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.     

Making the transition from information systems of the 1970s to medical information systems of the 1990s: The role of the Physician's Workstation

Many hospitals today have implemented widely disparate information systems on mainframe and mini-computer hardware. The advent of network technology in hospitals has made it possible to access information in these systems. Unfortunately, the user interfaces to applications on these systems are unique and difficult to learn, which makes them unsuitable for use by clinical services. In this paper we describe the development of a Physician's Workstation which integrates information from multiple existing information systems and discuss how the workstation makes it possible to move from the departmental systems of the present to the computer-based medical record system of the future.     

It's all about sex: gender, lung development and lung disease.

Accumulating evidence suggests that gender affects the incidence, susceptibility and severity of several lung diseases. Gender also influences lung development and physiology. Data from both human and animal studies indicate that sex hormones might contribute to disease pathogenesis or serve as protective factors, depending on the disease involved. In this review, the influence of gender and sex hormones on lung development and pathology will be discussed, with specific emphasis on pulmonary fibrosis, asthma and cancer.     

Comparison of antigen expression on normal urothelial cells in tissue section and tissue culture

Antigenic characterization of urothelial cells cultured from normal adult ureter was performed. These cells were cultured using a simplified isolation and culture technique and a commercially available serum-free medium. The cells growing in these cultures had epithelioid morphology and normal quantities of DNA. The antigen expression on these cultured normal urothelial cells was evaluated using a panel of monoclonal antibodies: 5G6.4, AN43, URO-5, anti-keratin and anti-blood group antibodies, and 425 (anti-epidermal growth factor receptor). Lower levels of anti-A and AN43 binding on cultured cells were observed than are seen on urothelial cells in sections of normal ureter, while the binding of anti-blood group H, 5G6.4, and URO-5 was unchanged. Binding of anti-epidermal growth factor receptor antibody 425 was improved if the cells were grown in medium lacking epidermal growth factor. These results confirm the urothelial origin of these cultured urothelial cells but indicate that some antigenic differences between cultured normal urothelial cells and urothelial cells in situ in the normal ureter exist.     

Path analysis and sib-pair linkage

When the distance between linked loci is expressed in terms of the correlation between the identity-by-descent (idb) values of the loci, then a path model may be used to order loci with data on sib-pairs and their parents. The relationship between the recombination fraction and the correlation coefficient is developed and a method for fitting a covariance matrix predicted by a specific ordering of loci to an observed covariance matrix is proposed. © 1993 Wiley-Liss. Inc.     

Morphological correlates of response dynamics and efferent stimulation in horizontal semicircular canal afferents of the toadfish, Opsanus tau.

1. We used the intraaxonal labeling technique to study correlations between the terminal dendritic morphology of horizontal semicircular canal primary afferents and their response dynamics to sinusoidal head rotation and combined electrical stimulation of central efferent vestibular neurons. Thirty-eight canal afferents were identified by their sensitivity and phase of response to rotation between 0.1 and 1.0 Hz (+/- 10 degrees/s) and were subsequently labeled with horseradish peroxidase or biocytin. The afferent's dendritic field and synaptic specializations in the neuroepithelium of the crista were examined under light microscopy. 2. Rate and regularity of background discharge of the afferent were not correlated with its axon diameter or relative location of its dendritic field in the crista. 3. Response sensitivity of the afferent to rotation was correlated both with the relative location of its dendritic field in the crista and with the number of terminal endings it possesses. Afferents having low sensitivities, slow dynamics, and few terminal endings supply the peripheral portions of the crista; afferents with higher sensitivities, faster dynamics, and greater number of terminal endings supply the more central portions. It is suggested that the differences in sensitivity among the afferents reflect principally the variations in both the cupular dynamics along the crista and the number of possible hair cell contact sites in the neuroepithelium. 4. Response phase of the afferent was correlated only with the extent of its dendritic processes along the transverse axis of the crista. Afferents having transversely oriented dendritic fields had less phase lags relative to acceleration than did those having a more longitudinally oriented dendritic field. 5. Efferent stimulation produced a change in both the afferent's discharge rate and its response sensitivity to rotation. Afferents discharge rate and its response sensitivity to rotation. Afferents having a centrally located dendritic field and acceleration afferents, defined by their response to rotation, were the most affected by efferent stimulation. These results suggest that efferent innervation is either directed toward, or most efficacious in, the central regions of the crista and that it may select specific hair cell-afferent complexes.     

Central pontine myelinolysis in liver transplantation.

Five cases of central pontine myelinolysis (CPM) were detected by neuropathological examination in a series of 50 patients coming to necropsy after liver transplantation. One patient also had extrapontine myelinolysis. In no case was the diagnosis made during life. Only two patients showed rapid rises in serum sodium concentrations. The incidence of hyponatraemia, before and after transplantation, and rapid rises in serum sodium in patients with CPM was significantly greater than in the 45 patients showing no neuropathological evidence of CPM. It is concluded that there is a high incidence of CPM after liver transplantation, that clinical diagnosis is difficult, and that there is no simple direct correlation between rapid serum sodium changes and the development of this condition. Avoidance of major electrolyte fluctuations at the time of liver transplantation is recommended but it must be emphasised that CPM may occur without any rapid rise in serum sodium concentration.     

Nosological considerations of the neurofibromatoses.

We are on the threshold of evaluating the NF1 and NF2 loci with respect to variant forms of the neurofibromatoses. Genetic mapping of NF1, gene cloning and characterization of its encoded product, neurofibromin, provides a framework for the evaluation of the variant forms of NF. This may also apply to NF2 variant forms in the near future. The mapping approach in evaluating variant forms of NF should begin with the rigorous clinical assessment of familial cases whereby the establishment of genetic linkage in families with overlap syndromes might determine if either NF1, NF2, or a separate locus is involved in the phenotype. Conditions mapping to the NF1 locus could then be screened for mutations in hopes of identifying the etiologies of the variant forms of NF. Mutation identification should provide a molecular-based classification scheme for the variant forms of NF, now tentatively divided into alternative and related forms. It is expected that the nosology of the neurofibromatoses will most certainly change as more is learned of the NF1 and NF2 loci.