Acceptability of high-resolution anoscopy for anal cancer screening in HIV-infected patients.

OBJECTIVES: HIV-infected individuals are at increased risk of anal cancer. Screening for anal cancer precursors using high-resolution anoscopy (HRA) may be clinically beneficial. In this study, we examined patient tolerability of this procedure. METHODS: The acceptability of HRA was evaluated among HIV-infected patients who completed a first-time HRA between July 2008 and December 2013 at Kaiser Permanente Northern California. We reviewed electronic medical records to identify lack of HRA acceptability, which was defined as receipt of HRA with sedation, dispensation of opioid analgaesia, and/or an urgent care visit following HRA, and to evaluate factors associated with patients not returning for a recommended repeat HRA (proxy for HRA acceptability). HRA acceptability was also assessed via a survey mailed to patients who completed HRA between January 2014 and August 2014. Logistic regression was used to model lack of acceptability of initial HRA and likelihood of not returning for a repeat HRA. RESULTS: Of 1857 HIV-infected patients, 94 were prescribed opioids and one had an urgent care visit. Lack of HRA acceptability was more likely in patients with pre-existing anal conditions [e.g. warts or fissure; adjusted odds ratio (aOR) 4.02; 95% confidence interval (CI) 2.4-6.7], those who had ever smoked (aOR 1.6; 95% CI 1.0-2.5) and women (aOR 5.3; 95% CI 1.6-17.5). Fifty per cent of patients returned for a repeat HRA, with younger patients less likely to return (per 10-year age interval, aOR 0.8; 95% CI 0.7-0.9). Of 48 survey respondents, 91.7% reported acceptable pain levels and all reported willingness to return for a repeat HRA. CONCLUSIONS: HRA was generally well tolerated and may be an acceptable screening approach for patients at high risk of anal cancer.

Role of erythrocyte-released ATP in the regulation of microvascular oxygen supply in skeletal muscle.

In a 1914 book entitled The Respiratory Function of the Blood, Joseph Barcroft stated that 'the cell takes what it needs and leaves the rest'. He postulated that there must be both a 'call for oxygen' and a 'mechanism by which the call elicits a response...' In the past century, intensive investigation has provided significant insights into the haemodynamic and biophysical mechanisms involved in supplying oxygen to skeletal muscle. However, the identification of the mechanism by which tissue oxygen needs are sensed and the affector responsible for altering the upstream vasculature to enable the need to be appropriately met has been a challenge. In 1995, Ellsworth et al. proposed that the oxygen-carrying erythrocyte, by virtue of its capacity to release the vasoactive mediator ATP in response to a decrease in oxygen saturation, could serve both roles. Several in vitro and in situ studies have established that exposure of erythrocytes to reduced oxygen tension induces the release of ATP which does result in a conducted arteriolar vasodilation with a sufficiently rapid time course to make the mechanism physiologically relevant. The components of the signalling pathway for the controlled release of ATP from erythrocytes in response to exposure to low oxygen tension have been determined. In addition, the implications of defective ATP release on human pathological conditions have been explored. This review provides a perspective on oxygen supply and the role that such a mechanism plays in meeting the oxygen needs of skeletal muscle.

Influence of tissue metabolism and capillary oxygen supply on arteriolar oxygen transport: a computational model.

We present a theoretical model for steady-state radial and longitudinal oxygen transport in arterioles containing flowing blood (plasma and red blood cells) and surrounded by living tissue. This model combines a detailed description of convective and diffusive oxygen transport inside the arteriole with a novel boundary condition at the arteriolar lumen surface, and the results provide new mass transfer coefficients for computing arteriolar O(2) losses based on far-field tissue O(2) tension and in the presence of spatially distributed capillaries. A numerical procedure is introduced for calculating O(2) diffusion from an arteriole to a continuous capillary-tissue matrix immediately adjacent to the arteriole. The tissue O(2) consumption rate is assumed to be constant and capillaries act as either O(2) sources or sinks depending on the local O(2) environment. Using the model, O(2) saturation (SO(2)) and tension (PO(2)) are determined for the intraluminal region of the arteriole, as well as for the extraluminal region in the neighbouring tissue. Our model gives results that are consistent with available experimental data and previous intraluminal transport models, including appreciable radial decreases in intraluminal PO(2) for all vessel diameters considered (12-100 µm) and slower longitudinal decreases in PO(2) for larger vessels than for smaller ones, and predicts substantially less diffusion of O(2) from arteriolar blood than do models with PO(2) specified at the edge of the lumen. The dependence of the new mass transfer coefficients on vessel diameter, SO(2) and far-field PO(2) is calculated allowing their application to a wide range of physiological situations. This novel arteriolar O(2) transport model will be a vital component of future integrated models of microvascular regulation of O(2) supply to capillary beds and the tissue regions they support.

Mass Transfer in a Rigid Tube With Pulsatile Flow and Constant Wall Concentration.

An approximate-analytical solution method is presented for the problem of mass transfer in a rigid tube with pulsatile flow. For the case of constant wall concentration, it is shown that the generalized integral transform (GIT) method can be used to obtain a solution in terms of a perturbation expansion, where the coefficients of each term are given by a system of coupled ordinary differential equations. Truncating the system at some large value of the parameter N, an approximate solution for the system is obtained for the first term in the perturbation expansion, and the GIT-based solution is verified by comparison to a numerical solution. The GIT approximate-analytical solution indicates that for small to moderate nondimensional frequencies for any distance from the inlet of the tube, there is a positive peak in the bulk concentration C(1b) due to pulsation, thereby, producing a higher mass transfer mixing efficiency in the tube. As we further increase the frequency, the positive peak is followed by a negative peak in the time-averaged bulk concentration and then the bulk concentration C(1b) oscillates and dampens to zero. Initially, for small frequencies the relative Sherwood number is negative indicating that the effect of pulsation tends to reduce mass transfer. There is a band of frequencies, where the relative Sherwood number is positive indicating that the effect of pulsation tends to increase mass transfer. The positive peak in bulk concentration corresponds to a matching of the phase of the pulsatile velocity and the concentration, respectively, where the unique maximum of both occur for certain time in the cycle. The oscillatory component of concentration is also determined radially in the tube where the concentration develops first near the wall of the tube, and the lobes of the concentration curves increase with increasing distance downstream until the concentration becomes fully developed. The GIT method proves to be a working approach to solve the first two perturbation terms in the governing equations involved.

A precise radiographic technique for the measurement of dimensional changes in heart valve biomaterials following fixation.

Accurate tissue thickness measurements are difficult to acquire by present techniques. Error is introduced by tissue compression during measurements or by tissue processing prior to measurement. In the field of valve replacement, tissue dimensional changes from fixation prior to implantation may predispose implants to premature tissue failure and it becomes important to have an accurate method for comparing cusp dimensions pre- and post-fixation. A new approach is to use high-resolution digital radiography to make thickness maps of entire specimens. For 25 matched porcine aortic valve cusps, we have evaluated this technique's ability to measure and compare thickness, surface area and volume before and after 7 days of aldehyde fixation. Digital radiographs were acquired pre- and post-0.5% glutaraldehyde (n=13) or 10% formaldehyde (n=12) fixation. Mean thickness, surface area, volume and four measurements to evaluate shape differences with fixation were obtained and compared pre- and post-fixation using paired t tests. The results demonstrate that this X-ray imaging technique can provide dimensions of matched fresh and fixed specimens and is sensitive enough to show statistically significant changes due to fixation. These findings also illustrate that aldehyde fixation can cause tissue contraction resulting in a significant overall increase in tissue thickness and a decrease in surface area. This technique could be used to gain further insights into tissue anatomy and mechanics.

Aortic valve cusp vessel density: relationship with tissue thickness.

OBJECTIVES: The presence of a microvasculature within aortic cusps implies that tissue oxygen requirements exceed the amount deliverable by diffusion from the tissue surfaces alone. For the design of a successful tissue-engineered valve replacement, the effect of diffusion distance (tissue thickness) on oxygen delivery must be considered. We therefore examined in normal aortic valve cusps the relationship between the presence of microvessels and the tissue thickness. METHODS: Thirty porcine aortic valve cusps were excised and examined after cusp microvessels were pressure filled with a carbon particle solution. Cusp images were captured for stereographic vessel density analysis, and cusp thickness was determined with a radiographic technique. Histologic cross-sections were evaluated to determine vessel depth from the cusp surface. RESULTS: Cusp basal regions measured 0.69 to 0.86 mm in thickness, significantly thicker (P =.001) than the rest of the cusp, which measured 0.36 to 0.48 mm. In general a vascular bed was present when cusp thickness exceeded 0.5 mm, with a median value of 5.16 vessels/mm(3). CONCLUSIONS: From published values of arterial wall oxygen consumption and diffusivity, we predicted that the probable maximum oxygen diffusion distance for valve tissue would be about 0.2 mm. This was consistent with our physical findings, which implies that central tissue anoxia is avoided by the capillary bed. An avascular tissue-engineered valve metabolically similar to an aortic valve should therefore not exceed a thickness of approximately 0.40 mm.

Oxygen diffusion and consumption of aortic valve cusps.

To maintain tissue oxygenation, normal aortic valves contain a vascular bed where tissue thickness is greatest. Avascular "living" tissue-engineered heart valves have been proposed, yet little information exists regarding the magnitude of valve tissue metabolic activity or oxygen requirements. We therefore set out to measure the oxygen diffusivity (DO(2)) and oxygen consumption (VO(2)) of seven porcine aortic valve cusps in vitro at 37 degrees C using a chamber with a Clark oxygen sensor. Mean DO(2) and VO(2) were 1.06 x 10(-5) cm(2)/s and 3.05 x 10(-5) x ml O(2). ml tissue(-1) x s(-1), respectively. When modeled as a three-layered structure by using these values and a boundary condition of 100 mmHg at both surfaces, the average aortic cusp predicted a central mean PO(2) of 27 mmHg (range of 0-50 mmHg). The DO(2) value obtained was similar to that found for other vascular structures, but because our studies were carried out in vitro, the VO(2) measurements may be lower than that required by the functioning valves. These values provide an initial understanding of the oxygen supply possible from the cusp surfaces and the oxygen needs of the tissue.

Effect of prophylactic transfusion of stored RBCs on oxygen reserve in response to acute isovolemic hemorrhage in a rodent model.

BACKGROUND: The storage of RBCs results in a time-related decline in 2,3 DPG that may reduce the ability to unload oxygen (O(2)) to tissue. The objective of this study was to compare the effect that transfusion of stored 2,3 DPG-depleted rat blood (7 days in CPDA-1) had on the O(2) reserve in conscious rats, with that of the transfusion of fresh blood (<2-hour storage). STUDY DESIGN AND METHODS: Anemic rats (Hb, 80 g/L) received either fresh packed RBCs or stored RBCs to raise Hb levels to 140 g per L. They then underwent isovolemic hemorrhage mimicking surgical blood loss to the point of O(2) supply dependency (OSD). Critical O(2) delivery (DO(2)crit), Hb concentration, and O(2) extraction at OSD were measured in a metabolic chamber. RESULTS: After transfusion, RBC DPG decreased by 50 percent in the stored-blood group, and the p50 value decreased by 5 mmHg (32.1 +/- 2.5 mmHg vs. 37.5 +/- 3.0). DO(2)crit was similar in the two groups (fresh blood: 2.79 +/- 0.44 mL/min x g(-1); stored blood, 2.99 +/- 0.76 mL/min x g(-1)). The critical Hb concentration at DO(2)crit was higher in the stored-blood group (44 +/- 4 g/L) than in the fresh-blood group (38 +/- 5 g/L); the cardiac index and O(2) extraction ratio in the two groups were not different. Under conditions of severe normovolemic anemia in rats, depletion of DPG and a decrease in p50 had only minor effects on the O(2) reserve. At OSD, under these conditions, O(2) consumption is not limited by diffusion. CONCLUSION: The physiologic impact of DPG depletion in transfused stored blood on oxygen availability in normal rats appears to be small and may be clinically inconsequential.

Role of erythrocyte in regulating local O2 delivery mediated by hemoglobin oxygenation.

The release of ATP from red blood cells (RBC) in response to low O2 levels is linked to ATP production and the oxygenation state of hemoglobin. Because O2 is unloaded from the RBC, the concentration of deoxygenated hemoglobin increases, displacing phosphofructokinase from the cytoplasmic domain of band 3. We hypothesize that the ATP molecules produced through this glycolytic stimulation at the membrane surface result in the release of ATP from the RBC. Rat whole blood exposed to 5 min of low PO2 in vitro increased plasma [ATP] by 1.0 miccroM (+45%). This increase was reduced to 0.1 microM (+12%, P < 0.05) after citrate incubation and reversed after fluoride treatment (both glycolytic inhibitors) by -0.2 microM (-23%, P < 0.05). Plasma [ATP] of control RBC decreased -0.3 microM (-12%) when 8% CO (P < 0.05) was added to the chamber. Because CO and O2 bind competitively to heme, these results support our hypothesis that the release of ATP from RBC is linked to ATP production through the oxygenation state of the hemoglobin molecule.

Erythrocyte deformability is a nitric oxide-mediated factor in decreased capillary density during sepsis.

Erythrocyte deformability has been recognized as a determinant of microvascular perfusion. Because nitric oxide (NO) is implicated in the modulation of red blood cell (RBC) deformability and NO levels increase during sepsis, we tested the hypothesis that a NO-mediated decrease in RBC deformability contributes to decreased functional capillary density (CD) in remote organs. With the use of a peritonitis model of sepsis in the rat [cecal ligation and perforation (CLP)] and aminoguanidine (AG) to prevent increases in NO, we measured CD in skeletal muscle (intravital microscopy), mean erythrocyte membrane deformability (; micropipette aspiration), systemic NO production [plasma nitrite/nitrate (NO(x)) chemiluminescence], and NO accumulation in RBC [NO bound to hemoglobin (HbNO) detected by electron paramagnetic resonance spectroscopy]. In untreated CLP animals relative to sham, NO(x) increased 254% (P < 0.05), stopped flow capillaries increased 149% (P < 0.05), and decreased 12.7% (P < 0.05), with a subpopulation (5%) of RBC with deformabilities below the normal range. AG prevented increases in NO(x), accumulation of HbNO, and decreases in both and functional CD. We found no evidence of leukocyte plugging postcapillary venules. Our findings suggest that decreased functional CD during sepsis resulted from a NO-mediated decrease in erythrocyte deformability.

Measurement temperature plays a pivotal role in the distribution of erythrocyte deformability after LPS.

Reductions in red blood cell membrane deformability (RBC(D)) may perturb microcirculatory blood flow and impair tissue O(2)-availability. We investigated the effect of assay temperature on the distribution of RBC(D) in endotoxin (LPS) incubated and control RBCs. Fresh blood from healthy rats was incubated with and without the presence of LPS for 6 hrs. An index of red blood cell membrane deformability, delta, was measured via the micropipette aspiration technique at 25 degrees C and 37 degrees C at 0, 2 and 6 hrs of incubation. The ATP content of RBC was measured by the luciferin-luciferase technique. At 25 degrees C, LPS caused a significant decrease in mean delta after 2 and 6 hours incubation compared to controls (-10.0%, p=0.03 and -24.0%, p=0.03, respectively) characterized by a left shift in the distribution (skewness: -1.4). However, at 37 degrees C a significant decrease in delta was only detected after 6 hrs of LPS incubation (-13.8%, p=0.01, compared to -5.1%, p=0.7 at 2 hours) and lacked the left shifted distribution (skewness: 0.2). No significant difference in ATP content of RBCs was observed between groups. We have shown that LPS incubation results in a significant decrease in RBC(D) and that room temperature measurement of physical membrane properties may exaggerate the differences between normal and perturbed RBCs.

The aortic valve blood supply.

BACKGROUND AND AIM OF THE STUDY: Normal valves are known to be metabolically active, yet the route of oxygen delivery is unclear. Although diffusion from the valve surface is the presumed source, the presence, distribution and importance of the aortic valve's vascular bed is unclear. METHODS: Seventeen porcine hearts (51 cusps) were obtained at slaughter. The coronary circulation was pressure-rinsed with a heparin solution and filled with an Aquablack solution at physiological pressure. The cusps were subsequently dissected and fixed for viewing with an inverted microscope. The anterior leaflet of the mitral valve was evaluated as a control for the vessel filling protocol. Using Adobe Photoshop and captured images, whole cusps were reconstructed, a grid was overlaid and vascular distribution evaluated. RESULTS: Of the 15 porcine aortic valves that filled, 32/45 (71%) of the cusps contained vessels. Nine valves had vasculature in all three cusps and two valves were completely avascular. Vessels were found predominantly in the basal third of the cusps and extended in from the commissures almost to the level of the free edge. There was a statistically significant difference (p<0.001) between the appearance of vessels in the basal region and in the mid and free edge regions of the valve. No difference in vascularization pattern was noted between the left, right or non-coronary cusps. CONCLUSIONS: The presence of a vasculature suggests that the metabolic activity of the cusp is greater than can be supported by diffusion from the cusp surface alone. The absence of functioning vessels might explain the failure associated with cryopreserved implants and may play a role in the durability problems faced by bioprosthetic valves. It will also be important to consider the role of this intrinsic circulation with the advent of tissue-engineered valves.

Child maltreatment, other trauma exposure, and posttraumatic symptomatology among children with oppositional defiant and attention deficit hyperactivity disorders.

Consecutive child psychiatric outpatient admissions with disruptive behavior or adjustment disorders were assessed by validated instruments for trauma exposure and posttraumatic stress disorder (PTSD) symptoms and other psychopathology. Four reliably diagnosed groups were defined in a retrospective case-control design: Attention Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), comorbid ADHD-ODD, and adjustment disorder controls. ODD and (although to a lesser extent) ADHD were associated with a history of physical or sexual maltreatment. PTSD symptoms were most severe if (a) ADHD and maltreatment co-occurred or (b) ODD and accident/illness trauma co-occurred. The association between ODD and PTSD Criterion D (hyperarousal/hypervigilance) symptoms remained after controlling for overlapping symptoms, but the association of ADHD with PTSD symptoms was largely due to an overlapping symptom. These findings suggest that screening for maltreatment, other trauma, and PTSD symptoms may enhance prevention, treatment, and research concerning childhood disruptive behavior disorders.

Effects of modest anemia on systemic and coronary circulation of septic sheep.

Although a lower transfusion trigger is generally recommended, little evidence is available about the physiological mechanisms of mild anemia in diseases with an imbalance between O2 supply and O2 demand such as sepsis. This study was undertaken to describe the systemic and coronary metabolic O2 reserve in an awake sheep model of hyperdynamic sepsis comparing two different hemoglobin levels. Twenty-four hours after sheep were rendered septic by cecal ligation and perforation (CLP), blood transfusion (n = 7, hemoglobin = 120 g/l) and isovolemic hemodilution (n = 8, hemoglobin = 70 g/l), respectively, were performed. Another 24 h later, we measured hemodynamics, organ blood flows, and systemic and myocardial O2 metabolism variables at baseline and through four stages of progressive hypoxia. Maximum coronary blood flow was 766.3 +/- 87.4 ml. min(-1). 100 g(-1) in hemodiluted sheep group versus 422.7 +/- 53.7 ml. min(-1). 100 g(-1) in the transfused sheep (P < 0.01). Myocardial O2 extraction was higher in the transfusion group (P = 0.03) throughout the whole hypoxia trial. In the hemodilution group, coronary blood flow increased more per increase in myocardial O(2) uptake than in transfused sheep (P < 0.01). This was accompanied by a lower left ventricular epicardial-to-endocardial flow ratio in hemodiluted sheep (1.13 +/- 0.07) than in transfused sheep (1.34 +/- 0.02, P < 0.05). We conclude that the lower coronary blood flow and greater myocardial O2 extraction in transfused septic sheep preserves transmyocardial O2 metabolism better in comparison to hemodiluted sheep.

Effects of FI(O(2)) on hemodynamic responses and O(2) transport during RSR13-induced reduction in P(50).

Reduced Hb-O(2) affinity facilitates O(2) release to tissue but may impair pulmonary O(2) uptake, affecting cardiac output and systemic vascular resistance (SVR). We studied the effects of shifting the O(2)-dissociation curve (ODC) to the right with a continuous infusion of RSR13, an allosteric modifier of Hb, and of different inspired O(2) fractions (FI(O(2))) on arterial O(2) saturations (Sa(O(2))) in Hb and on hemodynamics in nonanesthetized rats. At an FI(O(2)) of 0.21, Sa(O(2)) fell during RSR13 from 95 to 81%. Elevation of FI(O(2)) to 0.30 returned Sa(O(2)) to baseline in the RSR13 group. The decrease in mean arterial pressure (MAP) was significantly greater in the control than in the RSR13 group at 30% O(2). Cardiac index (CI) increased only during RSR13 at 21% O(2) and returned to baseline at 30% O(2). In contrast, SVR decreased after RSR13 was infused at 21% O(2) but returned to baseline at 30%O(2), whereas controls showed the opposite, a sustained SVR. In the follow-up period, when 21 O(2)% was reestablished and mild anemia was present, MAP and SVR fell significantly more in controls, whereas CI only increased in controls. Lactate was significantly lower in the RSR13 than in the control group during RSR13 and the follow-up period. These results demonstrate that 1) continuous infusion of RSR13 produces a constant shift in the O(2) tension at which Hb is 50% saturated (P(50)), 2) FI(O(2)) of 0.30 compensates for the effects of increased P(50) on pulmonary O(2) loading, and 3) right-shifted ODC combined with supplemental O(2) may improve tissue O(2) availability.

The Microcirculation Physiome Project.

Presented is a discussion of steps towards the creation of a database of the microcirculation encompassing anatomical and functional experimental data, and conceptual and computational models. The discussion includes issues of database utility, organization, data deposition, and linkage to other databases. The database will span levels from gene to tissue and will serve both research and educational purposes.

Fibroblast growth factor-2 potentiates vascular smooth muscle cell migration to platelet-derived growth factor: upregulation of alpha2beta1 integrin and disassembly of actin filaments.

Fibroblast growth factor-2 (FGF-2) has been implicated in vascular smooth muscle cell (SMC) migration, a key process in vascular disease. We demonstrate here that FGF-2 promotes SMC motility by altering beta1 integrin-mediated interactions with the extracellular matrix (ECM). FGF-2 significantly increased surface expression of alpha2beta1, alpha3beta1, and alpha5beta1 integrins on human SMCs, as assessed by flow cytometry. The greatest increase was for the collagen-binding alpha2beta1 integrin. Despite this, FGF-2 did not increase SMC adhesion to type I collagen but instead promoted SMC elongation and SMC motility. The latter was evaluated by using a microchemotaxis chamber and by digital time-lapse video microscopy. Although FGF-2 was not chemotactic for human SMCs, cells preincubated with FGF-2 displayed a 3.1-fold increase in migration to the undersurface of porous type I collagen-coated membranes and a 2.1-fold increase in migration speed on collagen. Furthermore, chemotaxis to platelet-derived growth factor-BB on collagen was significantly greater in SMCs exposed to FGF-2. FGF-2-induced elongation and migration on collagen were inhibited by a blocking anti-alpha2beta1 antibody; however, SMC adhesion to collagen was unaffected. SMC migration on fibronectin was also enhanced by FGF-2, although less prominently: migration through porous membranes increased 1.8-fold, and migration speed increased 1.3-fold. Also, FGF-2 completely disassembled the smooth muscle alpha-actin-containing stress fiber network contemporaneously with the change in integrin expression and cell shape. We conclude that (1) exogenous FGF-2 promotes SMC migration and potentiates chemotaxis to PDGF-BB; (2) the promigratory effect of FGF-2 is especially prominent on type I collagen and is mediated by upregulation of alpha2beta1 integrin; and (3) FGF-2 disassembles actin stress fibers, which may promote differential utilization of alpha2beta1 integrin for motility but not adhesion. This dynamic SMC-ECM interplay may be an important mechanism by which FGF-2 facilitates SMC motility in vivo.

Sepsis depresses the metabolic oxygen reserve of the coronary circulation in mature sheep.

This study was undertaken to describe the metabolic O2 reserve of the coronary circulation in an awake sheep model of hyperdynamic sepsis. Forty-eight hours after sheep were randomized to either a SHAM group (n = 8) or a cecal ligation and perforation (CLP) group (n = 8), we measured hemodynamics, organ blood flows, and systemic and myocardial O2 metabolism variables at baseline and through four stages of progressive hypoxia. A significant elevation in arterial lactate levels occurred at a higher O2 delivery in the CLP group (527 +/- 55 ml/min/m2) than in the SHAM group (357 +/- 29 ml/min/m2, p < 0.05). The heart's metabolic O2 reserve (difference in circulatory determinants of O2 availability between baseline and where O2 uptake could not be sustained) was exhausted at an O2 content of 56.9 +/- 4.2 ml O2/L in SHAM sheep and 79.6 +/- 7.2 ml O2/L (p < 0.05) in CLP sheep. An increase in coronary blood flow was three times greater in SHAM than in CLP animals. Myocardial O2 extraction increased in hypoxia in SHAM sheep (0.78 +/- 0.03 to 0.88 +/- 0.02, p < 0.05), but not in CLP sheep (0.79 +/- 0.02 to 0.80 +/- 0.04). We conclude that the metabolic O2 reserve of the coronary circulation is depressed in this model of hyperdynamic sepsis as the ability to increase both coronary blood flows and myocardial O2 extraction was significantly limited.

Chronic unhappiness. Investigating the phenomenon in family practice.

PURPOSE: To investigate the experience of chronic unhappiness as it presents in family practice. DESIGN: A descriptive, qualitative study of both patients and physicians using an existential phenomenologic approach. SETTING: Two village general practices in South Africa. PARTICIPANTS: Four patients who were difficult, "heartsink" patients, who gave their doctors an overwhelming feeling of exasperation and defeat. METHOD: We investigated the clinical records thoroughly and explored patients' relationships with others. Through interpretation and reflection, we tried to discover what role the doctor could play with these patients. FINDINGS: Chronic unhappiness was found to be not only a condition of life for the patients but also for the doctor. It was an important factor in the relationship they shared. Unhappiness was revealed in part by frequent visits by the patients, a constellation of negative feelings in the doctor, and difficult patient-doctor relationships. CONCLUSION: Chronic unhappiness is not "treatable" in the normal curative or therapeutic sense. This does not prevent our quest to diagnose and cure, but enlarges our horizons to recognizing and accepting our own human reactions to patients and understanding how we can meet their needs.