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We describe an unusual case of indolent peripheral T-cell lymphoma with multifocal involvement of the gastrointestinal tract. The patient, a 42-year-old Asian man, has been followed up for more than 10 years without chemotherapy and multiple gastrointestinal biopsies showing similar findings. Histologically, the neoplasm expanded into the lamina propria and/or focally extended into the submucosa and was composed of small- to medium-sized lymphocytes with slightly irregular nuclear contours and clear cytoplasm and rare large lymphocytes. The tumor cells were positive for CD3, CD8, granzyme B, and TIA-1 (subset) and negative for CD5, CD56, and Epstein-Barr virus-encoded RNA. Molecular studies for T-cell receptor γand/or β chain gene rearrangement demonstrated the same clone at different sites and times during the course of the disease. Rare cases of indolent peripheral T-cell lymphoma of the gastrointestinal tract have been previously described and need to be further characterized to avoid the use of aggressive chemotherapy. [ABSTRACT FROM AUTHOR]

Tubuloglomerular feedback (TGF)-mediated constriction of the afferent arteriole is modulated by a balance between release of superoxide (O2T) and nitric oxide (NO) in macula densa (MD) cells. Aldosterone activates mineralocorticoid receptors that are expressed in the MD and induces both NO and O2- generation. We hypothesize that aldosterone enhances O2- production in the MD mediated by protein kinase C (PKC), which buffers the effect of NO in control of TGF response. Studies were performed in microdissected and perfused MD and in a MD cell line, MMDD1 cells. Aldosterone significantly enhanced O2- generation both in perfused MD and in MMDD1 cells. When aldosterone (10-7 mol/l) was added in the tubular perfusate, TGF response was reduced from 2.4 ± 0.3 μm to 1.4 ± 0.2 μm in isolated perfused MD. In the presence of tempol, a O2- scavenger, TGF response was 1.5 ± 0.2 μm. In the presence of both tempol and aldosterone in the tubular perfusate, TGF response was further reduced to 0.4 ± 0.2 μm. To determine if PKC is involved in aldosterone-induced O2- production, we exposed the O2- cells to a nonselective PKC inhibitor chelerythrine chloride, a specific PKCα inhibitor Go6976, or a PKCα siRNA, and the aldosterone-induced increase in O2- production was blocked. These data indicate that aldosterone-stimulated O2- production in the MD buffers the effect of NO in control of TGF response, an effect that was mediated by PKCα. [ABSTRACT FROM AUTHOR]

Two major factors which regulate tubuloglomerular feedback (TGF)-mediated constriction of the afferent arteriole are release of superoxide (O2-) and nitric oxide (NO) by macula densa (MD) cells. MD O2- inactivates NO; however, among the factors that increase MD O2- release, the role of aldosterone is unclear. We hypothesize that aldosterone activates the mineralocorticoid receptor (MR) on MD cells, resulting in increased O2- production due to upregulation of cyclooxygenase-1 (COX-2) and NOX-2, and NOX-4, isoforms of NAD(P)H oxidase. Studies were performed on MMDD1 cells, a renal epithelial cell line with properties of MD cells. RT-PCR and Western blotting confirmed the expression of MR. Aldosterone (10-8 mol/l for 30 min) doubled MMDD1 cell O2- production, and this was completely blocked by MR inhibition with 10-5 mol/l eplerenone. RT-PCR, real-time PCR, and Western blotting demonstrated aldosterone-induced increases in COX-2, NOX-2, and NOX-4 expression. Inhibition of COX-2 (NS398), NADPH oxidase (apocynin), or a combination blocked aldosterone-induced O2- production to the same degree. These data suggest that aldosterone-stimulated MD O2- production is mediated by COX-2 and NADPH oxidase. Next, COX-2 small-interfering RNA (siRNA) specifically decreased COX-2 mRNA without affecting NOX-2 or NOX-4 mRNAs. In the presence of the COX-2 siRNA, the aldosterone-induced increases in COX-2, NOX-2, and NOX-4 mRNAs and O2- production were completely blocked, suggesting that COX-2 causes increased expression of NOX-2 and NOX-4. In conclusion 1) MD cells express MR; 2) aldosterone increases O2- production by activating MR; and 3) aldosterone stimulates COX-2, which further activates NOX-2 and NOX-4 and generates O2-. The resulting balance between O2- and NO in the MD is important in modulating TGF. [ABSTRACT FROM AUTHOR]

Neuronal nitric oxide synthase (nNOS), which is abundantly expressed in the macula densa cells, attenuates tubuloglomerular feedback (TGF). We hypothesize that splice variants of nNOS are expressed in the macula densa, and nNOS-β is a salt-sensitive isoform that modulates TGF. Sprague-Dawley rats received a low-, normal-, or high-salt diet for 10 days and levels of the nNOS-α, nNOS-β, and nNOS-γ were measured in the macula densa cells isolated with laser capture microdissection. Three splice variants of nNOS, α-, β-, and γ-mRNAs. were detected in the macula densa cells. After 10 days of high-salt intake, nNOS-α decreased markedly, whereas nNOS-β increased two- to threefold in the macula densa measured with real-time PCR and in the renal cortex measured with Western blot, NO production in the macula densa was measured in the perfused thick ascending limb with an intact macula densa plaque with a fluorescent dye DAF-FM When the tubular perfusate was switched from 10 to 80 mM NaCI, a maneuver to induce TGF, NO production by the macula densa was increased by 38 ± 3% in normal-salt rats and 52 ± 6% (P < 0.05) in the high-salt group. We found 1) macula densa cells express nNOS-α, nNOS-β, and nNOS-γ, 2) a high-salt diet enhances nNOS-β, and 3) TGF-induced NO generation from macula densa is enhanced in high-salt diet possibly from nNOS-β. In conclusion, we found that the splice variants of nNOS expressed in macula densa cells were α-. β-, and γ-isoforms and propose that enhanced level of nNOS-β during high-salt intake may contribute to macula densa NO production and help attenuate TGF. [ABSTRACT FROM AUTHOR]

We describe the clinicopathologic features of 15 patients who had histiocytic lesions that followed acute lymphoblastic leukemia (ALL). Twenty-one separate histiocytic lesions were evaluated that covered a wide spectrum, some conforming to the usual categories of juvenile xanthogranulomas (5), Langerhans' cell histiocytosis (1), Langerhans' cell sarcoma (4), Rosai-Dorfman disease (1), and histiocytic sarcoma (4). Most were atypical for the category by histology, phenotype, or abnormally high turnover rate. Seven low-grade lesions defied easy categorization and were characterized only as ''atypical histiocytic lesion'' following ALL. For those evaluated, the molecular signature of the prior leukemia was present in the histiocytic lesion. In 3 of 15 patients, the leukemia and histiocytic lesion shared immunoglobulin H or monoclonal TCR gene rearrangements and, in 4 of 15 patients, clonal identity was documented by fluorescence in situ hybridization. Four patients died of progressive disease, 3 of whom had histiocytic sarcoma and 1 who had an atypical lesion. One patient died of recurrent ALL. The other 10 patients are alive, 7 after recurrences and treatment with surgery and/or chemotherapy. The post- ALL lesions are more aggressive than their native counterparts, but despite the demonstration of the presence of the leukemia signature in 7 of 15 patients, the prognosis is generally favorable, except for patients with histiocytic sarcoma. It remains unclear whether the histiocytic lesions arise as a line from the original ALL or whether transdifferentiation is involved. [ABSTRACT FROM AUTHOR]

Gu JW, Manning RD Jr, Young E, Shparago M, Sartin B, Bailey AP. Vascular endothelial growth factor receptor inhibitor enhances dietary salt-induced hypertension in Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol 297: R142-Rl48, 2009. First published May 6, 2009; doi: 10.1152/ajpregu.90972.2008.-Clinical evidence links the inhibition of VEGF to hypertension. However, the mechanisms by which VEGF affects the pathogenesis of hypertension remain in question. We determined I) whether administration of VEGF receptor inhibitor SU5416 enhances dietary salt-induced hypertension in Sprague-Dawley (SD) rats, and 2) whether VEGF or SU5416 directly affects proliferation of cultured human renal proximal tubular epithelial cells (HRPTEC) and endothelial nitric oxide synthase (eNOS) expression in cultured human glomerular microvesset endothelial cells (HGMEC). Ten 10-wk-old male SD rats received a high sodium diet (HS; 8%) and the other 10 SD rats received a normal sodium diet (NS; 0.5%) for 4 wks. After 2 wks of the dietary program, five rats were administered with SU5416 at 10 mgkg day ip or DMSO (vehicle) for 14 days in HS and NS groups. Mean arterial pressure was significantly higher in rats treated with SU5416, as opposed to those treated with DMSO and fed with HS for 4 wk (157.6 ± 3.9 vs. 125.9 ± 4.3 mmHg, P < 0.01). Increased proteinuria and albuminuria were associated with marked renal histological abnormalities in HS group with SU5416 administration, compared with those in the vehicle HS group. 3H-thymidine incorporation assay showed that SU5416 blocked the actions of both exogenous and endogenous VEGF on the proliferation of HRPTEC. VEOF (10 ng/ml) significantly increased eNOS protein levels by 29% in cultured HGMEC, but its action was completely abolished by SU5416. These results suggest that VEGF receptor inhibition enhances dietary saltinduced hypertension and kidney injury, possibly by direct damage on renal cells and decreasing NO production by eNOS. [ABSTRACT FROM AUTHOR]

The goal of this study was to test the hypothesis that NADPH oxidase contributes importantly to renal cortical oxidative stress and inflammation, as well as renal damage and dysfunction, and increases in arterial pressure. Fifty-four 7- to 8-wk-old Dahl salt-sensitive (S) or R/Rapp strain rats were maintained for 5 wk on a high sodium (8%) or high sodium + apocynin (1.5 mmol/l in drinking water). Arterial and venous catheters were implanted on day 21. By day 35 in the high-Na S rats, mRNA expression of renal cortical gp91phox, p22phox, p47phox, and p67phox NADPH subunits in S rats increased markedly, and treatment of high-Na S rats with the NADPH oxidase inhibitor apocynin resulted in significant decreases in mRNA expression of these NADPH oxidase subunits. At the same time, in apocynin-treated S rats 1) renal cortical GSH/GSSG ratio increased, 2) renal cortical O2 release and NADPH oxidase activity decreased, and 3) renal glomerular and interstitial damage markedly fell. Apocynin also decreased renal cortical monocyte/macrophage infiltration, and apocynin, but not the xanthine oxidase inhibitor allopurinol, attenuated decreases in renal hemodynamics and lowered arterial pressure. These data suggest that NADPH oxidase plays an important role in causing renal cortical oxidative stress and inflammation, which lead to decreases in renal hemodynamics, renal cortical damage, and increases in arterial pressure. [ABSTRACT FROM AUTHOR]

The goal of this study was to test the hypothesis that increases in oxidative stress in Dahi S rats on a high-salt diet help to stimulate renal nuclear factor-κB (NF-κB), renal proinflammatory cytokines, and chemokines, thus contributing to hypertension, renal damage, and dysfunction. We specifically studied whether antioxidant treatment of Dahi S rats on high Na intake would decrease renal inflammation and thus attenuate the hypertensive and adverse renal responses. Sixty-four 7- to 8-wk-old Dahi S or R/Rapp strain rats were maintained for 5 wk on high Na (8%) or high Na + vitamins C (1 g/1 in drinking water) and E (5,000 IU/kg in food). Arterial and venous catheters were implanted at day 21. By day 35 in the high-Na S rats, antioxidant treatment significantly increased the renal reduced-to-oxidized glutathione ratio and decreased renal cortical H2O2 and O2·- release and renal NF-κB. Antioxidant treatment with vitamins C and E in high-Na S rats also decreased renal monocytes/macrophages in the glomeruli, cortex, and medulla, decreased tumor necrosis factor-α by 39%, and decreased monocyte chemoattractant protein-1 by 38%. Vitamin-treated, high-Na S rats also experienced decreases in arterial pressure, urinary protein excretion, renal tubulointerstitial damage, and glomerular necrosis and increases in glomerular filtration rate and renal plasma flow. In conclusion, antioxidant treatment of high-Na Dahi S rats decreased renal inflammatory cytokines and chemokines, renal immune cells, NF-κB, and arterial pressure and improved renal function and damage. [ABSTRACT FROM AUTHOR]

The goal of this study was to test the hypothesis that renal infiltration of immune cells in Dahl S rats on increased dietary sodium intake contributes to the progression of renal damage, decreases in renal hemodynamics, and development of hypertension. We specifically studied whether anti-immune therapy, using mycophenolate mofetil (MMF), could help prevent increases in renal NF-κB activation, renal infiltration of monocytes/macrophages, renal damage, decreases in glomerular filtration rate (GFR) and renal plasma flow, and increases in arterial pressure. Seventy-four 7-to 8-wk-old DahI S, Rapp strain rats were maintained on an 8% Na, 8% Na + MMF (20 mg·kg-1·day-1), 0.3% Na, or 0.3% Na + MMF diet for 5 wk. Arterial and venous catheters were implanted at day 21. By day 35, renal NF-κB in 8% Na rats was 47% higher than in 0.3% Na rats and renal NF-κB was 41% lower in 8% Na + MMF rats compared with the 8% Na group. MMF treatment significantly decreased renal monocyte/macrophage infiltration and renal damage and increased GFR and renal plasma flow. In high-NA DahI S rats mean arterial pressure increased to 1 82 ± 5 mmHg, and MMF reduced this arterial pressure to 124 ± 3 mmHg. In summary, in DahI S rats on high sodium intake, treatment with MMF decreases renal NF-κB and renal monocyte/macrophage infiltration and improves renal function, lessens renal injury, and decreases arterial pressure. This suggests that renal infiltration of immune cells is associated with increased arterial pressure and renal damage and decreasing GFR and renal plasma flow in DahI salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Molecular mechanisms of salt-sensitive (SS) hypertension related to renal inflammation have not been defined. We seek to determine whether a high-salt (HS) diet induces renal activation of NF-κB and upregulation of TNF-α related to the development of hypertension in Dahl SS rats. Six 8-wk-old male Dahl SS rats received a HS diet (4%), and six Dahl SS rats received a low-sodium diet (LS, 0.3%) for 5 wk. In the end, mean arterial pressure was determined in conscious rats by continuous monitoring through a catheter placed in the carotid artery. Mean arterial pressure was significantly higher in the HS than the LS group (177.9 ± 3.7 vs. 109.4 ± 2.9 mmHg, P < 0.001). There was a significant increase in urinary albumin secretion in the HS group compared with the LS group (22.3 ± 2.6 vs. 6.1 ± 0.7 mg/day; P < 0.001). Electrophoretic mobility shift assay demonstrated that the binding activity of NF-κB p65 proteins in the kidneys of DahI SS rats was significantly increased by 53% in the HS group compared with the LS group (P = 0.007). ELISA indicated that renal protein levels of TNF-α, but not IL-6, interferon-γ, and CCL28, were significantly higher in the HS than the LS group (2.3 ± 0.8 vs. 0.7 ± 0.2 pg/mg; P = 0.036). We demonstrated that plasma levels of TNF-α were significantly increased by fivefold in Dahl SS rats on a HS diet compared with a LS diet. Also, we found that increased physiologically relevant sodium concentration (10 mmol/l) directly stimulated NF-κB activation in cultured human renal proximal tubular epithelial cells. These findings support the hypothesis that activation of NF-κB and upregulation of TNF-α are the important renal mechanisms linking proinflammatory response to SS hypertension. [ABSTRACT FROM AUTHOR]

Changes in the microbial community during bioremediation of explosives-contaminated soil in a molasses-fed bioslurry process were examined. Upon addition of molasses to laboratory-scale reactors, total culturable heterotrophs increased rapidly by three to four orders of magnitude. However, heat-shocked heterotrophs and the percentage of gram-positive bacterial isolates did not increase until the soluble concentrations of 2,4,6-trinitrotoluene (TNT) and 2,4,6-trinitrobenzene (TNB) began to decrease. The number of identified phospholipid fatty acids (PLFA) and the total PLFA concentration also exhibited an immediate increase in response to molasses addition, while the concentration of branched PLFA, indicative of the gram-positive population, remained low until soluble TNT and TNB concentrations had significantly decreased. This same general relationship between explosives degradation and gram-positive-specific PLFA was observed during an experiment with a large field-scale bioslurry lagoon reactor. These results indicate that the gram-positive organisms, which have been shown to be severely impacted by even low concentrations of TNT and TNB [Current Microbiol. 35 (1997) 77; Environ. Toxicol. Chem. 17 (1998) 2185], are able to increase in concentrations after explosives compounds are reduced to non-inhibitory levels, and should therefore be able to reestablish themselves in remediated soils. [Copyright &y& Elsevier]

Oxidative stress occurs in a tissue or in the whole body when the total oxidant production exceeds the antioxidant capacity. Recent studies in human essential hypertension indicate that free radical production is increased and antioxidant levels are decreased, and more than one-half of these hypertensives have a salt-sensitive type of hypertension with progressive renal damage. Increased oxidative stress may also play a critical role in animal models of salt-sensitive hypertension. The stroke-prone spontaneously hypertensive rats (SHRSP) exhibits salt-sensitivity, vascular release of superoxide is increased, and total plasma antioxidant capacity is decreased. The superoxide release in the SHRSP rats inactivates nitric oxide, and superoxide dismutase (SOD) administration returns the bioactive nitric oxide levels to normal. The deoxycorticosterone acetate (DOCA)-salt hypertensive rat is salt-sensitive, aortic superoxide production is increased, and renal inflammation is significant. Treatment of the DOCA-salt rats with apocynin, an NADPH oxidase inhibitor, decreased aortic superoxide production and decreased arterial pressure. The Dahl salt-sensitive (S) rat has increased mesenteric microvascular and renal superoxide production and increased plasma levels of H2O2. The renal protein expression of SOD is decreased in the kidney of Dahl S rats, and long-term administration of Tempol, a superoxide mimetic, significantly decreased arterial pressure and renal damage. In conclusion, both human hypertension and experimental models of salt-sensitive hypertension have increased superoxide release, decreased antioxidant capacity and elevated renal damage. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine the role of renal medullary inducible nitric oxide synthase (iNOS) in the arterial pressure, renal hemodynamic, and renal excretory changes that occur in Dahl/Rapp saltresistant (R) and salt-sensitive (S) rats during high Na intake. Forty R and S rats, equipped with indwelling arterial, venous, and renal medullary catheters, were subjected to high (8%) Na intake, and selective iNOS inhibition was achieved with continuous intravenous or renal medullary interstitial infusion of aminoguanidine (AG; 3.075 mg·kg[sup -1]·h[sup -1]). After 5 days of AG, mean arterial pressure increased to 132 ± 2% control in the S rats with high Na intake and intramedullary AG compared with 121 ± 4% control (P < 0.05) in the S rats with high Na intake alone and 121 ± 2% control (P < 0.05) in the S rats with high Na intake and intravenous AG. AG did not change arterial pressure in R rats. AG also caused little change in renal hemodynamics, urinary Na, or H[sub 2]O excretion or AChinduced aortic vasorelaxation in R or S rats. The data suggest that during high Na intake, nitric oxide produced by renal medullary iNOS helps to prevent excessive increases in arterial pressure in the Dahl S rat but not the R rat. [ABSTRACT FROM AUTHOR]

The roles of oxidative stress and renal superoxide dismutase (SOD) levels and their association with renal damage were studied in Dahl salt-sensitive (S) and salt-resistant (R)/Rapp strain rats during changes in Na intake. After 3 wk of a high (8%)-Na diet in S rats, renal medullary Cu/Zn SOD was 56% lower and Mn SOD was 81% lower than in R high Na-fed rats. After 1, 2, and 3 wk of high Na, urinary excretion of F[sub 2]-isoprostanes, an index of oxidative stress, was significantly greater in S rats compared with R rats. Plasma F[sub 2]isoprostane concentration increased in the 2-wk S high Na-fed group. After 3 wk, renal cortical and medullary superoxide production was significantly increased in Dahl S rats on high Na intake, and urinary protein excretion, an index of renal damage, was 273 ± 32 mg/d in S high Na-fed rats and 35 ± 4 mg/d in R high Na-fed rats (P < 0.05). In conclusion, salt-sensitive hypertension in the S rat is accompanied by marked decreases in renal medullary SOD and greater renal oxidative stress and renal damage than in R rats. [ABSTRACT FROM AUTHOR]

Focuses on a study which analyzed criminal cases in the U.S. involving the Allen charge, a supplemental jury instruction issued by a federal judge, appealed from 1964 to March 1999. Origin of the Allen charge; Methodology of the study; Facts about the defendants' gender and race; Data on mean jury deliberation time prior to the issuance of the Allen charge; Types of crime committed.

Examines the effect of multiple-source drug entry on price competition after patent expiration in the pharmaceutical industry. Increase in the originator's prices after patent expiration; Decline in the price of and increase in sales of multiple-source drugs; Benefits derived from off-patented market by pharmaceutical consumers.