Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce ...neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease.
Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals.
The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.
Abstract Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicine, which has been used to effectively manage stress and depression-related disorders in China. As the ...active component of curcuma longa, curcumin possesses many therapeutic properties; we have previously described its antidepressant activity in our earlier studies using the chronic unpredictable stress model of depression in rats. Recent studies show that stress-induced damage to hippocampal neurons may contribute to the phathophysiology of depression. The aim of this study was to investigate the effects of curcumin on hippocampal neurogenesis in chronically stressed rats. We used an unpredictable chronic stress paradigm (20 days) to determine whether chronic curcumin treatment with the effective doses for behavioral responses (5, 10 and 20 mg/kg, p.o.), could alleviate or reverse the effects of stress on adult hippocampal neurogenesis. Our results suggested that curcumin administration (10 and 20 mg/kg, p.o.) increased hippocampal neurogenesis in chronically stressed rats, similar to classic antidepressant imipramine treatment (10 mg/kg, i.p.). Our results further demonstrated that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. In addition, curcumin significantly prevented the stress-induced decrease in 5-HT1A mRNA and BDNF protein levels in the hippocampal subfields, two molecules involved in hippocampal neurogenesis. These results raise the possibility that increased cell proliferation and neuronal populations may be a mechanism by which curcumin treatment overcomes the stress-induced behavioral abnormalities and hippocampal neuronal damage. Moreover, curcumin treatment, via up-regulation of 5-HT1A receptors and BDNF, may reverse or protect hippocampal neurons from further damage in response to chronic stress, which may underlie the therapeutic actions of curcumin.
CASS registry : Long term surgical survival MYERS, W. O; BLACKSTONE, E. H; DAVIS, K ...
Journal of the American College of Cardiology,
02/1999, Letnik:
33, Številka:
2
Journal Article
We sequenced the envelope (E) genes of 59 DEN-2 isolates collected from ten Caribbean islands, six South American countries, and two Central American countries between 1981 and 2000, a period ...characterized by hyperendemicity and increased incidence of severe dengue. Fifty-two isolates belonged to “American/Asian” subtype IIIb, possessing a characteristic polar residue at envelope aa position 390 (N
n = 48 or S
n = 4) common to that group. Six isolates from Trinidad (1981), Honduras (1991 4), and El Salvador (1987) fell into the “Native American” subtype V (D at aa 390), and one from Honduras (1986) belonged to “Asian” subtype I. The data suggest that after its first isolation in the Caribbean in 1981, genotype IIIb spread throughout the Americas and effectively replaced subtype V throughout the Caribbean basin. The strain also evolved into several distinct lineages, based on substitutions in the E glycoprotein (amino acids 91 and 131), two of which were still in circulation in 2000. Interestingly, a molecular clock did not fit the data well, suggesting that other sources of rate variation, such as differential selection or differences in effective population sizes, may exist among lineages. Our results indicate the importance of large temporal- and geographical-scale phylogenetic studies in understanding disease dynamics, particularly where replacements between regions can occur.
Laparoscopic Roux-en-Y gastric bypass is an effective treatment for morbid obesity. However, little information is available on gastrointestinal (GI) symptomatology in this population. This study ...compares GI symptoms in morbidly obese patients to that of control subjects.
A previously validated, 19-point GI symptom questionnaire was administered prospectively to each patient seen for surgical consultation for morbid obesity. The symptoms were then grouped into 6 clusters as follows: (1) abdominal pain, (2) irritable bowel, (3) GERD, (4) reflux, (5) sleep disturbance, (6) dysphagia. The result of each cluster of symptoms expressed as mean +/- standard deviation of obese versus control is compared using student's t-test with significance p = 0.05.
Forty-three patients (40 female, 3 male) age 37.3 +/- 8.6 with BMI 47.8 +/- 4.9, and 36 healthy control subjects (23 female, 13 male), age 39.8 +/- 11.2, completed the questionnaire. Results of each cluster for morbid obese vs control subjects are expressed as mean +/- standard deviation: Abdominal pain 25.3 +/- 18.0 vs 12.1 +/- 11.4, p = 0.0002; irritable bowel 23.0 +/- 14.8 vs 15.6 +/- 13.3, p = 0.02; GERD 40.3 +/- 18.9 vs 22.3 +/- 16.1, p = 0.0001; reflux 29.9 +/- 19.0 vs 11.8 +/- 13.4, p = 0.0001; sleep disturbance 50.6 +/- 28.9 vs 32.9 +/- 26.8, p = 0.006; dysphagia 10.9 +/- 15.6 vs 7.2 +/- 10.6, p = NS.
Morbidly obese patients experience more intense GI symptoms than normal subjects, whereas dysphagia is equivalent to normal subjects. These data may be important in counseling patients and understanding that their complaints are legitimate. Follow-up in the postoperative period is needed to determine if these symptoms are improved with an operation.
To identify genes involved in vascular remodeling, we applied differential mRNA display analysis to the rat carotid artery balloon injury model. One polymerase chain reaction product showing ...increased expression at days 2 to 14 after vascular injury was nearly identical to the mouse alpha 1 chain of type VIII collagen, a heterotrimeric short-chain collagen of uncertain function expressed by a limited number of cell types. By Northern analysis, expression of both chains of the type VIII collagen heterotrimer increased: collagen alpha 1 (VIII) mRNA expression was almost 4-fold higher than control by 7 days after vascular injury, and collagen alpha 2 (VIII) mRNA expression reached a maximum of almost 6-fold above baseline by 3 days after injury. By immunohistochemical analysis, type VIII collagen expression increased in the media and neointima in a localized pattern consistent with the distribution of activated dedifferentiated vascular smooth muscle cells (VSMCs). Cultured VSMCs expressed higher levels of type VIII collagen in response to serum and growth factors, notably platelet-derived growth factor (PDGF)-BB. VSMCs adhered significantly less to type VIII collagen than to type I collagen substrata and showed greater PDGF-BB-stimulated migration (by 2.2-fold) on type VIII collagen than on type I collagen. We hypothesize that increased expression of type VIII collagen by VSMCs after arterial injury may contribute to vascular remodeling through the promotion of VSMC migration.
Although surgery is the treatment of choice for rectal cancer, local recurrence is common even after apparently curative resection. We aimed to assess the role of postoperative radiotherapy in ...reducing rates of local recurrence, and improving disease-free and overall survival in patients with mobile Dukes' stage B and C rectal cancers.
We carried out a prospective, randomised trial of surgery alone (n=235) versus surgery followed 4–6 weeks later by radiotherapy (n=234), of 40 Gy in 20 fractions of 2 Gy over 4 weeks. The 469 patients, from 46 hospitals in the UK and the Republic of Ireland, were randomised between 1984 and 1989, and followed up for a minimum of 5 years or to death.
284 patients died, 145 of 235 allocated surgery alone and 139 of 234 allocated postoperative radiotherapy. The hazard ratio for overall survival was 0·84 (95% CI 0·65–1·07, p=0·17). At 5 years' follow-up 79 patients who received surgery alone and 48 who received postoperative radiotherapy had had local recurrence (hazard ratio 0·54 0·38–0·77, p=0·001). The corresponding numbers with distant recurrence were 83 and 75 (hazard ratio 0·85 0·63–1·114, p=0·18). The hazard ratio for disease-free survival was 0·85 (0·65–1·08; p=0·18). Radiotherapy was generally well tolerated; assessment of late events showed serious late bowel complications to be rare and not significantly increased after radiotherapy, even when this followed anterior resection.
Our results have provided further evidence of the ability of postoperative radiotherapy to delay and prevent local recurrence of rectal cancer. Although the local recurrence rate in the control group is in keeping with other multi-centre trials of the mid to late 1980s, it is undoubtedly higher than would be regarded as acceptable now. The combination of larger trials required to provide definitive answers on the impact that postoperative radiotherapy will have on survival.
A multiparameter approach is proposed for the characterization of fatigue crack growth in metallic materials. The model assesses the combined effects of identifiable multiple variables that can ...contribute to fatigue crack growth. Mathematical expressions are presented for the determination of fatigue crack growth rates, da/dN, as functions of multiple variables, including stress intensity factor range, ΔK, stress ratio, R, crack closure stress intensity factor, Kcl , the maximum stress intensity factor Kmax , nominal specimen thickness, t, frequency, Ω, and temperature, T. A generalized empirical methodology is proposed for the estimation of fatigue crack growth rates as a function of these variables. The validity of the methodology is then verified by making appropriate comparisons between predicted and measured fatigue crack growth data obtained from experiments on Ti–6Al–4V. The effects of stress ratio and specimen thickness on fatigue crack growth rates are then rationalized by crack closure considerations. The multiparameter model is also shown to provide a good fit to experimental data obtained for HY‐80 steel, Inconel 718 polycrystal and Inconel 718 single crystal. Finally, the implications of the results are discussed for the prediction of fatigue crack growth and fatigue life.
Teratomas of the testis in post-pubertal patients are histologically diverse tumors that often coexist with other types of germ cell tumors. Using laser capture microdissection and loss of ...heterozygosity analysis, we investigated the clonality of mature teratoma and its relationship to other components of malignant mixed germ cell tumors to gain potential insight into the histogenetic relationship of teratoma with other germ cell tumor components. All 16 patients had mature teratoma as one component of their mixed germ cell tumors. The other histological subtypes included immature teratoma, seminoma, embryonal carcinoma, yolk sac tumor, and choriocarcinoma. Laser-assisted microdissection was performed on the formalin-fixed, paraffin-embedded tissue. Polymerase chain reaction was used to amplify genomic DNA at specific loci on chromosome 1p36.2 (D1S508), 2q22–32 (D2S156), 9p21–22 (D9S162), 11p13 (D11S903), 12q22–23 (D12S1051), and 18q21 (D18S46). Fourteen of 16 (88%) cases showed allelic loss in one or more components of the mixed germ cell tumors. Fourteen of 16 mature teratomas showed allelic loss in at least one of six microsatellite polymorphic markers analyzed. The frequency of allelic loss in mature teratoma was 50% (7 of 14) with D1S508, 33% (5 of 15) with D2S156, 58% (7 of 12) with D9S162, 43% (6 of 14) with D11S903, 20% (3 of 15) with D12S1051, and 33% (5 of 15) with D18S46. Completely concordant allelic loss patterns between mature teratoma and all of the other germ cell tumor components were seen in 10 of 14 tumors in which mature teratoma showed loss of heterozygosity. Our data support the common clonal origin of mature teratoma with other components of malignant mixed germ cell tumors of the testis.
Circulating erythropoietin (EPO) stimulates erythrocytosis, whereas organ-specific local EPO receptor (EPOR) expression has been linked to angiogenesis, tissue growth, and development. On the basis ...of the observation of concurrent enhancement of lung growth and erythrocyte production during exposure to chronic hypoxia, we hypothesized that a paracrine EPO system is involved in mediating lung growth. We analyzed EPOR protein expression in normal dog lung tissue during postnatal maturation and during compensatory lung growth after right pneumonectomy (PNX). Membrane-bound EPOR was significantly more abundant in the immature lung compared with mature lung and in the remaining lung 3 wk after PNX compared with matched sham controls. COOH-terminal cytosolic EPOR peptides, which were even more abundant than membrane-bound EPOR, were also upregulated in immature lung but differentially processed after PNX. Apoptosis was enhanced during both types of lung growth in direct relationship to cellular proliferation and EPOR expression. We conclude that both developmental and compensatory lung growth involve paracrine EPO signaling with parallel upregulation but differential processing of EPOR.
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