Screening for gestational diabetes in the Lombardy region: A population-based study.

AIM: As the treatment of hyperglycaemia during pregnancy with diet or insulin reduces the risk of adverse maternal outcomes and perinatal complications, screening for gestational diabetes mellitus (GDM) is included, albeit to variable extents, in all guidelines of care for pregnant women. The aim of the present investigation was to estimate the proportion of pregnancies screened for GDM in Lombardy between 2007 and 2010, and to identify predictors of screening. METHODS: A retrospective cross-sectional study using regional healthcare utilization databases of Lombardy was conducted. The study included all residents of Lombardy without pregestational diabetes who delivered between 1 January 2007 and 31 December 2010. The proportion of pregnancies with at least one screening test for GDM was calculated, along with the odds ratios and 95% confidence intervals associated with selected covariates for GDM screening. RESULTS: Of the 362,818 pregnancies included in the sample, 30% were screened for GDM. The proportion of pregnancies screened increased slightly from 2007 (27%) to 2010 (33%) and with maternal age (from 28% among women<25 years to 32% among those ≥35 years), and varied widely across local health management organizations (HMOs) of residence (range: 20% to 68%). Socioeconomic indicators (education, immigrant status), obstetric history and prepregnancy hypertension were independent predictors of GDM screening. CONCLUSION: The study finding of a low rate of pregnant women screened for GDM among residents of Lombardy supports the need for programmes to improve training of healthcare professionals, to raise women's awareness of GDM and to eliminate barriers to GDM screening.

A model study for tethering of (bio)active molecules to biomaterial surfaces through arginine.

A new approach for tethering of bioactive molecules via arginine is proposed and validated on collagen 2D matrices. The method involves the introduction of a methyl ketone on arginine side-chains, followed by reaction with model alkoxyamino derivatives.

From cancer metabolism to new biomarkers and drug targets.

Great interest is presently given to the analysis of metabolic changes that take place specifically in cancer cells. In this review we summarize the alterations in glycolysis, glutamine utilization, fatty acid synthesis and mitochondrial function that have been reported to occur in cancer cells and in human tumors. We then propose considering cancer as a system-level disease and argue how two hallmarks of cancer, enhanced cell proliferation and evasion from apoptosis, may be evaluated as system-level properties, and how this perspective is going to modify drug discovery. Given the relevance of the analysis of metabolism both for studies on the molecular basis of cancer cell phenotype and for clinical applications, the more relevant technologies for this purpose, from metabolome and metabolic flux analysis in cells by Nuclear Magnetic Resonance and Mass Spectrometry technologies to positron emission tomography on patients, are analyzed. The perspectives offered by specific changes in metabolism for a new drug discovery strategy for cancer are discussed and a survey of the industrial activity already going on in the field is reported.

New targets for antibacterial design: Kdo biosynthesis and LPS machinery transport to the cell surface.

Lipopolysaccharide (LPS), which constitutes the lipid portion of the outer leaflet of Gram-negative bacteria, is essential for growth. It is also responsible for the variety of biological effects associated with Gram-negative sepsis. Recent advances have elucidated the exact chemical structure of this highly complex macromolecule and much of the enzymology involved in its biosynthesis. Enzymes involved in LPS biogenesis are optimal targets for the development of novel therapeutics since they are sufficiently conserved among diverse, clinically-relevant bacteria and no analogue counterpart is present in humans. During the last thirty years a number of inhibitors of LPS biosynthesis have been developed: some of these compounds have antibacterial properties, while others show excellent in vitro activity and are undergoing further investigation. The main focus of this review will be the biology of LPS in bacteria summarizing the knowledge about structure and enzymatic catalysis, as well as chemical efforts towards the synthesis of inhibitors of the key enzymes involved in the biosynthesis of Kdo, toward the minimal conserve structure Kdo(2)-LipA. In addition, very recent advances in deciphering the molecular mechanisms of LPS transport to the cell surface, as a new target to develop novel antibacterials, will be reported. Future directions and perspectives will also be outlined.

Beta amyloid aggregation inhibitors: small molecules as candidate drugs for therapy of Alzheimer's disease.

The progressive production and subsequent accumulation of ß-amyloid (Aß), a proteolytic fragment of the membrane-associated amyloid precursor protein (APP), plays a central role in Alzheimer's Disease (AD). Aß is released in a soluble form that may be responsible for cognitive dysfunction in the early stages of the disease, then progressively forms oligomeric, multimeric and fibrillar aggregates, triggering neurodegeneration. Eventually, the aggregation and accumulation of Aß culminates with the formation of extracellular plaques, one of the morphological hallmarks of the disease, detectable post-mortem in AD brains. In this review we report the known structural features of amyloid peptides and fibrils, and we give an overview of all small molecules that have been found to interact with Aß aggregation. Deeper knowledge of the mechanism leading to amyloid fibrils along with their molecular structure and the molecular interactions responsible for activity of small molecules could supply useful information for the design of new AD therapeutic agents.

Menopause hormone replacement therapy and cancer risk: an Italian record linkage investigation.

BACKGROUND: The effects of persistence with hormone replacement therapy (HRT) on the risk of hospitalization for cancer and of the route of HRT administration on the risk of breast and colorectal cancer were explored in a large cohort study. PATIENTS AND METHODS: The 73 505 women residing in Lombardia (Italy), aged 45-75 years, who received at least one HRT prescription during 1998-2000 were followed until 2005. Among these, 3687 experienced cancer hospitalization. Proportional hazards model was fitted to estimate the association between cumulative HRT persistence and cancer risk. RESULTS: Compared with women who took HRT for <6 months, those exposed for >2 years showed hazard ratios (HR) of 0.78 (95% confidence interval 0.68-0.92) for colorectal cancer and 1.34 (1.13-1.58) for breast cancer. HR for breast cancer associated with long-term use of transdermal and oral HRT were, respectively, 1.27 (1.07-1.51) and 2.14 (1.43-3.21). CONCLUSIONS: Evidence that long-term use of HRT is associated with increased risk of breast cancer and decreased risk of colorectal cancer is supplied from this study from a southern European population. Our findings indicate that transdermal therapy might have lower effect than oral therapy in increasing breast cancer risk.

Natural and synthetic cholera toxin antagonists.

Cholera Toxin (CT) recognizes the cell membrane through specific interactions with ganglioside GM1. Recent structural elucidation of the CT/GM1 complex has allowed the rational design of artificial receptors for the toxin, which could function as anti-cholera drugs. The efforts towards the rational design of Cholera Toxin inhibitors will be presented.

Synthesis and biological evaluation of an anticancer vaccine containing the C-glycoside analogue of the Tn epitope.

The C-saccharide analogue of the GalNAc (Tn epitope) has been covalently linked to the T cell epitope peptide (328)(-)(340)OVA using a chemoselective convergent synthetic approach. In this way, a non-hydrolyzable synthetic vaccine was obtained composed by a B epitope conjugated to a T cell epitope. This compound was tested in a proliferation assay with spleen cells from DO11.10 mice. The molecule was recognized by transgenic T cells although at a slightly lower efficiency if compared with the reference peptide OVA. An additional experiment with dendritic cells fixed with glutaraldehyde shows that the glycopeptide can bind to extracellular MHC molecules without need of internalization and processing and that the C-glycoside part does not interfere with TCR recognition. These observations constitute an important starting point for the use of this molecule as vaccine against the Tn-expressing TA3-Ha mouse mammary carcinoma.

Regioselection and orthogonality of the 1-phenyl-3-butenyl (PBU) protecting group in glucopyranosides.

The 1-phenyl-3-butenyl (PBU) protecting group was alternatively introduced in position 4 or 6 by regioselective opening of methyl 2,3-di-O-benzyl-4,6-O-benzylidene-alpha-D-glucopyranose with allyltrimethylsilane in the presence of the Lewis acid promoters TMSOTf or AlCl3. The PBU group was selectively removed, in presence of t-butyldimethylsilyl, trityl or acetyl protecting groups, with acids (TFA) or using Pd(CH3CN)2Cl2.

A highly convergent approach to O- and N-linked glycopeptide analogues.

Deprotected C-glycopyranosyl-ketones have been conjugated by a chemoselective approach to a peptide or an amino acid bearing an aminooxy group on the N-terminus or on the side-chain, respectively. The coupling reaction, performed in aqueous media, does not require protecting groups on the peptide or saccharide moieties, nor auxiliary coupling reagents.

Capsular polysaccharide of Streptococcus pneumoniae type 19F: synthesis of the repeating unit.

A new and more versatile synthesis of beta-D-ManpNAc-(1-->4)-alpha-D-Glcp-(1-->2)-alpha-L-Rhap, the trisaccharide repeating unit of the Streptococcus pneumoniae type 19F capsular polysaccharide, is described. The present approach allows a simple access to different fragments containing the trisaccharide and the conjugation of the product(s) to a protein through the selective manipulation of the anomeric position at the reducing end and of the HO-4 function at the nonreducing end. The synthetic scheme shows an efficient application of the sulfoxide method for the stereoselective and high yielding formation of the glycosidic linkages.

Synthesis of the disaccharides methyl 4-O-(2'/3'-O-sulfo-beta-D-glucopyranosyluronic acid)-2-amino-2-deoxy-alpha-D-glucopyranoside disodium salts, related to heparin biosynthesis.

The synthesis of the disaccharides methyl 4-O-(2'/3'-O-sulfo-beta-D-glucopyranosyluronic acid)-2-amino-2-deoxy-alpha-D-glucopyranoside 3 and 4 as disodium salts is described. Allyl 4,6-O-benzylidene-alpha-D-glucopyranoside 6 was converted to trichloroacetimidate 20. Glycosylation of 20 with 5 promoted by BF3.OEt2 gave disaccharide 21. Deacetylation of 21 followed by monoacetylation of the resultant diol 22 afforded the two monoacetylated disaccharides 23 and 24. Sulfation and deprotection of each disaccharide gave the desired sulfated compounds 3 and 4.

Role of 24- and 28-hydroxylated intermediates in the metabolism of beta-sitosterol in the insect Tenebrio molitor.

1. [28-3H]Stigmast-5-ene-3 beta, 28-diol and [23,23,25-3H]stigmast-5-ene-3 beta, 24-diol were synthesized. 2. Each of the samples was mixed with beta-[4-14C]sitosterol and administered to Tenebrio molitor larvae. 3. The former compound is not utilized by the insect; the latter, although metabolized to 24(28)-ethylidene sterols and cholesterol, is not a beta-sitosterol metabolite. 4. The above results are discussed in relation to the mechanism of formation of the 24(28)-double bond in beta-sitosterol metabolism in T. molitor.