A transient radio source consistent with a merger-triggered core collapse supernova.

A core collapse supernova occurs when exothermic fusion ceases in the core of a massive star, which is typically caused by exhaustion of nuclear fuel. Theory predicts that fusion could be interrupted earlier by merging of the star with a compact binary companion. We report a luminous radio transient, VT J121001+495647, found in the Very Large Array Sky Survey. The radio emission is consistent with supernova ejecta colliding with a dense shell of material, potentially ejected by binary interaction in the centuries before explosion. We associate the supernova with an archival x-ray transient, which implies that a relativistic jet was launched during the explosion. The combination of an early relativistic jet and late-time dense interaction is consistent with expectations for a merger-driven explosion.

Identification of a contractile function for renal medullary interstitial cells.

Renomedullary interstitial cells (RMIC) are unique to the renal medulla. By virtue of their anatomic location and arrangement, RMIC may hinder axial dissipation of the concentration gradient, thereby aiding urinary concentration. A more active role in urinary concentration has been postulated on the basis of speculations about RMIC contractile potential, however, RMIC contraction has not been investigated. To determine if these cells are contractile, cultured rat RMIC were exposed to endothelin-1 (ET-1), a potent vasoconstrictor which binds to RMIC, and examined using video microscopy. ET-1 (as low as 10 pM) caused a slowly developing and dose-dependent reduction in RMIC surface area. ET-1 markedly increased the number and intensity of F-actin microfilament staining. ET-1-induced RMIC contraction was not altered by nifedipine, was partially reduced by nickel, and was completely inhibited by H7, indicating that ET-1 action is mediated by protein kinase C and is partially dependent upon receptor-operated calcium channels. The ET-1 effect does not involve nitric oxide since NG-monomethyl-L-arginine did not alter ET-1-induced RMIC contraction; in addition, ET-1 had only a minor effect on cGMP levels and no effect on nitrite production. PGE2 acts in an autocrine manner to dampen ET action since indomethacin potentiates, while PGE2 inhibits, ET-1-induced RMIC contraction. The contractile response is not unique to ET-1 since vasopressin also reduces RMIC surface area and increases F-actin microfiliment staining. These studies demonstrate that RMIC in culture are contractile. The possibility is raised that contraction of RMIC plays a role in modifying urinary concentration as well as regulation of other renal medullary functions.

Alterations in renal endothelin-1 production in the spontaneously hypertensive rat.

Endothelin-1 inhibits sodium and water transport systems in the inner medullary collecting duct. Endothelin-1 levels are reduced in the medulla of spontaneously hypertensive rats (SHR), raising the possibility that decreased inner medullary collecting duct production of endothelin-1 could contribute to inappropriate sodium and water retention. In the current study, immunoreactive endothelin-1 was measured in the urine, blood, and eluates from cortex and outer and inner medulla of SHR before (age 3-4 weeks) and after (age 8-9 weeks) the development of hypertension and in age-matched Wistar-Kyoto (WKY) controls. There was no difference in endothelin-1 levels between prehypertensive SHR and WKY rats. In contrast, 8-9-week-old SHR had significantly reduced endothelin-1 in the urine and outer and inner medulla, but not in the cortex or serum compared with those of WKY controls. Furthermore, inner medullary collecting duct cells from 8-9-week-old SHR, either acutely isolated or cultured, released less endothelin-1 than did those from WKY rats. Finally, the level of endothelin-1 messenger RNA was only reduced in the inner medulla and in inner medullary collecting duct cells from 8-9-week-old SHR. In summary, renal medullary, and in particular terminal collecting duct, endothelin-1 production is reduced in SHR only after the development of hypertension. Such decreases in inner medullary collecting duct endothelin-1 production may contribute to the hypertensive state in SHR.

Bisantrene (NSC 337766) (CL 216,942) in advanced breast cancer. A cancer and leukemia group B study.

Bisantrene (NSC 337766) is an anthracenedicarboxaldehyde hydrazone demonstrating a wide spectrum of activity in animal tumor model systems with no evidence of cardiotoxicity or alopecia, in contrast to doxorubicin. Thirty-three women with advanced adenocarcinoma of the breast were treated with 260 mg/m2 IV every 3 weeks. All patients had received at least one prior combination chemotherapy regimen for metastatic disease and 32/33 were refractory to doxorubicin. Of 28 patients evaluable for response one had a partial response lasting 10 weeks and three patients had stable disease for 22, 22, and 9 weeks. The most significant toxicities were nonhematologic: nausea and vomiting (41%), phlebitic reactions (38%), hypotension, one fatal anaphylactic reaction, and the development of a 7th cranial nerve palsy during drug infusion. Hematologic toxicity, leukopenia, was dose-limiting but manageable without associated infections or bleeding. These results indicate that bisantrene in this dose and schedule is not a useful drug in heavily pretreated breast cancer patients. The incidence and severity of phlebitic reactions limited venous access and adversely affected patient compliance. Preliminary results of other phase II breast cancer trials indicate a similar spectrum of toxicity but suggest more significant antitumor activity even in patients previously treated with doxorubicin. Trials conducted in patients with minimal prior treatment and with bisantrene administered via central line appear warranted for definitive assessment of the activity of this agent in breast cancer.

Autocrine role of endothelin in rat IMCD: inhibition of AVP-induced cAMP accumulation.

Exogenous endothelin-1 (ET-1) inhibits arginine vasopressin (AVP)-induced adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in the inner medullary collecting duct (IMCD). Since ET-1 is produced by, and binds to specific receptors on, the IMCD, the possibility exists that ET-1 is an autocrine regulator of AVP action in this nephron segment. To test this hypothesis, rat IMCD cells grown on semipermeable membranes were exposed to rabbit anti-ET antisera or nonimmune rabbit sera (NRS). AVP (10(-9)M) caused a significantly greater accumulation of cAMP in confluent IMCD monolayers preincubated in ET-1 antisera compared with NRS. ET-1 (10(-8) M) inhibited the AVP-induced rise in cAMP by 65% in cells preincubated in ET-1 antisera, but had no effect in NRS-treated cells. Finally, 125I-ET-1 (30 pM) binding was increased sixfold in IMCD preincubated in anti-ET-1 antisera. These data indicate that ET causes tonic autocrine inhibition of AVP responsiveness in the IMCD.

Characterization of endothelin receptors in the inner medullary collecting duct of the rat.

Endothelins may be important regulators of renal inner medullary collecting duct (IMCD) function. These peptides are secreted in large amounts by IMCD cells and can, in turn, potently inhibit sodium and water transport systems in the IMCD. This study characterized endothelin (ET) receptors in the IMCD in order to gain insight into this unique renal autocrine system. Radioligand binding studies with 125I-ET-1 yielded a B(max) of 205.7 fmol/mg and a KD of 218 pM for ET-1. Similar studies with 125I-ET-3 yielded two populations of receptors for ET-3, one with a KD of 50 pM and one with a KD of 920 pM. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of IMCD cells covalently labeling with 125I-ET-1 yielded two bands, one at 97 kDa with affinities of ET-1 greater than ET-2 much greater than ET-3 and one at 47 kDa with affinities ET-1 greater than or equal to ET-2 = ET-3. Reverse transcription and polymerase chain reaction revealed the presence of both endothelin receptor types A and B. These data indicate that IMCD cells have high affinity, high density receptors for endothelin and express both known types of endothelin receptor.

Endothelin B receptor mediates ET-1 effects on cAMP and PGE2 accumulation in rat IMCD.

Endothelin (ET) potently inhibits arginine vasopressin (AVP)-induced adenosine 3',5'-cyclic monophosphate (cAMP) accumulation and Na-K-adenosinetriphosphatase (Na-K-ATPase) activity in the inner medullary collecting duct (IMCD). At least two types of ET receptors exist: ETA [binds ET-1 > ET-3 = sarafotoxin S6c (S6c)] and ETB (binds ET-1 = ET-3 = S6c). We examined which of these receptors mediates biological actions of ET in freshly isolated rat IMCD cells. Binding studies revealed comparable displacement of 125I-ET-3 by ET-1, ET-3, and S6c, whereas 125I-ET-1 was displaced by ET-1 >> ET-3 = S6c. Together, these studies confirm the presence of receptors in the IMCD with ETA and ETB binding characteristics. ET-1, ET-3, and S6c were equipotent in reducing AVP-stimulated cAMP accumulation. BQ-123, at concentrations selective for ETA receptor antagonism, did not alter the effect of ET-1, ET-3, or S6c. Pertussis toxin or protein kinase C blockade, but not indomethacin, inhibited the effect of ET-1 and S6c on AVP-stimulated cAMP accumulation, consistent with activation of the same signal transduction pathways. ET-1 and S6c were equipotent in reducing forskolin-stimulated cAMP accumulation, ruling out inhibition of AVP-receptor interaction as a common mechanism of action. Finally, ET-1, ET-3, and S6c caused comparable stimulation of prostaglandin E2 (PGE2) accumulation, an effect that was not blocked by BQ-123. These data indicate that an ETB-like receptor mediates ET stimulation of PGE2 and inhibition of AVP-enhanced cAMP accumulation in the IMCD. The function of the ETA-like receptor in the IMCD remains to be determined.

Shiga toxin-1 regulation of cytokine production by human proximal tubule cells.

BACKGROUND: Interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) levels are elevated in kidneys of patients with post-diarrheal hemolytic uremic syndrome (D+HUS) and may contribute to renal dysfunction. The renal cellular sources of these inflammatory cytokines in D+HUS are largely unknown, however, the proximal tubule has emerged as a potentially important candidate. Since Shiga toxin-1 (Stx-1) has been implicated in the genesis of D+HUS, we examined the effect of Stx-1 on cytokine production by human proximal tubule cells. METHODS: Stx-1 cytotoxicity, protein synthesis inhibition, and effect on IL-1, IL-6, and TNF protein release and mRNA levels were determined. The effect of another protein synthesis inhibitor, cycloheximide (CHX), on these parameters was also evaluated. RESULTS: Stx-1 greatly increased TNF release and mRNA levels while CHX, at concentrations that produced similar inhibition of protein synthesis, had no effect on TNF production. In contrast, Stx-1 and CHX caused comparable elevations in IL-1 release and mRNA accumulation. Stx-1 and CHX also stimulated IL-6 mRNA accumulation, but only at concentrations that either were cytotoxic or substantially blocked protein synthesis. Finally, lipopolysaccharide, which is likely to be elevated in the circulation of patients with D+HUS, had no effect alone, but synergized with Stx-1 to increase IL-1 production. CONCLUSIONS: These results indicate that Stx-1 stimulates proximal tubule inflammatory cytokine production and that this effect is due partially to nonspecific induction of mRNA levels as well as activation of Stx-1-specific mechanisms.

Cytotoxic effect of Shiga toxin-1 on human proximal tubule cells.

BACKGROUND: Cytolytic Shiga toxins (Stx) are believed to be largely responsible for renal damage in post-diarrheal hemolytic-uremic syndrome (D + HUS). Despite the general belief that endothelial cells are the primary target of Stx, there is evidence that proximal tubules may be a site of toxin action. We hypothesized that cultured proximal tubular cells are sensitive to the cytotoxic effects of Stx. METHODS: Cultured human proximal tubular cells were exposed to Stx-1 in the presence and absence of a variety of inflammatory factors likely to be elevated in the kidney or serum of patients with D + HUS. Cell survival, protein synthesis, total cell levels and synthesis of Stx receptors (GB3), and Stx binding were measured. RESULTS: Proximal tubules were extremely sensitive to the cytotoxic effect of Stx-1 with an LD50 at least equal to, if not less than, that seen with Vero cells. Interleukin-1 (IL-1), lipopolysaccharide (LPS), and butyrate (but not tumor necrosis factor or interleukin-6) up-regulated proximal tubule sensitivity to Stx-1. IL-1 increased Stx-1 binding, but did not alter total cell levels or synthesis of GB3, the glycosphingolipid receptor for Stx-1. In contrast, LPS and butyrate, despite increasing Stx-1 sensitivity, had no effect on Stx-1 binding. CONCLUSIONS: These studies indicate that proximal tubules are exquisitely sensitive to Stx-1 cytotoxicity and that inflammatory factors can increase toxin responsiveness through a variety of mechanisms. It is suggested that proximal tubules may be an important early target of Stx-1 action in D + HUS.

Shiga toxin-1 regulation of cytokine production by human glomerular epithelial cells.

BACKGROUND/AIMS: Inflammatory cytokines may enhance renal injury in post-diarrheal hemolytic uremic syndrome (Stx HUS) by enhancing the cytotoxic effect of Shiga toxins (Stx). The sources of inflammatory cytokines in Stx HUS are unclear. Since Stx-1 potently inhibits protein synthesis by glomerular epithelial cells (GEC) and increases cytokine release by renal epithelial cells, we examined Stx-1 regulation of cytokine production by human GEC. METHODS: Stx-1 (and cycloheximide (CHX), another protein synthesis inhibitor) cytotoxicity, protein synthesis inhibition, and effect on interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) release and mRNA levels were determined. RESULTS: Stx-1 alone had a modest stimulatory effect on inflammatory cytokine production by GEC that occurred at toxin concentrations ranging from minimal to 50% inhibition of protein synthesis. CHX, at concentrations that produced similar inhibition of protein synthesis, increased IL-1, IL-6, and TNF protein release and mRNA accumulation, but in a different time- and dose-dependent pattern than Stx. Lipopolysaccharide (LPS) did not change IL-1, but stimulated IL-6 and TNF production. LPS and Stx-1 combined stimulated production of all three cytokines to a greater extent than either toxin alone. CONCLUSION: These data indicate that: (1) Stx-1 alone modestly stimulates GEC inflammatory cytokine production; (2) LPS and Stx-1 combined can potently enhance GEC cytokine release, and (3) this action of Stx-1 may relate in part to inhibition of protein synthesis but cannot be fully attributed to this effect.

Mu-oxo-bis[eta5-1,2-dicarbaundecarboato)bis(N,N-dimethylacetamidinato)-tantalum] dichlooromethane hemisolvate.

The structure of the title compound, [Ta2O(C2B9H11)2(C4H9N2)4]*0.5CH2Cl2, contains two (C2B9H11)Ta[NC(Me)NMe2]2 units bridged by a nearly linear [Ta-O-Ta 163.4 (4) degrees ] mu-oxo ligand. The dichloromethane molecule lies on a twofold axis.

Endothelin-1 induction of cyclooxygenase-2 expression in rat mesangial cells.

Prostaglandin E2 (PGE2) may be an important negative feedback modulator of endothelin-1 (ET-1)-stimulated mesangial cell proliferation and contraction. Recent studies suggest that ET-1 may induce prolonged mesangial cell PGE2 production, however the mechanism of this effect is unknown. The current study was undertaken, therefore, to examine the long-term effect of ET-1 on mesangial cell PGE2 synthesis. ET-1 markedly increased PGE2 release by rat mesangial cells for at least six hours. Cyclooxygenase (COX) activity was increased by one hour and persisted for at least six hours. ET-1 increased COX-2, but not COX-1, protein and mRNA levels. Actinomycin D reduced ET-1-stimulated PGE2 synthesis and COX-2 mRNA expression, while cycloheximide superinduced COX-2 mRNA. Dexamethasone decreased ET-1-stimulated PGE2 release and COX-2 protein and mRNA levels. ET-1-stimulated PGE2 release was prevented by BQ-123, an endothelin receptor A antagonist. We conclude that ET-1, via activation of the endothelin A receptor, causes a prolonged increase in mesangial cell PGE2 production that is partially dependent on induction of dexamethasone-inhibitable COX-2.

Effect of reactive oxygen species on endothelin-1 production by human mesangial cells.

Reactive oxygen species (ROS) have been implicated in the pathophysiology of renal ischemia/reperfusion injury. Endothelin-1 (ET-1) is generated in abundance in renal ischemia/reperfusion with resultant decreases in renal blood flow and glomerular filtration rate. To determine if ROS regulate ET-1 production, the effect of ROS donors or scavengers on ET-1 protein and mRNA levels in cultured human mesangial cells was examined. Incubation with xanthine/xanthine oxidase, glucose oxidase, or H2O2 caused a dose-dependent rise in ET-1 release. Similarly, xanthine/xanthine oxidase or H2O2 augmented ET-1 mRNA levels. In contrast, the ROS scavengers dimethylthiourea (DMTU), dimethylpyrroline N-oxide, or pyrrolidine dithiocarbamate reduced basal ET-1 release, while DMTU lowered ET-1 mRNA levels. Deferoxamine, an iron chelator, also decreased basal ET-1 release. Superoxide dismutase potentiated the ET-1 stimulatory effect of xanthine/xanthine oxidase, while catalase abrogated the effect of xanthine/xanthine oxidase and H2O2. The effects of ROS were unrelated to changes in nitric oxide production or cytotoxicity. These data indicate that exogenously or endogenously-derived ROS can increase ET-1 production by human mesangial cells. While superoxide anion reduces ET-1 levels, H2O2 leads to enhanced production of the peptide. ROS stimulation of mesangial cell ET-1 production may contribute to impaired glomerular hemodynamics in the setting of renal ischemia/reperfusion injury.

Cytotoxic effect of Shiga toxin-1 on human glomerular epithelial cells.

BACKGROUND: Shiga toxin-1 (Stx-1) has been implicated in the pathogenesis of postdiarrheal hemolytic-uremic syndrome (Stx HUS). Endothelial cells had been felt to be the primary renal target of Stx-1; however, recent studies suggest that renal epithelial cells may also be responsive. To further examine this issue, we evaluated the responsiveness of human glomerular epithelial cells (GECs) to the cytotoxic effects of Stx-1. METHODS: Cultured GECs were exposed to Stx-1 in the presence and absence of a variety of inflammatory factors likely to be elevated in the kidney or serum of patients with Stx HUS. Cell survival, protein synthesis, total cell Gb3 levels and synthesis, and Stx-1 binding were measured. RESULTS: GECs were sensitive to Stx-1, with an LD50 of approximately 10-7 g/L (1.4 pmol/L). Interleukin-1 (IL-1), lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), and butyrate increased Stx-1 cytotoxicity and total cell Gb3 levels. These agents, with the exception of TNF-alpha, also increased Stx-1 binding to GECs. IL-6 failed to alter Stx-1 toxicity, binding, or Gb3 content. CONCLUSIONS: These studies indicate that GECs are sensitive to the cytotoxic effects of Stx-1 and that inflammatory factors can increase toxin responsiveness. GECs may be a target of Stx-1 action in Stx HUS.