No abstract
SUMMARY Babesiosis is an emerging, tick-transmitted, zoonotic disease caused by hematotropic parasites of the genus Babesia. Babesial parasites (and those of the closely related genus Theileria) are some of the most ubiquitous and widespread blood parasites in the world, second only to the trypanosomes, and consequently have considerable worldwide economic, medical, and veterinary impact. The parasites are intraerythrocytic and are commonly called piroplasms due to the pear-shaped forms found within infected red blood cells. The piroplasms are transmitted by ixodid ticks and are capable of infecting a wide variety of vertebrate hosts which are competent in maintaining the transmission cycle. Studies involving animal hosts other than humans have contributed significantly to our understanding of the disease process, including possible pathogenic mechanisms of the parasite and immunological responses of the host. To date, there are several species of Babesia that can infect humans, Babesia microti being the most prevalent. Infections with Babesia species generally follow regional distributions; cases in the United States are caused primarily by B. microti, whereas cases in Europe are usually caused by Babesia divergens. The spectrum of disease manifestation is broad, ranging from a silent infection to a fulminant, malaria-like disease, resulting in severe hemolysis and occasionally in death. Recent advances have resulted in the development of several diagnostic tests which have increased the level of sensitivity in detection, thereby facilitating diagnosis, expediting appropriate patient management, and resulting in a more accurate epidemiological description.
Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others1, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. We analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and Latin Americans: 3,848 with type 2 diabetes (T2D) and 4,366 non-diabetic controls. In addition to replicating previous findings2–4, we identified a novel locus associated with T2D at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P=3.9×10−13; odds ratio (OR)=1.29). The association was stronger in younger, leaner people with T2D, and replicated in independent samples (P=1.1×10−4; OR=1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ≈50% frequency in Native American samples and ≈10% in East Asian, but rare in European and African samples. Analysis of an archaic genome sequence indicated the risk haplotype introgressed into modern humans via admixture with Neandertals. The SLC16A11 mRNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite T2D having been well studied by genome-wide association studies (GWAS) in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for T2D with a possible role in triacylglycerol metabolism.
We examined the role of the cytokines gamma interferon (IFN-γ) and interleukin-12 (IL-12) in the model of acute babesiosis with the WA1 Babesia. Mice genetically deficient in IFN-γ-mediated responses (IFNGR2KO mice) and IL-12-mediated responses (Stat4KO mice) were infected with the WA1 Babesia, and observations were made on the course of infection and cytokine responses. Levels of IFN-γ and IL-12 in serum increased 24 h after parasite inoculation. The augmented susceptibility observed in IFNGR2KO and Stat-4KO mice suggests that the early IL-12- and IFN-γ-mediated responses are involved in protection against acute babesiosis. Resistance appears to correlate with an increase in nitric oxide (NO) production. In order to assess the contribution of different cell subsets to resistance against the parasite, we also studied mice lacking B cells, CD4+ T cells, NK cells, and macrophages. Mice genetically deficient in B lymphocytes or CD4+ T lymphocytes were able to mount protective responses comparable to those of immunosufficient mice. In contrast, in vivo depletion of macrophages or NK cells resulted in elevated susceptibility to the infection. Our observations suggest that a crucial part of the response that protects from the pathogenic Babesia WA1 is mediated by macrophages and NK cells, probably through early production of IL-12 and IFN-γ, and induction of macrophage-derived effector molecules like NO
with the rate of mitosis in several tissues, which has been It has been proposed that lipid peroxidation (LP) supported by the decreased LP found in subcellular fractions might be a modulator of cell division, influencing initiaof liver tumor cells. [2][3][4] However, some discrepancies have been tion and cessation of mitosis in regenerating liver. Howraised concerning the LP status during the characteristic acever, the understanding of the participating role of this tive cell proliferation following partial hepatectomy (PH). Acevent in the onset of liver proliferation has been hamtually, it was reported that both nicotinamide-adenine dinupered by the fact that both higher or lower LP have been cleotide phosphate-and tert-butyl hydroperoxide-induced reported after two-thirds partial hepatectomy (PH).LP were diminished after PH. [5][6][7] However, other research Therefore, the present study deals with the extent of LP groups have found an early increase of LP in homogenates in the main subcellular fractions from rat liver at early of regenerating liver. 8,9 Moreover, a transient enhancement stages of regeneration, induced by either PH of 70% or of mitochondrial LP has been reported to occur in preparaacute CCl 4 administration. Our results, using several tions obtained from hepatectomized rats. 10 methods to monitor LP, indicate a differential effect inThe present study was aimed at providing additional data the peroxidative pattern of specific subcellular fractions to settle the controversy about LP status during liver regenerfrom regenerating liver after 24 hours of PH: a decrease ation. We used two models to induce liver cell proliferation: in microsomes and an increase confined to plasma memtwo-thirds hepatectomy and acute intoxication with CCl 4 ; brane and cytosolic fractions, peaking after 24 hours of assessing LP by three different methods. The results show PH. In CCl 4 -treated rats, higher LP was also noted in that, in both models, an increased amount of LP activity is plasma membrane and cytosol, being maximal at the confined to the plasma membrane and cytosolic fractions, replicative stage in this experimental model (48 hours).whereas microsomes had a lower LP rate only in PH rats. In addition, increased LP was found in microsomal andThe changes in LP pattern, associated to liver regeneration, nuclear fractions, declining before the 48 hours. In hepashowed an organ specificity and correlated with the magnitectomized rats, changes in LP seem to be an organ-spetude of the loss of hepatic mass. The overall data suggest that cific event and related to only PHs capable of triggering controlled peroxidative modifications of membranes could be a synchronized proliferative response, namely above playing a role in the early steps of liver regeneration. fed ad libitum, and maintained under a 12-hour light/dark period. Surgical procedures were performed between 9 and 10 AM. Shamoperated animals were laparotomized under ether anesthesia to proThe liver is capable of recovering from damage or loss up vide a cont...
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