The purpose of these studies was to test the hypothesis that Randall's plaque develops in unique anatomical sites of the kidney and their formation is conditioned by specific stone-forming ...pathophysiologies. We performed intraoperative papillary biopsies from kidneys of idiopathic-calcium oxalate (CaOx), intestinal bypass for obesity, brushite (BR) and cystine stone formers (SF) during percutaneous nephrolithotomy. Tissues were examined by infrared analysis and light and electron microscopy. Our analysis revealed a distinct pattern of mineral deposition and papillary pathology for each type of SF. CaOx SF had interstitial apatite crystals beginning at thin loops of Henle. These deposits termed Randall's plaque are thought to serve as sites for stone attachment. No tubular injury was noted. Intestinal bypass patients possessed intraluminal apatite deposits in inner medullary collecting ducts (IMCD) with associated cell injury. BR SF showed the most severe form of cortical and medullary changes with sites of Randall's plaque, and yellowish intraluminal deposits of apatite in IMCD. Cystine SF had plugging of ducts of Bellini with cystine crystals and apatite deposits in IMCD and loops of Henle. Intratubular sites of crystalline deposits were always associated to adjacent regions of interstitial fibrosis. The metabolic, anatomic, and surgical pathologic findings in four distinct groups of SF clearly show that ‘the histology of the renal papilla from a stone former, is particular to the clinical setting’. We believe our approach to studying stone disease will provide insights into the pathogenesis of stone formation for each type of SF that will lead to improved clinical treatment.
We have biopsied the papillae of patients who have cystine stones asking if this stone type is associated with specific tissue changes. We studied seven cystine stone formers (SF) treated with ...percutaneous nephrolithotomy using digital video imaging of renal papillae for mapping and obtained papillary biopsies. Biopsies were analyzed by routine light and electron microscopy, infrared spectroscopy, electron diffraction, and micro-CT. Many ducts of Bellini (BD) had an enlarged ostium, and all such were plugged with cystine crystals, and had injured or absent lining cells with a surrounding interstitium that was inflamed to fibrotic. Crystal plugs often projected into the urinary space. Many inner medullary collecting ducts (IMCD) were dilated with or without crystal plugging. Apatite crystals were identified in the lumens of loops of Henle and IMCD. Abundance of interstitial Randall's plaque was equivalent in amount to that of non-SF. In the cortex, glomerular obsolescence and interstitial fibrosis exceeded normal. Cystine crystallizes in BD with the probable result of cell injury, interstitial reaction, nephron obstruction, and with the potential of inducing cortical change and loss of IMCD tubular fluid pH regulation, resulting in apatite formation. The pattern of IMCD dilation, and loss of medullary structures is most compatible with such obstruction, either from BD lumen plugs or urinary tract obstruction from stones themselves.
The Fermilab KTeV experiment has searched for lepton-flavor-violating decays of the K(L) meson in three decay modes. We observe no events in the signal region for any of the modes studied, and we set ...the following upper limits for their branching ratios at the 90% C.L.: BR(K(L) --> pi(0) micro(+/-) e(-/+)) <7.6 x 10(-11); BR(K(L) --> pi(0)pi(0) micro(+/-) e(-/+)) <1.7 x 10(-10); BR(pi(0) --> micro(+/-) e(-/+)) <3.6 x 10(-10). This result represents a factor of 82 improvement in the branching ratio limit for K(L) --> pi(0) micro(+/-) e(-/+) and is the first reported limit for K(L) --> pi(0)pi(0) micro(+/-) e(-/+).
Course-based undergraduate research experiences (CUREs) introduce research leading to skills acquisition and increased persistence in the major. CUREs generate enthusiasm and interest in doing ...science and serve as an intervention to increase equity and participation of historically marginalized students. In the second-semester laboratory of our introductory sequence for biology and marine science majors at California State University Monterey Bay (CSUMB), instructors updated and implemented a field-based CURE. The goals of the CURE were to promote increased scientific identity, systems thinking, and equity at a Hispanic-serving institution (HSI). Through the CURE, students engaged in scientific writing through a research paper with a focus on information literacy, critical thinking, and quantitative reasoning as important elements of thinking like a scientist. Course exams also revealed that students showed gains in their ability to evaluate a new biological system using systems thinking. More broadly, because such field-based experiences demonstrate equity gains among Latinx students and a much greater sense of scientific identity, they may have impacts beyond introductory biology including in students' personal and professional lives.
Inter-α-trypsin inhibitor heavy-chain proteins bind to the protease inhibitor bikunin and to hyaluronan, stabilizes extracellular matrix in various tissues, and also inhibits calcium oxalate ...crystallization in vitro. In both normal and stone-forming patients, we found heavy chain 3 and hyaluronan in the interstitial matrix of the kidney. Osteopontin was found in the collecting duct, thin loop of Henle, and urothelial cells. In stone formers, heavy chain 3 was also present in collecting duct, thin loop, and interstitial cells. Heavy chain 3 and osteopontin colocalized in plaque matrix and urothelial cells. Within individual plaque spherules, heavy chain 3 was found in the matrix layer while osteopontin was located along the crystal–matrix interface. Bikunin was present only in the collecting duct apical membranes and the loop cell cytoplasm of stone formers colocalizing with osteopontin and heavy chain 3. Widespread heavy chain 3 was only present in stone formers, whereas osteopontin was similarly expressed in normal and stone-forming subjects except for its localization in plaques of the stone formers. This is consistent with studies linking inter-α-trypsin inhibitor components to human stone disease, although their role is still unclear. Heavy chain 3 may also play a role in stabilizing hyaluronan in the renal interstitial matrix.
To define the renal tissue changes in stone-forming patients with distal renal tubular acidosis (dRTA), we performed intra-operative papillary and cortical biopsies in five patients. The main ...abnormalities were plugging of inner medullary collecting ducts (IMCD) and Bellini ducts (BD) with deposits of calcium phosphate in the form of apatite; epithelial cell injury and loss was marked. Plugged ducts were surrounded by interstitial fibrosis, but the fibrosis was generalized, as well, and was a main feature of the histopathology even when plugging was not present. In contrast, common idiopathic calcium oxalate stone formers (SF) never manifest intra-tubule crystals or interstitial fibrosis. Patients with brushite (calcium monohydrogen phosphate) stones and those with cystine stones have many fewer IMCD and BD plugged with apatite (or cystine, in cystinuria), and interstitial fibrosis is limited to the regions around plugged ducts. Patients with dRTA often present a radiographic picture of nephrocalcinosis. Our direct surgical observations reveal that these may be surgically removable stones, especially in patients with well preserved renal function. In all, dRTA SF have a more diffuse papillary renal disease than other SF thus studied, and are also unusual for the degree of interstitial fibrosis.
Control of calcium oxalate crystal structure and cell adherence by urinary macromolecules. Crystal polymorphism is exhibited by calcium oxalates in nephrolithiasis, and we have proposed that a shift ...in the preferred crystalline form of calcium oxalate (CaOx) from monohydrate (COM) to dihydrate (COD) induced by urinary macromolecules reduces crystal attachment to epithelial cell surfaces, thus potentially inhibiting a critical step in the genesis of kidney stones. We have tested the validity of this hypothesis by studying both the binding of monohydrate and dihydrate crystals to renal tubule cells and the effect of macromolecular urinary solutes on crystal structure. Renal tubule cells grown in culture bound 50% more CaOx monohydrate than dihydrate crystals of comparable size. The effects of macromolecules on the spontaneous nucleation of CaOx were examined in HEPES-buffered saline solutions containing Ca2+ and C2O42- at physiologic concentrations and supersaturation. Many naturally occurring macromolecules known to be inhibitors of crystallization, specifically osteopontin, nephrocalcin and urinary prothrombin fragment 1, were found to favor the formation of calcium oxalate dihydrate in this in vitro system, while other polymers did not affect CaOx crystal structure. Thus, the natural defense against nephrolithiasis may include impeding crystal attachment by an effect of macromolecular inhibitors on the preferred CaOx crystal structure that forms in urine.
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