Kathleen G. Davis

Demonstration of functional coupling between γ-aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles

l-Glutamic acid decarboxylase (GAD) exists as both membrane-associated and soluble forms in the mammalian brain. Here, we propose that there is a functional and structural coupling between the synthesis of γ-aminobutyric acid (GABA) by membrane-associated GAD and its packaging into synaptic vesicles (SVs) by vesicular GABA transporter (VGAT). This notion is supported by the following observations. First, newly synthesized [3H]GABA from [3H]l-glutamate by membrane-associated GAD is taken up preferentially over preexisting GABA by using immunoaffinity-purified GABAergic SVs. Second, the activity of SV-associated GAD and VGAT seems to be coupled because inhibition of GAD also decreases VGAT activity. Third, VGAT and SV-associated Ca2+/calmodulin-dependent kinase II have been found to form a protein complex with GAD. A model is also proposed to link the neuronal stimulation to enhanced synthesis and packaging of GABA into SVs.

Role of glutamate decarboxylase (GAD) isoform, GAD65, in GABA synthesis and transport into synaptic vesicles-Evidence from GAD65-knockout mice studies

In GAD65-knockout mice, lack of GAD65 expression was confirmed. The expression level of vesicular GABA transporter (VGAT) was upregulated, and no change in the synaptic vesicles (SV)-associated GAD67 was found. GAD65(-/-) SV transported cytosolic GABA much more efficiently than that of the wild type, further supporting our model that there is a structural and functional coupling between GABA synthesis and packaging into SV. Both full-length and truncated forms of GAD65 could bind to GABAergic SV, indicating the N-terminus is not required for the anchoring of GAD65 to SV. Although both GAD65(-/-) SV reconstituted with either GAD65 or GAD67 could synthesize GABA from [3H] glutamate and transport this newly synthesized GABA into SV, the combined evidence suggests that GAD65 plays a major role in GABA transmission in normal physiological condition. However, GAD67 could serve this role under some pathological conditions.

Carbamoylation of Brain Glutamate Receptors by a Disulfiram Metabolite

S-Methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), a metabolite of the drug disulfiram, is a selective carbamoylating agent for sulfhydryl groups. Treatment of glutamate receptors isolated from mouse brain with DETC-MeSO blocks glutamate binding. In vivo, carbamoylated glutathione, administered directly to mice or formed by reaction of DETC-MeSO with glutathione in the blood, also blocks brain glutamate receptors. Carbamoyl groups appear to be delivered to brain glutamate receptors or to liver aldehyde dehydrogenase in vivo by a novel glutathione-mediated mechanism. Seizures caused by the glutamate analogs N-methyl-d-aspartate and methionine sulfoximine, or by hyperbaric oxygen, are prevented by DETC-MeSO, indicating that carbamoylation of glutamate receptors gives an antagonist effect. These observations offer an explanation for some of the previously reported neurological effects of disulfiram, such as its ability to prevent O2-induced seizures. Furthermore, some of the physiology of the disulfiram-ethanol reaction, that could not be accounted for based on the known inhibition of aldehyde dehydrogenase alone, may be explained by disulfiram’s effect on glutamate receptors.

Educational needs of the terminally ill student.

It is the norm for medical professionals to encourage school reentry for the terminally ill student. Their commitment to and belief in the benefits of school involvement are to be commended. It is essential, however, that the hospital staff be directly involved with facilitating school reentry. Research into the needs of chronically and terminally ill students has historically been done by the medical community. Educators lack basic knowledge and the expertise to ensure that the school experience will be successful. It is hoped that the educational community will become more aware and actively seek to guarantee that every child is provided with an appropriate education in future years. For the time being, however, the medical professional must assume the role of coordinator, bringing together the terminally ill child, parents, peers, and educators, and fostering open, ongoing communication between all. The success of these efforts will bring about healthy attitudes toward death and dying; a rich, rewarding experience for all children involved; and ultimately an opportunity for a dying child to live life to its fullest.

Mode of Action of Taurine and Regulation Dynamics of Its Synthesis in the CNS

The regulation of taurine biosynthesis can be summarized as following: (i) When neurons are stimulated, the arrival of action potential will open the voltage-dependent Ca2+-channel, resulting in an increase of intracellular free Ca2+, [Ca2+]i, (ii) Elevation of [Ca2+]i will trigger release of taurine as well as activation of PKC, which in turn activates CSAD through protein phosphorylation; (iii) The activated CSAD then synthesizes more taurine to replenish that lost due to stimulation-mediated release; (iv) When intracellular taurine reach a certain level, it then inhibits the activation of PKC directly or indirectly (possibly through regulating Ca2+ availability), thus shutting down activation of CSAD through inhibition of CSAD phosphorylation by PKC; and (v) CSAD soon returns to its inactive state through the action of a protein phosphatase, most likely PrP-2C. The mode of action of taurine inlowering the level of [Ca2+]i, is at least partially due to its inhibition on the reverse mode of Na+-Ca2+ exchanger activity

Integrating Pediatric Palliative Care into the School and Community

Children and adolescents with complex chronic conditions often receive pediatric palliative care (PPC) from health care professionals. However, childrens needs exist both in a health care context and in the community where children interact with peers, including school, places of worship, sports, activities, and organizations. Partnerships between PPC professionals in health care settings and teachers, coaches, spiritual leaders, activity directors, and others, may lead to greater health and well-being. Children near the end of life or those with out-of-hospital do-not-resuscitate orders may also find palliation in their community. Cooperation between all caregivers benefit the child and family.

Pediatric Cancer and End-of-Life

Children continue to die from cancer. Despite the decline in mortality, pediatric cancer remains the leading cause of death from disease in children ages 1–14, exceeded only by accidental death. Childhood deaths due to cancer represent 58 % of disease-related deaths, outnumbering all other causes of death by disease combined (Curesearch 2015). The death of a child affects many individuals. In addition to the child’s parents and siblings, other family members such as grandparents, cousins and aunts and uncles may be devastated by the child’s death. Friends, teachers, coaches, spiritual leaders, doctors and nurses also experience grief and bereavement when a child dies. Several topics may aid in addressing the needs of various stakeholders including the dying child, parents, siblings, grandparents and a host of community members. In addition, the developmental level of the dying child, the siblings and friends is imperative to include in developing a plan of how to best support some of the key stakeholders. The pain of a child’s death cannot be denied. However, those who are feeling the loss can be best supported by employing some of the strategies included in this writing.