Contrasting effect of new HCMV pUL54 mutations on antiviral drug susceptibility: Benefits and limits of 3D analysis.

Human cytomegalovirus (HCMV) resistance to antiviral drugs is a major drawback of repeated or long-duration treatment in immunocompromised patients. Resistance testing is usually performed by genotypic assays. For accurate interpretation of these assays, the role of new mutations in HCMV resistance has to be assessed. Two previously unknown UL54 single point mutations (D515Y and V787A) were characterized for phenotypic drug-resistance by marker transfer analysis using bacterial artificial chromosome (BAC) mutagenesis. Increases in 50% inhibitory concentrations of ganciclovir and foscarnet were found for both mutated recombinant strains showing that mutations D515Y and V787A induce resistance to both antivirals. Importantly, none of those impacted the viral growth kinetics. For a better understanding of their molecular resistance mechanisms, a 3D homology model was used to localize the mutated amino-acids in functional domains of UL54 and predict their impact on UL54 function and resistance. However, 3D homology model analysis has limits and phenotypic characterization using BAC-HCMV is still essential to measure the role of unknown mutations.

[Wegener granulomatosis and aneurysmal subarachnoid hemorrhage: an insignificant association?]. / Hémorragie sous-arachnoïdienne anévrismale et maladie de Wegener: une association peu commune.

BACKGROUND: Wegener granulomatosis (WG) is an uncommon systemic necrotizing vasculitis that demonstrates renal and respiratory tropism. While the pathogenesis of WG remains controversial, autoimmune and inflammatory mechanisms are likely to be involved. The nervous system could be affected in up to 54% of cases. Although central nervous system involvement has been reported in 7-11% of cases, aneurysmal subarachnoid hemorrhage (SAH) occurrence is exceptional. METHODS: We describe the third reported case of WG-related aneurysmal SAH and then discuss the diagnosis and pathogenesis of WG along with the physiopathology of intracranial aneurysm in light of recent data reported in the literature. RESULTS: A 63-year-old woman with WG was referred to our neurosurgical department for aneurysmal SAH. The vasculitis diagnosis had been established 4 years earlier when she presented with chronic sinusitis, recurrent cystitis, and renal failure. The cerebral angiography revealed an anterior communicating artery dysplastic aneurysm. The neurosurgical management of the aneurysm was scheduled but delayed because the patient was experiencing a vasculitis flare-up. Immunosuppressive therapy and intravenous corticotherapy were given, with the patient's improvement, allowing neurosurgical clipping of the aneurysm. CONCLUSIONS: Wegener granulomatosis-related aneurysmal SAH is an exceptional condition in neurovascular pathology. As inflammatory mechanisms are involved in the pathogenesis of aneurysm, the vasculitis flare-up could account for this SAH. The management of WG could benefit from anti-inflammatory therapy, as could the vasculitis-related SAH. SAH occurrence in patients with systemic vasculitis could indicate a vasculitis flare-up.

The Impact of type 2 diabetes on mortality in end-stage renal disease patients differs between genders.

BACKGROUND/AIMS: In diabetics with end-stage renal disease (ESRD), risk of death has been reported to be non-constant after the first dialysis, and different outcomes have been observed between genders. We assessed the impact of type 2 diabetes (T2DM) on mortality in dialysis regarding its differential effect by gender using time-dependent analyses. METHODS: All T2DM and non-diabetic (no-DM) patients who started dialysis in two renal units in Lyon, France, between January 1, 1995, and December 31, 2007, were included. In multivariate analyses, the Cox model and Shoenfeld residual approach were used to assess the effect of T2DM on dialysis mortality by gender. RESULTS: We included 235 T2DM (males: 57.9%) and 480 no-DM (males: 65.6%) patients. In males, the adjusted hazard ratio (aHR) for death in T2DM versus no-DM was 0.83 (p = 0.20) and was constant over time after the first renal replacement therapy (RRT) (p = 0.88). In females, aHR for death in T2DM versus no-DM patients was not constant over time (p = 0.002). It was 0.64 (p = 0.13) within the first year after the first RRT and 2.10 (p = 0.002) after the first year. Evolutions with time of these aHR by gender were significantly different (p = 0.009). CONCLUSIONS: T2DM was associated with death only in females. This association was not constant over time after the first dialysis.

[Granulomatous arteritis through sarcoidosis]. / Antrite granulomateuse par sarcoïdose.

INTRODUCTION: Digestive localisation of sarcoidosis is rare. OBSERVATION: A 35 year-old man presented with sarcoidosis revealed by a mediastinal hilum lymphadenopathy 13 years earlier. Epigastric pain led to oeso-gastroduodenal fibroscopy and biopsies, showing inflammatory mucosa and numerous giant-cell epithelioid granulomas, without concomitant necrosis or fibrosis. COMMENTS: The clinical manifestations and endoscopic profile of gastric localisations of sarcoidosis are not specific. Diagnosis relies on several elements: presence of epithelioid granulomas without necrosis, history of sarcoidosis or the simultaneous existence of other localisations, evocative biological signs and the absence of elements evoking any other diagnosis. Treatment relies on corticosteroid therapy and sometimes requires endoscopic or surgical management.

Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression.

BACKGROUND: The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients. METHODS: This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1-2 mg/kg per day. RESULTS: At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P=0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P=0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P=0.009), leukopenia (37.3% vs. 9.5%, P<0.001), fever (25.2% vs. 10.1%, P=0.001), herpes simplex (17.9% vs. 5.7%, P=0.001), and thrombocytopenia (11.3% vs. 3.2%, P=0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction). CONCLUSION: Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

Transplanted renal artery: detection of stenosis with color Doppler US.

PURPOSE: To evaluate the influence of various parameters on peak systolic velocity in the transplanted renal artery and to define the normal range of peak systolic velocity. MATERIAL AND METHODS: Color Doppler ultrasonographic (US) findings in 105 patients were reviewed. There were no clinical or biologic findings suggestive of a stenosis in the transplanted renal artery in these patients. The peak systolic velocity in the transplanted renal and external iliac arteries and the renal resistive index were measured. RESULTS: A large range of peak systolic velocities was noted in the transplanted renal artery. Peak systolic velocity in the renal artery was statistically significantly correlated with that in the external iliac artery when there was no pronounced vessel curvature. There was no relationship between peak systolic velocity and resistive index or time between transplantation and US. High peak systolic velocity was associated with a pronounced vessel curvature. CONCLUSION: The normal range of peak systolic velocity in the transplanted renal artery has considerable variability. Because of the strong correlation, the ratio of velocity in the renal artery to that in the external iliac artery may be useful in detection of stenosis.

Transplant renal artery stenosis. Evaluation of diagnosis with magnetic resonance angiography compared with color duplex sonography and arteriography.

The goal of this study was to assess the value of a three-dimensional phase contrast magnetic resonance angiography (3D PC MRA) for diagnosing transplant renal artery stenosis (TRAS). Twelve consecutive patients clinically suspected of having TRAS were prospectively enrolled during a period of 18 months. Delays from transplantation varied from 3 months to 4 years (mean: 18.3 months). Patients first had color Doppler sonography, then MRA-and, on the following day, intraarterial digital subtraction angiography (IADSA). The site of the maximum peak systolic velocity was noted when doing the report of each color Doppler sonogram. On MRA images, any signal cutoff or any vascular narrowing of more than 50% of the diameter of the vessel was considered to be a significant stenosis. Eight patients were considered to have TRAS on MRA, but only two stenoses were noted on IADSA. The six false-positive results of MRA (due to major intravoxel phase dispersion) were observed when elevated peak systolic velocities were noted on doppler sonograms (mean: 214 cm/sec). These elevated peak systolic velocities were noted in the proximal part of the renal artery when there was a tortuous vessel or a sharp angle between the renal artery and the parent vessel. It is our opinion that 3D PC MRA is of limited value for the diagnosis of renal transplant artery stenosis because of a high number of false-positive results.

MR angiography of renal artery stenosis: value of the combination of three-dimensional time-of-flight and three-dimensional phase-contrast MR angiography sequences.

OBJECTIVE: It has been reported and also has been our preliminary experience that many false ostial stenoses are attributable to a loss of signal intensity at the origin of the renal arteries when three-dimensional (3D) phase-contrast MR angiography is used. Our objective was to add a 3D time-of-flight MR angiography sequence to the 3D phase-contrast MR angiography sequence to better analyze the origin of the main renal arteries. We assessed the value of the combination of these two MR angiography sequences for the depiction of renal artery stenosis. SUBJECTS AND METHODS: Forty-six patients suspected of having renal artery stenosis on the basis of clinical history, physical examination, and laboratory data were prospectively enrolled. Intraarterial digital subtraction angiography findings were available for all patients. Using intraarterial digital subtraction angiography, we considered stenosis to be significant when the vessel was narrowed more than 50%. During MR angiography, half of the data were reconstructed by interpolation to avoid long acquisition times. Total acquisition times were less than 15 min. MR angiography findings were interpreted independently by two radiologists who were unaware of the findings of intraarterial digital subtraction angiography. With 3D phase-contrast MR angiography, any cutoff in signal intensity or any narrowing of the vessel diameter of more than 50% from the renal ostium to the renal hilum was considered to represent significant stenosis. With 3D time-of-flight MR angiography, our image analysis was focused on the origin of the arteries. Any cutoff in signal intensity in the first centimeter of the renal artery was considered to represent significant stenosis. RESULTS: Intraarterial digital subtraction angiography showed 105 renal arteries, including 15 supernumerary renal arteries. Eleven stenoses were localized to the main hilar renal arteries. Using time-of-flight MR angiography, we found that polar supernumerary renal arteries of small caliber and intrarenal branches of renal arteries were not adequately displayed. Using phase-contrast MR angiography to evaluate only whether the main hilar renal arteries were stenotic, we calculated the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy to be 100%, 65%, 28%, 100%, and 69%, respectively. Using a combination of the two imaging sequences, we found that the specificity, positive predictive value, and accuracy were increased to 90%, 58%, and 92%, respectively. CONCLUSION: For detecting stenoses of the main renal arteries but not for visualizing small accessory renal arteries or distal branches, our results support the use of a combination of the two MR angiography sequences. For now, this combination of sequences should be viewed primarily as a technique for screening patients.

Hodgkin's disease after transplantation.

Hodgkin's disease (HD) has seldom been reported after transplantation. Epstein-Barr virus (EBV) is present in about 50% of Reed-Sternberg cells in HD developing in immunocompetent individuals, but is more frequently found in HD of acquired immune deficiency syndrome patients. We report 7 cases of HD that occurred in transplant recipients. Clinical and pathological data and studies of EBV reveal specific features of HD after transplantation. Six patients received kidney transplants and 1 patient received combined kidney and pancreas transplantation. Immunosuppressive therapy consisted of cyclosporine, steroids, azathioprine, and antilymphocyte globulins. One patient received, in addition, anti-CD3 mAb therapy and an EBV+ B cell lymphoma developed. Retrospective EBV serological data from patients were collected. Tumors were classified according to pathology. EBV studies were conducted by immunohistochemical methods with monoclonal antibodies to EBV-latent membrane protein (LMP) or EBV-nuclear antigen 2 (EBNA2), and by in situ hybridization for latent nuclear EBV-early RNAs (EBERs). The mean lapse of time between transplantation and HD was 49 months. Six patients presented with enlarged lymph nodes and 1 patient presented with liver involvement. HD was classified as IA in 2 patients, IIA in 3 patients, IIIB in 1 patient, and IVB in 1 patient. Four patients had primary EBV infection after graft, before HD, and the others reactivated latent EBV infection. Histological subtypes were mixed cellularity in 6 cases and lymphocytic depletion in 1 case. Latent EBV infection was detected with EBERs in all tumors. Reed-Sternberg cells expressed LMP, and were negative for EBNA2 expression. Six patients were treated: 2 patients at stage I received radiotherapy, and relapsed within 1 year with a more advanced stage of HD; chemotherapy was indicated as primary therapy in 5 patients, and as salvage therapy in 2 patients; it was associated with radiotherapy in 4 patients. Immunosuppressive therapy was reduced in all patients. Four patients were alive and in complete remission 18, 25, 31, and 67 months after chemotherapy, with a functioning graft in 3 patients. Two patients died of infection. Mixed cellularity is the most frequent histological subtype observed in HD occurring in transplant patients. EBV is present in all Reed-Sternberg cells. Posttransplant HD shows similarities with human immunodeficiency virus-associated HD. These facts argue for a role of EBV infection and immunosuppression in the progression of HD after transplantation.

Crescentic glomerulonephritis and crystals within glomerular capillaries in an AIDS patient treated with foscarnet.

We report on a 28-year-old AIDS patient who developed a rapidly progressive glomerulonephritis while being treated with foscarnet for cytomegalovirus retinitis. Renal biopsy showed crescentic proliferation related to crystals within the glomerular capillaries. The role of foscarnet in this unusual renal syndrome is discussed.