Teratogenic and neuro-behavioural toxic effects of bisphenol A (BPA) and B (BPB) on Xenopus laevis development.

Bisphenol A (BPA) is a plastic additive with endocrine disruptive activity, classified in 2017 by EU ECHA as substance of very high concern. A correlation between environmental exposure to BPA and congenital defects has been described in humans and in experimental species, including the amphibian Xenopus laevis. Among BPA analogues, bisphenol B (BPB) is used as alternative in different not-EU countries, including US, but seems to share with BPA its endocrine disruptor properties. Aim of the present work is the evaluation of the effects of BPB versus BPA exposure in a X. laevis developmental model. A windowed exposure (R-FETAX method) was applied covering the developmental phylotypic period (teratogenicity window), or the late tailbud stages (neuro-behavioural toxicity window, corresponding to the spontaneous swimming acquisition period). Samples were monitored for lethal effects during the full test period. External morphology evaluation and deglutition functional test were applied in any group. Abnormal tadpoles were also processed for cartilage staining. In groups exposed during neuro-behavioural toxicity window the swimming test was also applied. Lethality and malformations were obtained only in samples exposed during the teratogenicity window; these data were modelled using PROAST software and BPB relative potency resulted about 3 times higher than BPA. The day-by-day evaluation revealed that lethality was correlated to embryonic abnormal development of gills and apoptosis in gill primordia. Teratogenicity was never detected in groups exposed during the neuro-behavioural toxicity window, where some significant neuro-behavioural deficits were detected in tadpoles exposed to the highest tested concentrations of BPA and BPB.

Cellular pathways affected by carbon nanopowder-benzo(α)pyrene complex in human skin fibroblasts identified by proteomics.

One of the crucial and unsolved problems of the airborne carbon nanoparticles is the role played by the adsorbed environmental pollutants on their toxicological effect. Indeed, in the urban areas, the carbon nanoparticles usually adsorb some atmospheric contaminants, whose one of the leading representatives is the benzo(α)pyrene. Herein, we used the proteomics to investigate the alteration of toxicological pathways due to the carbon nanopowder-benzo(α)pyrene complex in comparison with the two contaminants administered alone on human skin-derived fibroblasts (hSDFs) exposed for 8 days in semi-static conditions. The preliminary confocal microscopy observations highlighted that carbon-nanopowder was able to pass through the cell membranes and accumulate into the cytoplasm both when administered alone and with the adsorbed benzo(α)pyrene. Proteomics revealed that the effect of carbon nanopowder-benzo(α)pyrene complex seems to be related to a new toxicological behavior instead of simple additive or synergistic effects. In detail, the cellular pathways modulated by the complex were mainly related to energy shift (glycolysis and pentose phosphate pathway), apoptosis, stress response and cellular trafficking.

Carbon nanopowder acts as a Trojan-horse for benzo(α)pyrene in Danio rerio embryos.

Carbon-based nanoparticles (CBNs) are largely distributed worldwide due to fossil fuel combustion and their presence in many consumer products. In addition to their proven toxicological effects in several biological models, attention in recent years has focussed on the role played by CBNs as Trojan-horse carriers for adsorbed environmental pollutants. This role has not been conclusively determined to date because CBNs can decrease the bioavailability of contaminants or represent an additional source of intake. Herein, we evaluated the intake, transport and distribution of one of the carbon-based powders, the so-called carbon nanopowder (CNPW), and benzo(α)pyrene, when administered alone and in co-exposure to Danio rerio embryos. Data obtained by means of advanced microscopic techniques illustrated that the "particle-specific" effect induced a modification in the accumulation of benzo(α)pyrene, which is forced to follow the distribution of the physical pollutant instead of its natural bioaccumulation. The combined results from functional proteomics and gene transcription analysis highlighted the different biochemical pathways involved in the action of the two different contaminants administered alone and when bound together. In particular, we observed a clear change in several proteins involved in the homeostatic response to hypoxia only after exposure to the CNPW or co-exposure to the mixture, whereas exposure to benzo(α)pyrene alone mainly modified structural proteins. The entire dataset suggested a Trojan-horse mechanism involved in the biological impacts on Danio rerio embryos especially due to different bioaccumulation pathways and cellular targets.

[Renal dysfunction as a marker of cardiovascular risk]. / La disfunsione renale come marcatore di rischio cardiovascolare.

The evaluation of urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) is suggested for the assessment of cardiovascular risk. It is unclear whether UAE and eGFR provide complementary information. UAE, eGFR, cardiovascular risk factors, and the incidence of cardiovascular disease were analyzed in 45- to 64-year-old individuals involved in the Gubbio study. UAE in the highest decile was defined as high (microng/min: > or = 18.6 in men and > or = 15.7 in women), eGFR in the lowest decile as low (mL/min/1.73 m(2): <64.2 in men and <57.9 in women). Kidney dysfunction was more frequent when defined by both markers than when defined by one marker only (UAE or eGFR) because high UAE and low eGFR tended to cluster in different individuals. The hazard ratio (HR) for incident cardiovascular disease was 1.85 in individuals with high UAE only (95%CI 1.04-3.25), 1.84 in individuals with low eGFR only (95%CI 1.04-3.26), and 5.93 in individuals with high UAE and low eGFR (95%CI 2.58-13.61). Concomitant evaluation of UAE and eGFR should be considered to adequately assess kidney dysfunction and cardiovascular risk.

The controlled pulsed laser deposition of Ag nanoparticle arrays for surface enhanced Raman scattering.

An effective method for the production of surface enhanced Raman scattering (SERS) active substrates is presented. Nanostructured silver thin films are pulsed laser deposited in an argon atmosphere. The films consist of arrays of nanoparticles whose size is controlled by the Ar pressure. The surface morphology of the films can be tuned by the laser pulse number. Nanoparticle size is calculated by a phenomenological model taking into account the dynamics of the laser generated silver plasma. The SERS activity of the films is investigated by Raman scattering of adsorbed rhodamine 6G at different concentrations.

[Health care based on patients' needs]. / Costruire una Sanita' che parta dalle esigenze dei malati.

Survival is not enough. We need to build a health system starting from patients' needs without wasting the resources of our grandchildren and great-grandchildren. We have to switch from curative to preventive medicine by firing managers who think they can resolve all problems by cutting expenditures. We need to educate a new cadre of managers able to govern by centering the system on the patients. Managers should consider health care as an asset and should reinforce clinical research. Such a program has been recently adopted in France.

[Survival is not enough: improving quality of life]. / Sopravvivere non basta--migliorare la qualità della vita.

We need a new health care system that is based on patients' needs. The present cadre of health managers who acquired power by cutting expenditures must be removed from office. We need to educate a new cadre of health managers who are 1) convinced that safeguarding health does not use up the resources of the next generations; 2) capable of switching the system from curative to preventive medicine; and 3) able to reinforce clinical research. Such principles have been recently adopted by the French President Sarkozy in devising the national health care program.

[Early detection of chronic kidney disease: epidemiological data on renal dysfunction]. / L'identificazione precoce della nefropatia cronica: dati epidemiologici sulla disfunzione renale.

Estimated glomerular filtration rate (eGFR) and urinary albumin (U-Alb) have been suggested as indicators for the early identification of persons with kidney dysfunction. The Gubbio Study collected data on serum creatinine, UAlb, other laboratory indices, blood pressure, and medical history in a population sample of 4574 adults (2083 men and 2491 women, age range 18- 95 years). The study included analyses on six disorders which are commonly associated with kidney disease (hypertension, cardiovascular disease, anemia, high serum uric acid, high serum phosphorus/low serum calcium, and high serum potassium). Low eGFR (<60 mL/min per 1.73 m2) was found in 6.6% of men and 6.2% of women. Low eGFR prevalence varied largely with age (from <1% at 18-24 years up to > 30% at > or =75 years in both sexes, p<0.001). On the basis of these data, it was estimated that the prevalence of low eGFR in the whole Italian population could be 1.3 million among men (95%CI 1.1/1.5) and 1.5 million among women (95%CI 1.3/1.8). Data available only for age 45-64 indicate that 6.4% of men and 3.0% of women have high U-Alb (> or =20 microg/min) in the presence of non-low eGFR. Low eGFR was associated with at least two disorders potentially due to kidney disease in the majority of persons but was rarely associated with a previous diagnosis of kidney disease (<5% of cases). These data support the use of eGFR for the screening of people with or at risk of developing kidney disease. Awareness of kidney disease is very low in the Italian population.

Endoscopic mucosal resection for early gastric cancer: comparison of two modifications of the cap method.

BACKGROUND AND STUDY AIM: Endoscopic mucosal resection using a cap (EMR-C) is an established method for curative resection of early neoplastic lesions; prelooping of the snare may however be difficult and lead to imprecise resection. We therefore compared two modifications of the conventional technique using outer snare placement with an accessory channel in a prospective, nonrandomized study. PATIENTS AND METHODS: Between October 2004 and March 2007, 54 patients (men 37, women 17; mean age 71 years) underwent EMR. One method involved an internally retained snare (IRS) cap, with a fixed prelooped snare inside the cap; the other method used an externally guided snare (EGS) cap with the snare guided over an oblique cap. The main outcome parameters were specimen size, en bloc resection, and complications. RESULTS: There was no difference between use of the IRS and EGS cap methods in relation to specimen size (27.6 vs. 27.1 mm), or rates of en bloc resection (88.9 % vs. 83.3 %); only one perforation occurred, and this was in the EGS group. CONCLUSION: Both techniques appeared to provide similar efficacy, the inner rim of the IRS cap stabilizes aspiration of the lesion compared with the EGS cap that does not have it.

High-tone external muscle stimulation in end-stage renal disease: effects on symptomatic diabetic and uremic peripheral neuropathy.

OBJECTIVE AND DESIGN: Pain and peripheral neuropathy are frequent complications of end-stage renal disease (ESRD). Because drug treatment is associated with numerous side effects and is largely ineffective in many maintenance hemodialysis (MHD) patients, nonpharmacologic strategies such as electrotherapy are a potential recourse. Among various forms of electrostimulation, high-tone external muscle stimulation (HTEMS) is a promising alternative treatment for symptomatic diabetic peripheral polyneuropathy (PPN), as demonstrated in a short-term study. Based on these novel findings, we performed a prospective, nonrandomized, pilot trial in MHD patients to determine (1) whether HTEMS is also effective in treating diabetic PPN in the uremic state, and (2) whether uremic PPN is similarly modulated. PATIENTS AND INTERVENTIONS: In total, 40 MHD patients diagnosed with symptomatic PPN (25 with diabetic and 15 with uremic PPN) were enrolled. Both lower extremities were treated intradialytically with HTEMS for 1 hour, three times a week. Initially, a subgroup of 12 patients was followed for 4 weeks, and a further 28 patients for 12 weeks. The patients' degree of neuropathy was graded at baseline before HTEMS and after 1 and 3 months, respectively. Five neuropathic symptoms (tingling, burning, pain, numbness, and numbness in painful areas) as well as sleep disturbances were measured, using the 10-point Neuropathic Pain Scale of Galer and Jensen (Neurology 48:332-338, 1997). A positive response was defined as the improvement of one symptom or more, by at least 3 points. Other parameters included blood pressure, heart rate, dry body weight, and a routine laboratory investigation. RESULTS: The HTEMS led to a significant improvement in all five neuropathic symptoms, and to a significant reduction in sleep disturbances for both diabetic and uremic PPN. The response was independent of the patient's age, with a responder rate of 73%. The improvement of neuropathy was time-dependent, with the best results achieved after 3 months of treatment. The HTEMS was well-tolerated by nearly all patients. CONCLUSIONS: This pilot study shows for the first time that HTEMS can ameliorate the discomfort and pain associated with both diabetic and uremic PPN in MHD patients, and could be a valuable supplement in the treatment of pain and neuropathic discomfort in patients who do not respond to, or are unable to participate in, exercise programs during hemodialysis treatment.

Prevalence and correlates of anemia and uncontrolled anemia in chronic hemodialysis patients--the Campania Dialysis Registry.

BACKGROUND: This study investigated prevalence and correlates of anemia and uncontrolled anemia in chronic hemodialysis patients. METHODS: A cross-sectional analysis was performed on registry data for 2,746 chronic (>6 months) hemodialysis patients aged 25-84. Data collection included years of dialysis, hours of dialysis/wk, disease causing hemodialysis, body mass index (BMI), erythropoietin (EPO) treatment, hemoglobin, markers of viral hepatitis, serum albumin, calcium, and phosphorus. RESULTS: Prevalence was 88.7% for anemia (hemoglobin <11 g/100 mL and EPO treatment at any Hb level), 39.4% for uncontrolled anemia (hemoglobin<11 g/100 mL). Gender, years of dialysis, hereditary cystic kidney disease (HCKD), and low BMI (<24 kg/m2) were independent correlates of anemia (P<0.001). Gender, HCKD, low BMI, serum albumin and calcium were independent correlates of uncontrolled anemia (P<0.05). An interaction was found between age (not correlated with anemia and uncontrolled anemia) and the association of gender with uncontrolled anemia (P<0.05). EPO doses were higher in patients with high prevalence of uncontrolled anemia than in patients with low prevalence (i.e., women vs men, other diseases vs HCKD, low vs not-low BMI, P<0.01). Gender, years of dialysis, HCKD, BMI, serum albumin, and calcium were independent correlates of the hemoglobin/EPO dose ratio in patients on EPO treatment (P<0.05). CONCLUSION: Anemia and uncontrolled anemia are more frequent in hemodialysis patients with shortterm dialysis, diseases other than HCKD, low BMI, and female gender. Gender effect was lower in elderly patients. Uncontrolled anemia was also associated with low serum albumin and calcium, suggesting that these parameters are indices of EPO resistance.

Nonisothermal reactors for the production of pure water from peritoneal dialysis waste waters.

The diffusion of peritoneal dialysis (PD) at home is somewhat restricted by the difficulty of transport and storage of a large amount of dialytic solutions. This problem is exacerbated in the case of hemodialysis. With the aim of producing pure water to be used in preparing the solution for peritoneal dialysis, or for hemodialysis in general, as one example, we purified the spent dialysate solution from PD. Experiments were carried out with 24 dialysate solutions taken from 8 patients. Pure water was obtained by means of a thermodialysis process in a hollow fiber reactor operating under nonisothermal conditions. Results show that the yield of the nonisothermal process is dependent on the temperature difference applied across the hydrophobic membranes. The production of pure water per square meter of membrane and per hour was equal to 0.55 or 1.2 or 2.0 liters, with a temperature difference of 11 degrees C or 21 degrees C or 28 degrees C, respectively. These results encourage the use of the thermodialysis process in the production of pure water for clinical uses.

[Hyperhomocysteinemia in chronic renal failure.]. / L'iperomocisteinemia nell'insufficienza renale cronica: aspetti clinici, nutrizionali e tossicità.

Chronic renal failure (CRF) is frequently associated with increased plasma levels of homocysteine (Hcy), an amino acid that can be considered a new uremic toxin according to recent evidence. Studies on Hcy described first homocystinuria, an inherited disease characterized by high plasma Hcy levels and premature cardiovascular disease, resulting in high mortal-ity rates. Hyperhomocysteinemia was then shown to be associated with cardiovascular events both in the general population and in CRF patients. Hcy is a sulfur amino acid derived from dietary methionine, an essential amino acid. Methionine is condensed with ATP to form S-adenosylmethionine (AdoMet), the universal methyl donor in transmethylation reactions. The AdoMet demethylated product is S-adenosylhomocysteine (AdoHcy), which is the direct precursor of Hcy in vivo. Hcy is toxic for the endothelium, it enhances vascular smooth muscle cell proliferation, increases platelet aggregation, and acts on the coagulation cascade and fibrinolysis. Several mechanisms have been discussed to explain Hcy toxicity. Hcy levels increase as renal function declines and progresses to ESRD; the causes of hyperhomocysteinemia are still unclear. Studies in humans show that renal metabolic extraction depends on renal plasma flow; in addition, an alteration of the extrarenal metabolic clearance, depending on uremic toxins, may occur. Among the consequences of hyperhomocysteinemia in renal failure are: impaired protein methylation, with altered protein repair processes; DNA hypomethylation, with an alteration in the allelic expression of genes regulated through methylation; and protein homocysteinylation. Further, this review is dealing with the 'reverse epidemiology' issue, outlining also the main Hcy-lowering strategies.

Low glomerular filtration in the population: prevalence, associated disorders, and awareness.

Estimated glomerular filtration rate (eGFR) was used for analysis of kidney disease prevalence in the United States. The study investigated on prevalence, associated disorders, and kidney disease awareness in an Italian population sample. Data were collected on serum creatinine, other laboratory indices, blood pressure, and medical history in the Gubbio Population Study (n=4574, both sexes, ages 18-95 years). Analyses were carried out on eGFR (equation of Modification Diet in Renal Disease study), disorders potentially secondary to kidney dysfunction (hypertension, high serum uric acid, high serum phosphorus/low serum calcium, high serum potassium, cardiovascular disease, anemia), and kidney disease awareness. The prevalence of eGFR <60 ml/min x 1.73 m(2) increased with age in both sexes (from <1% for ages 18-24 years to >30% for ages > or =75 years, P<0.001). In the group with eGFR <60 ml/min x 1.73 m(2), number of disorders secondary to kidney dysfunction was > or =2 in the majority of persons, was higher than in persons with eGFR > or =60 ml/min x 1.73 m(2) (P<0.001), and was inversely related to eGFR (P<0.001). The prevalence of reported kidney disease was 3.3% in the group with eGFR <60 ml/min x 1.73 m(2) and directly related to serum creatinine and number of disorders secondary to kidney dysfunction (P<0.001). Low kidney function is frequent in the older population and is associated with disorders typical of kidney disease. Persons with low kidney function are rarely aware of kidney disease unless of very high serum creatinine or presence of many disorders typical of kidney disease.

Water immersion is associated with an increase in aquaporin-2 excretion in healthy volunteers.

Here, we report the alterations in renal water handling in healthy volunteers during a 6 h thermoneutral water immersion at 34 to 36 degrees C. We found that water immersion is associated with a reversible increase in total urinary AQP2 excretion.

Sevelamer worsens metabolic acidosis in hemodialysis patients.

BACKGROUND: Sevelamer hydrochloride, a major phosphate binder for patients on maintenance hemodialysis (MHD) is associated with reduced serum bicarbonate concentration due to hydrochloric acid release in the gut and to the binding of short chain fatty acids in the large intestine. Since metabolic acidosis can be deleterious, a study was devised to compare the time course of serum bicarbonate concentration during treatment with sevelamer hydrochloride or calcium carbonate. METHODS: Sixteen well nourished patients on MHD who were in excellent clinical conditions and achieving target levels for blood pressure (BP) and hemoglobin (Hb), while on a protein intake of 1.1g/kg body weight (bw), were enrolled in the study. After a 2-week washout period, the patients were divided into two groups, each consisting of eight patients, and randomized either to 24 weeks of sevelamer followed by 24 weeks of calcium carbonate (group A) or to 24 weeks of calcium carbonate followed by 24 weeks of sevelamer (group B). Protein intake, n-protein catabolic rate (nPCR), serum concentrations of calcium, phosphate, calcium x phosphate (Ca x P) product, bicarbonate, intact parathyroid hormone (iPTH) and albumin were monitored. Time course changes in serum bicarbonate concentrations in relation to short and long dialytic intervals (48 vs. 72 hr) were also investigated. RESULTS: Both sevelamer and calcium carbonate effectively controlled serum phosphate and the Ca x P product. During calcium carbonate treatment plasma phosphate concentrations were significantly below those of patients on sevelamer. Plasma bicarbonate concentration fell within target DOQI values during calcium carbonate administration both in group A and in group B, a goal which was not achieved under sevelamer administration. After a long dialytic interval in patients on sevelamer, serum bicarbonate concentration averaged 17.3 +/- 1.1 mEq/L, whereas it averaged 21.1 +/- 0.7 mEq/L in patients on calcium carbonate (p<0.01). Finally, a 24-week sevelamer administration caused a statistically significant (p<0.05) reduction (0.8 g/dL) in serum albumin concentration, without affecting iPTH. Taken together, these results indicate that sevelamer worsens metabolic acidosis, which needs to be corrected.

Acid-base balance in heart failure.

In end-stage heart failure, various acid-base disorders can be discovered due to the renal loss of hydrogen ions and hydrogen ion movements into cells, the reduction of the effective circulating volume, hypoxemia and renal failure. This justifies the occurrence of metabolic alkalosis, metabolic acidosis, respiratory alkalosis, as well as respiratory acidosis alone or in combination. Several studies have been published on the acid-base state in heart failure. In a 1951 study, Squires et al analyzed the distribution of body fluid in congestive heart failure by taking into consideration the abnormalities in serum electrolyte concentration and in acid-base equilibrium. A recent study by Milionis et al, analyzed 86 patients with congestive heart failure receiving conventional treatment; the majority of these patients exhibited hypokalemia, hyponatremia, hypocalcemia and hypophosphatemia. Disorders in acid-base balance were noted in 37.2% of patients. In a recent study, 70 patients with severe congestive heart failure before heart transplantation showed high-normal pH, slightly reduced pCO 2 and a slight loss of hydrogen ions. After heart transplantation, stability of blood pH and hydrogen ion concentrations was found. In contrast, bicarbonate and pCO 2 increased significantly. The data led us to formulate the diagnosis of a mixed acid-base disorder that includes respiratory alkalosis and metabolic alkalosis before heart transplantation. In heart failure, the presence of acid-base imbalance associated with the activation of mechanisms that lead to salt and water retention reveals evidence concerning the pivotal role of the kidney in determining the outcome of these patients.

[Urinary albumin excretion and coronary artery disease]. / Albumina urinaria e malattia coronarica nella popolazione di età 45-64 anni.

The moderate elevation in urinary albumin excretion defined as microalbuminuria is common in the population and associated with cardiovascular (CV) risk factors. Microalbuminuria prevalence is low in the absence of CV risk factors and progressively increases with the number of the individual's CV risk factors. The main correlate of microalbuminuria is blood pressure (BP). The relationship between BP and microalbuminuria is continuous and graded since the prevalence of microalbuminuria increases with the severity of hypertension. Among hypertensives receiving treatment, BP control is associated with a low prevalence of microalbuminuria. Therefore, BP appears as a determinant of microalbuminuria rather than a mere correlate. For hypercholesterolemia, smoking and diabetes, the data are less strong, but point to an independent positive association with microalbuminuria. Altogether, data indicate that microalbuminuria in the population reflects the presence of CV risk factors. Data concerning microalbuminuria and coronary heart disease (CHD) support this idea. There is a continuous and graded relationship between urinary albumin excretion and CHD prevalence. High urinary albumin excretion is a likely sign of vascular damage existing both at renal and cardiac levels and induced by one or more uncontrolled CV risk factors.

[Promoting clinical research]. / Promuovere la ricerca clinica.

Although the development of science as any human activity is basic and practical at the same time, clinical science did not develop with the same pace of basic science. There is a need to support clinical science by granting independence, by enrolling young physician scientists, by giving them appropriate mentoring and economic support.