Morphological and functional effects of altered cysteine string protein at the Drosophila larval neuromuscular junction

The synaptic vesicle-associated cysteine string protein (CSP) is critical for neurotransmitter release at the neuromuscular junction (NMJ) of Drosophila, where the approximately 4% of mutant flies lacking CSP that survive to adulthood exhibit spastic jumping and shaking, temperature-sensitive paralysis, and premature death. Previously, it has been shown that CSP is also required for nerve terminal growth and the prevention of neurodegeneration in Drosophila and mice. At larval csp null mutant NMJs of Drosophila, intracellular recordings from the muscle showed that evoked release is significantly reduced at room temperature. However, it remained unclear whether the reduction in evoked release might be due to a loss of synaptic boutons, loss of synapses, and alterations in trafficking of vesicles to synapses. To resolve these issues, we have examined synaptic structure and function of csp null mutant NMJs at the level of single boutons. csp null mutations proportionally reduce the number of synaptic boutons of both motor neurons (1s and 1b) innervating larval muscles 6 and 7, while the number of synapses per bouton remains normal. However, focal recordings from individual synaptic boutons show that nerve-evoked neurotransmitter release is also impaired in both 1s and 1b boutons. Further, our ultrastructural analyses show that the reduction in evoked release at low stimulation frequencies is not due to a loss of synapses or to alterations in docked vesicles at synapses. Together, these data suggest that CSP promotes synaptic growth and evoked neurotransmitter release by mechanistically independent signaling pathways.     

Characterization of pharmacological and behavioral differences to nicotine in C57Bl/6 and DBA/2 mice

Approximately 50-70% of the risk for developing nicotine dependence is attributed to genetics; therefore, it is of great significance to characterize the genetic mechanisms involved in nicotine reinforcement and dependence in hopes of generating better smoking cessation therapies. The overall goal of these studies was to characterize behavioral and pharmacological responses to nicotine in C57Bl/6 (B6) and DBA/2 (D2) mice, two inbred strains commonly used for genetic studies on behavioral traits. B6 and D2 mice where subjected to a battery of behavioral tests to measure nicotine's acute effects, calcium-mediated antinociceptive responses, tolerance to chronic treatment with osmotic mini pumps, and following three days of nicotine withdrawal. In general, D2 mice were less sensitive than B6 mice to the acute effects of nicotine, but were more sensitive to blockade of nicotine-induced antinociceptive responses by a calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor. B6, but not D2 mice, developed tolerance to nicotine and nicotine conditioned place preference (CPP). While B6 and D2 mice both expressed some physical withdrawal signs, affective withdrawal signs were not evident in D2 mice. These results provide a thorough, simultaneous evaluation of the pharmacological and behavioral differences to experimenter-administered nicotine as measured in several behavioral tests of aspects that contribute to smoking behavior. The B6 and D2 strains show wide phenotypic differences in their responses to acute or chronic nicotine. These results suggest that these strains may be useful progenitors for future genetic studies on nicotine behaviors across batteries of mouse lines such as the BXD recombinant inbred panel.     

Antagonism of peripheral inflammation reduces the severity of status epilepticus

Status epilepticus (SE) is one of the most serious manifestations of epilepsy. Systemic inflammation and damage of blood-brain barrier (BBB) are etiologic cofactors in the pathogenesis of pilocarpine SE while acute osmotic disruption of the BBB is sufficient to elicit seizures. Whether an inflammatory-vascular-BBB mechanism could apply to the lithium–pilocarpine model is unknown. LiCl facilitated seizures induced by low-dose pilocarpine by activation of circulating T-lymphocytes and mononuclear cells. Serum IL-1β levels increased and BBB damage occurred concurrently to increased theta EEG activity. These events occurred prior to SE induced by cholinergic exposure. SE was elicited by lithium and pilocarpine irrespective of their sequence of administration supporting a common pathogenetic mechanism. Since IL-1β is an etiologic trigger for BBB breakdown and its serum elevation occurs before onset of SE early after LiCl and pilocarpine injections, we tested the hypothesis that intravenous administration of IL-1 receptor antagonists (IL-1ra) may prevent pilocarpine-induced seizures. Animals pre-treated with IL-1ra exhibited significant reduction of SE onset and of BBB damage. Our data support the concept of targeting systemic inflammation and BBB for the prevention of status epilepticus.     

Intensity-modulated radiotherapy (IMRT)/Tomotherapy following neoadjuvant chemotherapy in stage IIB-IVA/B undifferentiated nasopharyngeal carcinomas (UCNT): a mono-institutional experience

To evaluate the outcome of Undifferentiated Nasopharyngeal Carcinomas (UCNT) treated with intensity-modulated radiation therapy with Simultaneous Integrated Boost (SIB), following induction chemotherapy. Between January 2006 and June 2009, 52 patients with stage II B-IVA/B UCNT were treated either with linac-IMRT or Tomotherapy. All patients were scheduled to receive three cycles of cisplatin based neoadjuvant chemotherapy. With a median follow-up of 38.5 months (range 12.3–64.1), 3 year overall survival (OS), disease-free survival (DFS), and DFS by T2a–2b and T3–T4-stage were 95.0%, 84.6%, 89.0%, and 78.0%, respectively. At multivariate analysis, none of the examined prognostic factors reported statistical significance. N-classification was not a significant predictive factor for either OS or development of distant metastases. T-stage alone had a borderline effect on DFS and development of metastases. No difference between Tomotherapy and linac-IMRT emerged in terms of loco-regional control and development of severe, acute, and late toxicities. The most significant severe, acute toxicities were grade 3 (32.7%) and grade 4 (7.7%) mucositis. No grades 3 and 4 late toxicities were observed. The most commonly observed late effect was xerostomia, 11.5% patients complained grade 2 xerostomia. The severity of grade 2 xerostomia diminished over time with only four patients not improving salivation. IMRT-SIB following neoadjuvant chemotherapy was very satisfactory in terms of local control, regional control, DFS and OS rates in patients with stage IIB to IVB UCNT. In our experience, adding concurrent chemotherapy to IMRT after neoadjuvant chemotherapy in loco-regional widespread disease resulted to be the indicated approach.     

Pilot study: awareness of university students in Jordan of the positive health effects of garlic

Background  One of the most popular herbal remedies, garlic, is used for its many medicinal applications. These historically valuable applications could be summarized by its cardiovascular, antineoplastic, and antimicrobial properties. However, public knowledge of the health benefits of taking garlic is much better known than the adverse events that may result when garlic interacts with other medications. Aim  This study aims to investigate the public’s knowledge in Jordan regarding garlic’s healthy effects as well as the possibly undesired interactions with Western-style medications that may occur. Method  This cross-sectional randomized study investigated participants’ knowledge regarding the healthy effects of garlic. Selected individuals of the sample were interviewed by 117 well-trained senior pharmacy students (4th and 5th year students). Each individual was asked to fill out a questionnaire on his/her knowledge of the beneficial effects of garlic on health and its serious drug interactions. The interviewer checked the completed form and counseled the participant on the questions which were not known or answered incorrectly. Results  Participants were found to be very aware of the healthy effects of garlic. However, a smaller percentage (19–30%) of them knew it could have significant interactions with some medications. Conclusion  Public awareness in Jordan of the beneficial healthy effects of garlic is better than the awareness of its serious interactions with some drugs.