Efficacy of topical cobalt chelate CTC-96 against adenovirus in a cell culture model and against adenovirus keratoconjunctivitis in a rabbit model

BACKGROUND: Adenovirus (Ad), associated with significant morbidity, has no topical treatment. A leading CTC compound (CTC-96), a Co(III )chelate, was found to have potent in vitro and in vivo antiviral efficacy against herpes viruses. In this study CTC-96 is being tested for possible anti-Adenovirus activity. METHODS: The biological anti-adenovirus activity of CTC-96 in concentrations from 5 to 250 ug/ml, was evaluated initially by viral inactivation (viral exposure to CTC-96 followed by dilution and inoculation of cells), virucidal (viral exposure to CTC-96 and inoculation of cells without dilution) and antiviral (effect of CTC-96 on previously adsorbed virus) plaque assays on HeLa (human cervical carcinoma), A549 (human lung carcinoma) and SIRC (rabbit corneal) cells. After verifying the antiviral activity, New Zealand White rabbits were infected with Ad-5 into: 1) the anterior cul-de-sac scarifying the conjunctiva (Group "C+"); 2) the anterior cul-de-sac scarifying the conjunctiva and cornea (Group "CC+"); 3) the stroma (Group "CI+"). Controls were sham-infected ("C-", "CC-", "CI-"). Other rabbits, after "CC", were treated for 21 days with: 1) placebo, 9x/day ("-"); 2) CTC-96, 50 ug/ml, 9x/day ("50/9"); CTC-96, 50 ug/ml, 6x/day ("50/6"); CTC-96, 25 ug/ml, 6x/day ("25/6"). All animals were monitored via examination and plaque assays. RESULTS: In vitro viral inactivation, virucidal and antiviral assays all demonstrated CTC-96 to be effective against Adenvirus type 5 (ad-5). The in vivo model of Ad keratoconjunctivitis most similar to human disease and producing highest viral yield was "CC". All eyes (6/6) developed acute conjunctivitis. "CI" yielded more stromal involvement (1/6) and iritis (5/6), but lower clinical scores (area × severity). Infection via "C" was inconsistent (4/6). Fifty (50) ug/ml was effective against Ad-5 at 6x, 9x dosings while 25 ug/ml (6x) was only marginally effective. CONCLUSION: CTC-96 demonstrated virucidal activity against Ad5 in tissue culture with HeLa, A549 and SIRC cell lines. Animal Model Development: 1) "CC" produced conjunctival infection with occasional keratitis similar to human disease; "CI" yielded primarily stromal involvement; 2) "C" consistently produced neither conjunctivitis nor keratitis. CTC Testing: 1) Conjunctivitis in all eyes; 2) Resolution fastest in "50/9" ("50/9". "50/6" > "25/6" > "-"); 3) Efficacy in "50/6" was not statistically different than "50/9"; 4) Conjunctival severity was lower in treatment groups then controls; 5) Little corneal or intra-ocular changes were noted

Adolescent total knee arthroplasty

Background: Management of adolescent patients with end-stage arthritis is challenging. Nonoperative treatments may be ineffective and total knee arthroplasty (TKA) is rarely performed. Currently, minimal long-term data are available on the outcomes in this patient population. Our goal was to describe TKA for patients with end-stage arthritis who were aged 20 years and younger. Methods: The Joint Registry at our institution was used to identify 19 patients (29 TKAs) aged 20 years and younger that underwent a primary TKA. The average age was 18 years (range 14-20 years) and follow-up was 14.5 years (range: 2.1-25.5 years). Results: The preoperative diagnoses were juvenile idiopathic arthritis (n = 19), avascular necrosis (n = 4), sepsis (n = 2), trauma (n = 2), dysplasia (n = 1), and hemophilia (n = 1). There was a decrease in the number of TKAs performed for inflammatory arthritis over the last several decades. Implant survivorship at 5 and 10 years was 96% and 94%, respectively. Conclusions: We identified a 95% 10-year implant survivorship utilizing standard TKA components in pediatric patients. Performing a TKA in adolescent patients has long-term potential risks including infection and bone loss but may provide pain relief and good long-term results and should be used with caution

A molecular and cellular model to explain the differences in reactivation from latency by herpes simplex and varicella–zoster viruses

There are marked similarities in the biological properties of the human neurotropic herpesviruses herpes simplex virus type 1 (HSV–1) and varicella–zoster virus (VZV), including their ability to establish lifelong latent infections in human peripheral sensory ganglia (PSG). Despite this, their patterns of reactivation are quite different: HSV–1 reactivations occur many times during a lifetime, they are localized to the cutaneous distribution of a single sensory nerve, they are not associated with sensory symptomatology and their frequency decreases with age. VZV recurrence on the other hand is usually a single event which tends to appear with advancing age, its cutaneous eruption involves an entire dermatome and is usually extremely painful. To help explain these differences, we have formulated a model based on current knowledge of the molecular and cellular basis of latent infection in the nervous system. We suggest that the amount of latent viral DNA and RNA in the latently infected tissue (higher with HSV–1), the cellular location of latent virus (neuronal in HSV–1, probably non–neuronal in VZV), the presence or absence of viral replication in the PSG during reactivation together with the host immune response, are all key determinants of the clinical expression of viral reactivation