The development of anti-glomerular basement membrane nephritis in two children with Alport's syndrome after renal transplantation: characterization of the antibody target

Two children with Alport's syndrome are described, who developed anti-glomerular basement membrane (GBM) antibody-mediated nephritis after renal transplantation. The reactivity of antibodies in their serum with collagenase-solubilized normal GBM was examined by SDS-PAGE with one- and two-dimensional immunoblotting. The specificity was compared with that of antibodies present in serum from a patient with Goodpasture's syndrome, and a mouse monoclonal antibody (MCA-P1), directed against the Goodpasture antigen. All reacted in a similar way with collagenase-solubilized GBM. Since abnormalities in the composition of the GBM are present in Alport's syndrome, it is proposed that differing antigen composition of GBM in the host compared with the donor kidney, together with transplant rejection, may have provoked the development of post-transplant anti-GBM antibodies.     

Actin-free Gc globulin: a rapidly assessed biomarker of organ dysfunction in acute liver failure and cirrhosis.

Reductions in serum levels of Gc globulin, a hepatically synthesized component of the extracellular actin scavenger system responsible for complexing circulating actin and attenuating intravascular microthrombus formation, are associated with poor outcome in acute liver failure. Clinically applicable assays of the important actin-free fraction (Af-Gc) have not been available until now. We measured actin-free Gc globulin levels with a novel, rapid assay in 61 cases of acute liver failure (ALF) and in 91 patients with cirrhosis (40 of whom were clinically unstable with extrahepatic organ dysfunction), and studied associations with liver dysfunction, extrahepatic organ dysfunction, indices of disseminated coagulation, and outcome. Reductions in Af-Gc levels mirrored hepatic dysfunction and organ dysfunction in both groups, and discriminated patients with poor prognosis from those with good prognosis in the ALF cohort. Levels were lowest in patients with ALF (10% of control values), but levels were also markedly reduced in both unstable (28%) and stable (44%) patients with cirrhosis. Associations with markers of disseminated intravascular coagulation were seen in both groups, most notably in the cirrhosis cohort, supporting a pathophysiological role for reduced Af-Gc in the evolution of organ dysfunction. In acetaminophen-induced ALF, Af-Gc identified patients with poor prognosis as well as did the Acute Physiology and Chronic Health Evaluation (APACHE II) score (area under the receiver operating characteristic curve, 0.7), and in cirrhosis, Af-Gc was an independent predictor of mortality by multifactorial analysis. In conclusion, the importance of Af-Gc reductions in the development of multiple organ dysfunction in ALF and cirrhosis is highlighted, probably resulting from reduced hepatic production and peripheral exhaustion of this arm of the extracellular actin scavenger system.     

Changes in the nature of sentence production during the period of grammatical development.

The sentence production capabilities of young children undergo major changes during the same period in which grammar develops. This article reports data from a cross-sectional sample of 52 children between the ages of 1;10 (years; months) and 4;0, and looks specifically at the dichotomy between stalls, sentence disruptions that are the result of glitches in sentence production, and revisions, sentence disruptions that involve self-monitoring and the rapid replacement of words or morphosyntactic alternatives. It was found that revision rate increased with level of grammatical development, but that stall rate was not related to grammatical development. These results indicate that children's capacities for self-monitoring and maintenance of multiple linguistic alternatives increase during the period of grammatical development.     

Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment.

Three years of daily alendronate treatment increases microdamage in vertebral bone but does not significantly increase it beyond levels of microdamage found after 1 yr of treatment. This suggests microdamage accumulation peaks during the early period of bisphosphonate treatment and does not continue to accumulate with longer periods of treatment. INTRODUCTION: Clinically relevant doses of alendronate increase vertebral microdamage by 4- to 5-fold in skeletally mature beagles after 1 yr of treatment. The goal of this study was to determine whether microdamage would continue to accumulate with 3 yr of alendronate treatment in an intact beagle dog model. MATERIALS AND METHODS: One-year-old female beagles were treated with daily oral doses of vehicle (VEH, 1 ml/kg/d) or alendronate (ALN, 0.2 or 1.0 mg/kg/d) for 3 yr. These ALN doses were chosen to approximate, on a milligram per kilogram basis, those used to treat osteoporosis (ALN0.2) and Paget's disease (ALN1.0). Microdamage accumulation, static and dynamic histomorphometry, densitometry, and mechanical properties of lumbar vertebrae were assessed. Comparisons were made among the three groups treated for 3 yr and also within each treatment group to animals treated under the same conditions for 1 yr. RESULTS: Overall microdamage accumulation (crack surface density) was not significantly higher in animals treated for 3 yr with either dose of ALN, whereas crack density increased significantly (100%; p < 0.05) with the higher dose of ALN compared with VEH. Both ALN doses significantly suppressed the rate of bone turnover (-60% versus VEH). There was no difference among groups for any of the structural biomechanical properties-ultimate load, stiffness, or energy absorption. However, when adjusted for areal BMD, ALN-treated animals had significantly lower energy absorption (-20%) compared with VEH. Toughness, the energy absorption capacity of the bone tissue, was significantly lower than VEH for both ALN0.2 (-27%) and ALN1.0 (-33%). Compared with animals treated for 1 yr, there was no significant difference in microdamage accumulation for either ALN dose. VEH-treated animals had significantly lower bone turnover (-58%) and significantly higher levels of microdamage (+300%) compared with values in 1-yr animals. Toughness was significantly lower in animals treated for 3 yr with ALN1.0 (-18%) compared with animals treated for 1 yr, whereas there was no difference in toughness between the two treatment durations for either VEH or ALN0.2. CONCLUSIONS: Although 3 yr of ALN treatment resulted in higher microcrack density in vertebral trabecular bone compared with control dogs, the amount of microdamage was not significantly higher than animals treated for 1 yr with similar doses. This suggests that bisphosphonate-associated increases in microdamage occur early in treatment. Because toughness continued to decline significantly over 3 yr of treatment at the higher ALN dose, decreases in toughness are probably not dependent on damage accumulation.     

Clinical risk factors for fractures in multi-ethnic women: the Women's Health Initiative.

To identify risk factors for fractures in multi-ethnic women, we studied 159,579 women enrolled in the Women's Health Initiative. In general, risk factors for fractures were similar across ethnic groups. However, irrespective of their ethnicity, women with multiple risk factors have a high risk of fracture. Targeting these high-risk women for screening and intervention could reduce fractures. INTRODUCTION: Fracture rates tend to be lower in minority women, but consequences may be greater. In addition, the number of fractures is expected to increase in minority women because of current demographic trends. There are limited prospective data on risk factors for fractures in minority women. MATERIALS AND METHODS: We studied 159,579 women 50-79 yr of age enrolled in the Women's Health Initiative. Information on risk factors was obtained by questionnaire or examination. Nonspine fractures that occurred after study entry were identified over an average follow-up of 8 +/- 2.6 (SD) yr. RESULTS: Annualized rates (%) of fracture in whites, blacks, Hispanics, Asians, and American Indians were 2.0, 0.9, 1.3, 1.2, and 2.0, respectively. Significant predictors [HR (95% CI)] of fractures by ethnic group were as follows: blacks: at least a high school education, 1.22 (1.0, 1.5); (+) fracture history, 1.7 (1.4, 2.2); and more than two falls, 1.7 (1.9, 2.0); Hispanics: height (>162 cm), 1.6 (1.1, 2.2); (+) fracture history, 1.9 (1.4, 2.5); more than two falls, 1.8 (1.4, 2.3); arthritis, 1.3 (1.1, 1.6); corticosteroid use, 3.9 (1.9, 8.0); and parental history of fracture, 1.3 (1.0, 1.6); Asians: age (per 5 yr), 1.2 (1.0, 1.3); (+) fracture history, 1.5 (1.1, 2.0); current hormone therapy (HT), 0.7 (0.5, 0.8); parity (at least five), 1.8 (1.1, 3.0); more than two falls, 1.4 (1.1, 1.9); American Indian: (+) fracture history, 2. 9 (1.5, 5.7); current HT, 0.5 (0.3, 0.9). Women with eight or more risk factors had more than a 2-fold higher rate of fracture compared with women with four or fewer risk factors. Two ethnicity x risk factor interactions were identified: age and fall history. CONCLUSIONS: Irrespective of their ethnicity, women with multiple risk factors have a high risk of fracture. Targeting these high-risk women for screening and intervention could reduce fractures.     

Screening for type 2 diabetes mellitus in children and adolescents: attitudes, barriers, and practices among pediatric clinicians.

OBJECTIVE: The American Diabetes Association (ADA) recommends screening children at risk for type 2 diabetes with a fasting plasma glucose test or an oral glucose tolerance test. The purpose of this study was to describe attitudes, barriers, and practices related to type 2 diabetes screening in children among pediatric clinicians. METHODS: Pediatricians, nurse practitioners and physician assistants from a multispecialty, group practice in Eastern Massachusetts completed a mailed survey. To assess screening practice, three vignettes were presented representing pediatric patients with low, moderately high, and high risk for type 2 diabetes. The moderately high-risk and high-risk patients met ADA criteria for screening. ADA-consistent practice was defined as only screening the moderately high-risk and high-risk patients; lower-threshold practice was defined as also screening the low-risk patient; and higher threshold practice was screening only the high-risk patient. RESULTS: Sixty-two of 90 clinicians responded (69%). Based on intent to screen in the 3 vignettes, 21% of respondents reported ADA-consistent screening practice, 39% lower-threshold, and 35% higher-threshold screening practice. Five percent had incomplete or nonclassifiable responses. Many clinicians ordered screening tests other than those recommended by the ADA; few (< or =8% in any vignette) ordered only an ADA-recommended test. Preferences for nonfasting tests were influenced by nonmedical factors such as access to or cost of transportation. Inadequate patient education materials and unclear recommendations for appropriate screening methods were the most frequently reported moderate/strong barriers to screening. CONCLUSIONS: Most respondents reported type 2 diabetes screening practices that differed from current ADA recommendations. Our findings suggest that type 2 diabetes screening tests must be practical for clinicians and patients if they are to be used in pediatric practice. Further study of the benefits and cost-effectiveness of type 2 diabetes screening in children is warranted to clarify the role and optimal methods for screening in pediatric primary care.