Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation.

PURPOSE: This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid-induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes.. METHODS: This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo. RESULTS: Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t½z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (>90 %). All tested doses were well tolerated. CONCLUSIONS: Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min.

The constructal-law physics of why swimmers must spread their fingers and toes.

Here we show theoretically that swimming animals and athletes gain an advantage in force and speed by spreading their fingers and toes optimally. The larger force means larger body mass lifted and greater speed, in accord with the constructal theory of all animal locomotion. The spacing between fingers must be twice the thickness of the boundary layer around one finger. This theoretical prediction is confirmed by computational fluid dynamics simulations of flow across two and four cylinders of diameter D. The optimal spacing is in the range 0.2D-0.4D, and decreases slightly as the Reynolds number (Re) increases from 20 to 100. For example, the total force exerted by two optimally spaced cylinders exceeds by 53% the total force of two cylinders with no spacing when Re=20. These design features hold for both time-dependent and steady-state flows.

Short communication: glucose and fructose concentrations and expression of glucose transporters in 4- to 6-week pregnancies collected from Holstein cows that were either lactating or not lactating.

Glucose is an essential nutrient for the conceptus. The objective was to determine if lactation affected the amount of glucose crossing the placenta by measuring glucose and fructose in placental fluids in lactating and nonlactating cows. Holstein cows were assigned to one of 2 treatments immediately after parturition [lactating (n=23) or nonlactating (dried off immediately after calving; n=20)]. Pregnant cows were slaughtered at one of 3 d of pregnancy (d 28, 35, or 42) and tissues were collected. Plasma glucose and insulin were less in lactating cows. Pregnancies collected from lactating cows had less glucose and fructose in placental fluids compared with those from nonlactating cows. Relative to endometrium, the placenta expressed greater amounts of the glucose transporters SLC2A1 (Glut1), SLC2A3 (Glut3) and SLC2A4 (Glut4) mRNA. The mRNA for SLC2A1 decreased whereas the mRNA for SLC2A4 increased from d 28 to d 42 of pregnancy. Stepwise regression analyses for fetal and placental weight (dependent variable) retained day of pregnancy and maternal plasma insulin concentrations in the final model. The conclusion is that lower blood glucose and insulin in lactating cows may lead to less glucose crossing the placenta and slower fetal development during lactation. The slower fetal development may predispose lactating cows to fetal loss if developmental milestones are not reached.

Social disparities in musculoskeletal disorders and associated mental malaise: findings from a population-based survey in France.

AIMS: Various types of musculoskeletal disorders (MSDs) have comorbid mental disorders, which may in turn have a negative influence on disease course and role impairment, but the contribution of social factors to this type of comorbidity is a much under-researched area. This study investigates whether there is a socially patterned association of MSDs with different dimensions of mental malaise. METHODS: The sample included 3,368 economically active participants aged 18-64 years, randomly selected from the Lorraine region in north-eastern France. Information was provided through a post-mailed questionnaire on fatigue, sadness/depression (Duke questionnaire) and cognitive disability during the last eight days. RESULTS: MSDs were significantly more prevalent in manual workers, clerks and other occupations than in upper and intermediate professionals, and similar occupational disparities were found for cognitive disability, fatigue and sadness/ depression. Stratifying the sample, we found the occupational disparities in cognitive disability to be much stronger among participants suffering from MSDs than among participants not suffering from MSDs, and the occupational disparities in fatigue and sadness/depression to be limited to the subsample of subjects suffering from MSDs. CONCLUSIONS: The findings demonstrate that the association of MSDs with mental malaise is much stronger in the lower occupational groups than in the higher groups. Given that psychological factors are implicated in disease prognosis and in the development of disabilities, awareness of the social dimension of the association and treatment of the comorbid mental disorders could open a promising avenue for reducing social inequalities in disability related to MSDs.

Uterine and hepatic gene expression in relation to days postpartum, estrus, and pregnancy in postpartum dairy cows.

The somatotropic axis consisting of growth hormone, the growth hormone receptor (GHR) insulin-like growth factor (IGF)-I, and IGF binding proteins changes with the stage of lactation and nutrition of the cow and may be 1 mechanism through which lactation and nutrition affect the establishment of pregnancy. The objective of this study was to quantify GHR, IGF-I, and IGF binding protein-2 (IGFBP-2) mRNA in liver and uterine endometrial tissue at 4 stages of lactation (40, 80, 120, and 160 days in milk) and around the time of artificial insemination. Estrus was synchronized with GnRH and PGF2alpha, and cows were inseminated 12 h after estrus. Uterine biopsies were collected immediately before the second injection of PGF2alpha (before estrus), at the initiation of standing estrus, and 4 d after estrus. Liver biopsies were collected once on 4 d after estrus. The abundance of GHR, IGF-I, and IGFBP-2 mRNA in liver and uterus was determined by real-time quantitative PCR. The amount of liver IGF-I mRNA was positively correlated with plasma IGF-I concentrations. Cows that became pregnant after AI had more GHR and IGFBP-2 mRNA in their liver than cows that did not become pregnant. There was no effect of DIM or pregnancy status on abundance of uterine mRNA; however, uterine GHR and IGF-I mRNA was most abundant at estrus. In summary, cows at different stages of lactation or with different pregnancy statuses had similar quantities of uterine mRNA. In contrast, liver quantities of mRNA differed relative to pregnancy status. These data provide evidence that liver indices of metabolic state may be indicative of pregnancy success.

Growth hormone receptor, insulin-like growth factor (IGF)-1, and IGF-binding protein-2 expression in the reproductive tissues of early postpartum dairy cows.

The growth hormone/insulin-like growth factor (IGF) system plays a critical endocrine role controlling nutrient metabolism in dairy cattle. In liver, growth hormone receptor (GHR) and IGF-1 are dynamically regulated by lactation and energy balance. Less is known about the regulation of GHR, IGF-1, and IGF-binding protein mRNA in reproductive tissues (uterus, ovarian follicle, and corpus luteum). The objective was to determine expression patterns for GHR, IGF-1, and IGF-binding protein (IGFBP)-2 mRNA in the liver, uterus, dominant follicle, and corpus luteum in Holstein cows (n = 21) sampled at 3 times during early lactation. The first postpartum ovulation was induced with an injection of GnRH within 15 d of calving. Nine days after ovulation [23 +/- 1 d postpartum; 20 d in milk (DIM)], the liver, uterus, dominant follicle, and corpus luteum were biopsied. Prostaglandin F(2alpha) and GnRH were injected 7 and 9 d after each biopsy to synchronize the second (41 +/- 1 d postpartum; 40 DIM) and third (60 +/- 1 d postpartum; 60 DIM) tissue collections. Total RNA was isolated and used for mRNA analysis by real-time quantitative reverse transcription PCR. Liver had more GHR, IGF-1, and IGFBP-2 mRNA than the reproductive tissues that were tested. Gene expression for GHR, IGF-1, and IGFPB-2 within tissues did not change across the sampling interval (20 to 60 DIM). The only detected change in gene expression across days was for cyclophilin in uterus (increased after 20 DIM). Parity had an effect on gene expression for GHR in corpus luteum. Neither level of milk production nor body condition score affected the amount of GHR, IGF-1, or IGFBP-2 mRNA in the respective tissues. The repeatability of gene expression within a tissue was 0.25 to 0.5 for most genes. In most instances, expression of a single gene within a tissue was correlated with other genes in the same tissue but was not correlated with the same gene in a different tissue. We did not find evidence for major changes in gene expression within reproductive tissues in postpartum cows. Differences between cows (independent of their BCS and milk production) accounted for a major portion of the variation that we observed.

Timed artificial insemination of two consecutive services in dairy cows using prostaglandin F2alpha and gonadotropin-releasing hormone.

Timed artificial insemination (TAI) protocols use PGF(2alpha) and GnRH injections to synchronize ovulation. The objective was to evaluate the PGPG protocol (d 0, PGF(2alpha); d 3, GnRH; d 11, PGF(2alpha); d 13, GnRH and TAI) for first TAI and also examine methods for second TAI in nonpregnant cows. A factorial test of the first PGF(2alpha) and first GnRH injections within the PGPG protocol was performed (the last PGF(2alpha) and GnRH injections were deemed essential to the TAI). Lactating dairy cows (n = 804) in a commercial herd were assigned to 1 of 5 first-TAI treatments, which were PGPG, GPG (d 0, no treatment; d 3, GnRH; d 11, PGF(2alpha); d 13, GnRH and TAI), PPG (d 0, PGF(2alpha); d 3, no treatment; d 11, PGF(2alpha); d 13, GnRH and TAI), and PG (d 0, no treatment; d 3, no treatment; d 11, PGF(2alpha); d 13, GnRH and TAI); the Ovsynch protocol (GnRH, 7 d, PGF(2alpha), 2 d, GnRH and TAI) was the positive control. For resynchronization, cows received either GnRH or the control (no injection) on d 22 after TAI. Nonpregnant cows on d 28 were then treated with PGF(2alpha) on d 29, GnRH on d 31, and TAI [i.e., resynchronization treatments of ReGPG (received GnRH on d 22) and RePG (did not receive GnRH on d 22)]. Pregnancy rates for PGPG, GPG, PPG, PG, and Ovsynch were similar at d 28 after first TAI. Analyses of multiple explanatory factors by logistic regression detected an effect of uterine or ovarian abnormality on the d-28 pregnancy rate (normal more likely to be pregnant). Day-42 pregnancy rates were affected by uterine or ovarian abnormality (normal more likely to be pregnant), postpartum disease occurrence (healthy cows more likely to be pregnant), milk production, and days in milk. Treatment was not significant for the d-42 pregnancy rate. Effects of postpartum disease, milk production, and days in milk on the d-42 pregnancy rate were apparently manifested through their effects on embryonic loss between d 28 and 42 of pregnancy. High-producing cows that received TAI early postpartum were most likely to experience embryonic loss. Day-42 pregnancy rates after the resynchronization treatment were affected by an interaction of the first synchronization treatment with the resynchronization treatment. We concluded that although PGPG can be used for TAI, a simpler TAI protocol that includes the last 2 injections (PGF(2alpha), 2 d; GnRH and TAI) would be equally effective.

Comparison of physiological and subjective strains of two protective coveralls in two short physically simulated demanding tasks.

A total of 15 physically active male students carried out a normalised task (T(N)) and a task of access by ladder and scaffolding (T(L)) in two impermeable protective coveralls and a reference sports wear to compare the physiological and subjective strains. Heart rate (HR) was recorded and sweat loss was checked. Subjective evaluations of comfort parameters, acceptable exposure durations and physical exhaustion were recorded at the end of the tasks. Results show that both protective clothing, compared to the sport wear, increase significantly HR, RPE and CR10 in both tasks. However the strains of both protective clothing are not significantly different except in sweat loss and cumbersomeness.

Synthesis using a Fmoc-based strategy and biological activities of some reduced peptide bond pseudopeptide analogues of dynorphin A1.

Eight analogues of Dyn A(1-11)-NH2 incorporating the enzymatically stable psi(CH2-NH) isosteric peptide bond replacement were synthesized and tested for binding affinity at the central opioid mu, delta, and kappa receptors in guinea pig brain (GPB) homogenates and for activity at the peripheral kappa (and mu) receptors in the guinea pig ileum (GPI). The peptidic analogues were synthesized by solid phase techniques using a Fmoc/tert-butyl strategy, and the psi(CH2-NH) bond, or reduced bond, was introduced via reductive alkylation of the N-terminal amino group of the growing peptide with a Fmoc-N(alpha)-protected amino aldehyde. The synthesis of Fmoc-N(alpha)-protected amino aldehydes also is described. Several other peptides have been previously synthesized incorporating this modification and showed for instance increased enzymatic stability and antagonist properties. Results obtained in the GPB show that modifications of the peptide bond in the address site (analogues 4-9) do not affect the binding at the kappa receptor and, with a few exceptions, at the mu and delta receptors. On the other hand, analogues 2 and 3, modified in the message segment of Dyn A(1-11)-NH2, show a decrease in binding affinity at all three receptors. In the GPI, the results are more varied as the influence of the peptide bond modification seems to be more important than in the GPB. Finally, selected analogues were tested with no indication for antagonist activity at the kappa peripheral receptor.

Structural model of a cyclic dynorphin A analog bound to dodecylphosphocholine micelles by NMR and restrained molecular dynamics.

The compound c[Cys5,11]dynorphin A-(1-11)-NH2, 1, is a cyclic dynorphin A analog that shows similar selectivity and potency at the kappa-opioid receptor when compared to the native form of the peptide in central nervous system assays. Previous molecular mechanics calculations have shown that the ring portion of the isoform that is trans about the Arg9-Pro10 omega bond contains either a beta-turn from residues Arg6 to Arg9 or an alpha-helical conformation. Our results from solution state NMR indicate that the compound exhibits cis-trans isomerism about the Arg9-Pro10 omega bond in both aqueous solution and when bound to dodecylphosphocholine micelles. Restrained molecular dynamics calculations show that the cis isoform of the peptide contains a type III beta-turn from residues Arg7 to Pro10. Similar calculations on the trans isoform show it to contain a beta-turn from residues Cys5 and Arg8. In this report we describe the generation of three-dimensional models from NMR data for the ring portions of both the cis and trans isoforms of 1 bound to dodecylphosphocholine micelles. Comparison with other dynorphin A structural information indicates that both the cis and trans isoforms of the peptide may be active as kappa-opioid agonists.

Design, synthesis, and biological properties of highly potent cyclic dynorphin A analogues. Analogues cyclized between positions 5 and 11.

We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand. Several of these analogues, bridged between positions 5 and 11 of Dyn A1-11-NH2, exhibited unexpected selectivities for the kappa and mu receptors of the central over the peripheral nervous systems. In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A1-11-NH2 analogues incorporating the sulfydryl containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11, thus producing 16 cyclic peptides. In addition, Dyn A1-11-NH2, [D-Leu5]Dyn A1-11-NH2, and [D-Lys11]Dyn A1-11-NH2 were synthesized as standards. Several of these cyclic analogues, especially c[Cys5,D-Cys11] Dyn A1-11-NH2, c[Cys5, L- or D-Pen11]Dyn A1-11-NH2, c[Pen5, L-Pen11]Dyn A1-11-NH2 and c[Pen5, L- or D-Cys11]Dyn A1-11-NH2, retained the same affinity and selectivity (vs the mu and delta receptors) as the parent compound Dyn A1-11-NH2 in the guinea pig brain (GPB). These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously. In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at kappa opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the kappa, mu, or delta central receptors.

Effects of modifications of residues in position 3 of dynorphin A(1-11)-NH2 on kappa receptor selectivity and potency.

Tyrosine1 and phenylalanine4 in dynorphin A (Dyn A) have been reported to be important residues for opioid agonist activity and for potency at kappa receptors. The glycine residues in the 2 and 3 positions of dynorphin A may affect the relative orientation of the aromatic rings in positions 1 and 4, but their flexibility precludes careful analysis. To examine these effects on dynorphin A, we previously have synthesized the linear analogues [D-Ala3]Dyn A(1-11)-NH2 (2) and [Ala3]Dyn A(1-11)-NH2 (3) and reported their biological activities. Analogues 2 and 3 displayed affinities for the central kappa opioid receptor (IC50 = 0.76 and 1.1 nM, respectively) similar to that of Dyn A(1-11)-NH2 (1) (IC50 = 0.58 nM) and greatly enhanced selectivities for kappa vs mu and kappa vs delta receptors (IC50 ratios of 350 and 1300 for 2, and 190 and 660 for 3, respectively). These results suggest that the structure and lipophilicity of the amino acid present in position 3 of Dyn A(1-11)-NH2 as well as the conformational changes they induce in the message sequence of dynorphin have important effects on potency and selectivity for kappa opioid receptors. To further investigate structure-activity relationships involving the residue at the 3 position of Dyn A(1-11)-NH2, a series of Dyn A analogues with aromatic, charged, and aliphatic side chain substitutions at the 3 position was designed, synthesized, and evaluated for their affinities for kappa, mu, and delta opioid receptors. It was found that analogues with lipophilic amino acids at the 3 position of Dyn A(1-11)-NH2 generally displayed higher affinity but similar selectivities for the kappa receptor than analogues with charged residues at the same position. It is suggested that the structural, configurational, and steric/lipophilic effects of amino acids at position 3 of Dyn A(1-11)-NH2 may play an important role in potency and selectivity for the kappa receptor.

Early experience with in situ saphenous vein bypass for distal arterial reconstruction.

During a 36-month period 74 patients underwent infrainguinal in situ saphenous vein bypass to the popliteal or tibial vessels. The first 54 operations were performed with standard valvulotomes and valve-cutting scissors, while in the last 20 operations a new intraluminal valve-cutting device was used to incise the valves. Ninety-four percent of bypasses were performed for limb salvage, 80% of all operations were done to the tibial vessels, and 31% of bypasses were done to the ankle vessels. The operation was attempted in 81 patients and completed in 74 patients, for a vein utilization rate of 91%. Fifty-five percent of all veins had a distal diameter of less than 4 mm (average 3.6 mm). The patency rates were 92% at 3 months and 90% at 12 and 36 months for all grafts. There were six failed grafts, all within the first 6 months, and eight diabetic patients required reoperation, two for missed valve leaflets, and three needed revision of the distal anastomosis; however, all these grafts were patent at the time of reexploration. There were four perioperative deaths and two patients had nonfatal postoperative myocardial infarctions. This study demonstrates that in situ saphenous vein grafting provides for a high vein utilization rate and suggests that the technique provides for higher graft patency and limb salvage rates than do more traditional types of procedures.

Mandatory vs selective exploration for penetrating neck trauma. A prospective assessment.

To determine the optimal management of patients with penetrating wounds to zone II of the neck, we performed a prospective evaluation of 120 consecutive patients with such injuries, correlating the results of clinical and diagnostic examinations with operative findings. Seven patients presenting with life-threatening hemorrhage from the neck wound were operated on immediately; the remaining 113 patients underwent arteriography, laryngotracheoscopy, esophagoscopy, and esophagography, followed by neck exploration. Forty-eight major injuries were identified in 35 neck explorations. Five patients were identified with clinical and diagnostic findings that were considered normal preoperatively; however, at operation six major injuries were found in these patients. This study indicates that potentially lethal injuries to major vascular and visceral structures in the neck may go undetected if selective exploration criteria are used in the decision to explore penetrating wounds to zone II of the neck.

Internal iliac artery revascularization in the treatment of vasculogenic impotence.

Five impotent men underwent internal iliac artery revascularization in conjunction with end-to-side aortobifemoral bypass after preoperative testing suggested a vasculogenic cause for impotence. All patients had abnormal preoperative penile/brachial arterial pressure indices (mean, 0.42 +/- 0.12). Following operation, all patients regained erectile capability and had normal postoperative penile/brachial indices (mean, 0.80 +/- 0.06). One patient developed retrograde ejaculation, emphasizing the need for meticulous nerve-sparing dissection with this operation. Internal iliac artery revascularization in conjunction with end-to-side aortobifemoral bypass is effective in relieving vasculogenic impotence in properly selected patients.

Risk factors affecting the natural history of intermittent claudication.

To determine the prognostic significance of the level of arterial disease in claudicators, risk factors affecting the progression of intermittent claudication, including hemodynamic variables obtained from noninvasive vascular laboratory examinations, were assessed. We identified 378 patients with intermittent claudication by characteristic history and the presence of abnormal treadmill exercise examination results. Results of serial examinations were available for 195 of these patients, who had 310 claudicating limbs. Life-table analysis revealed that after eight years, 41% of these patients had progressed to critical ischemia, defined as rest pain or tissue loss, and 50% had died. Cox proportional hazards general linear regression analysis found that at a patient's first examination in the vascular laboratory, the ankle-brachial index and the decrease in ankle-brachial index after exercise were significantly associated with the subsequent development of critical ischemia. The level of disease at the initial examination in the vascular laboratory was not a significant risk factor for progression to critical ischemia and therefore should not be used as an indicator for or against operation in patients with intermittent claudication.

Peripheral vascular trauma from close-range shotgun injuries.

This report summarizes an eight-year experience (1976 to 1983) with 49 close-range shotgun blasts with associated major vascular injuries seen in a large urban hospital. Injuries to the upper extremity (40%), lower extremity (56%), and neck (4%) were seen. A high frequency of associated deep venous injury (82%), nerve injury (37%), fracture (33%), massive soft-tissue loss (43%), and compartmental hypertension (39%) was observed. There were no deaths in this series, and the limb salvage rate was 96%. Neither patient with multiple carotid artery injuries suffered a neurologic deficit. We attribute our success in the management of these complex injuries to rapid fracture immobilization, early and aggressive use of fasciotomy, adequate débridement of devitalized tissue, repair of deep venous injuries, arterial repair with autogenous tissue, and extra-anatomic bypass grafting in selected cases.

Results of venous reconstruction after civilian vascular trauma.

The treatment of venous injuries remains controversial. In an attempt to evaluate the results of current management of venous injuries, we retrospectively reviewed our experience between 1979 and 1984. During this period 142 patients had sustained injuries to 158 veins in the neck (31 patients), abdomen (45 patients), upper extremity (20 patients), and lower extremity (62 patients). Overall, 90 venous injuries (61%) were repaired, including 83% of caval and iliac vein injuries and 90% of injuries to the common femoral, superficial femoral, and popliteal veins. There was no morbidity after repair of 73 major veins. Morbidity occurred in four of 11 patients after ligation of major veins (edema in two patients and above-knee amputation in two others). Both ligation (N = 51) and repair (N = 17) of lesser veins (jugular, brachial, profunda femoral, tibial, and minor abdominal veins) resulted in no morbidity. Overall mortality was 6% with all deaths occurring in patients with abdominal venous trauma. These data indicate that repair of venous injuries can be performed without morbidity and that minor veins can be ligated without adverse sequelae. However, in view of the morbidity associated with ligation of major veins, efforts to restore flow to these injured vessels appear appropriate unless contraindicated by life-threatening injury.

The role of isolated profundaplasty for the treatment of rest pain.

This study was undertaken to determine the efficacy and durability of profundaplasty and define preoperative factors predictive of success. The hospital charts, vascular laboratory data, and arteriograms of 20 patients having 21 isolated profundaplasties for ischemic rest pain between 1979 and 1987 were reviewed. Follow-up extended to 72 months (mean, 26 months). Early success was achieved in 12 extremities (57%) and life-table analysis showed continued success to six years in 11 extremities (55%). Of the multiple preoperative factors assessed, only a low-thigh/ankle gradient pressure index (TAGI) of less than 0.55 was predictive of success. Life-table analysis for limbs with a TAGI of less than 0.55 showed an 89% success rate at six years compared with only a 32% success rate for limbs with a TAGI of more than 0.55. Isolated profundaplasty for the treatment of ischemic rest pain can be an efficacious and durable procedure when patients are selected based on objective hemodynamic measurements.

Crush syndrome due to limb compression.

Four patients with the crush syndrome due to prolonged limb compression were treated at Cook County Hospital, Chicago. Limb injury was caused when the obtunded patient fell asleep lying on the involved extremity. Prolonged limb compression may cause an acute compartment syndrome with ischemic muscle injury. Continued muscle ischemia may lead to myonecrosis resulting in shock or renal failure. A history of prolonged limb compression with a swollen limb should suggest the diagnosis of crush syndrome. Prompt therapy, including rapid correction of volume and metabolic derangements, extensive open fasciotomy, and dialysis for severe acute renal failure should provide good functional results in the majority of patients.