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81.
Repeated injections of cocaine and morphine in laboratory rats cause a variety of molecular neuroadaptations in the cAMP signaling pathway in nucleus accumbens and ventral tegmental area. Here we report similar neuroadaptations in postmortem tissue from the brains of human smokers and former smokers. Activity levels of two major components of cAMP signaling, cAMP-dependent protein kinase A (PKA) and adenylate cyclase, were abnormally elevated in nucleus accumbens of smokers and in ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of the catalytic subunit of PKA were correspondingly higher in the ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of other candidate neuroadaptations, including glutamate receptor subunits, tyrosine hydroxylase, and other protein kinases, were within normal range. These findings extend our understanding of addiction-related neuroadaptations of cAMP signaling to tobacco smoking in human subjects and suggest that smoking-induced brain neuroadaptations can persist for significant periods in former smokers. 相似文献
82.
83.
Huang MT; Lou YR; Xie JG; Ma W; Lu YP; Yen P; Zhu BT; Newmark H; Ho CT 《Carcinogenesis》1998,19(9):1697-1700
Female Sencar mice (6 weeks old) were administered 1 mg of 7,12-
dimethylbenz[a]anthracene (DMBA) by oral gavage once a week for 5 weeks. At
20 weeks after the first dose of DMBA, 68% of mice developed mammary tumors
(the average 1.08 tumors per mouse) and 45% had lymphomas/leukemias.
Feeding 1% dibenzoylmethane (DBM) in AIN 76A diet, starting at 2 weeks
before the first dose of DMBA and continuing until the end of the
experiment, inhibited both the multiplicity and incidence of DMBA-induced
mammary tumor by 97%. The incidence of lymphomas/leukemias was completely
inhibited by 1% DBM diet. In contrast, feeding 2% curcumin diet had little
or no effect on the incidence of mammary tumors, and the incidence of
lymphomas/leukemias was reduced by 53%.
相似文献
84.
Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice 总被引:4,自引:3,他引:4
Lamb BT; Call LM; Slunt HH; Bardel KA; Lawler AM; Eckman CB; Younkin SG; Holtz G; Wagner SL; Price DL; Sisodia SS; Gearhart JD 《Human molecular genetics》1997,6(9):1535-1541
Missense mutations in the beta-amyloid precursor protein gene (APP) co-
segregate with a small subset of autosomal dominant familial Alzheimer's
disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid
(A beta) peptide and neurodegeneration are principal neuropathological
hallmarks. To accurately examine the effect of missense mutations on APP
metabolism and A beta production in vivo, we have introduced yeast
artificial chromosomes (YACs) containing the entire approximately 400 kbp
human APP gene encoding APP harboring either the asparagine for lysine and
leucine for methionine FAD substitution at codons 670 and 671
(APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717
(APP(V7171)) or a combination of both substitutions into transgenic mice.
We demonstrate that, relative to YAC transgenic mice expressing wild-type
APP, high levels of A beta peptides are detected in the brains of YAC
transgenic mice expressing human APP(K670N/M671L) that is associated with a
concomitant diminution in the levels of apha-secretase-generated soluble
APP derivatives. Moreover, the levels of longer A beta peptides (species
terminating at amino acids 42/43) are elevated in YAC transgenic mice
expressing human APP(V7171). These mice should prove valuable for detailed
analysis of the in vivo effects of the APP FAD mutations in a variety of
tissues and throughout aging and for testing therapeutic agents that
specifically alter APP metabolism and A beta production.
相似文献
85.
86.
AJIW Bergman IET van den Berg W Brink BT Poll-The JK Ploos van Amstel R Berger 《Human mutation》1998,12(1):19-26
Hereditary tyrosinemia type 1 (HT1) is a rare metabolic disease caused by a deficient activity of the enzyme fumarylacetoacetase (FAH). To investigate the molecular heterogeneity of tyrosinemia, the geographic distribution and the genotype–phenotype relationship, we have analyzed the FAH genotype of 25 HT1 patients. Mutation screening was performed by PCR amplification of exons 1-14 of the FAH gene, followed by SSCP analysis and direct sequencing of the amplified exons. Fourteen different mutations were found, of which seven were novel, viz. Three missense mutations (G158D, P261L, F405H), a deletion of three nucleotides causing a deletion of serine (DEL366S) and three splice site mutations: IVS2+1(g-t), IVS6-1(g-c), IVS8-1(g-c). The splice site mutations IVS6-1(g-t) and IVS12+5(g-a) were frequently found in countries around the Mediterranean and northerwestern Europe, respectively. No clear correlation between the genotype and the three major HT1 subtypes could be established. Hum Mutat 12:19–26, 1998. © 1998 Wiley-Liss, Inc. 相似文献
87.
Y Liu D Kim BT Himes SY Chow T Schallert M Murray A Tessler I Fischer 《The Journal of neuroscience》1999,19(11):4370-4387
Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been attributed to scar tissue and inhibitory molecules at the injury site that block the regenerating axons, a lack of trophic support for the axotomized neurons, and intrinsic neuronal changes that follow axotomy, including cell atrophy and death. We studied whether transplants of fibroblasts genetically engineered to produce brain-derived neurotrophic factor (BDNF) would promote rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were modified by retroviral-mediated transfer of a DNA construct encoding the human BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and neomycin resistance genes. The modified fibroblasts produce biologically active BDNF in vitro. These cells were grafted into a partial cervical hemisection cavity that completely interrupted one RST. One and two months after lesion and transplantation, RST regeneration was demonstrated with retrograde and anterograde tracing techniques. Retrograde tracing with fluorogold showed that approximately 7% of RST neurons regenerated axons at least three to four segments caudal to the transplants. Anterograde tracing with biotinylated dextran amine revealed that the RST axons regenerated through and around the transplants, grew for long distances within white matter caudal to the transplant, and terminated in spinal cord gray matter regions that are the normal targets of RST axons. Transplants of unmodified primary fibroblasts or Gelfoam alone did not elicit regeneration. Behavioral tests demonstrated that recipients of BDNF-producing fibroblasts showed significant recovery of forelimb usage, which was abolished by a second lesion that transected the regenerated axons. 相似文献
88.
M C Hammond S S Fitts G H Kraft P B Nutter M J Trotter L M Robinson 《Archives of physical medicine and rehabilitation》1988,69(5):348-351
Co-contraction of antagonist muscles is a recognized clinical phenomenon in patients surviving a cerebrovascular accident. Yet, discrepancies persist in the literature as to whether or not antagonist electromyographic activity is increased in hemiparesis. We have developed a technique to obtain simultaneous counts of motor unit activity in a wrist flexor and extensor muscle using monopolar needle electromyography. Stable stroke patients and age/sex matched control subjects were tested during maximal voluntary isometric wrist flexion and extension. Fewer agonist events (p less than 0.05) and more antagonist events (p less than 0.10) were counted in paretic than in control muscles. A co-contraction ratio of antagonist activity to total (agonist and antagonist) activity was much greater for patients than controls (p less than 0.01). We conclude that both agonist recruitment and antagonist inhibition are impaired in the hemiparetic arm. 相似文献
89.
The purpose of this study was to assess the referral patterns and the use of unenhanced renal tract CT (CT KUB) for investigating patients presenting with clinically suspected renal colic. We retrospectively reviewed 500 consecutive CT KUB studies requested for suspected renal colic carried out at a single institution between December 2006 and July 2007. Follow‐up radiology reports and discharge summaries on the hospital clinical Intranet were also reviewed. Studies were analysed for characteristics including patient demographics, referring clinical team, time of referral, final diagnosis and requirement for further imaging. The majority of requests were from Emergency (ED) or Urology Departments (49%, 245 out of 500, and 37%, 186 out of 500, respectively). The positive rate for urolithiasis was 67% (337 out of 500), the negative rate was 25% (123 out of 500), and 8% (40 out of 500) of patients had alternative significant findings. Female patients were more likely to have a negative study than male patients (35 versus 20%, P < 0.0001) and more likely to have alternative significant pathology (12 versus 6%, P < 0.0001). Patients referred by specialities other than Urology and ED were more likely to be female and have a negative or alternative finding (P < 0.0001). CT KUB is a widely used first method of investigation for patients with suspected renal colic with a high positive predictive value allowing rapid diagnosis and intervention. However, given the high rate of negative or alternative findings on CT KUB in young women, especially those referred by specialities other than ED or Urology, ultrasound should be considered as an alternative imaging method to minimise unnecessary radiation exposure. 相似文献
90.
Vitamin B6 metabolism has been investigated in several highly and well-differentiated Morris hepatomas. Comparisons have been made with two poorly differentiated Morris hepatomas, with host livers obtained from tumor-bearing animals, and with fetal, neonatal, and adult rat liver. The pyridoxal phosphate content and the activities of pyridoxine kinase and pyridoxine phosphate oxidase of all Morris hepatomas examined were significantly less than those in adult host or control livers and generally fell in the range determined for fetal and neonatal liver. A similar pattern was not evident for the activity of pyridoxine phosphate phosphatase. Relative to control and host livers, the activity in hepatomas of the pyridoxal phosphate (PLP)-dependent enzyme, ornithine decarboxylase, was generally elevated. Dexamethasone, at a dose which caused an elevation in the activity of PLP-dependent tumor tyrosine aminotransferase, had no effect on PLP metabolism. The data indicate that tumor progression in the Morris hepatoma spectrum in relation to vitamin b6 metabolism falls into an onco-developmental pattern characterized by a diminished amount of tissue PLP and a diminished capability to metabolize precursor vitamer forms to PLP. 相似文献