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PubMed1999

Persistent postnatal transgene expression in both muscle and liver after fetal injection of recombinant adenovirus.

BACKGROUND/PURPOSE: Immune responses to both vector and transgene antigens have limited the efficacy of postnatal gene therapy. We hypothesize that the fetal period may offer immunologic and developmental advantages for successful gene therapy. In this study we examined the efficacy, persistence, and immunologic effects of recombinant adenovirus after intramuscular delivery into fetal mice. METHODS: E1-deleted adenovirus (AdCMVlacZ) containing the beta-galactosidase marker gene was used for injection. Fetal Balb/c mice (14 to 15 days' gestation) were injected with AdCMVlacZ in 10-microL volume in either the shoulder or hindlimb musculature. Animals were killed at 18 to 20 days' gestation and up to 4 months postnatally for analysis of transgene expression and adenoviral genome persistence. RESULTS: Fetuses were injected with doses of AdCMVlacZ from 1 x 10(8) to 2 x 10(10) viral particles (n = 80). Optimal survival rate was 83% at 18 to 20 days' gestation and 55% at 4 weeks of age using a dose of 1 x 10(9) particles. Expression of beta-galactosidasae at 18 to 20 days localized to multiple muscle groups surrounding the site of injection, as well as bone marrow stroma, liver, lung, and dorsal root ganglia. Persistent muscle and liver transgene expression was observed for as long as 16 and 8 weeks, respectively, after injection. The pattern of liver expression was confined to discrete foci of hepatocytes, which appeared to increase in size in older animals. No histological evidence of muscle or liver inflammation was observed at any time after injection. No neutralizing antibodies were observed postnatally. CONCLUSIONS: Our results confirm that gene therapy in the fetus may be advantageous. Distribution of vector in the fetus at the site of injection is clearly broader than in the adult setting. Furthermore, the absence of immune response and persistence of transgene expression suggests that fetal exposure to foreign transgene and vector antigens may induce tolerance. Although we have not proven genomic integration, the histological appearance of transgene expression in the liver supports this conclusion. By understanding the mechanisms that underlie persistent transgene expression, fetal gene therapy may become a feasible strategy for the treatment of fatal genetic diseases.

Adenoviridae↗
PubMed1998

Normalized functioning in youths with persistent attention-deficit/hyperactivity disorder.

OBJECTIVE: The goal of this study was to examine normalization of functioning among youths with persistent attention-deficit hyperactivity/disorder (ADHD) symptoms. RESEARCH DESIGN: Subjects were 85 referred boys with persistent ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) who were followed up prospectively into mid adolescence and 68 boys without ADHD. These subjects were assessed at baseline and follow-up visits by using measures from 3 domains of functioning: school, social, and emotional. For each of these domains, we defined boys with ADHD as having normalized functioning if they attained scores above the 5th percentile of scores in the non-ADHD group. RESULTS: Twenty percent of boys with ADHD were functioning poorly in all 3 domains, 20% were functioning well in all 3 domains, and 60% had intermediate outcomes. Increased exposure to maternal psychopathology, larger family size, DSM-III-R psychiatric comorbidity, and symptoms of impulsivity were negatively associated with normalization of functioning among children with persistent ADHD. CONCLUSION: Our results show that children with ADHD have a variable emotional, educational, and social adjustment despite syndromatic persistence. This suggests that normalization of functioning and syndromatic persistence of ADHD may be partially independent.

Adolescent↗
PubMed1998

Persistence of developmental dyscalculia: what counts? Results from a 3-year prospective follow-up study.

OBJECTIVE: To study the natural history of developmental dyscalculia (DC), a specific learning disability affecting approximately 5% of the normal school age population and to identify factors that contribute to persistence. STUDY DESIGN: Of a cohort of 3029 fourth-grade students, 185 children were classified as having DC; 140 participated in phase 1 in which they underwent IQ testing; arithmetic, reading, and writing evaluations; and an assessment for attention-deficit/hyperactivity disorder over a 3-year period. Three years later (phase 2), 88% of the children (123 of 140) were retested. RESULTS: The arithmetic scores of 95% of the 123 children with DC fell within the lowest quartile for their class. At phase 2, 47% (57 of 123) of the children were reclassified as having persistent DC, scoring in the lowest 5% for their age group (13 to 14 years old). Factors significantly associated with persistence of DC in a multivariate model were severity of the arithmetic disorder and arithmetic problems in siblings of the probands. Factors that were not associated with persistence included socioeconomic status, gender, the presence of another learning disability, and educational interventions. CONCLUSIONS: The outcome of DC is similar to that of other learning disabilities, with a persisting course in almost half of affected children; the remainder continue to perform poorly in arithmetic. The ultimate outcome of children with dyscalculia and the effect on education, employment, and psychologic well-being have yet to be determined.

Adolescent↗
PubMed2001

Estrogen replacement therapy: determinants of persistence with treatment.

OBJECTIVE: To evaluate the persistence rate for estrogen therapy and to identify its determinants. METHODS: From the Quebec health insurance database we chose a cohort of 4527 women 35 years and older who received social assistance and were new users of estrogen between January 1989 and December 1997. Incident use was defined by the absence of any dispensed prescription of estrogen in the 3 years before the index date (date of first dispensed prescription). We estimated the cumulative persistence rate of treatment by Kaplan-Meier failure time analysis and identified its determinants with the Cox proportional hazards model. RESULTS: From the initial cohort, 3395 women (75%) renewed their first dispensed prescription and 905 (20%) continued treatment after 4 years. The determinants measured at the index date and significantly associated with a better persistence rate (relative risk [RR]) were younger than 60 years (RR 1.15, 95% confidence interval [CI] 1.01, 1.30), low dosage (RR 1.49, 95% CI 1.32, 1.70), continuous progestin combination (RR 1.40, 95% CI 1.27, 1.54), and a gynecologist as the first prescribing physician (RR 1.15, 95% CI 1.03, 1.21). Also, coronary heart disease or at least one risk factor for it in the year before the index date was associated with a better persistence rate for estrogen replacement therapy (RR 1.15, 95% CI 1.05, 1.22). CONCLUSIONS: The persistence rate for estrogen therapy is poor, implying that few women take it long enough to benefit from it.

Adult↗
PubMed2003

Persistent fetal occiput posterior position: obstetric outcomes.

OBJECTIVE: To evaluate the obstetric outcomes associated with persistent occiput posterior position of the fetal head in term laboring patients. METHODS: We performed a cohort study of 6434 consecutive, term, vertex, laboring nulliparous and multiparous patients, comparing those who delivered infants in the occiput posterior position with those who delivered in the occiput anterior position. We examined maternal demographics, labor and delivery characteristics, and maternal and neonatal outcomes. RESULTS: The prevalence of persistent occiput posterior position at delivery was 5.5% overall, 7.2% in nulliparas, and 4.0% in multiparas (P <.001). Persistent occiput posterior position was associated with shorter maternal stature and prior cesarean delivery. During labor and delivery, the occiput posterior position was associated with prolonged first and second stages of labor, oxytocin augmentation, use of epidural analgesia, chorioamnionitis, assisted vaginal delivery, third and fourth degree perineal lacerations, cesarean delivery, excessive blood loss, and postpartum infection. Newborns had lower 1-minute Apgar scores, but showed no differences in 5-minute Apgar scores, gestational age, or birth weight. CONCLUSION: Persistent occiput posterior position is associated with a higher rate of complications during labor and delivery. In our population, the chances that a laboring woman with persistent occiput posterior position will have a spontaneous vaginal delivery are only 26% for nulliparas and 57% for multiparas.

Apgar Score↗
PubMed1997

Methotrexate prophylaxis for persistent ectopic pregnancy after conservative treatment by salpingostomy.

OBJECTIVE: To investigate whether the incidence of persistent ectopic pregnancy after linear salpingostomy can be reduced by prophylactic administration of a single dose of methotrexate postoperatively. METHODS: Women who underwent linear salpingostomy for treatment of unruptured ectopic pregnancy and who agreed to participate in the study (n = 129) were randomly assigned to the prophylaxis or control group. Women with anemia, renal insufficiency, or liver disease were excluded. In the prophylaxis group, patients received a single dose of methotrexate, 1 mg/kg intramuscularly, within 24 hours postoperatively. No treatment was used in the control group. Both groups were followed with serial serum beta-hCG titers; titers were measured on the seventh postoperative day, then every 72 hours until levels were lower than 15 mIU/mL. A blood count and chemistry panel were also obtained on postoperative day 7, and any side effects related to methotrexate were noted. Persistent ectopic pregnancy was defined as a rise in the serum beta-hCG level or a decline of less than 20% between two consecutive measurements taken 3 days apart. RESULTS: A total of 116 women completed the postoperative follow-up: 54 in the prophylaxis group and 62 in the control group. Ten women had persistent ectopic pregnancy, one in the prophylaxis group (1.9%) and nine among the controls (14.5%); this difference was statistically significant (P < .05). The relative risk of developing persistent ectopic pregnancy after prophylactic methotrexate was 0.13 (95% confidence interval 0.02, 0.97). Three women (5.5%) reported mild side effects after methotrexate, but these resolved spontaneously. CONCLUSION: The incidence of persistent ectopic pregnancy was significantly reduced after a single prophylactic dose of systemic methotrexate administered postoperatively. This regimen is safe and can be used to decrease the extent of postoperative monitoring after conservative treatment of unruptured ectopic pregnancy.

Adult↗
PubMed1995

Persistent or recurrent hyperparathyroidism in patients with double adenomas.

BACKGROUND: Are double parathyroid adenomas a discrete clinical entity or are all hyperplastic parathyroid glands of varying size? This investigation was done to determine whether patients with persistent or recurrent hyperparathyroidism and double adenomas (DA) differ in clinical profile or in response to treatment from patients with hyperplasia. METHODS: From 1982 to 1993, 37 unselected patients with persistent (11) or recurrent hyperparathyroidism (26) were treated. Twenty-one had DA and 16 had hyperplasia. DAs were defined as two abnormal and two normal parathyroid glands. RESULTS: Patients with persistent or recurrent hyperparathyroidism caused by DA were older and had more muscle weakness, neuropsychiatric disorders, constipation, and weight loss (p < 0.001) than patients with persistent or recurrent hyperparathyroidism caused by hyperplasia. Nephrolithiasis was more common in patients with recurrent hyperparathyroidism caused by hyperplasia than in patients with recurrent hyperparathyroidism caused by DA (p < 0.001). Serum Ca2+ levels before operation were similar in these groups with variable parathyroid hormone levels. No recurrences occurred in either group (DA [mean, 6 yr]; hyperplasia [mean, 5 yr]). Postoperative levels of serum Ca2+ and parathyroid hormone were normal in both groups. CONCLUSIONS: Patients with persistent or recurrent hyperparathyroidism caused by DA are older, have different clinical manifestations, and are cured by resection of the second adenoma. These findings support the concept that DA and hyperplasia are distinct entities.

Adenoma↗
PubMed2003

A comparison of three different stochastic population models with regard to persistence time.

Results are summarized from the literature on three commonly used stochastic population models with regard to persistence time. In addition, several new results are introduced to clearly illustrate similarities between the models. Specifically, the relations between the mean persistence time and higher-order moments for discrete-time Markov chain models, continuous-time Markov chain models, and stochastic differential equation models are compared for populations experiencing demographic variability. Similarities between the models are demonstrated analytically, and computational results are provided to show that estimated persistence times for the three stochastic models are generally in good agreement when the models are consistently formulated. As an example, the three stochastic models are applied to a population satisfying logistic growth. Logistic growth is interesting as different birth and death rates can yield the same logistic differential equation. However, the persistence behavior of the population is strongly dependent on the explicit forms for the birth and death rates. Computational results demonstrate how dramatically the mean persistence time can vary for different populations that experience the same logistic growth.

Animals↗
PubMed1999

Spatio-temporal contrast sensitivity, coherent motion, and visible persistence in developmental dyslexia.

Three experiments measured spatio-temporal contrast sensitivity, coherent motion, and visible persistence in a single group of children with developmental dyslexia and a matched control group. The findings were consistent with a transient channel disorder in the dyslexic group which showed a reduction in contrast sensitivity at low spatial frequencies, a significant reduction in sensitivity for coherent motion, and a significantly longer duration of visible persistence. The results were also examined by classifying the dyslexic group into dyseidetic, dysphonetic, and mixed (dysphoneidetic) subgroups. There were no differences between the control and dyseidetic groups in contrast sensitivity, in coherent motion and in visible persistence. In comparison to the control group, the mixed (dysphoneidetic) dyslexic subgroup was found to have a significant reduction in contrast sensitivity at low spatial frequencies, a significant reduction in sensitivity for coherent motion, and a significantly longer duration of visible persistence. In comparison to the control group, the dysphonetic group only showed a reduction in contrast sensitivity at low spatial frequencies. Comparisons between the dyseidetic, dysphonetic and mixed dyslexic subgroups showed that there were no substantive differences in contrast sensitivity, coherent motion, and visible persistence. The results support the proposal and findings by Borsting et al. (Borsting E, Ridder WH, Dudeck K, Kelley C, Matsui L, Motoyama J. Vis Res 1996;36:1047-1053) that a transient channel disorder may only be present in a dysphoneidetic dyslexic subgroup. Psychometric assessment revealed that all the children with dyslexia appear to have a concurrent disorder in phonological coding, temporal order processing, and short-term memory.

Adolescent↗
PubMedDate not supplied

QSAR approach to POPs screening for atmospheric persistence.

The environmental behaviour of a persistent organic pollutant (POP) is mainly controlled by its persistence, its tendency to undergo long-range transport (LRT) and its physicochemical properties. Atmospheric half-life is one of the criteria commonly used to study air persistence and LRT potential. For the 12 UNEP POPs and another 48 possible POPs, the mean and maximum half-life estimations for degradation in air are modelled using different molecular structure descriptors (atom and fragment counts, topological and WHIM descriptors), selected by Genetic Algorithm, in QSAR regression models. Both values are modelled to obtain an average estimate and a precautionary value for ranking and screening purposes. The models, validated for their predictivity, could be applied to predict unavailable data. Principal component analysis (PCA) was then used to explore the half-life data in addition to the physicochemical properties that are most relevant to atmospheric mobility; the aim has been to screen and rank POPs with regard to their tendency towards atmospheric persistence and mobility, and to obtain a persistence index in air and an LRT index. These indexes were also modelled by molecular descriptors, thus allowing a preliminary screening of new compounds.

Air Movements↗
PubMed2002

Protection against persistence of hepatitis C.

BACKGROUND: Neither previous hepatitis C virus (HCV) infection nor vaccination with HCV-derived antigens protects against reinfection. However, HCV infection and vaccination in chimpanzees has been shown to reduce the magnitude and duration of viraemia with re-challenge. We aimed to establish whether similar immunity could be achieved in man. METHODS: From a study of injecting drug users, we identified 164 people who had no evidence of previous HCV infection and 98 individuals who had been previously, but were not currently, infected with HCV. We compared the incidence and persistence of HCV viraemia in these two groups over four consecutive 6-month periods. FINDINGS: Of participants without previous infection, the incidence of HCV infection was 21% (35/164). By contrast, people previously infected were half as likely to develop new viraemia (12% [12/98]), even after accounting for risk behaviour (hazard ratio, 0.45; 95% CI 0.23-0.88). Furthermore, in HIV-1-negative people, those previously infected were 12 times less likely than people infected for the first time to develop persistent infection (odds ratio 0.05, 95% CI 0.01-0.30), and median peak HCV RNA concentration was two logs lower. HCV persisted in six of six HIV-1-positive people, even in one man who had previously cleared HCV infection when he was HIV-1 negative. INTERPRETATION: There is an alarming frequency of HCV infection and persistence among injecting drug users. Our data suggest that immunity against viral persistence can be acquired, and that vaccines should be tested to reduce the burden of HCV-related liver disease.

Adult↗
PubMed1994

Epstein-Barr virus persistence and virus-associated tumours.

The Epstein-Barr virus (EBV) has been implicated in the aetiology of many human lymphoid and epithelial malignancies. Although EBV is B lymphotropic in vitro, it has been hypothesised that oropharyngeal epithelium is important in primary EBV infection, replication, and persistence in vivo, and that infection of B lymphocytes is secondary. This hypothesis has been challenged by several recent studies. On the basis of current evidence, we propose that primary EBV infection and virus persistence are mediated through B lymphocytes, and that latent infection of epithelial cells is accidental and irrelevant to virus persistence, although important in the development of certain carcinomas. To what extent T cells are involved in EBV persistence remains uncertain. Clarification of the possible part played by EBV in the development of virus-associated tumours requires a better understanding of the mode of EBV persistence and the identification of the stage in the carcinogenic process at which EBV infection occurs.

B-Lymphocytes↗
PubMed1992

Atypical healing of cytomegalovirus retinitis. Significance of persistent border opacification.

PURPOSE: To analyze a phenomenon seen in patients with acquired immune deficiency syndrome (AIDS) with cytomegalovirus (CMV) retinitis undergoing systemic antiviral treatment: a persistent white border opacification on the edge of healed CMV retinitis. PATIENTS AND METHODS: The authors prospectively evaluated a population of 137 patients with AIDS and CMV retinitis during a 44-month period. Eleven patients (12 eyes) who were undergoing maintenance antiviral treatment were identified with an atypical healing response--the persistence of a white flat border opacification that did not advance for many weeks to months. Patient records and photographs were reviewed. Results of one autopsy were analyzed with histopathology and special stains. RESULTS: The persistent white edge maintained (without advancement or smoldering) for an average of 11.6 weeks (range, 4 to 41 weeks). This border opacification was not affected by reinduction treatment in the six patients to whom reinduction was given. Results from histopathologic examination of one patient with a persistent white border are presented: these results show that dead cytomegalic cells formed stable structures within the retina, causing white opacification that could be confused with active lesions. Immunoperoxidase stains identified CMV antigens. CONCLUSION: This persistent white border opacification, which does not advance or smolder, represents an important clinical entity that should be recognized during antiviral treatment for CMV retinitis. It can often be observed. If it is not recognized as a stable configuration, patients may undergo unnecessary reinductions with potentially toxic doses of antiviral medications.

AIDS-Related Opportunistic Infections↗
PubMed2001

Emergence and persistence of late life depression: a 3-year follow-up of the Longitudinal Aging Study Amsterdam.

BACKGROUND: The present study was designed to assess onset and persistence of late-life depression, systematically comparing the factors associated with prevalence, onset and prognosis. METHODS: The data were derived from a large (n=2200), random, age and sex stratified sample of the elderly (55-85 years) in The Netherlands. Using a 3-year, prospective longitudinal design, both the onset and the persistence of depression were assessed. Depression was measured using the Center for Epidemiologic Studies Depression Scale. Risk factors associated with prevalence, onset and persistence were compared using both bivariate and multivariate analyses. RESULTS: In those not depressed at index assessment, the onset of depression was 9.7%. Among those depressed at baseline, persistence occurred in 50.4%. Risk factors predicting onset were almost identical to those associated with prevalence. Persistence was predicted by very few factors (external locus of control and chronic physical illness). CONCLUSIONS: The data suggest that cross-sectional studies are biased due to their overrepresenting chronic depressive episodes. However, the risk factors derived from cross-sectional studies do seem to adequately reflect factors associated with onset. The prognosis is not adequately predicted by variables usually included in epidemiological studies of late life depression. It is speculated that including more biological correlates of depression and data concerning positive life-changes may improve our understanding of the prognosis of late life depression.

Age of Onset↗
PubMed2002

Protection against tetanus toxin after intragastric administration of two recombinant lactic acid bacteria: impact of strain viability and in vivo persistence.

Non-pathogenic lactic acid bacteria (LAB) are attractive as live carriers to deliver protective antigens to the mucosal immune system. Both persisting and non-persisting strains of lactic acid bacteria have been evaluated and seem to work equally well by the systemic and nasal routes of administration. However, it is not known if persistence and viability of the strain play a critical role when immunizing by the oral route. To address this question, recombinant LAB strains, able to persist (Lactobacillus plantarum NCIMB8826/pMEC127) or not (Lactococcus lactis MG1363/pMEC46) in the gastro-intestinal tract of mice and producing equivalent amounts of the tetanus toxin fragment C (TTFC) were compared to each other. A very strong ELISA TTFC-specific and protective humoral response was elicited by either live or UV-inactivated recombinant Lb. plantarum strains. In a similar protocol, recombinant Lc. lactis seemed to be somewhat less efficient than the former host. It is thus tempting to propose that the difference in the capacity of the bacterial vector to persist in the gastro-intestinal tract impacts on its immunogenicity and on the level of protection it may induce. Protection was slightly superior after administration of live strains.

Administration, Oral↗
PubMed2001

Postoperative day 3 serum human chorionic gonadotropin decline as a predictor of persistent ectopic pregnancy after linear salpingotomy.

OBJECTIVE: To evaluate the ability of preoperative clinical, ultrasonographic, intraoperative findings and pre-postoperative serum human chorionic gonadotropin (hCG) levels to predict persistent ectopic pregnancy (EP). STUDY DESIGN: Retrospective cohorts study. SETTING: Tertiary care, university hospital. In all, 61 women with EP treated with laparoscopic linear salpingostomy between January 1995 and December 1999. RESULT: Out of 61 patients, 10 (9%) were diagnosed with a persistent EP. When compared with 51 (91%) successfully treated patients there were no differences in preoperative clinical and ultrasonographic findings, preoperative serum hCG levels and intraoperative findings. The postoperative decline of hCG levels were different in both groups. No case of persistent EP was found if the postoperative day 3 decline of hCG was more than 55%. CONCLUSION: Postoperative serum hCG follow-up is important after salpingotomy to prevent persistent EP. A decline of less than 55% at day 3 predicts persistent EP and may select early cases for second line methotrexate therapy.

Adult↗
PubMed1998

Contributing factors to the persistence of musculoskeletal pain in preadolescents: a prospective 1-year follow-up study.

A 1-year follow-up of two preadolescent age cohorts with musculoskeletal pain at least once a week was conducted to analyze predictive factors for the persistence of musculoskeletal pain. Of the 564 children with pain at baseline, representing one third of the sample studied, 515 (91.3%) could be followed and 452 (80.1%) children with complete data were included for the logistic regression analysis. A structured questionnaire included questions on pain and also on several psychosomatic symptoms and amount of exercise. Joint hypermobility together with the questionnaire data were included in the logistic regression analysis. One half of subjects with pain at baseline still reported pain at follow-up, indicating persistent pain. Boys had a lower risk for the persistence of pain than girls and the risk for the persistence of pain increased 1.2 times per age year. When further adjusted for all the other studied risk determinants, high subjective disability index due to pain (OR 3.2, 95% CI 1.5-6.6) and day tiredness (OR 1.9, 95% CI 1.2-3.0) were the most significant predictors. This might indicate that psychological distress contributes to the persistence of non-specific musculoskeletal pain of different locations in preadolescents. In clinical work not only pain but its interference with daily activities should be noticed.

Child↗
PubMed1997

Persistent efficacy: importance and impact of trial design.

The persistent efficacy of some anthelmintics brings advantages in nematode control in domestic animals. However, scientific assessment of persistent efficacy is relatively new, and a feature of published data has been variability in the reported endpoint for this activity. Trial design and method of calculating efficacy have a large bearing on the results obtained. Three types of studies used to evaluate the persistent efficacy of anthelmintics are briefly discussed and compared. In the first type of study, animals are treated followed by a single infection at 7, 14 or more days after treatment. The reduction in worm counts compared to an untreated control group gives a good indication of the persistent efficacy of the product at each time point. One control group can be used for several time points. In the second type of study, the animals are treated and then infected daily from day 1 until 7 days, 14 days or longer after treatment. The animals are slaughtered approximately 3 weeks after the last infection. This approach may better mimic a natural infection but the results obtained are an average reduction over the whole infection period. At the end of the evaluated period, the actual protection may be considerably lower than the average. From this test, it is difficult to define when the protection decreases or disappears. In this test, a control group is required for each period. In the third type of study, a modification of the second, the animals are treated and infected as before but animals are slaughtered soon (2-5 days) after the last infection. Based on the reduction of, for example, the different Ostertagia stages a more specific determination of the persistent efficacy 0-3 days (L3), 3-7 (EL4), 7-14 (LL4 + EL5) and more than 14 days (LL5 + adults) before slaughter can be obtained. Only two groups of animals are required to cover a 3 week period and the average efficacies can be reduced to about one week.

Animals↗