Gamma-hydroxybutyric Acid Tolerance and Withdrawal in a Rat Model

Long-term daily use of gamma-hydroxybutyrate (GHB) and related compounds has recently been associated with a withdrawal syndrome. To the best of the authors' knowledge, there are currently no animal models of GHB withdrawal. OBJECTIVES: The authors studied and described the effect of chronic dosing of GHB (3-6 days) on tolerance and withdrawal in a rat model. METHODS: Rats were administered GHB every three hours via intraperitoneal catheter. Groups of rats (2 per group) were dosed with GHB for either 3 (24 doses), 4 (32 doses), 5 (40 doses), or 6 (48 doses) days. The GHB dose was 0.25 g/kg for doses 1-8, 0.75 g/kg for doses 9-12, 1 g/kg for doses 13-16, 1.25 g/kg for doses 17-24, 1.5 g/kg for doses 25-32, 1.75 g/kg for doses 33-40, and 2 g/kg for doses 41-48. Following the last dose of GHB, the rats were scored using a 16-point ethanol intoxication-withdrawal scale rating spontaneous behaviors, response to handling, grooming, and neurological signs. Lower scores indicate intoxication, while higher scores indicate withdrawal. Scores were recorded at hours 0, 1, 2, 3, 4, 5, 6, 9, 12, and 24. RESULTS: Tolerance: Rats dosed with GHB for more days were less intoxicated one hour after their last GHB dose despite receiving higher doses. WITHDRAWAL: The scores for all rats dosed with GHB increased at hours 4 (p = 0.028), 5 (p = 0.037), 6 (p = 0.007), and 9 (p = 0.024) after the last dose, indicating withdrawal. The scores demonstrated a linear increase dependent upon the number of days of GHB dosing at hours 3 (p < 0.000), 4 (p = 0.004), 5 (p = 0.002), and 12 (p = 0.039) as well as prior to the last dose at hour 0 (p = 0.000). No rats developed seizures. CONCLUSIONS: Tolerance and mild withdrawal in rats can be induced by administering intraperitoneal GHB every three hours for 3-6 days. More prolonged dosing and higher doses of GHB may be necessary to induce severe withdrawal.     

The effect of pressurized carbon dioxide as a temporary plasticizer and foaming agent on the hot stage extrusion process and extrudate properties of solid dispersions of itraconazole with PVP-VA 64.

The aim of the current research project was to explore the possibilities of combining pressurized carbon dioxide with hot stage extrusion during manufacturing of solid dispersions of itraconazole and polyvinylpyrrolidone-co-vinyl acetate 64 (PVP-VA 64) and to evaluate the ability of the pressurized gas to act as a temporary plasticizer as well as to produce a foamed extrudate. Pressurized carbon dioxide was injected into a Leistritz Micro 18 intermeshing co-rotating twin-screw melt extruder using an ISCO 260D syringe pump. The physicochemical characteristics of the extrudates with and without injection of carbon dioxide were evaluated with reference to the morphology of the solid dispersion and dissolution behaviour and particle properties. Carbon dioxide acted as plasticizer for itraconazole/PVP-VA 64, reducing the processing temperature during the hot stage extrusion process. Amorphous dispersions were obtained and the solid dispersion was not influenced by the carbon dioxide. Release of itraconazole from the solid dispersion could be controlled as a function of processing temperature and pressure. The macroscopic morphology changed to a foam-like structure due to expansion of the carbon dioxide at the extrusion die. This resulted in increased specific surface area, porosity, hygroscopicity and improved milling efficiency.     

Physiologic mechanism and preoperative prediction of new-onset dysphagia after laparoscopic Nissen fundoplication

The aim of this study was to determine whether preoperative physiologic factors can account for and be used to predict the development of postoperative dysphagia after laparoscopic Nissen fundoplication. One hundred sixty-three patients with gastroesophageal reflux disease underwent laparoscopic Nissen fundoplication with a median follow-up of 14 months (range 6 to 81 months). Preoperative dysphagia was present in 37% (60 of 163) and was relieved in all but five patients (92%). Female sex (P = 0.01) and the presence of a stricture (P = 0.02) were the only preoperative variables associated with the presence of preoperative dysphagia. Eight percent (8 of 103) of patients without preoperative dysphagia developed new-onset dysphagia, and of these 63% (5 of 8) had a normal lower esophageal sphincter (LES) (pressure >6 mm Hg; length >2 cm; abdominal length >1 cm). New-onset dysphagia was significantly more common in patients with a normal LES (22% [5 of 23] vs. 4% [3 of 80], P = 001). Patients with a normal LES had almost a sixfold increase in the risk of developing dysphagia as those with an abnormal LES (relative risk = 5.8). Only a preoperative normal LES (P = 0.02) or mean LES pressures (P = 0.04) were positively associated with the development of postoperative dysphagia. The severity of this dysphagia also showed a strong positive trend of increasing with mean preoperative LES pressures (P = 0.07). Finally, preoperative LES pressure significantly correlated with postoperative LES pressure (r = 0.48, P = 0.01) and with mean residual LES (nadir) pressure (r = 0.33, P = 0.05) offering insight into the mechanism of this dysphagia. In conclusion, preoperative LES parameters play a role in the development of dysphagia after laparoscopic Nissen fundoplication. Patients with a normal LES or high mean LES pressures are at increased risk for developing this complication and should be informed of this before laparoscopic Nissen fundoplication. Presented at the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Ga., May 20–23, 2001.     

Importance of speech production for phonological awareness and word decoding: The case of children with cerebral palsy

The goal of this longitudinal study was to investigate the precursors of early reading development in 52 children with cerebral palsy at kindergarten level in comparison to 65 children without disabilities. Word Decoding was measured to investigate early reading skills, while Phonological Awareness, Phonological Short-term Memory (STM), Speech Perception, Speech Production and Nonverbal Reasoning were considered reading precursors. Children with cerebral palsy lag behind on all reading precursors at the beginning of the second year of kindergarten. For the children without disabilities, early reading skills in Grade 1 were best predicted by Phonological Awareness and Phonological STM while Speech Production was the most important predictor of early reading success for the children with cerebral palsy, followed by Phonological Awareness and Speech Perception. Furthermore, for children with cerebral palsy, Speech Production appears to dominate reading development, as Speech Production measured at the beginning of the second year of kindergarten was strongly predictive of all other reading precursors measured at the end of the second year of kindergarten. The results of this study reveal that children with cerebral palsy with additional speech impairments are at risk for limited literacy development. Clinical implications are discussed.     

Crediting his critics' concerns: Remaking John Snow's map of Broad Street cholera, 1854

Few cases in the history of epidemiology and public health are more famous than John Snow's investigation of a neighborhood cholera outbreak in the St. James, Westminster, area of London in 1854. In this study Snow is assumed to have proven that cholera was water rather than airborne through a methodology that became, and to a great extent remains, central to the science and social science of disease studies. And yet, Snow's work did not satisfy most of his contemporaries who considered his proof of a solely waterborne cholera interesting but unconvincing. Uniquely, this paper asks whether the caution of Snow's contemporaries was reasonable, and secondly, whether Snow might have been more convincing within the science of the day. The answers significantly alter our understanding of this paradigmatic case. It does so in a manner offering insights both into the origins of nineteenth century disease analysis and more generally, the relation of mapping in the investigation of an outbreak of uncertain origin. The result has general relevance—pedagogically and practically—in epidemiology, medical geography, and public health.     

Survey of psychiatric disorders in a Taiwanese village population six months after a major earthquake.

BACKGROUND AND PURPOSE: The catastrophic Chi-Chi earthquake of September 21, 1999 in Taiwan provided a unique opportunity to study the disaster's psychiatric impact on survivors. This study assessed the development of psychiatric disorders among residents in a Taiwanese village near the epicenter of the earthquake within 6 months of the disaster. METHODS: A total of 442 of the 602 actual living residents of Tong-Chi village who were over 16 years of age and were present in the community at the time of the earthquake were included in this population survey. Subjects were interviewed by psychiatrists using the Mini-International Neuropsychiatric Interview and questionnaires to collect demographic information and risk factors for psychiatric disorders 4 to 6 months after the earthquake. RESULTS: The prevalence rates were 9.5% for current major depression, 2.8% for past major depressive episode, and 7.9% for post-traumatic stress disorder (PTSD). Females had significantly higher rates of most psychiatric disorders. After controlling for covariates, the significant risk factors for PTSD were female gender and having sought medical service after the earthquake. Significant risk factors for major depressive episode were divorced/widowed status, education level equal to or below primary school, and prominent house damage. CONCLUSION: This population survey of earthquake disaster survivors found an increased prevalence of psychiatric disorders after exposure to a catastrophic earthquake. These results highlight the need for prompt therapeutic attention to residents of earthquake disaster areas after the event.     

阴茎勃起神经再生模型和机制的研究

探明神经性勃起功能障碍(NED)的分子生物学机制以期对该类疾病进行神经调控干预,是男科学研究的当务之急。本文回顾了急性神经损伤、前列腺癌、糖尿病和帕金森病所致的NED的研究进展。通过利用大鼠阴茎勃起神经的盆腔大神经节(MPG),在体外构建一个三维培养体系来研究各种生长因子和细胞信号通路对神经再生的影响。体外结果表明脑源性神经生长因子(BDNF)通过JAK/STAT信号通路可显著促进NED的恢复,并在体内证实了该效应。因此,通过调控JAK/STAT信号通路来达到神经调控干预措施预防治疗神经性勃起功能障碍成为可能。     

Curcumin Reduces Burn Progression in Rats

Objectives Cutaneous burns are dynamic injuries with a central zone of necrosis surrounded by a zone of ischemia. Conversion of this ischemic zone to full necrosis over the days following injury is due in part to highly reactive oxygen radicals. Curcumin is a component of the Oriental spice turmeric that has been shown to have antioxidant and antiapoptotic properties. The authors hypothesized that treatment of burns with curcumin would reduce the conversion of the ischemic zone to full necrosis. Methods This was a randomized controlled experiment. Twenty Sprague‐Dawley rats were used. Two burns were created on each animal's dorsum using a brass comb with four rectangular prongs preheated in boiling water and applied for 30 seconds, resulting in four rectangular 10 × 20–mm full‐thickness burns separated by three 5 × 20–mm unburned interspaces (zone of ischemia). Animals were randomized to curcumin or vehicle by oral gavage 30 minutes before injury and at 24, 48, and 72 hours after injury. Wounds were observed at one, two, and three days after injury for visual evidence of necrosis in the unburned interspaces. Full‐thickness biopsy specimens from the interspaces were evaluated with hematoxylin and eosin staining seven days after injury for evidence of necrosis. The percentage of interspaces that progressed to necrosis was compared with chi‐square tests. Results Forty comb burns with 120 unburned interspaces were created, evenly distributed between curcumin and vehicle alone. The percentage of interspaces that progressed to full‐thickness necrosis at one, two, three, and seven days after injury in the curcumin and vehicle groups were 30% versus 63% (p = 0.003), 30% versus 70% (p < 0.001), 63% versus 95% (p = 0.02), and 63% versus 95% (p = 0.02), respectively. Conclusions Pretreatment of rats with oral curcumin followed by once‐daily oral treatment for three days reduced the percentage of unburned skin interspaces that progressed to full necrosis.