Novel UL23 and UL30 substitutions in HSV1 and HSV2 viruses related to polymorphism or drug resistance.

Data on herpes simplex virus (HSV) polymorphism as well as acyclovir (ACV) and foscarnet (FOS) resistance mutations are not exhaustive and may hinder accurate diagnosis by next-generation sequencing (NGS). Here, we report novel UL23 and UL30 substitutions for HSV1 and HSV2 identified in immunocompromised patients treated for hematological malignancies during the last 6 years of HSV resistance surveillance at the University Hospital of Lyon. For HSV1, 35 novel UL23 substitutions and 52 novel UL30 substitutions were identified. For HSV2, 2 novel UL23 substitutions and 12 novel UL30 substitutions were identified. These results allow to complete the database of HSV1 and HSV2 substitutions, related either to polymorphism or to ACV and FOS resistance.

Sustained intra-cartilage delivery of interleukin-1 receptor antagonist using cationic peptide and protein-based carriers.

OBJECTIVE: Blocking the interleukin-1 (IL-1) catabolic cascade following joint trauma can be achieved using its receptor antagonist, IL-1Ra. However, its clinical translation for osteoarthritis therapy has been unsuccessful due to its rapid joint clearance and lack of targeting and penetration into deep cartilage layers at therapeutic concentrations. Here, we target the high negative charge of cartilage aggrecan-glycosaminoglycans (GAGs) by attaching cationic carriers to IL-1Ra. IL-1Ra was conjugated to the cartilage targeting glycoprotein, Avidin, and a short length optimally charged cationic peptide carrier (CPC+14). It is hypothesized that electro-diffusive transport and binding properties of IL-1Ra-Avidin and IL-1Ra-CPC+14 will create intra-cartilage depots of IL-1Ra, resulting in long-term suppression of IL-1 catabolism with only a single administration. DESIGN: IL-1Ra was conjugated to Avidin or CPC+14 using site specific maleimide linkers, and confirmed using gel electrophoresis, high-performance liquid chromatography (HPLC), and mass spectrometry. Intra-cartilage transport and retention of conjugates was compared with native IL-1Ra. Attenuation of IL-1 catabolic signaling with one-time dose of IL-1Ra-CPC+14 and IL-1Ra-Avidin was assessed over 16 days using IL-1α challenged bovine cartilage and compared with unmodified IL-1Ra. RESULTS: Positively charged IL-1Ra penetrated through the full-thickness of cartilage, creating a drug depot. A single dose of unmodified IL-1Ra was not sufficient to attenuate IL-1-induced cartilage deterioration over 16 days. However, when delivered using Avidin, and to a greater extent CPC+14, IL-1Ra significantly suppressed cytokine induced GAG loss and nitrite release while improving cell metabolism and viability. CONCLUSION: Charge-based cartilage targeting drug delivery systems hold promise as they can enable long-term therapeutic benefit with only a single dose.

Impact of Wilms' tumor 1 expression on outcome of patients undergoing allogeneic stem cell transplantation for AML.

The monitoring of the minimal residual disease by Wilms' tumor 1 expression (MRDWT1) is a standardized test, which can be used in over 80% of patients with AML. To investigate the prognostic value of MRDWT1 in patients undergoing allogeneic stem cell transplantation (allo-SCT) for AML, MRDWT1 was monitored 3 months after transplantation in 139 patients. MRDWT1 positivity did not lead to any therapeutic intervention. Median follow-up was 39.3 (6.4-99.8) months. Patients with positive MRDWT1 at 3 months experienced more often post-transplant relapse (27/30, 90%) than those with negative MRDWT1 (16/109, 14.7%) (P<0.0001). Similarly, a shorter 3-year event-free survival (EFS) was observed in MRDWT1-positive patients (10% vs 72.3% in MRDWT1-negative patients, P<0.0001). The correlation between relapse and MRDWT1 was stronger in blood than in bone marrow samples. Multivariate analysis confirmed the detrimental role of 3-month positive MRDWT1 for relapse (hazard ratio (HR): 15.42; 95% confidence interval (CI): 7.53-31.59; P<0.0001) and EFS (HR: 10.71; 95% CI: 5.41-21.21; P<0.0001). Interestingly, 3-month chimerism was less predictive of relapse than positive MRDWT1. In conclusion, our results demonstrate the usefulness of peripheral blood MRDWT1 monitoring in identifying very high-risk patients, who could benefit from an early preemptive treatment, and those who do not need such an intervention.

[Renal extramedullary hematopoietic tumor revealing a hereditary spherocytosis in an adult patient]. / Révélation à l'âge adulte d'une sphérocytose héréditaire devant une tumeur rénale: forme frontière entre myélolipome et foyer d'hématopoïèse extra-médullaire.

INTRODUCTION: Myelolipomas and extramedullary hematopoietic tumors are uncommon benign tumors. They are variably composed of mature adipose tissue and hematopoietic tissue. Myelolipoma is usually observed in the adrenal gland and extramedullary hematopoietic tumors in the liver and spleen but may occasionally be found within solid tumors. CASE REPORT: A 62-year-old man without previous haematological history presented with a voluminous solitary bilateral renal tumor. Contrast-enhanced ultrasound CT-scan and scintigraphy with technetium-99m-nanocolloid and indium-111-chloride bone marrow were highly suggestive of extramedullary hematopoietic tumor. CT-guided biopsy suggested a diagnosis of myelolipoma. An atypical hereditary spherocytosis, undiagnosed until now, was demonstrated. CONCLUSION: We report, for the first time to our knowledge, a border form between extramedullary hematopoiesis tumor and myelolipoma of renal localisation revealing a hereditary spherocytosis in an adult patient.

Assessment of arthroscopic management of femoroacetabular impingement. A prospective multicenter study.

INTRODUCTION: Surgical treatment of femoroacetabular impingement can be performed under arthroscopic control, to limit associated morbidity. Encouraged by recent good reports, arthroscopy is replacing alternative techniques for this indication. HYPOTHESIS: Arthroscopy enables femoroacetabular impingement to be corrected with a low rate of associated morbidity. AIM OF STUDY: To assess the indications for and quality of the technique and its impact on preliminary results and complications. To investigate preoperative prognostic factors. PATIENT AND METHODS: One hundred and eleven hips in 110 patients (78 male, 32 female; mean age, 31 years) were operated on under arthroscopic control for femoroacetabular impingement, by six senior surgeons. Sixty-five patients showed no radiographic sign of osteoarthritis, and 36 showed grade-1 early osteoarthritis on the Tönnis scale. RESULTS: Mean WOMAC score rose from 60.3 preoperatively to 83 (p<0.001) at a mean 10 months' FU (range, 6-18 mo). Seventy-seven percent of patients were satisfied or very satisfied with their result. Patients with early osteoarthritis had significantly lower WOMAC and satisfaction scores than those free of osteoarthritis. Operative crossover to open surgery occurred in only one case. Five patients (4%) had revision: total hip replacement or resurfacing. There were seven complications (6%): three cases of heterotopic ossification, one of crural palsy, one of pudendal palsy, one of labium majus necrosis, and one non-displacement stress fracture of the femoral head/neck junction (managed by non-weight-bearing). There was no palsy of the territory of the lateral cutaneous nerve of the thigh. DISCUSSION: Results confirmed the efficacy and low associated morbidity of arthroscopy in the management of femoroacetabular impingement. Short-term functional results matched those of the literature. Planning and assessment seem not yet to be fully standardized. Preoperative osteoarthritis on X-ray was associated with poorer functional results. This attitude does not seem to be indicated for hips showing evolved osteoarthritis (>grade 1).

Descriptive epidemiology of mechanical hip pathology in adults under 50 years of age. Prospective series of 292 cases: Clinical and radiological aspects and physiopathological review.

Two hundred and ninety-two patients, aged between 16 and 50 years and presenting with mechanical hip pathology, were included in a prospective multicenter study. The descriptive study concerned the clinical examination and analysis of three X-ray views (AP pelvic, Lequesne false profile and lateral axial view). The series comprised 62% males, mean age 35 years, with 53% right side and 22% bilateral involvement. Initial trauma was reported in 19% of cases, and direct familial history of hip pathology in 20%. Seventy percent of the patients played sports, 30% were high-level athletes, and 17% played combat sports. The physical impingement sign was present in 18% to 65% of cases depending on the variant studied. On imaging (n=241), 62% of hips showed osteoarthritis, with 25% at the evolved stage. In the series, as a whole, there was a 35% rate of dysplasia, 63% of impingement and 5% of normal X-ray results. The radiologic impingement aspects were 58% cam-type, 19% pincer-type and 23% mixed. Twenty-two percent of dysplasia cases showed signs of associated impingement. Pain experienced exclusively in flexion/internal rotation/adduction on examination showed little sensitivity (20%) but considerable specificity (86%) for the main diagnosis of impingement. The links between impingement and dysplasia are discussed, and an integrative schema of all risk factors is put forward.

Imaging data in a prospective series of adult hip pain in under-50 year-olds.

Two hundred and ninety-two patients under the age of 50 years, presenting with mechanical hip pain, were included in a prospective multicenter study. In 241 cases, imaging assessment included AP standing pelvic X-ray and Lequesne's false profile (LFP) and/or lateral neck (Ducroquet, Dunn or variant) hip X-ray. Cross-sectional arthroscan and/or arthro-MRI images were available in 81 cases. Exploration looked for acetabular and femoral head/neck dysplasia liable to induce cam or pincer anterior femoroacetabular impingement (AFAI), respectively. Labral and chondral lesions arise secondarily to hip osteoarthritis (HOA) and/or AFAI. Two-thirds of patients showed HOA. Only 6% showed a strictly normal aspect on imaging. More than half (52%) of cases had cam AFAI, half of these involving an osteophytic neck, associated in more than 90% of cases with large multifocal bone spurs of the head, neck and acetabula. These cases were considered ambiguous, due to the uncertainty as to the congenital nature of the cervico-cephalic dysmorphy; if they are excluded, only 23% of the series involved cam AFAI. Crossover sign on AP standing pelvic X-ray is the best assessment criterion for acetabular retroversion, the most frequent form of acetabular dysplasia underlying pincer AFAI, and should be explored for. Secondary neck lesions were visible only on lateral neck view in 42% of cases: this view should be included in standard radiologic work-up in under-50 year-olds. The alpha angle can be measured on this type of lateral view and on axial arthroscan and arthro-MR images; more than half of the cases in which it was pathological involved an osteophytic neck and thus a pseudo-cam effect.

Arthroscopy in primary synovial chondromatosis of the hip: description and outcome of treatment.

Between 1985 and 2000, 120 patients underwent arthroscopic management for primary synovial chondromatosis of the hip. We report the outcome of 111 patients with a mean follow-up of 78.6 months (12 to 196). More than one arthroscopy was required in 23 patients (20.7%), and 42 patients (37.8%) went on to require open surgery. Outcomes were evaluated in greater detail in 69 patients (62.2%) treated with arthroscopy alone, of whom 51 (45.9%) required no further treatment and 18 (16.2%) required further arthroscopies. Of the 111 patients, 63 (56.7%) had excellent or good outcomes. At the most recent follow-up, 22 patients (19.8%) had undergone total hip replacement. Hip arthroscopy proved beneficial for patients diagnosed with primary synovial chondromatosis of the hip, providing good or excellent outcomes in more than half the cases.

[Arthroscopic treatment of calcifying tendinitis of the rotator cuff]. / Traitement arthroscopique des calcifications de l'épaule.

The treatment of symptomatic calcifying tendinitis of the rotator cuff is usally medical. Whereas, chronic and painfull features can beneficiate of a surgical treatment. With shoulder arthroscopy it's possible to remove the type A and B calcifications and to perform a bursectomy and acromioplasty in type C uncollected. The clinical and radiological results with one year of follow-up upgrate 90% of good and excellent results. Calcifying tendinitis reatment appear like one of the best indications of the shoulder arthroscopy.

BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor.

Mutational inactivation of BRCA1 confers a cumulative lifetime risk of breast and ovarian cancers. However, the underlying basis for the tissue-restricted tumor-suppressive properties of BRCA1 remains poorly defined. Here we show that BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor alpha (ERalpha), a principal determinant of the growth, differentiation, and normal functional status of breasts and ovaries. In Brca1-null mouse embryo fibroblasts and BRCA1-deficient human ovarian cancer cells, ERalpha exhibited ligand-independent transcriptional activity that was not observed in Brca1-proficient cells. Ectopic expression in Brca1-deficient cells of wild-type BRCA1, but not clinically validated BRCA1 missense mutants, restored ligand-independent repression of ERalpha in a manner dependent upon apparent histone deacetylase activity. In estrogen-dependent human breast cancer cells, chromatin immunoprecipitation analysis revealed the association of BRCA1 with ERalpha at endogenous estrogen-response elements before, but not after estrogen stimulation. Collectively, these results reveal BRCA1 to be a ligand-reversible barrier to transcriptional activation by unliganded promoter-bound ERalpha and suggest a possible mechanism by which functional inactivation of BRCA1 could promote tumorigenesis through inappropriate hormonal regulation of mammary and ovarian epithelial cell proliferation.

Serum hyaluronic acid in patients with veno-occlusive disease following bone marrow transplantation.

The development of hepatic veno-occlusive disease following bone marrow transplantation is associated with high-dose combination cytoreductive therapy. Experimental models have suggested that drug-induced injury to hepatic sinusoidal endothelial cells is involved in the pathogenesis of this syndrome. Hyaluronic acid is a polysaccharide that is metabolized, almost exclusively, by hepatic sinusoidal endothelial cells. The aim of the present study was to evaluate serum hyaluronic acid as a marker for endothelial cell injury in patients with veno-occlusive disease following bone marrow transplantation. Hyaluronic acid was measured in sera from patients with and without veno-occlusive disease using an enzyme-linked protein binding assay. Mean peak serum hyaluronic acid levels were significantly greater in patients who had a diagnosis of VOD compared to those transplant patients who did not, 1173.4 +/- 982.9 vs 444.9 +/- 735.6 ng/ml (P = 0.01). Serial serum samples obtained from a separate cohort of patients also demonstrated that serum hyaluronic acid levels were higher in patients with moderate or severe veno-occlusive disease compared to those with none or mild disease at days 7, 17 and 25 following transplantation (greatest difference at day 25: 366 +/- 327 vs 126 +/- 151, P = 0.01). Serum hyaluronic acid levels are increased in veno-occlusive disease and increase over time in patients with severe disease. Further studies are required to determine if elevated serum hyaluronic acid levels are due to decreased clearance by injured hepatic sinusoidal endothelial cells or increased production from early hepatic fibrogenesis associated with the acute liver injury.

Genome mining for human cancer genes: wherefore art thou?

In an initial data-mining effort, the draft human genome was searched to find paralogs of known tumor suppressor genes, and for gene arrangements, which are typical of oncogenes, in cancer cells. The results were disappointing, indicating that although knowledge of the human genome will undoubtedly be of great help, other approaches to identify new oncogenes are needed.

Autoimmune hepatitis in African Americans: presenting features and response to therapy.

OBJECTIVES: African Americans are at an increased risk for certain diseases and more frequently suffer complications of those diseases relative to their white counterparts. Most studies of autoimmune hepatitis consist of entirely white populations. The Emory University system of hospitals serves a large African American population, including a significant number of African Americans with autoimmune hepatitis. The goal of this study was to determine if the presentation and response to therapy in African Americans is, like other diseases, different than in whites. METHODS: This is a retrospective study from a tertiary referral center that examines the initial presenting features and response to therapy of African Americans (n = 27) and whites (n = 24) with autoimmune hepatitis. RESULTS: Eighty-five percent of African Americans had cirrhosis on the initial liver biopsy, as compared with 38% of whites. Although not statistically significant, the African Americans presented at an earlier age than white patients. The disease also appeared more advanced in African Americans, as bilibubin levels tended to be higher, but not significantly, and PTs were more prolonged. Both groups responded well to therapy, with significant falls in serum levels of AST, ALT, and bilirubin. Fifty percent of African Americans and 48% of whites entered a biochemical remission. The amount of prednisone required to maintain remission at follow-up was greater in African Americans. CONCLUSION: In contrast to whites, the majority of African Americans present with cirrhosis. Despite the high prevalence of cirrhosis, the response to therapy is good. However, more immunosuppression is required to control the disease in African Americans.

Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1.

BRCA1 has been implicated in the transcriptional regulation of DNA damage-inducible genes that function in cell cycle arrest. To explore the mechanistic basis for this regulation, a novel human gene, ZBRK1, which encodes a 60 kDa protein with an N-terminal KRAB domain and eight central zinc fingers, was identified by virtue of its interaction with BRCA1 in vitro and in vivo. ZBRK1 binds to a specific sequence, GGGxxx CAGxxxTTT, within GADD45 intron 3 that supports the assembly of a nuclear complex minimally containing both ZBRK1 and BRCA1. ZBRK1 represses transcription through this recognition sequence in a BRCA1-dependent manner. These results thus reveal a novel corepressor function for BRCA1 and provide a mechanistic basis for the biological activity of BRCA1 through sequence-specific transcriptional regulation.

Lessons learned from BRCA1 and BRCA2.

BRCA1 and BRCA2 are breast cancer susceptibility genes. Mutations within BRCA1 and BRCA1 are responsible for most familial breast cancer cases. Targeted deletion of Brca1 or Brca2 in mice has revealed an essential function for their encoded products, BRCA1 and BRCA2, in cell proliferation during embryogenesis. Mouse models established from conditional expression of mutant Brca1 alleles develop mammary gland tumors, providing compelling evidence that BRCA1 functions as a breast cancer suppressor. Human cancer cells and mouse cells deficient in BRCA1 or BRCA2 exhibit radiation hypersensitivity and chromosomal abnormalities, thus revealing a potential role for both BRCA1 and BRCA2 in the maintenance of genetic stability through participation in the cellular response to DNA damage. Functional analyses of the BRCA1 and BRCA2 gene products have established their dual participation in transcription regulation and DNA damage repair. Potential insight into the molecular basis for these functions of BRCA1 and BRCA2 has been provided by studies that implicate these two tumor suppressors in both the maintenance of genetic stability and the regulation of cell growth and differentiation.

Contribution of arthroscopy and magnetic resonance imaging to the evaluation of painful knee osteoarthritis.

In knee osteoarthritis, arthroscopy provides valuable information that suggests an original approach to the disease. In combination with recent imaging study data, this information can be used to develop a novel concept of the evaluation of knee osteoarthritis. The main mechanisms responsible for flares of the disease seem to be synovitis, degenerative meniscal disease, and subchondral bone lesions. Treatments targeted at each of these mechanisms can be used as appropriate. Determination of the exact nature of the lesions can be difficult and relies at present on sophisticated investigations not readily available in everyday practice. Further work is needed to determine how a finer analysis of symptoms and signs in combination with simple investigations can differentiate between the various pathological patterns of knee osteoarthritis.