Context Diarrhea-associated hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children. Most cases are caused by an intestinal infection with Shiga toxin-producing strains of Escherichia coli.Objective To determine if administration of an oral agent that binds Shiga toxin could diminish the severity of diarrhea-associated HUS in pediatric patients. Design, Setting, and Patients Multicenter, randomized, double-blind, placebocontrolled clinical trial of 145 children (96 experimental and 49 placebo) aged 6 months to 18 years with diarrhea-associated HUS conducted between July 27, 1997, and April 14, 2001, at 26 tertiary care pediatric nephrology centers in the United States and Canada. Trial included 2 phases, the hospital course for treatment of the acute illness and a 60-day outpatient follow-up period after discharge from the hospital.Intervention Patients were assigned to receive the binding agent, 500 mg/kg daily, or cornmeal placebo orally for 7 days in a 2:1 randomization scheme.
Main Outcome MeasuresCombined frequency of death or serious extrarenal events and need for dialysis in the experimental vs placebo group.Results A total of 62 patients (43%) were male and 123 (85%) were white. The median age of the patients was 4.2 years. Most patients (59%) were transferred from other hospitals to participating sites. The severity of disease at the time of randomization was comparable in the 2 groups. The prevalence of death or serious extrarenal events was 18% and 20% in the experimental and placebo groups, respectively (P=.82). Dialysis was required in 42% of experimental and 39% of placebo groups (P=.86).Conclusions Oral therapy with a Shiga toxin-binding agent failed to diminish the severity of disease in pediatric patients with diarrhea-associated HUS.
Background and objectives: Diarrhea-associated hemolytic uremic syndrome (D؉HUS) is a common cause of acute kidney injury in children. Mutations in alternative pathway (AP) complement regulatory proteins have been identified in severe cases of thrombotic microangiopathy, but the role of the AP in D؉HUS has not been studied. Therefore, we determined whether plasma levels of markers of activation of the AP are increased in D؉HUS and are biomarkers of the severity of renal injury that predict the need for dialysis.Design, setting, participants, & measurements: Patients were randomly selected from among participants in the HUS-SYNSORB Pk trial. Plasma samples were collected on days 1, 4, 7, and 10 after enrollment and day 28 after discharge from the hospital. Levels of two complement pathway products, Bb and SC5b-9, were determined by ELISA.Results: Seventeen children (6 boys and 11 girls; age, 5.4 ؎ 3.5 yr) were studied. Eight (47%) required dialysis support, and two had serious extrarenal events. On the day of enrollment, plasma levels of Bb and SC5b-9 were significantly increased in all patients compared with healthy controls (P < 0.01). The elevated concentrations normalized by day 28 after discharge. Circulating levels of complement pathway fragments did not correlate with severity of renal injury or occurrence of complications.Conclusions: Patients with acute-onset D؉HUS manifest activation of the AP of complement that is temporally related to the onset of disease and that resolves within 1 mo. Therapies to inhibit the AP of complement may be useful in attenuating the severity of renal injury and extrarenal complications.
Objective-The view that everyday function is preserved in mild cognitive impairment may be problematic. The objectives of this study were to determine the magnitude of impairment in everyday function in patients with mild cognitive impairment and Alzheimer's disease using a novel sensitive performance-based measure (the UCSD Performance-Based Skills Assessment; UPSA), contrast it with use of an informant-based measure (the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory; ADCS-ADL), and model the relationship between cognitive measures and the performance-based measure.Method-Fifty cognitively normal elders, 26 patients who met criteria for amnestic mild cognitive impairment, and 22 patients who suffered from mild to moderate Alzheimer's disease were assessed on the UPSA, the ADCS-ADL, and a battery of neurocognitive tests.Results-Patients with mild cognitive impairment had significant impairments on the UPSA but not on the ADCS-ADL. The magnitude of the effect size between the cognitively healthy and the mild cognitive impairment group for the UPSA was large (d=0.86). A strong and significant relationship was observed between cognitive performances in speed (R 2 =0.37), episodic memory (R 2 =0.10), and semantic processing (R 2 =0.03) and UPSA score using multiple regression models. The psychometric properties of the UPSA were acceptable, as were its sensitivity and specificity in contrasts between cognitively normal elders and patients with mild cognitive impairment and between the latter group and patients with Alzheimer's disease.Conclusions-These findings indicate that performance-based measures of function may be a sensitive tool in studies of Alzheimer's disease and mild cognitive impairment and suggest the need for a reconceptualization of the relationship between cognition and function in mild cognitive impairment so that they can be usefully aligned.Mild cognitive impairment is a less-than-benign diagnosis because it is associated with an elevated risk of incident Alzheimer's disease and more rapid cognitive decline (1,2). The rate of conversion from mild cognitive impairment to Alzheimer's disease may be 10%-12% per year (3). Neuropathologically, mild cognitive impairment (in many but not all cases) appears to be a transitional state of evolving Alzheimer's disease (4,5
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript imaging using the amyloid binding ligand carbon-11-PIB has suggested that the amyloid burden in mild cognitive impairment is intermediate between healthy comparison subjects and patients with Alzheimer's disease (6,7). By recommended diagnostic criteria, individuals with mild cognitive impairment have an impairment of 1.5 standard deviations in episodic memory but essentially preserved everyday function (8,9).Several lines of evidence suggest that the diagnostic criterion relating to function may be problematic. First, neuropsychiatric conditions with associated cognitive impairments are also reliably associated with sequelae in ...
The majority of patients with D+HUS have renal tubular epithelial injury, as evidenced by elevated urinary NGAL excretion. Urinary NGAL levels below 200 ng/ml within five days of hospitalization may be an adjunctive marker that defines less severe renal involvement.
Hereditary hemorrhagic telangiectasia (HHT) is a highly debilitating and life-threatening genetic vascular disorder arising from endothelial cell (EC) proliferation and hypervascularization, for which no cure exists. Because HHT is caused by loss-of-function mutations in bone morphogenetic protein 9 (BMP9)-ALK1-Smad1/5/8 signaling, interventions aimed at activating this pathway are of therapeutic value. We interrogated the whole-transcriptome in human umbilical vein ECs (HUVECs) and found that ALK1 signaling inhibition was associated with a specific pro-angiogenic gene expression signature, which included a significant elevation of DLL4 expression. By screening the NIH clinical collections of FDA-approved drugs, we identified tacrolimus (FK-506) as the most potent activator of ALK1 signaling in BMP9-challenged C2C12 reporter cells. In HUVECs, tacrolimus activated Smad1/5/8 and opposed the pro-angiogenic gene expression signature associated with ALK1 loss-of-function, by notably reducing Dll4 expression. In these cells, tacrolimus also inhibited Akt and p38 stimulation by vascular endothelial growth factor, a major driver of angiogenesis. In the BMP9/10-immunodepleted postnatal retina-a mouse model of HHT vascular pathology-tacrolimus activated endothelial Smad1/5/8 and prevented the Dll4 overexpression and hypervascularization associated with this model. Finally, tacrolimus stimulated Smad1/5/8 signaling in C2C12 cells expressing BMP9-unresponsive ALK1 HHT mutants and in HHT patient blood outgrowth ECs. Tacrolimus repurposing has therefore therapeutic potential in HHT.
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