Mesograde amnesia during the sleep onset transition: replication and electrophysiological correlates

The present study was designed to explore mechanisms of amnesia for meaningful auditory material presented during the sleep onset transition. Thirty undergraduate subjects (17 female, 13 male) were presented with auditory stimuli in an oddball paradigm until sleep onset. Subjects were allowed to accumulate either 30 seconds or 10 minutes of sleep, then awakened and tested on free recall and recognition memory for the meaningful stimuli. After 10 minutes of sleep, but not after 30 seconds of sleep, subjects had profound amnesia on free recall for stimuli presented in the 4-minute window prior to sleep onset. Increased beta electroencephalograph (EEG) power during the sleep period correlated positively with recall of stimuli in the 4-minute presleep window. Event-related potential recordings provided suggestive evidence that subjects continued to process the auditory stimuli to some extent during the sleep onset transition. When allowed to sleep for 10 minutes, subjects evidenced a mixed anterograde and retrograde amnesia for auditory stimuli presented in the 4-minute window prior to sleep onset. The results are discussed in terms of stimulus encoding, consolidation, and retrieval.     

Selective reconstitution of gastrin-releasing peptide receptor with G alpha q

Identification of the molecular mechanisms that determine specificity of coupling interactions between gastrin-releasing peptide receptors (GRPrs) and their cognate heterotrimeric GTP-binding proteins is a fundamental step in understanding the signal transduction cascade initiated by receptor-ligand interaction. To explore these mechanisms in greater detail, we have developed an in situ reconstitution assay in chaotrope-extracted membranes from mouse fibroblasts expressing the GRPr, and we have used it to measure GRPr-catalyzed binding of GTP gamma S to purified G protein alpha subunits. Binding studies with 125I-labeled [D-Tyr6]bombesin(6-13) methyl ester (125I-Tyr-ME), a GRPr specific antagonist, show a single binding site with a Kd = 1.4 nM +/- 0.4 (mean +/- SD, n = 3) and capacity of 15-22 pmol of receptor per mg of protein in the extracted membrane preparations, representing a 2- to 3-fold enrichment of binding sites compared with the membranes before extraction. Quantitative ligand displacement analysis using various unlabeled GRPr agonists shows a rank order of potency characteristic of the GRPr: bombesin > or = GRP > > neuromedin B. Reconstitution of urea extracted membranes with a purified G alpha q showed that receptor-catalyzed binding of GTP gamma S was dependent on agonist (GRP) and G beta gamma subunits. The EC50 for GRP was 3.5 nM, which correlates well with the reported Kd of 3.1 nM for GRP binding to GRPr expressed in mouse fibroblasts [Benya, R. V., et al. (1994) Mol. Pharmacol. 46, 235-245]. The apparent Kd for bovine brain G beta gamma in this assay was 60 nM, and the Km for squid retinal G alpha q was 90 nM. The GRPr-catalyzed binding of GTP gamma S is selective for G alpha q, since we did not detect receptor-catalyzed exchange using either G alpha i/o or G alpha t. These data demonstrate that GRPr can functionally couple to G alpha q but not to the pertussis toxin-sensitive G alpha i/o or retinal specific G alpha t. This in situ receptor reconstitution method will allow molecular characterization of G protein coupling to other heptahelical receptors.     

Paget bone disease involving young adults in 3 generations of a Korean family

Pancreatic cancer is an aggressive disease with a dismal prognosis. It has long been regarded as one of the most difficult cancers to accurately diagnose and stage preoperatively. The purpose of this review is to provide an update of the state-of-the-art for early detection, diagnosis, and staging of pancreatic cancer. These methods include spiral CT scans, magnetic resonance imaging, positron emission tomography (PET) imaging, laparoscopy, endoscopic ultrasound, CA 19-9 serology, fine needle aspiration cytology, ERCP brush cytology, and screening for p53 and ras oncogenes. These advanced techniques should help us to detect pancreatic cancers in high-risk populations at a curative stage and to decrease pancreaticoduodenectomies for benign disease which could otherwise be treated with less morbid procedures. In addition, these tests will help reliably diagnose pancreatic cancer preoperatively.     

Late-onset life-threatening angioedema and upper airway obstruction caused by angiotensin-converting enzyme inhibitor: report of a case

Angioedema is a rare but potentially lethal adverse effect when associated with upper airway obstruction. Sporadic cases of angioedema secondary to angiotensin converting enzyme inhibitors (ACEI) have been reported in the literature. The overall incidence is around 0.1% to 0.2%, and the time of onset is usually during the first week of ACEI therapy. Late-onset angioedema secondary to treatment with ACEIs is much more frequent than appreciated, and is largely unrecognized because of the absence of temporal correlation between ACEI therapy and the development of angioedema. Since angioedema may progress to upper airway obstruction, otolaryngologists must be aware of this association. Most importantly, late-onset angioedema should alert the clinician to discontinue the ACEI immediately to prevent further morbidity. This report presents an example of late-onset angioedema which was precipitated by taking a double dose of captopril incidentally. The case is discussed, and the literature, pathophysiology and treatment of angioedema are reviewed.     

Characterization of hemolytic and cytotoxic Gallysins: a relationship with arylphorins

The efficacy of injecting antibodies raised against turkey prolactin to prevent the expression of incubation behaviour has been investigated in turkey hens. Medium white turkey hens (n = 15 x 2) were injected three times weekly for 4 consecutive weeks starting on week 5 of egg production. The hens were injected im with a volume of 1 mL per injection for the 1st week and 0.5 mL thereafter, of normal rabbit serum or serum containing antibodies raised against turkey prolactin (Guémené et al, 1994a). None of the 15 passively immunised hens expressed incubation behaviour, whereas, more than half (53%) of the control hens did express it. Plasma prolactin concentrations observed in the two groups presented comparable profiles until week 9 and from week 19 of egg production onward. Differences were, therefore, observed from week 10 until week 17 with the non immunised hens showing higher plasma prolactin concentrations than the immunised ones. This difference was related to the presence of incubating hens in the control group. A higher percentage of non immunised hens disrupted egg production during the course of the study and consequently immunised hens laid more eggs than the control ones. No change in plasma LH and oestradiol concentrations can be related to the immunisation procedure. We conclude that prevention of incubation behaviour can be achieved using passive immunisation against prolactin, prevention which resulted in more egg production under our experimental protocol.     

5'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter

PURPOSE: General use of nucleoside analogues in the treatment of viral infections and cancer is often limited by poor oral absorption. Valacyclovir, a water soluble amino acid ester prodrug of acyclovir has been reported to increase the oral bioavailability of acyclovir but its absorption mechanism is unknown. This study characterized the intestinal absorption mechanism of 5' -amino acid ester prodrugs of the antiviral drugs and examined the potential of amino acid esters as an effective strategy for improving oral drug absorption. METHODS: Acyclovir (ACV) and Zidovudine (AZT) were selected as the different sugar-modified nucleoside antiviral agents and synthesized to L-valyl esters of ACV and AZT (L-Val-ACV and L-Val-AZT), D-valyl ester of ACV (D-Val-ACV) and glycly ester of ACV (Gly-ACV). The intestinal absorption mechanism of these 5' -amino acid ester prodrugs was characterized in three different experimental systems; in situ rat perfusion model, CHO/hPEPT1 cells and Caco-2 cells. RESULTS: Testing 5' -amino acid ester prodrugs of acyclovir and AZT, we found that the prodrugs increased the intestinal permeability of the parent nucleoside analogue 3- to 10-fold. The dose- dependent permeation enhancement was selective for L-amino acid esters. Competitive inhibition studies in rats and in CHO cells transfected with the human peptide transporter, hPEPT1, demonstrated that membrane transport of the prodrugs was mediated predominantly by the PEPT1 H+/dipeptide cotransporter even though these prodrugs did not possess a peptide bond. Finally, transport studies in Caco-2 cells confirmed that the 5' - amino acid ester prodrugs enhanced the transcellular transport of the parent drug. CONCLUSIONS: This study demonstrates that L-amino acid-nucleoside chimeras can serve as prodrugs to enhance intestinal absorption via the PEPT1 transporter, providing a novel strategy for improving oral therapy of nucleoside drugs.     

Successful delayed thrombolytic therapy in a patient with massive pulmonary embolism

Pica is the persistent, culturally and developmentally inappropriate ingestion of non-nutritive substances (DSM-IV). AB is a 75-year-old lady with a 40-year history of schizophrenia and a 20-year history of pica who, at emergency laparotomy, had 175.32 Pounds of loose change in her stomach. Although pica has been reported to coexist with schizophrenia, she had had no positive symptoms of schizophrenia for at least 20 years. She has CT evidence of fronto-tempotal atrophy most marked on the left in the temporal lobe and on the right in the frontal lobe. Pica has been found to be related to cognitive deficits and hyperoral behaviour to temporal lesions. Neuropsychological testing reveals deficits closely related to these changes.     

Increased tendency towards gingival bleeding caused by joint effect of alpha-tocopherol supplementation and acetylsalicylic acid

Alpha-tocopherol (vitamin E) may play a role in the treatment of arterial thromboembolic disease, possibly by inhibiting platelet aggregation. Thus far, no clinical evidence exists for this effect. The objective of this study was to assess the effect of alpha-tocopherol supplementation on gingival bleeding either in combination with acetylsalicylic acid (ASA) or without it. This study was an end-point examination of a random sample of male smokers who had participated in a controlled clinical trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) for 5-7 years. The study included 409 men aged 55-74 years of whom 191 received alpha-tocopherol supplementation (50 mg/day); 56 used ASA, 30 received both and 132 received neither. Gingival bleeding was examined by probing with a WHO probe and reported as a percentage of bleeding sites adjusted by the logistic regression model. Gingival bleeding was more common in those who received alpha-tocopherol compared with nonreceivers among subjects with a high prevalence of dental plaque (P < 0.05). ASA alone increased bleeding only slightly. The highest risk of gingival bleeding was among those who took both alpha-tocopherol and ASA (33.4% of probed sites bleeding vs 25.8% among subjects taking neither alpha-tocopherol nor ASA, P < 0.001). In the ATBC Study, more deaths from haemorrhagic stroke and fewer from ischaemic heart disease were observed among those participants who received alpha-tocopherol compared with those who did not. Based on the results of the present study and the ATBC Study, we conclude that alpha-tocopherol supplementation may increase the risk of clinically important bleedings, particularly when combined with ASA.