Zonal cortical scarring and tubular thyroidization in kidney biopsies of patients with SLE-histologic indicator for antiphospholipid antibodies.

Antiphospholipid antibody syndrome (APS) is an acquired prothrombotic autoimmune disease caused by the presence of antibodies against anionic phospholipids or plasma proteins bound to phospholipids on cell membranes. It can be a primary disease or secondary to other autoimmune diseases, most commonly systemic lupus erythematosus (SLE). Laboratory testing for antiphospholipid antibodies (aPL) may be only transiently positive, so APS could be missed until a catastrophic thrombotic episode or pregnancy morbidity occurs. In the kidneys, this manifests as thrombotic microangiopathy (TMA), and patients present with hypertensive urgency and acute kidney injury. However, APS may not always have a catastrophic presentation but instead a more smoldering course. Kidney biopsy may not show obvious active TMA lesions but rather only chronic injury in the form of zonal cortical scarring and tubular thyroidization. Still, it may warrant anticoagulation therapy. So it is important to recognize this pattern of injury in the biopsy. Herein, we retrospectively study the correlation between presence of this histologic feature in kidney biopsies of SLE patients and positive aPL testing results (anticardiolipin antibodies and/or lupus anticoagulant). Kidney biopsies of SLE patients from 2004 to 2015 ( n = 186) were screened for presence or absence of zonal cortical scarring. Their electronic medical records were reviewed for aPL results. Our study showed low sensitivity (33%) but higher positive predictive value (62%), specificity (89%) and negative predictive value (71%). This histologic finding is therefore not a sensitive screening tool, but if present, greatly increases the likelihood of underlying aPL. We want to emphasize that recognition of this histologic feature in the biopsies of SLE patients is important so as not to miss the opportunity to treat with anticoagulation therapy and possibly slow down the chronic renal damage.

Prospective validation of a novel renal activity index of lupus nephritis.

Objectives The renal activity index for lupus (RAIL) score was developed in children with lupus nephritis as a weighted sum of six urine biomarkers (UBMs) (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin and kidney injury molecule 1) measured in a random urine sample. We aimed at prospectively validating the RAIL in adults with lupus nephritis. Methods Urine from 79 adults was collected at the time of kidney biopsy to assay the RAIL UBMs. Using receiver operating characteristic curve analysis, we evaluated the accuracy of the RAIL to discriminate high lupus nephritis activity status (National Institutes of Health activity index (NIH-AI) score >10), from low/moderate lupus nephritis activity status (NIH-AI score ≤10). Results In this mixed racial cohort, high lupus nephritis activity was present in 15 patients (19%), and 71% had proliferative lupus nephritis. Use of the identical RAIL algorithm developed in children resulted in only fair prediction of lupus nephritis activity status of adults (area under the receiver operating characteristic curve (AUC) 0.62). Alternative weightings of the six RAIL UBMs as suggested by logistic regression yielded excellent accuracy to predict lupus nephritis activity status (AUC 0.88). Accuracy of the model did not improve with adjustment of the UBMs for urine creatinine or albumin, and was little influenced by concurrent kidney damage. Conclusions The RAIL UBMs provide excellent prediction of lupus nephritis activity in adults. Age adaption of the RAIL is warranted to optimize its discriminative validity to predict high lupus nephritis activity status non-invasively.

Key role for CD4 T cells during mixed antibody-mediated rejection of renal allografts.

We utilized mouse models to elucidate the immunologic mechanisms of functional graft loss during mixed antibody-mediated rejection of renal allografts (mixed AMR), in which humoral and cellular responses to the graft occur concomitantly. Although the majority of T cells in the graft at the time of rejection were CD8 T cells with only a minor population of CD4 T cells, depletion of CD4 but not CD8 cells prevented acute graft loss during mixed AMR. CD4 depletion eliminated antidonor alloantibodies and conferred protection from destruction of renal allografts. ELISPOT revealed that CD4 T effectors responded to donor alloantigens by both the direct and indirect pathways of allorecognition. In transfer studies, CD4 T effectors primed to donor alloantigens were highly effective at promoting acute graft dysfunction, and exhibited the attributes of effector T cells. Laser capture microdissection and confirmatory immunostaining studies revealed that CD4 T cells infiltrating the graft produced effector molecules with graft destructive potential. Bioluminescent imaging confirmed that CD4 T effectors traffic to the graft site in immune replete hosts. These data document that host CD4 T cells can promote acute dysfunction of renal allografts by directly mediating graft injury in addition to facilitating antidonor alloantibody responses.

5/6 nephrectomy as a validated rat model mimicking human warfarin-related nephropathy.

BACKGROUND/AIMS: We previously reported that patients with chronic kidney disease (CKD) receiving warfarin therapy and whose international normalized ratio increases to >3.0 may develop acute kidney injury (AKI) as a result of glomerular hemorrhage and formation of obstructive red blood cell (RBC) casts. We named this condition warfarin-related nephropathy (WRN). We also previously reported that acute excessive anticoagulation with brodifacoum (superwarfarin) induces AKI in 5/6 nephrectomy (5/6NE) rats. Limitations of the brodifacoum model precluded a careful assessment of dose-response relationships. METHODS: Warfarin treatment was used in 5/6NE. RESULTS: Herein we report that warfarin treatment of 5/6NE rats resulted in a dose-dependent increase in serum creatinine (SC). The increase in SC following warfarin treatment was greater at 3 and 19 weeks after the ablative surgery, than that observed 8 weeks after the ablative surgery. The SC increase was correlated with the prothrombin time increase. Morphologically, 5/6NE, but not control rats, had acute tubular injury with RBC and RBC casts in the tubules. Treatment with vitamin K prevented SC increase and morphologic changes in the kidney associated with warfarin treatment. A single episode of WRN did not affect the progression of CKD in 5/6NE. CONCLUSION: (1) The 5/6NE model of CKD is an appropriate animal model to study the pathogenesis of WRN. (2) The pharmacokinetics of warfarin is better suited to the study of WRN than that of brodifacoum. (3) The more advanced stages of 5/6NE are more susceptible to WRN than the earlier stages. (4) Vitamin K treatment prevents WRN.

Discrepancies in glomerular and tubulointerstitial/vascular immune complex IgG subclasses in lupus nephritis.

BACKGROUND AND OBJECTIVES: Lupus nephritis is characterized by glomerular and extraglomerular immune complex deposition in the kidney. It is unclear whether the same circulating immune complexes deposit in the glomeruli and in extraglomerular structures, or whether they are pathogenetically different. Differences in the IgG subclass composition may point towards different pathways in the formation of glomerular and extraglomerular immune complexes. Therefore we investigated IgG subclass distribution in the immune complex deposits at these anatomic sites. DESIGN: A total of 84 biopsies diagnosed as lupus nephritis and classified according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification, were examined by direct immunofluorescence staining for IgG subclasses. The IgG subclass composition in the glomerular, tubular basement membrane (TBM) and vascular wall deposits was compared. We also correlated the presence/absence of interstitial inflammation and IgG subclasses in the TBM and vascular deposits. Lastly, we looked for correlation between staining for IgG subclasses and complement C1q and C3 staining. RESULTS: IgG staining was present in the TBM in 52/84 biopsies, and in the vascular walls in 40/84 biopsies. IgG subclass distribution was discrepant between glomerular and TBM deposits in 36/52 biopsies, and between glomerular and vascular deposits in 27/40 biopsies. Interstitial inflammation did not correlate with the presence of IgG staining or distribution of IgG subclasses in the TBM. Interstitial inflammation was more common in biopsies of African-American patients than Caucasian patients. The IgG subclass staining correlated with C1q staining in all the three compartments. CONCLUSIONS: The antibody composition of the glomerular and extraglomerular immune complex deposits appear to differ from each other. They may not represent the same preformed immune complexes from the circulation. It is likely that their pathogenesis and site of formation are different.

Electron in a transverse harmonic cavity.

Recent experiments with heavy ions and planned experiments with ultraintense lasers require nonperturbative solutions to quantum field theory for predicting and interpreting the results. To propel this theoretical direction, we solve the nonperturbative problem of an electron in a strong transverse confining potential using Hamiltonian light-front quantum field theory. We evaluate both the invariant mass spectra and the anomalous magnetic moment of the lowest state for this two-scale system. The weak external field limit of the anomalous magnetic moment agrees with the result of QED perturbation theory within the anticipated accuracy.

De novo thrombotic microangiopathy in renal allograft biopsies-role of antibody-mediated rejection.

The most common cause of thrombotic microangiopathy (TMA) in renal allografts is thought to be calcineurin inhibitor toxicity. Antibody-mediated rejection (AMR) can also cause TMA, but its true impact on de novo TMA is unknown. In a retrospective review of renal allograft biopsies from January 2003 to December 2008 at our institution, we determined the prevalence of TMA in patients with C4d positive (n = 243) and C4d negative (n = 715) biopsies. Over 90% of patients received cyclosporine in both groups. De novo TMA was seen in 59 (6.1%) patients; most of them (55%) with C4d positive biopsy. Among patients with C4d positive biopsies, 13.6% had TMA, as compared to only 3.6% patients with C4d negative biopsies (p < 0.0001). Incidence of graft loss between C4d positive and C4d negative TMA groups was not significantly different, but 70% of patients with C4d positive TMA who received plasmapheresis had slightly lower graft loss rate. In biopsies with AMR-associated TMA, glomerulitis and peritubular capillaritis were significantly more prominent. AMR is the most common cause of TMA in renal allografts in our patient population. It is important to recognize AMR-related TMA because plasmapheresis treatment may be beneficial.

Clinical implications of stigma in HIV/AIDS and other sexually transmitted infections.

This study sought to identify stigma differences between HIV/AIDS and other sexually transmitted infections (STIs). Interviewees from Alabama, USA (n = 537) rated two types of stigma (damage to social reputation and 'moral weakness') for seven infections ranging from 'nuisance' conditions (e.g. pubic lice) to life-threatening disease (e.g. HIV/AIDS). When asked which of the seven STIs would be most damaging to reputation, 74.8% of respondents chose HIV/AIDS. However, when asked to choose which STI represented moral weakness in infected persons, HIV/AIDS was rated as significantly lower than the other STIs, which suggests that HIV/AIDS is perceived differently than non-HIV STIs. This study addresses the possibility that advances in public awareness of HIV/AIDS have not necessarily been extrapolated into awareness of other STIs. Clinicians should be aware of these high levels of stigma as potential barriers to treatment for all STIs. Public health officials should consider the impact of undifferentiated stigma on STI prevention messages.

Normal distribution and medullary-to-cortical shift of Nestin-expressing cells in acute renal ischemia.

Nestin, a marker of multi-lineage stem and progenitor cells, is a member of intermediate filament family, which is expressed in neuroepithelial stem cells, several embryonic cell types, including mesonephric mesenchyme, endothelial cells of developing blood vessels, and in the adult kidney. We used Nestin-green fluorescent protein (GFP) transgenic mice to characterize its expression in normal and post-ischemic kidneys. Nestin-GFP-expressing cells were detected in large clusters within the papilla, along the vasa rectae, and, less prominently, in the glomeruli and juxta-glomerular arterioles. In mice subjected to 30 min bilateral renal ischemia, glomerular, endothelial, and perivascular cells showed increased Nestin expression. In the post-ischemic period, there was an increase in fluorescence intensity with no significant changes in the total number of Nestin-GFP-expressing cells. Time-lapse fluorescence microscopy performed before and after ischemia ruled out the possibility of engraftment by the circulating Nestin-expressing cells, at least within the first 3 h post-ischemia. Incubation of non-perfused kidney sections resulted in a medullary-to-cortical migration of Nestin-GFP-positive cells with the rate of expansion of their front averaging 40 microm/30 min during the first 3 h and was detectable already after 30 min of incubation. Explant matrigel cultures of the kidney and aorta exhibited sprouting angiogenesis with cells co-expressing Nestin and endothelial marker, Tie-2. In conclusion, several lines of circumstantial evidence identify a sub-population of Nestin-expressing cells with the mural cells, which are recruited in the post-ischemic period to migrate from the medulla toward the renal cortex. These migrating Nestin-positive cells may be involved in the process of post-ischemic tissue regeneration.

Partonic calculation of the two-photon exchange contribution to elastic electron-proton scattering at large momentum transfer.

We estimate the two-photon exchange contribution to elastic electron-proton scattering at large momentum transfer through the scattering off a parton in the proton. We relate the two-photon exchange amplitude to the generalized parton distributions which appear in hard exclusive processes. We find that when taking the polarization transfer determinations of the form factors as input, adding in the 2-photon correction does reproduce the Rosenbluth cross sections.

Oxidative and nitrosative stress in acute renal ischemia.

Generation of reactive oxygen species and nitric oxide in hypoxia-reperfusion injury may form a cytotoxic metabolite, peroxynitrite, which is capable of causing lipid peroxidation and DNA damage. This study was designed to examine the contribution of oxidative and nitrosative stress to the renal damage in ischemic acute renal failure (iARF). iARF was initiated in rats by 45-min renal artery clamping. This resulted in lipid peroxidation, DNA damage, and nitrotyrosine modification confirmed both by Western and immunohistochemical analyses. Three groups of animals were randomly treated with an inhibitor of inducible nitric oxide synthase (NOS), L-N(6)-(1-iminoethyl)lysine (L-Nil), cell-permeable lecithinized superoxide dismutase (SOD), or both. Each treatment resulted in amelioration of renal dysfunction, as well as reduced nitrotyrosine formation, lipid peroxidation, and DNA damage, thus suggesting that peroxynitrite rather than superoxide anion is responsible for lipid peroxidation and DNA damage. Therefore, in a separate series of experiments, a scavenger of peroxynitrite, ebselen, was administered before the reperfusion period. This treatment resulted in a comparable degree of amelioration of iARF. In conclusion, the present study provides the first attempt to elucidate the role of peroxynitrite in initiation of the cascade of lipid peroxidation and DNA damage to ischemic kidneys. The results demonstrate that L-Nil, lecithinized SOD, and ebselen treatments improve renal function due to their suppression of peroxynitrite production or its scavenging, consequently preventing lipid peroxidation and oxidative DNA damage.

Plasmin-dependent and -independent effects of plasminogen activators and inhibitor-1 on ex vivo angiogenesis.

Plasminogen activator (PA) inhibitor-1 (PAI-1) has been recognized as a surrogate marker of endothelial dysfunction in diseases associated with impaired angiogenesis, including atherosclerosis, diabetic vasculopathy, and nephropathy. To establish the necessary and sufficient components of the PA system [PAI-1, urokinase-type PA (uPA), or tissue-type PA (tPA), and plasminogen (Plg)] for angiogenesis, we examined angiogenic competence of vascular explant cultures obtained from mice deficient in PAI-1, tPA, uPA, and Plg. To gain insight into the requirement for different matrix-degrading systems during endothelial cell migration across plasmin-degradable basement membranes compared with profibrotic areas containing plasmin-nondegradable collagen, we contrasted vascular sprouting in collagen with Matrigel lattices. PAI-1(-/-) vessels showed an increased capillary sprouting in both collagen and Matrigel. Deficiency of uPA significantly reduced the rate of sprouting, whereas tPA(-/-) vessels showed a profound inhibition of capillary sprouting. The Plg(-/-) vessels failed to sprout, a defect that was restored not only by exogenous Plg, but also by the addition of PAs; a nonproteolytic effect of tPA was observed in Matrigel. Zymography revealed no differences in the activity of metalloproteinase (MMP)-2 and -9 in wild-type and PAI-1(-/-) vessels, but demonstrated reduced MMP-9 activity in all angiogenesis-deficient vessels. In summary, 1) PAI-1 by itself is a modest inhibitor of endothelial sprouting, 2) tPA and Plg are indispensable for angiogenesis in this model, 3) Plg is not the only substrate for PAs, and 4) the activity of MMP-9 is undetectable in explant cultures from tPA and Plg knockout mice.

Temporal changes in natriuretic and antinatriuretic systems after closure of a large arteriovenous fistula.

OBJECTIVE: Surgical closure of a large arteriovenous (A-V) fistula in patients and animals is associated with prompt diuresis and natriuresis. However, the mechanisms underlying these changes remained largely unknown. METHODS: The present study evaluated the hormonal balance between major antinatriuretic systems (plasma renin activity, PRA, and arginine vasopressin, AVP) and natriuretic systems (atrial natriuretic peptide, ANP, and renal nitric oxide, NO) in Wistar rats with an A-V fistula (1.2 mm O.D., side to side) between the abdominal aorta and inferior vena cava. RESULTS: The placement of an A-V fistula caused progressive sodium retention (UNaV decreased from 1500 to 100 microequiv./day), a significant drop in mean arterial blood pressure (MAP) from 127+/-3 to 75+/-2 mmHg (P<0.01), and a significant increase in ANP (from 94+/-12 to 389+/-135 pg/ml, P<0.05), PRA (from 22.1+/-2.0 to 47+/-14 ng angiotensin I [Ang I]/ml/h, P<0.05), AVP (from 14.2+/-3.6 to 37.7+/-9.6 pg/ml, P<0.05), norepinephrine (from 184.2+/-40.5 to 1112.6+/-293.2 pg/ml, P<0.05) and epinephrine (from 667.5+/-175.9 to 2049.8+/-496.9 pg/ml, P<0.05). Furthermore, these changes were associated with a 3-fold increase in the renal medullary immunoreactive levels of endothelial NO synthase (eNOS), an endogenous vasodilator that plays an important role in the regulation of medullary blood flow. After 6 days, rats with A-V fistula and maximal sodium retention underwent surgical closure of the A-V fistula. The A-V fistula closure was associated with dramatic natriuresis (UNaV=2563+/-78 and 1918+/-246 microEq/day on days 3 and 6 following the closure, respectively) and restoration of MAP to normal levels (111+/-6 mmHg); PRA decreased to 29+/-5 ng Ang I/ml/h, AVP to 20.3+/-7.1 pg/ml, and medullary eNOS declined to basal levels, whereas plasma ANP concentrations remained elevated (380+/-90 pg/ml) after 3 days and returned to normal (92+/-12 pg/ml) on day 6. CONCLUSIONS: These results demonstrate that the creation of A-V fistula is associated with activation of both natriuretic and antinatriuretic systems. Closure of A-V fistula is characterized by shifting the balance in favor of the natriuretic substances. Moreover, the observed alterations in medullary eNOS following the creation and closure of A-V fistula suggest that this system, an important determinant of medullary blood flow, may contribute significantly to the regulation of sodium excretion in this model.

Delayed branching of endothelial capillary-like cords in glycated collagen I is mediated by early induction of PAI-1.

Development of micro- and macrovascular disease in diabetes mellitus (DM) warrants a thorough investigation into the repertoire of endothelial cell (EC) responses to diabetic environmental cues. Using human umbilical vein EC (HUVEC) cultured in three-dimensional (3-D) native collagen I (NC) or glycated collagen I (GC), we observed capillary cord formation that showed a significant reduction in branching when cells were cultured in GC. To gain insight into the molecular determinants of this phenomenon, HUVEC subjected to GC vs. NC were studied using a PCR-selected subtraction approach. Nine different genes were identified as up- or downregulated in response to GC; among those, plasminogen activator inhibitor-1 (PAI-1) mRNA was found to be upregulated by GC. Western blot analysis of HUVEC cultured on GC showed an increase in PAI-1 expression. The addition of a neutralizing anti-PAI-1 antibody to HUVEC cultured in GC restored the branching pattern of formed capillary cords. In contrast, supplementation of culture medium with the constitutively active PAI-1 reproduced defective branching patterns in HUVEC cultured in NC. Ex vivo capillary sprouting in GC was unaffected in PAI-1 knockout mice but was inhibited in wild-type mice. This difference persisted in diabetic mice. In conclusion, the PCR-selected subtraction technique identified PAI-1 as one of the genes characterizing an early response of HUVEC to the diabetic-like interstitial environment modeled by GC and responsible for the defective branching of endothelial cells. We propose that an upregulation of PAI-1 is causatively linked to the defective formation of capillary networks during wound healing and eventual vascular dropout characteristic of diabetic nephropathy.

Workshop: endothelial cell dysfunction leading to diabetic nephropathy : focus on nitric oxide.

Clinical manifestations of diabetic nephropathy are an expression of diabetic microangiopathy. This review revisits the previously proposed Steno hypothesis and advances our hypothesis that development of endothelial cell dysfunction represents a common pathophysiological pathway of diabetic complications. Specifically, the ability of glucose to scavenge nitric oxide is proposed as the initiation phase of endothelial dysfunction. Gradual accumulation of advanced glycated end products and induction of plasminogen activator inhibitor-1, resulting in the decreased expression of endothelial nitric oxide synthase and reduced generation of nitric oxide, are proposed to be pathophysiologically critical for the maintenance phase of endothelial dysfunction. The proposed conceptual shift toward the role of endothelial dysfunction in diabetic complications may provide new strategies for their prevention.

Nitric oxide attenuates signal transduction: possible role in dissociating caveolin-1 scaffold.

Caveolae harbor different serpentine receptors, intracellular components of signaling cascades, and certain enzymes, including endothelial nitric oxide synthase (eNOS). The regulation of eNOS activity by Ca(2+)/calmodulin and caveolin has been described. We have previously demonstrated that nitric oxide (NO) can modulate signaling initiated via receptors localized to caveolae. In the present study, we show that NO donors induced an increase in the monomeric form of this scaffolding protein in cultured endothelial cells, the effect mimicked by 8-bromo cGMP. Proximity imaging of endothelial cells transfected with the thermotolerant green fluorescent protein-caveolin-1 construct demonstrated that sodium nitroprusside resulted in the increased fluorescence ratio of 410:470 nm, consistent with the distancing of fluorescently tagged caveolin-1. Pulse labeling of endothelial cells with cholera toxin B subunit indicated that sodium nitroprusside reversibly decreased its binding. Signaling via G protein-coupled receptors resident to caveolae was inhibited by pretreatment with NO donor. The data demonstrate that NO modulation of cell signaling is accomplished in part by regulating the state of caveolin-1 oligomerization. NO-induced attenuation of signaling involves reversible dissociation of caveolin scaffold, thus providing both spatial and temporal modulation of signal transduction.

Glucose scavenging of nitric oxide.

Endothelial dysfunction accompanies suboptimal glucose control in patients with diabetes mellitus. A hallmark of endothelial dysfunction is a deficiency in production or bioavailability of vascular nitric oxide (NO). Here we demonstrate that acute exposure of human endothelial cells to glucose, at levels found in plasma of diabetic patients, results in a significant blunting of NO responses to the endothelial nitric oxide synthase (eNOS) agonists bradykinin and A-23187. Monitoring of NO generation by purified recombinant bovine eNOS in vitro, using amperometric electrochemical detection and an NO-selective porphyrinic microelectrode, showed that glucose causes a progressive and concentration-dependent attenuation of detectable NO. Addition of glucose to pure NO solutions similarly elicited a sharp decrease in NO concentration, indicating that glucose promotes NO loss. Electrospray ionization-tandem mass spectrometry, using negative ion monitoring, directly demonstrated the occurrence of a covalent reaction involving unitary addition of NO (or a derived species) to glucose. Collectively, our findings reveal that hyperglycemia promotes the chemical inactivation of NO; this glucose-mediated NO loss may directly contribute to hypertension and endothelial dysfunction in diabetic patients.

Intrarenal expression and distribution of cyclooxygenase isoforms in rats with experimental heart failure.

The generation of PGs from arachidonic acid is mediated by cyclooxygenase (COX), which consists of a constitutive (COX-1) and an inducible (COX-2) isoform. The present study evaluated the relative expression and immunoreactive levels of COX-1 and COX-2, by means of RT-PCR, Western blot analysis, and immunohistochemistry, in the renal cortex and medulla of rats with congestive heart failure (CHF), induced by the placement of an aortocaval fistula. In addition, we examined the effects of a COX-1 inhibitor (piroxicam), COX-2 inhibitor (nimesulide), and nonselective COX inhibitor (indomethacin) at a dose of 5 mg/kg, on intrarenal blood flow by laser Doppler flowmetry. COX-1 and COX-2 mRNAs were abundantly expressed in the renal medulla of control and CHF rats and only minimally in the cortex. Moreover, both RT-PCR (32-36 cycles) and Western blot techniques revealed upregulation of medullary COX-2, but not of COX-1, in rats with advanced heart failure. In line with these findings, all three tested COX inhibitors provoked significant and sustained decreases (Delta approximately -20%) in medullary blood flow (MBF), which were similar in magnitude and duration in control animals. However, in CHF rats, indomethacin produced a greater reduction in MBF than that obtained with either piroxicam or nimesulide. Taken together, these results indicate that 1) both COX-1 and COX-2 are predominantly expressed in the renal medulla and 2) experimental CHF is associated with selective overexpression of COX-2. The latter may represent a mechanism aimed at defending MBF in the face of a decrease in renal perfusion pressure during the development of CHF.

Dynamic laryngotracheal closure for aspiration: a preliminary report.

OBJECTIVES/HYPOTHESIS: An estimated 500,000 patients per year in the United States. are affected by stroke-related dysphagia. Approximately half experience aspiration, which can lead to pneumonia or death. Aspiration may result from many factors, including delayed transport of the bolus, faulty laryngeal elevation, and poor coordination or inappropriate timing of vocal cord closure. Interventions carried out to protect the lungs are usually irreversible, destructive to the upper airway, and rarely prevent the need for enteral tube feeding. STUDY DESIGN: We present a report of the first implantations of a new device in an FDA-approved study to restore dynamic laryngotracheal separation. Two stroke patients needing tracheostomy were selected based on chronic aspiration verified by clinical and radiologic criteria (modified barium swallow [MBS]). METHODS: The left recurrent laryngeal nerve was exposed and electrically stimulated to verify vocal fold adduction. Huntington Medical Research Institute Bipolar Helical Electrodes were then implanted around the nerve. The leads were tunneled and linked to a NeuroControl Implantable Receiver-Stimulator placed subcutaneously on the chest wall. Activation of the stimulator was performed through an external transmitter linked by induction. RESULTS: The device was successfully triggered intra- and postoperatively. Serial flexible fiberoptic endoscopies and MBS demonstrate that aspiration is systematically arrested using low levels of electrical stimulation (42 Hz, 48-100 microsec, 1 mA). DISCUSSION: This pioneering work has shown that aspiration can be controlled without airway damage for a wide population of neurologically impaired patients because it appears more physiological than standard therapies. CONCLUSION: Based on the first two patients, paced laryngotracheal separation is clinically effective in controlling aspiration.

Effects of A-192621.1, a specific endothelin-B antagonist, on intrarenal hemodynamic responses to endothelin-1.

The present study examined the effects of A-192621.1, a highly selective endothelin-B- (ETB) receptor antagonist, on the renal hemodynamic and systemic actions of endothelin-1 (ET-1). Intravenous injection of ET-1 (1.0 nmol/kg) into anesthetized rats produced a sustained decrease in renal blood flow (assessed by ultrasonic flowmeter) and a significant increase in renal vascular resistance, as well as an increase in mean arterial pressure. These changes were significantly augmented by pretreatment with A-192621.1 (3.0 mg/kg/h). Analysis of intrarenal blood flow by laser-Doppler flowmeter revealed that ET-1 caused a marked and sustained decrease in cortical blood flow, associated with a transient increase in medullary blood flow. The reduction in cortical blood flow in response to ET-1 was further enhanced by pretreatment with A-192621.1, whereas the ET-1-induced medullary vasodilatation was completely abolished and reversed into a vasoconstrictor response. These findings suggest that the ETB-receptors mediate the systemic and renal vasodilatory actions of ET-1 in the rat, and that their activation may serve as a physiological counterbalance that modulates ET-1-induced vasoconstriction.