Good mid- to long-term results of the cemented oxford phase 3 unicompartmental knee arthroplasty in a non-designer centre.

PURPOSE: Unicompartmental knee arthroplasty (UKA) provides patients with an alternative treatment to TKA in isolated medial compartment osteoarthritis providing better functional outcomes and faster recovery in the short term. Our aim was to quantify revision rates, predictors of revision, mortality rate and functionality of the Oxford Phase 3 UKA in a non-designer institution. METHODS: This was a retrospective review of prospectively collected regional registry data. All Oxford Phase 3 UKAs performed for medial tibio-femoral osteoarthritis of the knee joint were included from a single academic institution between the period of January 1st 2006 and December 30th 2009. Kaplan-Meier survivorship curves adjusting for loss to follow-up and deceased patients were generated. Primary outcome variables included all-cause and aseptic revision. Secondary outcome variables included functional outcome scores. Patients were reviewed at 6 months, 2 years, 5 years, 10 years and 15 years. RESULTS: A total of 64 cemented Oxford phase 3 UKAs were performed between January 2006 and November 2009. Fifteen-year follow-up data were available for 51 patients, of these 12 required revision. Survival rates, adjusting for patients that were either lost to follow-up or deceased, were 87.5% at 5 years, 81.4% at 10 years and 76.4% at 15 years. The overall aseptic revision rate at the time of review was 18.75% (n = 12). The only significant predictor of postoperative WOMAC score at 15 years was the preoperative WOMAC score (p = 0.03). CONCLUSION: The Oxford Phase 3 UKA for medial tibio-femoral arthritis has promising outcomes at 15-year follow-up with a survival rate of 76.4% in a non-designer centre. LEVEL OF EVIDENCE: III.

Gender disparities operate in opposite directions for hospitalizations and mortality among individuals receiving long-term ART in rural Uganda.

OBJECTIVES: We conducted an analysis to determine if differences in health-seeking behaviour can explain gender disparities in mortality among long-term survivors receiving antiretroviral therapy (ART) in rural Uganda. METHODS: From June 2012 to January 2014, we enrolled patients receiving a first-line ART regimen for at least 4 years without previous viral load (VL) testing in Jinja, Uganda. We measured HIV VL at study entry. We switched participants to second-line therapy, if VL was ≥ 1000 copies/mL on two measurements, and followed participants for 3 years. We collected clinical and behavioural data at enrolment and every 6 months after that. We used Poisson regression to examine factors associated with hospitalizations and Cox proportional hazards modelling to assess mortality to September 2016. RESULTS: We enrolled 616 participants (75.3% female), with a median age of 44 years and a median duration of ART use of 6 years. Of these, 113 (18.3%) had VLs ≥ 1000 copies/mL. Hospitalizations occurred in 101 participants (7% of men vs. 20% of women; P < 0.001). A total of 22 (3.6%) deaths occurred, 9% of men vs. 2% of women (P < 0.001). Multivariate modelling revealed that mortality was associated with age [adjusted hazard ratio (AHR) = 1.07 per year increase; 95% confidence interval (CI): 1.01-1.13], male gender (AHR = 2.57; 95% CI 1.06-6.23) and time-updated CD4 counts (AHR = 0.67 per 100 cell increment; 95% CI: 0.52-0.88). Virological failure was not associated with mortality (P = 0.762). CONCLUSION: Female patients receiving ART in rural Uganda were three times more likely to be hospitalized than men, but male mortality was nearly four times higher. Facilitating care for acute medical problems may help to improve survival among male ART patients.

Lack of effectiveness of adherence counselling in reversing virological failure among patients on long-term antiretroviral therapy in rural Uganda.

OBJECTIVES: The current World Health Organization and Uganda Ministry of Health HIV treatment guidelines recommend that asymptomatic patients who have a viral load (VL) ≥ 1000 HIV-1 RNA copies/mL should receive adherence counselling and repeat VL testing before switching to second-line therapy. We evaluated the effectiveness of this strategy in a large HIV treatment programme of The AIDS Support Organisation Jinja in Jinja, Uganda. METHODS: We measured the HIV VL at enrolment, and for participants with VL ≥ 1000 copies/mL we informed them of their result, offered enhanced adherence counselling and repeated the VL measurement after 3 months. All blood samples with VL ≥ 1000 copies/mL were sequenced in the polymerase (pol) region, a 1257-bp fragment spanning the protease and reverse transcriptase genes. RESULTS: One thousand and ninety-one participants were enrolled in the study; 74.7% were female and the median age was 44 years [interquartile range (IQR) 39-50 years]. The median time on antiretroviral therapy (ART) at enrolment was 6.75 years (IQR 5.3-7.6 years) and the median CD4 cell count was 494 cells/µL (IQR 351-691 cells/µL). A total of 113 participants (10.4%) had VLs ≥ 1000 copies/mL and were informed of the VL result and its implications and given adherence counselling. Of these 113 participants, 102 completed 3 months of follow-up and 93 (91%) still had VLs ≥ 1000 copies/mL. We successfully genotyped HIV for 105 patients (93%) and found that 103 (98%) had at least one mutation: eight (7.6%) had only one mutation, 94 (89.5%) had two mutations and one sample (1%) had three mutations. CONCLUSIONS: In this study, enhanced adherence counselling was not effective in reversing virologically defined treatment failure for patients on long-term ART who had not previously had a VL test.

Characteristic pro-inflammatory cytokines and host defence cathelicidin peptide produced by human monocyte-derived macrophages infected with Neospora caninum.

Neospora caninum is a coccidian intracellular protozoan capable of infecting a wide range of mammals, although severe disease is mostly reported in dogs and cattle. Innate defences triggered by monocytes/macrophages are key in the pathogenesis of neosporosis, as these cells are first-line defenders against intracellular infections. The aim of this study was to characterize infection and innate responses in macrophages infected with N. caninum using a well-known cell model to study macrophage functions (human monocyte THP-1 cells). Intracellular invasion of live tachyzoites occurred as fast as 4 h (confirmed with immunofluorescence microscopy using N. caninum-specific antibodies). Macrophages infected by N. caninum had increased expression of pro-inflammatory cytokines (TNFα, IL-1ß, IL-8, IFNγ). Interestingly, N. caninum induced expression of host-defence peptides (cathelicidins), a mechanism of defence never reported for N. caninum infection in macrophages. The expression of cytokines and cathelicidins in macrophages invaded by N. caninum was mediated by mitogen-activated protein kinase (MEK 1/2). Secretion of such innate factors from N. caninum-infected macrophages reduced parasite internalization and promoted the secretion of pro-inflammatory cytokines in naïve macrophages. We concluded that rapid invasion of macrophages by N. caninum triggered protective innate defence mechanisms against intracellular pathogens.

Does age matter? Sexual event-level analysis of age-disparate sexual partners among gay, bisexual and other men who have sex with men (GBM) in Vancouver, Canada.

BACKGROUND: To determine factors associated with age-disparate sexual partners among Vancouver gay, bisexual and other men who have sex with men (GBM). METHODS: Sexually active GBM aged ≥16 years were recruited from February 2012 to February 2014. Participants self-completed a questionnaire on demographics, attitudes and sexual behaviour and substance use at last sexual event with five most recent partners. Two generalised linear mixed models identified factors associated with: (1) 'same-age' (referent), 'younger' or 'much-younger' and (2) 'same-age' (referent), 'older' or 'much-older' partners. Statistical interactions between age and HIV status were tested. RESULTS: Participants (n=719) were predominantly gay (85.1%), White (75.0%), HIV-negative/unknown status (72.9%) with median age of 33 years (Q1,Q3: 26,47). A minority of sexual events were reported with much-older/much-younger partners (13.7%). In the multivariable models, GBM reporting older partners were more likely to be Asian or Latino, have greater Escape Motivation scores, report their partner used erectile dysfunction drugs (EDDs) and have received something for sex; compared with condom-protected insertive anal sex, participants with older partners were more likely to report condomless insertive anal sex with a serodiscordant or unknown status partner or no insertive anal sex. GBM reporting older partners were less likely to be bisexual-identified, have given something for sex and report event-level alcohol and EDD use. GBM reporting younger partners were more likely to have annual incomes >$30 000 and have met their partner online. As per significant statistical interactions, age-disparate relations were more common for younger HIV-positive and older HIV-negative GBM. CONCLUSIONS: Differences among age-disparate partners highlight important targets for health promotion and future research.

Reductions in all-cause and cause-specific mortality among HIV-infected individuals receiving antiretroviral therapy in British Columbia, Canada: 2001-2012.

OBJECTIVES: Since 2006, the British Columbia HIV/AIDS Drug Treatment Program (DTP) has expanded enrolment and dramatically increased its number of participants. We examined the effect this expansion has had on the underlying cause of death in HIV-infected individuals. METHODS: We analysed data from participants aged 18 years and older in the DTP to measure 2-year mortality rates and causes of death from 2001 to 2012. We conducted tests of trend for all-cause and cause-specific mortality, and compared demographics and characteristics of individuals. Cox proportional hazard models were used to determine the risk of death. RESULTS: A total of 8185 participants received antiretroviral therapy (ART) during the study period. Mortality declined from 3.88 per 100 person-years (PY) in 2001-2002 to 2.15 per 100 PY in 2011-2012 (P = 0.02). There were significant decreases in HIV-related deaths (2.34 to 0.56 per 100 PY; P = 0.02) and deaths attributable to chronic liver disease (0.20 to 0.09 per 100 PY; P = 0.01), cardiovascular disease (0.24 to 0.05 per 100 PY; P = 0.03) and suicides (0.47 to 0 per 100 PY; P = 0.003). Multivariate models, adjusted for age, gender, history of injecting drug use, AIDS diagnoses and baseline CD4 cell counts, demonstrated that initiation of ART in all time periods after 2001-2002 was independently associated with reduced mortality (P < 0.001). CONCLUSIONS: We observed declines in HIV-related mortality and certain non-HIV-related causes of death among participants in the BC DTP from 2001 to 2012. These findings suggest that there may be broader benefits to the increasingly liberal HIV treatment guidelines, including reductions in death caused by cardiovascular disease and chronic liver disease.

Awareness and use of nonoccupational post-exposure prophylaxis among men who have sex with men in Vancouver, Canada.

OBJECTIVES: Nonoccupational post-exposure prophylaxis (nPEP) is a strategy to reduce the risk of HIV infection in those with high-risk exposure. This study characterized nPEP awareness among gay, bisexual and other men who have sex with men (MSM) in Metro Vancouver, British Columbia, Canada after a pilot nPEP programme established in 2012. METHODS: Momentum Health Study participants were MSM aged ≥16 years recruited via respondent-driven sampling (RDS) who completed a computer-assisted self-interview. Stratifying patients by HIV status, we used multivariable logistic regression with backward selection to identify factors associated with nPEP awareness. All analyses were RDS-adjusted. RESULTS: A total of 51.9% (112 of 173) of HIV-positive and 48.5% (272 of 500) of HIV-negative participants had heard of nPEP. Only 3% (five of 106) of HIV-negative participants who reported recent high-risk sex used nPEP. Generally, nPEP awareness was higher for participants who engaged in sexual activities with increased HIV transmission potential. Factors associated with greater awareness among HIV-negative participants included recent alcohol use, higher communal sexual altruism, previous sexually transmitted infection diagnosis, and greater perceived condom use self-efficacy. Other factors associated with greater awareness among HIV-negative participants included white race/ethnicity, gay sexual identity, more formal education, lower personal sexual altruism, and Vancouver residence. Greater nPEP awareness among HIV-positive participants was associated with greater perceived agency to ask sexual partners' HIV status and more frequently reporting doing so, a higher number of lifetime receptive sex partners, and greater access to condoms. CONCLUSIONS: Following implementation of an nPEP pilot programme, nPEP awareness among HIV-negative MSM was 51% and use was 3%. These data support the need to expand access to and actively promote nPEP services.

Declines in highly active antiretroviral therapy initiation at CD4 cell counts ≤ 200 cells/µL and the contribution of diagnosis of HIV at CD4 cell counts ≤ 200 cells/µL in British Columbia, Canada.

OBJECTIVES: The aim of the study was to examine trends in initiating highly active antiretroviral therapy (HAART) with a CD4 count ≤ 200 cells/µL and the contribution of having a CD4 count ≤ 200 cells/µL at the time of diagnosis to these trends, in British Columbia (BC), Canada. METHODS: We included in the analysis treatment-naïve BC residents aged ≥ 19 years who initiated HAART from 2003 to 2012. Participants were classified as follows: Group 1: diagnosed and initiated HAART with a CD4 count > 200 cells/µL; Group 2: diagnosed with a CD4 count > 200 cells/µL and initiated HAART with a CD4 count ≤ 200 cells/µL; and Group 3: diagnosed and initiated HAART with a CD4 count ≤ 200 cells/µL. We measured trends in initiating HAART with a CD4 count ≤ 200 cells/µL and used logistic regression models to measure factors associated with initiating HAART with a CD4 count ≤ 200 cells/µL, stratified by having a CD4 count ≤ 200 cells/µL or > 200 cells/µL at the time of diagnosis. RESULTS: Between 2003 and 2012, 3506 BC residents initiated HAART. Of these, 44% (1558 of 3506) initiated HAART with a CD4 count ≤ 200 cells/µL. This proportion declined from 69% (198 of 287) in 2003 to 21% (81 of 330) in 2012 (P < 0.001). The proportion of those in Group 3 increased from 49% (97 of 198) in 2003 to 69% (56 of 81) in 2012 (P < 0.001). Overall, 56% (1948), 22% (776) and 22% (782) made up Groups 1, 2, and 3, respectively. In adjusted analyses, seeing a specialist was significantly associated with being in Group 3. Using injection drugs and seeing a specialist were associated with being in Group 2. CONCLUSIONS: In recent years, among individuals who ever initiated HAART in BC, being diagnosed with low CD4 cell counts has become a greater contributor to initiating HAART with low CD4 cell counts.

Staff attitudes to an ultrasound-guided peripheral nerve block room for orthopaedic patients.

Ultrasound-guided peripheral nerve blocks have well recognised benefits in orthopaedic patients. Some hospitals, to maximise these benefits, establish dedicated "block rooms" to deliver this service. Orthopaedic surgery makes up a large proportion of our hospitals work load, and many of these patients would benefit from ultrasound-guided peripheral nerve blocks. We analysed the attitudes of key staff in our hospital towards the establishment of a block room. Sixty questionnaires were distributed and 47 (78%) were completed. Orthopaedic surgeons (n = 6) were concerned ultrasound-guided peripheral nerve blocks would delay theatre lists (83%), and cause patients pain (67%) and increased anxiety (67%). Anaesthetists (n = 10) and Nurses (n = 30) were concerned there was insufficient experience in their departments to deliver this service (80% and 77%, respectively). However, 91% of all staff believed funding should be available for a block room. Our survey has identified areas of concern, and deficiencies that we must address before proceeding with the development of such a service.

The effect of injecting drug use history on disease progression and death among HIV-positive individuals initiating combination antiretroviral therapy: collaborative cohort analysis.

BACKGROUND: We examined whether determinants of disease progression and causes of death differ between injecting drug users (IDUs) and non-IDUs who initiate combination antiretroviral therapy (cART). METHODS: The ART Cohort Collaboration combines data from participating cohort studies on cART-naïve adults from cART initiation. We used Cox models to estimate hazard ratios for death and AIDS among IDUs and non-IDUs. The cumulative incidence of specific causes of death was calculated and compared using methods that allow for competing risks. RESULTS: Data on 6269 IDUs and 37 774 non-IDUs were analysed. Compared with non-IDUs, a lower proportion of IDUs initiated cART with a CD4 cell count <200 cells/µL or had a prior diagnosis of AIDS. Mortality rates were higher in IDUs than in non-IDUs (2.08 vs. 1.04 per 100 person-years, respectively; P<0.001). Lower baseline CD4 cell count, higher baseline HIV viral load, clinical AIDS at baseline, and later year of cART initiation were associated with disease progression in both groups. However, the inverse association of baseline CD4 cell count with AIDS and death appeared stronger in non-IDUs than in IDUs. The risk of death from each specific cause was higher in IDUs than non-IDUs, with particularly marked increases in risk for liver-related deaths, and those from violence and non-AIDS infection. CONCLUSION: While liver-related deaths and deaths from direct effects of substance abuse appear to explain much of the excess mortality in IDUs, they are at increased risk for many other causes of death, which may relate to suboptimal management of HIV disease in these individuals.

Exercise induced fatigue: unfit or unwell?

This case report outlines the diagnoses of a rare myophosphorylase deficiency (McArdle Syndrome) in a unique way. A set of characteristic values from a Cardiopulmonary Exercise Test (CPET) combined with a typical patient history pointed to a failure of the glycolytic pathway in the skeletal muscle. McArdle Syndrome was confirmed with a skeletal muscle biopsy. There is no evidence of such a diagnostic method in the literature.

Studies on the pathogenesis of fever. 18. Activation of leukocytes for pyrogen production.

Blood leukocytes, in contrast to exudate leukocytes, release little or no pyrogen when incubated in 0.15 M NaCl unless previously activated by exposure to endotoxin or to a protein activator that is present in acute exudate fluid. The activation process, which also occurs during phagocytosis, involves the synthesis of cellular protein, presumably related to the pyrogen molecule. Evidence is presented that generation of pyrogen in sterile inflammatory lesions depends on both the activator and the anaerobic conditions in the exudate fluid.

Studies on the pathogenesis of fever. XVII. The cationic control of pyrogen release from exudate granulocytes in vitro.

Evidence has been presented that the release of active endogenous pyrogen from rabbit exudate granulocytes incubated in isotonic NaCl is a relatively prompt energy-dependent process that is preceded by a rise in intracellular pyrogen, and involves a rise in total intracellular cations and an increased permeability of the cell membranes, but does not require the synthesis of new proteins.

Synthesis of endogenous pyrogen by rabbit leukocytes.

Rabbit ieukocytes from peritoneal exudates and from blood were stimulated to form leukocyte pyrogen in the presence of radiolabeled amino acids. The stimuli used were endotoxin, phagocytosis, and tuberculin. The crude leukocyte pyrogen samples were purified; pyrogen from exudate cells was rendered homogeneous; pyrogen from blood cells was still contaminated with other proteins. All the purified pyrogens were radioactive; and for all it was shown that radioactivity and pyrogenic activity coincided on electrophoresis at pH 3.5 and pH 9 in acrylamide and on isoelectric focusing in acrylamide. Furthermore, pyrogens obtained from exudate cells stimulated in different ways, or from blood cells and exudate cells stimulated with endotoxin, appeared to be identical. These results suggest that leukocyte pyrogen was synthesized de novo from amino acid precursors and that leukocytes made the same pyrogen whatever the stimulus used to activate them.

Studies on the pathogenesis of fever. XX. Suppression and regeneration of pyrogen-producing capacity of exudate granulocytes.

Suppression of the pyrogen-producing capacity of exudate granulocytes results from incubation of the cells in plasma, serum, or Ringer's solution. When transferred in this state and incubated in isotonic NaCl, the cells release much less pyrogen than untreated exudate cells. The suppressive effect is reversible and appears to involve the cellular uptake of calcium ions. In contrast, regeneration of pyrogen-producing capacity in depleted exudate cells occurs only when the cells are incubated in serum. The process resembles activation and requires the cellular synthesis of protein.

Non-medically supervised treatment interruptions among participants in a universally accessible antiretroviral therapy programme.

BACKGROUND: We examined clinical outcomes, patient characteristics and trends over time of non-medically supervised treatment interruptions (TIs) from a free-of-charge antiretroviral therapy (ART) programme in British Columbia (BC), Canada. METHODS: Data from ART-naïve individuals > or =18 years old who initiated triple combination highly active antiretroviral therapy (HAART) between January 2000 and June 2006 were analysed. Participants having > or =3 month gap in HAART coverage were defined as having a TI. Cox proportional hazards modelling was used to examine factors associated with TIs and to examine factors associated with resumption of treatment. RESULTS: A total of 1707 participants were study eligible and 643 (37.7%) experienced TIs. TIs within 1 year of ART initiation decreased from 29% of individuals in 2000 to 19% in 2006 (P<0.001). TIs were independently associated with a history of injection drug use (IDU) (P=0.02), higher baseline CD4 cell counts (P<0.001), hepatitis C co-infection (P<0.001) and the use of nelfinavir (NFV) (P=0.04) or zidovudine (ZDV)/lamivudine (3TC) (P=0.009) in the primary HAART regimen. Male gender (P<0.001), older age (P<0.001), AIDS at baseline (P=0.008) and having a physician who had prescribed HAART to fewer patients (P=0.03) were protective against TIs. Four hundred and eighty-eight (71.9%) participants eventually restarted ART with male patients and those who developed an AIDS-defining illness prior to their TI more likely to restart therapy. Higher CD4 cell counts at the time of TI and unknown hepatitis C status were associated with a reduced likelihood of restarting ART. CONCLUSION: Treatment interruptions were associated with younger, less ill, female and IDU participants. Most participants with interruptions eventually restarted therapy. Interruptions occurred less frequently in recent years.

Cohort profile: the STOP HIV/AIDS Program Evaluation (SHAPE) study in British Columbia, Canada.

PURPOSE: The Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) Program Evaluation (SHAPE) study is a longitudinal cohort developed to monitor the progress of an HIV testing and treatment expansion programme across the province of British Columbia (BC). The study considers how sociostructural determinants such as gender, age, sexual identity, geography, income and ethnicity influence engagement in HIV care. PARTICIPANTS: Between January 2016 and September 2018, 644 BC residents who were at least 19 years old and diagnosed with HIV were enrolled in the study and completed a baseline survey. Participants will complete two additional follow-up surveys (18 months apart) about their HIV care experiences, with clinical follow-up ongoing. FINDINGS TO DATE: Analyses on baseline data have found high levels of HIV care engagement and treatment success among SHAPE participants, with 95% of participants receiving antiretroviral therapy and 90% having achieved viral suppression. However, persistent disparities in HIV treatment outcomes related to age, injection drug use and housing stability have been identified and require further attention when delivering services to marginalised groups. FUTURE PLANS: Our research will examine how engagement in HIV care evolves over time, continuing to identify barriers and facilitators for promoting equitable access to treatment and care among people living with HIV. A qualitative research project, currently in the formative phase, will compliment quantitative analyses by taking a strengths-based approach to exploring experiences of engagement and re-engagement in HIV treatment among individuals who have experienced delayed treatment initiation or treatment interruptions.

Cloned viral protein vaccine for foot-and-mouth disease: responses in cattle and swine.

A DNA sequence coding for the immunogenic capsid protein VP3 of foot-and-mouth disease virus A12, prepared from the virion RNA, was ligated to a plasmid designed to express a chimeric protein from the Escherichia coli tryptophan promoter-operator system. When Escherichia coli transformed with this plasmid was grown in tryptophan-depleted media, approximately 17 percent of the total cellular protein was found to be an insoluble and stable chimeric protein. The purified chimeric protein competed equally on a molar basis with VP3 for specific antibodies to foot-and-mouth disease virus. When inoculated into six cattle and two swine, this protein elicited high levels of neutralizing antibody and protection against challenge with foot-and-mouth disease virus.

Hybridization in bottlenose dolphins-A case study of Tursiops aduncus × T. truncatus hybrids and successful backcross hybridization events.

The bottlenose dolphin, genus Tursiops is one of the best studied of all the Cetacea with a minimum of two species widely recognised. Common bottlenose dolphins (T. truncatus), are the cetacean species most frequently held in captivity and are known to hybridize with species from at least 6 different genera. In this study, we document several intra-generic hybridization events between T. truncatus and T. aduncus held in captivity. We demonstrate that the F1 hybrids are fertile and can backcross producing apparently healthy offspring, thereby showing introgressive inter-specific hybridization within the genus. We document that female F1 hybrids can reach sexual maturity at 4 yr and 3 mo of age, and can become pregnant and give birth before being fully weaned. The information presented has implications for understanding hybrid reticulation among cetacean species and practical implications for captive facilities housing either Tursiops species or hybrids thereof.

Transendothelial insulin transport is not saturable in vivo. No evidence for a receptor-mediated process.

In vitro, insulin transport across endothelial cells has been reported to be saturable, suggesting that the transport process is receptor mediated. In the present study, the transport of insulin across capillary endothelial cells was investigated in vivo. Euglycemic glucose clamps were performed in anesthetized dogs (n = 16) in which insulin was infused to achieve concentrations in the physiological range (1.0 mU/kg per min + 5 mU/kg priming bolus; n = 8) or pharmacologic range (18 mU/kg per min + 325 mU/kg priming bolus; n = 8). Insulin concentrations were measured in plasma and hindlimb lymph derived from interstitial fluid (ISF) surrounding muscle. Basal plasma insulin concentrations were twice the basal ISF insulin concentrations and were not different between the physiologic and pharmacologic infusion groups (plasma/ISF ratio 2.05 +/- 0.22 vs 2.05 +/- 0.23; p = 0.0003). The plasma/ISF gradient was, however, significantly reduced at steady-state pharmacologic insulin concentrations (1.37 +/- 0.25 vs 1.98 +/- 0.21; P = 0.0003). The reduced gradient is opposite to that expected if transendothelial insulin transport were saturable. Insulin transport into muscle ISF tended to increase with pharmacologic compared with physiologic changes in insulin concentration (41% increase; 1.37 +/- 0.18 10(-2) to 1.93 +/- 0.24 10(-2) min-1; P = 0.088), while at the same time insulin clearance out of the muscle ISF compartment was unaltered (2.53 +/- 0.26 10(-2) vs 2.34 +/- 0.28 10(-2) min-1; P = 0.62). Thus, the reduced plasma/ISF gradient at pharmacologic insulin was due to enhanced transendothelial insulin transport rather than changes in ISF insulin clearance. We conclude that insulin transport is not saturable in vivo and thus not receptor mediated. The increase in transport efficiency with saturating insulin is likely due to an increase in diffusionary capacity resulting from capillary dilation or recruitment.