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PubMed2001

Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence.

BACKGROUND: The present study investigated polysomnographically assessed sleep parameters in alcohol-dependent patients after withdrawal and in healthy control subjects during baseline and after a cholinergic stimulation paradigm. The aim of the study was to test whether sleep parameters, especially rapid eye movement (REM) sleep variables, may serve as predictors for relapse in alcohol-dependent patients. METHODS: Forty patients diagnosed with alcohol dependence were admitted to a specialized ward for alcohol withdrawal and were investigated by polysomnography at three time points: 2-3 weeks after withdrawal (T0) and at follow-up investigations 6 (T1) and 12 (T2) months after discharge from the hospital. A subgroup of patients (n = 17) was studied at T0 after challenge with galanthamine, a reversible cholinesterase inhibitor (cholinergic REM induction test, CRIT). Patients were compared with two control groups: a) 30 healthy control subjects (matched for age- and gender-distribution) for comparison at baseline conditions; and b) 17 age- and gender-matched control subjects for comparison with the CRIT. RESULTS: At baseline the patients showed significant disturbances of sleep continuity and sleep architecture (decreased slow-wave sleep, SWS) and exhibited an increase of "REM sleep pressure" (a combined index of REM latency, REM density, and REM sleep percent). Galanthamine provoked significant alterations of sleep continuity, sleep architecture (reduced SWS), and increased most of the components of REM pressure, taking patients and control subjects together. Apart from SWS %SPT (sleep period time) no significant drug-group interactions occurred. Patients who remained abstinent (n = 11) for at least 6 months at follow-up exhibited significantly less abnormalities of REM sleep at T0 compared to the group of patients that relapsed at 6 months follow-up. CONCLUSIONS: It is concluded that increased REM sleep pressure after alcohol withdrawal is a robust predictor of vulnerability to relapse. Thus, a subgroup of alcoholic patients appears to exhibit distinct neurobiological abnormalities assessable by polysomnography that are related to an increased vulnerability for alcoholism and early relapse.

Adult↗

PubMed2003

Detection of resistance to isoniazid by denaturing gradient-gel electrophoresis DNA sequencing in Mycobacterium tuberculosis clinical isolates.

Isoniazid (INH) resistance was genotypically assessed in 104 (37 INH-susceptible, 67 INH-resistant) genetically unrelated Mycobacterium tuberculosis strains cultured in North Italy. The PCR products of selected regions of the katG gene, the oxyR-ahpC intergenic region, and the inhA regulatory region were analyzed utilizing the double gradient-denaturing gradient gel electrophoresis (DG-DGGE) technique and confirmed by DNA sequencing. Mutations were detected in 61 (91%) of the INH-resistant strains, the relative frequency of the mutations being 65.7% in katG, 23.9% in oxyR-ahpC, and 13.4% in inhA. Previously described alterations, invariably associated with drug resistance, accounted for 95.1% of the mutations. No alterations were found in the INH-susceptible strains. DG-DGGE analysis and DNA sequencing were equally sensitive, but the former is cheaper, easier and more robust. Rapid genotypic assessment of INH resistance by means of the methodology described here could reasonably be used in clinical mycobacteriology laboratories.

Antitubercular Agents↗

PubMed1986

[A thalamo-cerebral connection in vocal center of canary].

Canary song is controlled by two groups of thalamo-cerebral nuclei. One, the hyperstriatum ventrale pars caudale (HVc) and the robust nucleus of the archistriatum (RA), is a motor driving system for vocalization. The other group, which includes the HVc, the nucleus magnocellularis of neostriatum (MAN), Area X and the nucleus dorsointermedius posterior thalami (DIP), modulates the driving system. The HVc receives synaptic projections from the MAN and sends fibers to Area X. Axons of Area X monosynaptically innervate the thalamic nucleus, the DIP, from which neurons extend axons back to the cerebral nucleus, the MAN. DIP neurons relay incoming impulses by way of Area X to the MAN. Double labeling of DIP neurons with HRP and Fast Blue shows that axonal terminals from Area X connect directly with DIP neurons which send fibers to the MAN. The axon formed a bulge from which multiple branches extended to the postsynaptic cell bodies covering most of the surface. The structure of the DIP synapse may be related to a characteristic pattern of discharge of the DIP neuron, which is transmitted over thalamic projection to cerebral vocal nuclei.

Animals↗

PubMed1998

Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials.

BACKGROUND: beta-Blockers have improved symptoms and reduced the risk of cardiovascular events in studies of patients with heart failure, but it is unclear which end points are most sensitive to the therapeutic effects of these drugs. METHODS AND RESULTS: We combined the results of all 18 published double-blind, placebo-controlled, parallel-group trials of beta-blockers in heart failure. From this combined database of 3023 patients, we evaluated the strength of evidence supporting an effect of treatment on left ventricular ejection fraction, NYHA functional class, hospitalizations for heart failure, and death. beta-Blockers exerted their most persuasive effects on ejection fraction and on the combined risk of death and hospitalization for heart failure. beta-Blockade increased the ejection fraction by 29% (P<10(-9)) and reduced the combined risk of death or hospitalization for heart failure by 37% (P<0.001). Both effects remained significant even if >90% of the trials were eliminated from the analysis or if a large number of trials with a neutral result were added to the analysis. In contrast, the effect of beta-blockade on NYHA functional class was of borderline significance (P=0.04) and disappeared with the addition or removal of only 1 moderate-size study. Although beta -blockade reduced all-cause mortality by 32% (P=0.003), this effect was only moderately robust and varied according to the type of ss-blocker tested, ie, the reduction of mortality risk was greater for nonselective beta-blockers than for beta1-selective agents (49% versus 18%, P=0.049). However, selective and nonselective beta-blockers did not differ in their effects on other measures of clinical efficacy. CONCLUSIONS: These analyses indicate that there is persuasive evidence supporting a favorable effect of beta-blockade on ejection fraction and the combined risk of death and hospitalization for heart failure. In contrast, the effect of these drugs on other end points requires additional study.

Adrenergic beta-Antagonists↗

PubMed2003

Characteristics of organic transformations in a confined dendritic core: studies on the AIBN-initiated reaction of dendrimer cobalt(II) porphyrins with alkynes.

Cobalt(II) complexes of poly(aryl ester) dendrimer porphyrins [(m-[Gn]TPP)Co(II)] (generation number n=0-4), in the presence of azobisisobutyronitrile (AIBN) at 60 degrees C, underwent alkenylation with several alkynes at the metal center. A complete inhibition of double-bond migration (secondary transformation) was observed for [(m-[Gn]TPP)Co(II)] (n=3 and 4), which gave [(m-[Gn]TPP)Co(III)-C(=CH(2))R] (n=3 and 4) exclusively. Overall reaction rates for [(m-[Gn]TPP)Co(II)] (n=0-3) were hardly dependent on the size of the dendritic substituents, while a notable retardation was observed for the largest dendrimer, [(m-[G4]TPP)Co(II)]. Mechanistic studies on double-bond migration with pure [(m-[Gn]TPP)Co(III)-C(=CH(2))Bu] (n=0-4) demonstrated that the secondary transformation involves participation of [(m-[Gn]TPP)Co(III)H] (n=0-4), derived from [(m-[Gn]TPP)Co(II)] and AIBN, rather than [(m-[Gn]TPP)Co(II)] alone. Crossover experiments using [(m-[Gn]TPP)Co(III)-C(=CH(2))Bu] (n=2-4), in combination with nondendritic [(m-[G0]TPP)Co(II)] and AIBN, indicated a high level of steric protection of the active center by a robust [G4]-dendritic cage, as suggested by a (1)H NMR pulse relaxation time profile of m-[G4]TPPH(2).

Alkynes↗

PubMed2003

The central domain of core RAG1 preferentially recognizes single-stranded recombination signal sequence heptamer.

RAG1 and RAG2 initiate V(D)J recombination by introducing DNA double strand breaks between each selected gene segment and its bordering recombination signal sequence (RSS) in a two-step mechanism in which the DNA is first nicked, followed by hairpin formation. The RSS consists of a conserved nonamer and heptamer sequence, in which the latter borders the site of DNA cleavage. A region within RAG1, referred to as the central domain (residues 528-760 of 1040 in the full-length protein), has been shown previously to bind specifically to the double-stranded (ds) RSS heptamer, but with both weak specificity and affinity. However, additional investigations into the RAG1-RSS heptamer interaction are required because the DNA substrate forms intermediate conformations during the V(D)J recombination reaction. These include the nicked and hairpin products, as well as likely base unpairing to produce single-stranded (ss) DNA near the cleavage site. Here, it was determined that although the central domain showed substantially higher binding affinity for ss and nicked versus ds substrate, the interaction with ss RSS was particularly robust. In addition, the central domain bound with greater sequence specificity to the ss RSS heptamer than to the ds form. This study provides important insight into the V(D)J recombination reaction, specifically that significant interaction of the RSS heptamer with RAG1 occurs only after the induction of conformational changes at the RSS heptamer.

Animals↗

PubMed2005

Three-dimensional mixed-wet random pore-scale network modeling of two- and three-phase flow in porous media. I. Model description.

We present a three-dimensional network model to simulate two- and three-phase capillary dominated processes at the pore level. The displacement mechanisms incorporated in the model are based on the physics of multiphase flow observed in micromodel experiments. All the important features of immiscible fluid flow at the pore scale, such as wetting layers, spreading layers of the intermediate-wet phase, hysteresis, and wettability alteration are implemented in the model. Wettability alteration allows any values for the advancing and receding oil-water, gas-water, and gas-oil contact angles to be assigned. Multiple phases can be present in each pore or throat (element), in wetting and spreading layers, as well as occupying the center of the pore space. In all, some 30 different generic fluid configurations for two- and three-phase flow are analyzed. Double displacement and layer formation are implemented as well as direct two-phase displacement and layer collapse events. Every element has a circular, square, or triangular cross section. A random network that represents the pore space in Berea sandstone is used in this study. The model computes relative permeabilities, saturation paths, and capillary pressures for any displacement sequence. A methodology to track a given three-phase saturation path is presented that enables us to compare predicted and measured relative permeabilities on a point-by-point basis. A robust displacement-based clustering algorithm is also presented.

Absorption↗

PubMed1998

Advancing AIDSVAX to phase 3. Safety, immunogenicity, and plans for phase 3.

AIDSVAX (VaxGen, Inc., South San Francisco, CA), a possible vaccine to protect against human immunodeficiency virus type 1 (HIV-1) infection, is being tested for efficacy in phase 3 studies. It has been tested for potential efficacy in chimpanzees, and tested for safety and immunogenicity in human clinical studies. Four candidate vaccines, each with a different envelope protein antigen or combination of antigens, have been produced in alum formulations. In both design and clinical testing, AIDSVAX has an excellent safety profile. Because these highly purified proteins were prepared using recombinant DNA technology, there is no possibility of these vaccines causing HIV infection. Having been administered to over 1200 people, the only side effects attributable to AIDSVAX have been local pain and inflammation at the injection site. After immunization, essentially all recipients developed a robust antibody response, including binding and neutralizing antibodies. The neutralizing antibodies peaked after a 12-month boost. Excellent memory is induced. Two phase 3 trials of two bivalent formulations will evaluate their efficacy. One trial will use a bivalent subtype B formulation. This trial in North America will involve 5000 men who have sex with men and heterosexual women at high risk. The other study will use a bivalent subtype B/subtype E formulation. This trial in Thailand and will involve 2500 intravenous drug users. Both studies will be randomized, double-blinded and placebo controlled. The volunteers will be followed for 3 years. The end points of the studies are infection, as defined by seroconversion to standard diagnostic tests, and viral load, as defined by commercial polymerase chain reaction (PCR) tests.

AIDS Vaccines↗

PubMed2001

Ventral mesopontine projections of the caudomedial shell of the nucleus accumbens and extended amygdala in the rat: double dissociation by organization and development.

The shell of the nucleus accumbens and central division of the extended amygdala are telencephalic structures that influence motor activity and lately have been regarded by some as components of a single functional-anatomic continuum. Each has a highly differentiated internal organization and output system and distinct pharmacologic responses however, and it is thus likely that each subserves distinct contributions to behavior. In this investigation, nucleus accumbens and extended amygdala outputs were compared by using retrograde tracing in adult and postnatal rats. Fluoro-Gold, when injected into the ventral tegmental area, produced substantial retrograde labeling in the adult nucleus accumbens shell, but only trivial amounts in the central division of the extended amygdala. Injection sites in the lateral mesopontine tegmentum produced robust labeling in the central extended amygdala but little in the nucleus accumbens. The projections of extended amygdala were substantially developed by postnatal day 1, whereas those of the caudomedial shell of the nucleus accumbens only reached the ventral tegmental area by approximately postnatal day 6. Few neurons projecting from the caudomedial shell of the accumbens to the ventral tegmental area were observed even at postnatal day 21. In consideration of the reported importance of the nucleus accumbens, particularly the caudomedial shell, in neural processing related to reward and motivation and the central nervous system response to antipsychotic drugs, it may be important to determine whether processes occurring during the protracted postnatal development of the caudomedial shell are vulnerable to destructive circumstances, such as drug intoxication, maternal separation, or social isolation.

Aging↗

PubMed1999

Toward high-resolution myocardial tagging.

Magnetic resonance imaging with preceding tissue tagging is a robust method for assessing cardiac motion of the entire heartbeat cycle with a high degree of accuracy. One limitation of this technique, however, is the low resolution of the obtained displacement map of the labeled points within the myocardium. By a new tagging technique, which is based on the combination of two or more measurements of the same slice but with different grid positions, a highly improved resolution of cardiac motion data can be achieved. In combination with a multi-heart-phase echo-planar imaging sequence, such images with doubled grid frequency can be acquired in two short breath-hold periods.

Contrast Media↗

PubMed2000

Corticosteroids for the resolution of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer.

BACKGROUND: Gastrointestinal and ovarian cancers are common cancers. The incidence of associated malignant bowel obstruction in patients with advanced cancers of these types is not known, and the best management of these patients is controversial. Inappropriate management may result in uncontrolled (faeculant) vomiting, pain and distress. Management of the symptoms can include palliative surgery, nasogastric tube suction together with intravenous fluids, or pharmacological means, such as corticosteroids. There is uncertainty regarding both the efficacy and possible harmful effects of corticosteroids, and also the most effective type, dose/dosing regime, route and period of administration. OBJECTIVES: To locate, appraise and summarise evidence from scientific studies on intestinal obstruction due to advanced gynaecological and gastrointestinal cancer, in order to assess the efficacy of corticosteroids. SEARCH STRATEGY: A comprehensive list of all studies was provided by an extensive search of the electronic databases, relevant journals, reference lists, the grey literature, contact with investigators and other search strategies outlined in the methods. SELECTION CRITERIA: As the review concentrates on the 'best evidence' available of the role of corticosteroids in malignant bowel obstruction due to advanced gynaecological and gastrointestinal cancer the inclusion criteria were kept fairly broad so as to include all studies relevant to the question DATA COLLECTION AND ANALYSIS: Data extraction forms were used to collect data from the studies included in the review. The data was checked by a secondary searcher to reduce error. A qualitative analysis was performed of the dichotomous data of resolution of obstruction and death at one month, obtained from the randomised controlled trials of corticosteroids versus placebo. Both fixed and random effect models were used. Number needed to treat (NNT) was derived from the odds ratio. Kaplan-Meier survival curves from individual patient data were also analysed. Studies of lower methodological quality were assessed in a qualitative manner. MAIN RESULTS: Three unpublished, randomised, placebo, double blind controlled trials and seven published (prospective and retrospective) trials were considered eligible. Using only the randomised trials, there is a trend, which is not statistically significant, for the resolution of bowel obstruction using corticosteroids. There is no statistically significant difference in mortality at one month, nor in the Kaplan-Meier curves, which describe the survival of patients on corticosteroids or placebo. Number needed to treat is 6 (3, infinity) ie six patients need to be treated with corticosteroids to resolve one episode of bowel obstruction. The results are robust to fixed and random effects models and to 'best' and 'worst case' scenarios on the missing data from patients. The morbidity associated with corticosteroids appears to be very low, though the quality of the data limits this conclusion. No other outcomes were available from the published data or from the authors. REVIEWER'S CONCLUSIONS: There is a trend for evidence that corticosteroids of dose range 6-16 mg dexamethasone given intravenously may bring about the resolution of bowel obstruction. Equally, the incidence of side effects in all the included studies is extremely low. Corticosteroids do not seem to affect the length of survival of these patients.

Female↗

PubMed2026

Multi-omics characterization of flavor profile differences in the Longissimus thoracis between Angus and Hereford cattle.

BACKGROUND: Angus and Hereford cattle are premier breeds widely used in genetic improvement and crossbreeding programs to enhance meat quality, yet the flavor differences between them remain poorly understood. RESULTS: In this study, we performed an integrated analysis using headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME-GC-MS)-based volatile metabolomics, lipidomics, and untargeted metabolomics to characterize the flavor profiles of the Longissimus thoracis (LT) muscle from both breeds and to identify potential precursor substances underlying flavor formation. In total, we identified 76 differential volatile organic compounds (VOCs) among the 493 candidate VOCs. By combing relative odor activity value (ROAV) and sensory attribute annotation, 2,3-butanedione which may contribute to the creamy aroma was revealed as the core differential VOC between the two breeds. This finding was robustly validated across SHAP (Shapley additive explanations) analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment, and flavor annotation. Lipidomic analysis revealed 689 differential lipids primarily belonging to classes such as phosphatidylcholine, triglycerides, and phosphatidylethanolamine. Correlation analysis further linked these lipid profiles to flavor, showing that fatty acids (FAs) including FA(19:0), FA(18:2 + O), FA(14:1), FA(16:1), and FA(14:0) were significantly correlated with 2,3-butanedione. Notably, the unsaturated fatty acids (UFAs) in the Longissimus thoracis (LT) of Hereford cattle exhibited higher double bond content compared to Angus cattle, suggesting a greater potential for rich flavor development. Untargeted metabolomics revealed that nine of the 9474 metabolites were significantly correlated with both 2,3-butanedione and FAs, including norepinephrine, l-beta-aspartyl-l-leucine, and artemetin. CONCLUSIONS: Overall, our research has identified differential flavor compounds and potential precursor substances between Angus cattle and Hereford cattle, providing targeted guidance for breed improvement. © 2026 Society of Chemical Industry.

2,3‐butanedione↗

PubMed1998

Strategy for lipid suppression in lactate imaging using STIR-DQCT: a study of hypoxic-ischemic brain injury.

In vivo lactate detection using gradient enhanced double quantum coherence transfer (DQCT) was significantly improved by addition of short-time-inversion-recovery (STIR). Phantom studies demonstrated lipid suppression down to the background noise level with 33% loss of lactate signal. In vivo studies using a rabbit model of hypoxic and unilateral-ischemic brain injury showed reduction down to 29 +/- 11% in lipids with inversion times between 140 and 170 ms. Lactate signals on the ischemic side were 51 +/- 53% higher than the nonischemic side at the peak of hypoxia. STIR-DQCT can be a useful robust method of obtaining metabolic maps of lactate in vivo.

Animals↗

PubMed2005

Photooxidation of A2-PE, a photoreceptor outer segment fluorophore, and protection by lutein and zeaxanthin.

A2-PE is a pigment that forms as a byproduct of the visual cycle, its synthesis from all-trans-retinal and phosphatidylethanolamine occurring in photoreceptor outer segments. A2-PE is deposited in retinal pigment epithelial (RPE) cells secondary to phagocytosis of shed outer segment membrane and it undergoes hydrolysis to generate the RPE lipofuscin fluorophores, A2E, iso-A2E and other minor cis-isomers of A2E. We have demonstrated that A2-PE can initiate photochemical processes that involve the oxidation of A2-PE and that, by analogy with A2E are likely to include the formation of reactive moieties. We also show that potential sources of protection against the photooxidation of A2-PE are the lipid-soluble carotenoids zeaxanthin and lutein (xanthophylls), that constitute the yellow pigment of the macula. Irradiation of A2-PE in the presence of lutein or zeaxanthin suppressed A2-PE photooxidation and in experiments in which we compared the antioxidant capability of zeaxanthin and lutein to alpha-tocopherol, the carotenoids were more potent. Additionally, the effect with zeaxanthin was consistently more robust than with lutein and when alpha-tocopherol was combined with either carotenoid, the outcome was additive. Lutein, zeaxanthin and alpha-tocopherol were all efficient quenchers of singlet oxygen. We have also shown that lutein and zeaxanthin can protect against A2-PE/A2E photooxidation without appreciable consumption of the carotenoid by chemical reaction. This observation contrasts with the pronounced susceptibility of A2E and A2-PE to photooxidation and is of interest since lutein, zeaxanthin, A2E and A2-PE all have conjugated systems of carbon-carbon double bonds terminating in cyclohexenyl end-groups. The structural features responsible for the differences in quenching mechanisms are discussed. It has long been suspected that macular pigment protects the retina both by filtering high-energy blue light and by serving an antioxidant function. Evidence presented here suggests that the photochemical reactions against which lutein and zeaxanthin protect, may include those initiated by the A2-PE. Quantitative HPLC analysis revealed that in eyecups of C57BL/6J and BALB/cByJ mice, levels of A2-PE were several fold greater than the cleavage product, A2E. Taken together, these results may have implications with respect to the involvement of A2-PE formation in mechanisms underlying blue light-induced photoreceptor cell damage and may be significant to retinal degenerative disorders, such as those associated with ABCA4 mutations, wherein there is a propensity for increased A2-PE synthesis.

Animals↗

PubMed1996

NIRCA: a rapid robust method for screening for unknown point mutations.

We describe a method for screening for dispersed point mutations, based on the observation that RNase frequently cleaves both strands of base pair mismatches in duplex RNA targets. The mismatched substrates are generated by in vitro transcription of wild-type and mutant templates amplified by the PCR or reverse transcription (RT)-PCR; bacteriophage promoters are incorporated into the PCR primers to permit both strands of the products to be transcribed into RNA. Complementary wild-type and mutant transcripts are hybridized and treated with RNase, and the cleavage products are separated on agarose gels and detected by visualization of the ethidium-stained sample under UV light. The method is thus non-isotopic, and since the cleavage products remain double-stranded during analysis, the labor-intensive RNase inactivation steps required in the original procedure can be eliminated. Also, nonspecific background cleavage is reduced so that longer target regions (1 kb) can be screened in a single step. The Non-Isotopic RNase Cleavage Assay (NIRCA) achieved a detection rate of 88%-90% in blind studies in a Factor IX model system, and it was also used to detect unknown p53 mutations in breast tumor samples. NIRCA provides a rapid method for sensitive, non-isotopic, high-throughput genetic screening.

Base Sequence↗

PubMed1998

IL-2 and IL-4 double knockout mice reject islet allografts: a role for novel T cell growth factors in allograft rejection.

T cell growth factors (TCGFs) play a critical role in allograft rejection by promoting the activation and proliferation of alloreactive T cells. To determine whether IL-2 and IL-4 are of quintessential importance in allograft rejection and to identify possible alternative TCGFs, we have bred IL-2(-/-) and IL-4(-/-) double knockout (DKO) mice and studied islet allograft rejection using the DKO mice as allograft recipients. Although mononuclear leukocytes from DKO mice did not mount a proliferative response in vitro in response to anti-CD3 stimulation, crude islet allografts were vigorously rejected by DKO mice (mean survival time 17 +/- 7, n = 8) as compared with wild-type controls (mean survival time 13 +/- 4, n = 7). Treatment of DKO mice with anti-CD3 or rapamycin markedly prolonged the islet allograft survival. An analysis of intragraft cytokine gene transcripts showed robust expression of IL-7 and IL-15. In contrast, intragraft IL-9 gene transcripts were not detected in either wild-type or DKO mice. Provision of exogenous IL-2, IL-4, IL-7, or IL-15, but not IL-9, supports the proliferation of anti-CD3 activated DKO splenic leukocytes in vitro. Blocking the common gamma c of IL-2 receptor, a shared essential signaling component by receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, prolonged the survival of islet allografts in DKO mice. Hence, a T cell dependent allograft rejection enabled by rapamycin-sensitive signals or signals mediated by binding of the gamma c chain occurs in the absence of both IL-2 and IL-4. Non-T cell-derived TCGFs, especially IL-7 and IL-15, may play an active role in supporting allograft rejection.

Animals↗

PubMed1993

Nedocromil sodium is more effective than cromolyn sodium for the treatment of chronic reversible obstructive airway disease.

In a multicenter, double-blind, group comparative trial, the efficacy of nedocromil sodium (nedocromil, 4 mg, four times daily [qid]), cromolyn sodium (2 mg, qid), and placebo was compared in patients receiving inhaled beta 2-agonists and inhaled corticosteroids for the treatment of chronic reversible obstructive airway disease. After a 2-week baseline period, 132 patients (8 centers) between the ages of 20 and 75 years entered a 4-week run-in period in which the dose of inhaled corticosteroid was reduced by 50 percent. During the run-in phase, deterioration of symptoms (total symptom score) by ten points qualified patients to enter the 6-week drug trial period. Patients in the nedocromil treatment group showed the most robust and consistent improvements over placebo and cromolyn sodium for all daily dairy variables. Statistically significant improvements over placebo were noted for both active treatment groups for daytime, nighttime, and total symptom score. Symptom scores for nedocromil were statistically significantly improved over both cromolyn sodium and placebo for both daytime and nighttime asthma. Patients treated with nedocromil also demonstrated a significant reduction in the use of nighttime as needed (prn) beta 2-agonists as compared with either the placebo- or cromolyn sodium-treated groups. Only nedocromil-treated patients demonstrated a statistically significant improvement in morning peak expiratory flow rate (PEFR) as compared with placebo. Both nedocromil and cromolyn sodium groups demonstrated statistically significant improvements in afternoon and evening PEFRs. Collectively, the improvements in nighttime symptoms, decreased bronchodilator use, and improved morning PEFR show that patients treated with nedocromil had improved nocturnal symptoms. Pulmonary function tests (FEV1, FVC, PEFR) demonstrated no statistically significant differences between the two active treatments, although trends favored nedocromil for both FEV1 and PEFR. Although symptoms improved in patients treated with cromolyn sodium, the level of symptom control was less than that achieved by nedocromil. As compared with baseline control (regular dose of inhaled steroids), patients treated with nedocromil plus the 50 percent reduced dosage of inhaled corticosteroid consistently demonstrated comparable or better symptom control. Although both active drugs reduced symptoms, nedocromil proved to be more effective than cromolyn sodium for treatment of reversible obstructive airway disease in patients normally well maintained on regimens of low to moderate doses of inhaled corticosteroids.

Adult↗

PubMed2001

Assessment of protein gene product 9.5 as a marker of neural crest-derived precursor cells in the developing enteric nervous system.

The neurons and glial cells of the enteric nervous system (ENS) are derived from the neural crest. To study the developmental events involved in congenital abnormalities of the ENS, it is essential to identify all neural-crest cells (NCC) in the prenatal gut. The low-affinity neurotrophin receptor p75 is currently considered to be a gold-standard marker, but because it is a membrane protein, it is lost during procedures that permeabilise cells that are necessary to identify intracellular components and in apoptosis and cell-proliferation assays. We have therefore assessed the potential of the intracellular neuronal marker protein gene product (PGP) 9.5 as a label for neural-crest-derived precursor cells during gut development. Gut was taken from mouse embryos at 11.5 days post-coitum, at which time NCC had reached the proximal colon. Cellular p75 and PGP9.5 expression was determined by double-labelling immunofluorescence. The leading edge of neural-crest migration was defined as the 10 most distal p75-labelled cells. The neuronal marker PGP9.5 labelled NCC as they migrated along the gut at day 11.5. At the leading edge of migration, over 95% of p75-positive cells also expressed PGP9.5, and all PGP9.5-positive cells were also labelled for p75. PGP9.5 is expressed by at least 95% of neural-crest-derived precursor cells at the leading edge of migration along the gut. Thus, it can be used as a robust marker for developing NCC in the gut.

Animals↗