Lazabemide for the treatment of Alzheimer's disease: rationale and therapeutic perspectives.
Explore the source record for details and available documents.
Alzheimer Disease↗
Biomedical subjects
C Kuhn
Publications and source records attributed to C Kuhn.
Modulation of bleomycin-induced pulmonary toxicity in the hamster by the antioxidant amifostine.
BACKGROUND: Bleomycin produces lung fibrosis in a wide variety of species. In humans, it can cause significant morbidity and mortality when used to treat malignancies such as lymphoma and testicular carcinoma. In rodents, it has been extensively used to study key mechanisms of lung injury and repair. Bleomycin pulmonary toxicity is mediated, at least in part, by the generation of active oxygen species. Amifostine, an aminothiol compound, is a cytoprotectant that is used with many antitumor agents and can act as a potent scavenger of free radicals. The authors hypothesized that amifostine could ameliorate bleomycin lung injury. METHODS: Hamsters weighing 120 g were given an intraperitoneal (IP) injection of amifostine (200 mg/kg, 1180 mg/m2) or saline with intratracheal (IT) bleomycin (1 unit) or saline, followed by daily IP amifostine or saline for 6 days. Lungs were assessed on Day 2 for acute lung injury, which was determined by wet-to-dry lung weight ratios. On Day 21, histologic assessment of fibrosis and biochemical analysis of lung hydroxyproline content were performed. RESULTS: No significant differences in morbidity or mortality were observed among the groups. Animals who received IT bleomycin, when compared with controls, had increased lung water measurements on Day 2 that were consistent with acute inflammation; on Day 21, they had pulmonary fibrosis, as measured by morphometric analysis, as well as increased hydroxyproline content. For animals treated with amifostine and bleomycin, significant decreases in wet-to-dry lung weight ratios were observed (mean +/- standard deviation, 4.5+/-1.2 vs. 10.2+/-2.7), as well as significant decreases in the percentage of fibrosis per lung (15.03%+/-3.27 vs. 37.26%+/-5.76) and hydroxyproline content (1.132+/-0.30 vs. 1.831+/-0.243). CONCLUSIONS: Amifostine significantly decreased the amount of acute lung injury and subsequent fibrosis in the hamster model of bleomycin-induced lung injury.
Amifostine↗
Flock worker's lung: chronic interstitial lung disease in the nylon flocking industry.
BACKGROUND: Two young men working at a nylon flocking plant in Rhode Island developed interstitial lung disease of unknown cause. Similar clusters at the same company's Canadian plant were reported previously. OBJECTIVE: To define the extent, clinicopathologic features, and potential causes of the apparent disease outbreak. DESIGN: Case-finding survey and retrospective cohort study. SETTING: Academic occupational medicine program. PATIENTS: All workers employed at the Rhode Island plant on or after 15 June 1990. MEASUREMENTS: Symptomatic employees had chest radiography, pulmonary function tests, high-resolution computed tomography, and serologic testing. Those with unexplained radiographic or pulmonary function abnormalities underwent bronchoalveolar lavage, lung biopsy, or both. The case definition of "flock worker's lung" required histologic evidence of interstitial lung disease (or lavage evidence of lung inflammation) not explained by another condition. RESULTS: Eight cases of flock worker's lung were identified at the Rhode Island plant. Three cases were characterized by a high proportion of eosinophils (25% to 40%) in lavage fluid. Six of the seven patients who had biopsy had histologic findings of nonspecific interstitial pneumonia, and the seventh had bronchiolitis obliterans organizing pneumonia. All seven of these patients had peribronchovascular interstitial lymphoid nodules, usually with germinal centers, and most had lymphocytic bronchiolitis and interstitial fibrosis. All improved after leaving work. Review of the Canadian tissue specimens showed many similar histologic findings. Among the 165-member study cohort, a 48-fold or greater increase was seen in the sex-adjusted incidence rate of all interstitial lung disease. CONCLUSIONS: Work in the nylon flocking industry poses substantial risk for a previously unrecognized occupational interstitial lung disease. Nylon fiber is the suspected cause of this condition.
Adult↗
Children with asthma have improved pulmonary functions after massage therapy.
Thirty-two children with asthma (16 4- to 8-year-olds and 16 9- to 14-year-olds) were randomly assigned to receive either massage therapy or relaxation therapy. The children's parents were taught to provide one therapy or the other for 20 minutes before bedtime each night for 30 days. The younger children who received massage therapy showed an immediate decrease in behavioral anxiety and cortisol levels after massage. Also, their attitude toward asthma and their peak air flow and other pulmonary functions improved over the course of the study. The older children who received massage therapy reported lower anxiety after the massage. Their attitude toward asthma also improved over the study, but only one measure of pulmonary function (forced expiratory flow 25% to 75%) improved. The reason for the smaller therapeutic benefit in the older children is unknown; however, it appears that daily massage improves airway caliber and control of asthma.
Adolescent↗
Critical level and detection limit: performance measures for PCR-based assays.
In clinical diagnostic work, sensitivity and specificity are key assay features. In this note we introduce two clinically relevant statistical assay performance measures, the critical level (CL), and the detection limit (DL) for the PCR-based assay. To allow for easy access to these characteristics a Windows-based program has been developed. The application of CL and DL by means of examples is described.
HIV-1↗
Identification and characterization of a novel kind of nuclear protein occurring free in the nucleoplasm and in ribonucleoprotein structures of the "speckle" type.
We have identified, by cDNA cloning and immunodetection, a novel type of constitutive nuclear protein which occurs in diverse vertebrate species, from Xenopus laevis to man, in the form of two different gene products (79.1 kDa and 82.1 kDa in Xenopus, 81.6 kDa and 84.6 kDa in man), remarkably differing in pI (5.4-7.2). This type of protein is characterized by a carboxyterminal domain extremely rich in hydroxyamino acid residues, notably Ser (S), and tetrapeptide repeats of the type XSRS, and hence is termed "domain rich in serines" (DRS) protein. It has been immunolocalized exclusively in the cell nucleus such as in blood cell smears, cultured cells of very different origins and tissue sections, and has also been identified in Xenopus oocyte nuclei, both in sections and by biochemical methods in manually isolated nuclei. In many cell types the protein appears in two different physical states: (i) nuclear granules, identified as ribonucleoprotein (RNP) structures of the "speckle" category by colocalization and cofractionation with certain splicing factors and Sm-proteins, and (ii) in molecules diffusible throughout the nucleoplasm. During mitosis and also in meiosis (Xenopus eggs) the protein is transiently dispersed throughout the cytoplasm but rapidly reaccumulates into the reforming daughter-nuclei. In agreement with this, biochemical experiments have shown that during meiosis (eggs) the protein is recovered in a approximately 11-13S complex of the fraction of soluble cell components. We discuss general constitutive nuclear functions of this apparently ubiquitous and evolutionarily conserved protein.
Amino Acid Sequence↗
The H+-sucrose cotransporter NtSUT1 is essential for sugar export from tobacco leaves
In many species translocation of sucrose from the mesophyll to the phloem is carrier mediated. A sucrose/H+-symporter cDNA, NtSUT1, was isolated from tobacco (Nicotiana tabacum) and shown to be highly expressed in mature leaves and at low levels in other tissues, including floral organs. To study the in vivo function of NtSUT1, tobacco plants were transformed with a SUT1 antisense construct under control of the cauliflower mosaic virus 35S promoter. Upon maturation, leaves of transformants expressing reduced amounts of SUT1 mRNA curled downward, and strongly affected plants developed chloroses and necroses that led to death. The leaves exhibited impaired ability to export recently fixed 14CO2 and were unable to export transient starch during extended periods of darkness. As a consequence, soluble carbohydrates accumulated and photosynthesis was reduced. Autoradiographs of leaves show a heterogenous pattern of CO2 fixation even after a 24-h chase. The 14C pattern does not change with time, suggesting that movement of photosynthate between mesophyll cells may also be impaired. The affected lines show a reduction in the development of the root system and delayed or impaired flowering. Taken together, the effects observed in a seed plant (tobacco) demonstrate the importance of SUT1 for sucrose loading into the phloem via an apoplastic route and possibly for intermesophyll transport as well.
Journal Article↗
Oxidant stress stimulates Na/K pump activity in bovine pulmonary arterial endothelial cells.
Explore the source record for details and available documents.
Animals↗
Aromatherapy positively affects mood, EEG patterns of alertness and math computations.
EEG activity, alertness, and mood were assessed in 40 adults given 3 minutes of aromatherapy using two aromas, lavender (considered a relaxing odor) or rosemary (considered a stimulating odor). Participants were also given simple math computations before and after the therapy. The lavender group showed increased beta power, suggesting increased drowsiness, they had less depressed mood (POMS) and reported feeling more relaxed and performed the math computations faster and more accurately following aromatherapy. The rosemary group, on the other hand, showed decreased frontal alpha and beta power, suggesting increased alertness. They also had lower state anxiety scores, reported feeling more relaxed and alert and they were only faster, not more accurate, at completing the math computations after the aromatherapy session.
Adult↗
Polydrug-using adolescent mothers and their infants receiving early intervention.
This study investigated the effects of an intervention for polydrug-using adolescent mothers. The program included educational, vocational, and parenting classes; social and drug rehab; and day care for their infants while they attended school half-day. The drug-exposed infants were similar to the nonexposed infants on traditional birth measures, although they had inferior Brazelton Neonatal Behavioral Assessment Scale scores, including habituation, orientation, abnormal reflexes, general irritability, and regulatory capacity. The drug-exposed infants also spent less time in quiet sleep and more time crying and showing stress behaviors. Both the mothers and the infants in the drug groups demonstrated inferior interactions, and their dopamine and serotonin levels were significantly higher. As early as 3 months (following 3 months of intervention), the drug rehab mothers and their infants looked more like the nondrug group in their interactions; by 6 months, they looked similar on virtually every measure. At 12 months, the infants of drug rehab mothers (versus the drug control group) had superior Early Social Communication Scale scores and Bayley Mental scale scores, as well as significantly greater head circumference and fewer pediatric complications. The drug rehab mothers also improved on several lifestyle variables. They demonstrated a lower incidence of continued drug use and repeat pregnancy, and a greater number continued school, received a high school or general equivalency diploma, or were placed in a job. Thus, a relatively cost-effective high school based intervention had positive effects on both adolescent mothers who had used drugs and their infants.
Adolescent↗
Bulimic adolescents benefit from massage therapy.
Twenty-four female adolescent bulimic inpatients were randomly assigned to a massage therapy or a standard treatment (control) group. Results indicated that the massaged patients showed immediate reductions (both self-report and behavior observation) in anxiety and depression. In addition, by the last day of the therapy, they had lower depression scores, lower cortisol (stress) levels, higher dopamine levels, and showed improvement on several other psychological and behavioral measures. These findings suggest that massage therapy is effective as an adjunct treatment for bulimia.
Adolescent↗
Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes.
Standard overexpression transgenic approaches are limited in their ability to model waxing and waning diseases and frequently superimpose development-dependent and -independent phenotypic manifestations. We used the clara cell 10-kD protein (CC10) promoter and the reverse tetracycline transactivator (rtTA) to create a lung-specific, externally regulatable, overexpression transgenic system and used this system to express human interleukin 11 (IL-11) in respiratory structures. Gene induction could be achieved in utero, in neonates and in adult animals. Moreover, gene expression could be turned off by removal of the inducing stimulus. When gene activation was initiated in utero and continued into adulthood, subepithelial airway fibrosis, peribronchiolar mononuclear nodules, and alveolar enlargement (emphysema) were noted. Induction in the mature lung caused airway remodeling and peribronchiolar nodules, but alveolar enlargement was not appreciated. In contrast, induction in utero and during the first 14 d of life caused alveolar enlargement without airway remodeling or peribronchiolar nodules. Thus, IL-11 overexpression causes abnormalities that are dependent (large alveoli) and independent (airway remodeling, peribronchiolar nodules) of lung growth and development, and the CC10-rtTA system can be used to differentiate among these effector functions. The CC10-rtTA transgenic system can be used to model waxing and waning, childhood and growth and development-related biologic processes with enhanced fidelity.
Aging↗
Studies on the mechanism of short-term regulation of pulmonary artery endothelial cell Na/K pump activity.
The Na/K pump is critically important in maintenance of cell homeostasis in the face of injury. Little is known about the regulation of endothelial cell Na/K-pump activity. We previously reported that short-term (30-minute) oxidant-induced endothelial cell perturbation increased Na/K-pump activity in intact monolayers of bovine pulmonary artery endothelial cells (BPAECs). In this study we investigated the mechanism of oxidant-induced increases in endothelial Na/K-pump activity, focusing on short-term modulation of alpha1-pump subunit. By using immunofluorescence microscopy and confocal scanning laser microscopy, we found alpha1 subunit on both apical and basal aspects of BPAECs without polarized distribution. Short-term (30-minute) incubation of PAEC monolayers with H2O2 (1 mmol/L) did not change the relative amounts of alpha1 subunit in membrane fractions, as assessed by immunoblotting. Phosphorylation of the alpha1 subunit also was not affected by H2O2 treatment. Because protein kinases have been reported to alter Na/K-pump activity in several tissues and because H2O2 has been reported to increase PKC activity of endothelial cells, we determined the effects of inhibition and activation of protein kinase C (PKC) on Na/K-pump activity quantitated as ouabain-inhibitable uptake of 86Rb. We also determined the effects of PKC activation and inhibition on H2O2-induced increases in Na/K-pump activity. Inhibitors of PKC increased Na/K-pump activity over a 30-minute period in intact monolayers. Inhibition or depletion of PKC did not prevent H2O2-induced increases in pump activity. These results indicate that PKC is an endogenous regulator of pulmonary artery endothelial cell Na/K-pump activity but that the effects of H2O2 are not mediated by activation of PKC or by changes in the expression or phosphorylation of alpha1 subunit.
Animals↗
Immediate early gene expression to examine neuronal activity following acute and chronic stressors in rat pups: examination of neurophysiological alterations underlying behavioral consequences of prenatal cocaine exposure.
Altered behavioral responses to stressors have been observed in animals exposed to cocaine prenatally. In the present study, both behavioral and physiological responses to repeated and single stressor exposure were measured in animals prenatally exposed to cocaine. Offspring were derived from 3 prenatal treatment groups: dams that were administered 40 mg/kg cocaine from gestational day 8-20 (C40); dams that were pair-fed and -watered to weight-matched C40 dams (PF); and untreated dams (LCC). Starting on postnatal day 16-17 (P16-17), offspring from the 3 prenatal treatment groups were exposed to either footshock or isolation daily for 5 days. Two days after the last day of stressor exposure (P21-22), subjects were given 1 final exposure to the stressor to which they were previously exposed. In addition, at P21-22, littermates of animals given repeated exposure to stressors were exposed to either footshock or isolation for the first and only time. During all footshock sessions, the duration of freezing behavior was recorded. Plasma adrenocorticotrophin (ACTH) and corticosterone levels were determined from blood samples taken immediately following the final stressor session and brains were processed for C-FOS immunoreactivity (FOS-IR). Plasma corticosterone was increased following either single or repeated exposure to either stressor compared to homecage control animals. Plasma ACTH was increased by exposure to both repeated and single footshock exposure, but the increase was not as great following repeated footshock exposure, suggesting adaptation to repeated exposure to this stressor. Following both single and repeated footshock exposure, FOS-IR was increased relative to baseline levels in the paraventricular nucleus of the hypothalamus (PVN) and in the supraoptic nucleus (SON), but not the locus coeruleus (LC). Repeatedly footshocked animals exhibited more time freezing than animals given a single footshock session. Prenatal exposure to cocaine resulted in more time spent freezing in C40 than LCC animals during the chronic footshock exposure period; however, no differences were seen in any of the physiological measures taken from these 2 groups on the final test day. The implications of these findings are discussed in the context of other research examining the effects of prenatal cocaine exposure on stress responses.
Animals↗
Gender difference in cocaine-induced HPA axis activation.
The study investigates the influence of gender on the activation of the hypothalamo-pituitary-adrenal (HPA) axis by cocaine and other monamine uptake inhibitors. Drug-induced secretion of adrenocorticotrophic hormone (ACTH) was used to pursue this question. Cocaine produced a dose-related rise in serum ACTH levels in both male and female rats, but the rise was significantly greater in females than in males. Females also showed enhanced HPA axis activation following administration of the dopamine uptake inhibitor GBR 12909, the serotonin uptake inhibitor fluoxetine, and the norepinephrine uptake inhibitor desipramine. No gender difference in HPA axis activation was observed in a dose-response study of cocaine-induced HPA activation in 10 day old rats. Ovariectomy of females decreased the ACTH response to cocaine, but castration did not affect the response of males. To evaluate the role of the pituitary in this gender difference, ACTH levels were determined after corticotropin-releasing factor (CRF) administration. Females showed greater ACTH responses to CRF than males. These studies demonstrate that female rats show exaggerated HPA responses to monoamine uptake inhibitors and that enhanced pituitary responsivity to CRF contributes to this gender difference.
Adrenocorticotropic Hormone↗
Juvenile rheumatoid arthritis: benefits from massage therapy.
Studied children with mild to moderate juvenile rheumatoid arthritis who were massaged by their parents 15 minutes a day for 30 days (and a control group engaged in relaxation therapy). The children's anxiety and stress hormone (cortisol) levels were immediately decreased by the massage, and over the 30-day period their pain decreased on self-reports, parent reports, and their physician's assessment of pain (both the incidence and severity) and pain-limiting activities.
Adolescent↗
Repairing the cables of the lung.
Explore the source record for details and available documents.
Collagen↗
Relation of mood ratings and neurohormonal responses during daily life in employed women.
Diurnal variations in urinary norepinephrine, epinephrine, cortisol, and self-reported mood states were examined in 101 employed women. Urine was collected on 2 consecutive workdays at 3 time periods: (1) overnight, (2) daytime, and (3) evening. Self-reports of 14 mood states were combined to correspond with the urinary collection periods. Factor analyses revealed 3 mood factors: Pressured (rushed, busy, stressed, hassled, and tense), Distressed (afraid, depressed, bored, and nervous), and Contented (satisfied, thoughtful, excited, and calm). The Distressed factor was significantly associated with norepinephrine excretion (p <.001). The Pressured factor was significantly associated with cortisol, epinephrine, and norepinephrine excretion (p <.001) independent of age, ethnicity, marital status, parental status, department within the company and activity level. Secretion of urinary hormones and the Pressured factor followed the same diurnal pattern. Specifically, as women's self-ratings of feeling pressured initially increased and then decreased over the course of the workday, urinary hormones also peaked and then dropped. Once time of day was statistically controlled, however, the mood factors were no longer significantly related to the urinary hormones.
Journal Article↗