Efficacy and safety of combined cataract surgery with 2 trabecular microbypass stents versus ab interno trabeculotomy.

PURPOSE: To compare the outcomes of combined cataract surgery with trabecular microbypass stents and ab interno trabeculotomy in patients with open-angle glaucoma. SETTING: University of Toronto, Toronto, Ontario, and University of Montreal, Montreal, Quebec, Canada, and Glaucoma Associates of Texas, Dallas, Texas, USA. DESIGN: Retrospective case series. METHODS: Patients with primary open-angle, pseudoexfoliative, or pigmentary dispersion glaucoma were included. Primary outcome measures were intraocular pressure (IOP), postoperative medications, success (IOP ≤18 mm Hg, no glaucoma medications or reoperations), and postoperative adverse events. RESULTS: The average patient age was 76.5 years ± 12 [SD]. Forty-nine eyes had phacoemulsification and 2 had stent implantations; 52 eyes had phacoemulsification and trabeculotomy surgery with a 12-month postoperative follow-up. The analysis of variance indicated a significant reduction in mean IOP from baseline to 12 months for stent (19.6 ± 5.3 mm Hg to 14.3 ± 3.1 mm Hg; P < .001) and trabeculotomy (20.6 ± 6.8 mm Hg to 17.3 ± 6.5 mm Hg; P < .001) and lower mean IOP at 12 months in the stent group (P = .01). The median number of glaucoma medications decreased from baseline to 12 months in both groups and was lower in the stent group at 3, 6, and 12 months. Thirty-nine percent (19 eyes) in the stent group and 14% (7 eyes) in the trabeculotomy group achieved success at 12 months (P = .006). The incidence of hyphema was lower in the stent group (P = .008). CONCLUSIONS: Both types of surgery achieved a significant reduction in IOP and medication use at 12 months, with the stent group achieving higher success and a reduced incidence of postoperative hyphema. FINANCIAL DISCLOSURE: Dr. Ahmed is a consultant to and investigator for Glaukos Corp., Ivantis, Inc., Transcend Medical, Inc., and Aquesys, Inc., and has received speaker honoraria from Neomedix, Inc. Dr. Saheb has received travel funding from Glaukos Corp., Ivantis, Inc., and Transcend Medical, Inc., and a research grant from Ivantis, Inc. Dr. Harasymowycz has received a research grant from Ivantis, Inc. Dr. Fellman is a consultant to Endo Optiks, Inc., and has received honoraria from Optous and research funds from Ivantis, Inc., Glaukos Corp., and Transcend Medical, Inc. No other author has a financial or proprietary interest in any material or method mentioned.

Rift Valley fever virus infection in golden Syrian hamsters.

Rift Valley fever virus (RVFV) is a formidable pathogen that causes severe disease and abortion in a variety of livestock species and a range of disease in humans that includes hemorrhagic fever, fulminant hepatitis, encephalitis and blindness. The natural transmission cycle involves mosquito vectors, but exposure can also occur through contact with infected fluids and tissues. The lack of approved antiviral therapies and vaccines for human use underlies the importance of small animal models for proof-of-concept efficacy studies. Several mouse and rat models of RVFV infection have been well characterized and provide useful systems for the study of certain aspects of pathogenesis, as well as antiviral drug and vaccine development. However, certain host-directed therapeutics may not act on mouse or rat pathways. Here, we describe the natural history of disease in golden Syrian hamsters challenged subcutaneously with the pathogenic ZH501 strain of RVFV. Peracute disease resulted in rapid lethality within 2 to 3 days of RVFV challenge. High titer viremia and substantial viral loads were observed in most tissues examined; however, histopathology and immunostaining for RVFV antigen were largely restricted to the liver. Acute hepatocellular necrosis associated with a strong presence of viral antigen in the hepatocytes indicates that fulminant hepatitis is the likely cause of mortality. Further studies to assess the susceptibility and disease progression following respiratory route exposure are warranted. The use of the hamsters to model RVFV infection is suitable for early stage antiviral drug and vaccine development studies.

Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment.

Rift Valley fever is a zoonotic, arthropod-borne disease that affects livestock and humans. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) is primarily transmitted through mosquito bites, but can also be transmitted by exposure to infectious aerosols. There are presently no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. In addition, efficacy has also been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, hamsters challenged with the highly pathogenic ZH501 strain of RVFV were used to evaluate the activity of favipiravir against lethal infection. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2-3 days of infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater of hamsters challenged with RVFV when administered within 1 or 6h post-exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden observed in the brain in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin.

Single-dose intranasal treatment with DEF201 (adenovirus vectored consensus interferon) prevents lethal disease due to Rift Valley fever virus challenge.

Rift Valley fever virus (RVFV) causes severe disease in humans and ungulates. The virus can be transmitted by mosquitoes, direct contact with infected tissues or fluids, or aerosol, making it a significant biological threat for which there is no approved vaccine or therapeutic. Herein we describe the evaluation of DEF201, an adenovirus-vectored interferon alpha which addresses the limitations of recombinant interferon alpha protein (cost, short half-life), as a pre- and post-exposure treatment in a lethal hamster RVFV challenge model. DEF201 was delivered intranasally to stimulate mucosal immunity and effectively bypass any pre-existing immunity to the vector. Complete protection against RVFV infection was observed from a single dose of DEF201 administered one or seven days prior to challenge while all control animals succumbed within three days of infection. Efficacy of treatment administered two weeks prior to challenge was limited. Post­exposure, DEF201 was able to confer significant protection when dosed at 30 min or 6 h, but not at 24 h post-RVFV challenge. Protection was associated with reductions in serum and tissue viral loads. Our findings suggest that DEF201 may be a useful countermeasure against RVFV infection and further demonstrates its broad-spectrum capacity to stimulate single dose protective immunity.

Inhibition of severe acute respiratory syndrome coronavirus replication in a lethal SARS-CoV BALB/c mouse model by stinging nettle lectin, Urtica dioica agglutinin.

Urtica dioica agglutinin (UDA) is a small plant monomeric lectin, 8.7 kDa in size, with an N-acetylglucosamine specificity that inhibits viruses from Nidovirales in vitro. In the current study, we first examined the efficacy of UDA on the replication of different SARS-CoV strains in Vero 76 cells. UDA inhibited virus replication in a dose-dependent manner and reduced virus yields of the Urbani strain by 90% at 1.1 ± 0.4 µg/ml in Vero 76 cells. Then, UDA was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. BALB/c mice were infected with two LD50 (575 PFU) of virus for 4 h before the mice were treated intraperitoneally with UDA at 20, 10, 5 or 0 mg/kg/day for 4 days. Treatment with UDA at 5 mg/kg significantly protected the mice against a lethal infection with mouse-adapted SARS-CoV (p < 0.001), but did not significantly reduce virus lung titers. All virus-infected mice receiving UDA treatments were also significantly protected against weight loss (p < 0.001). UDA also effectively reduced lung pathology scores. At day 6 after virus exposure, all groups of mice receiving UDA had much lower lung weights than did the placebo-treated mice. Thus, our data suggest that UDA treatment of SARS infection in mice leads to a substantial therapeutic effect that protects mice against death and weight loss. Furthermore, the mode of action of UDA in vitro was further investigated using live SARS-CoV Urbani strain virus and retroviral particles pseudotyped with SARS-CoV spike (S). UDA specifically inhibited the replication of live SARS-CoV or SARS-CoV pseudotyped virus when added just before, but not after, adsorption. These data suggested that UDA likely inhibits SARS-CoV infection by targeting early stages of the replication cycle, namely, adsorption or penetration. In addition, we demonstrated that UDA neutralizes the virus infectivity, presumably by binding to the SARS-CoV spike (S) glycoprotein. Finally, the target molecule for the inhibition of virus replication was partially characterized. When UDA was exposed to N-acetylglucosamine and then UDA was added to cells just prior to adsorption, UDA did not inhibit the virus infection. These data support the conclusion that UDA might bind to N-acetylglucosamine-like residues present on the glycosylated envelope glycoproteins, thereby preventing virus attachment to cells.

Single-dose intranasal administration with mDEF201 (adenovirus vectored mouse interferon-alpha) confers protection from mortality in a lethal SARS-CoV BALB/c mouse model.

Interferons (IFNs) are a first line of defense against viral infection. Herein we describe the use of an adenovirus vectored mouse IFN alpha gene (mDEF201) as a prophylactic and treatment countermeasure in a SARS-CoV-infected BALB/c mouse model. Complete survival protection was observed in mice given a single dose of mDEF201 administered intranasally 1, 3, 5, 7, or 14 days prior to lethal SARS-CoV challenge (p<0.001), and body weights of these treated mice were unaffected by the challenge. In addition, low doses of mDEF201 protected lungs in a dose dependent manner as measured by a reduction in gross pathology. Intranasal treatment with mDEF201 ranging from 10(6) to 10(8)PFU significantly protected mice against a lethal SARS-CoV infection in a dose dependent manner up to 12h post infection (p<0.001). The data suggest that mDEF201 is a new class of antiviral agent further development as treatment for SARS-CoV infections.

Clinical and radiographic results after implant removal in idiopathic scoliosis.

STUDY DESIGN: Prospective radiographic and clinical analysis of patients with idiopathic scoliosis who had complete implant removal following posterior spinal fusion (PSF) at least 2 years previously. OBJECTIVE: To evaluate the clinical and radiographic effect of implant removal after PSF for idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Occasionally, implants must be removed following instrumented PSF. Indications for removal include infection and late operative site pain. Previously, it has been thought that there was little morbidity associated with implant removal in the presence of a solid fusion. However, recent studies have reported loss of coronal correction after implant removal in patients who had a PSF for adolescent idiopathic scoliosis. Few long-term studies have assessed the clinical or radiographic results of complete implant removal after PSF. METHODS: We identified 56 patients who had undergone PSF for idiopathic scoliosis and subsequently had complete removal of all instrumentation. None of these patients had a pseudarthrosis at the time of implant removal. After IRB approval, 43 of 56 (77%) patients returned for new standing posteroanterior and lateral spine radiographs and completion of an SRS-22 questionnaire. RESULTS: For the 43 patients who had new radiographs and completed an SRS-22, the time from the original PSF to complete implant removal averaged 2.9 years (range, 7 months to 7.25 years). Twenty-two patients had implants removed because of infection, and 21 patients had implants removed secondary to pain. The average time from implant removal to completion of the most recent radiographs and SRS-22 questionnaire was 9.5 years (range, 3.2-17.9 years). Patients were considered to have had progression of deformity after implant removal if their Cobb angle measurements increased by more than 10 degrees . Two patients had 11 degrees to 20 degrees of coronal plane progression of their main thoracic curve. No patient had more than 10 degrees of coronal plane progression of a lumbar curve. Sagittal curve progression was identified more frequently. Nineteen patients had between an 11 degrees and 20 degrees increase in thoracic kyphosis, and 5 patients had >20 degrees of thoracic kyphosis progression. Patients with >20 degrees of thoracic kyphosis progression after implant removal had greater thoracic kyphosis before surgery and larger main thoracic and lumbar coronal curves at the time of implant removal. Progressive kyphosis did not correlate with: reason for implant removal, length of follow-up, or time from fusion to implant removal. Although total SRS-22 scores correlated inversely with increased thoracic kyphosis, this trend did not reach statistical significance. CONCLUSION: Implant removal after PSF for idiopathic scoliosis may be complicated by progression of deformity. Patients requiring implant removal should be appropriately counseled and monitored.