Mary D. King

Consistent, high-level, vaccine-induced protection against human malaria has only been achieved by inoculation of Plasmodium falciparum (Pf) sporozoites (SPZ) by mosquito bites. We report that the PfSPZ Vaccine--composed of attenuated, aseptic, purified, cryopreserved PfSPZ--was safe and well tolerated when administered four to six times intravenously (IV) to 40 adults. Zero of six subjects receiving five doses and three of nine subjects receiving four doses of 1.35 × 10(5) PfSPZ Vaccine and five of six nonvaccinated controls developed malaria after controlled human malaria infection (P = 0.015 in the five-dose group and P = 0.028 for overall, both versus controls). PfSPZ-specific antibody and T cell responses were dose-dependent. These data indicate that there is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards.

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

OBJECTIVE: To determine the effect on balance and strength of 3 months of intensive balance and/or weight training followed by 6 months of low intensity Tai Chi training for maintenance of gains. DESIGN: Randomized control intervention. Four groups in 2 x 2 design: Control, Balance, Strength, Balance + Strength, using blinded testers. SETTING: Exercise and balance laboratory at University of Connecticut Health Center. PARTICIPANTS: Subjects were 110 healthy community dwellers (mean age 80) who were free of dementia, neurological disease, and serious cardiovascular or musculoskeletal conditions. INTERVENTIONS: Short-term training (3 months) occurred 3 times/week (45 minutes Balance and Strength, 90 minutes Balance + Strength). Balance training included equilibrium control exercises of firm and foam surfaces and center-of-pressure biofeedback. Strengthening consisted of lower extremity weight-lifting. All subjects than received long-term group Tai Chi instruction (6 months, 1 hour, 1 time/week). MEASUREMENTS: Losses of balance during Sensory Organization Testing (LOB), single stance time (SST), voluntary limits of stability (FBOS), summed isokinetic torque of eight lower extremity movements (ISOK), and usual gait velocity (GVU). RESULTS AND CONCLUSIONS: Balance training meaningfully improved all balance measures by restoring performance to a level analogous to an individual 3 to 10 years younger: LOB = -2.0 +/- 0.3 (adjusted paired differences, P < .005 ANOVA); SST = 7.0 +/- 1.2 sec; and FBOS = 9.0 +/- 2.0% of foot length (P < .05). Strengthening increased ISOK by 1.1 +/- 0.1 Nm kg-1 (P < .005). There was no interaction between balance and strength training. Significant gains persisted after 6 months of Tai Chi, although there was some decrement.