NIH Disease Funding Levels and Burden of Disease

BACKGROUND: An analysis of NIH funding in 1996 found that the strongest predictor of funding, disability-adjusted life-years (DALYs), explained only 39% of the variance in funding. In 1998, Congress requested that the Institute of Medicine (IOM) evaluate priority-setting criteria for NIH funding; the IOM recommended greater consideration of disease burden. We examined whether the association between current burden and funding has changed since that time. METHODS: We analyzed public data on 2006 NIH funding for 29 common conditions. Measures of US disease burden in 2004 were obtained from the World Health Organization's Global Burden of Disease study and national databases. We assessed the relationship between disease burden and NIH funding dollars in univariate and multivariable log-linear models that evaluated all measures of disease burden. Sensitivity analyses examined associations with future US burden, current and future measures of world disease burden, and a newly standardized NIH accounting method. RESULTS: In univariate and multivariable analyses, disease-specific NIH funding levels increased with burden of disease measured in DALYs (p = 0.001), which accounted for 33% of funding level variation. No other factor predicted funding in multivariable models. Conditions receiving the most funding greater than expected based on disease burden were AIDS ($2474 M), diabetes mellitus ($390 M), and perinatal conditions ($297 M). Depression ($719 M), injuries ($691 M), and chronic obstructive pulmonary disease ($613 M) were the most underfunded. Results were similar using estimates of future US burden, current and future world disease burden, and alternate NIH accounting methods. CONCLUSIONS: Current levels of NIH disease-specific research funding correlate modestly with US disease burden, and correlation has not improved in the last decade

Raised tone reveals ATP as a sympathetic neurotransmitter in the porcine mesenteric arterial bed

The relative importance of ATP as a functional sympathetic neurotransmitter in blood vessels has been shown to be increased when the level of preexisting vascular tone or pressure is increased, in studies carried out in rat mesenteric arteries. The aim of the present study was to determine whether tone influences the involvement of ATP as a sympathetic cotransmitter with noradrenaline in another species. We used the porcine perfused mesenteric arterial bed and porcine mesenteric large, medium and small arteries mounted for isometric tension recording, because purinergic cotransmission can vary depending on the size of the blood vessel. In the perfused mesenteric bed at basal tone, sympathetic neurogenic vasocontractile responses were abolished by prazosin, an α1- adrenoceptor antagonist, but there was no significant effect of α,β-methylene ATP, a P2X receptor-desensitizing agent. Submaximal precontraction of the mesenteric arterial bed with U46619, a thromboxane A2 mimetic, augmented the sympathetic neurogenic vasocontractile responses; under these conditions, both α,β-methylene ATP and prazosin attenuated the neurogenic responses. In the mesenteric large, medium and small arteries, prazosin attenuated the sympathetic neurogenic contractile responses under conditions of both basal and U46619-raised tone. α,β-Methylene ATP was effective in all of these arteries only under conditions of U46619- induced tone, causing a similar inhibition in all arteries, but had no significant effect on sympathetic neurogenic contractions at basal tone. These data show thatATP is a cotransmitter with noradrenaline in porcine mesenteric arteries; the purinergic component was revealed under conditions of partial precontraction, which is more relevant to physiological conditions

Functional properties and pharmacological inhibition of ASIC channels in the human SJ-RH30 skeletal muscle cell line

The rhabdomyosarcoma cell line (SJ-RH30) exhibits both ultrastructural and electrophysiological hallmarks of mammalian skeletal muscle. We have used patch-clamp electrophysiology to study acid-gated currents in these cells. At a holding potential of −60 mV, rapid application of extracellular solutions of pH 6.5 produced inward current responses in ∼85% of cells. The amplitude of these responses exhibited a marked pH dependence. In addition, the kinetics of both activation and desensitization were faster at more acidic pH, whereas the deactivation rate was pH independent. Repeated applications of a pH 6.0 solution produced a tachyphalaxis that could be substantially attenuated by reducing the duration of the acid challenge and increasing the interstimulus interval. The current–voltage relationship of the acid-induced currents was linear at positive potentials but an area of negative slope conductance was observed in the negative potential range. This was not eliminated by removal of extracellular Ca(2+), a manoeuvre which did, however, substantially increase current amplitude. Changing the transmembrane Na(+) gradient altered the current–voltage relationship in a fashion commensurate with an underlying conductance predominantly permeable to Na(+). Pharmacologically, acid-induced currents were blocked 84.4 ± 1.2% by 30 μm amiloride and 91.8 ± 3.0% by a 1 : 1000 dilution of Psalmopoeus cambridgei venom. Inhibition by both agents could be reversed by a short period of compound washout. By contrast, APETx2 had no significant effect on acid-evoked currents. These observations strongly suggest the acid-induced current is mediated by ASIC1 channels. In agreement with this, current responses of SJ-RH30 cells to a pH 6.0 challenge were greatly enhanced by extracellular lactate. These data demonstrate the presence of ASIC1 channels in a cell line with skeletal muscle characteristics. In addition, significant levels of ASIC1 and ASIC3 mRNA were found in skeletal muscle tissue samples. These findings are discussed with regard to the role such a conductance might play if present in skeletal muscle in vivo

Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage

Genetic variation within the factor H–related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury

From HMOs to ACOs: The Quest for the Holy Grail in U.S. Health Policy

The United States has been singularly unsuccessful at controlling health care spending. During the past four decades, American policymakers and analysts have embraced an ever changing array of panaceas to control costs, including managed care, consumer-directed health care, and most recently, delivery system reform and value-based purchasing. Past panaceas have gone through a cycle of excessive hope followed by disappointment at their failure to rein in medical care spending. We argue that accountable care organizations, medical homes, and similar ideas in vogue today could repeat this pattern. We explain why the United States persistently pursues health policy fads—despite their poor record—and how the promotion of panaceas obscures critical debate about controlling health care costs. Americans spend too much time on the quest for the “holy grail”—a reform that will decisively curtail spending while simultaneously improving quality of care—and too little time learning from the experiences of others. Reliable cost control does not, contrary to conventional wisdom, require fundamental delivery system reform or an end to fee-for-service payment. It does require the U.S. to emulate the lessons of other nations that have been more successful at limiting spending through budgeting, systemwide fee schedules, and concentrated purchasing