The glutathione cycle shapes synaptic glutamate activity.

Glutamate is the most abundant excitatory neurotransmitter, present at the bulk of cortical synapses, and participating in many physiologic and pathologic processes ranging from learning and memory to stroke. The tripeptide, glutathione, is one-third glutamate and present at up to low millimolar intracellular concentrations in brain, mediating antioxidant defenses and drug detoxification. Because of the substantial amounts of brain glutathione and its rapid turnover under homeostatic control, we hypothesized that glutathione is a relevant reservoir of glutamate and could influence synaptic excitability. We find that drugs that inhibit generation of glutamate by the glutathione cycle elicit decreases in cytosolic glutamate and decreased miniature excitatory postsynaptic potential (mEPSC) frequency. In contrast, pharmacologically decreasing the biosynthesis of glutathione leads to increases in cytosolic glutamate and enhanced mEPSC frequency. The glutathione cycle can compensate for decreased excitatory neurotransmission when the glutamate-glutamine shuttle is inhibited. Glutathione may be a physiologic reservoir of glutamate neurotransmitter.

Burden of palliative care issues encountered by radiation oncologists caring for patients with advanced cancer.

PURPOSE: Radiation oncologists frequently provide care for patients with advanced cancer who are in their last months or weeks of life. This study examined the previously not well-characterized types and frequencies of palliative care issues encountered in consultations for palliative radiation therapy (PRT). METHODS AND MATERIALS: This prospective, survey-based study assessed consecutive consults for PRT from May 19, 2014, to September 26, 2014 at 3 Boston-area community and academic, hospital-based centers. Participating physicians and nurse practitioners completed a survey to identify and rank the relevance (5-point Likert scale, not at all to extremely) of palliative care issues. Eight domains adapted from national palliative care guidelines (physical symptoms, psychosocial issues, cultural considerations, spiritual needs, care coordination, advance care planning, goals of care, and ethical and legal issues) were evaluated. A total of 162 consecutive consultations were surveyed with 140 responses received (86% response rate). RESULTS: Most (82%) consults had 2 or more palliative care domains ranked as highly (very or extremely) relevant to care. The domains of physical symptoms (91%), care coordination (70%), goals of care (59%), and psychosocial issues (52%) were the most commonly reported domains as highly relevant to care. Forty-six percent of consults involved a high palliative care burden (4 or more palliative care domains identified as highly relevant to care). Predictors of high palliative care burden in multivariable analysis were Eastern Cooperative Oncology Group performance status >2 (odds ratio, 3.57; P = .047), a plan for no further anticancer therapy after PRT (odds ratio, 3.46; P = .03), and a recommendation against PRT (odds ratio, 4.80; P = .01). CONCLUSIONS: Radiation oncology clinicians encounter multiple palliative care issues when consulting on patients for PRT. Clinicians identified physical symptoms, care coordination, and goals of care as the most relevant palliative care domains. These findings can help guide palliative care development within radiation oncology, including education and structures of care delivery.