Rai stage 0 with recent diagnosis (less than 5 years, from analysis), (low amount of decorin) and less recent diagnosis (more than 5 years), (high amount of decorin).

Several reports have shown that a number of cytokines such as tumor necrosis-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-beta (IL-1beta) are capable to induce hyaluronan sinthases (HASs) mRNA expression in different cell culture types. The obvious consequence of this stimulation is a marked increment in hyaluronan (HA) production. It has been also reported that oxidative stress, by itself, may increase HA levels. The aim of this study was to evaluate how TNF-alpha, IFN-gamma,IL-1beta, and exposition to oxidative stress may modulate HAS activities in normal human skin fibroblasts. Moreover, the effects on HAS mRNA expression of the concomitant treatment with cytokines and oxidants, and the HA concentrations after treatments, were studied. TNF-alpha, IFN-gamma, and IL-1beta were added to normal or/and exposed to FeSO(4) plus ascorbate fibroblast cultures and HAS1, HAS2 and HAS3 mRNA content, by PCR-real time, was assayed 3,h later. HA levels were also evaluated after 24,h incubation. The treatment of fibroblasts with cytokines up-regulated HASs gene expression and increased HA production. IL-1beta induced HAS mRNA expression and HA production more efficiently than TNF-alpha and IFN-gamma. The exposition of the fibroblasts with the oxidant system markedly increased HAS activities while slightly HA production. The concomitant treatment of cells with the cytokines and the oxidant was able to further enhance, in a dose dependent way, with synergistic effect on HAS mRNA expression. On the contrary HA levels resulted unaffected by the concomitant treatment, and resemble those obtained with the exposure to FeSO(4) plus ascorbate only. This lack in HA production could be due to the deleterious action of free radicals on the HA synthesis.

Context: Newborns with ambiguous genitalia or males with nonpalpable gonads usually require an early assessment of the presence and functional state of testicular tissue., Objective: Our objective was to characterize the precise ontogeny of the serum patterns of gonadotropins, testosterone, anti-Müllerian hormone (AMH), and inhibins in normal newborn boys., Design: We conducted a cross-sectional and longitudinal study., Subjects: Serum samples were obtained in 57 boys and 13 girls on d 2 of life. A second sample was obtained on d 7, 10, 15, 20, and 30 (boys) and on d 30 (girls)., Main Outcome Measures: Serum levels of gonadotropins, testosterone, AMH, and inhibins were measured., Results: In males, LH and FSH were undetectable or very low on d 2. By d 7, LH increased to 3.94 +/- 3.19 IU/liter (mean +/- sd) and FSH to 2.04 +/- 1.67 IU/liter. LH/FSH ratios were 0.40 +/- 0.11 (d 2) and 2.02 +/- 0.20 (d 30). AMH rose from 371 +/- 168 pmol/liter (d 2) to 699 +/- 245 pmol/liter (d 30), and inhibin B rose from 214 +/- 86 ng/liter (d 2) to 361 +/- 93 ng/liter (d 30). The inhibin alpha-subunit precursor (pro-alphaC) remained stable during the first month of life. Testosterone levels were 66 +/- 42 ng/dl (d 2), 82 +/- 24 ng/dl (d 20), and 210 +/- 130 ng/dl (d 30). A sexual dimorphism was observed in AMH and inhibin B (lower in girls on d 2 and 30), in LH/FSH ratio (lower in girls on d 30) and in testosterone (lower in girls on d 30)., Conclusions: Sertoli cell markers AMH and inhibin B are the earliest useful markers indicating the existence of normal testicular tissue.

Aim: The utility of serum alpha-fetoprotein (alpha-FP) in the detection of hepatocellular carcinoma (HCC) is questionable. Very high circulating levels of nociceptin/orphanin FQ (N/OFQ), a ligand for a novel opioid receptor, have recently been reported in HCC. The aim of this study was to assess the role of plasma N/OFQ in the diagnosis of HCC arising in patients with liver cirrhosis., Methods: Plasma N/OFQ levels were measured by ELISA in 58 patients (28 HCC and 30 liver cirrhosis) and in 25 healthy controls. The values were correlated with clinical and laboratory features including alpha-FP. Spearman index, biserial correlation coefficient, non parametric combination (NPC) test and discriminant stepwise analysis were used for statistical evaluation of data., Results: The upper normal limit of nociceptin was 122 pg/mL. Plasma levels above this cut-off were found in 21.4% of patients with HCC, in 23.3% of those with cirrhosis and in 8% of healthy subjects. alpha-FP serum levels > 200 ng/mL were found in 46.4% of the patients with HCC and in none of those with cirrhosis. No correlation was found between N/OFQ levels and any of the clinical and laboratory features, including alpha-FP. By NPC test, HCC and cirrhotic patients were different with regard to alpha-FP (P = 0.000) but not in terms of nociceptin (P = 0.595). By point biserial correlation, HCC presence was positively correlated with alpha-FP (rpb = 0.52, P = 0.000) but not with N/OFQ (rpb = 0.16, P = 0.157). In a discriminant analysis, alpha-FP was significant in the Wilks test (Y = -0.709 + 0.03 alpha-FP) and properly classified 81% of all patients and 61% of HCC. N/OFQ had lower sensitivity, specificity and predictive values than alpha-FP., Conclusion: Nociceptin is increased in patients with chronic liver disease, independently of the presence of HCC, although the underlying mechanism has yet to be clarified. We conclude it is not a useful marker for HCC.

Background: Premature ovarian failure (POF) is characterized by hypergonadotropic amenorrhoea before the age of 40. Inhibin alpha-subunit (INHalpha) gene is proposed as a candidate gene due to its role in negative feedback control of FSH., Methods: Polymorphism -16C>T of INHalpha gene was studied in 61 POF patients and 82 controls above 40 years old (C > 40). Substitution 769G>A was studied in 59 POF patients, 76 C > 40 and 73 controls below 40 years old (C < 40)., Results: No significant difference in risk of POF development for -16T allele was found when comparing idiopathic POF (I-POF) with C > 40 (Odds ratio = 1.46; 95% confidence interval = 0.63-3.19). Implication of -16C>T polymorphism in serum inhibin levels was analysed in 46 controls, and no significant differences (P > 0.05) were found between CC and CT + TT genotype groups when comparing either mid-follicular phase Pro-alphaC and inhibin B values or mid-luteal phase Pro-alphaC and inhibin A values. Heterozygosity for substitution 769G>A was found in 1 of 59 POF woman, 2 of 76 C > 40 and 6 of 73 C < 40. Presence of this substitution in a relevant number of control subjects is herein described for the first time., Conclusion: Our results indicate that -16C>T and 769G>A variants in INHalpha gene may not be associated to POF disease.

Background: The association of normal serum levels of immunoassayable gonadotrophins with anovulation during lactational amenorrhoea (LA) has not been fully explained., Methods: Serum FSH polymorphism was analysed in 10 women during LA between days 60 and 70 post-partum and again, in the mid-follicular phase (MFP), after resuming menstrual cyclicity. FSH microheterogeneity was characterized according to charge, using preparative isoelectric focusing, and according to the inner structure of carbohydrate chains, using lectin chromatography., Results: A significantly higher proportion of FSH charge isoforms isolated below pH 4.10 and a lower proportion of FSH isoforms bearing highly branched oligosaccharides were observed during LA when compared to MFP. Further analysis with higher resolution showed that FSH charge isoforms, isolated in the lower pH range in LA, corresponded to FSH molecules bearing highly branched and biantennary oligosaccharides. FSH isoforms bearing hybrid-type oligosaccharides were only present during LA. The circulating FSH isoform mix was significantly less bioactive in LA than in MFP. LA is characterized by a more acidic mix of FSH isoforms, containing hormone bearing less processed oligosaccharides, with decreased biopotency in comparison with the follicular phase., Conclusions: This FSH microheterogeneity may be one of the critical factors contributing to incomplete follicular development and anovulation during LA.

In order to test the hypothesis that transforming growth factor beta (TGF-beta) acts by FS regulation on bovine granulosa cells in in vitro differentiation, we analyzed the effect of TGF-beta1 on follistatin mRNA expression in three differentiation states of bovine granulosa cells. We showed a positive regulation of FS mRNA after TGF-beta1 (1 ng/ml) treatment of freshly isolated granulosa cells from small-medium antral follicles (2-8 mm). This effect was abolished by the addition of exogenous follistatin (100 ng/ml), suggesting that this effect could be mediated by activin. Although these cells showed a similar effect on FS mRNA expression after treatment with activin-A, a soluble form of activin receptor type IIA was unable to inactivate the TGF-beta effect. When we tested the TGF-beta effect on FS mRNA in different granulosa cell states, TGF-beta1 regulation was associated with progesterone production only in freshly isolated cells. The amount of total activin-A produced by first passage cells (dedifferentiated cells), was ten times smaller than the one measured in a conditioned medium from freshly isolated cells (mature cells). The TGF-beta1-dependent FS mRNA expression persisted in first passage cells without changes with FS addition. On the other hand, the BGC-1 granulosa cell line (immature cells) produced large amounts of activin-A regulated by TGF-beta1 and an invariable steady state of FS mRNAs. In summary, our results showed that FS mRNA expression is regulated by TGF-beta1 independently of activin effects in differentiated granulosa cells.

ST2146biot is a biotinylated anti-tenascin monoclonal antibody (mAb) to be used for Pretargeted Antibody Guided Radioimmunotherapy (PAGRIT) of solid tumors. In vivo biodistribution studies of (125)I-labeled ST2146biot were done in nude mice transplanted with human HT-29 colon carcinoma and/or human U-118MG glioblastoma cells characterized for low and high tenascin expression, respectively. In vitro results show that ST2146 retains immunoreactivity upon biotinylation, in contrast to other anti-tenascin mAbs. In vivo biodistribution of ST2146 shows specific tumor accumulation up to 10 days after the i.v. injection, with no relevant differences between biotinylated and nonbiotinylated ST2146. A dose of 4 microg/mouse saturates the low tenascin-expressing human colon carcinoma HT-29, whereas the high tenascin-expressing human glioblastoma U-118MG seems to be saturated at a ST2146biot dose between 320 and 640 microg/mouse. The percentage of injected dose per gram of tumor ranges from 10% to 30%, corresponding to an amount of ST2146biot/g of tumor of approximately 400 ng/g and >200 microg/g for HT-29 and U-118MG, respectively. Tumor to normal organs uptake ratios are between 15 and 60, confirming high tumor selectivity of ST2146biot despite its cross-reactivity with the tenascin expressed at low level in the normal mouse organs. The ST2146biot localization data are substantially confirmed even when both low and high tenascin-expressing tumors are implanted in the same animal. To our knowledge, the absolute amount of ST2146biot, specifically localized in xenotransplanted human tumors, is the highest thus far described and supports the clinical use of this mAb in PAGRIT(R).

Background: Comparisons of follicular development and hormonal profile in the same women during and after lactational amenorrhoea (LA) are scarce. We report follicular growth, pituitary and ovarian hormone serum levels in the same women during LA and in follicular phases after resumption of menstrual cyclicity., Methods: Serum samples were obtained from 10 women during LA between days 60 and 89 post-partum and between days 1 and 4 (early follicular phase; EFP) and 7 and 10 (mid-follicular phase; MFP) of the second and third cycles after LA., Results: The number of follicles >3 mm and diameter of the largest follicle were significantly higher during LA when compared to EFP and MFP. Serum levels of inhibin B were similar in LA and EFP and increased significantly in MFP. Pro-alphaC was significantly higher in EFP than in LA and MFP. Estradiol was similar during all stages. In comparison with EFP and MFP, LA is associated with higher prolactin levels, normal or slightly elevated gonadotrophins and increased number and size of follicles without a parallel increase in estradiol, inhibin B and Pro-alphaC., Conclusions: During LA, there is a profound dissociation between follicular growth and follicular endocrine activity, which suggests an alteration in the stimulus-response relationship at the follicular level.

Background: Systemic hypertension is one of the main risk factors for atherothrombosis. Tissue factor (TF) is found in the adventitia of blood vessels and in the lipid core of atherosclerotic plaques, and is specifically expressed on monocyte or macrophage cell membrane surfaces. TF plays a pivotal role in blood clotting physiology and is involved in pro-inflammatory action and atherosclerotic plaque destabilization., Objective: In this study we investigated whether there is any relationship between TF messenger RNA expression and activity in blood monocytes isolated from hypertensive patients with clinical signs of atherosclerosis, uncomplicated hypertensive individuals and normotensive control subjects., Methods: Eighty subjects (41 men and 39 women, mean age 41 +/- 12 years) with untreated essential hypertension and 41 control subjects matched for sex and age were enrolled in the study. Patients were classified according to whether they had a normal ( 1 mm, 39 patients) intima-media thickness (IMT)., Results: TF mRNA expression and activity in hypertensive individuals with no carotid atherosclerosis were no different from control subjects in unstimulated and stimulated monocytes. Abnormal IMT patients showed a higher TF mRNA expression compared with normal IMT hypertensive subjects (P < 0.001)., Conclusions: We demonstrated that TF mRNA and activity levels in monocytes obtained from uncomplicated hypertensive individuals are comparable with those of normotensive subjects, whereas atherosclerotic hypertensive patients showed increased levels of these parameters.

Cecropins are a family of antimicrobial peptides, which constitute an important key component of the immune response in insects. Here, we demonstrate that transgenic rice (Oryza sativa L.) plants expressing the cecropin A gene from the giant silk moth Hyalophora cecropia show enhanced resistance to Magnaporthe grisea, the causal agent of the rice blast disease. Two plant codon-optimized synthetic cecropin A genes, which were designed either to retain the cecropin A peptide in the endoplasmic reticulum, the ER-CecA gene, or to secrete cecropin A to the extracellular space, the Ap-CecA gene, were prepared. Both cecropin A genes were efficiently expressed in transgenic rice. The inhibitory activity of protein extracts prepared from leaves of cecropin A-expressing plants on the in vitro growth of M. grisea indicated that the cecropin A protein produced by the transgenic rice plants was biologically active. Whereas no effect on plant phenotype was observed in ER-CecA plants, most of the rice lines expressing the Ap-CecA gene were non-fertile. Cecropin A rice plants exhibited resistance to rice blast at various levels. Transgene expression of cecropin A genes was not accompanied by an induction of pathogenesis-related (PR) gene expression supporting that the transgene product itself is directly active against the pathogen. Taken together, the results presented in this study suggest that the cecropin A gene, when designed for retention of cecropin A into the endoplasmic reticulum, could be a useful candidate for protection of rice plants against the rice blast fungus M. grisea.

College students' processing of alcohol social norms messages, related effects on normative judgments, attitudes toward their own behaviors, and perception of undergraduate attitudes were examined using expectancy violation theories and social norms marketing. Data were collected from 2 universities (N = 393). Following message exposure, the majority moved their normative judgments toward the statistic provided in the message. Slight attitude change occurred but not always in the desired direction. Those most likely to develop unhealthier attitudes drank more than those who developed healthier attitudes, consistent with psychological reactance to the messages. Therefore, the effects of social norms campaigns on those at greatest risk for primary and secondary alcohol effects due to their increased alcohol consumption could lead to increased risk for those participants, indicating that the widespread use of social norms campaigns needs to be scrutinized.

Recent health campaigns on college campuses have used a social norms approach, which suggests that one's perceptions of others' attitudes and behaviors are the key components in attitude and behavior change. However, the efficacy of social norms campaigns has been mixed. This study was conducted to assess the relationships among sociodemographics, normative perceptions, and individual attitudes on 3 health behaviors. Students at 2 universities (N = 393) completed questionnaires assessing how these variables related to their consumption of alcohol, tobacco use, and exercise behaviors. Regressions indicated that each of these variables was associated with behavior, but varied independent variables emerged as the salient predictors among behaviors. In several conditions the effect of normative perceptions on behaviors was not significant, a finding in direct opposition to social norms marketing. In all 3 behavioral conditions, the variable accounting for the greatest variance was whether or not the individual liked participating in that particular behavior. Thus, although some social norms marketing may be meeting with success, it may be the case that predicted attitudinal and behavioral changes will not be found when applied across diverse health topics.

Imbalance between matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases (TIMPs) is an important control point in tissue remodelling. Several findings have reported a marked MMP/TIMP imbalance in a variety of in vitro models in which oxidative stress was induced. Since previous studies showed that commercial hyaluronan and chondroitin-4-sulphate are able to limit lipid peroxidation during oxidative stress, we investigated the antioxidant capacity of purified human plasma chondroitin-4-sulfate in reducing MMP and TIMP imbalance in a model of ROS-induced oxidative injury in fibroblast cultures. Purified human plasma chondroitin-4-sulfate was added to the fibroblast cultures exposed to FeSO4 plus ascorbate. We assayed cell death, MMP and TIMP mRNA expression and protein activities, DNA damage, membrane lipid peroxidation, and aconitase depletion. FeSO4 plus ascorbate produced severe death of cells and increased MMP-1, MMP-2 and MMP-9 expression and protein activities. It also caused DNA strand breaks, enhanced lipid peroxidation and decreased aconitase. TIMP-1 and TIMP-2 protein levels and mRNA expression remain unaltered. Purified human plasma C4S, at three different doses, restored the MMP/TIMP homeostasis, increased cell survival, reduced DNA damage, inhibited lipid peroxidation and limited impairment of aconitase. These results further support the hypothesis that these biomolecules possess antioxidant activity and by reducing ROS production C4S may limit cell injury produced by MMP/TIMP imbalance.

Background/aims: Patients with chronic renal failure show the presence of massive oxidative genome damage but the role played by dialysis is still a controversial issue. The aim of our study was to verify the genomic damage in B- and T-lymphocyte subpopulations of uremic patients after a single hemodiafiltration session., Methods: We enrolled 30 patients on maintenance acetate-free biofiltration and 25 age-matched healthy volunteers and studied chromosomal alterations., Results: Our data show that the basal levels of DNA damage, the number of sister chromatid exchanges and basal high-frequency cells levels are significantly higher in patients on hemodiafiltration than in controls and in T lymphocytes than in B cells., Conclusions: These findings suggest that hemodialytic treatment could represent a potential source of damage, maybe through the oxidative action of the extracorporeal circuit components, which might explain the well-known T-specific immunodeficiency correlated with uremia.

Media framing of infant feeding has the ability to influence knowledge and views of the barriers, benefits, and solutions inherent in breastfeeding or formula-feeding. This study examined how seven popular U.S. parenting, general women's, and African American magazines framed breastfeeding and formula-feeding messages to determine whether a sense-making approach was used and the extent to which visual images portrayed feeding practices. Analysis included 615 articles published from 1997 to 2003 that referred to infant feeding. Text and images were analyzed. The magazines provided more information on breastfeeding than formula feeding. Parenting magazines included more advice than barriers or benefits. African American magazines presented more breastfeeding benefits, and general women's magazines contained the least infant-feeding information. Messages were focused on individualized breastfeeding barriers and advice, seldom covered social and environmental issues, and placed much of the responsibility of infant feeding on the mother, while the role of social and partner support was diminished. Bottle-feeding images were nearly as common as breastfeeding images. Findings can be used by public health practitioners to increase the likelihood of reaching certain target audiences through popular magazines.

Introduction: Recently, the identification of the SEN virus as a possible etiological agent of parental transmission hepatitis led to the study of the prevalence of such pathogen agents, particularly SENV-H, in our population. This paper compares the rate prevalence in high-risk subjects, such as dialysis patients, and low-risk subjects, such as blood donors., Material and Methods: The study was carried out on SEN virus DNA extracted from serum of dialysis patients and blood donors, and the presence of viral genomes was performed by the nested PCR method., Results: The results showed a higher prevalence in male blood donors, supporting the hypothesis of an epidemiological role for sexual and also parental transmission, as is clearly demonstrated by the high prevalence in dialysis patients. The result reduced the importance of the possible etiological role of the SEN virus due to the high percentage of positivity in healthy population, and it induces one to consider poorly significant the pathogenicity of such viral agents., Conclusion: For this instance, the authors, in agreement with the phylogenically related TT virus, described SEN viruses as absolutely not pathogens and considered them as "simple guests."

The nephrotic syndrome is characterized by metabolic disorders leading to an increase in circulating lipoproteins levels. Hypertriglyceridemia and hypercholesterolemia in this case may depend on a reduction in triglyceride-rich lipoproteins catabolism and on an increase in hepatic synthesis of Apo B-containing lipoproteins. These alterations are the starting point of a self-maintaining mechanism, which can accelerate the progression of chronic renal failure. Indeed, hyperlipidemia can affect renal function, increase proteinuria and speed glomerulosclerosis, thus determining a higher risk of progression to dialysis. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme in cholesterol synthesis from mevalonate and its inhibitors, or statins, can therefore interfere with the above-mentioned consequences of hyperlipidemia. Statins are already well known for their effectiveness on primary cardiovascular prevention, which cannot be explained only through their hypolipemic effect. As far as kidney diseases are concerned, statin therapy has been shown to prevent creatinine clearance decline and to slow renal function loss, particularly in case of proteinuria, and its favorable effect may depend only partially on the attenuation of hyperlipidemia. Statins may therefore confer tissue protection through lipid-independent mechanisms, which can be triggered by other mediators, such as angiotensin receptor blockers. Possible pathways for the protective action of statins, other than any hypocholesterolemic effect, are: cellular apoptosis/proliferation balance, inflammatory cytokines production, and signal transduction regulation. Statins also play a role in the regulation of the inflammatory and immune response, coagulation process, bone turnover, neovascularization, vascular tone, and arterial pressure. In this study, we would like to provide scientific evidences for the pleiotropic effects of statins, which could be the starting point for the development of new therapeutical strategies in different clinical areas., ((c) 2005 Wiley Periodicals, Inc.)

The main role of superoxide dismutases (SODs) is to eliminate reactive oxygen species in cells and tissues. Extracellular SOD (EC-SOD/SOD3) is a major superoxide scavenger and it is located on cell surfaces and primarily in extracellular matrix, and binds heparan sulfates by its carboxyterminal portion. Human EC-SOD gene is located on chromosome 4 and comprises three exons and two introns. The SOD3 coding sequence is entirely located within exon 3 and has missense polymorphisms. The Arg213Gly mutation affects the function of the carboxyterminus and correlates with several diseases. In this work, we explored genetic variants within EC-SOD gene of subjects living in southern Italy. Four new variations were detected: one was silent mutation, while three were missense variations that give rise to amino acid substitutions at position 131 (F>C), 160 (V>L) and 202 (R>L) in the mature product. The Arg213Gly variant was not found. The missense mutations in the DNA of assayed 2400 chromosomes had frequencies of 5.34% for the F131C variation, 0.25% for the V160L variation and 0.84% for the R202L variation. The effect of these alterations on the metabolic activity and diseases remains to be further explained.

Interleukin-6 (IL-6) plays a central role in the pathogenesis of several autoimmune and inflammatory diseases as well as B-cell lymphoproliferative disorders. This work describes the effects of the recombinant or adenovirally-delivered IL-6 superantagonist Sant7, anti-IL-6 and IL-6 receptor monoclonal antibodies in a severe murine model of human B-cell lymphoma induced in SCID mice by transplantation of an LCL-41 cell line variant (isotype-switched IgM>IgG). Survival of 60% of the animals treated with anti-gp130 was observed up to day 33, while about 20% of the animals survived with anti-gp80 and Sant7 treatment. No survival was observed with the anti-IL-6 monoclonal antibody treatment. No significant change in serum and peritoneal levels of human IL-6 (hIL-6) and soluble human IL-6 receptor (shIL-6R) was observed in the recombinant Sant7-treated group towards the control group. The anti-gp80 monoclonal antibody induced significant increase of both hIL-6R and hIL-6 in serum and peritoneum. The anti-gp130 monoclonal antibody treatment determined a reduction of the seric shIL-6R and a significant increase of the seric hIL-6. Anti-IL-6 monoclonal antibody administration resulted in a reduction of serum and in an increase of peritoneal hIL-6. Treatment with adenoviral Sant7 was associated with a reduction of circulating shIL-6R, hIgG and mSAP. However, only marginal anti-tumor efficacy of the adenoviral Sant7 was observed. Overall, the present data suggest a potential for anti-hIL-6 therapy in B-cell lymphomas. Less severe animal models might be useful to better evaluate Sant7 efficacy alone or in combination with other anti-IL-6 therapeutics.

A number of studies in vivo and in vitro showed that high levels of glycosaminoglycans (GAGs) are found as a consequence of free radical damage. The GAG over production may represent an endogenous mechanism capable to limit oxidative damage. Based on these hypotheses, the aim of this study was to evaluate the antioxidant property of GAGs of human origin in fibroblast cultures. Purified human plasma GAGs were added to the fibroblast cultures in which oxidative stress was induced by the oxidizing system employing iron (Fe2+) plus ascorbate. We assessed cell death, lactate dehydrogenase activity, membrane lipid peroxidation, DNA damage, protein oxidation, hydroxyl radical (OH*) generation and endogenous antioxidant depletion. The exposure of fibroblasts to FeSO4 produced cell death and increased OH* production. It also caused DNA strand breaks and protein oxidation as shown by the DNA fragment analysis and protein carbonyl content, respectively. In addition, FeSO4 enhanced lactate dehydrogenase activity and lipid peroxidation while decreased antioxidant defences. Purified human GAGs, at three different doses, reduced cell death, limited DNA fragmentation and protein oxidation, decreased OH* generation and lactate dehydrogenase activity, inhibited lipid peroxidation and improved endogenous antioxidant defences. These results further support the hypothesis that these molecules may function as antioxidants.