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PubMed2005

Gestational diabetes is associated with depressed adiponectin levels.

OBJECTIVE: Adiponectin is a 29-kd adipocyte-secreted protein that has been linked to insulin resistance in obesity and diabetes. The aim of the present study was to evaluate adiponectin levels in the insulin-resistant state of diabetes in gestation. METHODS: Term, gravid subjects with diabetes (n = 31; age, 30.0 +/- 0.9 years; weight, 98.8 +/- 4.6 kg) and healthy, term, gravid subjects (n = 27; age, 26.1 +/- 1.1 years; weight, 91.2 +/- 3.78 kg) were examined. The diabetes group consisted of 11 class A1, 11 class A2, and nine class B subjects. Plasma insulin, glucose, adiponectin, and leptin were measured on samples obtained immediately before Cesarean or vaginal delivery. Data were presented as means +/- SE, and significance is set at P < or = .05. RESULTS: We observed decreased adiponectin levels in class A2 (4.93 +/- 0.58 microg/mL; P = .013) and class B diabetics (3.33 +/- 0.56 microg/mL; P = .001) as compared to controls (8.17 +/- 0.82 microg/mL), while a nonsignificant decrease was also observed in class A1 (6.58 +/- 1.13 microg/mL; P = .213). When grouping all gravid subjects, we observed that non-Caucasian subjects (n = 42) (5.51 +/- 0.51 microg/mL; P = .003) had lower adiponectin levels than Caucasian subjects (n = 16) (8.88 +/- 1.11 microg/mL). Within the non-Caucasian group, we found significantly lower adiponectin levels in diabetic gravid subjects (class A2: 4.24 +/- 0.75 microg/mL; P = .044; and class B: 3.33 +/- 0.56 microg/mL; P = .005) compared with nondiabetic gravid subjects (7.05 +/- 0.80 microg/mL). CONCLUSION: Class A2 and B gestational diabetes are associated with suppressed levels of adiponectin, similar to that found in other insulin-resistant states (type II diabetes and obesity).

Adiponectin↗
PubMed2006

Role of the radiation oncology nurse.

OBJECTIVES: To discuss the role of the radiation oncology nurse as changes in technology and treatment impact care delivery. DATA SOURCES: Published articles and texts, professional organizations, and the authors' experience. CONCLUSION: Patients receiving cancer treatment today face a myriad of treatment options that can be delivered over days, weeks, and months. As treatments become more complex and standard chemotherapy regimens are combined with new agents and targeted agents, radiation oncology nurses need to have the knowledge and skills to accurately assess and intervene. The radiation oncology nurse is the cornerstone of patient advocacy, care, and education. IMPLICATIONS FOR NURSING PRACTICE: Changes in treatment and technology continue to drive cancer care. Radiation oncology nurses need to collaborate with colleagues and incorporate evidence into practice.

Clinical Competence↗
PubMed2002

The elderly nutrition program: an effective national framework for preventive nutrition interventions.

OBJECTIVE: To guide national policy, Congress mandated the 1992 research evaluation of the Elderly Nutrition Program (ENP), the nation's oldest framework for providing community- and home-based preventive nutrition and health-related services to older persons. This article summarizes key findings on the program's influence on nutritional health, the targeting and costs of its nutrition services, and the study's policy implications. DESIGN: The research included a nationally representative sample of ambulatory and homebound ENP participants And a matched sample of nonparticipants drawn from the US Health Care Financing Administration's Medicare beneficiary listings. Interviews conducted in respondents' homes considered demographic and health characteristics and assessed anthropometry and physical functioning, nutrient intake and socialization patterns, and utilization of ENP program services (participants only). Administrative and service delivery data were gathered from all levels of the ENP infrastructure. RESULTS: The ENP program currently provides congregate and home-delivered meals and other nutrition- and health-related services to about 7% of the older population overall, including an estimated 20% of the nation's poor elders. Compared with nonparticipants, ambulatory and homebound ENP participants are better nourished (4% to 31% higher mean daily nutrient intakes; P<.001) and achieve higher levels of socialization (17% higher average monthly social contacts; P<.001). Federal spending on ENP nutrition services is efficiently leveraged by funding from other public and private sources, allowing ENP to more than double the nutrition services it provides to program participants. CONCLUSIONS: ENP is a well-targeted, effective, and efficient federal program available to dietetics and other professionals for providing elderly persons with community-based and home-delivered nutrition and related services. The ENP infrastructure offers a potential model for preventive nutrition intervention programs in ambulatory and homebound at-risk older populations.

Activities of Daily Living↗
PubMed1993

An experimental algorithm versus standard advanced cardiac life support in a swine model of out-of-hospital cardiac arrest.

STUDY OBJECTIVE: To compare an experimental algorithm with standard advanced cardiac life support in a swine model of out-of-hospital cardiac arrest. DESIGN: Randomized, controlled experimental trial. SETTING/TYPE OF PARTICIPANT: Animal laboratory using swine. INTERVENTIONS: Eighteen swine (17.8 to 23.7 kg) were sedated, intubated, anesthetized, and instrumented for monitoring of arterial and central venous pressures and ECG. Ventricular fibrillation was induced using a bipolar pacing catheter. Animals were randomized to treatment with the experimental algorithm or standard advanced cardiac life support therapy after eight minutes of untreated ventricular fibrillation. The experimental algorithm consisted of starting CPR; giving high-dose epinephrine (0.20 mg/kg), lidocaine (1.0 mg/kg), bretylium (5.0 mg/kg), and propranolol (0.5 to 1.0 mg) by peripheral IV; hyperventilating (20 to 25 breaths per minute); and delaying countershock (5 J/kg) 60 seconds after completion of drug delivery. Data were analyzed with the Student's t-test and Fisher's exact test. MEASUREMENTS AND MAIN RESULTS: Outcome variables were arterial and central venous pressures, return of spontaneous circulation, and one-hour survival. Hemodynamics were not different between groups during CPR. Return of spontaneous circulation occurred in seven of nine swine (77%) in the experimental algorithm group versus two of nine swine (22%) in the advanced cardiac life support group (P = .057). Four of nine swine (44%) in the experimental algorithm group survived to one hour versus none of the animals in the advanced cardiac life support group (P = .041). CONCLUSION: In this swine model of out-of-hospital cardiac arrest, animals treated with an experimental algorithm had a significant improvement in one-hour survival compared with those treated with advanced cardiac life support.

Algorithms↗
PubMed2002

A simple spatial alternation task for assessing memory function in zebrafish.

A series of studies was initiated to examine learning and memory function in the zebrafish (Danio rerio) by using a simple spatial alternation paradigm for a food reward. Fish were fed on alternating sides of a divided fish tank, with a red card displayed on one side serving as a visual means of orientation. Although responses were recorded at cue (light tap on the tank), 5 s after cue (as food was delivered), and 5 s after food delivery, the learning test was choice of a correct side of the tank to receive food. Therefore, an accurate level of an animal's achievement of the spatial task was represented by responses at food delivery. Data collected from 11 separate experiments indicated that zebrafish learned to alternate for a food reward. Further, statistical analysis showed that the zebrafish learned the task in the first half of the experiment as exhibited by a calculated t1/2 of 13.9 trials. Zebrafish could recall the task after a short period of 10 days with no testing. The alternating behavior was extinguished by withholding the food reward. Thus, the spatial alternation task can be learned easily by zebrafish, and may be useful in addressing learning and memory functions in vertebrate animals using zebrafish as a model organism.

Journal Article↗
PubMedDate not supplied

Neurobehavioral effects of prenatal lamivudine (3TC) exposure in preweaning mice.

The present study provides a characterization of the behavioral changes induced in preweaning mice by prenatal exposure to lamivudine (3TC), an antiviral drug recently entered in the clinical practice to treat HIV patients. Pregnant CD1 mice were given per os bidaily either 3TC at different doses (125, 250, or 500 mg/kg) or vehicle solution (saline 0.9%) from pregnancy day 10 to delivery. Data on reproductive performance, such as gestation length, litter size, and offspring viability, were collected. Offspring were then examined for a series of different somatic and behavioral end points, including sensorimotor development, ontogenetic pattern of ultrasonic vocalization, passive avoidance learning, and locomotor activity. In the absence of gross changes in somatic and sensorimotor development, a slight change in ultrasound emission was found on postnatal day (PND) 3, with 125 and 500 mg/kg 3TC-treated offspring emitting a lower number of ultrasounds. Learning and retention performances of a passive-avoidance task on PND 20-21 were unaffected by 3TC treatment, while decreased habituation in an automated locomotor activity test was evident in male offspring exposed to 250 and 500 mg/kg 3TC.

Animals↗
PubMed1998

Balloon mitral valvotomy in pregnancy: maternal and fetal outcomes.

BACKGROUND: Rheumatic mitral valve stenosis contributes to significant morbidity in pregnancy. Surgical commissurotomy has been performed during pregnancy in patients with severe mitral stenosis for several decades, but the efficacy and safety of percutaneous balloon mitral valvotomy (BMV) in this subset has not been clearly defined. STUDY DESIGN: In 1996 and 1997, 40 pregnant women aged 24+/-5 years underwent BMV at 21+/-11 weeks of pregnancy. Special shielding was used during BMV to limit radiation to the fetus, except in those who were to undergo medical termination of pregnancy subsequently. A detailed echocardiographic evaluation was performed before and after BMV. After the BMV, the 29 patients in whom pregnancy was continued were assessed every 2 weeks for symptoms and fetal growth. RESULTS: The BMV procedure was successful in 39 patients with an increase in mitral valve area from 0.8+/-0.2 cm2 to 1.7+/-0.2 cm2 (p < 0.001) and marked symptomatic relief. Fluoroscopy time was 7.8+/-1.9 minutes. Eleven patients whose BMV was performed before 20 weeks of pregnancy, subsequently underwent medical termination of pregnancy uneventfully. Eighteen patients had a normal delivery, three underwent cesarean section for fetal distress, one had a preterm delivery, and there was one stillbirth. Four patients are continuing pregnancy and two are lost to followup. Fullterm delivery data were available in 23 babies, whose birth weights were 2.32+/-0.5 kg. None of these babies needed any special care and were healthy at discharge. CONCLUSIONS: During pregnancy, BMV by the Inoue technique is feasible, safe, and effective. There is marked symptomatic relief, along with excellent maternal and fetal outcomes.

Adult↗
PubMed1988

The Northwestern University Twin Study. V: Twin deliveries at Prentice Women's Hospital and Maternity Center, 1978-83.

Two hundred fifty-one twin deliveries between January 1, 1978 and June 30, 1983 at Prentice Women's Hospital and Maternity Center were reviewed. Cases were excluded if birth weight was less than 500 g, if gestational age was less than 26 weeks or if an antenatal fetal demise had occurred. Maternal demographic characteristics, delivery data and infant characteristics are described. The effect of providing care to a high-risk population of mothers in whom approximately 60% either deliver their infants preterm or with a birth weight of less than 2,500 g is discussed in terms of costs of care.

Adolescent↗
PubMed2005

Development of a quantitative method for the analysis of tobacco-specific nitrosamines in mainstream cigarette smoke using isotope dilution liquid chromatography/electrospray ionization tandem mass spectrometry.

An improved method has been developed for the determination of the four major tobacco-specific nitrosamines (TSNA) in mainstream cigarette smoke. The new method offers decreased sample preparation and analysis time as compared to traditional methodologies. This method uses isotope dilution liquid chromatography coupled to a tandem mass spectrometer with electrospray ionization and is significantly more sensitive than traditional methods. It also shows no evidence of artifactual formation of TSNA. Sample concentrations were determined for four TSNA in mainstream smoke using two isotopically labeled TSNA analogues as internal standards. Mainstream smoke was collected on an industry standard 44-mm Cambridge filter pad, extracted with an aqueous buffer solution, and analyzed without further sample cleanup. This method has been validated through intra- and interlaboratory studies and has shown excellent recoveries, sensitivity, and repeatability. The limits of detection of each TSNA varied from 0.01 to 0.1 ng/mL, and the linear calibration range of the instrument in sample matrix spanned 0.5-200 ng/ mL, which allowed for the determination of the TSNA levels in cigarettes with a wide range of deliveries. Data are also reported from two commercially available industry reference cigarettes and show excellent agreement and reproducibility over a six-month time period (n > 50).

Artifacts↗
PubMed2003

Malnutrition in institutionalized seniors: the iatrogenic component.

OBJECTIVES: To provide practitioners with benchmarks for micronutrient supplementation policies for older residents of long-term care (LTC) facilities, based upon residents' usual energy intake. DESIGN: Retrospective secondary analysis of nutrient intake and delivery data, obtained from 21 consecutive collection days. SETTING: A fully accredited geriatric teaching facility, affiliated with the University of Toronto's Medical School, that includes a chronic care hospital and a home for the aged, housing more than 800 senior residents. PARTICIPANTS: Twenty-three cognitively impaired residents who retained the ability to feed themselves. MEASUREMENTS: Average daily micronutrient (vitamin and mineral) content of two common diet types--unrestricted diet as tolerated and lactose-free--were evaluated based upon all foods served during a 28-day cycle of menus, providing an estimate of total possible micronutrient intake. Energy intake needed to meet recommended intakes for each of the micronutrients was then determined and compared with actual dietary intakes. RESULTS: Even if entirely consumed, neither diet (providing approximately 2,000 kcal/d) supplied sufficient quantities of vitamins (vitamin E, pantothenic acid) and minerals (calcium, zinc, copper and manganese) to enable residents to meet recommended intakes, making these deficiencies iatrogenic in nature. As projected intake levels fell to reflect ranges more consistently observed in LTC residents (1,000-1,500 kcal/d), the number and severity of risk nutrients increased. Similar predictions, based upon actual intake measurements, were made and confirmed. CONCLUSIONS: The traditional approach of developing LTC menus using resources such as Canada's Food Guide or the Food Guide Pyramid of the United States results in iatrogenic malnutrition. New guidelines are needed that are targeted toward the special needs of older adults who have low food intakes. In the interim, all older LTC residents require full-spectrum vitamin and mineral supplements.

Aged↗
PubMed2005

Evaluation of the reinforcing effects of monoamine reuptake inhibitors under a concurrent schedule of food and i.v. drug delivery in rhesus monkeys.

Most medications prescribed for attention-deficit-hyperactivity disorder are psychomotor stimulants with reinforcing effects in laboratory animals (eg methylphenidate). The present studies were conducted to evaluate the reinforcing effects of the recently approved medication atomoxetine in monkeys trained to 'choose' between automated deliveries of either an i.v. injection or food. Rhesus monkeys were trained to lever-press under concurrent schedules of reinforcement; responses on one lever resulted in an injection of either saline or drug, and responses on the alternative lever resulted in food delivery. Data were collected on four measures: response rates, percentage of total responses occurring on the injection-lever (% ILR), number of injections earned, and number of food pellets earned. Dose-effect functions were determined for cocaine (0.003-0.3 mg/kg/inj), methylphenidate (0.003-0.1 mg/kg/inj), amphetamine (0.003-0.1 mg/kg/inj), atomoxetine (0.01-0.3 mg/kg/inj), and desipramine (0.03-1.0 mg/kg/inj) using a double alternation schedule of saline and drug availability. Results indicate that the distribution of behavior changed according to the drug and dose available for self-injection. Saline availability was typically associated with high rates of food-maintained responding. The % ILR increased from 3+/-1% when saline was available to >90% when >0.03 mg/kg/inj of cocaine, methylphenidate or d-amphetamine was available. However, no dose of atomoxetine or desipramine maintained self-administration behavior on the injection-lever. The number of food pellets earned per session decreased as the dose of each drug increased, indicative of behavioral activity with all five drugs. The reinforcing effects of cocaine, methylphenidate, and d-amphetamine in these studies are consistent with previous findings in nonhuman primates and with their documented abuse liability. The absence of reinforcing effects of atomoxetine support the view that, like desipramine, it has no evident abuse potential.

Adrenergic Uptake Inhibitors↗
PubMed2006

Multiple pregnancy in rural Burkina Faso: frequency, survival, and use of health services.

OBJECTIVE: To assess the birth of twins in rural Burkina Faso with respect to prevalence, mortality, and provision of obstetric care. METHODS: A descriptive demographic analysis of population-based and health service data was performed with multivariate modeling by Poisson regression. Health service data were derived from a document review in health facilities in the Nouna District for the years 1994-2001. The district hospital provides obstetric care for the entire district with its 252,000 population (1998). Population-based data (deliveries, live births, deaths) were derived from the demographic surveillance system in the surveillance area within the Nouna District, Burkina Faso (population under surveillance: 30,988 in 1998). All births in the period from January 1, 1993 to December 31, 1998 (9457 recorded deliveries with 9,610 live births) were included and followed up until April 30, 2002. The main outcome measures were the prevalence of twin delivery as well as age- and sex-specific mortality risks. RESULTS: Mortality of twins is high, with one out of three dying before reaching the age of five years--2.5 times the mortality risk of singletons. Among twins, mortality is particularly high in the neonatal period (RR 5.16; CI: 3.6-7.5) and in twins born to mothers above the age of 35 (RR 5.12; CI: 3.5-7.6). The overall population-based prevalence of twin delivery is 1.6% (CI: 1.4-1.9) versus a hospital-based prevalence of 2.8% (CI: 2.2-3.1). Despite this moderate trend towards hospital-based obstetric care, most twins (90.5%) are still delivered outside a hospital setting. CONCLUSIONS: The high neonatal mortality in twins points to the need for special care in pregnancy, child birth, and postpartum. Maternity services fail to adequately cover the vast majority of multiple pregnancies and deliveries.

Adult↗
PubMed1998

Toxicity evaluation of petroleum blending streams: reproductive and developmental effects of a distillate from light alkylate naphtha.

A distillate of light alkylate naphtha (CAS number 64741-66-8; LAN distillate) was administered via inhalation, 6 h/d, 7 d/wk to 4 groups of Sprague-Dawley rats (10/sex/dose) at target concentrations of 0 (filtered air control), 5, 12.5, or 25 g/m3 with the highest dose exceeding 60% of the lower explosive limit of LAND. Exposure began 2 wk prior to mating and continued throughout gestation until postnatal d 4 for females or for 8 consecutive weeks for males. No apparent clinical signs indicative of systemic toxicity were observed in the F0 and F1 animals of either sex. Inhalation exposure to LAND up to and including the 25 g/m3 dose level had no effect on parental food consumption, body weights, absolute and relative organ weights, and reproductive indices. All groups had comparable delivery data and a fertility index > or 80%. Pups in all groups showed comparable birth weights, weight gain, a viability index (postnatal d 4) for all groups of > or = 97%, and no histopathological changes. In the dams, there were no significant differences in the mean numbers of corpora lutea, implantation sites, and resorptions recorded at necropsy. In the males, the only remarkable findings at necropsy were a small right epididymis and testis seen in one mid-dose male and an abscess on the right epididymis of a high-dose male. In both cases, the dams that had been bred to these males produced normal litters. There were no test material-related microscopic changes observed in the testes and epididymis of the F0 male rats or ovaries of the F0 female rats exposed to LAND. Under the conditions of this experiment, the no-observed-adverse-effect level (NOAEL) for LAND via inhalation in rats is established at greater than 24.7 g/m3 (analytical concentration).

Administration, Inhalation↗
PubMed2006

Developing new services for eating disorders: an evaluation study.

OBJECTIVE: This paper aims to evaluate the structures and processes of eating disorders services in two regional cities in Australia. METHOD: Stakeholder evaluation undertaken between 2002 and 2005 uses interviews, questionnaires and service delivery data to examine: structure and patient profile of the two services, barriers and success factors and local factors influencing development of the services. RESULTS: The Bendigo service provided secondary consultation and specialist management with upskilling of primary care workers as a key goal. Patients were referred to the service via mental health triage. The Geelong service initially offered assessment only, with direct access for the general public. Treatment was offered from early 2004. The Bendigo service assessed 41 patients, 63% were diagnosed with anorexia nervosa or bulimia nervosa. Most patients had a moderate or severe eating disorder. The Geelong service assessed 186 patients, 55% were diagnosed with anorexia nervosa or bulimia nervosa and 80% of this subset had not previously been treated for an eating disorder. General practitioners identified barriers to development of the services as: problems with capacity building and unrealistic expectations. The success factors were providing a locally based service with credible clinicians and effective communication. CONCLUSIONS: Activity analysis demonstrates that the goals for both services were met. There is a need to measure both short- and long-term patient outcomes in order to fully assess effectiveness and applicability to other settings. Local factors, such as availability of specialist providers, would need to be taken into account.

Anorexia Nervosa↗
PubMed2005

Circadian blood pressure variability in normotensive pregnant women as a function of parity, maternal age, and stage of gestation.

Studies based on conventional office blood pressure (BP) measurements concluded that both maternal age and parity have significant effects on BP during pregnancy. Previous results have also indicated predictable trends of BP variability with gestational age. Accordingly, we have evaluated possible differences in the circadian pattern of ambulatory BP as a function of parity, maternal age, and stage of gestation in normotensive women who were systematically studied by ambulatory BP monitoring during their pregnancies. We analyzed 1408 BP profiles obtained from 126 nulliparous and 109 multiparous pregnant women sampled for 48 consecutive h every 4 weeks from the first obstetric visit (usually within the first trimester of pregnancy) until delivery. Data were divided for comparative analysis according to parity (nulliparous versus multiparous), age (< or = 25, 26-30, 31-35, and > or = 36 yrs), and trimester of gestation. Circadian BP parameters established by population multiple-components analysis were compared between groups using a nonparametric test. A highly statistically significant circadian pattern described by a model that includes components with periods of 24 and 12h is demonstrated for systolic and diastolic BP for all groups of pregnant women in all trimesters (always p < 0.001). There was no significant difference in the 24h mean among groups divided by parity at any age or stage of pregnancy. A trend of increasing BP with age was found for diastolic but not for systolic BP. Although statistically significant, differences in the 24h mean of diastolic BP among groups divided by age were always less than 2 mm Hg. Data obtained from systematic ambulatory monitoring in normotensive pregnant women indicate the lack of differences in BP according to parity. The small, although significant, increase in diastolic BP with age may have scarce influence in the proper identification of women with gestational hypertension. Reference thresholds for BP to be used in the early identification of hypertensive complications in pregnancy could thus be developed as a function of the rest-activity cycle and gestational age only, and independently of parity or maternal age.

Adult↗
PubMed1994

The evolution and outcome of pregnancies from oocyte donation.

A total of 199 patients participated in the oocyte donation programme in 336 replacement cycles in whom 69 clinical pregnancies were achieved, of which 53 reached term and delivery. Data concerning the evolution and outcome of pregnancies were retrieved in 52 cases, which involved 39 women with ovarian failure and 18 with functional ovaries. The most frequent complications of pregnancy were uterine bleeding in the first trimester in 18 cases (34.6%), hypertension in 17 (32.7%) and intra-uterine growth retardation (IUGR: 11.5%). These complications were more prominent in twin pregnancies. The Caesarean section rate was 63.5% and a high percentage of elective sections (54.5%) was observed. Of singleton pregnancies, 54.6% had a birth weight of > 3000 g at full term (> 37 weeks), while 62.5% of twins weighed between 2000 and 3000 g. One intra-uterine death occurred, so that the perinatal mortality was 1.7% and one newborn was operated on for stenosis of the pulmonary artery, while the incidence of premature labour was low (1.9%). A comparison of complications between pregnancies associated with ovarian failure and with functional ovaries revealed a higher frequency of bleeding in the first trimester (38.2% and 27.8% respectively) and of hypertension (38.2% and 22.2% respectively) in those with ovarian failure, although the differences were not statistically significant. In conclusion, women who become pregnant after oocyte donation and especially those with ovarian failure should be considered as high-risk obstetric patients.

Adult↗
PubMed1993

Alcohol and pregnancy: an international comparison.

A study was set up to compare the drinking habits of women of childbearing age in two cities (Milan and Southampton) in two countries, Italy and the United Kingdom, and to look at the effects of alcohol consumption on the weight of the babies born to these women. The sample consisted of 1516 women in Milan and 996 in Southampton, who were interviewed after delivery; data on their drinking history, before and during pregnancy, were gathered, together with social, demographic and health data. The clinical records of the women and their babies were examined. On average, both groups drank less than one unit/day before pregnancy, but there were differences in drinking habits between the two countries, as well as in the modifications induced by pregnancy. The possible effects of alcohol on birthweight were then considered. After controlling for confounding factors, there was no general association between birthweight and alcohol consumption. The impact on health education policy is discussed.

Adult↗
PubMed1994

Gene transfer for transplantation. Prolongation of allograft survival with transforming growth factor-beta 1.

OBJECTIVE: The authors tested the ability of plasmid gene transfer to express transforming growth factor-beta 1 (TGF-beta 1), prolong allograft survival, and evaluate promoter effects on gene expression. SUMMARY BACKGROUND DATA: Delivery of immunosuppressants directly to allografts using gene transfer and gene therapy approaches may inhibit immune activation while avoiding the systemic toxicity of conventional immunosuppression. Candidate genes include soluble cytokines, which could be expressed at low levels throughout the graft while inducing a local immunosuppressive effect. Transforming growth factor-beta 1 is a soluble cytokine that has pleiotropic immunosuppressive effects. METHODS: Cardiac grafts from syngeneic (CBA/J, H-2k) or allogenic (C57BL/6, H-2b) donors were placed into CBA/J recipients. Purified plasmid DNA-encoding murine TGF-beta 1 or beta-galactosidase (Lac Z) under the control of RSV, SV40, MMTV, or pancreatic elastase promoters was injected into grafts at surgery. The Lac Z expression was determined by histologic examination and TGF-beta 1 expression by graft survival. Cytotoxic T lymphocyte and flow cytometric analyses were performed to evaluate the immunosuppressive effects of TGF-beta 1 in vitro. RESULTS: Plasmid DNA-encoding TGF-beta 1 prolonged survival from 12.6 +/- 1.1 days to 26.3 +/- 2.5 days (p < 0.02, Student's t test). The SV40 promoter was superior to the MMTV promoter in its ability to prolong survival. The effects of the plasmids were specific because Lac Z, antisense TGF-beta 1 inserts, or pancreatic elastase promoter did not prolong allograft survival. Histologic examination demonstrated Lac Z expression at least 14 days post-transplant in myocardial cells. Both RSV and SV40 promoters were effective in this respect, while a control null promoter was not. Toxicity testing showed that gene transfer of TGF-beta 1 did not alter survival or histology of syngeneic grafts. In addition, plasmids and purified TGF-beta 1 protein were not toxic to myoblasts in vitro. Recombinant TGF-beta 1 inhibited cytotoxic T lymphocyte generation and altered T cell surface receptor expression and subset expansion in vitro. CONCLUSION: Gene transfer/therapy with plasmid DNA encoding TGF-beta 1 in vivo achieves immunologic effects that prolong allograft survival. Multiple promoters effectively induce plasmid expression, which is achieved in cardiac myocytes for at least 2 weeks without toxicity or adverse systemic effects. Transforming growth factor-beta 1 inhibits immune responses by different mechanisms, revealed by in vitro analysis of T cell cytolytic function, subset distribution, and receptor display.

Animals↗