Association Of Sickle Cell Trait With Exertional Rhabdomyolysis And Atrial Fibrillation.

Sickle cell trait (SCT), sickle cell disease’s carrier status, is a common genetic variant found in many people of African, South Asian, Middle Eastern and Mediterranean descent. While overall considered a benign carrier status, it has been associated with an increased risk of several diseases, including exertional rhabdomyolysis (ER), and chronic kidney disease. While epidemiological evidence links SCT with ER, the actual pathophysiological mechanism less understood. Additionally, while there is an increased prevalence of atrial fibrillation (AF) documented in people with sickle cell disease, studies in individuals with SCT are lacking. The objectives of this thesis are twofold: The first chapter is a literature review of studies to examine the physiological mechanisms linking SCT and exertional rhabdomyolysis. The second chapter is original research into the associations of SCT with AF. The first chapter reviews studies that identify aggravating factors that may promote ER. It then reviews observed pathophysiological changes in people with SCT that may increase the risk of ER. It summarizes studies that assess mitigating factors that decrease the risk of ER. It then presents a postulated pathway of mechanisms that associate SCT with ER. The second chapter uses data from African-American participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study to assess the association of SCT with prevalent AF (by electrocardiogram or medical history) using logistic regression models adjusting for age, sex, income, education, history of stroke, myocardial infarction, diabetes, hypertension, and chronic kidney disease. In 10,409 participants with baseline ECG data and genotyping, 778 (7.5%) had SCT and 811 (7.8%) had prevalent AF. After adjusting for age, sex, education and income, SCT was associated with AF, OR 1.32 (95% CI 1.03-1.70). SCT remained associated with prevalent AF after adjusting for potential factors on the causal pathway such as hypertension and chronic kidney disease suggesting alternate mechanisms for the increased risk. SCT was associated with a higher prevalence of AF and a non-significantly higher incident AF over a 9.2 year period independent of AF risk factors

Thrombotic Thrombocytopenic Purpura Associated with Pazopanib

A 76-year-old male with metastatic renal carcinoma on day 24 of pazopanib was admitted with complaints of emesis, confusion, and hematuria. Laboratory testing showed acute kidney injury, hyperbilirubinemia, and thrombocytopenia. Scattered schistocytes were seen on peripheral smear, and he was diagnosed with thrombotic microangiopathy (TMA). He was started on daily, one-volume plasma exchange with rapid improvement in thrombocytopenia. ADAMTS13 activity returned as undetectably low with no inhibitor detected. After cessation of plasmapheresis, repeat ADAMTS13 activity returned as normal. Unfortunately, his platelet count started to downtrend within four days after developing septicemia thought to be due to a catheter-associated infection. He was placed on comfort care measures after discussion with his family. An autopsy listed the major cause of death as metastatic renal cell carcinoma. According to two separate systematic reviews, there have been no cases of proven drug-induced TMA where decreased ADAMTS13 activity was the identified mechanism. While pazopanib is also associated with TMA, this unique case suggests a novel potential mechanism for TMA associated with pazopanib and brings forth “drug-induced thrombotic thrombocytopenic purpura” that quickly responds to plasmapheresis as a possible new diagnostic entity requiring prompt recognition and treatment

Probable Locally Acquired Babesia divergens–Like Infection in Woman, Michigan, USA

We report an asplenic patient who was infected with Babesia divergens–like/MO-1. The clinical course was complicated by multiorgan failure that required intubation and dialysis. The patient recovered after an exchange transfusion and antimicrobial drug therapy. Physicians should be alert for additional cases, particularly in asplenic persons

Probable locally acquired babesia divergens-like infection in woman, Michigan, USA

We report an asplenic patient who was infected with Babesia divergens-like/MO-1. The clinical course was complicated by multiorgan failure that required intubation and dialysis. The patient recovered after an exchange transfusion and antimicrobial drug therapy. Physicians should be alert for additional cases, particularly in asplenic persons

Supplementary information files for article Targeted delivery of narrow-spectrum protein antibiotics to the lower gastrointestinal tract in a murine model of Escherichia coli colonization

Supplementary information files for Targeted delivery of narrow-spectrum protein antibiotics to the lower gastrointestinal tract in a murine model of Escherichia coli colonization Bacteriocins are narrow-spectrum protein antibiotics that could potentially be used to engineer the human gut microbiota. However, technologies for targeted delivery of proteins to the lower gastrointestinal (GI) tract in preclinical animal models are currently lacking. In this work, we have developed methods for the microencapsulation of Escherichia coli targeting bacteriocins, colicin E9 and Ia, in a pH responsive formulation to allow their targeted delivery and controlled release in an in vivo murine model of E. coli colonization. Membrane emulsification was used to produce a water-in-oil emulsion with the water-soluble polymer subsequently cross-linked to produce hydrogel microcapsules. The microcapsule fabrication process allowed control of the size of the drug delivery system and a near 100% yield of the encapsulated therapeutic cargo. pH-triggered release of the encapsulated colicins was achieved using a widely available pH-responsive anionic copolymer in combination with alginate biopolymers. In vivo experiments using a murine E. coli intestinal colonization model demonstrated that oral delivery of the encapsulated colicins resulted in a significant decrease in intestinal colonization and reduction in E. coli shedding in the feces of the animals. Employing controlled release drug delivery systems such as that described here is essential to enable delivery of new protein therapeutics or other biological interventions for testing within small animal models of infection. Such approaches may have considerable value for the future development of strategies to engineer the human gut microbiota, which is central to health and disease. </p

Probing the depths of the India-Asia collision : U-Th-Pb monazite chronology of granulites from NW Bhutan

Rocks metamorphosed to high temperatures and/or high pressures are rare across the Himalayan orogen, where peak metamorphic conditions recorded in the exposed metamorphic core, the Greater Himalayan Sequence (GHS), are generally at middle to upper amphibolite facies. However, mafic garnet-clinopyroxene assemblages exposed at the highest structural levels in Bhutan, eastern Himalaya, preserve patchy textural evidence for early eclogite-facies conditions, overprinted by granulite-facies conditions. Monazite hosted within the leucosome of neighboring granulite-facies orthopyroxene-bearing felsic gneiss yields LA-MC-ICP-MS U-Th-Pb ages of 13.9 ± 0.3 Ma. Monazite associated with sillimanite-grade metamorphism in granulite-hosting migmatitic gneisses yields U-Th-Pb rim ages between 15.4 ± 0.8 Ma and 13.4 ± 0.5 Ma. Monazite associated with sillimanite-grade metamorphism in gneiss at structurally lower levels yields U-Pb rim ages of 21–17 Ma. These data are consistent with Miocene exhumation of GHS material from a variety of crustal depths at different times along the Himalayan orogen. We propose that these granulitized eclogites represent lower crustal material exhumed by tectonic forcing over an incoming Indian crustal ramp and that they formed in a different tectonic regime to the ultrahigh-pressure eclogites in the western Himalaya. Their formation and exhumation in the Miocene therefore do not require diachroneity in the timing of the initial India-Asia collision