Aging has been associated with a series of pathophysiological processes causing general decline in the overall health of the afflicted population. The cumulative line of evidence suggests an important role of oxidative stress in the development and progression of the aging process and metabolic abnormalities, exacerbating adipocyte dysfunction, cardiovascular diseases, and associated complications at the same time. In recent years, robust have established the implication of Na/K-ATPase signaling in causing oxidative stress and alterations in cellular mechanisms, in addition to its distinct pumping function. Understanding the underlying molecular mechanisms and exploring the possible sources of pro-oxidants may allow for developing therapeutic targets in these processes and formulate novel intervention strategies for patients susceptible to aging and associated complications, such as obesity and cardiovascular disease. The attenuation of oxidative stress with targeted treatment options can improve patient outcomes and significantly reduce economic burden.

Background: Oxidant stress plays a key role in the development of chronic kidney disease (CKD). Experimental CKD leads to accumulation of uremic toxins (UT) in the circulation resulting in increased ROS production, which in turn, is known to activate the Na/K-ATPase/ROS amplification loop. Studies in a murine model of obesity have shown that increased oxidative stress in plasma is due to increased ROS and cytokine production from dysfunctional adipocytes. Therefore, we hypothesized that adipocytes exposed to UTs will activate the Na/K-ATPase oxidant amplification loop causing redox imbalance and phenotypic alterations in adipocytes. We also aimed to demonstrate that the Na/K-ATPase signaling antagonist, pNaKtide, attenuates these pathophysiological consequences. Methods: In the first set of experiments, 3T3-L1 murine pre-adipocytes were treated with varying concentrations of UTs, indoxyl sulfate (IS) (50, 100 and 250 µM) and p-cresol (50, 100 and 200 µM), with or without pNaKtide (0.7 µM) for five days in adipogenic media, followed by Oil Red O staining to study adipogenesis. RT-PCR analysis was performed to study expression of adipogenic, apoptotic and inflammatory markers, while DHE staining evaluated the superoxide levels in UT treated cells. In a second set of experiments, visceral fat was obtained from the West Virginian population. MSCs were isolated and cultured in adipogenic media for 14 days, which was treated with indoxyl sulfate (0, 25, 50 and 100 µM) with or without pNaKtide (1 µM). MSC-derived adipocytes were evaluated for morphological and molecular analysis of the above markers. Results: Our results demonstrated that 3T3-L1 cells and MSCs-derived adipocytes, treated with UTs, exhibited a significant decrease in adipogenesis and apoptosis through activation of the Na/K-ATPase/ROS amplification loop. The treatment with pNaKtide in 3T3-L1 cells and MSC-derived adipocytes negated the effects of UTs and restored cellular redox in adipocytes. We noted a varying effect of pNaKtide, in adipocytes treated with UTs, on inflammatory markers, adipogenic marker and superoxide levels in 3T3-L1 cells and MSC-derived adipocytes. Conclusions: This study demonstrates for the first time that the Na/K-ATPase/ROS amplification loop activated by elevated levels of UTs has varying effect on phenotypic alterations in adipocytes in various in vitro models. Thus, we propose that, if proven in humans, inhibition of Na/K-ATPase amplification of oxidant stress in CKD patients may ultimately be a novel way to combat adipocyte dysfunction and metabolic imbalance in these patients.

Human Herpesvirus 6 (HHV-6) is a virus known to cause mild infection in children. In adults, HHV-6 reactivation has been described in immunocompromised individuals.Rarely, viral reactivation occurs in immunocompetent adults causing significant disease and morbidity. The use of certain medications, like amoxicillin, has been found to induce HHV-6 reaction in a number of cases. We report a 63-year-old immunocompetent female who presented with headache, fever and altered mental status. Past medical history included two bouts of HHV-6 encephalitis treated at external facilities. According to her medical history, both episodes of encephalitis were preceded by amoxicillin use. Her lumbar puncture analysis was consistent with viral etiology and a cerebrospinal fluid (CSF) PCR was positive for HHV-6. She was successfully treated with intravenous ganciclovir. It is important to keep a broad differential diagnosis in mind when approaching encephalitis in adults, and to be aware of unusual triggers for viral reactivation. Clinicians who suspect the infection in the correct clinical setting can successfully treat patients with recurrent HHV-6.

Discussion: IS is typically asymptomatic but may present with chronic, watery diarrhea or vague abdominal pain. Diagnosis is made incidentally on histology of colonic mucosal biopsies. Some reports have described polypoid and erythematous lesions associated with IS, but they are typically not easily identifiable. Histologically, silver stains or immunostains for Treponema pallidum may be necessary to identify these organisms . A hallmark of IS is the "false brush border" formed by a band of spirochetes adhering to the epithelial layer . Originally, IS was mainly found in areas of low socioeconomic status in veterinary medicine. Human colonization has been observed more recently predominantly in HIV and homosexual male populations. IBD patients are at a higher risk of infection due to immunocompromised status. Asymptomatic patients do not require treatment. However, for those requiring treatment, a trial of metronidazole can be use. One case report documented IS in an IBD patient with symptoms of abdominal pain and watery diarrhea that was successfully treated with metronidazole leading to complete resolution of symptoms. (Figure) This case highlights a rare etiology of chronic diarrhea that should be considered, especially in immunocompromised patients with no other clear cause of symptoms.[2739] Figure 1. A -Attached to the luminal border are fuzzy basophilic structures, recall that colonic mucosa does not have a microvillus border, and even if it did, this is too thick (hematoxylin and eosin 40X). B -The organisms are positive on silver based stains.