Long-term persistence of cellular hyporesponsiveness to filarial antigens after clearance microfilaraemia

The persistence of parasite-specific cellular hyporesponsiveness after clearance of blood microfilariae (mf) was studied in 18 individuals who had been treated with a single dose of ivermectin, diethylcarbamazine, or a combination 2-3 years previously and who had initially cleared their parasitemia. At recruitment into the present study, 50% were again mf+ and 50% remained mf-. There were no significant differences between the mf+ and mf- groups in the amount of interferon- g (IFN- g) produced by peripheral blood mononuclear cells in response to adult or microfilarial antigens, although IFN- g production in response to purified protein derivative was greater in the mf+ group (geometric mean [gm] = 3,791 pg/ml; P = 0.02) than in the mf- group (gm = 600 pg/ml). These data suggest that although microfilaremic individuals may temporarily regain the ability to produce IFN- g to parasite antigens post-treatment, they subsequently revert to a state of hyporesponsiveness to mf-containing antigens that appears to be independent of the recurrence of microfilaremia and the response to nonparasite antigens

Australian Aboriginal children with otitis media have reduced antibody titers to specific nontypeable Haemophilus influenzae vaccine antigens

Indigenous populations experience high rates of otitis media (OM), with increased chronicity and severity, compared to those experienced by their nonindigenous counterparts. Data on immune responses to otopathogenic bacteria in these high-risk populations are lacking. Nontypeable Haemophilus influenzae (NTHi) is the predominant otopathogen in Australia. No vaccines are currently licensed to target NTHi; however, protein D (PD) from NTHi is included as a carrier protein in the 10-valent pneumococcal polysaccharide conjugate vaccine (PHiD10-CV), and other promising protein vaccine candidates exist, including outer membrane protein 4 (P4) and protein 6 (P6). We measured the levels of serum and salivary IgA and IgG against PD, P4, and P6 in Aboriginal and non-Aboriginal children with chronic OM who were undergoing surgery and compared the levels with those in healthy non-Aboriginal children (controls). We found that Aboriginal cases had lower serum IgG titers to all NTHi proteins assessed, particularly PD. In contrast, serum IgA and salivary IgA and IgG titers to each of these 3 proteins were equivalent to or higher than those in both non-Aboriginal cases and healthy controls. While serum antibody levels increased with age in healthy controls, no changes in titers were observed with age in non-Aboriginal cases, and a trend toward decreasing titers with age was observed in Aboriginal cases. This suggests that decreased serum IgG responses to NTHi outer membrane proteins may contribute to the development of chronic and severe OM in Australian Aboriginal children and other indigenous populations. These data are important for understanding the potential benefits of PHiD10-CV implementation and the development of NTHi protein-based vaccines for indigenous populations

A controlled trial of ivermectin and diethylcarbamazine in lymphatic filariasis

Ivermectin is a new antifilarial drug that can be given in a single oral dose. To compare the efficacy and side effects of ivermectin with those of diethylcarbamazine, the standard antifilarial treatment, we conducted a randomized, double-blind trial in 40 south Indian men with lymphatic filariasis caused by Wuchereria bancrofti. Patients were randomly assigned to one of three treatments: a single low dose of ivermectin (mean [+ SE], 21.3+0.7 g per kilogram of body weight; n = 13) followed by placebo for 12 days; a single high dose of ivermectin (mean, 126.2+3.7 g per kilogram; n = 13) followed by placebo for 12 days; or diethylcarbamazine for 13 days (6 mg per kilogram per day for 12 days preceded by 3 mg per kilogram for 1 day; n = 14). Eleven patients were initially assigned to receive placebo and after five days were re-assigned to one of the three treatment groups. At day 12 there was complete clearance of microfilariae from the blood in all 26 men who took ivermectin and in 11 of the 14 men who took diethylcarbamazine. At six months the numbers of detectable microfilariae (as a percentage of the pretreatment values) were 18.3 percent after low-dose ivermectin and 19.5 percent after high-dose ivermectin, as compared with 6.0 percent after diethylcarbamazine (P<0.05). The side effects were confined to the first five days and were similar in the three treatment groups. We conclude that in lymphatic filariasis, the clinical response to a single dose of ivermectin compares favourably with that after the standard 12-day course of diethylcarbamazine. Given the practical advantages of single-dose administration, ivermectin should become a useful medication for the control of bancroftian filariasis

Synthetic Hydrogel as an Artificial Vitreous Body. A One-Year Animal Study of Its Effects on the Retina

A hydrogel with a high water content was assessed in vitro and in vivo as a possible vitreous substitute. From a large series of polymers produced by the aqueous polymerization of methyl acrylamidoglycolate methyl ether (MAGME), a gel synthesized in 80% water was selected for an animal study. The gel was injected intravitreally into rabbit eyes and followed clinically by ophthalmoscopy, tonometry, and fundus photography. The gel was clinically well tolerated, but after 6 months ophthalmoscopy revealed progressive pallor of the optic nerve head. The eyes were enucleated one year after injection of polymer. Histopathological examination by light microscopy of retinal and vitreal sections revealed significant retinal disorganization, degeneration of the optic nerve and retinal neural elements, retinal detachment, and inflammatory changes. Analysis of immunohistochemically labeled retinal sections revealed loss of ganglion cells and extensive pathological reaction of the Muller cells and astrocytes. All these findings were consistent with a toxic effect of the polymer itself or some residual contaminants. The cytotoxicity of the hydrogel was assessed in vitro using cultured mouse (Balb/c-3T3) fibroblasts. The bioassay showed both cytostatic and cytocidal effects of the polymer. Our results indicate that hydrogels produced from MAGME monomer cannot function as vitreous substitutes because of severe toxic reaction elicited to the posterior segment of the eye

Cleft lip repair simulation: an Australian trainee experience

**Background**: Cleft lip repair is technically challenging surgery that requires an appreciation of the complex anatomy of the lip and nose. Effective transference of skill has been demonstrated through the use of simulations. We established a cleft lip and palate simulation workshop to improve training. In this report we assessed the confidence of plastic surgery trainees to perform a cleft lip repair before and after the simulation exercise. **Design**: We purchased 3D high-fidelity simulation models for the workshop. Participants watched a short video depicting cleft lip markings, incisions and repair. Two senior cleft surgeons provided additional commentary and teaching throughout the workshop. **Method**: A 'confidence scale' questionnaire was distributed to 11 plastic surgery trainees. The questionnaire comprised of eight questions on a Likert scale of 1–5 (total score = 40) that prompted a self-assessment of confidence, surgical skill, knowledge and level of 'anxiety' in carrying out a cleft lip repair. Questions about the level of training and prior experience were added to the survey. Participants completed the survey before and after the simulation. **Results**: Comparison of pre and post-simulation surveys showed an average increase of 53.5 per cent in total scores. Improvements were found for all attendees regardless of their level of training or prior experience. **Conclusion**: Simulation training is a validated solution that aids in the acquisition of skills and knowledge. Using simulations in the surgical curriculum has the potential to improve operative learning

High concentrations of middle ear antimicrobial peptides and proteins and proinflammatory cytokines are associated with detection of middle ear pathogens in children with recurrent acute otitis media

Recurrent and chronic otitis media (OM) are often refractory to antibiotics due to bacterial persistence in biofilm within the middle ear. In vitro and in vivo studies have demonstrated that antimicrobial proteins and peptides (AMPs) are bactericidal against otopathogens, indicating potential therapeutic value for recalcitrant OM. We measured concentrations of 6 AMPs and 14 cytokines in middle ear effusion (MEE) from 67 children undergoing ventilation tube insertion for recurrent acute OM. Sixty one percent of children had bacterial otopathogens detected in their MEE, 39% by PCR and 22% by PCR and culture. Groups were defined as: PCR-negative/culture-negative (absence of bacterial otopathogen), n = 26; PCR-positive/culture-negative (presence of nonculturable bacterial otopathogen), n = 26; PCR-positive/culture-positive (presence of culturable bacterial otopathogen), n = 15. Age, antibiotic usage, day-care attendance, presence of respiratory viruses in MEE and number of AOM episodes were similar between groups. AMP and cytokine concentrations were higher in children with bacterial otopathogens in their MEE compared to those with no bacterial otopathogens. Median concentrations of AMPs (except HBD2) were 3 to 56-fold higher in MEE from children with bacterial otopathogens detected in their MEE (P ≤ 0.01). Similarly, median cytokine concentrations (except TGFβ) were >16-fold higher in MEE with bacterial otopathogens detected (P ≤ 0.001). This is the first study to measure AMPs in MEE and together with the cytokine data, results suggest that elevated AMPs and cytokines in MEE are a marker of inflammation and bacterial persistence. AMPs may play an important role in OM pathogenesis

Retinal toxicity of intravitreal tenecteplase in the rabbit

Aim: To investigate the retinal toxicity of intravitreal injection of a novel fibrinolytic tenecteplase in rabbit eyes. Methods: Tenecteplase (25–350 μg in 0.1 ml BSS) was injected into the vitreous cavity of normal rabbit eyes. Control (fellow) eyes received 0.1 ml of BSS. One day, 1 week, and 2 months post-injection, the eyes were examined by slit lamp biomicroscopy, indirect ophthalmoscopy, and electroretinography, and then harvested for histopathological examination. Results: No evidence of retinal toxicity was seen with tenecteplase doses up to and including 50 μg. At a dose of 150 μg ophthalmoscopy was normal, but histology showed mild retinal damage in the inner nuclear layer and electroretinography showed a temporary reduction in B-wave amplitude. At doses of 200 μg and above, there was evidence of retinal toxicity on electroretinography, ophthalmoscopy, and histology. Ophthalmoscopic findings included vitreal fibrosis, retinal necrosis and tractional retinal detachment and light microscopy revealed necrosis of retinal pigment epithelium and other retinal layers. Damage was centred around the injection site but was more widespread with the higher doses. Conclusion: A dose of 50 μg tenecteplase appears safe for intravitreal injection in the rabbit. Tenecteplase could have potential applications in the treatment of submacular haemorrhage and retinal vein occlusion