Structure guided mutagenesis of Henipavirus Receptor Binding Proteins reveals molecular determinants of receptor usage and antibody binding epitopes.

Nipah virus (NiV) is a highly lethal, zoonotic henipavirus (HNV) that causes respiratory and neurological signs and symptoms in humans. Similar to other paramyxoviruses, HNVs mediate entry into host cells through the concerted actions of two surface glycoproteins: a receptor binding protein (RBP) that mediates attachment and a fusion glycoprotein (F) that triggers fusion in an RBP-dependent manner. NiV uses ephrin-B2 (EFNB2) and ephrin-B3 (EFNB3) as entry receptors. Ghana virus (GhV), a novel HNV identified in a Ghanaian bat, use EFNB2 but not EFNB3. In this study, we employ a structure-informed approach to identify receptor interfacing residues and systematically introduce GhV-RBP residues into a NiV-RBP backbone to uncover the molecular determinants of EFNB3 usage. We reveal two regions that severely impair EFNB3 binding by NiV-RBP and EFNB3-mediated entry by NiV pseudotyped viral particles. Further analyses uncovered two point mutations (NiVN557SGhV and NiVY581TGhV) pivotal for this phenotype. Moreover, we identify NiV interaction with Y120 of EFNB3 as important for usage of this receptor. Beyond these EFNB3-related findings, we reveal two domains that restrict GhV binding of EFNB2, identify the HNV-head as an immunodominant target for polyclonal and monoclonal antibodies, and describe putative epitopes for GhV and NiV-specific monoclonal antibodies. Cumulatively, the work presented here generates useful reagents and tools that shed insight to residues important for NiV usage of EFNB3, reveals regions critical for GhV binding of EFNB2, and describes putative HNV antibody binding epitopes.

Management of gunshot wound to the lumbosacral spine in a 17-year-old girl without neurological impairment.

We report the case of a young girl (17-year-old) wounded by an accidental gunshot. The bullet entered through the skin midline over the navel area, passed through the stomach perforating the vena cava and, by breaking the right pedicle of L4, moved inside the vertebral canal (bridging the cauda equina) stopping just in front of the body of S2. Because of the sudden onset of acute abdomen due to a massive retroperitoneal hematoma, the patient underwent emergency explorative laparotomy with the evacuation of the hematoma and the suture of the perforated cava vein, the peritoneum, and the stomach. No neurological deficits were observed after the gunshot. Two weeks later, the patient underwent spinal surgery to remove the bullet from the spinal canal, which was performed successfully without any instrumentation and with no onset of new neurological signs and symptoms or surgery-related complications. Patient was discharged on day 9 after surgery in good general conditions.

Video-assisted anterior retroperitoneal approach to the lumbar spine. A minimally invasive technique improved by the use of an endoscopic camera to treat lumbar spinal diseases. Consideration over 269 patients.

We describe the technique we routinely use to perform the retroperitoneal anterior approach using a rigid endoscope coupled to a HDD screen to assist mini-open retroperitoneal anterior approach. Our experience was compared to those reported in the literature for the standard mini-open retroperitoneal approach. We retrospectively analyzed a total of 269 consecutive patients, 109 males and 160 females, underwent anterior lumbar approach in our department, using video-assisted anterior retroperitoneal approach to the lumbar spine. 202 patients had a single L5-S1 or L4-5 ALIF (75.09%), 14 patients received a double level ALIF (5.3%), while 53 patients underwent a double anterior and posterior approach (19.8%). The average preoperative VAS and Oswestry Disability Index (ODI) scores were 9.1±6.3 and 79.3±11.9. At least 16 months follow-up (from 16 months to 5 years), the average VAS and ODI values had improved to 1.6±1.5 and 13.1±13.2, respectively (p <0.05). The mean length of stay was 4.3±3.5 days. There were 6 major complications (2.2%) related to the approach: major vascular injuries (iliac vein injury) occurred in a total of 3 patients (1.1% of cases), whereas retrograde ejaculation occurred in 3 patients (2,75% of male cases in the series). No wound or deep infections occurred. In our opinion, this technique, compared with other mini-open approach, potentially reduces perioperative morbidity, length of surgery, surgical approach-related complications, and hospitalization.

Modifications of spinopelvic parameters and acetabular orientation after spinal surgery for adult deformity in patient who underwent bilateral total hip arthroplasty.

The spine and the hip are two anatomical districts that have close biomechanical relationship. The management of their degenerative disorders involves an in-depth biomechanical analysis of the patient, in order to define the proper hip-spine relation, using different biomechanical classifications that have been proposed in recent years. The changes in the spino-pelvic and acetabular parameters induced by prosthetic hip surgery and spinal surgery must be carefully evaluated, calculated and foreseen in the pre-operative phase, as they play a crucial role in defining the clinical success or failure of the operations. In this paper we present a case of a patient who underwent spinal surgery after a bilateral THA analyzing both spino-pelvic parameters and acetabular orientation and highlighting the strict relations between spine and hip.

Bilateral THA in the same sitting for avascular necrosis of the head of the femur in sickle cell patient: our African experience.

Sickle cell anemia is protective against the malaria protozoan. The heterozygous form of the disease is not fatal, and may cause musculoskeletal disorders when sickling occurs, and small vessels are occluded. When the head of the femur is involved, this may result in hip arthritis, often bilateral, at a young age. This article describes three patients in whom bilateral total hip arthroplasty (THA) was performed in the context of a humanitarian mission in Togo, Africa.

Periprosthetic joint infection from Mycobacterium Tuberculosis in Togo, Africa.

Mycobacterium Tuberculosis infections are moderately frequent in developing countries. Because of migratory flows, these diseases will always have an increasing prevalence even in those countries that do not usually present these types of cases. Extra-pulmonary tuberculosis often affects the musculoskeletal system. The sites most involved are the spine (Pott's disease) and the large joints, especially hips and knees. We describe a patient with tuberculosis of the hip, who underwent total hip arthroplasty.

Histological assessment of new bone formation with biomimetic scaffold in posterolateral lumbar spine fusion.

Spinal fusion procedures often require the use of bone grafts (autograft or allograft) to help bone healing and to increase stability. However, the application of autografts is frequently limited by donor site morbidity. In recent years, different synthetic bone substitutes have been introduced in the clinical practice to overcome these limitations. The purpose of this paper is to report a case where a biomimetic, synthetic and osteoconductive bone graft substitute was successfully implanted in a patient during lumbar spine arthrodesis. The case of a 58-year-old female subjected to lumbar spine arthrodesis with bone augmentation is described. The bone graft substitute RegenOss® (Finceramica, Faenza, Italy) was implanted during spinal arthrodesis. The successful bone integration was evaluated by X-rays. After 11 months, the patient underwent a second surgery due to spine imbalance; the debris of the bone graft was therefore collected and analyzed by macroscopic evaluation and by histology. The bone substitute was successfully implanted during a spinal arthrodesis procedure. Histologic evaluation of the removed bone graft debris showed the complete resorption of the implant and the formation of new bone, which was well integrated with the host bone. This bone substitute may represent a safe and effective alternative to autologous bone grafts, avoiding adverse events related to donor-site morbidity.

One-stage Bilateral Total Hip Arthroplasty in patient with sickle cell disease and previous Girdlestone procedure on the right side: First presentation in Togo.

80% of Sickle Cell Disease cases are estimated to be in Sub-Saharan Africa. It can lead to various acute and chronic complications and osteonecrosis of the femoral head is one of these. Girdlestone procedure is an option to treat osteonecrosis in patients who could not afford arthroplasty. We report here the first case of bilateral total hip arthroplasty in a patient with a previous Girdlestone procedure on the right side and an osteonecrosis of the femoral hip on the left side.

Clinical anatomy of the meniscus in animal models: pros and cons.

Nowadays, despite the possibility to use in vitro or computer models in research, animal models are still essential. Different animal models are available for meniscal repair investigation. Although a unique perfect model for the structure of the human's knee does not exist, the choice of the proper animal model is crucial for a correct research. The principal animal models in the meniscal repair are sheep, goats, pigs and dogs. Each of these has pros and cons for their utilization. Analysing each pro and con is essential for optimizing the choice of the animal model, which depends on the experimental question, avoiding unnecessary waste of resources and minimizing the animal suffering, according to the Russell and Burch's three "Rs" principles (Reduce, Refine and Recycle). In this concise review, we resume the meniscus anatomical features of the main large animals, to help choose the most suitable animal model for subsequent studies on meniscal repair.

Total hip arthroplasty for osteonecrosis of the femoral head in sickle cell disease: a case series from our African experience.

Sickle cell disease causes osteonecrosis (20% to 50% of patients) and collapse of the femoral head that result in secondary osteoarthritis. Total hip arthroplasty (THA) is a valid alternative for these patients. We define the difficulties that can be encountered when undertaking THA in sickle cell disease patients and give advice on how to deal with these technically demanding procedures. We undertook total hip arthroplasty procedures on 12 patients (4 females and 8 males) with osteonecrosis of the femoral head. Two bilateral prostheses were performed. We had only one type of stem, only one type of acetabular cup and only 28 mm cobalt chrome heads. The procedures were performed through either an anterior or a direct lateral approach. The average size of the Cup was 46 (Versafit, Medacta), the average size of the femoral stem was 0 (Amistem, Medacta), the most used size of the modular head was a S. Standard stem that was used in nine patients, while three patients received a lateralizing stem. Three patients had periprosthetic fracture, treated by cerclage. Total hip replacement is an excellent alternative for patients with osteonecrosis from sickle cell disease. The preparation of the acetabulum and the femur is difficult and requires attention, time and appropriate equipment.

Histological assessment of new bone formation with biomimetic scaffold in the presence of bone loss in trauma surgery.

Open reduction and internal fixation (ORIF) surgery may require the use of bone grafts (usually allogeneic). In the context of traumatology surgeries, the use of autologous grafts is almost never used and allogeneic grafts are not always available. In recent years, bone substitutes have been introduced in clinical practice to overcome these limitations. The purpose of this paper is to report two cases in which the use of a bone substitute was used to overcome the bone loss during surgeries of ORIF. Two patients, one with a tibial plateau fracture (Schatzker 6) and one with a proximal humerus fracture (Neer 4), underwent ORIF surgery. In both cases, due to a loss of bone stock, a synthetic bone substitute (OrthOss®) was used. One year after surgery, the complete osseointegration of the synthetic bone substitute was seen, both radiologically and histologically. This bone substitute may represent a safe and effective alternative to autologous bone grafts, avoiding adverse events related to donor-site morbidity.

Lateral ankle ligament anatomic reconstruction for chronic ankle instability: Allograft or autograft? A systematic review.

BACKGROUND: To investigate if there is any evidence in favour of autograft or allograft use for anatomic reconstruction of lateral ankle ligaments in patients with symptomatic chronic ankle instability. METHODS: A literature search was performed in PubMed MEDLINE, Cochrane Library, EMBASE and Google Scholar databases, over the years 1994-2017, to identify the studies presenting clinical results of anatomic lateral ankle ligaments reconstruction using various combinations of the keywords "lateral ankle ligaments reconstruction", "anatomic reconstruction", "chronic ankle instability", "allograft", "autograft". The surgical procedure was considered anatomic if consistent with the description of lateral ankle ligaments made by Burks and Morgan in 1994. RESULTS: Among the 89 papers matching the search terms, only 12 could be included in which 357 anatomic lateral ankle ligaments reconstructions were performed. One was a comparative case series (level of evidence III - LOE III) while other papers were retrospective case series (LOE IV), the mean Modified Coleman Methodology Score (MCMS) was fair: 56.7 (SD±5.2). Due to the low level of evidence of the available literature only a qualitative analysis was performed. The limited evidence from the studies analysed suggests that there is no difference in graft survivorship, graft-dependent variables, patient's satisfaction, clinical outcome measures and radiographic results between allograft and autograft. CONCLUSIONS: Given the low number of studies, their poor methodology score and their low level of evidence it is not possible to determine if allograft is better or safer than autograft. LEVEL OF EVIDENCE: Level IV, review paper of level III and level IV studies.

Effectiveness of delayed-release dimethyl fumarate on patient-reported outcomes and clinical measures in patients with relapsing-remitting multiple sclerosis in a real-world clinical setting: PROTEC.

BACKGROUND: Patient-reported outcomes (PRO) and clinical outcomes give a broad assessment of relapsing-remitting multiple sclerosis (RRMS) disease. OBJECTIVE: The aim is to evaluate the effectiveness of delayed-release dimethyl fumarate (DMF) on disease activity and PROs in patients with RRMS in the clinic. METHODS: PROTEC, a phase 4, open-label, 12-month observational study, assessed annualized relapse rate (ARR), proportion of patients relapsed, and changes in PROs. Newly diagnosed and early MS (≤3.5 EDSS and ≤1 relapse in the prior year) patient subgroups were evaluated. RESULTS: Unadjusted ARR at 12 months post-DMF versus 12 months before DMF initiation was 75% lower (0.161 vs. 0.643, p < 0.0001) overall (n = 1105) and 84%, 77%, and 71% lower in newly diagnosed, ≤3.5 EDSS, and ≤1 relapse subgroups, respectively. Overall, 88% of patients were relapse-free 12 months after DMF initiation (84%, newly diagnosed; 88%, ≤3.5 EDSS; 88%, ≤1 relapse). PRO measures for fatigue, treatment satisfaction, daily living, and work improved significantly over 12 months of DMF versus baseline. CONCLUSION: At 12 months after versus 12 months before DMF initiation, ARR was significantly lower, the majority of patients were relapse-free, and multiple PRO measures showed improvement (overall and for subgroups), suggesting that DMF is effective based on clinical outcomes and from a patient perspective.Clinical trial: A Study Evaluating the Effectiveness of Tecfidera (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC), NCT01930708, https://clinicaltrials.gov/ct2/show/NCT01930708.

Atypical Post-Injection Reactions with Delayed Onset Following Glatiramer Acetate 40 mg: Need for Titration?

BACKGROUND: Glatiramer acetate (GA) 20 mg/day (GA20) is associated with immediate post-injection reactions (PIRs). For convenience of use, approved GA 40 mg three times weekly (GA40) delivers a similar weekly dose. The dose and concentration of a single GA40 injection are, however, twice as high as for GA20, and post-injection adverse events may differ. Cases of atypical PIRs to GA40 prompted us to systematically monitor such events. OBJECTIVE: The aim was to characterize atypical PIRs in multiple sclerosis (MS) patients treated with GA40. METHODS: Clinical practice data were prospectively collected in consecutive relapsing-remitting MS patients. Descriptive statistics for categorical and continuous variables, Mann-Whitney and Chi-squared tests for baseline comparisons, and Cox regression models for association of variables to first atypical PIRs were applied. RESULTS: Forty-six out of 173 patients (26.6%) given GA40 experienced any PIRs. Of those, 38 (22.0%) had atypical, 14 (8.1%) had combined typical and atypical, and 26 (15.0%) had recurrent atypical PIRs, most frequently shivering (13.3%) and nausea/vomiting (8.1%). Compared to typical PIRs, onset of atypical PIRs was significantly delayed (median 30 vs 1 min, p < 0.0001), and their median duration longer (median 120 vs 6 min, p = 0.00013). Previous exposure to GA20 was associated with a lower risk of atypical PIRs [hazard ratio (HR) = 0.35, 95% confidence interval (CI) 0.17-0.72, p = 0.0039]. Patients experiencing PIRs with GA20 were at elevated risk for atypical PIRs with GA40 (HR = 5.75, 95% CI 1.66-19.94, p = 0.0059). CONCLUSIONS: Atypical PIRs with GA40, especially gastrointestinal symptoms and/or fever/shivering, had a delayed onset and occurred in a significant proportion of our patients. Their real prevalence should be assessed in appropriately designed studies accounting for  nocebo responses. Initial dose titration might reduce PIR frequency.

Autoimmune bullous diseases in non-HIV Kaposi's sarcoma: a retrospective study in a large cohort of patients.

BACKGROUND: Kaposi's sarcoma (KS) is a rare endothelial neoplasm caused by the human herpesvirus 8 (HHV-8). Its risk is increased in immunocompromised patients, including those undergoing immunosuppressive therapy for autoimmune bullous diseases. Conversely, HHV-8 infection has been hypothesized to be a triggering factor of bullous diseases, especially pemphigus. Given the fact that both KS and autoimmune bullous diseases have a low incidence in the general population, it could be expected that the association between these disorders would be exceptional. OBJECTIVES: To assess the frequency of bullous diseases in a large cohort of non-HIV KS patients and to describe our experience concerning the clinical features, natural history and treatment options in this setting. METHODS: We performed a retrospective review of all patients with non-HIV KS in association with bullous disease followed at our department between 1990 and 2016. Medical records were reviewed for demographics, medical history, clinical characteristics and treatment. RESULTS: Among 1362 patients with classic or iatrogenic KS, 14 (1.03%) also suffered from bullous disease. The mean age at diagnosis of both disorders was 85.8 years with a male/female ratio of 9 : 5. Among these 14 cases, nine (0.66%) were associated with bullous pemphigoid (BP), three (0.22%) with localized BP and two (0.15%) with pemphigus vulgaris. Seven had developed a bullous disease after being diagnosed with KS, while in the remaining seven cases, KS developed after the onset of bullous disease. As expected, KS worsened when corticosteroids were used. CONCLUSION: Bullous diseases seem to be more frequent among patients with KS, supporting the hypothesis that HHV-8 may be involved in their pathogenesis. Therapeutic management of these cases should take into account KS-inducing potential of corticosteroids.

Piper regnellii extract biopolymer-based microparticles: production, characterization and antifungal activity.

AIMS: This study aims to improve characteristics of Piper regnellii extract to make it applicable in formulations to treat dermatophytosis, also known as ringworm. METHODS AND RESULTS: Microparticles (MPs) were produced by spray drying with gelatin, alginate and chitosan as encapsulating agents; characterized by scanning electron microscopy, encapsulation efficiency, thermal analyses and X-ray diffraction; and tested against Trichophyton rubrum by broth microdilution. Produced MPs had a mean diameter less than 2 µm, an increase in stability and release of the extract and good results for encapsulation efficiency, being 85·6% to gelatin MP, 71·3% to chitosan MP and 60·6% to alginate. MPs preserved the antifungal activity of P. regnellii extract T. rubrum. CONCLUSION: Microencapsulation provided a significant improvement in the stability of the P. regnellii extract and better solubilization of chemical compounds, maintaining the antifungal effect against T. rubrum. SIGNIFICANCE AND IMPACT OF THE STUDY: These results are useful for developing a formulation to treat fungal infections caused by dermatophyte species.

Toe web intertrigo in Kaposi's sarcoma patients: a microbiological study in a large cohort of patients.

Kaposi 's sarcoma (KS) is a rare multifocal angioproliferative disease associated with human herpes virus 8 (HHV-8) infection, characterized by cutaneous nodules or plaques especially on the lower limbs. Some skin modifications, such as chronic lymphedema, plantar hyperkeratosis and interdigital desquamation, may be associated with consequent impairment of the local immunosurveillance and increased risk of some bacterial or mycotic infections. With the objective of evaluating if bacterial or mycotic infections in KS patients are supported by different microorganisms compared to control patients, we performed an observational retrospective study, comparing positive cultural swabs of interdigital intertrigo of KS patients with positive cultural swabs of interdigital intertrigo of patients admitted to our dermatologic unit during the last 10 years. One hundred KS patients and 84 control patients were admitted to this study. Some of the skin swabs from interdigital spaces were positive for more than one microorganism, and therefore we found 187 microorganisms among the KS group and 182 microorganisms in the control group. The most common microrganisms among KS patients were T. mentagrophytes (16%), S. aureus (14.9%), P. aeruginosa (13.9%), S. marcescens (5,9%), while among non-KS patients were S. aureus (26,9%), C. albicans (22%), S. agalactiae (7.7%) and E. coli (9.9%). These differences are statistically significant (p < 0.01). KS patients may be more affected by toe web intertrigo due to other bacteria and dermatophytes than the general population. During clinical examination, a careful inspection is necessary for an early diagnosis of toe web intertrigo, in order to prevent serious complications, such as cellulitis and sepsis. Consequently, a cultural examination with antibiogram is required to identify the causative agent of intertrigo and guide antimicrobial therapy.

Metal-enhanced Förster resonance energy transfer (ME-FRET) in anthracene/tetracene-doped crystal systems.

Anthracene tetracene-doped crystals (TA) dispersed in a thin polymer film matrix have been reported as efficient down converting systems based on Förster Resonance Energy Transfer (FRET) which occurs efficiently from donor (anthracene) to acceptor (tetracene) molecules. In this work, we demonstrate that the efficiency of this system can be further improved by a metal-enhanced FRET, which is obtained by incorporating metal nanoparticles into the polymer matrix. We report on the preparation and optical responses of polymeric transparent thin films where dodecanethiol-capped silver or gold nanoparticles are dispersed with TA in a polymethylmethacrylate (PMMA) matrix. A maximum of 11-fold and 6.5-fold enhancement was achieved with silver and gold nanoparticles, respectively. Efficiency is discussed in terms of film morphology and plasmon resonance induced effects.