Harmaline toxicity on dorsal striatal neurons and its role in tremor.

Harmaline is one of the ß-carboline derivative compounds that is widely distributed in the food chain and human tissues. Harmine, a dehydrogenated form of harmaline, appeared to have a higher concentration in the brain, and appeared to be elevated in essential tremor (ET) and Parkinson's disease. Exogenous harmaline exposure in high concentration has myriad consequences, including inducing tremor, and causing neurodegeneration of Purkinje cells in the cerebellum. Harmaline-induced tremor is an established animal model for human ET, but its underlying mechanism is still controversial. One hypothesis posits that the inferior olive-cerebellum pathway is involved, and CaV3.1 T-type Ca2+ channel is a critical target of action. However, accumulating evidence indicates that tremor can be generated without disturbing T-type channels. This implies that additional neural circuits or molecular targets are involved. Using in vitro slice Ca2+-imaging and patch clamping, we demonstrated that harmaline reduced intracellular Ca2+ and suppressed depolarization-induced spiking activity of medium spiny striatal neurons (MSN), and this effect of harmaline can be partially attenuated by sulpiride (5 µM). In addition, the frequencies of spontaneous excitatory post-synaptic currents (sEPSCs) on MSNs were also significantly attenuated. Furthermore, the induced tremor in C57BL/6 J mice by harmaline injections (i.p. 12.5-18 mg/kg) was also shown to be attenuated by sulpiride (20 mg/kg). This series of experiments suggests that the dorsal striatum is a site of harmaline toxic action and might contribute to tremor generation. The findings also provide evidence that D2 signaling might be a part of the mechanism underlying essential tremor.

Addition of a third field significantly increases dose to the brachial plexus for patients undergoing tangential whole-breast therapy after lumpectomy.

Our goal was to evaluate brachial plexus (BP) dose with and without the use of supraclavicular (SCL) irradiation in patients undergoing breast-conserving therapy with whole-breast radiation therapy (RT) after lumpectomy. Using the standardized Radiation Therapy Oncology Group (RTOG)-endorsed guidelines delineation, we contoured the BP for 10 postlumpectomy breast cancer patients. The radiation dose to the whole breast was 50.4 Gy using tangential fields in 1.8-Gy fractions, followed by a conedown to the operative bed using electrons (10 Gy). The prescription dose to the SCL field was 50.4 Gy, delivered to 3-cm depth. The mean BP volume was 14.5 ± 1.5 cm(3). With tangential fields alone, the median mean dose to the BP was 0.57 Gy, the median maximum dose was 1.93 Gy, and the irradiated volume of the BP receiving 40, 45, and 50 Gy was 0%. When the third (SCL field) was added, the dose to the BP was significantly increased (P = .01): the median mean dose to the BP was 40.60 Gy, and the median maximum dose was 52.22 Gy. With 3-field RT, the median irradiated volume of the BP receiving 40, 45, and 50 Gy was 83.5%, 68.5%, and 24.6%, respectively. The addition of the SCL field significantly increases dose to the BP. The possibility of increasing the risk of BP morbidity should be considered in the context of clinical decision making.

Postoperative radiotherapy for carcinoma of the prostate: impact on both local control and distant disease-free survival.

The role of postoperative irradiation in patients with clinically localized prostate cancer, either as an adjuvant or salvage radiotherapy, remains controversial. In this study, we evaluate the impact of postoperative radiotherapy on patients diagnosed with prostate cancer with respect to biochemical and clinical disease free survival. Between 1987 and 1996, 179 patients with clinically localized prostate cancer were found to have adverse histopathologic findings on radical prostatectomy specimens (positive surgical margins, extracapsular extension, and seminal vesicle invasion). Of these patients, 42 were referred for postoperative adjuvant radiotherapy, whereas 73 were referred for salvage irradiation because of rising serum prostate-specific antigen (PSA) levels postoperatively. The remaining 64 patients underwent prostatectomy only. The 10-year biochemical relapse-free survival (RFS) from date of surgery were 88%, 45%, and 25% for patients treated with postoperative adjuvant radiotherapy, salvage irradiation, and with surgery alone, respectively (p = 0.046). Ten-year distant RFS from date of surgery were 82%, 74%, and 44% for adjuvantly treated patients, those with salvage radiotherapy, and those with surgery alone, respectively (p = 0.0180). Ten-year overall disease RFS from date of surgery was 89%, 76%, and 30% for adjuvantly treated patients, those with salvage radiotherapy, and those with surgery alone, respectively (p = 0.0237). Multivariate analyses revealed that a preoperative PSA greater than 20 ng/ml and pathologic Gleason Score of 8 to 10 were adverse predictors for biochemical relapse, whereas pathologic Gleason Score of 8 to 10, seminal vesicle invasion, and extracapsular extension were adverse predictors of distant metastases. Postoperative radiotherapy, either delivered as adjuvant treatment for adverse histopathologic findings or as salvage therapy for local relapses, appear to confer superior local, distant disease RFS, and overall disease RFS than surgery alone.