Preferential resistance of dopaminergic neurons to glutathione depletion in a reconstituted nigrostriatal system

Depletion of glutathione in the substantia nigra is one of the earliest changes observed in Parkinson's disease (PD), and could initiate dopaminergic neuronal degeneration. Nevertheless, we have previously demonstrated that mesencephalic dopaminergic neurons in primary monolayer cultures are more resistant to the toxicity of glutathione depletion than nondopaminergic neurons. To extend this finding to a system that more closely resembles the in vivo situation, we characterized the effects of glutathione depletion on reaggregate cultures derived from ventral mesencephalic and their striatal target neurons, as well as supporting elements including glia. Dopaminergic neurons were found to be more resistant to the toxicity of buthionine-(S,R)-sulfoximine, an inhibitor of glutathione synthesis, than other nigrostriatal neurons, while striatal target cells exhibited an intermediate susceptibility when examined after 48 h. Glutathione depletion, however, decreased the intracellular content of catecholamines after 48 h and eventually led to the loss of dopaminergic neurons after 7 days. Our data indicate that the intrinsic resistance of dopaminergic neurons to the toxicity of glutathione depletion occurs in a variety of experimental paradigms, and suggest that global glutathione depletion alone is unlikely to account for the selective loss of dopaminergic neurons in PD. Rather, it is more likely that either the selective loss of glutathione from dopaminergic neurons, or the combination of glutathione loss with other insults contributes to the preferential death of dopaminergic neurons in PD.     

Differential expression of the PSD-95 gene family in electrosensory neurons

The PSD-95 family of membrane-associated guanylate kinase (MAGUK) proteins are involved in the assembly and organization of neurotransmitter receptors at excitatory synapses in the vertebrate nervous system. We have isolated partial cDNAs for five PSD-95 family members from Apteronotus leptorhynchus brain RNA using a degenerate PCR method. The amino acid sequences deduced indicate that A. leptorhynchus neurons express homologues of the mammalian PSD-93, SAP-97, and SAP-102 MAGUKs and two homologues of mammalian PSD-95. In situ hybridization experiments have been carried out to localize the cellular expression of all five MAGUK mRNAs in the central nervous system of A. leptorhynchus. In the cerebellum the expression patterns are highly similar to patterns reported for mammalian cerebellum, suggesting an evolutionary conservation of the functional roles in this gene family. Cellular levels of expression of the PSD-95 MAGUK mRNAs and the NMDAR-1 mRNA were highly correlated in neurons of the dorsal forebrain but were not correlated in neurons of the electrosensory lateral line lobe (ELL) or the cerebellum. These results suggest that the expression of PSD-95 MAGUK genes in forebrain neurons may provide mechanisms for synaptic organization that are not shared by neurons in the ELL and cerebellum.     

Interpretation of Wada memory test for lateralization of seizure focus by use of (99m)technetium-HMPAO SPECT

PURPOSE: Although the intracarotid amobarbital procedure (IAP) or Wada test is useful in lateralizing seizure focus in patients with temporal lobe epilepsy (TLE), the results of the IAP memory test are frequently nonlateralizing. An insufficient suppression of the medial temporal region contralateral to the seizure focus may contribute to the failure of lateralization. We tried to correlate IAP memory results with the functional changes in the contralateral medial temporal region as measured by single photon emission computed tomography (SPECT) during IAP. METHODS: We performed a (99m)technetium-(Tc) hexamethylene-propylene-amine-oxime (HMPAO) brain SPECT in 19 medial TLE patients during a contralateral IAP (sodium amobarbital injected contralateral to the seizure focus). Regional cerebral blood flow (rCBF) was measured in the contralateral medial temporal region. The amount of decrease in the rCBF was calculated by subtracting the previous measurement from the one obtained with the interictal SPECT. RESULTS: Ten (53%) patients passed and nine (47%) failed the contralateral IAP. The mean percentage decrease in rCBF was 5.3+/-5.3%. There was a significant negative correlation between a decrease in the rCBF and the IAP memory-retention score by Spearman correlation (p = -0.53: p<0.021). Patients with smaller decreases in rCBF (<5%) more frequently passed the contralateral IAP memory test than did those with larger decreases (80 vs. 22%; p<0.023). CONCLUSIONS: We suggest that an insufficient suppression of the contralateral medial temporal function is partly responsible for nonlateralizing IAP memory tests. An IAP-SPECT may be useful in interpreting IAP memory tests for the lateralization of seizure focus in TLE patients.     

Safety and efficacy of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. multicenter phase III clinical trials (safety)

The short-term safety of mangafodipir trisodium (MnDPDP) injection was studied in 546 adults with known or suspected focal liver lesions. An initial contrast-enhanced computed tomography examination was followed by unenhanced magnetic resonance imaging (MRI), injection of MnDPDP (5 micromol/kg), and enhanced MRI. Adverse events were reported for 23% of the patients; most were mild to moderate in intensity, did not require treatment, and were not drug related. The most commonly reported adverse events were nausea (7%) and headache (4%). The incidence of serious adverse events was low (nine events in six patients) and not drug related. Injection-associated discomfort was reported for 69% of the patients, and the most commonly reported discomforts included heat (49%) and flushing (33%). Changes in laboratory values and vital signs were generally transient, were not clinically significant, and did not require treatment. There were no clinically significant short-term risks from exposure to MnDPDP.     

Delayed Administration of the K+ Channel Activator Cromakalim Attenuates Cerebral Vasospasm after Experimental Subarachnoid Hemorrhage

Summary ? Background. Delayed cerebral vasospasm remains an unpredictable and inadequately treated complication of aneurysmal subarachnoid hemorrhage (SAH). Recent evidence indicates that the potassium channel activator cromakalim is capable of limiting cerebral vasospasm in rabbits when administered immediately after experimental SAH (i.e. before spastic constriction has been initiated). However, the ultimate clinical value of cromakalim for treating vasospasm will depend in part on its effectiveness when administered after SAH-induced constriction has already been initiated. The present study examined the effects of cromakalim on vasospasm when treatment was initiated after SAH-induced constriction was underway.  Methods. New Zealand white rabbits were subjected to experimental SAH by injecting autologous blood into the cisterna magna. Cromakalim (0.03, 0.1 or 0.3 mg/kg) or vehicle was injected intravenously at 8 hour intervals beginning 24 hours post-SAH. Animals were killed by perfusion fixation 48 hours after SAH. Basilar arteries were removed and sectioned, and cross-sectional area was measured.  Findings. The average cross sectional areas of basilar arteries were reduced by 64% and 68% in the SAH-only and SAH+vehicle groups, respectively. Treatment with cromakalim dose-dependently attenuated SAH-induced constriction. The groups treated with 0.03, 0.1, and 0.3 mg/kg cromakalim exhibited average decreases in cross-sectional area of 57%, 42%, and 19%, respectively.  Interpretation. These findings indicate that cromakalim dose-dependently attenuates cerebral vasospasm when administered 24 hours after experimental SAH in the rabbit. The results suggest K_ATP channel activators, such as cromakalim, could be of benefit for reversing cerebral vasospasm after aneurysmal SAH.     

Sexual dysfunction, informed consent and multimodality therapy for rectal cancer

BACKGROUND: This study assessed the presurgical and preradiation discussion of the risk of posttherapy sexual dysfunction among patients who underwent potentially curative therapy for rectal cancer. The incidence of sexual dysfunction after treatment for rectal cancer was then determined. METHODS: A retrospective review of the medical records of 52 consecutive patients who underwent potentially curative procedures for rectal cancer within 15 cm from the anal verge was performed. RESULTS: Presurgical discussion of the risk of sexual dysfunction was not documented in the consent in 37 of 52 patients (71%). Among the 5 males who underwent local excision, none reported posttherapy sexual dysfunction. Of the 6 males who were treated by low anterior resection, only 1 had a postoperative complaint of sexual dysfunction. Five of 15 males (33%) treated with abdominoperineal resection (APR) alone reported postprocedure sexual dysfunction, whereas 6 of 8 males (75%) treated with APR and radiation reported dysfunction. Of the entire female cohort, only 1 of the 16 reported sexual dysfunction posttherapy. CONCLUSION: A discussion of the risks of posttherapy sexual dysfunction was documented for fewer than one third of the patients. Among males after APR, the use of postoperative radiation showed a trend toward an increase in sexual dysfunction. Surgery and/or radiation therapy did not impact on sexual dysfunction in females.     

Beacon: a novel gene involved in the regulation of energy balance

The hypothalamus plays a major role in the control of energy balance via the coordination of several neuropeptides and their receptors. We used a unique polygenic animal model of obesity, Psammomys obesus, and performed differential display polymerase chain reaction on hypothalamic mRNA samples to identify novel genes involved in obesity. In this study, we describe a novel gene that encodes a small protein we have termed "beacon." Beacon mRNA gene expression in the hypothalamus was positively correlated with percentage of body fat. Intracerebroventricular infusion of beacon resulted in a dose-dependent increase in food intake and body weight and an increase in hypothalamic expression of neuropeptide Y (NPY). Simultaneous infusion of beacon and NPY significantly potentiated the orexigenic response and resulted in rapid body weight gain. These data suggest a role for beacon in the regulation of energy balance and body weight homeostasis that may be mediated, at least in part, through the NPY pathway.     

Development of a Regionalized,Comprehensive Care Network for Pediatric Sickle Cell Disease to Improve Access to Care in a Rural State

Sickle cell disease (SCD), an inherited group of blood disorders, is a major public health problem worldwide. Patients experience severe anemia, increased risk of life-threatening infections, painful crisis, and chronic organ damage. Access to comprehensive care for SCD is known to improve outcomes; however, it is only reported from large urban centers serving one metropolitan area. Alabama, US, is a largely rural state with a significant number of children born each year with SCD. Prior to the development of our regional clinic network, the Children and Youth Sickle Network (CYSN^SM), 50% of patients identified by newborn screening were not enrolled in comprehensive sickle cell care. The majority of non-enrolled patients lived in southern Alabama. Rural areas in this region are particularly plagued by poverty and poor access to healthcare. Life expectancy is equivalent to residents of Sri Lanka. This area has 15.7 doctors/10 000 residents compared with the statewide ratio of 41.9 doctors/10 000 residents.To improve access to care, a regional clinic network, the CYSN^SM, was established in 1995. This paper reviews the impact of the CYSN^SM on pediatrie SCD in Alabama over the first 5 years of implementation.Since its inception in 1995, the CYSN^SM has provided care for 923 patients compared with 450 prior to the development of the clinic network. Currently, 90% of all cases identified by newborn screening are enrolled compared with 50% pre-CYSN^SM. Prior to the network, the average age of patients at their first clinic visit was 21 months. In the post-CYSN^SM period, the average age at first clinic visit decreased substantially to 5.3 months. Prior to the CYSN^SM, patients traveled on average 90 miles to a comprehensive clinic. Post-CYSN^SM, this distance has been cut in half to an average of 45 miles. A total of 70% of patients now live within 30 miles of a clinic. Most importantly, the infection death rate has decreased from 5.71 deaths/100 patient years to 1.94 deaths/100 patient years.The development, implementation, and evaluation of the CYSN^SM show that comprehensive care delivery in a rural setting is feasible and improves outcomes in pediatric SCD.