Evaluation of the mass balance assumption with respect to the two-resistance model of intestinal absorption by using in situ single-pass intestinal perfusion of theophylline in rats.

Methods of analyzing drug absorption data from rat intestinal-perfusion experiments are discussed in terms of mass-transfer resistances, or reciprocal permeabilities, and mass balances. Typically, a two-resistance model is used to determine the dimensionless effective permeability (P*eff) by measuring the disappearance of drug from the perfusing solution. Unstated assumptions in two-resistance models are (1) the portal blood is under sink conditions and (2) complete transfer of drug occurs from the intestinal perfusate to the portal vein. The assumption of sink conditions is generally acceptable, because the drug concentration in portal blood is approximately two orders of magnitude less than in the perfusate. Single-pass intestinal-perfusion experiments were performed on rats with theophylline as a model compound. The drug mass leaving the intestinal perfusate was substantially less than the drug mass appearing in the portal plasma; that is, the assumption of complete transfer did not hold for theophylline in this experimental system. These data indicate that models based on the two-resistance theory can lead to overestimation of P*eff by the ratio of the drug mass leaving the perfusate to the drug mass appearing in the plasma. For compounds for which the assumption of complete transfer does not hold, a more accurate estimate of P*eff may be determined by dividing the value derived from perfusate data by the mass balance ratio (i.e., the drug mass leaving the perfusate divided by the drug mass appearing in the plasma).     

Evoked potentials in head injury and states of increased intracranial pressure

Recent clinical studies have addressed the utility of sensory evoked potentials (auditory, somatosensory, and visual) in head injury. The clinical significance of evoked potentials in head trauma, states of increased intracranial pressure, and post-traumatic syndrome is discussed. Emphasis is placed on up-to-date studies discussing evoked potential correlation with clinical findings, lesion localization, intracranial pressure, brain herniation, and prognosis.     

Ulnar neuropathy at the wrist associated with aberrant flexor carpi ulnaris insertion

A 36-year-old man who sustained an industrial hyperextension injury of the wrist complained of dysesthesia and pain in the ulnar nerve distribution, aggravated for months by wrist movement until exploration. The operation revealed an anomalous insertion of the flexor carpi ulnaris tendon disrupting a major portion of the ulnar nerve proximal to the pisiform. the symptoms were relieved completely after neurolysis and modification of the insertion of the tendon.     

Perturbation of copper (Cu) homeostasis and expression of Cu-binding proteins in cadmium-resistant lung fibroblasts.

To probe mechanisms of cadmium (Cd) damage to the lung extracellular matrix (ECM), we developed Cd-resistant (CdR) rat lung fibroblasts (RFL6) by incubation with graded concentrations of Cd. CdR cells downregulated lysyl oxidase (LO), a copper (Cu)-dependent enzyme essential for crosslinking of collagen and elastin in the ECM, in conjunction with upregulation of other Cu-binding proteins including Cu,Zn-superoxide dismutase (SOD1), copper chaperone for SOD1 (CCS1), metallothionein (MT), and Menkes P-type ATPase (ATP7A), a Cu transporter in the membrane of the Golgi apparatus, as well as gamma-glutamylcysteine synthetase (gamma-GCS), an enzyme for glutathione biosynthesis. Reduction and loss of cytoplasmic distribution of LO in CdR cells were accompanied by its dislocation with the Menkes P-type ATPase and the endoplasmic reticulum marker. CdR cells displayed a defect in LO catalytic activity but an enhancement in Cu,Zn-SOD catalytic activity consistent with the protein expression levels of these enzymes. Although long-term Cd exposure of cells enhanced the Menkes P-type ATPase protein expression, actually, it reduced Cu-dependent catalytic activity of this enzyme in parallel with the deficiency of LO. The low level of 64Cu bound to the LO fraction and the high level of 64Cu bound to the MT fraction provide direct evidence for limitation of Cu bioavailability for LO existing in the CdR cells. These results suggest that downregulation of LO is linked with upregulation of other Cu-binding proteins and with alteration in Cu homeostasis in the CdR phenotype.     

Anxiolytic activity of adenosine receptor activation in mice.

1. Purine analogues have been examined for anxiolytic- and anxiogenic-like activity in mice, by use of the elevated plus-maze. 2. The selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) had marked anxiolytic-like activity at 10 and 50 microg kg(-1), with no effect on locomotor performance at these doses. 3. The A1 selective adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (CPX) had no significant effect on anxiety-related measures or locomotor behaviour, but blocked the anxiolytic-like activity of CPA. The hydrophilic xanthine, 8-(p-sulphophenyl) theophylline did not prevent anxiolysis by CPA. 4. Caffeine had anxiogenic-like activity at 30 mg kg(-1) which was prevented by CPA at 50 micro kg(-1). 5. The A2 receptor agonist, N6-[2-(3,5-dimethoxyphenyl)-2(2-methylphenyl)-ethyl]adenosine (DPMA) had no effect on anxiety behaviour but depressed locomotor activity at the highest dose tested of 1 mg kg(-1). The A2 receptor antagonist, 1,3-dimethyl-l-propargylxanthine (DMPX) had no effect on anxiety-related measures or locomotion and did not modify the anxiolytic-like activity of CPA. 6. Administration of DPMA in combination with anxiolytic doses of CPA prevented the anxiolytic-like activity of the latter. 7. The results suggest that the selective activation of central A1 adenosine receptors induces anxiolytic-like behaviour, while the activation of A2 sites causes locomotor depression and reduces the effects of A1 receptor activation. The absence of any effect of CPX alone suggests that the receptors involved in modulating behaviour in the elevated plus-maze in mice are not activated tonically by endogenous adenosine.     

Induction of a novel form of hippocampal long-term depression by muscimol: involvement of GABAA but not glutamate receptors.

1. Unlike long-term potentiation, long-term depression (LTD) in the central nervous system remains poorly understood. The present study was undertaken to investigate the role of GABAA receptors in LTD and synaptic plasticity. 2. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). 3. Muscimol induced a time- and concentration-dependent LTD of the amplitude of orthodromic potentials. Increasing the stimulation frequency from 0.01 Hz to 1 Hz for 10 s reversed the LTD induced by muscimol. Muscimol also induced LTD in the absence of electrical stimulation. 4. Adenosine decreased the spike size in a concentration-dependent manner, but failed to induce LTD. 5. Alphaxalone and 5 alpha-pregnan-3 alpha-ol-20-one at concentrations that did not have any effect themselves on the population spike (0.5 and 1 microM), potentiated the inhibitory effect of muscimol on the population spike size, including concentrations which were not effective by themselves. Both steroids were able to potentiate the ability of muscimol to induce LTD. 6. Bicuculline, 5 microM, reversed the LTD induced by muscimol, 10 microM. 7. The NMDA receptor antagonist (+/-)-2-amino-5-phosphonopentanoic acid (2-AP5), the NMDA/metabotropic antagonist 2-AP3 and selective metabotropic antagonist L-(+)-2-amino-3-phosphonopropionic acid (L(+)-AP3) failed to modify the LTD. Similarly, quisqualic acid and (1S, 3R)-aminocyclopentane dicarboxylic acid (ACPD) a selective agonist at metabotropic receptors did not induce LTD or short-term depression, whereas kynurenic acid prevented the reversal of the LTD obtained at 1 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carcinoma of the papilla of vater: Are endoscopic appearance and endoscopic biopsy discordant?

Carcinoma of the papilla of Vater is classified as periampullary cancer representing 5% of all gastrointestinal tract malignancies. Early and accurate diagnosis is important for those patients with a tumor of the papilla, as the prognosis is more favorable than in other periampullary neoplasms. Endoscopically obtained biopsies from suspicious papillae can detect an early tumor, although even for skilled pathologists it is often difficult to differentiate carcinomas from noninvasive lesions on the basis of forceps biopsies. The purpose of this study was to assess the preoperative diagnostic accuracy of duodenoscopy appearance and biopsy in all cases with suspicion of tumor. Thirty patients with suspicion of carcinoma of the papilla of Vater and with final diagnosis established by pancreatoduodenectomy were included in this retrospective study. In each case, a comparison was made between endoscopic biopsy and duodenoscopic appearance. Duodenoscopic appearance sensitivity and accuracy for malignancy were 86% and 83%, respectively, whereas endoscopic biopsy sensitivity and accuracy were 65% and 67%, respectively. Although preoperative diagnosis of carcinoma of the papilla of Vater is useful for making therapeutic decisions, the diagnostic value of the endoscopic appearance was superior to endoscopic biopsy in this series. Presented at the 2003 American Hepato-Pancreato-Biliary Association Congress, Miami, Florida, February 27-March 3, 2003. Supported by FADA-CAPES/PROP 200J (M.L.D.).