Hemostasis defects underlying the hemorrhagic syndrome caused by mammarenaviruses in a cynomolgus macaque model.

Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. Although hemostatic dysfunction appears to be a major determinant of the severity of the disease, it is still unclear what pathogenic mechanisms lead to it. In clinical studies it is found that arenaviruses, such as Lassa, Machupo, and Guanarito viruses cause HF that vary in symptoms and biological alterations. In this study we aimed to characterize the hemostatic dysfunction induced by arenaviral HF to determine its implication in the severity of the disease and to elucidate the origin of this syndrome. We found that lethal infection with Machupo, Guanarito, and Lassa viruses is associated with cutaneomucosal, cerebral, digestive, and pulmonary hemorrhages. The affected animals developed a severe alteration of the coagulation system, which was concomitant with acute hepatitis, minor deficit of hepatic factor synthesis, presence of a plasmatic inhibitor of coagulation, and dysfunction of the fibrinolytic system. Despite signs of increased vascular permeability, endothelial cell infection was not a determinant factor of the hemorrhagic syndrome. There were also alterations of the primary hemostasis during lethal infection, with moderate to severe thrombocytopenia and platelet dysfunction. Finally, we show that lethal infection is accompanied by a reduced hematopoietic potential of the bone marrow. This study provides an unprecedented characterization of the hemostasis defects induced by several highly pathogenic arenaviruses.

PiT2 deficiency prevents increase of bone marrow adipose tissue during skeletal maturation but not in OVX-induced osteoporosis.

The common cellular origin between bone marrow adipocytes (BMAds) and osteoblasts contributes to the intimate link between bone marrow adipose tissue (BMAT) and skeletal health. An imbalance between the differentiation ability of BMSCs towards one of the two lineages occurs in conditions like aging or osteoporosis, where bone mass is decreased. Recently, we showed that the sodium-phosphate co-transporter PiT2/SLC20A2 is an important determinant for bone mineralization, strength and quality. Since bone mass is reduced in homozygous mutant mice, we investigated in this study whether the BMAT was also affected in PiT2-/- mice by assessing the effect of the absence of PiT2 on BMAT volume between 3 and 16 weeks, as well as in an ovariectomy-induced bone loss model. Here we show that the absence of PiT2 in juveniles leads to an increase in the BMAT that does not originate from an increased adipogenic differentiation of bone marrow stromal cells. We show that although PiT2-/- mice have higher BMAT volume than control PiT2+/+ mice at 3 weeks of age, BMAT volume do not increase from 3 to 16 weeks of age, leading to a lower BMAT volume in 16-week-old PiT2-/- compared to PiT2+/+ mice. In contrast, the absence of PiT2 does not prevent the increase in BMAT volume in a model of ovariectomy-induced bone loss. Our data identify SLC20a2/PiT2 as a novel gene essential for the maintenance of the BMAd pool in adult mice, involving mechanisms of action that remain to be elucidated, but which appear to be independent of the balance between osteoblastic and adipogenic differentiation of BMSCs.

Anti-EBOV GP IgGs Lacking α1-3-Galactose and Neu5Gc Prolong Survival and Decrease Blood Viral Load in EBOV-Infected Guinea Pigs.

Polyclonal xenogenic IgGs, although having been used in the prevention and cure of severe infectious diseases, are highly immunogenic, which may restrict their usage in new applications such as Ebola hemorrhagic fever. IgG glycans display powerful xenogeneic antigens in humans, for example α1-3 Galactose and the glycolyl form of neuraminic acid Neu5Gc, and IgGs deprived of these key sugar epitopes may represent an advantage for passive immunotherapy. In this paper, we explored whether low immunogenicity IgGs had a protective effect on a guinea pig model of Ebola virus (EBOV) infection. For this purpose, a double knock-out pig lacking α1-3 Galactose and Neu5Gc was immunized against virus-like particles displaying surface EBOV glycoprotein GP. Following purification from serum, hyper-immune polyclonal IgGs were obtained, exhibiting an anti-EBOV GP titer of 1:100,000 and a virus neutralizing titer of 1:100. Guinea pigs were injected intramuscularly with purified IgGs on day 0 and day 3 post-EBOV infection. Compared to control animals treated with IgGs from non-immunized double KO pigs, the anti-EBOV IgGs-treated animals exhibited a significantly prolonged survival and a decreased virus load in blood on day 3. The data obtained indicated that IgGs lacking α1-3 Galactose and Neu5Gc, two highly immunogenic epitopes in humans, have a protective effect upon EBOV infection.

Coccygectomy for coccygeal spicule: a study of 33 cases.

PURPOSE: To report the results of coccygectomy for coccygeal spicule. METHODS: We report the results of a retrospective series of 33 patients who underwent coccygectomy for coccygeal spicule. There were 31 women and 2 men. The mean age was 42 ± 12 years (range 23-62). There was a pit in the skin overlying the spicule in 14 cases and the spicule was bulky in 8 cases. In three cases, weight loss had preceded the occurrence of the coccygodynia. The coccyx was rigid or had very reduced mobility (less than 5°) in 25 cases and normal mobility (between 5° and 20° of flexion) in 8 cases. All the patients had initially been managed conservatively with injections targeted on the spicule. As they did not obtain sufficient relief, they were offered surgery. Ten patients were followed up for more than 72 months, 10 patients for 48-66 months, and 13 for 30-42 months. The outcome analysis involved functional criteria only. RESULTS: Twenty-six patients (79%) had a very satisfactory outcome and 7 (21%) an unsatisfactory outcome. When asked 'Would you have the surgery again?', only one patient answered in the negative. CONCLUSIONS: Surgical treatment for coccygeal spicules that are causing coccygodynia and are resistant to conservative treatment gives satisfactory outcomes, similar to those obtained from surgery for instability of the coccyx.

The mini postero-postero-lateral mini incision in total hip arthroplasty.

PURPOSE: Mini invasive incisions in THA and femoral hip prostheses tend to minimise healing and recovery time. We have used a very posterior approach with technical modifications and precise skin landmarks to decrease surgical complexity, and we describe this experience here. METHODS: From 2010 to 2012, 140 patients aged 79 years (range 53-93 years) were operated upon by the same surgeon in a continuous series using the same minimally invasive skin incision and six different types of implants. The incision was very posterior in the hip allowing direct visualisation of the acetabulum in the hip flexion position and visualisation of the femoral shaft extremity in a leg flexion position. RESULTS: The mean operating time was 100 minutes (range 75-110 min). Estimated blood loss was 385 cc (20-585 cc). Twenty-six patients had blood transfusion. The mean hospital stay was 6.8 days (5-20 days) including the time waiting for a rehabilitation centre. No operative complications related to the technique were recorded. On the postoperative radiograph, the femoral stem was aligned with the femoral axis within 3° in all patients. The mean acetabular angle to the ground plane was 40° (35-48°). No patient had a leg length discrepancy of more than four millimetres. The mean skin incision length was seven centimetres (six to eight centimetres). All patients were seen at the clinic after six weeks and the data were unchanged at this time point. CONCLUSION: The method and skin landmarks we describe appear to be a safe way to perform minimally invasive total hip replacement.

Balloon reduction and cement fixation in calcaneal articular fractures: a five-year experience.

PURPOSE: Balloon reduction and cement fixation of displaced articular fractures of the calcaneus have been described elsewhere but support for it lacks clinical evidence. We have been performing the technique since October 2006 and describe here our clinical experience including three to five-year follow up of our first ten cases with no patient lost to follow up. METHODS: From September 2006 to September 2009, ten patients were admitted with a calcaneus fracture, six were female and four male, one case was bilateral (11 fractures). Patients were operated upon in the prone position according to the technique we have described. Reduction was obtained in all cases. Patients were discharged after an average of four days postoperatively and were allowed weight bearing after two to three months. All patients were followed up regularly and were examined by an independent observer at the latest follow up. The clinical results were assessed using the AOFAS ankle score, the Babin score and the RAND-36 physical components score. A CT scan was obtained in all patients before, after the operation and at the latest follow up. RESULTS: After a minimal follow up of 36 months (three to five years), no patient was lost to follow up and none required further surgery. The AOFAS clinical results were rated good or excellent in 81.8 % of cases (nine fractures, eight patients), and the physical component of the RAND-36 was 74.6. One patient only (one fracture) had a bad clinical result and evidence of subtalar arthritis on the CT scan and was offered a subtalar fusion; she refused. All patients had returned to their former professional activities at the same level as before the fracture except one who had retired but had resumed leisure walking. CONCLUSION: Balloon reduction and cement fixation of fresh calcaneal fractures ("balloon calcaneoplasty") appears a safe and effective procedure in a variety of calcaneal fractures with lasting and excellent clinical results. More studies are needed to further refine the indications and the limits of the procedure.

Recombinant measles virus vaccine expressing the Nipah virus glycoprotein protects against lethal Nipah virus challenge.

Nipah virus (NiV) is a member of the genus Henipavirus, which emerged in Malaysia in 1998. In pigs, infection resulted in a predominantly non-lethal respiratory disease; however, infection in humans resulted in over 100 deaths. Nipah virus has continued to re-emerge in Bangladesh and India, and person-to-person transmission appeared in the outbreak. Although a number of NiV vaccine studies have been reported, there are currently no vaccines or treatments licensed for human use. In this study, we have developed a recombinant measles virus (rMV) vaccine expressing NiV envelope glycoproteins (rMV-HL-G and rMV-Ed-G). Vaccinated hamsters were completely protected against NiV challenge, while the mortality of unvaccinated control hamsters was 90%. We trialed our vaccine in a non-human primate model, African green monkeys. Upon intraperitoneal infection with NiV, monkeys showed several clinical signs of disease including severe depression, reduced ability to move and decreased food ingestion and died at 7 days post infection (dpi). Intranasal and oral inoculation induced similar clinical illness in monkeys, evident around 9 dpi, and resulted in a moribund stage around 14 dpi. Two monkeys immunized subcutaneously with rMV-Ed-G showed no clinical illness prior to euthanasia after challenge with NiV. Viral RNA was not detected in any organ samples collected from vaccinated monkeys, and no pathological changes were found upon histopathological examination. From our findings, we propose that rMV-NiV-G is an appropriate NiV vaccine candidate for use in humans.

Thoracic spinal cord compression indicating Wegener's granulomatosis in a patient with a previous presumptive diagnosis of microscopic polyangiitis.

Neurological signs are observed in 20-50% of cases of Wegener's granulomatosis consisting of peripheral and cranial neuropathy, and central nervous system involvement during the disease and rarely as initial symptom. We report here a case of thoracic spinal cord compression due to dural masses in a patient with a previous presumptive diagnosis of microscopic polyangiitis indicating Wegener's granulomatosis on histological examination. No other site of involvement was found. Slight clinical improvement was observed under immunosuppressive treatment probably because of spinal cord vessels lesions.