Pharmacokinetics of dolasetron with coadministration of cimetidine or rifampin in healthy subjects

This study examines normative bone mineral density (BMD) data, as measured by peripheral quantitative computed tomography of the ultradistal radius, in 332 Scottish women aged 18-90 years, comparing it to a recently reported normal German population. The normative Scottish data were higher in almost all decades compared with German counterpart, percentage differences being +0.002%-+21.6% for total (Qtot), and -0.06%-+31.9% for trabecular (Qtrab) BMD. Differences in calibration of the Stratec XCT-960 and XCT-900 systems are thought to be largely responsible for these differences. Estimated age-related changes were determined in the Scottish population. A cubic regression model best fitted age-related changes in the whole population, and changes as a function of years postmenopause in the postmenopausal subgroup, for Qtot, subcortical (Qscort), and cortical (Qcort) BMD, whereas a parabolic regression model best fitted corresponding changes in Qtrab BMD. Percentage age-related changes (5 years: 10 years postmenopause) in Qtot (-0. 79%-1.12%/year) and Qscort (-0.72%-1.12%/year) were greater than Qtrab (-0.53%-0.56%/year) in the early postmenopausal years. Maximum age-related changes were found at 20 years postmenopause for Qtot (-1.36%/year), Qscort (-1.39%/year), and Qcort (-1.39%/year). This study has highlighted variation in normative data derived by different Stratec pQCT systems. The estimated age-related changes suggest that early postmenopausal bone loss preferentially affects subcortical rather than trabecular bone at the radius.     

Increased DNA oxidation and decreased levels of repair products in Alzheimer's disease ventricular CSF

One of the leading etiologic hypotheses regarding Alzheimer's disease (AD) is the involvement of free radical-mediated oxidative stress in neuronal degeneration. Although several recent studies show an increase in levels of brain DNA oxidation in both aging and AD, there have been no studies of levels of markers of DNA oxidation in ventricular CSF. This is a study of levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), the predominant marker of oxidative DNA damage, in intact DNA and as the "free" repair product that results from repair mechanisms. Free 8-OHdG was isolated from CSF from nine AD and five age-matched control subjects using solid-phase extraction columns and measured using gas chromatography/mass spectrometry with selective ion monitoring. Intact DNA was isolated from the same samples and the levels of 8-OHdG determined in the intact structures. Quantification of results was carried out using stable isotope-labeled 8-OHdG. By using this sensitive methodology, statistically significant elevations (p < 0.05) of 8-OHdG were observed in intact DNA in AD subjects compared with age-matched control subjects. In contrast, levels of free 8-OHdG, removed via repair mechanisms, were depleted significantly in AD samples (p < 0.05). Our results demonstrate an increase in unrepaired oxygen radical-mediated damage in AD DNA as evidenced by the increased presence of 8-OHdG in intact DNA and decreased concentrations of the free repair product. These data suggest that the brain in AD may be subject to the double insult of increased oxidative stress, as well as deficiencies in repair mechanisms responsible for removal of oxidized bases.     

Interactions between neuropeptide Y and gamma-aminobutyric acid in stimulation of feeding: a morphological and pharmacological analysis

Neuropeptide Y (NPY) produced in neurons in the arcuate nucleus and brain stem and released in the paraventricular nucleus (PVN) and surrounding areas is involved in stimulation of feeding in rats. We recently reported that gamma-aminobutyric acid (GABA) is coexpressed in a subpopulation of NPY neurons in the arcuate nucleus. To determine whether GABA is colocalized in NPY terminals in the PVN, the site of NPY action, light and electron microscopic double staining for NPY and GABA using pre- and postembedding immunolabeling was performed on rat brain sections. GABA was detected in NPY-immunopositive axons and axon terminals within both the parvocellular and magnocellular divisions of the PVN. These morphological findings suggested a NPY-GABA interaction in the hypothalamic control of feeding. Therefore, the effects of muscimol (MUS), a GABA(A) receptor agonist, on NPY-induced food intake were examined in sated rats. When injected intracerebroventricularly, both NPY and MUS elicited dose-dependent feeding responses that were blocked by the administration of 1229U91 (a putative Y1 receptor antagonist) or bicuculline (a GABA(A) receptor antagonist), respectively. Coadministration of NPY and MUS intracerebroventricularly amplified the feeding response over that evoked by NPY or MUS alone. Similarly, microinjection of either NPY or MUS into the PVN stimulated food intake in a dose-related fashion, and coinjection elicited a significantly higher response than that evoked by either individual treatment. These results suggest that GABA and NPY may coact through distinct receptors and second messenger systems in the PVN to augment food intake.     

Recovery of fMRI activation in motion area MT following storage of the motion aftereffect

We used functional magnetic resonance imaging (fMRI) during storage of the motion aftereffect (MAE) to examine the relationship between motion perception and neural activity in the human cortical motion complex MT+ (including area MT and adjacent motion-selective cortex). MT+ responds not only to physical motion but also to illusory motion, as in the MAE when subjects who have adapted to continuous motion report that a subsequent stationary test stimulus appears to move in the opposite direction. In the phenomenon of storage, the total decay time of the MAE is extended by inserting a dark period between adaptation and test phases. That is, when the static test pattern is presented after a storage period equal in duration to the normal MAE, the illusory motion reappears for almost as long as the original effect despite the delay. We examined fMRI activation in MT+ during and after storage. Seven subjects viewed continuous motion, followed either by an undelayed stationary test (immediate MAE) or by a completely dark storage interval preceding the test (stored MAE). Like the perceptual effect, activity in MT+ dropped during the storage interval then rebounded to reach a level much higher than after the same delay without storage. Although MT+ activity was slightly enhanced during the storage period following adaptation to continuous motion (compared with a control sequence in which the adaptation grating oscillated and no MAE was perceived), this enhancement was much less than that observed during the perceptual phenomenon. These results indicate that following adaptation, activity in MT+ is pronounced only with the presentation of an appropriate visual stimulus, during which the MAE is perceived.     

Triggering of chloride ion efflux from human neutrophils as a novel function of leukocyte beta 2 integrins: relationship with spreading and activation of the respiratory burst

PMN residing on immobilized fibronectin have been shown to respond to TNF with an intense and long lasting Cl- efflux that leads to a marked decrease of the unusually high basal Cl- content of these phagocytes. The finding that this Cl- efflux depends, at least in part, on beta2 integrin engagement stimulated the present investigation, which addresses the question as to whether beta2 integrins per se, in the absence of PMN agonists, are able to generate signals triggering Cl- efflux. We induced beta2 integrin cross-linking by plating PMN onto surface-bound mAbs directed against either the common beta-chain (CD18) or the individual alpha-chains (CD11a, CD11b, CD11c) of LFA-1, CR3, and gp150/95. Anti-CD18 mAbs triggered a marked release of Cl- ions, which was accompanied by spreading and activation of the respiratory burst. Cross-linking of gp150/95 and LFA-1 generated the most powerful signals for the activation of Cl- efflux. The results of three independent experimental approaches, i.e., kinetic studies, use of Cl- transport inhibitors, and modulation of Cl- efflux with different amounts of anti-beta2 integrin mAbs, indicated that Cl- efflux regulates both spreading and respiratory burst triggered by beta2 integrin cross-linking. Cl- efflux appears to be independent on either alterations of [Ca2+]i or changes in the plasma membrane potential and shows sensitivity to a raise in pHi. This study uncovers a new signaling ability of beta2 integrins and contributes to highlight the role of Cl- efflux in the outside-in signal transduction pathway regulating adherence-dependent PMN responses.     

The neonatal presentation of Prader-Willi syndrome revisited

We describe 6 newborns evaluated for hypotonia, later diagnosed with Prader-Willi syndrome despite the absence of the classical neonatal features of this syndrome. Specific genetic testing for Prader-Willi syndrome should be considered for all neonates with undiagnosed central hypotonia even in the absence of the other major features of this syndrome.     

Rapid spread of HIV among injecting drug users in north-eastern states of India

Manipur, a north-eastern state of India bordering Myanmar, has experienced very rapid transmission of the human immunodeficiency virus (HIV) among its vast drug-injecting population. Seroprevalence among intravenous drug users increased from 0 per cent in September 1989 to 50 per cent within six months. With a minimum injecting population of 15,000 and seropositivity of over 50 per cent, the infection quickly spread to the population at large. One per cent of antenatal mothers tested seropositive by 1991. Forming part of the area of South-East Asia known as the Golden Triangle, and producing opium and its derivatives, Myanmar shares a long international border with four States of the region, and populations with a common language and culture move freely across borders. Two other north-eastern states of India bordering Myanmar have faced a similar epidemic within a short period of time. As a result of serosurveillance for HIV since 1986, the epidemic could be detected at an early stage. The present paper provides an account of the results of ongoing comprehensive studies conducted in the north-eastern states of India on drug-related HIV infection, already a serious problem, but possibly still restricted to that region of the country. The prevalence of intravenous drug users, their HIV serological status, the demographic profile, risk behaviour, the spread of the infection to other groups and the problems of harm minimization are also covered.     

Platelet alpha-granules

Platelets contain a vast number of biologically active molecules within cytoplasmic granules which are classified according to their respective distinct ultrastructures, densities and content. The alpha-granule is a unique secretory organelle in that it exhibits further compartmentalization and acquires its protein content via two distinct mechanisms: (1) biosynthesis predominantly at the megakaryocyte (MK) level (with some vestigial platelet synthesis) (e.g. platelet factor 4) and (2) endocytosis and pinocytosis at both the MK and circulating platelet levels (e.g. fibrinogen (Fg) and IgG). The currently known list of alpha-granular proteins continues to enlarge and includes many adhesive proteins (e.g. Fg, von Willebrand factor (vWf) and thrombospodin (TSP)), plasma proteins (e.g. IgG and albumin), cellular mitogens (e.g. platelet derived growth factor and TGF beta), coagulation factors (e.g. factor V) and protease inhibitors (e.g. alpha 2-macroglobulin and alpha 2-antiplasmin). More recently the inner lining of the alpha-granule unit membrane has been demonstrated to contain a number of physiologically important receptors including glycoprotein IIb/IIIa (alpha IIb beta 3) and P-selectin. The alpha-granules originate from small precursor granules which can be observed budding from the trans-Golgi network within the platelet precursor cell the MK. During MK maturation the alpha-granules become very prominent and are ultimately packaged into platelets during thrombopoiesis. The alpha-granular contents are destined for release during platelet activation at sites of vessel wall injury and thus play an important role in haemostasis, inflammation, ultimate wound repair and in the pathogenesis of atherosclerosis.     

Combined preoperative and postoperative immunotherapy for murine C1300 neuroblastoma

Preoperative treatment of murine C1300-neuroblastoma (C1300) with triple immunotherapy using low-dose cyclophosphamide (CY), retinyl palmitate (RP), and interleukin-2 (IL2), followed by tumor resection leads to significant initial tumor control and prolonged survival. However, because long-term tumor recurrence is 67%, the efficacy of continued postoperative immunotherapy is now evaluated. Thirty-two A/J mice with 1 cm subcutaneous C1300 tumors were treated for 13 days with CY-100 mg/kg, intraperitoneally (IP), on day 2 of treatment then 25 mg/kg on day 9, RP-2500 IU IP 2 x/week, and IL2 1.6 x 10(5) U IP BID on days 4 to 9 and 11 to 13. On day 14, mice were divided into five treatment groups: (1) OP (operated-tumor resection, n = 6); (2) OP+CY (resection and postoperative CY, n = 7); (3) OP+CY+RP (resection and postoperative CY+RP, n = 7); (4) OP+CY+RP+IL2 (resection and postoperative CY+RP+IL2, n = 7); and (5) CY+RP+IL2 (continued CY+RP+IL2 with no resection, n = 5). Survival and postoperative tumor recurrence were followed for 60 days. The cure rates were group 1 33% (2/6), group 2 43% (3/7), group 3 29% (2/7), group 4 71% (5/7), and group 5 20% (1/5). After surgery, tumors that recurred did so in 8 to 22 days, with no statistical difference noted between groups. MHC class I antigenic expression of tumors resected on day 14 and recurrent tumors was determined with monoclonal antibodies and flow cytometry. In tumors resected on day 14, class I expression measured by mean fluorescence, was 374.8 +/- 27.40.(ABSTRACT TRUNCATED AT 250 WORDS)     

The association between Chlamydia trachomatis serology and pelvic damage in women with tubal ectopic gestations

OBJECTIVE: To determine whether pelvic damage is associated with positive Chlamydia trachomatis serology in women with tubal ectopic pregnancy. DESIGN: Cross-sectional retrospective study. SETTING: A prepaid health maintenance organization. PATIENTS: Two-hundred eighty-one women admitted with confirmed tubal ectopic pregnancy were interviewed for history of sexually transmitted diseases. Chlamydia serology was obtained for 135 subjects, and operative findings were available for 121 of these. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Pelvic damage, as determined by review of operative findings of the pelvis at the time of ectopic surgery. RESULTS: Pelvic damage was associated with positive chlamydia serology with an adjusted odds ratio of 4.2 (95% confidence interval: 1.8 to 9.7). Moderate and severe pelvic damage were more strongly associated with positive serology than mild damage. CONCLUSIONS: Women with ectopic pregnancies and antibodies to C. trachomatis are more likely to have damaged pelves than women with ectopic pregnancies without such antibodies. Prevention or early treatment of C. trachomatis infection may reduce pelvic damage and, therefore, reduce incidence of ectopic pregnancy.