The Jewel in the Crown: Specific Aims Section of Investigator-Initiated Grant Proposals.

The specific aims section of National Institutes of Health and other grants is the most important component, as it summarizes the scientific premise, gap in current knowledge, hypotheses, methods, and expected results of the project proposed. The reviewer usually reads this section first and forms an immediate opinion, usually confirmed on reading the entire grant. This treatise reviews the philosophical background underlying generation of hypotheses, emphasizes the important characteristics of the specific aims section, and offers a point-by-point roadmap for writing.

Pharmacokinetic Model of the Transport of Fast-Acting Insulin From the Subcutaneous and Intradermal Spaces to Blood.

Pharmacokinetic (PK) models describing the transport of insulin from the injection site to blood assist clinical decision making and are part of in silico platforms for developing and testing of insulin delivery strategies for treatment of patients with diabetes. The ability of these models to accurately describe all facets of the in vivo insulin transport is therefore critical for their application. Here, we propose a new model of fast-acting insulin analogs transport from the subcutaneous and intradermal spaces to blood that can accommodate clinically observed biphasic appearance and delayed clearance of injected insulin, 2 phenomena that are not captured by existing PK models.

Cardiovascular and pulmonary responses to increased acceleration forces during rest and exercise.

Background: The reduced cardiac output (CO) secondary to increased acceleration forces (+Gz) has applicability to daily life and pathophysiology. Increased +Gz and reduced CO affect the lung, resulting in reduced oxygen transport. A variety of studies have examined tolerance to high +Gz.

Revised one-step method for determination of cardiac output.

Cardiac output (Q) is a determinant of blood pressure and O(2) delivery and is critical in the maintenance of homeostasis, particularly during environmental stress and exercise. Cardiac output can be determined invasively in patients; however, indirect methods are required for other situations. Soluble gas techniques are widely used to determine (Q).

Observation of an exotic baryon with S=+1 in photoproduction from the proton.

The reaction gamma p-->pi(+)K(-)K(+)n was studied at Jefferson Laboratory using a tagged photon beam with an energy range of 3-5.47 GeV. A narrow baryon state with strangeness S=+1 and mass M=1555+/-10 MeV/c(2) was observed in the nK(+) invariant mass spectrum.

Measurement of the proton spin structure function g1(x,Q2) for Q2 from 0.15 to 1.6 GeV2 with CLAS.

Double-polarization asymmetries for inclusive ep scattering were measured at Jefferson Lab using 2.6 and 4.3 GeV longitudinally polarized electrons incident on a longitudinally polarized NH3 target in the CLAS detector.

Cardiac output: a view from Buffalo.

Cardiac output (Q) is a primary determinant of blood pressure and O2 delivery and is critical in the maintenance of homeostasis, particularly during environmental stress. Cardiac output can be determined invasively in patients; however, indirect methods are required for other situations. Soluble gas techniques are widely used to determine Q.

Photoproduction of the omega meson on the proton at large momentum transfer.

The differential cross section, dsigma/dt, for omega meson exclusive photoproduction on the proton above the resonance region (2.6 View Article and Find Full Text PDF

Eta photoproduction on the proton for photon energies from 0.75 to 1.95 GeV.

Differential cross sections for gammap-->etap have been measured with tagged real photons for incident photon energies from 0.75 to 1.95 GeV.

Q2 Dependence of quadrupole strength in the gamma*p --> Delta(+)(1232) --> p pi(0) transition.

Models of baryon structure predict a small quadrupole deformation of the nucleon due to residual tensor forces between quarks or distortions from the pion cloud. Sensitivity to quark versus pion degrees of freedom occurs through the Q2 dependence of the magnetic (M1+), electric (E1+), and scalar (S1+) multipoles in the gamma*p-->Delta(+)-->p pi(0) transition. We report new experimental values for the ratios E(1+)/M(1+) and S(1+)/M(1+) over the range Q2 = 0.

First measurement of the double spin asymmetry in (-->)e(-->)p-->e(prime)pi(+)n in the resonance region.

The double spin asymmetry in the (-->)e(-->)p --> e(prime)pi(+)n reaction has been measured for the first time in the resonance region for four-momentum transfer Q2 = 0.35-1.5 GeV(2).

Photoproduction of the rho(0) meson on the proton at large momentum transfer.

The differential cross section, d sigma/dt, for rho(0) meson photoproduction on the proton above the resonance region was measured up to a momentum transfer -t = 5 GeV2 using the CLAS detector at the Thomas Jefferson National Accelerator Facility. The rho(0) channel was extracted from the measured two charged-pion cross sections by fitting the pi(+)pi(-) and p pi(+) invariant masses. The low momentum transfer region shows the typical diffractive pattern expected from Reggeon exchange.

The ep -->e'p eta reaction at and above the S11(1535) baryon resonance.

New cross sections for the reaction e p-->e p eta are reported for total center of mass energy W = 1.5--1.86 GeV and invariant momentum transfer Q2 = 0.

Cardiovascular response to submaximal exercise in sustained microgravity.

Cardiac output (Q), heart rate (HR), blood pressure, and oxygen consumption (VO2) were measured repeatedly both at rest and at two levels of exercise in six subjects during microgravity exposure. Exercise was at 30 and 60% of the workload producing the individual's maximal VO2 in 1 G. Three of the subjects were on a 9-day flight, Spacelab Life Sciences-1, and three were on a 15-day flight, Spacelab Life Sciences-2.

Cardiorespiratory response to lower body negative pressure.

The cardiovascular effects of supine lower body negative pressure (LBNP, 0 mm Hg, -8 mm Hg, -15 mm Hg, -25 mm Hg, -35 mm Hg, and -45 mm Hg) were studied in humans (n = 10). The LBNP's were applied in a random order (three per session) for 20 min, with 15 min between each LBNP. Leg blood flow, cardiac output (Q), stroke volume (SV) and estimated lung blood volume were significantly reduced at -15 mm Hg.

Local pulmonary blood flow: control and gas exchange.

We studied the local response of the pulmonary vasculature to combined changes in alveolar PO2 and PCO2 in the right apical lobe (RAL) of six conscious sheep. That lobe inspired an O2-CO2-N2 mixture adjusted to produce one of 12 alveolar gas compositions: end-tidal PCO2 (PETCO2) of 40, 50, and 60 Torr, each coupled with end-tidal PO2 (PETO2) of 100, 75, 50, and 25 Torr. In addition, at each of the four PETO2, the inspired CO2 was set to 0 and PETCO2 was allowed to vary as RAL perfusion changed.

Pulmonary hypoxic vasoconstriction: how strong? How fast?

We have developed a minimally invasive technique for studying regional blood flow in conscious sheep, bypassing the complications of open-chest surgery, flow probes and tracer infusion. We quantitate regional perfusion continuously on the basis of regional clearance of methane (methane is produced in the sheep rumen, enters the circulation and is eliminated nearly completely (greater than 95%) in the lung). Tracheal intubation with a dual-lumen catheter isolates the gas exchange of the right apical lobe (RAL; less than 15% of the lung) from that of the remainder of the lung, which serves as a control (CL).

Prolonged lobar hypoxia in vivo enhances the responsivity of isolated pulmonary veins to hypoxia.

The hypoxic response of pulmonary vessels isolated from eight sheep whose right apical lobes (RAL) had inspired 100% N2 for 20 h was studied. The RAL of these conscious sheep inspired hypoxic gas and the remainder of the lung inspired air. During hypoxia, RAL perfusion was 33 +/- 3% of its air value, carotid arterial PO2 averaged 86 +/- 3 mm Hg and pulmonary perfusion pressure was not significantly different from the initial control period when the RAL inspired air.

Pulmonary circulation and systemic circulation: similar problems, different solutions.

Both the systemic and the pulmonary circulations respond to local hypoxia in the appropriate manner, the former by vasodilating, thereby providing more oxygen, and the latter by constricting and rerouting blood flow to areas where more O2 is available. In either case, changes in local conductance affect total conductance, and through that variable, the perfusing pressure; as a result, the effects of local vasomotion should be reduced. In the systemic circulation, arterial pressure can be prevented from falling by two important mechanisms: vasoconstriction of other vascular beds, and an increase in cardiac output.

Biomedical support of man in space.

In its broadest sense, biomedical support of man in space must not be limited to assisting spacecraft crew during the mission; such support should also ensure that flight personnel be able to perform properly during landing and after leaving the craft. Man has developed mechanisms that allow him to cope with specific stresses in his normal habitat; there is indisputable evidence that, in some cases, the space environment, by relieving these stresses, has also allowed the adaptive mechanisms to lapse, causing serious problems after re-entry. Inflight biomedical support must therefore include means to simulate some of the normal stresses of the Earth environment.

Gravity-induced hyperventilation is caused by a reduced brain perfusion.

The suggestion that hyperventilation caused by increased gravity is mediated by a decrease in brain perfusion has led us to propose a mathematical model based on: (1) the CO2 balance equation for the respiratory center (RC), and (2) the relationship between RC blood flow (QRC), foot-to-head acceleration (Gz) and PRCCO2, namely, QRC = [1 - a(Gz - 1)](b X PRCCO2 + c), where the coefficients a, b and c can be calculated from data in the literature. QRC is significantly affected by + GZ only at high PaCO2. The model can be used to calculate oxygen pressure in the RC; the numbers so obtained are in good agreement with measurements of jugular vein PO2 obtained by others.

Acid-base status immediately following rapid changes of alveolar gas composition in awake dogs.

To study the interrelationship between blood O2, CO2, and acid-base status during rapid changes of alveolar gas composition unanesthetized dogs were made to inhale high CO2 gas mixtures following air breathing or to rebreathe high CO2 and O2 mixtures following hypoxia. Before and immediately after each change in alveolar gases, sequential blood samples were taken from the carotid artery for measurement of pH, PCO2 and PO2. In the experiments at normoxia the calculated base excess (BE) decreased by about 0.

Blood-gas transport in awake rabbits exposed to normobaric hyperoxia.

The time course and terminal effects of normobaric oxygen exposure on the gas transport chain were studied in awake, catheterized rabbits exposed to air (n = 8) for 96 h or 100% O2 (n = 10) until death. O2-breathing animals survived 60.2 (+/- 13.