Novel Application of Localized Nanodelivery of Anti-Interleukin-6 Protects Organ Transplant From Ischemia-Reperfusion Injuries.

Ischemia-reperfusion injury (IRI) evokes intragraft inflammatory responses, which markedly augment alloimmune responses against the graft. Understanding the mechanisms underlying these responses is fundamental to develop therapeutic regimens to prevent/ameliorate organ IRI. Here, we demonstrate that IRI results in a marked increase in mitochondrial damage and autophagy in dendritic cells (DCs). While autophagy is a survival mechanism for ischemic DCs, it also augments their production of interleukin (IL)-6. Allograft-derived dendritic cells (ADDCs) lacking autophagy-related gene 5 (Atg5) showed higher death rates posttransplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice showed marked reduction in intragraft expression of IL-6 compared with controls. To antagonize the effect of IL-6 locally in the heart, we synthesized novel anti-IL-6 nanoparticles with capacity for controlled release of anti-IL-6 over time. Compared with systemic delivery of anti-IL-6, localized delivery of anti-IL-6 significantly reduced chronic rejection with a markedly lower amount administered. Despite improved allograft histology, there were no changes to splenic T cell populations, illustrating the importance of local IL-6 in driving chronic rejection after IRI. These data carry potential clinical significance by identifying an innovative, targeted strategy to manipulate organs before transplantation to diminish inflammation, leading to improved long-term outcomes.

Fatal hypertrophic cardiomyopathy in the fetus of a woman with diabetes.

BACKGROUND: Hypertrophic cardiomyopathy is recognized in infants of diabetic mothers, and when it occurs it is generally benign and transient. We describe a case of fetal cardiac death caused by hypertrophic cardiomyopathy in an infant of a diabetic mother. CASE: Hydrops fetalis caused by hypertrophic cardiomyopathy resulted in the death of a macrosomic male fetus of a young woman who had well-controlled diabetes mellitus and was treated with insulin therapy during pregnancy. CONCLUSION: It is important to monitor fetal heart function in macrosomic infants of diabetic mothers. Hypertrophic cardiomyopathy might explain otherwise unexplained fetal deaths in women with diabetes.

Evaluation of a measurement strategy for Parkinson's disease: assessing patient health-related quality of life.

This study evaluated the feasibility and psychometric properties of self-completed and telephone interview versions of a patient health-related quality-of-life (HQL) questionnaire for Parkinson's disease that included the SF-36 Health Survey (SF-36), the Parkinson's Disease Questionnaire (PDQ-39), and the Medical Outcomes Study Sexual Function Survey. Parkinson's disease patients (n = 150) completed the questionnaire twice: once at the study site and once over the telephone in a randomized order. Ninety-four percent of enrolled patients completed the first HQL assessment and 88% completed both assessments. Cronbach's alpha exceeded 0.70 for all scales except for the self-completed PDQ-39 Social Support subscale (0.57) and the telephone interview PDQ-39 Social Support (0.60) and Cognitions (0.67) subscales and the SF-36 General Health (0.60) and Social Function (0.61) subscales. There were no statistically significant differences in mean HQL scale scores across the two modes of administration. Mean scores for 3 of the PDQ-39 subscales and the Summary Index were significantly poorer (p < 0.05) for patients at later clinical stages. Similarly, patients with dyskinesias reported significantly poorer scores for 4 of the PDQ-39 subscales and the Summary Index and patients with self-reported comorbidities reported poorer SF-36 Physical Function and General Health subscale scores than patients without dyskinesias and comorbidities, respectively. This study suggests that the self-completed and telephone interview versions of the patient HQL questionnaire are feasible and valid for future clinical trial applications.

Evaluation of a short form for measuring health-related quality of life among pediatric asthma patients.

BACKGROUND: This study was undertaken to derive and validate a short form parent-completed questionnaire to measure health-related quality of life (HRQL) in pediatric asthma patients. OBJECTIVE: The objectives of this study were to (1) use stepwise analysis to derive a shorter questionnaire from the original long-form questionnaire and (2) determine the tradeoff in precision between the long- and short-form surveys. METHODS: One hundred eighty-one pediatric asthma patients were enrolled from 4 sites. A parent of each patient completed a general and an asthma-specific questionnaire during routine office visits from June 1995 to January 1997. The questionnaire included the Child Health Questionnaire Parent Form 50, a general HRQL survey, and a 17-item asthma-specific battery assessing daytime symptoms, nighttime symptoms, and functional limitations. All scales were scored from 0 to 100, with higher scores indicating better HRQL. Analysis of variance models were used to derive short-form scales from the 17-item long-form scales, and the final asthma-specific short-form scale structure was confirmed with use of stepwise regression. Scale reliability was assessed with Cronbach's alpha. Validity of the short-form questionnaire was assessed by comparing mean scale scores according to the level of asthma severity defined by several clinical criteria. Asthma severity was assessed with use of percent predicted FEV(1), frequency and type of symptoms, parent rating of disease severity, physician rating of disease severity, and resource use (emergency department use and hospitalizations). The relative validity of each of the short-form scales was measured by comparing the proportion of variance explained by each of the short-form scales compared with the respective long-form scales. RESULTS: The 17-item asthma-specific battery was reduced to 8 items, the Integrated Therapeutics Group Child Asthma Short Form. The daytime and nighttime symptom scales for each contain 2 items and the functional limitations scale 4 items. Reliability was greater than 0.70 for each of the short-form scales. The absence of ceiling and floor effects indicates each scale's ability to detect changes at both low and high levels of functioning. Lower (poorer) mean HRQL scores for severe cases compared with mild cases, for all disease severity indicators, demonstrated clinical validity. Relative validity estimates, comparing the proportion of explained variance of the short-form scales with that of the long-form scales, ranged from 0. 85 to 1.20, indicating a similar ability to measure change. CONCLUSIONS: This study documents the development of a brief, multidimensional, 8-item questionnaire for measuring HRQL in pediatric asthma patients. The brevity of the questionnaire makes it practical for use in practice settings and to monitor patients.

Longitudinal neurologic follow-up in neonatal intensive care unit survivors with various neonatal morbidities.

OBJECTIVE: The purpose of this prospective longitudinal study was to examine neurocognitive and school performance outcomes of low birth weight infants with reference to neonatal morbidity and socioeconomic status. We further evaluated the cognition and school performance based on their neurologic status at the time of assessment. METHODS: One hundred eighty-eight children (39 healthy full-term and 149 preterm infants) were classified into 4 subgroups based on their neonatal medical status: healthy, sick (without neurologic complications), small for gestational age, and neurologically compromised infants. Neurologic status was classified as normal, suspect, or abnormal at hospital discharge, 18 months, 30 months, 4 years, and 8 years of age. Socioeconomic status, cognitive, and school performances were assessed. RESULTS: Neurologically, both full-term and healthy preterm groups did well during the 8-year period. There were significant fluctuations between suspect and abnormal neurologic classifications among the 3 preterm groups with neonatal complications. Preterms with neurologic abnormality during the neonatal period did the poorest with 45% of the group remaining abnormal at 8 years of age. Children who were neurologically normal had higher cognitive scores at ages 4 and 8 than those categorized as suspect or abnormal. Preterm infants with neurologic abnormality required significantly more academic resources in the school. Reading and math achievement scores were the lowest for the preterm groups classified as neurologically suspect or abnormal. CONCLUSIONS: Neonatal morbidities exert a significant impact in neurologic outcomes among preterm children during the 8 years of assessment. Compromised neurologic status adversely affects cognitive and school performances. Neonatal medical status is an important variable indicating neurocognitive and school performance outcomes in low birth weight infants.

Medical and ecological factors in estimating motor outcomes of preschool children.

The twofold purpose of this study was to compare motor function in preschool children born with varying degrees of medical risk and to determine the independent contribution to motor function of three domains of ecological influence. One hundred and eighty-four 4-year-old children and their mothers participated. Three predictor sets, proximal, distal, and child, and four motor outcomes were measured by multiple methods. Children born prematurely scored lower on all dimensions of motor function. Prematurity complications had a different effect on motor function. Hierarchical regression models explained 16-40% of motor score variance. Results are discussed in relation to heterogeneity of prematurity and ecological influences on motor outcomes.

Proximal and distal correlates of maternal control style.

Control, as an aspect of maternal interaction, has been found to be an important component to optimal child development. Maternal control style is defined as a mother's tendency to be controlling or supportive of her child's autonomy. The relationship between two types of maternal characteristics, proximal and distal, and maternal control style was investigated in a sample of 184 mothers and their 4-year-old children. Global ratings of videotaped data of two problem-solving tasks were made on a 5-point scale. An optimal maternal control style was associated with higher levels of the distal maternal characteristics of maternal education, age, occupation, and higher levels of the proximal characteristics of maternal responsivity and involvement. A hierarchical regression model explaining 26% of the variance in maternal control style scores supports the importance of both types of maternal characteristics. The results are discussed in relation to the methodology and the theoretical framework of role.

Maternal interaction patterns and preschool competence in high-risk children.

BACKGROUND: The influence of specific maternal interaction patterns as compensatory mechanisms in promoting development of medically high-risk children has been understudied. OBJECTIVES: To investigate the association of three maternal interaction patterns, maternal responsivity, involvement, and control style, with preschool competency in a medically heterogeneous sample. METHOD: Children (N= 184) and their mothers participating in a prospective longitudinal study were assessed in a laboratory protocol and home visit. The methods of measurement were maternal self-report, global rating scales, interview, and nationally standardized instruments. RESULTS: Evidence of a maternal compensatory mechanism was exhibited in mothers' higher involvement with their children who were born at high medical risk (F(1,183) = 6.26, p = .01). Mothers of the most competent children demonstrated higher maternal responsivity, involvement, and more appropriate control than mothers of children who were not as competent. In hierarchical regression models, the three maternal interaction patterns were significant predictors after perinatal risk and maternal education were controlled explaining 29-37% of the variance in child competence scores. CONCLUSION: These findings imply that differential child outcomes are associated with specific maternal interaction patterns. It suggests that a combination of diverse information revealed in specific maternal interaction pattern is needed to predict cognitive, linguistic, and problem-solving competencies. Future research should consider individual differences in mother-child interaction patterns in order to isolate their significance for optimal child development.

Medical-resource use for suspected tuberculosis in a New York City hospital.

OBJECTIVE: To compare resource use by diagnostic outcome among hospital admissions during which tuberculosis (TB) was suspected. DESIGN: Retrospective study based on chart review and microbiology laboratory data. SETTING: The department of medicine in a municipal hospital serving central Brooklyn, New York. PARTICIPANTS: We identified all adult admissions in 1993 during which TB was suspected. We assigned each admission to one of four mutually exclusive groups defined by the results of microbiological tests (acid-fast bacilli [AFB] smear and culture): culture-positive and smear-positive (C+S+); culture-positive and smear-negative (C+S-); culture-negative and smear-positive (C-S+); or culture-negative and smear-negative (C-S-). Each admission was divided into two separate periods to which the utilization of medical resources was assigned: the diagnostic and the postdiagnostic periods, which were separated by the date of receipt of the first definitive culture report. RESULTS: Data on 519 admissions (93 C+S+; 57 C+S-; 30 C-S+; and 339 C-S-) were analyzed. Although C+S+ were more likely than other groups to have an admitting diagnosis of TB, approximately one quarter of the admissions without TB (C-S+, C-S-) were admitted with the principal diagnosis of TB. For the four groups, C+S+, C+S-, C-S+, and C-S-, the respective rates of TB isolation and anti-TB treatment, and median lengths of isolation were 98%, 87%, and 34 days; 74%, 74%, and 7 days; 83%, 83%, and 15 days; and 44%, 29%, and 0 days. During the diagnostic period, the rate and length of isolation were similar in the AFB-smear-positive groups (C+S+ and C-S+). We estimated that admissions without culture-proven TB (C-S+ and C-S-) accounted for 3,174 (36%) of the 8,712 days of TB isolation expended and for 65% of the 16,671 days of anti-TB treatment. The vast majority of this resource consumption (2,737 [86%] of 3,174 days of isolation) occurred during the diagnostic period before a definitive culture result was known. CONCLUSIONS: Our results suggest that prolonged diagnostic uncertainty and misclassification of cases due to false-positive and false-negative smears are associated with substantial medical-resource consumption. New diagnostic modalities that reduce the period of diagnostic uncertainty could reduce the utilization of resources later found to be unnecessary.

Assessment of health-related quality of life in kidney transplant patients receiving tacrolimus (FK506)-based versus cyclosporine-based immunosuppression. FK506 Kidney Transplant Study Group.

BACKGROUND: We evaluated health-related quality of life (HQL) in kidney transplant patients participating in a multicenter, prospective, randomized, phase III trial comparing tacrolimus to cyclosporine. HQL data were available for 303 of 412 patients and assessed with the SF-36 Health Survey and six multi-item scales: Current Health, Health Outlook, Health Distress, Fleming Self-Esteem, Bergner Physical Appearance, and Sexual Functioning. METHODS: Patients completed surveys at baseline, week 6, and months 3, 6, and 12. The mean change in HQL was evaluated by rejection occurrence and number of hospitalizations. Analysis of covariance was used to model endpoint HQL scores as a function of treatment group and baseline HQL. RESULTS: All scales but two met psychometric standards for group-level comparisons. Baseline demographics and HQL scores were not different by treatment. The mean HQL change was lower for patients with rejection compared with no rejection in seven of eight SF-36 scales and three of four remaining supplemental scales. One year after transplantation, study patients were functioning at least as well as half of the general population in Vitality and Role-Emotional Functioning, moving from the 18th percentile of the U.S. population scores to the 50th percentile for Vitality and 54th percentile for Role-Emotional Functioning. Patients improved their percentile ranking by at least 20 points in five of eight SF-36 scales. CONCLUSIONS: Patients with kidney disease demonstrate substantial HQL burden before transplantation, and transplantation is associated with substantial HQL improvements. Rejection is associated with less HQL improvement. Endpoint HQL values were significantly different (P<0.05) by treatment, favoring tacrolimus, in the Bergner Physical Appearance scale, which was designed to measure the HQL impact of side effects such as gingival hyperplasia and facial hirsutism on physical appearance.

Costs and charges associated with three alternative techniques of hysterectomy.

BACKGROUND: Many hysterectomies are now performed by a laparoscopically assisted vaginal technique. This procedure is controversial, partly because of concern about cost. We studied hospital charges and costs for the procedure as compared with those for total abdominal hysterectomy and total vaginal hysterectomy in clinically similar groups of patients. METHODS: From hospital-discharge data and patients' charts, we identified hysterectomies performed in 1993 and 1994 by 96 surgeons at a community teaching hospital to treat benign conditions. The patients were grouped according to the surgical procedures performed in conjunction with the hysterectomy. Data on hospital charges and cost-to-charge ratios for 64 hospital cost centers were used to assess charges and costs for specific resources, as well as for the hospitalization overall. RESULTS: Of 1049 patients studied, 26 percent underwent laparoscopically assisted vaginal hysterectomy, 54 percent underwent abdominal hysterectomy, and 20 percent underwent vaginal hysterectomy. The average hospital stays were 2.6, 3.9, and 2.9 days, respectively, and the mean total charges (facility charges plus professional fees) for the hospitalizations were $6,116, $5,084, and $4,221 (P<0.001 for the comparison of the laparoscopic technique with both other techniques). The mean facility costs were $4,914, $3,954, and $3,116, respectively (P<0.001 for the same comparison), with similar findings in all subgroups. The higher charges and costs for laparoscopically assisted vaginal hysterectomy were due to higher supply costs, particularly when disposable supplies were used, and to longer operating-room time. CONCLUSIONS: Despite shorter hospital stays, in-hospital charges and costs for laparoscopically assisted vaginal hysterectomy are higher than for either alternative procedure, because of the disposable supplies that are typically used and the longer operating-room time.

Vaginal birth after cesarean. Physicians' perceptions and practice.

OBJECTIVE: To determine physician's perceptions about vaginal birth after cesarean section and compare them to the physicians' actual practice experience. STUDY DESIGN: Physicians responded to a questionnaire on their perceptions of vaginal birth after cesarean section. Between July 1, 1991, and June 30, 1992, all attempts at vaginal birth after cesarean section were reviewed. All cesarean deliveries were also reviewed to determine which repeat cesarean sections could have been avoided. RESULTS: One hundred twenty-four patients attempted vaginal birth after cesarean section, and 95 (76.6%) were successful. Physician perceptions revealed a success rate of 73.6%. Those patients whose labor was induced in their attempt at vaginal birth after cesarean section were less successful (41.9%) than those who did not require induction (88.2%) (P < .001). Upon review, 47% of patients who underwent elective repeat cesarean section did not have a contraindication to a trial of labor. CONCLUSION: Physicians had an accurate perception of the success of vaginal birth after cesarean section in their practices. Vaginal birth after cesarean section success rates were consistent with those reported in the literature. Despite a high attempt rate (72.5%) among those eligible for vaginal birth after cesarean section, almost half the patients undergoing a repeat elective cesarean section did not have a contraindication to a trial of labor.

Economic savings and costs of periodic mammographic screening in the workplace.

This article discusses the costs and benefits of mammographic screening in the workplace. The cost of mammography itself and of diagnostic work-up are two of the largest costs involved. Therefore, the most efficient approach to providing mammography depends on the number of employees receiving mammography; and the diagnostic accuracy of mammography and underlying incidence of breast cancer in the screened population strongly influence the number of suspicious mammograms that are not associated with breast cancer. The health benefit of mammographic screening is due to reduced mortality and morbidity through early detection and more effective treatment, which may also result in economic savings if early-stage cancer is less expensive to treat. However, the total lifetime cost of treating early-stage cancer may be greater than treating late-stage cancer because of improved survival of early-stage patients. Thus, although periodic mammographic screening is not likely to result in overall economic savings, in many populations of working-age women, especially those with identifiable risk factors, screening is cost-effective because the expenditure required to save a year of life through early detection of breast cancer is low compared to other types of health services for which employers commonly pay.

The use of a generic, patient-based health assessment (SF-36) for evaluation of patients with anterior cruciate ligament injuries.

The MOS 36-item short-form health survey is a generic, patient-based health assessment tool. It has been used to assess functional outcome for many medical conditions, both acute and chronic. The use of this survey in evaluating the effects of treatment of any specific disease or injury allows comparison of treatments across a broad spectrum of disease categories. The purpose of this study was to see if this assessment tool could 1) be used to identify those patients requiring anterior cruciate ligament reconstruction, 2) detect changes in the patients with treatment over time, and 3) correlate with the commonly used knee assessment scales. The short-form health survey could not identify those patients requiring anterior cruciate ligament reconstructive surgery. However, it did show important and significant changes with treatment (surgical and nonsurgical) over time. There was a significant correlation between the short-form health survey and the Lysholm and International Knee Documentation Committee scores during this study. The addition of the MOS 36-item short-form health survey to our traditional knee ligament evaluation tools is encouraged. Its use will permit the orthopaedic community to demonstrate the value of our treatment of anterior cruciate ligament injuries to health care planners and generalist physicians.

Adolescent development and transitions to motherhood.

OBJECTIVE: To use both qualitative and quantitative methods to examine the experience of motherhood during adolescence and to evaluate developmental influences on the concept of maternal role. DESIGN: (1) A grounded theory approach was initially used to generate a hypothesis. Focus groups and individual interviews were analyzed for concept and theme. (2) A quantitative method using correlational analysis was used to test the hypothesis generated by qualitative study. A structured interview using five specific, scored questions about self and about motherhood was used to examine the relationship between developmental complexity of responses to questions about self and questions about motherhood. SETTING AND PARTICIPANTS: The qualitative study involved group and individual interviews with 42 teenage mothers. The quantitative study involved individual interviews with 25 mothers, ages 14 to 18 years, at an innercity clinic for young parents and their infants. Race and ethnicity were heterogeneous, and 100% received Aid to Families With Dependent Children. RESULTS: The major hypothesis generated from the qualitative analysis was that an adolescent mother's conceptualization of her maternal role is related to her own psychosocial and cognitive development. The quantitative study revealed a strong correlation between the developmental complexity of responses to questions about self and the complexity of responses to questions about motherhood (r2 = .81). CONCLUSION: The experience of motherhood and the conceptualization of the maternal role in adolescence is related to young mothers' psychosocial cognitive development.

Developmental outcome as a function of the goodness of fit between the infant's cry characteristics and the mother's perception of her infant's cry.

OBJECTIVE: To determine whether the "goodness of fit" between infant cry characteristics and the mother's perception of the cry is related to developmental outcome at 18 months of age. DESIGN: This was a prospective, longitudinal study from birth to 18 months performed in a blinded manner. SETTING: The study was conducted in a maternity hospital, including normal and special care nurseries and a laboratory for developmental follow-up. PATIENTS: The 121 term and preterm infants and their mothers were selected to meet medical criteria. MEASUREMENT: Acoustic analysis of 1-month infant cry and the mother's perception of the same cry was used to divide subjects into four groups representing matches and mismatches between infant cry characteristics and maternal cry perception. Primary outcome measures of cognitive, language, motor, and neurologic outcome were administered at 18 months. Caretaking environment measures were also recorded. RESULTS: Statistically significant (P < .05) findings showed that matched groups scored higher on measures of language and cognitive performance than infants in the mismatch groups, with a particular advantage for infants in the matched group in which mothers accurately perceived the higher-pitched cries of their infants. There were no differences between the groups in biologic or sociodemographic factors. Group differences were observed in social support and maternal self-esteem. CONCLUSIONS: Matches and mismatches between infant cry characteristics at 1 month and the mother's perception of the cry are related to cognitive and language outcome at 18 months in term and preterm infants. This relation is probably due to transactional processes in which developmental outcome is affected by the clarity of the infants' signals and by the ability of the mother to accurately perceive her infant's signals. The mother's ability to read her infant's cues may be affected by factors such as social support and self-esteem.

Maternal self-esteem: from theory to clinical practice in a special care nursery.

Maternal self-esteem is examined from theoretical and clinical perspectives. The construct of maternal self-esteem is described, and infant and maternal factors affecting it are delineated. These factors include infant health, maternal perception of infant health, and newborn characteristics. Particular emphasis is placed on maternal perception of the infant's health and behavior. The preterm infant within the context of the special care nursery is used as a clinical illustration, thus bridging the gap from theory to clinical practice. General unit guidelines and clinical intervention strategies, for all disciplines, are suggested to enhance the maternal self-esteem of preterm mothers.