Abstract-Inhibition of xanthine oxidase (XO) in failing hearts improves cardiac efficiency by an unknown mechanism.We hypothesized that this energetic effect is due to reduced oxidative stress and critically depends on nitric oxide synthase (NOS) activity, reflecting a balance between generation of nitric oxide (NO) and reactive oxygen species. In dogs with pacing-induced heart failure (HF), ascorbate (1000 mg) mimicked the beneficial energetic effects of allopurinol, increasing both contractility and efficiency, suggesting an antioxidant mechanism. Allopurinol had no additive effect beyond that of ascorbate. Crosstalk between XO and NOS signaling was assessed. NOS inhibition with N G -monomethyl-L-arginine (L-NMMA; 20 mg/kg) had no effect on basal contractility or efficiency in HF, but prevented the ϩ26.2Ϯ3.5% and ϩ66.5Ϯ17% enhancements of contractility and efficiency, respectively, observed with allopurinol alone. Similarly, improvements in contractility and energetics due to ascorbate were also inhibited by L-NMMA. Because of the observed NOS-XO crosstalk, we predicted that in normal hearts NOS inhibition would uncover a depression of energetics caused by XO activity. In normal conscious dogs, L-NMMA increased myocardial oxygen consumption (MV O 2 ) while lowering left ventricular external work, reducing efficiency by 31.1Ϯ3.8% (PϽ0.005). Lowered efficiency was reversed by XO inhibition (allopurinol, 200 mg) or by ascorbate without affecting cardiac load or systemic hemodynamics. Single-cell immunofluorescence detected XO protein in cardiac myocytes that was enhanced in HF, consistent with autocrine signaling. These data show that both NOS and XO signaling systems participate in the regulation of myocardial mechanical efficiency and that upregulation of XO relative to NOS contributes to mechanoenergetic uncoupling in heart failure. Key Words: xanthine oxidase Ⅲ oxidative stress Ⅲ nitric oxide Ⅲ heart failure Ⅲ ascorbate T he failing heart displays substantial energetic inefficiency in both isolated muscle 1,2 and intact chambers. [3][4][5] This phenomenon can be best described as "mechanoenergetic uncoupling," given that the depression of contractile force is not matched by a concomitant depression of energy consumption. Among the proposed mechanisms is enhanced oxidative stress stemming from mitochondrial 6 and cytosolic free radical generating systems. 7 Xanthine oxidase (XO) is prominent among these enzymes, because it produces superoxide as a byproduct of the terminal two steps of purine metabolism. 3 XO is upregulated in failing myocardium of experimental animals 3,8 and humans, 9 and its inhibition by allopurinol improves the mechanical efficiency (the ratio between ventricular work performed and oxygen consumed) of intact failing hearts 3,9 ; such an effect was predicted by the initial observations that allopurinol and oxypurinol augment calcium-activated force without increasing activator Ca 2ϩ in isolated cardiac muscle. 2 To date, however, the signal transduction mechanisms of the salutary effects o...

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With the rising incidence of diabetes mellitus (DM) in the US, it is of paramount importance that practitioners understand the complications of DM and how best to manage them. Diabetes affects every organ system and the skin is no exception. There are numerous cutaneous manifestations of DM that have similar etiologies and result from the same pathologic mechanisms as the internal complications of this disease state. In addition, skin manifestations may precede the diagnosis of diabetes. The present article reviews both the common and less common cutaneous manifestations of DM, including presenting lesions, pathogenesis, and management.

Acne vulgaris is a chronic inflammatory disease of pilosebaceous follicles commonly affecting adolescents and young adults. This disease has a profound psychological impact on affected individuals and treatment has been shown to significantly improve both self-esteem and quality of life. Isotretinoin is an effective medication used primarily in severe cystic acne patients. Over the past 30 years, this medication has revolutionized the treatment of acne. However, despite its popularity there are numerous side effects associated with its use. Most of its side effects are predictable and dose dependent, which has led to the development of variable dose regimens. Unfortunately, rare but significant side effects (e.g., depression, inflammatory bowel disease) do occur and necessitate careful monitoring to improve clinical outcomes and minimize potential adverse events.