Quantitative Renal Vascular Casting in Nephrology Research

The present paper describes the use of a quantitative renal vascular casting method to study the changes associated with kidney disease. Several animal models of hypertension (spontaneously hypertensive rat, SHR, with its normotensive rat the Wistar Kyoto, WKY; Dahl salt sensitive DS - hypertensive, and salt resistant DR -normotensive) were examined at time points when the systemic blood pressure was rising (6 and 12 weeks of age) and following renal denervation (in SHR-WKY rats). The SHR appears to have a smaller caliber afferent arteriole at both 6 and 12 weeks of age. This difference is probably not entirely due to sympathetic vasoconstriction since the strain related afferent arteriolar diameter difference was still present after renal denervation. In the Dahl rats, there is not much of an intrarenal vascular difference between the DS and DR rats with the only real finding of a smaller distal afferent arteriolar diameter found in outer cortical nephrons of the DR. The two models of acute renal failure (ARF) that were studied include, a) the glycerol model (known to initially cause an intense vasoconstriction) and b) gentamicin, a nephrotoxic antibiotic. Two time points were examined for each of these models. As expected in the glycerol model there was an intense vasoconstriction at three hours which essentially was gone at 3 days-a time when the renal failure was fulminant. The glomerulus appeared to be contracted at three hours as well. In the gentamicin model no renal vascular alteration was seen at 6 days, when renal failure was mild while at 10 days, when renal failure was pronounced, outer cortical afferent arterioles appeared to be moderately constricted. In the 5/6 nephrectomy model of chronic renal failure, the glomeruli were smaller in rats in renal failure than in the controls

On Predictive Modeling for Optimizing Transaction Execution in Parallel OLTP Systems

A new emerging class of parallel database management systems (DBMS) is designed to take advantage of the partitionable workloads of on-line transaction processing (OLTP) applications. Transactions in these systems are optimized to execute to completion on a single node in a shared-nothing cluster without needing to coordinate with other nodes or use expensive concurrency control measures. But some OLTP applications cannot be partitioned such that all of their transactions execute within a single-partition in this manner. These distributed transactions access data not stored within their local partitions and subsequently require more heavy-weight concurrency control protocols. Further difficulties arise when the transaction's execution properties, such as the number of partitions it may need to access or whether it will abort, are not known beforehand. The DBMS could mitigate these performance issues if it is provided with additional information about transactions. Thus, in this paper we present a Markov model-based approach for automatically selecting which optimizations a DBMS could use, namely (1) more efficient concurrency control schemes, (2) intelligent scheduling, (3) reduced undo logging, and (4) speculative execution. To evaluate our techniques, we implemented our models and integrated them into a parallel, main-memory OLTP DBMS to show that we can improve the performance of applications with diverse workloads.Comment: VLDB201

Idiopathic hypercalciuria and formation of calcium renal stones

The most common presentation of nephrolithiasis is idiopathic calcium stones in patients without systemic disease. Most stones are primarily composed of calcium oxalate and form on a base of interstitial apatite deposits, known as Randall’s plaque. By contrast some stones are composed largely of calcium phosphate, as either hydroxyapatite or brushite (calcium monohydrogen phosphate), and are usually accompanied by deposits of calcium phosphate in the Bellini ducts. These deposits result in local tissue damage and might serve as a site of mineral overgrowth. Stone formation is driven by supersaturation of urine with calcium oxalate and brushite. The level of supersaturation is related to fluid intake as well as to the levels of urinary citrate and calcium. Risk of stone formation is increased when urine citrate excretion is 200 mg per day also increase stone risk and often result in negative calcium balance. Reduced renal calcium reabsorption has a role in idiopathic hypercalciuria. Low sodium diets and thiazide-type diuretics lower urine calcium levels and potentially reduce the risk of stone recurrence and bone disea

Exposure of Vascular Smooth Muscle Cells for Analysis with the Scanning Electron Microscope

There has been interest in using the scanning electron microscope (SEM) to study the structure of tissues obscured by other cellular or non-cellular elements almost since the SEM was first used to examine biological tissues. Such interest includes the vessel wall and, in particular, the vascular smooth muscle cells. This paper presents a review of the three basic methodologies that have been employed to allow examination of the vascular smooth muscle, 1) blunt dissection, 2) digestion and 3) microdissection. Discussion of other perivascular elements was not a focus of this review. Also presented is the application of these different methodologies to different pathophysiologic conditions

Hyperplasia and Fluid Accumulation in Epithelial Cyst Formation and Growth

Epithelial cysts may develop in virtually any epithelium. All cysts, regardless of their origins, are characterized by epithelial hyperplasia and fluid accumulation. Additional features may include tubular atrophy, basement membrane alterations and association with inflammatory cells. In spite of the intense research effort in recent years directed at uncovering the cellular mechanisms of cyst development and growth, we still do not know the primary events that lead to cyst formation. However, there are at least three candidate mechanisms. These include: 1) increased cell proliferation (epithelial hyperplasia) in the cyst wall, 2) net fluid accumulation in the cyst cavity and 3) alterations of extracellular matrix components linked to cyst formation and growth. This review discusses the evidence to support the role of each mechanism as a possible primary event necessary for cyst initiation and continued enlargement. Present data on the pathogenesis of epithelial cyst formation strongly suggests that no single mechanism, as yet described, can adequately account for all situations of cyst occurrence

Integration and utilization of modern technologies in nephrolithiasis research

Nephrolithiasis, or stones, is one of the oldest urological diseases, with descriptions and treatment strategies dating back to ancient times. Despite the enormous number of patients affected by stones, a surprising lack of conceptual understanding of many aspects of this disease still exists. This lack of understanding includes mechanisms of stone formation and retention, the clinical relevance of different stone compositions and that of formation patterns and associated pathological features to the overall course of the condition. Fortunately, a number of new tools are available to assist in answering such questions. New renal endoscopes enable kidney visualization in much higher definition than was previously possible, while micro-CT imaging is the optimal technique for assessment of stone microstructure and mineral composition in a nondestructive fashion. Together, these tools have the potential to provide novel insights into the aetiology of stone formation that might unlock new prevention and treatment strategies, and enable more effective management of patients with nephrolithiasis

Influenza D virus M2 protein exhibits ion channel activity in Xenopus laevis oocytes

A new type of influenza virus, known as type D, has recently been identified in cattle and pigs. Influenza D virus infection in cattle is typically asymptomatic; however, its infection in swine can result in clinical disease. Swine can also be infected with all other types of influenza viruses, namely A, B, and C. Consequently, swine can serve as a mixing vessel for highly pathogenic influenza viruses, including those with zoonotic potential. Currently, the only antiviral drug available targets influenza M2 protein ion channel is not completely effective. Thus, it is necessary to develop an M2 ion channel blocker capable of suppressing the induction of resistance to the genetic shift. To provide a basis for developing novel ion channel- blocking compounds, we investigated the properties of influenza D virus M2 protein (DM2) as a drug target

Decapodes: A Diagrammatic Tool for Representing, Composing, and Computing Spatialized Partial Differential Equations

We present Decapodes, a diagrammatic tool for representing, composing, and solving partial differential equations. Decapodes provides an intuitive diagrammatic representation of the relationships between variables in a system of equations, a method for composing systems of partial differential equations using an operad of wiring diagrams, and an algorithm for deriving solvers using hypergraphs and string diagrams. The string diagrams are in turn compiled into executable programs using the techniques of categorical data migration, graph traversal, and the discrete exterior calculus. The generated solvers produce numerical solutions consistent with state-of-the-art open source tools as demonstrated by benchmark comparisons with SU2. These numerical experiments demonstrate the feasibility of this approach to multiphysics simulation and identify areas requiring further development

Mechanisms of human kidney stone formation

The precise mechanisms of kidney stone formation and growth are not completely known, even though human stone disease appears to be one of the oldest diseases known to medicine. With the advent of the new digital endoscope and detailed renal physiological studies performed on well phenotyped stone formers, substantial advances have been made in our knowledge of the pathogenesis of the most common type of stone former, the idiopathic calcium oxalate stone former as well as nine other stone forming groups. The observations from our group on human stone formers and those of others on model systems have suggested four entirely different pathways for kidney stone formation. Calcium oxalate stone growth over sites of Randall's plaque appear to be the primary mode of stone formation for those patients with hypercalciuria. Overgrowths off the ends of Bellini duct plugs have been noted in most stone phenotypes, do they result in a clinical stone? Micro-lith formation does occur within the lumens of dilated inner medullary collecting ducts of cystinuric stone formers and appear to be confined to this space. Lastly, cystinuric stone formers also have numerous small, oval, smooth yellow appearing calyceal stones suggestive of formation in free solution. The scientific basis for each of these four modes of stone formation are reviewed and used to explore novel research opportunities

Prospective Phase II trial of drug-eluting bead chemoembolization for liver transplant candidates with hepatocellular carcinoma and marginal hepatic reserve.

Purpose: To determine whether chemoembolization using drug-eluting beads (DEB-TACE) is safe and effective for liver transplantation candidates with liver-limited hepatocellular carcinoma (HCC) without vascular invasion and baseline hepatic dysfunction. Materials and methods: Seventeen adult liver transplantation candidates (median age 66 years, range 58-73 years; 13 men) with HCC were treated with DEB-TACE as a part of Stage 1 of a prospective single-institution Phase II trial. All patients had marginal hepatic reserve based on at least one of the following criteria: ascites (n=14), bilirubin between 3 and 6 mg/dL (n=5), AST 5-10 times upper normal limit (n=1), INR between 1.6 and 2.5 (n=4), portal vein thrombosis (n=2), and/or portosystemic shunt (n=2). Primary study objectives were safety and best observed radiographic response. Results: Thirty-seven DEB-TACE procedures were performed. Objective response rate and disease control rate were 63% and 88%, respectively. HCC progression was observed in 12 patients. Median time to progression was 5.6 months (range 0.9-13.6 months). Within 1 month following DEB-TACE, 13 patients (76%) developed grade 3 or 4 AE attributable to the procedure. Four patients (all within Milan Criteria) were transplanted (2.7-6.9 months after DEB-TACE), and 12 patients died (1.8-32 months after DEB-TACE). All deaths were due to liver failure that was either unrelated to HCC (n=5), in the setting of metastatic HCC (n=5), or in the setting of locally advanced HCC (n=2). Mortality rate at 1 month was 0%. Conclusions: DEB-TACE achieves tumor responses but carries a high risk of hepatotoxicity for liver transplant candidates with HCC and marginal hepatic reserve