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.

F74 plasmids are major vectors of virulence genes in bovine NTEC2.

Necrotoxigenic Escherichia coli 2 (NTEC2) are defined as E. coli producing the toxin known as cytotoxic necrotizing factor 2 (CNF2), a potent toxin primarily found in bovine but also in humans. NTEC2 are mostly associated with bovine, and cnf2 is known to be carried by pVir-like plasmids. In this study, we looked for NTEC2 in a collection of E. coli collected between 2011 and 2018 in French bovine. Thirty-two isolates, collected from both sick (n = 19) and healthy (n = 13) animals, were identified and characterized using whole-genome sequencing. One F74 plasmid of this bacterial collection was long-read sequenced: its size was 138 121 bp and it carried the cnf2, F17cA-eG, cdtB, iutA, iucC and ompP virulence factors (VFs), but no resistance gene. A large variety of genetic backgrounds was observed, but all cnf2-carrying plasmids belonged to the IncF family, and most of them (78·1%) were of the F74 group. Similar F74 plasmids were also reported from bovine in the United Kingdom and the United States, as identified in the publically available databases. Consequently, these F74 plasmids, which are widely disseminated among E. coli from cattle in the French territory, are vectors of virulence determinants that largely went unnoticed until now.

Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.

BACKGROUND: The goal of hepatorenal syndrome type 1 (HRS-1) treatment is to improve renal function. Terlipressin, a synthetic vasopressin analogue, is a systemic vasoconstrictor used for the treatment of HRS-1, where it is available. AIM: To compare the efficacy of terlipressin plus albumin vs. placebo plus albumin in patients with HRS-1. METHODS: Pooled patient-level data from two large phase 3, randomised, placebo-controlled studies were analysed for HRS reversal [serum creatinine (SCr) value ≤133 µmol/L], 90-day survival, need for renal replacement therapy and predictors of HRS reversal. Patients received intravenous terlipressin 1-2 mg every 6 hours plus albumin or placebo plus albumin up to 14 days. RESULTS: The pooled analysis comprised 308 patients (terlipressin: n = 153; placebo: n = 155). HRS reversal was significantly more frequent with terlipressin vs. placebo (27% vs. 14%; P = 0.004). Terlipressin was associated with a more significant improvement in renal function from baseline until end of treatment, with a mean between-group difference in SCr concentration of -53.0 µmol/L (P < 0.0001). Lower SCr, lower mean arterial pressure and lower total bilirubin and absence of known precipitating factors for HRS were independent predictors of HRS reversal and longer survival in terlipressin-treated patients. CONCLUSIONS: Terlipressin plus albumin resulted in a significantly higher rate of HRS reversal vs. albumin alone in patients with HRS-1. Terlipressin treatment is associated with improved renal function. (ClinicalTrials.gov identifier: OT-0401, NCT00089570; REVERSE, NCT01143246).

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.

Effect of interwall interaction on the electronic structure of double-walled carbon nanotubes.

Through this study, the results of density functional theory calculations within the local density approximation of the electronic structure of zigzag-zigzag double-walled carbon nanotubes (DWCNTs), with chiral indices (n, 0)@(m, 0) for n = 7-15, and m = 15-26, has been presented and the effects of interwall interaction and orbital hybridization on the electronic structure of these systems has been discussed. It was observed that the electronic band gap of the aforementioned DWCNTs depends on the interwall distance only for metallic-semiconductor configurations and on the intrinsic properties of the constituent tubes in all other combinations. It was also observed that the calculated band gap for most of the metallic-metallic DWCNTs was smaller than semiconductor-metallic, metallic-semiconductor, and semiconductor-semiconductor configurations. Metallic-semiconductor DWCNTs were found to be desirable for band gap tuning applications because of their dependence on interwall distance, opening up the possibility of using such systems in electronic device applications, such as transistors. Other applications include the use of DWCNTs in macroscopic carbon nanotube conducting wires, for which metallic-metallic and semiconducting-metallic zigzag-zigzag DWCNTs were found to be the most desirable configurations due to their small band gaps.

Tropical infection after a case of total hip arthroplasty.

In non-endemic areas, malaria is mainly an imported disease. This article reports a case of transfusion-related Plasmodium falciparum malaria in a non-endemic area. Despite initial clinical signs consistent with malaria, the diagnosis was not elicited because of the absence of any identified epidemiological risk factors. The case indicates that transfusion-transmitted malaria still occurs in non-endemic countries. The role of laboratory testing to prevent and diagnose transfusion-transmitted malaria in non-endemic malaria countries is crucial.

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.

[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.

Phosphorylation of the human ubiquitin-conjugating enzyme, CDC34, by casein kinase 2.

The ubiquitin-conjugating enzyme, CDC34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(Kip1), IkappaBalpha, Wee1, and MyoD. We show that mammalian CDC34 is a phosphoprotein that is phosphorylated in proliferating cells. By yeast two-hybrid screening, we identified the regulatory (beta) subunit of human casein kinase 2 (CK2) as a CDC34-interacting protein and show that human CDC34 interacts in vivo with CK2beta in transfected cells. CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. Importantly, this phosphorylation is inhibited by heparin, a substrate-specific inhibitor of CK2. We have also identified a kinase activity associated with CDC34 in proliferating cells, and we show that this kinase is sensitive to heparin and can utilize GTP, strongly suggesting it is CK2. Phosphorylation of CDC34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm. These results suggest a potential role for CK2-mediated phosphorylation in the regulation of CDC34 cell localization and function.

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.