Humorally mediated posttransplantation septal capillary injury syndrome as a common form of pulmonary allograft rejection: a hypothesis

BACKGROUND: Cellular immunity is the reputed mechanism of lung allograft failure. Humoral immunity is not a commonly recognized pathway. MATERIAL AND METHODS: We describe 22 patients who developed a posttransplantation septal capillary injury syndrome in the absence of panel-reactive antibodies. Factor VIII levels served as an index of microvascular injury. Routine light microscopic studies were performed in a total of 73 biopsies; 54 biopsy specimens were analyzed for deposition of C1q, C4d, C5b-9, and immunoglobulin (IgG, IgM, and IgA). Indirect immunofluorescent testing to assess for antiendothelial cell antibodies was performed using patient serum and human pulmonary microvascular endothelial cell cultures as substrate. Control samples were based on patients who were clinically well at the time of the biopsy. RESULTS: All presented with a deterioration in respiratory function. All patients had elevated factor VIII levels; the levels were significantly greater compared with pretransplantation baseline values (P =<0.03). The biopsy specimens were remarkable for septal capillary necrosis with significant septal capillary deposition of C1q, C3, C4d, and/or C5b-9 along with immunoglobulin, including IgG, with variable endothelial cell localization. The degree of septal capillary necrosis was significantly less in posttransplantation patients who were clinically doing well ( P<0.0001) as was the degree of C1q, C3, C4d, and C5b-9 ( P<0.05). Indirect antiendothelial cell antibody studies were positive in most patients. Treatment interventions included plasmapheresis, resulting in functional improvement: the postpheresis biopsy specimens showed a reduction in both the degree of septal capillary injury (P <0.0003) and the amount of C1q, C3, C4d, and C5b-9 deposition (P <0.05). CONCLUSIONS: Septal capillary injury accompanied by direct and indirect immunofluorescent evidence of humoral immunity is a frequent finding on transbronchial biopsies. The findings suggest that humoral immunity to endothelial-based alloantigen is a common occurrence in lung grafts and may be a critical factor in chronic graft dysfunction.     

Impact of anti-hepatitis Bc-positive grafts on the outcome of liver transplantation for HBV-related cirrhosis

BACKGROUND: The present scarcity of organ donors requires consideration of grafts from sources not previously used. Several studies have addressed the use of grafts from donors who have antibodies to the hepatitis B core antigen (anti-HBc+). The aim of this study was to evaluate the impact of the use of anti-HBc+ grafts in patients transplanted for hepatitis B virus (HBV)-related cirrhosis. METHODS: Recipients of first hepatic transplants from donors with antibodies to HBV were identified retrospectively. All patients who had serology suggestive of active HBV and were negative for hepatitis C and D were included in the analysis. The Kaplan-Meier method was used to assess the actuarial recurrence-free survival on patients with graft survival longer than 1.5 months. The stepwise Cox regression model was used to identify independent predictors of HBV recurrence. RESULTS: One thousand seven hundred seventeen first liver transplants were performed at the Thomas E. Starzl Transplantation Institute from September 1, 1990, to December 31, 1999. HBV was the cause of cirrhosis in 112 patients (6.5%). Thirty-three patients had coexistent viral infection (23 HCV and 10 HDV). Fourteen donors (17.2%) were positive for HBV markers, with nine anti-HBc+ and with five both anti-HBc+ and anti-HB surface-positive; of these, 13 anti-HBc+ organ recipients had long-term survival. Nine (69.2%) of these cases were reinfected versus 20 (35.7%) in the group that received grafts from HBV- donors (P<0.05, Fisher's exact test). The mean time to reinfection was shorter in the anti-HBc+ group (2.9 yr vs. 6.4 yr, P<0.005). There were no statistical differences in graft or patient survival between the two groups. HBV prophylaxis with combined lamivudine and hepatitis B immunoglobulin (HBIG) significantly reduced the reinfection rate (P<0.03). Hepatitis Be (Hbe) antigen-positive recipients trended to faster reinfection (not significant). Cox regression analysis revealed that both anti-HBc graft donor status (RR, 2.796; P=0.020) and combination of lamivudine/HBIG (RR, 0.249; P=0.021) are independently associated with reinfection. CONCLUSIONS: The use of anti-HBc+ liver grafts does not affect graft or patient survival. However, patients who receive these organs are 2.5 times more likely to develop HBV recurrence. Lamivudine and HBIG combination decreases HBV recurrence 4-fold.     

Altered primate glomerular development due to in utero urinary tract obstruction

BACKGROUND: In utero urinary tract obstruction is an important cause of newborn and childhood renal failure. Ureteric obstruction during active nephrogenesis results in cystic renal dysplasia; the earlier and longer the obstruction the more severe the histopathological changes of dysplasia. We have reported on a non-human primate model of non-surgical in utero fetal ureteric obstruction that accurately reflects the human equivalent of obstructive renal dysplasia. A striking feature of this model is the effect of obstruction on normal glomerular development and podocyte survival. METHODS: To study the effect of urinary obstruction on glomerular development, kidneys were studied from fetuses undergoing unilateral ureteric obstruction by ultrasound guided injection of alginate beads as early as 75 days gestation (term gestation = 165 +/- 10 days). These kidneys displayed all the features of human obstructive cystic dysplasia, had reduced weights, and significant deficiencies in terminal ureteric duct branching. RESULTS: A combination of histochemistry, histomorphometry, and immunocytochemistry was used to demonstrate deficient cortical ureteric duct development and branching, reduced glomerular number, and altered glomerular basement membrane formation with in utero urinary tract obstruction. CONCLUSIONS: These data suggest that urinary tract obstruction during active nephrogenesis results in a defect in ureteric duct branching morphogenesis, and altered vascularization of the glomerulus with consequent podocyte dropout and decreased glomerular number. These abnormalities reflect human renal dysplasia, which is associated with compromised postnatal renal function and, thus, should be predictive of postnatal outcome.     

Morbidity after procurement of radial arteries in diabetic patients and the elderly undergoing coronary revascularization

BACKGROUND: The use of radial arteries for coronary revascularization is increasing. There remain concerns regarding alteration of upper extremity function after radial artery procurement. This study evaluates the functional morbidity in higher risk patients. METHODS: Between April 1997 and September 1999, 374 patients underwent unilateral or bilateral radial artery procurement. A questionnaire was used to evaluate symptoms related to motor and sensory function and changes in appearance after radial artery harvest. RESULTS: Two hundred eighty-nine patients were successfully interviewed. The average age was 63 years. Median follow-up was 9.5 months (range, 2 to 23 months). No patient suffered limb loss. Altered gross and fine motor function, residual pain, paresthesias, numbness, pallor, swelling, and altered temperature sensation were compared among diabetic patients, patients older than 70 years, and patients without these characteristics. CONCLUSIONS: Radial artery procurement for elective coronary revascularization can be done with minimal serious morbidity in higher risk patients. The most common symptoms were numbness and paresthesia. Despite the finding of greater residual pain in diabetic patients, we do not believe the use of radial artery conduits is contraindicated in these patients.     

Cognitive research enhances accuracy of food frequency questionnaire reports: results of an experimental validation study

OBJECTIVE: To test whether changing a food frequency questionnaire (FFQ) on the basis of cognitive theory and testing results in greater accuracy. Accuracy was examined for 4 design issues: a) Grouping: asking about foods in a single vs multiple separate questions; b) different forms of a food: asking consumption frequency of each form of a food (eg, skim, 2%, whole milk) vs a nesting approach--asking frequency of the main food (eg, milk) and proportion of times each form was consumed; c) additions (eg, sugar to coffee): asking independent of the main food vs nested under the main foods; d) units: asking frequency and portion size vs frequency of units (eg, cups of coffee). DESIGN: Participants in two randomly assigned groups completed 30 consecutive daily food reports (DFRs), followed by 1 of 2 FFQs that asked about foods consumed in the past month. One was a new, cognitively-based National Cancer Institute (NCI) Diet History Questionnaire; the other was the 1992 NCI-Block Health Habits and History Questionnaire. SUBJECTS/SETTING: 623 participants, age range 25 to 70 years, from metropolitan Washington, DC. Statistical analyses performed Accuracy was assessed by comparing DFR and FFQ responses using categorical (percent agreement) and continuous (rank order correlation, discrepancy scores) agreement statistics. RESULTS: Grouping: accuracy was greater using separate questions. Different forms of food: accuracy was greater using nesting. Additions: neither approach was consistently superior; accuracy of the addition report was affected by accuracy of the main food report. Units: both approaches were similarly accurate. CONCLUSIONS: Accuracy of FFQ reporting can be improved by restructuring questions based on cognitive theory and testing.     

Thyroid hormone,brain development,and the environment

Thyroid hormone is essential for normal brain development. Therefore, it is a genuine concern that thyroid function can be altered by a very large number of chemicals routinely found in the environment and in samples of human and wildlife tissues. These chemicals range from natural to manufactured compounds. They can produce thyroid dysfunction when they are absent from the diet, as in the case of iodine, or when they are present in the diet, as in the case of thionamides. Recent clinical evidence strongly suggests that brain development is much more sensitive to thyroid hormone excess or deficit than previously believed. In addition, recent experimental research provides new insight into the developmental processes affected by thyroid hormone. Based on the authors' research focusing on the ability of polychlorinated biphenyls to alter the expression of thyroid hormone-responsive genes in the developing brain, this review provides background information supporting a new way of approaching risk analysis of thyroid disruptors.     

Use of an index to reflect the aggregate burden of long-term exposure to criteria air pollutants in the United States

Air pollution control in the United States for five common pollutants--particulate matter, ground-level ozone, sulfur dioxide, nitrogen dioxide, and carbon monoxide--is based partly on the attainment of ambient air quality standards that represent a level of air pollution regarded as safe. Regulatory and health agencies often focus on whether standards for short periods are attained; the number of days that standards are exceeded is used to track progress. Efforts to explain air pollution to the public often incorporate an air quality index that represents daily concentrations of pollutants. While effects of short-term exposures have been emphasized, research shows that long-term exposures to lower concentrations of air pollutants can also result in adverse health effects. We developed an aggregate index that represents long-term exposure to these pollutants, using 1995 monitoring data for metropolitan areas obtained from the U.S. Environmental Protection Agency's Aerometric Information Retrieval System. We compared the ranking of metropolitan areas under the proposed aggregate index with the ranking of areas by the number of days that short-term standards were exceeded. The geographic areas with the highest burden of long-term exposures are not, in all cases, the same as those with the most days that exceeded a short-term standard. We believe that an aggregate index of long-term air pollution offers an informative addition to the principal approaches currently used to describe air pollution exposures; further work on an aggregate index representing long-term exposure to air pollutants is warranted.     

Pulses and lipaemia,short- and long-term effect: potential in the prevention of cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of death in most developed countries. Most CVD deaths are preventable through life-style measures such as diet, exercise and avoidance of cigarette smoking. Decreased intake of saturated fat and cholesterol and increased intake of cholesterol-reducing foods, such as pulses, deserve a high priority for activities designed to prevent CVD. Epidemiological and observational studies indicate that habitual intakes of large amounts of dietary fibre or of vegetables are associated with significantly lower rates of CVD. Studies over four decades document the hypocholesterolaemic effect of pulses and soyabeans. We performed a meta-analysis of eleven clinical trials that examined the effects of pulses (not including soyabeans) on serum lipoproteins. Intake of non-soya pulses was associated with these changes: fasting serum cholesterol, -7.2 %, 95 % CI -5.8, -8.6 %; LDL-cholesterol, -6.2 %, 95 % CI -2.8, -9.5 %; HDL-cholesterol, +2.6 %, 95 % CI +6.3, -1.0 %; triacylglycerols, -16.6 %, 95 % CI -11.8 %, -21.5 %; and body weight, -0.9 %, 95 % CI +2.2 %, -4.1 %. The hypocholesterolaemic effects of pulses appear related, in estimated order of importance, to these factors: soluble dietary fibre, vegetable protein, oligosaccharides, isoflavones, phospholipids and fatty acids, saponins and other factors. Intake of pulses may also reduce risk for CVD by favourable effects on blood pressure, glycaemia and risk for diabetes, and risk for obesity. Overall, the available evidence indicates that regular consumption of pulses may have important protective effects on risk for CVD.     

Intestinal brush border membrane catalyzes hydrolysis of pyridoxine-5'-beta-D-glucoside and exhibits parallel developmental changes of hydrolytic activities toward pyridoxine-5'-beta-D-glucoside and lactose in rats

Pyridoxine-5'-beta-D-glucoside (PNG) is a major form of vitamin B-6 in plant foods that exhibits partial bioavailability as vitamin B-6 in humans. We previously identified an intestinal mucosal cytosolic PNG hydrolase that catalyzes the partial hydrolysis of PNG absorbed without prior deglycosylation. Recent observations that the brush border membrane also catalyzes PNG hydrolysis led to the hypothesis that PNG hydrolysis may be another function of the beta-glucosidase lactase-phlorizin hydrolase (LPH) and, thus, brush border PNG hydrolysis would undergo a developmental decline similar to that of lactose hydrolysis. In this study, the relationships among hydrolytic activities in small intestinal cytosolic and brush border fractions in rats (n = 9 per group) of various ages (1-2 d and 2, 4, 8, 12 and 24 wk) were examined. In vitro specific activities toward PNG and lactose were greater in brush border than cytosol, and these were greater in newborn rats than in all other age groups (P < 0.01). Brush border activities toward PNG and lactose and were closely correlated (r = 0.84; P < 0.0001). These findings suggest that the hydrolysis of PNG is catalyzed at least partially at the brush border and that the bioavailability of PNG may be influenced by the residual LPH activity in children and adults.     

Assessment of chronic illness care (ACIC): a practical tool to measure quality improvement

OBJECTIVE: To describe initial testing of the Assessment of Chronic Illness Care (ACIC), a practical quality-improvement tool to help organizations evaluate the strengths and weaknesses of their delivery of care for chronic illness in six areas: community linkages, self-management support, decision support, delivery system design, information systems, and organization of care. DATA SOURCES: (1) Pre-post, self-report ACIC data from organizational teams enrolled in 13-month quality-improvement collaboratives focused on care for chronic illness; (2) independent faculty ratings of team progress at the end of collaborative. STUDY DESIGN: Teams completed the ACIC at the beginning and end of the collaborative using a consensus format that produced average ratings of their system's approach to delivering care for the targeted chronic condition. Average ACIC subscale scores (ranging from 0 to 11, with 11 representing optimal care) for teams across all four collaboratives were obtained to indicate how teams rated their care for chronic illness before beginning improvement work. Paired t-tests were used to evaluate the sensitivity. of the ACIC to detect system improvements for teams in two (of four) collaboratives focused on care for diabetes and congestive heart failure (CHF). Pearson correlations between the ACIC subscale scores and a faculty rating of team performance were also obtained. RESULTS: Average baseline scores across all teams enrolled at the beginning of the collaboratives ranged from 4.36 (information systems) to 6.42 (organization of care), indicating basic to good care for chronic illness. All six ACIC subscale scores were responsive to system improvements diabetes and CHF teams made over the course of the collaboratives. The most substantial improvements were seen in decision support, delivery system design, and information systems. CHF teams had particularly high scores in self-management support at the completion of the collaborative. Pearson correlations between the ACIC subscales and the faculty rating ranged from .28 to .52. CONCLUSION: These results and feedback from teams suggest that the ACIC is responsive to health care quality-improvement efforts and may be a useful tool to guide quality improvement in chronic illness care and to track progress over time.