Lifestyle interventions for "diabesity": the state of the science

Lifestyle is an expression of individual choices and their interaction with the environment and is closely associated with risks for obesity, diabetes, and cardiovascular disorders. If taken cumulatively this syndrome may be referred to as "diabesity." The escalating prevalence of obesity among both children and adults is one modifiable dominant risk factor in this triad. An increase in body weight of approximately 2.2 pounds (1 kg) has been shown to increase risk for diabetes by 4.5%. Alternatively, a 5% to 10% decrease in body weight improves diabetes control. The metabolic syndrome of diabetes has been described as a consortium of conditions including dyslipidemia, hypertension, and abdominal obesity. In randomized controlled clinical trials, dietary and physical activity interventions have been shown to be effective in decreasing risk for, as well as delaying conversion to, these disorders. Since 1977, 4 hallmark multisite clinical trials have been conducted in the United States, the United Kingdom, and Finland confirming that improved glycemic and hypertensive control of patients through lifestyle interventions can have positive effects on associated complications and longitudinal outcomes. A fifth robust and well-controlled study is currently being conducted in multiple sites in the United States. Dietary behaviors are modulating factors not only in these metabolic and systemic conditions but also in risk for oral diseases such as dental caries. The association between obesity, diabetes, cardiovascular diseases, and oral health status may be linked by these lifestyle behaviors. Promotion of weight management involves approaches that include diet, physical activity, and behavior modification. Established effective guidelines within these domains may be applicable to current practice and future studies designed to examine the associations between diabesity and oral health status.     

Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancer

Estrogens have been implicated to be complete carcinogens in breast and gynecologic tissues. Possible mechanisms may include differential metabolism with subsequent formation of reactive oxygen species and/or a receptor-mediated pathway, which may also involve indirect modulation of intracellular redox state. Estrogen-mediated oxidative DNA damage in mammary gland epithelia includes the induction of 8-oxo-2'-deoxyguanosine, both in vitro and in vivo, thereby suggesting a role for oxidative stress in the initiation and/or progression of breast neoplasia. In order to study this phenomenon, we have treated estrogen receptor alpha (ER-alpha)-positive MCF-7 cells and ER-alpha-negative MDA-MB-231 cells with 10 nM 17beta-estradiol (E2), while measuring changes in antioxidant status and sensitivity to DNA damage by peroxide. Treatment of MCF-7 cells with E2 resulted in a marked decrease in the ability for these cells to metabolize peroxide, which paralleled a decrease in catalase activity and total glutathione levels. These observations also correlated with an increased sensitivity to peroxide-induced DNA damage. The estrogen-induced effects were all opposed by the anti-estrogen tamoxifen. In addition, the estrogen-mediated down regulation of peroxide metabolism, catalase activity, and sensitivity to DNA damage were not observed in the MDA-MB-231 cell line. Treatment of MCF-7 cells with E2 also resulted in increased glutathione peroxidase, superoxide dismutases (I) and (II) and glucose-6-phosphate dehydrogenase activities. Therefore, in this breast cancer model antioxidant status is modulated through the actions of the ER. The data may explain some of the estrogen-induced pro-oxidant effects previously reported in vivo. In addition, this is the first report indicating that E2 is capable of inducing an increase in sensitivity to oxidative DNA damage through an ER-mediated mechanism.     

Traffic at the intersection of neurotrophic factor signaling and neurodegeneration

Advances in understanding the biology of neurotrophic factors and their signaling pathways have provided important insights into the normal growth, differentiation and maintenance of neurons. Stimulated by neuropathological observations and genetic discoveries, studies in cell and animal models of neurodegenerative disorders have begun to clarify pathogenetic mechanisms. We examine the intersection of these research themes and identify several potential mechanisms for linking failed neurotrophic factor signaling to neurodegeneration. Studies of nerve growth factor signaling in a mouse model of Down syndrome encourage the views that neuronal dysfunction and atrophy might be linked to failed neurotrophic support and that additional studies focused on this possibility would enhance our understanding of the mechanisms of neurodegenerative disorders and their treatment.     

Delivery of an adenoviral vector to the crushed recurrent laryngeal nerve

OBJECTIVES: Objectives were to create a model of recurrent laryngeal nerve injury for testing the efficacy of potential therapeutic viral gene therapy vectors and to demonstrate that remote injection of a viral vector does not cause significant additional neuronal injury. STUDY DESIGN: Animal model. METHODS: Rats were randomly assigned to three groups of 10 animals each. In group I, the recurrent laryngeal nerve was crushed. In group II, the nerve was crushed and then injected with an adenoviral vector containing no transgene. In group III, the nerve was identified but was not crushed. Rats were killed at 1 week, and their larynges and brainstems were cryosectioned in 15-microm sections. Laryngeal cryosections were processed for acetylcholine histochemical analysis (motor endplates) followed by neurofilament immunoperoxidase (nerve fibers). Percentage of nerve-endplate contact was determined and compared between groups. Fluorescent in situ hybridization was performed on brainstem sections from rats in group II to confirm the presence of virus. RESULTS: No significant difference in percentage of nerve-endplate contact exists between the two crushed-nerve groups (groups I and II) (P =.88). The difference between both crushed-nerve groups and the group with noncrushed nerves (group III) was highly significant (P <.0001). The presence of virus was confirmed in group II rats. CONCLUSIONS: Crush provides a significant measurable injury to the recurrent laryngeal nerve and may be used as a model to explore therapeutic interventions for nerve injury. The remote injection of viral vector did not cause significant additional neuronal injury. Remote delivery of viral vectors to the central nervous system holds promise in the treatment of recurrent laryngeal nerve injury and central nervous system diseases.     

Measurement of oxidative DNA damage by catechol estrogens and analogues in vitro

The growth-promoting effects of estrogens in hormone-dependent tumor tissues involve receptor-mediated pathways that are well-recognized; however, the role of estrogens in tumor initiation remains controversial. Estrogen metabolites, primarily the catechol estrogens (CE's), have been implicated in tumor initiation via a redox cycling mechanism. We have developed metabolically stable CE analogues for the study of receptor versus redox cycling effects on DNA damage. Comparisons between hydroxy estradiols (HE2's), methoxy estradiols (ME2's), and hydroxymethyl estradiols (HME2) in potentiometric and DNA damaging studies were made. DNA damage was assessed in calf thymus DNA using 8-oxo-2'-deoxyguanosine (8-oxo-dG) as a genotoxic marker for oxidative stress. Increases in the number of 8-oxo-dG/10(5) dG were significant for each 2-HE2 and 4-HE2. Cu(II)SO4, a transition metal known to catalyze the redox cycling of o-quinones, substantially increased the amount of DNA damage caused by both CE's. However, DNA damage was only observed at concentrations of 10 microM or higher, much greater than what is found under physiologic conditions. Furthermore, the presence of endogenous antioxidants such as glutathione, SOD, and catalase drastically reduced the amount of DNA damage induced by high concentrations of 2-HE2. There was no DNA damage observed for the non-redox cycling HME2's, making these compounds useful probes in the study of receptor-mediated carcinogenesis. Thus, both 2-HE2 and 4-HE2 are capable of producing oxidative DNA damage at micromolar concentrations in vitro. However, since the amount of CE's has not been shown to surpass nanomolar levels in vivo, it is unlikely that free radical production via redox cycling of CE's is a causative factor in human tumorigenesis.     

Use of intravesical cisplatin and mitomycin-C for recurrent transitional cell carcinoma of bladder refractory to thiotepa

Superficial transitional cell carcinoma of the bladder (TCCaB) has a high incidence of recurrence. Intravesical thiotepa is the drug used most often for treatment. Intravesical mitomycin-C also has shown promise. Cisplatin has proven activity in patients with metastatic TCCaB and in experimental bladder cancer models. Patients who have no response to one intravesical agent such as thiotepa may respond to other agent(s) such as mitomycin-C or cisplatin. In this report we have evaluated 10 patients with superficial recurrent TCCaB who showed no response to intravesical thiotepa and were subsequently treated with mitomycin-C or cisplatin. Six patients were treated with cisplatin and 4 with mitomycin-C. The 4 treated with mitomycin-C had complete response or partial response within three months. Of the 6 treated with cisplatin, 4 had complete response within three months, and 2 had no response.     

Clonidine inhibits the isoproterenol-induced desensitization of the beta noradrenergic activated adenylate cyclase system in astrocytes

Studies were conducted to determine if alpha agonists could influence the desensitization of the beta-noradrenergic receptor activated adenylate cyclase system. Pretreatment of astrocyte cultures with isoproterenol results in a rapid decrease in the cyclic AMP response to subsequent re-exposure to this agonist. The cyclic AMP response to isoproterenol in astrocytes pre-exposed for 2 h to isoproterenol plus clonidine was 2–3 times higher than in cells pre-exposed to isoproterenol alone. The response in astrocytes pretreated with phenylephrine plus isoproterenol was not different from that in cells pretreated with isoproterenol alone. Cyclic AMP may be involved in the effects elicited by clonidine, since this agonist can inhibit the accumulation of cyclic AMP in these cells. Also pretreatment with isobutylmethylxanthine decreases the cyclic AMP response to isoproterenol. The results suggest that clonidine can effect the desensitization of the noradrenergic receptor coupled adenylate cyclase system independent of effects on neurotransmitter release.     

Interventional radiology in the spleen

Despite the widespread use of interventional radiologic techniques, there has been reluctance to apply these to the spleen. Concern for bleeding and difficulty in negotiating around the colon and pleura have limited its use. The authors report their experience with interventional radiology of the spleen in 35 cases, including percutaneous biopsy (n = 5), diagnostic and therapeutic fluid aspiration (n = 14), and catheter drainage of abscesses (n = 9), hematomas (n = 2), intrasplenic pancreatic pseudocysts (n = 2), and necrotic tumor (n = 1). Transsplenic fluid aspiration and biopsy of the pancreas and adrenal gland were performed as well (n = 2). All procedures were performed under computed tomographic or ultrasound guidance. Biopsies were performed with 22- or 20-gauge needles only; no complications were encountered. Diagnoses included primary and secondary malignancies and an infectious process. Drainages were successful in 11 of 14 patients; pleural effusions occurred in two cases, but neither required specific therapy. Interventional radiologic procedures in the spleen are feasible, and the authors discuss methods to promote their safe application.