: Medicine Articles
Letter: Hepatic insulin resistance directly promotes formation of cholesterol gallstonesPeople with the metabolic syndrome often develop gallstones. Why these two disorders are linked has not been not clear, but now Kahn and his colleagues have shown that lack of insulin signaling in the liver leads to dysregulation of genes that control the transport and synthesis of bile acids, thus altering the proper profile of bile salts and resulting in the formation of gallstones. Nature Medicine, vol. 14 #7, pp778-782 |
Letter: SNO-hemoglobin is not essential for red blood cell–dependent hypoxic vasodilationThe coupling of hemoglobin sensing of physiological oxygen gradients to stimulation of nitric oxide (NO) bioactivity is an established principle of hypoxic blood flow. One mechanism proposed to explain this oxygen-sensing–NO bioactivity linkage postulates an essential role for the conserved Cys93 residue of the hemoglobin β-chain (βCys93) and, specifically, for S-nitrosation of βCys93 to form S-nitrosohemoglobin (SNO-Hb). The SNO-Hb hypothesis, which conceptually links hemoglobin and NO biology, has been debated intensely in recent years. This debate has precluded a consensus on physiological mechanisms and on assessment of the potential role of SNO-Hb in pathology. Here we describe new mouse models that exclusively express either human wild-type hemoglobin or human hemoglobin in which the βCys93 residue is replaced with alanine to assess the role of SNO-Hb in red blood cell–mediated hypoxic vasodilation. Substitution of this residue, precluding hemoglobin S-nitrosation, did not change total red blood cell S-nitrosothiol abundance but did shift S-nitrosothiol distribution to lower molecular weight species, consistent with the loss of SNO-Hb. Loss of βCys93 resulted in no deficits in systemic or pulmonary hemodynamics under basal conditions and, notably, did not affect isolated red blood cell–dependent hypoxic vasodilation. These results demonstrate that SNO-Hb is not essential for the physiologic coupling of erythrocyte deoxygenation with increased NO bioactivity in vivo. Nature Medicine, vol. 14 #7, pp773-777 |
Letter: Aggravation of viral hepatitis by platelet-derived serotoninMore than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8+ T cell–dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8+ T cell–dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8+ T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology. Nature Medicine, vol. 14 #7, pp756-761 |
Letter: Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugsSiliciano and his colleagues propose a new index for measuring the antiviral activity of anti-HIV drugs in vitro, which suggests that there are limitations to the efficacy of antiviral drugs on the basis of their mechanism of action. They suggest that the new index is a more accurate way of measuring antiviral activity and that it correlates well with clinical outcomes. Nature Medicine, vol. 14 #7, pp762-766 |
Letter: Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature agingStatins and aminobisphosphonates inhibit post-translational modifications and membrane accumulation of progerin, the protein that causes Hutchinson-Gilford progeria syndrome, pointing to a potential combination therapy for this disease. Nature Medicine, vol. 14 #7, pp767-772 |
News and Views: Chipping away at gallstonesGallstone disease occurs more frequently in subjects with the metabolic syndrome and type 2 diabetes. Findings in a mouse model suggest that the forkhead transcription factor FoxO1 lies behind this association (pages 778–782). Nature Medicine, vol. 14 #7, pp715-716 |
News and Views: Rejuvenating premature agingTwo commonly prescribed drugs, statins and aminobisphosphonates, may be helpful in combating the rare aging disorder, Hutchinson-Gilford progeria syndrome (pages 767–772). Nature Medicine, vol. 14 #7, pp713-715 |
News and Views: Imatinib buys time for brain after strokeThe most effective drug to treat acute ischemic stroke, tissue plasminogen activator (tPA), must be applied within three hours after symptom onset because of the risk of hemorrhage and other complications such as neurotoxicity. The anticancer drug imatinib (Gleevec) may help overcome these limitations by counteracting the ability of tPA to increase the permeability of the blood-brain barrier (pages 731–737). Nature Medicine, vol. 14 #7, pp712-713 |
News and Views: Regulatory RNA goes awry in Alzheimer's diseaseAn antisense RNA may contribute to Alzheimer's disease by upregulating β-secretase (pages 723–730). Nature Medicine, vol. 14 #7, pp711-712 |