Metabolic consequences of peritoneal dialysis treatment.

Energy and protein metabolism are both altered in chronic kidney disease (CKD) from its early stages. Patients undergoing peritoneal dialysis (PD) use peritoneal solutions with glucose as osmotic agent, which exposes them to an increased glucose load (40-80 g/day) and during PD there is a net loss of proteins through the peritoneum (4-8 g/day). Insulin resistance may lead to a reduction of the anabolic effects of insulin, while its proliferative effects on adipose tissue are potentially enhanced. Insulin resistance is also an important factor in the development of hypertriglyceridemia in PD patients: it increases free fatty acid availability, which then stimulates the release of large triglyceride-rich VLDL. Moreover, inhibitors of lipolytic enzymes (apoC-III, inflammation, oxidative modification and carbamoylation of apolipoproteins) may reduce lipid clearance, contributing to the development of dyslipidemia. Inflammatory molecules also play an important role in regulating glucose metabolism, and the excessive activation of inflammatory pathways may represent a fundamental step in the development of insulin resistance, including an over-expression of cytokines. Frequently, protein intake is reduced in PD because of under-dialysis, glucose load, abdominal discomfort and abnormal hormones levels, leading to a complex "protein-energy malnutrition". Optimization of dialysis dose, correction of acidosis and anemia and nutritional counseling, together with "non-traditional" management strategies, such as the use of PD solutions without glucose, like icodextrin and amino acid based solutions, represent the best strategies to prevent and correct malnutrition in PD patients. The mainstay of therapy is a reduction of glucose-based PD solutions and a correct dietary prescription.

[Vascular access in the elderly: AVF vs CVC. A comment]. / L'accesso vascolare nell'anziano: confronto FAV versus CVCp, commento.

The aging population starting hemodialysis treatment raises the question as to which is the best vascular access in an older patient with multiple complications. The center effect is an important element in the choice of a vascular access, as shown by the DOPPS data and by a recent audit held in Lombardy. However, other data show an increase in the use of permanent CVCs in the last years and other factors must be taken into account in this clinical choice. Also the timing of proposing a vascular access to a patient has changed over the years (see K-DOQI 2006 vs 2000). Most of the literature agrees on the strategy of a global clinical evaluation of the patient to decide when to place a vascular access and which type of access to use. Native and prosthetic fistulas are considered superior to CVCs although the latter have certain advantages in selected patients, such as those with severe cardiac problems. The nephrologist has a major role in vascular access management as part of a team made up also by a vascular surgeon and an interventional radiologist. Only in a center where both native and prosthetic fistulas can be constructed and permanent CVCs be placed can a nephrologist choose the most appropriate vascular access for individual patients after evaluation not only of their renal function but their cardiovascular risk as well.

Interactions of selected gold(III) complexes with DNA G quadruplexes.

The interactions of three representative gold(III) complexes with human telomeric DNA sequences were analysed using a variety of biophysical methods, including DNA melting, circular dichroism, SPR and ESI MS; remarkable interactions were highlighted for all tested complexes, although they were associated to significantly different binding profiles. The most interesting compound was Auoxo6, a dinuclear gold(III) complex, which beyond manifesting a conspicuous binding affinity for the G-quadruplex conformation, turned out to be very effective in inducing a non-canonical secondary structure. These findings may clear the way for novel biological and pharmacological applications of this class of metal compounds.

Growth hormone response to growth hormone releasing hormone and to clonidine stimulation in peripubertal patients with major depressive disorder.

The responses of growth hormone (GH) to administration of growth hormone-releasing hormone (GHRH-1 micrograms/kg b.w.) and of clonidine (clon-2.5 micrograms/kg b.w.) and basal levels of somatomedin C (SmC) were measured in nine peripubertal patients with Major Depressive Disorder (MDD) and in 9 age- and gender-matched controls. Basal GH and SmC levels, and GH response to GHRH did not differ in patients and controls, whereas responses to clonidine were significantly higher in some and lower in other patients than in controls.

Effects of long-lasting sulpiride therapy on growth hormone secretion in mentally disturbed children.

The effects of chronic sulpiride therapy on growth hormone (GH) secretion were studied in 11 mentally disturbed children, aged 5 to 13 years, five with personality disorders, three with childhood psychoses, one with hysteria, one with anxiety reactions, and one with neurosis. The basal GH secretion and response to insulin-induced hypoglycemia were studied before the beginning of therapy and after ten days and three months of treatment with sulpiride (8 mg/kg body weight). No modifications in basal levels of GH or in the response to the stimulus were observed after ten days of therapy. After three months of treatment a blunted GH response to the stimulation was observed in three subjects, one of whom showed increased basal levels of GH.

Neuroendocrine investigation in children and adolescents with dysthymic disorders: the DST, TRH and clonidine tests.

A neuroendocrine study was conducted in eight children and adolescents with dysthymic disorders (three females and five males) and in eight age- and sex-matched psychologically normal controls. The dexamethasone suppression test (DST), TSH and GH responses to TRH stimulation and GH response to clonidine stimulation were studied in parallel in each patient. Depressive symptomatology was monitored with the Poznanski Rating Scale. The DST, TRH and clonidine tests revealed normal responses in each patient. TRH induced abnormal GH rises in five of the eight patients. There were no correlations between neuroendocrine parameters and degree of depression, age, sex or weight of the patients, age of onset, duration and family history of the disease.

Pt-based drugs: the spotlight will be on proteins.

Platinum-complexes represent some of the most successful groups of clinically used anticancer drugs. Their mechanism of action relies on the formation of stable DNA adducts occurring at the nitrogen in position 7 of guanine (N7) and involving one or two spatially close residues. The formation of stable DNA adducts is recognized as a DNA damaging event and, ultimately, drives cells to death. Nevertheless, nucleobases are not the only reliable targets of these drugs and other biomolecules can be involved. Among them large interest has been devoted to proteins since they contain several potential reactive sites for platinum (His, Met, and Cys) and, in particular, because the reaction of the metal with sulfur containing groups is a kinetically favored process. As a result, the occurrence of protein adducts and DNA-protein cross-links must be further taken into account in order to fully define cisplatin mechanism of action. Herein, we will summarize the most recent experimental evidence collected so far on protein-cisplatin adduct formation to better dissect its correlation with the drug pharmacological profile. Indeed, in addition to modulation of drug bioavailability and toxicity, the potential role of proteins as reaction intermediates or reservoir systems in platinum drugs can be envisaged. Additionally, the effects of Pt-coordinating groups on the chemical reactivity of the metal complexes will be reviewed. From all these outcomes a general model for Pt-based drugs mechanism of action can be drawn which is more articulate than the one currently supported. It claims proteins as reactive intermediates for DNA platination and it defines them as relevant to fully describe the clinical potential of this class of anticancer drugs.

Immune function assay (immunknow) drop over first 6 months after renal transplant: a predictor of opportunistic viral infections?

BACKGROUND: The Immuknow assay (IKA; Cylex) is a T-cell immune function assay that evaluates immunoreactivity in immunocompromised patients. The aim of this study was to analyze IKA values in a cohort of kidney transplantation (KT) recipients to investigate correlations between single-time point low IKA values and their trend over time with cytomegalovirus (CMV) or BK virus (BKV) reactivation. METHODS: A total of 118 adult patients receiving deceased-donor KT were enrolled (55.6±11.9 years old; 79 [66.9%] male). IKA CMV and BKV viremia determinations and were performed at months 1, 3, and 6 after surgery. RESULTS: Overall, 272 IKA determinations were performed: IKA values significantly decreased from month 1 (422±184 ng/mL) to month 3 (330±159 ng/mL; P<.001) and from month 3 to month 6 (300±128 ng/mL; P=.030). IKA values did not correlate with renal function or viral reactivation at any time. However, patients with either CMV or BKV viremia had a trend to higher IKA values at month 1 and lower IKA values at month 6, even if the difference did not reach a statistical significance (P=.115). CONCLUSIONS: Our study suggests that presence of low immunologic reactivity (IKA<225 ng/mL) is not associated with an increased risk of CMV and BKV reactivation over the 1st 6 months after KT. However, a trend to a more pronounced drop in IKA values over time was observed in patients with viral reactivation. These preliminary results suggests that drop in IKA values within the 1st post-KT months, unlike single-time point immune function assay, may predict the risk of opportunistic viral infections.

Bis-phenanthroline derivatives as suitable scaffolds for effective G-quadruplex recognition.

Selective recognition of DNA folding is central to multiple biological and pharmacological applications aimed at precise targeting of distinct genomic regions. Here, we focused on the recognition of physiologically relevant G-quadruplex (G-4) structures by bis-phenanthroline (bis-Phen) ligands containing two Phen moieties covalently linked through an amine or thioether bond. The transition metal ions Mn(2+), Ni(2+), Cu(2+), and the biologically relevant Mg(2+) and Zn(2+) efficiently form 1 : 1 bis-Phen complexes characterised by a large planar structure fit to successfully recognise G-quartet arrangements.Interestingly, metal ion complexation dramatically affects ligand-stabilising effects on G-quadruplex, the melting temperature of the folded structure being increased up to 30 degrees C at ligand concentrations as low as 1 microM in the presence of Ni(2+) and Cu(2+). In addition, the test complexes were able to induce G-4 formation from essentially unfolded G-rich sequences even in the absence of K(+) ions as shown by gel shift and circular dichroism experiments. In line with their G-4 stabilising properties bis-Phen complexes are effective inhibitors of telomerase activity, Ni(II) complexes being effective in the sub-micromolar range. This is combined with lack of unselective DNA-damaging activity and short-term cellular toxicity, which makes the novel compounds (above all their Ni(II) complexes) interesting antiproliferative drug leads.

Cortisol responses of depressed children and adolescents to clonidine administration.

The responses of cortisol to acute administration of saline and of clonidine (2.5 micrograms/kg B.W.) were examined in 10 children and adolescents with major depressive disorder and in 10 age- and sex-matched controls. Clonidine administration did not inhibit cortisol secretion in controls or in patients, contrary to what has been observed in depressed adults. In controls, but not in patients, clonidine administration induced a transitory increase of the steroid.

Beta-endorphin and cholecystokinin 8 concentrations in peripheral blood mononuclear cells of autistic children.

beta-Endorphin (beta-EP) and cholecystokinin 8 (CCK-8) concentrations in peripheral blood mononuclear cells were measured in 12 drug-free autistic (AU) children, in 10 drug-free children with pervasive developmental disorders (PDD) and in 11 healthy controls. The aim of the study was to see whether or not there was an alteration of beta-EP and CCK-8 concentrations in this peripheral compartment, in which it has been suggested that secretion and regulation of the two peptides mimic those of neurons in the central nervous system. Mean beta-EP values were significantly higher in AU than in PDD and control children, while there were no differences in CCK-8 values of the three groups.