Health-related quality of life in patients who develop bronchiolitis obliterans syndrome following allo-SCT.

Bronchiolitis obliterans syndrome (BOS) remains an important complication following allo-SCT. The development of this condition portends a higher morbidity and mortality but the effect on heath-related quality of life (HRQL) is unknown. The aim of this study was to determine whether the development of BOS impacted HRQL compared with patients without BOS. This Institutional Review Board-approved prospective study analyzed 126 patients who underwent allo-SCT at our institution. Patients were administered three HRQL survey tools (SF-36, European Organization for Research and Treatment of Cancer QLQ-c30 and St George Respiratory Questionnaire (SGRQ)) before transplant and then again at 6 months, 1 year and 2 years after transplant. Patients were analyzed in three groups determined by highest chronic GVHD (cGVHD) severity and BOS status. Overall, our study group had improving HRQL after transplant when measured over time, measured by the SF-36 with stable HRQL, when measured by the SGRQ total score and QLQ-c30. Patients that developed BOS had significantly worse HRQL scores measured by the SGRQ and the SF-36 physical composite score. This difference was not explained by the severity of cGVHD that patients with BOS developed.

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.

Prevalence of tremor and Parkinson's disease.

To determine the prevalence of essential tremor (ET) and Parkinson's disease (PD) in a retirement community, all residents of Carefree, Arizona, aged over 65 years were contacted. All participants completed validated questionnaires for PD and ET, and were examined using the Unified Parkinson's Disease Rating Scale. Of 356 individuals evaluated, 155 (43.5%) had tremor; 73 (20.5%) had ET; 26 (7.3%) had PD; and 56 (15.7%) had postural tremor (PT). Thus, a large percentage of individuals were found to have tremor, in the plurality of whom it could be classified as ET. The number of individuals with Parkinson's disease exceeded our expectations.

Identification of secreted beta-amyloid precursor protein binding sites on intact human fibroblasts.

Based upon recent evidence that the secreted form of APP can cause the release of cytokines and elicit other biological activities, we sought to identify whether a receptor could be identified on the surface of cells. The secreted amyloid precursor protein containing the Kunitz domain (scAPP751) is identical to protease nexin II, a protease inhibitor which has been shown to form complexes with labeled EGF binding protein that subsequently binds to cells. Results of [125I]scAPP751-trypsin complex incubated with intact fibroblast cells show that the complex appears to bind in a saturable time-dependent and reversible manner. The kinetic constants from the binding studies demonstrate a k1 = 2.5 x 10(7) M-1 s-1 and k2 = 4.7 x 10(-4) s-1 and thus a KD (= k2/k1) = 20 pM. Furthermore, the complex formation of [125I]scAPP751 with a protease appears to be a requirement for optimal binding. The binding affinity of secreted APP demonstrated in this study is consistent with its potency in eliminating a range of biological efforts that have been documented.

Effect of bronchopulmonary lavage on lung retention and clearance of particulate material in hamsters.

Hamsters were exposed to an aerosol of fused aluminosilicate particles (FAP) labeled with 57Co. Three groups of animals were given bronchopulmonary lavage, beginning at either 1 week, 1 month, or 6 months after exposure. Each treated group was lavaged eight times over a period of 25 days. Each lavage involved 10 saline washes of the lungs. For each group, about 60-70% of the body content of 57Co at the start of lavage treatment was removed; nearly half of this was recovered in the first two lavages. A positive correlation was demonstrated between the macrophage content and 57Co activity of the washings. The subsequent fractional clearance rate of 57Co from lavaged animals was not significantly different from that in a group of untreated control animals.

Effect of activity on supraventricular tachyarrhythmias after coronary artery bypass surgery.

The purpose of this study was to evaluate patient activities, professional staff activities, backrest position, and diurnal variations as factors that may contribute to the onset of supraventricular tachyarrhythmias (SVT) after coronary artery bypass surgery (CABG). The activities surrounding the recognition of first-onset SVT, as well as preoperative and postoperative data and patient characteristics were examined in 249 patients having CABG. One hundred seventy-three patients qualified for the study; 28% of these patients (n = 49) had SVT. No statistical difference was found between the subjects with SVT and those without SVT when sex, cross-clamp time, creatine kinase peak, hemoglobin and hematocrit levels, and number of bypasses were examined. Patients who had SVT were older than those who did not: 64.8 years for the SVT group versus 60.7 years for the non-SVT group (p less than 0.01). SVT was rare in the first 24 hours after surgery, whereas 60% of the cases occurred during the next 48 hours, without significant diurnal variation: mean time of onset was 11:50 AM. No particular activity of the patient or nurse influenced the onset of SVT during the postoperative period in this group.

The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II.

The A4 protein (or beta-protein) is a 42- or 43-amino-acid peptide present in the extracellular neuritic plaques in Alzheimer's disease and is derived from a membrane-bound amyloid protein precursor (APP). Three forms of APP have been described and are referred to as APP695, APP751 and APP770, reflecting the number of amino acids encoded for by their respective complementary DNAs. The two larger APPs contain a 57-amino-acid insert with striking homology to the Kunitz family of protease inhibitors. Here we report that the deduced amino-terminal sequence of APP is identical to the sequence of a cell-secreted protease inhibitor, protease nexin-II (PN-II). To confirm this finding, APP751 and APP695 cDNAs were over-expressed in the human 293 cell line, and the secreted N-terminal extracellular domains of these APPs were purified to near homogeneity from the tissue-culture medium. The relative molecular mass and high-affinity binding to dextran sulphate of secreted APP751 were consistent with that of PN-II. Functionally, secreted APP751 formed stable, non-covalent, inhibitory complexes with trypsin. Secreted APP695 did not form complexes with trypsin. We conclude that the secreted form of APP with the Kunitz protease inhibitor domain is PN-II.

Vagally mediated gastric motor and emetic reflexes evoked by stimulation of the antral mucosa in anaesthetized ferrets.

1. In the urethane-anaesthetized ferret chemical (NaCl, NaOH or HCl) or mechanical (stroking) stimulation of the gastric antral mucosa evoked a decrease in corpus pressure and inhibition of contractions in the presence of guanethidine, adrenalectomy and sectioned greater splanchnic nerves. 2. The fall in corpus pressure was present following administration of atropine but was abolished by vagotomy. 3. Preliminary evidence, using 100 mM-NaOH as the stimulus, is presented that the effects on corpus motility are due to simultaneous activation of the vagal efferents supplying the intramural non-adrenergic non-cholinergic inhibitory neurones and inhibition of those supplying the intramural cholinergic neurones. 4. The possible roles of this antro-corpus vago-vagal reflex in the regulation of gastric emptying and in the prodromal phase of vomiting are discussed.

Injection of baclofen into the ventromedial hypothalamus stimulates gastric motility in the rat.

Injection of 2 micrograms (+/-)-baclofen into the ventromedial hypothalamus (VMH) of urethane-anaesthetized rats resulted in an increase in gastric tone and amplitude of contractions. This effect was curtailed by administration of atropine methyl nitrate (20 mg/kg i.p.) or bilateral cervical vagotomy. These results provide evidence for a hypothalamic modulation of gastric motility by the vagus. Baclofen, possibly acting on receptors insensitive to gamma-aminobutyric acid (GABA), may be mimicking a vagal activation system, located within the ventro-medial hypothalamus.

Selective antagonism of platelet-activating factor (PAF)-induced aggregation and secretion in washed rabbit platelets by CV-3988, L-652731, triazolam and alprazolam.

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine or AGEPC) is a potent phospholipid mediator elaborated by a variety of mammalian cells. CV-3988 (a unique structural analog of AGEPC), L-652731 (a lignan derivative of a natural product) and two triazolobenzodiazepines (triazolam and alprazolam) were evaluated for their ability to selectively antagonize aggregation and secretion responses in washed, [3H]serotonin-labeled rabbit platelets stimulated with graded doses of AGEPC. When 0.2 nM AGEPC was used as the stimulus, the concentration of antagonist needed for 50% inhibition (IC50) of secretion was obtained at 0.05 uM, 0.15 uM, 0.6 uM and 2.5 uM, for L-652732, CV-3988, triazolam and alprazolam, respectively. The corresponding IC50 values for aggregation were obtained at 0.2 uM, 0.1 uM, 1.5 uM and 6.5 uM, respectively. The inhibitory effects could be overcome by increasing the amount of AGEPC used to stimulate the platelets. Of the four compounds tested, L-652731 was the most potent antagonist of AGEPC-induced activation of washed rabbit platelets.

Modulation of the vagal drive to the intramural cholinergic and non-cholinergic neurones in the ferret stomach by baclofen.

1. In the urethane-anaesthetized ferret vagotomy (cervical and abdominal) and hexamethonium both produced an increase in gastric corpus pressure after treatment with atropine and guanethidine, section of the greater splanchnic nerves and adrenalectomy. 2. The pressure increase was due to an interruption of a tonic vagal drive to the intramural non-adrenergic, non-cholinergic inhibitory neurones. 3. The GABAB receptor agonist baclofen (8 mg/kg s.c.) produced an increase in gastric pressure and enhanced the amplitude of the rhythmic contractions. Baclofen was without effect in vagotomized animals. 4. In the presence of atropine, guanethidine, adrenalectomy and section of the greater splanchnic nerves, baclofen produced only a slight enhancement of rhythmic contractions but the large increase in gastric pressure was still present. Under the above conditions the effects of baclofen on the whole stomach were virtually identical to those observed in the corpus region alone. 5. Baclofen was without effect on the magnitude of the corpus relaxation produced by the submaximal vagal efferent stimulation in the presence of atropine. 6. These results demonstrate that the GABAB agonist baclofen, probably acting at a central site, enhanced rhythmic gastric activity by increasing the vagal drive to the intramural cholinergic neurones. Simultaneously gastric pressure was increased primarily by a reduction in the tonic vagal drive to the intramural non-adrenergic, non-cholinergic inhibitory neurones in the corpus region. The results of both the baclofen and vagotomy studies further demonstrate the importance of the vagal innervation of the non-adrenergic, non-cholinergic inhibitory neurones in the regulation of gastric pressure.

Systemic baclofen stimulates gastric motility and secretion via a central action in the rat.

Intravenous (0.5 mg kg-1) or subcutaneous (2-16 mg kg-1) administration of the gamma-aminobutyric acid (GABA) analogue baclofen resulted in a stimulation of gastric motility and secretion in the rat, anaesthetized with urethane. The motility response to subcutaneous injection was dose-related. This effect was abolished by vagotomy or atropine. There was no response to baclofen in decerebrate animals. These results indicate that systemic baclofen, probably acting at a site rostral to the brainstem, stimulates gastric motility and acid secretion by a vagally-dependent mechanism.

An extract of rat submandibular glands activates platelets and enhances cutaneous vascular permeability in rats and guinea pigs.

Washed, [3H]serotonin-labeled platelets from rats and guinea pigs were stimulated in vitro with a novel protein extracted from rat submandibular salivary glands (RS-PAP) and with the phospholipid platelet- activating factor 1-0-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine (AGEPC). Rat platelets, which are refractory to AGEPC stimulation, underwent shape-change, aggregation and secretion of [3H]serotonin in response to graded doses of RS-PAP and AGEPC. Intradermal injections of histamine, RS-PAP and AGEPC caused a dose-related increase in local microvascular permeability in rats, as measured by the extravasation of plasma containing Evans blue dye. Similarly, histamine, RS-PAP and AGEPC increased cutaneous vascular permeability when injected intradermally in guinea pigs. The vascular permeability induced by histamine and RS-PAP, but not by AGEPC, was partially inhibited by pretreatment with an antihistamine (diphenhydramine HCl). Pretreatment of guinea pigs with captopril, an inhibitor of angiotensin-converting enzyme (ACE), partially inhibited cutaneous responses to subsequent intradermal injections of histamine, RS-PAP and AGEPC. Regardless of pretreatment with diphenhydramine or captopril, skin test sites injected with large amounts of RS-PAP became hemorrhagic within minutes and necrotic within 12 hours.