A dynamic model for the evolution of protein structure

Protein domains are three-dimensional arrangements of atomic structure that are recurrent in the proteomes of organisms. Since the three-dimensional structure of a protein determines its function, it is the fold, much more than the underlying protein sequence and underlying chemistry, that is evolutionarily conserved. We are interested in probing the history of life with these domain structures and glimpsing qualitative changes over time by studying a dynamic model of protein evolution. Using standard phylogenetic methods and a census of protein domain structure in hundreds of genomes, we have reconstructed phylogenetic trees of protein domains, defined using the Structural Classification of Proteins (SCOP), where the nodes are folds or fold superfamilies (FSFs), the character vector for each node is a list of abundances of said fold or FSF across a range of species that spans all three superkingdoms of life, and the character states are linearly polarized by abundance; higher abundance within and among species equates to older structures and determines tree structure. Here we explore at what rate fold or FSF variants and new folds or FSFs appear in evolution. We also explore what collective model of proteome evolution explains such rates. Briefly, what are the dynamics of change? A set of birth-death differential equations was selected to capture the change of interest, with one set for folds and another for FSFs. The models assume that at any given moment there are a certain number of different folds or FSFs, with various abundances, and as each fold or FSF diversifies there are slight changes in the folds or FSFs, producing fold or FSF variants. Eventually as the variants continue to diversify and change as well, a new fold or FSF is born. Thus, there are two rate parameters in each model: the growth rate of fold or FSF variants and the rate of appearance of new folds or FSFs. The model governs the rate change of the average total abundance of a fold or FSF with time. It is fit to the tree so only those fold or FSF transitions actually present in the tree are assumed possible in the equations. It assumes a global perspective: the total abundance of a fold or FSF is that of the fold or FSF across all species, not within one organism. This perspective is used to properly discount terms of horizontal transfer in a birth-death model since such a transfer contributes no new folds or FSFs to the net abundance across all organisms. Our model determines 1) that there is a tight connection between the history of folds and FSFs, 2) that the corresponding transition probabilities to new variants of a fold experienced a sharp increase just as the transition probabilities to new folds experienced a steep decline and 3) that this simultaneous sharp increase and decline is explainable by and consistent with the combinatorial explosion of structural domains, referring to the period of high combination and rearrangement of domains and distribution of these new combinations in novel lineages, and the rise of organismal diversification. Our simulations suggest a picture of the past in which exploration of protein structure space proceeds much like that of a budding field of knowledge: first, coarse grain discoveries are made, followed by fine-grain elaboration of each once the coarse-grain discoveries have been exhausted

Amiodarone-induced Loculated Pleural Effusion Without Pulmonary Parenchymal Involvement: a Case Report and Literature Review

Amiodarone is an extremely effective antiarrhythmic drug that is known to cause many adverse effects such as pulmonary, thyroid, and liver toxicities. Of these, pulmonary toxicity is most serious. Pulmonary toxicity can present as interstitial pneumonitis, organizing pneumonia, pulmonary nodules and masses, and very rarely pleural effusions. We present a case of a 73-year-old male who presented with progressive exertional dyspnea, nonproductive cough, generalized fatigue, and weakness. He was found to have multiorgan toxicity secondary to long-term treatment with high doses of amiodarone. This case illustrates that amiodarone may cause toxicity involving multiple organs simultaneously in patients receiving long-term therapy and represents the first reported case of amiodarone-induced loculated pleural effusion without associated lung parenchymal involvement

Value of Neutrophil to Lymphocyte Ratio as a Predictor of Mortality in Patients Undergoing Aortic Valve Replacement

Background: Neutrophil to lymphocyte ratio (NLR) has been studied as a measure of inflammation and as a prognosticating factor in various medical conditions including neoplastic, inflammatory and cardiovascular. The prognostic role of NLR in predicting mortality in patients with aortic stenosis undergoing surgical aortic valve replacement (AVR) has not been studied. The aim of our study is to explore the utility of NLR as a predictor of both, short and long-term mortality, in patients undergoing surgical AVR. Methods: Consecutive patients with aortic stenosis admitted for AVR to our institution were evaluated for study inclusion. Of the 335 patients admitted from January 2007 to September 2011, 234 met study inclusion criteria. Patients were divided into two groups depending on their initial preoperative NLR level with a cutoff value of 3. Three-year vital status was accessed with electronic medical records and Social Security Death Index. Survival analysis, stratified by NLR, was used to evaluate the predictive value of preoperative NLR levels. Results: Patients with NLR \u3e/=3, when compared to those with NLR /=3 had 4.77 fold increase in 3-year mortality (1.48-15.32, P=0.0090). Conclusions: NLR is an independent predictor of short-term and long-term mortality in patients with aortic stenosis undergoing AVR surgery, especially those with NLR \u3e/=3. We strongly suggest the use of NLR as a tool to risk stratify patients with aortic stenosis undergoing AVR surgery

Left ventricular noncompaction diagnosed following Graves′ disease

Isolated left ventricular noncompaction (LVNC) is a rare genetic cardiomyopathy. Clinical manifestations are variable; patients may present with heart failure symptoms, arrhythmias, and systemic thromboembolism. However, it can also be asymptomatic. When asymptomatic, LVNC can manifest later in life after the onset of another unrelated condition. We report a case of LVNC which was diagnosed following a hyperthyroid state secondary to Graves′ disease. The association of LVNC with other noncardiac abnormalities including neurological, hematological, and endocrine abnormalities including hypothyroidism has been described in isolated case reports before. To the best of our knowledge, this is the first reported case of LVNC diagnosed following exacerbation in contractile dysfunction triggered by Graves′ disease

Amiodarone Induced Myxedema Coma: Two Case Reports and Literature Review

Amiodarone is a benzofuran derivative that contains 37% iodine by weight and is structurally similar to the thyroid hormones. Amiodarone has a complex effect on the thyroid gland, ranging from abnormalities of thyroid function tests to overt thyroid dysfunction, with either thyrotoxicosis or hypothyroidism. Myxedema coma secondary to amiodarone use has been rarely reported in the literature. Our two case reports are an add on to the literature, and illustrate that amiodarone is an important cause of thyroid dysfunction including hypothyroidism and myxedema coma. Hence, healthcare providers should have a high index of suspicion for these conditions while treating patients who are taking amiodarone therapy as early recognition and management are essential to optimize outcomes

Spontaneous rupture of hepatocellular carcinoma

This is a very interesting case of a 64-year-old female with a history of chronic hepatitis C infection, with abdominal pain and was found to have ruptured hepatocellular carcinoma (HCC). She was managed with the two-stage therapeutic approach first using transarterial embolization to provide adequate hemostasis and then surgical resection with an excellent outcome. This case report exemplifies the importance of early diagnosis and treatment of ruptured HCC

Skin rash, eosinophilia, and renal impairment in a patient recently started on allopurinol

Allopurinol is a hypoxanthine analog which inhibits xanthine oxidase, it is a widely used medication for the treatment of hyperuricemia and gout. Allopurinol-induced drug-induced rash with eosinophilia and systemic symptoms syndrome is an infrequent, life-threatening adverse reaction of allopurinol therapy that is remarkable for the higher mortality rate with the use of allopurinol than with the use of another agent. We present a case of a 62-year-old male with a history of chronic kidney disease stage 3, hypertension and gout who developed skin rash, eosinophilia, and renal impairment 2 weeks after he was started on allopurinol therapy for gout. Allopurinol was stopped, and the patient was started on steroids. This case emphasizes that although allopurinol is commonly used the drug for the treatment of gout. However, it can be associated with serious life-threatening complications. Therefore, care should be taken when prescribing allopurinol, and it should be prescribed only for the appropriate indications

Warfarin-induced leukocytoclastic vasculitis and proteinuria

Warfarin is typically prescribed for patients with thromboembolic diseases and atrial fibrillation. In addition to the complications of bleeding, allergic skin reaction is one of its rare adverse effects. We herein report a case of a 79 year old male patient with leukocytoclastic vasculitis and proteinuria secondary to warfarin. The warfarin was discontinued and oral prednisone therapy was initiated. The cutaneous lesions and the proteinuria resolved thereafter