Summary Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential. To address this need, we applied in vivo directed evolution to engineer potent retrograde functionality into the capsid of adeno-associated virus (AAV) — a vector that has shown promise in neuroscience research and the clinic. A newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers, and enables sufficient sensor/effector expression for functional circuit interrogation and in vivo genome editing in targeted neuronal populations.

Hypertrophic cardiomyopathy is a common complication of Friedreich's ataxia (FRDA). Histological sections reveal abnormal cardiomyocytes, muscle fiber necrosis, reactive inflammation, and increased endomysial connective tissue. Scattered muscle fibers display perinuclear collections of minute iron-positive granules that lie in rows between myofibrils. Frataxin deficiency in FRDA causes mitochondrial iron dysmetabolism. We studied total iron and the iron-related proteins ferritin, mitochondrial ferritin, divalent metal transporter 1 (DMT1), and ferroportin in FRDA hearts by biochemical and histological techniques. Total iron in the left ventricular wall of FRDA patients (30.7+/-19.3 mg/100 g dry weight) was not significantly higher than normal (31.3+/-24.1 mg/100 g dry weight). Similarly, cytosolic holoferritin levels in FRDA hearts (230+/-172 microg/g wet weight) were not significantly elevated above normal (148+/-86 microg/g wet weight). The iron-positive granules exhibited immunoreactivity for cytosolic ferritin, mitochondrial ferritin, and ferroportin. Electron microscopy showed enhanced electron density of mitochondrial deposits after treatment with bismuth subnitrate supporting ferritin accumulation. The inflammatory cells in the endomysium were reactive for CD68, cytosolic ferritin, and the DMT1 isoform(s) translated from messenger ribonucleic acids containing iron-responsive elements (DMT1+). Progressive cardiomyopathy in FRDA is the likely result of iron-catalyzed mitochondrial damage followed by muscle fiber necrosis and a chronic reactive myocarditis.

Tunneled intraspinal catheters and catheter-pump systems are increasingly common treatments for severe chronic pain, but these long-term catheters have caused meningitis, epidural abscesses, and other serious infections. At a cancer referral center, 81 catheters were placed in 72 patients over a 7-year period. There were seven catheter-associated infections: two were meningeal (one was accompanied by an epidural abscess and one by a pocket infection and bacteremia), four were associated with a pocket, and one was associated with a tunnel. The infection rate was 0.77 per 1,000 catheter-days. Pathogenic organisms that were isolated were primarily normal skin flora. By multivariate Cox analysis, the only factor significantly associated with catheter infection was prolonged catheter placement surgery, i.e., a procedure lasting at least 100 minutes (RR, 8.8; 95% CI, 1.6-50). Three patients were cured by removal of the catheter and treatment with antibiotics, and symptoms were satisfactorily suppressed in four patients with antibiotics alone. Considering the severity of illness in catheter recipients, the infection rate was relatively low. Removal of the catheter does not appear mandatory when the goal is suppression of infection-related symptoms, especially when the infection has not spread to the CNS, the infecting organism has an intrinsically low virulence, and the infected patient is terminally ill.