Late onset of hepatitis B virus reactivation following hematopoietic stem cell transplantation: successful treatment with combined entecavir plus tenofovir therapy.

Prophylaxis with lamivudine (LAM) is recommended for hepatitis B core antibody-positive allogenic hematopoietic stem cell transplant (HSCT) recipients, but the optimal timing for the institution and duration of the prophylaxis is still unknown. Furthermore, considering the high rate of mortality associated with hepatitis B virus reactivation (HBV-R), the most potent and long-term effective antiviral regimen should be considered. We report here a case of late onset of HBV-R after a long-term prophylaxis with LAM in a patient who underwent HSCT for non-Hodgkin lymphoma and who was successfully treated with a combination antiviral regimen including entecavir and tenofovir disoproxil fumarate.

Post-kala-azar dermal leishmaniasis as an immune reconstitution inflammatory syndrome in a patient with acquired immune deficiency syndrome.

Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL) observed mainly in Sudan and India where it follows treated VL in 50% and 10% of cases, respectively. We report a 46-year-old patient with acquired immune deficiency syndrome who, 7 months after diagnosis of VL, developed PKDL and uveal leishmaniasis following HAART-induced immune recovery. In southern Europe PKDL seems to be an emerging clinical presentation among human immunodeficiency virus (HIV)-infected patients experiencing HAART-induced immune recovery after a previous diagnosis of VL. The best treatment among HIV-infected patients remains to be determined.

Effect of calcineurin inhibitors on extracellular matrix turnover in isolated human glomeruli.

INTRODUCTION: Although chronic cyclosporine toxicity is mainly characterized by tubular atrophy and interstitial fibrosis, glomerular injury with expansion of mesangial matrix and sclerosis is not uncommon. Tacrolimus is a newer calcineurin inhibitor that has been used in renal transplant recipients as primary or rescue therapy. Clinical trials suggest an improved long-term graft survival among patients treated with tacrolimus. Recently we have shown that tacrolimus and cyclosporine have similar effects on extracellular matrix turnover in cultured cells. The present study was performed to investigate the effects of the calcineurin inhibitors on whole glomeruli extracellular matrix turnover. METHODS: Human glomeruli isolated from kidney biopsies just before transplantation were incubated with culture media containing either cyclosporine (200 ng/mL) or tacrolimus (10 ng/mL) for 24 hours. Glomeruli incubated only with culture medium were used as control. RESULTS: The expressions of (alpha2)IV collagen, metalloprotease 9 (MMP9), tissue inhibitors of metalloproteases 2 (TIMP-2), and TGFbeta were evaluated by in situ reverse transcription and polymerase chain reactions (RT-PCR). beta-actin was used as a control gene. Cyclosporine (but not tacrolimus) increased the expression of (alpha2)IV collagen and TIMP2 in isolated glomeruli. TGF-beta was markedly increased by cyclosporine. MMP9 expression was not affected by the calcineurin inhibitors. By light microscopy kidney biopsies did not show pathologic changes. CONCLUSION: Cyclosporine treatment modulates extracellular matrix turnover in isolated human glomeruli, inducing an imbalance between synthesis and degradation. This effect, not observed in tacrolimus-treated human glomeruli, may induce the extracellular matrix deposition and sclerosis characteristic of chronic cyclosporine toxicity.

Hyperkalemia-induced ECG abnormalities in patients with reduced renal function.

Hyperkalemia is a potentially lethal condition to be aware of in the presence of ECG abnormalities especially in patients with reduced renal function. However, ECG abnormalities are not always dependent on the degree ofhyperkalemia but may be aggravated by the rapidity of the development of hyperkalemia and by associated electrolyte disorders. We describe 3 patients with renal failure and different ECG changes induced by hyperkalemia. More severe changes were observed when hyperkalemia developed rapidly, but not in presence of electrolyte disorders. Even minor ECG abnormalities must alarm physicians in patients with renal failure since severe hyperkalemia is not always associated with critical ECG changes.

[Hepatocyte growth factor (HGF) reduces the expression of profibrotic factors in human isolated glomeruli]. / Hepatocyte growth factor (HGF) riduce l'espressione di fattori profibrotici in glomeruli umani isolati.

BACKGROUND: The imbalance between the synthesis and degradation of the mesangial matrix causes glomerulosclerosis and ultimately leads to chronic renal failure. HGF is a pleiotropic cytokine involved in angiogenesis, morphogenesis, organogenesis, and bone remodeling. Recently, we and other investigators have shown that HGF has a central role in the recovery of acute renal failure. Furthermore, HGF treatment halts the progression of kidney disease in a murine model of chronic renal failure. The aim of the present study was to evaluate the effect of HGF on the mRNA levels of molecules involved in the extracellular matrix turnover and of the c-met receptor in isolated human glomeruli. METHODS: Human glomeruli were isolated by microdissection from donor kidney biopsies just before transplantation. Glomeruli were extensively washed and incubated with culture media containing HGF (50 ng/mL) for 24 h at 37 C. Glomeruli incubated without HGF were used as controls. After 24 h, glomeruli were washed and freezed and thawed three times. The expression of c-met, (alpha2) IV collagen, TGF-beta, metalloproteases 9 (MMP9), and of the inhibitor of metalloproteases-1, TIMP-1 was evaluated by in situ reverse transcription (RT) and polymerase chain reaction (PCR). beta-actin was used as a housekeeping gene. RESULTS: The (alpha2)IV collagen mRNA level was decreased by HGF in human glomeruli. TGF-beta and TIMP-1 gene expression was markedly reduced by HGF treatment, whereas the expression of MMP-9 and c-met did not change. Under light-microscopic examination, kidney biopsies showed neither glomerular hypercellularity nor mesangial expansion. CONCLUSIONS: HGF treatment reduces the expression of extracellular matrix components and of profibrotic factors in human glomeruli. Our results confirm a protective role of HGF in glomerulosclerosis.

Long-term exposure to high glucose up-regulates VCAM-induced endothelial cell adhesiveness to PBMC.

BACKGROUND: The changes induced on endothelial cells by a long-term exposure to high glucose, a situation that mimics the hyperglycemia of diabetics, have not yet been determined. We compared short- and long-term effects of elevated glucose on macrovascular and microvascular endothelial cells. METHODS: Endothelial cells were grown in high-glucose media for 24 hours and for 8 weeks. Cell proliferation was evaluated by cell counting, apoptosis and expression of adhesion molecules by flow cytometry; nitric oxide (NO) by measuring the concentration of nitrite/nitrate in the cell supernatant; alpha 2(IV) collagen mRNA and protein by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The adhesion of peripheral blood mononuclear cells (PBMCs) to endothelial cells was evaluated by adhesion assay. In some experiments, endothelial cells were preincubated with anti-vascular cell adhesion molecule-1 (VCAM-1) and anti-receptor for advanced glycation end product (RAGE) blocking antibodies. RESULTS: At 24 hours, but not at 8 weeks, high glucose increased endothelial cell proliferation and apoptosis. High glucose did not modify NO synthesis at 24 hours and 8 weeks. Collagen production and expression were increased only after eight weeks. VCAM-1 but not intercellular adhesion molecule-1 was up-regulated after 8 weeks, a change not observed after 24 hours. The adhesion of PBMCs was significantly increased at eight weeks and was completely abrogated by anti--VCAM-1 and by anti-RAGE antibodies. After 24 hours, there was a modest increase of PBMC adhesion that was not blunted by anti-RAGE antibodies. CONCLUSIONS: Increased adhesion of PBMCs, caused by up-regulation of VCAM-1 with a mechanism involving advanced glycation end product (AGE) adducts, and augmented collagen deposition are critical effects of long-term high glucose on endothelial cells, and may eventually promote the atherosclerotic process.

Hepatocyte growth factor, but not insulin-like growth factor I, protects podocytes against cyclosporin A-induced apoptosis.

Cyclosporin A (CsA) nephropathy is associated with altered expression of apoptosis regulatory genes such as Fas-ligand and Bcl-2 family members in the glomerular, tubulointerstitial, and vascular compartments. Both hepatocyte growth factor (HGF) and insulin-like growth factor (IGF-I) protect against apoptosis, and HGF specifically up-regulates Bcl-xL, a protein that regulates apoptosis. We investigated whether Bcl-xL and Fas/Fas-ligand were regulated by CsA in cultured podocytes and whether CsA-induced apoptosis was prevented by HGF or IGF-I. A murine podocyte cell line was treated with CsA in the presence or absence of HGF or IGF-I. Apoptosis was quantitated by ELISA and by flow cytometry; Bcl-xL, Fas, and Fas-ligand were measured by Western blotting. Inhibitors of MAP kinase/ERK kinase (MEK)-1 and of phosphatidylinositol 3'-kinase (PI3'-K) were used to determine the signaling pathways involved in Bcl-xL regulation. Apoptosis was induced by CsA in a dose- and time-dependent fashion. CsA also decreased Bcl-xL levels. HGF, but not IGF-I, prevented apoptosis and restored Bcl-xL levels. The regulation of Bcl-xL by HGF was mediated by the PI3'-K but not by the MEK-1 pathway. In summary, we showed that CsA induces apoptosis in podocytes. Apoptosis was prevented by pretreatment with HGF but not IGF-I. Decreased apoptosis appeared to be mediated by regulation of Bcl-xL via the PI3'-K pathway. Our data suggest that the effect of CsA on podocytes may contribute to the glomerular damage and that HGF could provide protection.

Cyclosporine induces different responses in human epithelial, endothelial and fibroblast cell cultures.

BACKGROUND: Nephrotoxicity, accelerated atherosclerosis, and graft vascular disease are common complications of cyclosporine long-term treatment characterized by a wide disruption of organ architecture with increased interstitial areas and accumulation of extracellular matrix (ECM). How cyclosporine induces these changes is not clear, but it is conceivable that they are the sum of changes induced at the cell level. METHODS: We studied the effects of cyclosporine on human endothelial (HEC), epithelial (HK-2), and fibroblast (MRC5) cells. Cell proliferation was evaluated by cell counting, apoptosis and collagen production by enzyme-linked immunosorbent assay, and nitric oxide by measuring the concentration of nitrite/nitrate in the cell supernatant. (alpha1)I and (alpha2)IV collagen, matrix metalloprotease-9 (MMP9), and tissue inhibitors of metalloprotease-1 (TIMP-1) mRNA levels were measured by reverse transcription-polymerase chain reaction. Proteolytic activity was evaluated by zymography. RESULTS: Cyclosporine showed a marked antiproliferative and proapoptotic effect on endothelial and epithelial cells. Fibroblast growth was not affected by cyclosporine. Nitric oxide was up-regulated by cyclosporine in epithelial cells and fibroblasts but not in endothelial cells. (alpha1)I and (alpha2)IV collagen synthesis was increased in cyclosporine-treated endothelial and epithelial cells, respectively. Proteolytic activity was increased in endothelial and epithelial cells. TIMP-1 mRNA was up-regulated by cyclosporine in fibroblasts. CONCLUSIONS: Our results demonstrate that cyclosporine exhibits an antiproliferative effect on endothelial and epithelial cells. This effect is associated with induction of apoptosis probably via nitric oxide up-regulation in epithelial cell cultures. Cyclosporine treatment induces ECM accumulation by increasing collagen synthesis in endothelial and epithelial cells and reducing its degradation by up-regulating TIMP-1 expression in fibroblasts. We conclude that cyclosporine affects cell types differently and that the disruption of organ architecture is the result of multiple effects at the cell level.

Henoch-Schönlein purpura in a chronic hemodialysis patient.

We describe a patient on maintenance hemodialysis who developed purpura, abdominal pain with bloody stool, and gross hematuria. A skin biopsy revealed leukocytoclastic vasculitis with IgA deposits. This is the first report of Henoch-Schönlein purpura in a hemodialysis patient.

Accelerated coronary reperfusion through the use of rapid bedside cardiac markers--case reports.

Each year, acute myocardial infarctions (AMI) account for more than half a million deaths in the United States. Complicating treatment of AMI is the difficulty in accurately diagnosing the event, for patients have nondiagnostic electrocardiograms (ECG) more than 50% of the time. In this population, cardiac markers are essential to confirm the diagnosis. The new bedside cardiac markers, which use eight drops of whole blood and require 15 minutes to be read negative, make it possible to shorten time needed to diagnose AMI. One hundred twenty-seven consecutive patients presented to the emergency department complaining of atypical chest pain. All had ECGs that were nondiagnostic for myocardial infarction. Serial cardiac markers were performed: myoglobin, troponin I, rapid myoglobin, and rapid troponin I. One hundred eighteen patients with negative serial cardiac markers had exercise treadmill tests in the emergency department. Nine patients with positive serial cardiac markers received emergent primary angioplasty. Six of the nine patients were treated based on the positive results of the rapid bedside cardiac markers. A 100% correlation existed between the quantitative serum results and the rapid bedside markers. With the availability of rapid bedside assays, dependency on the laboratory can be minimized, since quantitative cardiac markers require at least 1 hour of turnaround time. Rapidly and correctly diagnosing AMIs in patients with ECGs nondiagnostic for AMI has always been a dilemma. Rapid bedside assays enable the physician to accurately diagnose myocardial infarction and safely decrease the time in evaluating chest pain, thus maximizing the benefits of early reperfusion.

Massive bilateral pulmonary embolism in a patient with subsequent occurrence of severe mitral regurgitation due to ruptured chordae tendineae--a case report.

This report concerns an apparently healthy woman who presented simultaneously with acute massive bilateral pulmonary embolism and mitral regurgitation, subsequently, a month later, resulting in pulmonary edema secondary to chordae rupture of the mitral valve. The authors believe that massive pulmonary embolism predisposed to chordal rupture in this case. It is suggested that increased awareness of ruptured chordae tendineae as a cause of mitral regurgitation and the prompt use of transesophageal echocardiography will facilitate the early recognition of this potentially fatal, but treatable, cause of mitral regurgitation in patients with pulmonary embolism.

Acute results, complications, and effect of lesion characteristics on outcome with the solid-state, pulsed-wave, mid-infrared laser angioplasty system: final multicenter registry report. Holmium:YAG Laser Multicenter Investigators.

BACKGROUND AND OBJECTIVE: The solid-state, mid-infrared holmium:YAG laser (2.1 microm wavelength) is a relatively new percutaneous device that has recently been evaluated in a multicenter study. Because of its unique wavelength and photoacoustic effects on atherosclerotic plaques, this laser may be useful in treatment of symptomatic patients with coronary artery disease. This study sought to evaluate the safety and efficacy of mid-infrared laser angioplasty in the treatment of coronary artery lesions. PATIENTS AND METHODS: Laser angioplasty was performed on 2,038 atherosclerotic lesions in 1,862 consecutive patients with a mean age of 61 +/- 11 years. Clinical indications included unstable angina (69%), stable angina (20%), acute infarction (6%), and positive exercise test (5%). Complex lesion morphology included eccentricity (62%), thrombus (30%), total occlusion (27%), long lesions (14%), and saphenous vein grafts (11%). RESULTS: This laser catheter alone successfully reduced stenosis (>20%) in 87% of lesions. With adjunct balloon angioplasty, 93% procedural success was achieved. The presence of thrombus within the target lesion was a predictor of procedural success (OR = 2.0 [95% confidence interval 2.0, 4.0], P = .04). Bifurcation lesions (OR = 0.5 [95% confidence interval 0.2, 1.0], P = .05) and severe tortuosity of the treated vessel (OR = 0.4 [95% confidence interval 0.2, 0.9], P = .02) were identified as significant predictors of decreased laser success. Calcium within the lesion was associated with reduced procedural success (OR = 0.57 [95% confidence interval 0.34, 0.97], P = .03), and calcified lesions required significantly more energy pulses than noncalcified lesions (119 +/- 91 pulses vs. 101 +/- 86 pulses, respectively, P = .0002). Complications included in-hospital bypass surgery 2.5%, Q-wave myocardial infarction 1.2%, and death 0.8%. Perforation occurred in 2.2% of patients; major dissection in 5.8% of patients, and spasm in 12% of patients. No predictor of major complications was identified. Six-month angiographic restenosis was documented in 54% of patients, and clinical restenosis occurred in 34% of patients. CONCLUSION: Mid-infrared laser has a safety profile similar to that of other debulking devices. This laser may be useful in select patients presenting with acute ischemic syndromes associated with intracoronary thrombus; however, like other coronary lasers, it is limited by the need for adjunctive balloon angioplasty and/or stenting to achieve adequate final luminal diameter. No beneficial effects on reducing 6-month restenosis rates were observed.

Referral pattern and outcome in men and women undergoing coronary artery bypass surgery--a critical review.

Women with coronary artery disease are less likely to undergo coronary artery bypass surgery, and this may represent a potential referral bias in favor of men. A higher in-hospital mortality rate in women compared with men has been reported earlier. Accumulating evidence currently suggests, however, that variables other than gender, such as advanced age, late referral, angina classification, diabetes mellitus, concurrent medical conditions, the number of diseased vessels, the caliber of coronary arteries, and the decreased body surface area in women may have accounted for this difference. In fact, when these variables are taken into account, female gender is no longer a statistically significant predictor of operative mortality. Women appear to have comparable immediate and late survival rates. Recurrent angina, perioperative myocardial infarction, congestive heart failure, incomplete revascularization, and early and late graft reocclusion following surgery are, however, more prevalent in women. Men and women show differences in recovery experiences after discharge following bypass surgery. When coronary bypass surgery is offered to women, the decision should be individualized, based on the patients' perioperative baseline clinical risk factors and coronary anatomy. Coronary artery bypass surgery should not be withheld in women who are considered to be appropriate candidates for fear of a reduced success rate.

Prospective, randomized, multicenter comparison of laser-facilitated balloon angioplasty versus stand-alone balloon angioplasty in patients with obstructive coronary artery disease. The Laser Angioplasty Versus Angioplasty (LAVA) Trial Investigators.

OBJECTIVES: The goal of this study was to examine the relative safety and efficacy of laser-facilitated percutaneous transluminal coronary angioplasty (PTCA) versus "stand-alone" PTCA. BACKGROUND: Plaque debulking with lasing before PTCA may result in improved lumen dimensions and decreased rates of periprocedural ischemic complications, thus improving short- and long-term outcomes after percutaneous intervention. The mid-infrared holmium:yttrium-aluminum-garnet (YAG) laser has been shown to be effective in a variety of plaque subtypes and may be particularly useful in high risk acute ischemic syndromes. METHODS: A total of 215 patients (mean [+/-SD] age 61 +/- 12 years) with 244 lesions were prospectively randomized at 14 clinical centers to laser versus stand-alone PTCA. After laser treatment, all patients underwent PTCA; 148 patients (69%) had unstable angina. RESULTS: The procedural success rate without major catheterization laboratory complications was similar in patients assigned to laser treatment or PTCA alone (96.6% vs. 96.9%, p = 0.88), as was the in-hospital clinical success rate (89.7% vs. 93.9%, p = 0.27). There was no difference in postprocedural diameter stenosis after laser treatment compared with PTCA (18.3% +/- 13.6% vs. 19.5% +/- 15.1%, p = 0.50). However, use of the laser, versus PTCA alone, did result in significantly more major and minor procedural complications (18.0% vs. 3.1%, p = 0.0004), myocardial infarctions (4.3% vs. 0%, p = 0.04) and total in-hospital major adverse events (103% vs. 4.1%, p = 0.08). At a mean follow-up time of 11.2 +/- 7.7 months, there were no differences in late or event-free survival in patients assigned to laser treatment versus PTCA alone. CONCLUSIONS: Compared with stand-alone PTCA, laser-facilitated PTCA results in a more complicated hospital course, without immediate or long-term benefits.

Trends in success rate after percutaneous transluminal coronary angioplasty in men and women with coronary artery disease.

Women with coronary artery disease are less likely to undergo percutaneous transluminal coronary angioplasty (PTCA) because of the potential referral bias in favor of men with coronary artery disease in the use of invasive diagnostic procedures and interventions. This difference may represent a sex bias in the delivery of medical care. The apparent sex difference in short-term success of PTCA seen in the early 1980s has not persisted in subsequent studies. The higher in-hospital mortality rate, if any, in women compared with men after PTCA is related more to the severity of their underlying disease rather than sex alone. In addition, women have a better long-term PTCA success rate. PTCA should not be withheld in women who are considered appropriate anatomic candidates for fear of reduced success or increased major complications.

Clinical experience with the use of the angled-balloon dilatation catheter.

A special balloon catheter has been developed for use in coronary angioplasty. The balloon portion has a 135 degrees - 145 degrees angle at its mid portion. It is designed for stenosis located at an angle of the coronary artery. We investigated the use of this catheter in 39 patients who underwent percutaneous transluminal coronary angioplasty (PTCA): 29 men and 10 women. PTCA was attempted in 43 stenotic sites. Thirty-two stenoses were located at the angled portion of the dilated arteries. Eleven stenoses were located at the side branches of the acutely angled bifurcations. Twenty stenoses were in the right coronary artery distribution. Twenty-two stenoses were in the left coronary artery distribution. One stenosis was at the origin of the left internal mammary artery. Forty-one stenoses were angioplastied successfully (95.4%). No angiographic evidence of intimal tear or dissection was noted in all of the dilated vessels. Acute closure was not observed. The mean follow-up period was 239.5 days. Six patients (15.4%) were found to have restenosis. We conclude that the use of the angled-balloon dilatation catheter provides the potential benefit of reducing intimal trauma and dissection during PTCA of certain coronary anatomies--stenosis at the angled portion or at the takeoff of the side branch of a bifurcation.

Laser angioplasty of totally occluded coronary arteries and vein grafts: preliminary report on a current trial.

CLINICAL PERSPECTIVE: Among the various laser angioplasty systems and atherectomy devices currently in clinical trials, the Lastac system appears to be particularly suitable for treating totally occluded coronary arteries and vein grafts. Preliminary results of a clinical trial in more than 35 patients show a recanalization rate of 92% and no complications attributable to the laser. Restenosis has occurred in five cases; in three of these, the arteries were reopened with laser or conventional angioplasty.

Percutaneous transluminal angioplasty of a stenosis at the origin of the left internal mammary artery graft: a case report.

A case of percutaneous transluminal angioplasty of a high-grade stenosis at the origin of the left internal mammary graft is presented. An investigational angled-balloon dilating catheter was used.