Vascular gene therapy: a reality of the 21st century

Current therapies for the treatment of atherosclerotic vascular disease are aimed at either disrupting or bypassing flow-limiting lesions. Preventative strategies are necessary to decrease the burden of disease but are limited by genetic predispositions to certain diseases and the body's innate response to injury. Gene therapy, defined as the purposeful therapeutic overexpression or attenuation of a gene product, has enormous potential benefits in vascular disease prevention and treatment strategies. This article reviews the scientific considerations involved in the development of gene therapy strategies and outlines some of the gene products that are currently being used. These interventional genetic approaches will be reviewed in the context of specific vascular disease processes, including atherosclerosis, restenosis, and thrombosis. Gene therapy will serve an enhancing and adjuvant role to evolving surgical therapies.     

Behavior, neurochemistry and histology after intranigral lipopolysaccharide injection

Inflammation and neuronal degeneration of the substantia nigra (SN) occur in Parkinson's disease (PD). We studied the effects of intranigral lipopolysaccharide (LPS) injection on adult Sprague-Dawley rats. Locomotor activity measurement, neurotransmitter determination and perfusion fixation for immunohistochemistry were done on the 7th day. Bilateral LPS injection increased locomotor activity 2- to 3-fold. In the SN, dopamine (DA) and serotonin (5-HT) decreased but the ratios dihydroxyphenylacetic acid (DOPAC)/DA, homovanillic acid (HVA)/DA and 5-hydroxyindole-acetic acid (5-HIAA)/5-HT increased. In the striatum, DA, DOPAC, HVA, 3-methoxytyramine and epinephrine decreased but HVA/DA and 5-HIAA/5HT ratios increased. Unilateral LPS decreased dopamineric neurons ipsilaterally but increased contralaterally. This study provides the first evidence of behavioral hyperactivity, epinephrine suppression and neuronal plasticity in the LPS model of PD.     

Second trimester maternal serum hCG level in an Asian population: normal reference values by ultrasound dating

OBJECTIVE: To establish normative data of maternal serum chorionic gonadotropin (hCG) during the second trimester in an Asian population. METHODS: We measured the maternal serum hCG levels in 17,955 normal singleton pregnancies between 15 and 21 weeks of gestation. The gestation age was estimated by measurement of fetal biparietal distance (BPD) in all cases. Median values of hCG at various gestational weeks were calculated and the values of hCG were converted to multiple of median (MoM). The incidences of low MoM value and high MoM value were also calculated. RESULTS: The mean and median values of hCG were 57,153 mIU/ml and 50,120 mIU/ml, respectively, at 15 weeks of gestation and then decreased to 30,898 mIU/ml and 26,226 mIU/ml, respectively, at 21 weeks. We found 8.6% and 9.4% of normal singleton pregnancies have hCG MoM values >2.0 MoM and <0.5 MoM, respectively. CONCLUSIONS: Our report provides a normal reference data of second trimester maternal hCG levels by ultrasound dating in an Asian population.     

Height and weight change across menarche of schoolgirls with early menarche

OBJECTIVE: To describe growth before and after menarche. DESIGN: Nine hundred five fourth grade school girls were identified as a closed cohort from the first semester of 1993 for the observational study of the onset of menarche and its predictive factors. SETTINGS: Eight elementary schools in Taipei City and Taipei County, Taiwan. MAIN OUTCOME MEASURES: Data were collected from self-administered questionnaires and school records. Height and weight were measured in September, January, February, and June, or only in September and February of each year. RESULTS: All subjects remained in the cohort until sixth grade, 410 of whom had their first menstruation before graduating from elementary school. Height, weight, and body mass index (calculated as weight in kilograms divided by the square of height in meters) at each time point were plotted against 2 time scales: chronological age and time from the onset of menarche. Growth velocity of height and weight across the onset of menarche was assessed with slope change using the mixed-effect model analysis. CONCLUSIONS: The results support the hypothesis that height velocity reaches a peak 1 year before menarche but height velocity stopped increasing within 1 year after menarche. The change in weight velocity reveals no obvious growth spurt at age of menarcheal onset.     

Effect of a lower-dose cetrorelix acetate protocol on in-vitro fertilization outcome

OBJECTIVE: To determine whether a low initial dosage of cetrorelix acetate could prevent a premature luteinizing hormone (LH) surge in women undergoing controlled ovarian stimulation. METHOD: Treatment with a recombinant follicle stimulating hormone was started on Day 3 of the menstrual cycle, and 0.125 mg of cetrorelix was injected daily from Day 5 of the ovarian stimulation until the diameter of the dominant follicle reached at least 16 mm. The dosage was then doubled and maintained at 0.250 mg/day until the day before the injection of human chorionic gonadotropin. RESULT: There was a significant decrease in serum LH concentration 1 day after doubling the cetrorelix dosage, and the LH concentration remained low during the follicular phase. Clinical pregnancy occurred in 18 women (42.8%), with 2 intrauterine fetal deaths before the 12th week. CONCLUSION: Increasing the cetrorelix dosage from 0.125 to 0.250 mg/day when the follicular size is appropriate can prevent a premature LH surge.     

Prevention of pulmonary morbidity for patients with neuromuscular disease

STUDY OBJECTIVE: To evaluate the effects of a respiratory muscle aid protocol on hospitalization rates for respiratory complications of neuromuscular disease. DESIGN: A retrospective cohort study. METHODS: A home protocol was developed in which oxyhemoglobin desaturation was prevented or reversed by the use of noninvasive intermittent positive-pressure ventilation and manually and mechanically assisted coughing as needed. The patients who had more than one episode of respiratory failure before having access to the protocol were considered to have had preprotocol periods (group 1). Other patients were given access to the protocol when their assisted peak cough flows decreased to < 270 L/min before any episodes of respiratory distress (group 2). The number of hospitalizations and days hospitalized were compared longitudinally for preprotocol and protocol access periods (group 1). In addition, avoided hospitalizations were identified as "episodes" of need for continuous ventilatory support and desaturations reversed by assisted coughing that were managed at home. Data were segregated by access to protocol and by extent of baseline ventilator use. RESULTS: Of the 47 group 1 patients with preprotocol periods who have subsequently had episodes, 10 had episodes before requiring ongoing ventilator use. They had 1.06 +/- 0.84 preprotocol hospitalizations per year per patient and 20.76 +/- 36.01 hospitalization days per year per patient over 3.42 +/- 3.36 years per patient vs 0.03 +/- 0.11 hospitalizations per year per patient and 0.06 +/- 0.20 hospitalization days per year per patient with protocol use over 1.94 +/- 0.74 years per patient. Of these 47 group 1 patients, 33 eventually required part-time ventilatory aid and, using the protocol as needed, had 0.08 +/- 0.17 hospitalizations per year per patient and 1.43 +/- 3.71 hospitalization days per year per patient over 3.91 +/- 3.50 years per patient, as opposed to 1.40 +/- 1.96 hospitalizations per year per patient and 20.14 +/- 41.15 hospitalization days per year per patient preprotocol and preventilator use over 5.89 +/- 6.89 years per patient. Twelve patients in group 1 eventually required continuous noninvasive ventilation and, using the protocol as needed, had 0.07 +/- 0.14 hospitalizations per year per patient and 0.39 +/- 0.73 hospitalization days per year per patient over 5.35 +/- 5.10 years per patient by comparison with 0.97 +/- 0.74 hospitalizations per year per patient and 10.39 +/- 8.66 hospitalization days per year per patient over 2.18 +/- 1.91 years per patient preprotocol and preventilator use. For the 94 patients overall when having access to the protocol, 1.02 +/- 0.99 hospitalizations per year per patient were avoided by 14 patients before requiring ongoing ventilator use over 4.82 +/- 1.61 years, 0.99 +/- 1.12 hospitalizations per year per patient were avoided by 73 part-time ventilator users over 3.21 +/- 3.15 years, and 0.80 +/- 0.85 hospitalizations per year per patient were avoided by 31 full-time ventilator users over 4.78 +/- 4.88 years. All preprotocol and protocol rate comparisons were statistically significant at p < 0.004. CONCLUSION: Patients have significantly fewer hospitalizations per year and days per year when using the protocol as needed than without the protocol. The use of inspiratory and expiratory aids can significantly decrease hospitalization rates for respiratory complications of neuromuscular disease.     

Evolutionary-based grouping of haplotypes in association analysis

Haplotypes incorporate more information about the underlying polymorphisms than do genotypes for individual SNPs, and are considered as a more informative format of data in association analysis. To model haplotypes requires high degrees of freedom, which could decrease power and limit a model's capacity to incorporate other complex effects, such as gene-gene interactions. Even within haplotype blocks, high degrees of freedom are still a concern unless one chooses to discard rare haplotypes. To increase the efficiency and power of haplotype analysis, we adapt the evolutionary concepts of cladistic analyses and propose a grouping algorithm to cluster rare haplotypes to the corresponding ancestral haplotypes. The algorithm determines the cluster bases by preserving common haplotypes using a criterion built on the Shannon information content. Each haplotype is then assigned to its appropriate clusters probabilistically according to the cladistic relationship. Through this algorithm, we perform association analysis based on groups of haplotypes. Simulation results indicate power increases for performing tests on the haplotype clusters when compared to tests using original haplotypes or the truncated haplotype distribution.     

Synthesis and anticancer evaluation of certain 4-anilinofuro[2,3-b]quinoline and 4-anilinofuro[3,2-c]quinoline derivatives

Certain linear 4-anilinofuro[2,3-b]quinoline and angular 4-anilinofuro[3,2-c]quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCI's 60 cancer cell lines. For the linear 4-anilinofuro[2,3-b]quinoline derivatives, 1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (5a) is the most cytotoxic with a mean GI50 value of 0.025 microM. Substitution at either furo[2,3-b]quinoline ring (2a, 2b, and 5b) or 4-anilino moiety (3-7) led to a decrease of cytotoxicity. For the angular 4-anilinofuro[3,2-c]quinoline derivatives, (E)-1-[3-(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone oxime (14a) exhibited potent inhibitory activities on UO-31, UACC-257, and UACC-62, with GI50 values of 0.03,<0.01, and<0.01 microM respectively. The same cytotoxicity profile was observed for its methyl counterpart, 14b, in which the GI50 values against UO-31, UACC-257, and UACC-62 was<0.01, 0.04 and<0.01 microM respectively. These results deserve full attention especially because 14a and 14b are relatively non-cytotoxic with the mean GI50 value of 7.73 and 8.91 microM respectively.