Following cerebral ischemia, certain populations of neurons degenerate. Excessive accumulation of excitatory amino acids in the synaptic cleft, activation of excitatory amino acid receptors, and influx of calcium into neurons play a key role in the development of ischemia-induced neuronal death. We hypothesized that neuroprotection may be achieved by enhancing inhibitory (i.e., gamma-aminobutyric acid, GABA) neurotransmission to offset excitation. Diazepam, a drug that increases GABA-induced chloride channel opening, was administered (10 mg/kg, i.p.) to rats 1 and 2 hr following 15 min of transient global ischemia, when hippocampal GABA levels, increased during ischemia, returned to basal. Rats were maintained normothermic during ischemia and became hypothermic following the injections of diazepam. Four days later, rats were sacrificed and the brains were examined for neuronal degeneration and the presence of GABAA receptors labeled by 35S-t- butylbicyclophosphorothionate (35S-TBPS). There was substantial neuroprotection of striatal neurons and pyramidal neurons in the CA1 area of the hippocampus. In addition, diazepam prevented the loss of 35S-TBPS binding sites in the striatum and in the dendritic fields of the CA1 hippocampus following ischemia. Since hypothermia, itself, is neuroprotective, we determined if hypothermia was required for the ability of diazepam to produce neuroprotection. Diazepam was microinjected into the CA1 hippocampus 1 and 2 hr following ischemia, and rats remained normothermic. Four days later, diazepam still produced substantial protection of hippocampal neurons. Thus, postischemic hypothermia may have contributed to the neuroprotection by diazepam when it was administered systemically, but the neuroprotective effect of diazepam did not require hypothermia. We conclude that delayed enhancement of GABAergic neurotransmission directly at the site of vulnerability following an ischemic event protects the vulnerable neurons from death.

This prospective study investigated associations between cord blood vitamin D, risk factors for low vitamin D, and pregnancy and neonatal outcomes. The study included 65 maternal-fetal dyads delivering between December and February in Saskatoon, Saskatchewan. Eighty-five percent of mothers reported taking daily prenatal vitamin D but 70% of their newborns had insufficient or deficient cord blood vitamin D, suggesting that usual prenatal supplementation may be inadequate to achieve sufficient cord blood vitamin D in most newborns.

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Introduction: High-dose melphalan and autologous stem cell transplantation is the accepted therapy for most patients with multiple myeloma (MM) following steroid-based induction therapy. In a significant proportion of patients, however, the disease is refractory to standard induction. The use of dose-intense combination chemotherapy, such as D-PACE (dexamethasone, doxorubicin, cyclophosphamide, and cisplatin), may affect the ability to harvest an adequate number of hematopoeitic stem cells prior to transplantation. In addition, in those patients not achieving adequate cytoreduction despite combination chemotherapy, there is a theoretical risk of stem cell product contamination by malignant plasma cells. Bortezomib is a therapeutic agent with a novel mechanism of action, which in preliminary studies appears to be synergistic to alkylating agents and does not appear to affect stem cell yield. We piloted the addition of bortezomib to high-dose cyclophosphamide during stem cell harvesting in a series of patients failing to achieve an adequate response to D-PACE salvage. Patients and Methods: Between 2002 and 2006, fifteen MM patients refractory to standard dexamethasone-based induction therapy received ≥ 2 cycles of D-PACE prior to proceeding to autologous stem cell harvest and transplantation. 7/15 patients achieved adequate cytoreduction and proceeded to high-dose cyclophosphamide (3 g/m2) and filgrastim plus ancestim stimulation for stem cell mobilization. However, 8 patients in this cohort did not achieve adequate disease cytoreduction following D-PACE. Therefore, bortezomib was added to the mobilization regimen on days 1, 4, 8, and 11, in addition to high-dose cyclophosphamide given on day 11. Identical growth factor stimulation was provided. Response assessment included days to stem cell harvest, number of CD34 cells harvested, plasma cells in the product, disease response, and hematologic parameters. Results: Pre-treatment toxicities from D-PACE were similar in both groups. The addition of bortezomib to cyclophosphamide during stem cell mobilization did not lead to increased symptomatic toxicity. Grade 3/4 thrombocytopenia occurred in 5/8 patients receiving combination bortezomib/cyclophosphamide. No episodes of significant bleeding, peripheral neuropathy, or skin rash were noted. The average CD34-positive stem cell harvest in both groups was >5.0 × 106/kg. Time to stem cell harvesting was not significantly different between the groups. Flow cytometric examination of the harvested product from the bortezomib/cyclophosphamide group consistently demonstrated <2% cells bearing plasma cell markers. One patient in each group failed to mobilize sufficient stem cells. Bone marrow plasmacyte counts following combination therapy and harvesting decreased in all assessed patients. Time to engraftment was similar in both groups. Post-transplant disease control and survival remains to be assessed, as some patients in the combination group have only recently undergone transplantation. Conclusion: The addition of bortezomib to high-dose cyclophosphamide during stem cell mobilization does not increase toxicity or decrease stem cell harvest yield or quality, and appears to achieve adequate disease reduction in patients otherwise refractory to combination chemotherapy. This may result in improved relapse-free survival in patients with refractory MM.