Magnetite albumin microspheres: a new MR contrast material

A superparamagnetic MR contrast agent was synthesized by incorporating 150-250-A particles of magnetite (Fe3O4, Fe2O3) in 1-5 microns human serum albumin microspheres. Magnetite albumin microspheres (MAM) target almost exclusively to the reticuloendothelial system after IV administration, are stable in vitro and in vivo, and possess a long shelf life. The agent has a large magnetic susceptibility effect that selectively reduces T2 with little effect on T1. Biodistribution studies that use a dose of 20 mg MAM/kg show prompt clearance from the blood pool with marked decrease in T2 for rat liver (40%) and spleen (45%) with a small decrease in liver (5%) and spleen (10%) T1 values. Pulmonary T1 and T2 decrease transiently over the first 24 hr, while no significant changes were observed in other tissues. Imaging of a rabbit VX2 tumor model resulted in a 200% increase in the contrast ratio of VX2 tumor to normal liver on T2-weighted and mixed T1-/T2-weighted pulse sequences after administration of contrast agent. The extreme potency, excellent targeting, and apparent lack of toxicity of this agent suggest that MAM probably will have a clinical application in detecting focal hepatic and splenic lesions.     

Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases

PURPOSE: Excessive accumulation of lipofuscin is observed in numerous degenerative retinal diseases. A toxic vitamin A-based fluorophore (A2E) present within lipofuscin has been implicated in the death of RPE and photoreceptor cells. Here, we used an animal model that manifests accelerated lipofuscin accumulation (ABCA4-/- mutant) to evaluate the efficacy of a therapeutic approach based on reduction of serum retinol. METHODS: N-(4-hydroxyphenyl)retinamide (HPR) potently and reversibly reduces serum retinol. The interaction of HPR with retinol binding protein (RBP) and transthyretin was studied by spectrofluorometry and size-exclusion chromatography. To assess the effects of HPR on visual cycle retinoids and A2E biosynthesis, HPR was chronically administered to ABCA4-/- mice. Mice were evaluated using biochemical, electrophysiological, and morphologic techniques. RESULTS: Administration of HPR to ABCA4-/- mice caused immediate, dose-dependent reductions in serum retinol and RBP. Chronic administration produced commensurate reductions in visual cycle retinoids and arrested accumulation of A2E and lipofuscin autofluorescence in the RPE. Physiologically, HPR treatment caused modest delays in dark adaptation. Chromophore regeneration kinetics, light sensitivity of photoreceptors, and phototransduction processes were normal. Histologic examinations showed no alteration of retinal cytostructure or morphology. CONCLUSIONS: These findings demonstrate the vitamin A-dependent nature of A2E biosynthesis and validate a novel therapeutic approach with potential to halt the accumulation of lipofuscin fluorophores in the eye.     

Impact of interhospital transfer on patient outcomes in emergency general surgery

BackgroundEmergency general surgery patients are at an increased risk for morbidity and mortality compared to their elective surgery counterparts. The complex nature of emergency general surgery conditions can challenge community hospitals, which may lack appropriate systems and personnel. Outcomes related to transfer have not been well-established. We aimed to compare postoperative outcomes of patients who were transferred from another hospital to a center with dedicated acute care surgery services with patients admitted directly to the acute care surgery centers.MethodsWe performed a secondary analysis of a national, multicenter review of emergency general surgery patients undergoing complex emergency general surgery at 5 centers across Canada. The primary outcome was the development of any complication. The adjusted odds of postoperative complication was assessed using logistic regression, controlling for age, comorbidities, duration of stay before transfer, American Society of Anesthesiologists classification, and booking priority.ResultsA total of 1,846 patients were included in the study, and 176 (9.5%) were transferred. Of these 21% (n = 37) underwent an operative procedure, and 15% (n = 27) underwent an operation at the transferring center. Transferred patients were more likely to have at least 1 comorbidity (68% vs 57%; P = .004), were classified as greater urgency on arrival (<2 hours booking priority, 43% vs 17%; P < .001), had a greater American Society of Anesthesiologists classification (American Society of Anesthesiologists ≥3 = 81% vs 65%; P < .001), a greater duration of operation (119 vs 110 minutes; P = .004), and were more likely to undergo a second operation (28% vs 14%; P < .001) compared to patients directly admitted to an acute care surgery center. On univariate analysis, transferred patients had greater rates of complications (48% vs 31%; P < .001), mortality (14% vs 7%; P = .005), and admission to the intensive care unit (22% vs 12%; P < .001). Transfer status remained an independent predictor of complication (odds ratio 1.9 [95% confidence interval 1.3–2.7]; P < .001) and intensive care unit admission (odds ratio 1.9 [95% confidence interval 1.2–3.0]; P = .007), but not mortality (odds ratio 1.1 [95% confidence interval 0.6–1.9]; P = .79) on regression analysis.ConclusionComplex emergency general surgery patients transferred to acute care surgery centers may have worse outcomes and greater use of resources compared to those admitted directly. This finding has clinically and financially important implications for the design and regionalization of acute care surgery services as well as resource allocation at acute care surgery centers.     

The fallibility of medical judgment as a consequence of the inexactness of observations

The paper attempts to give an account of the fallibility of medical judgments without recourse to the incompleteness of scientific knowledge. It is argued that because of the inexactness of observations and thus the existence of borderline cases any theory applied for explanation and predicition will produce some false results. This state of affairs is independent of the nature of a theory, i.e., it applies both for non-probabilistic and for probabilistic theories. Some epistemological issues and consequences with regard to a better understanding of clinical reasoning are discussed and the view is compared with the theory of medical fallibility of Gorovitz and MacIntyre.¹ This revised version was published online in July 2006 with corrections to the Cover Date.     

The immunoregulatory influence of transforming growth factor beta in thyroid autoimmunity: TGF beta inhibits autoreactivity in Graves' disease.

The immunoregulatory influence of transforming growth factor beta (TGF beta) was studied in patients with Graves' disease and in normal controls. Special attention was given to determine how TGF beta affects the interaction between thyroid epithelial cells and T lymphocytes. Human recombinant TGF beta 1 (rTGF beta 1) was immunosuppressive in patients with Graves' disease and in controls. In both groups it inhibited the proliferation of peripheral blood mononuclear cells and of peripheral and thyroid derived T cell lines and clones in response to non-specific stimuli. It also decreased the number of serine esterases expressing cytotoxic T cells and suppressed the recognition of thyroid epithelial cells by thyroid autoantigen specific T cell clones. Inhibition of autoantigen recognition was not only observed when rTGF beta 1 was added to the thyroid epithelial cell/lymphocyte co-culture, but was also found when thyroid epithelial cells were preincubated with rTGF beta 1, which was then removed before the initiation of co-culture. This was probably as a result of a decrease in the antigenicity of the target cells, as rTGF beta 1 also suppressed thyroid peroxidase as well as HLA class II autoantigen expression, in cultured thyroid epithelial cells. These results demonstrate that TGF beta may exert a variety of down-regulatory influences in Graves' disease. It may be of importance for the suppression of autoaggression in persons predisposed to autoimmunity; may be quantitatively overrun by immunostimulatory influences in the acute phase of the disease; and may be important for the induction of remission in patients with Graves' disease.     

Prognostic value of NT-proBNP in patients with systemic morphological right ventricles: A single-centre experience

In systemic morphological right ventricles after atrial redirection surgery, NT-proBNP is correlated with NYHA-class, ventricular function and subaortic AV-valve regurgitation (TR). The impact of NT-proBNP on adverse clinical outcomes is, however, unknown.