Exocrine pancreatic cancer,cigarette smoking,and diabetes mellitus: a case-control study in northern Italy

The role of cigarette smoking and diabetes mellitus as risk factors for exocrine pancreatic cancer (PC) was investigated in a hospital based case-control study. Current smokers were at increased risk for PC (OR = 2.36, 95% CI 1.53-3.63): the magnitude of the risk was related to the lifetime amount of smoking (chi2(trend) = 17.00; P < 0.0001). Among former smokers, after 15 years from ceasing smoking, the risk for PC dropped to the level of a lifetime non-smoker, whichever the lifetime smoking amount. Diabetes was associated with a 2.89-fold increased risk for PC (95% CI 1.71-4.86): the risk was 4.76 (95% CI 1.99-11.53) for diabetes diagnosed up to 2 years before the diagnosis of PC and dropped to 2.07 (95% CI 1.02-4.20) for diabetes diagnosed more than 5 years before PC. The risk for PC was estimated according to the treatment used to control diabetes: it was 6.49 (95% CI 2.28-18.48) for insulin treated diabetes and 2.12 (95% CI 1.16-3.87) for diabetes treated with oral hypoglycemic drugs. The risk of PC for diabetes treated for more than 5 years before the diagnosis of PC was 6.21 (95% CI 1.61-23.96) for patients treated with insulin and 1.21 (95% CI 0.50-2.92) for those treated with oral hypoglycemic drugs: the type of treatment needed to control the disease may discriminate between the diabetes that represents a consequence of cancer from the diabetes that could represent an etiological co-factor. More studies are needed to clarify whether long-lasting insulin-treated diabetes is an etiological co-factor in PC.     

Ultrafast 2D NMR spectroscopy using sinusoidal gradients: principles and ex vivo brain investigations.

A new methodology capable of delivering complete 2D NMR spectra within a single scan was recently introduced. The resulting potential gain in time resolution could open new opportunities for in vivo spectroscopy, provided that the technical demands of the methodology are satisfied by the corresponding hardware. Foremost among these demands are the relatively short switching times expected from the applied gradient-echo trains. These rapid transitions may be particularly difficult to accomplish on imaging systems. As a step toward solving this problem, we assessed the possibility of replacing the square-wave gradient train currently used during the course of the acquisition by a shaped sinusoidal gradient. Examples of the implementation of this protocol are given, and successful ultrafast acquisitions of 2D NMR spectra with suitable spectral widths on a microimaging probe (for both phantom solutions and ex vivo mouse brains) are demonstrated.     

Early developmental exposure to BDE 99 or Aroclor 1254 affects neurobehavioural profile: interference from the administration route

Among the most persistent and bio-accumulative environmental pollutants are the polybrominated diphenyl ethers (PBDEs), a class of chemicals widely used as flame retardants in plastics and textile coating, and the polychlorinated biphenyls (PCBs), previously used as coolants and lubricants in electrical equipment. Monitoring programs revealed high levels of both these classes of compounds in human breast milk, raising concerns for their potential noxious effects on infants. The aim of the present study was to investigate the neurotoxic effects of 2,2',4,4',5-penta BDE (BDE 99: 18mg/kg/day) or Aroclor 1254 (A1254, a PCB mixture: 10mg/kg/day) administration, from gestational day (GD) 6 to postnatal day (PND) 21, on neurobehavioral development in the CD-1 Swiss mouse. In addition, we investigated whether the administration route affects the emergence or the magnitude of the toxic effects of BDE 99 or A1254. In particular, we compared self-administration, consisting in letting the mouse drink spontaneously the compound dissolved in oil from a syringe, with gavage, consisting in force-feeding a substance by a tube inserted in the mouth and then into the stomach, a procedure reported to be stress-inducing. Both compounds induced hyperactivity, though BDE 99 affected activity profile only during adolescence and A1254 mainly at adulthood. Levels of total circulating thyroxine were decreased by both BDE 99 and A1254 administration, though only in the latter group the decrease was statistically significant. These findings suggest a different neurotoxic action exerted by PBDEs and PCBs. An effect of the administration route, independent from the compound administered, was found on thigmotactic behavior and gavage administration affected pup body weight gain only in the A1254 group, suggesting that the stress induced by gavage procedure may either affect results per se or modulate the detrimental action of selected compounds.     

Polybrominated diphenyl ethers: neurobehavioral effects following developmental exposure

Polybrominated diphenyl ethers (PBDEs), a class of widely used flame retardants, are becoming widespread environmental pollutants, as indicated by studies on sentinel animal species, as well as humans. Of particular concern are the reported increasingly high levels of PBDEs in human milk, as should be given that almost no information is available on their potential effects on developing organisms. In order to address this issue, studies have been conducted in mice and rats to assess the potential neurotoxic effects of perinatal exposure to PBDEs (congeners 47, 99, 153 and the penta-BDE mixture DE-71). Characteristic endpoints of PBDE neurotoxicity are, among others, endocrine disruption (e.g. decreased thyroid hormone levels), alteration in cholinergic system activity (behavioral hyporesponsivity to nicotine challenge), as well as alterations of several behavioral parameters. In particular, the main hallmark of PBDE neurotoxicity is a marked hyperactivity at adulthood. Furthermore, a deficit in learning and memory processes has been found at adulthood in neonatally exposed animals. Some of neurotoxic effects of PBDEs are comparable to those of polychlorinated biphenyls (PCBs), though the latter class of compounds seems to exert a stronger toxic effect. Available information on PBDE neurotoxicity obtained from animal studies and the possibility of neonatal exposure to PBDEs via the mother's milk suggest that these compounds may represent a potential risk for neurobehavioral development in humans.     

Challenges in the diagnosis and management of acromegaly: a focus on comorbidities

Introduction

Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life.

Methods

We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment.

Findings and conclusions

Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.

     

Cytoplasmic CUG RNA Foci Are Insufficient to Elicit Key DM1 Features

The genetic basis of myotonic dystrophy type I (DM1) is the expansion of a CTG tract located in the 3′ untranslated region of DMPK. Expression of mutant RNAs encoding expanded CUG repeats plays a central role in the development of cardiac disease in DM1. Expanded CUG tracts form both nuclear and cytoplasmic aggregates, yet the relative significance of such aggregates in eliciting DM1 pathology is unclear. To test the pathophysiology of CUG repeat encoding RNAs, we developed and analyzed mice with cardiac-specific expression of a beta-galactosidase cassette in which a (CTG)₄₀₀ repeat tract was positioned 3′ of the termination codon and 5′ of the bovine growth hormone polyadenylation signal. In these animals CUG aggregates form exclusively in the cytoplasm of cardiac cells. A key pathological consequence of expanded CUG repeat RNA expression in DM1 is aberrant RNA splicing. Abnormal splicing results from the functional inactivation of MBNL1, which is hypothesized to occur due to MBNL1 sequestration in CUG foci or from elevated levels of CUG-BP1. We therefore tested the ability of cytoplasmic CUG foci to elicit these changes. Aggregation of CUG RNAs within the cytoplasm results both in Mbnl1 sequestration and in approximately a two fold increase in both nuclear and cytoplasmic Cug-bp1 levels. Significantly, despite these changes RNA splice defects were not observed and functional analysis revealed only subtle cardiac dysfunction, characterized by conduction defects that primarily manifest under anesthesia. Using a human myoblast culture system we show that this transgene, when expressed at similar levels to a second transgene, which encodes expanded CTG tracts and facilitates both nuclear focus formation and aberrant splicing, does not elicit aberrant splicing. Thus the lack of toxicity of cytoplasmic CUG foci does not appear to be a consequence of low expression levels. Our results therefore demonstrate that the cellular location of CUG RNA aggregates is an important variable that influences toxicity and support the hypothesis that small molecules that increase the rate of transport of the mutant DMPK RNA from the nucleus into the cytoplasm may significantly improve DM1 pathology.     

Effects of soy isoflavones on endothelial function in healthy postmenopausal women

OBJECTIVE: To evaluate the effects of soy isoflavone administration on endothelial function in healthy postmenopausal women. DESIGN: Sixty naturally postmenopausal women were randomly assigned to receive isoflavone or placebo tablets for 6 months. Endothelium-dependent vasodilatation was measured by brachial reactivity technique along with levels of plasma soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, P-selectin and soluble thrombomodulin, von Willebrand factor, and tissue plasminogen activator. Differences between endothelium-dependent and endothelium-independent vasodilatation were assessed by evaluating brachial reactivity parameters after reactive hyperemia and after sublingual administration of nitroglycerin; furthermore, in the active group, the effect of isoflavones was also evaluated during the intra-arterial infusion of N-monomethyl-L-arginine. Serum levels of lipids [high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides and lipoprotein(a)] and hemostatic factors (prothrombin, fibrinogen, plasminogen activator inhibitor-1, and fibrin D-dimer) were also measured. To confirm the absorption of isoflavones, their blood concentrations were determined. RESULTS: Isoflavone treatment versus placebo was associated with a significant improvement in endothelium-dependent vasodilatation but had no impact on endothelial-independent arterial diameter and flow. Intra-arterial infusion of N-monomethyl-L-arginine inhibited the significant effect of isoflavones on endothelium-mediated vasodilatation. Furthermore, isoflavone group experienced statistically significant reductions in plasma concentrations of ICAM-1, VCAM-1, and E-selectin. Levels of soluble thrombomodulin, von Willebrand factor, tissue plasminogen activator, lipids, and hemostatic factors did not change significantly throughout the study in both groups. CONCLUSIONS: Our findings suggest a positive influence of soy isoflavones on endothelial function in healthy postmenopausal women as evidenced by an improvement in endothelium-dependent vasodilatation and a reduction in plasma adhesion molecule levels.