Effect of acute intravenous administration of isoproterenol on cardiorenal hemodynamics in man

By the direct Fick, or the indocyanine-green or both, methods and by renal clearance of inulin and para-aminohippurate (PAH), simultaneous cardiorenal hemodynamic observations were made before and during isoproterenol infusion (0.9-2.6 micrograms/min) into three patients without, and 10 patients with, heart disease. Although a consistent increase in cardiac output (11 to 147%) was noted in all patients, no significant change in glomerular filtration rate or renal blood flow was observed. The percentage of the cardiac output delivered to the kidney during drug infusion decreased in all subjects. The renal extraction of PAH, measured in three patients, was not changed during isoproterenol administration. The infusion of isoproterenol to normovolemic and hypervolemic dogs (10 dogs) increased the cardiac output in all animals but produced no significant change in glomerular filtration rate or renal blood flow. Because the renal blood flow is not affected by the increased cardiac output produced by isoproterenol, the data suggest that there is either a weak or an absent beta-receptor response in the kidney in the dog and man.     

Manganese-enhanced MRI of human choroidal melanoma xenografts

PURPOSE: To test the hypothesis that the structure and function of an experimental human choroidal melanoma xenograft and neighboring non-tumor-bearing retina can be simultaneously assessed by using manganese-enhanced MRI (MEMRI). METHODS: Spheroids grown from the human choroidal melanoma cell line C918 were implanted in the superior suprachoroidal space of 11 WAG/Nij-rnu nude rats. Two weeks later, MRI data were collected 4 hours after intraperitoneal injection of saline or MnCl(2), an MRI contrast agent that can act as a biomarker of cellular demand for ions, such as calcium. The following parameters were measured: (1) tumor signal intensity, (2) inner and outer retinal signal intensity in non-tumor-bearing inferior retina, and (3) whole and inner retinal thickness of inferior retina. Separate MEMRI experiments were performed on spheroids in vitro after MnCl(2) exposure and washing. RESULTS: In vitro, spheroids exposed to MnCl(2) retained sufficient Mn(2+) to demonstrate contrast enhancement during MEMRI. In vivo, injection of MnCl(2) resulted in a 30% increase in tumor signal intensity compared with tumors in rats injected with saline (P < 0.05). In inferior retina of tumor-bearing eyes, outer retinal signal intensity increased by 17% relative to a similar region in control eyes (P < 0.05), but there was no change in the inferior inner retinal intensity. Total retinal thickness of the inferior retina in the tumor-bearing eyes increased by 8%, compared with that in the non-tumor-bearing eyes (P < 0.05). CONCLUSIONS: The present identification of regions of enhanced Mn(2+) uptake in choroidal melanoma and a somewhat unexpected edema and increased outer retinal ion demand in neighboring non-tumor-bearing retina highlights MEMRI as a potentially powerful method for noninvasively monitoring tumor progression and treatment response and efficacy.     

Intestinal pseudo-obstruction as an initial presentation of systemic sclerosis in two children

Two children are reported in whom intestinal pseudo-obstruction was the initial manifestation of systemic sclerosis. Gastrointestinal symptoms and skin changes resolved or improved in both children following treatment with prednisone and penicillamine (case 1) or methotrexate (case 2), although radiological changes of the gastrointestinal tract persisted at 3 and 2 yr of follow-up, respectively.      

Campylobacter enteritis: clinical and epidemiologic features.

Campylobacter fetus subspecies (ssp.) jejuni has been recently recognized to cause diarrheal disease in man. To assess its importance as an enteric pathogen, we prospectively studied 514 patients with diarrhea. Campylobacter fetus ssp. jejuni was isolated from the feces of 26 patients (5%) and seven of 11 of their symptomatic household contacts. This organism was isolated from the feces of only one of 18 asymptomatic household contacts and not at all from 157 other healthy persons. Seventeen of 20 patients from whom C. fetus ssp. jejuni was isolated from fecal culture showed at least a fourfold rise in specific IgG titers. Review of 35 cases of campylobacter enteritis identified a typical clinical syndrome with acute onset of diarrhea, abdominal pain, fever, and constitutional symptoms. Stool examination revealed blood in 60% and polymorphonuclear leukocytes in 78% of patients. Epidemiologic investigation strongly suggested an external source for the infection in 22 of 35 patients.     

Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study

Background

Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20?mg once-daily.

Methods

EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20?mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18?years.A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3?months with the option to continue treatment in 3-month increments, up to a total of 12?months. However, based on most common current practice, children younger than 2?years with catheter-related thrombosis will have a main treatment period of 1?month with the option to prolong treatment in 1-month increments, up to a total of 3?months.

Conclusions

EINSTEIN-Jr will compare previously established 20?mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials.

Trial registration

Clinicaltrials.gov NCT02234843, registered on 9 September 2014.