Are adverse outcome rates higher in multiple sclerosis patients after total hip arthroplasty?

Aims: This study compared multiple sclerosis (MS) patients who underwent primary total hip arthroplasty (THA) with a matched cohort. Specifically, we evaluated: 1) implant survivorship; 2) functional outcomes (modified Harris Hip Scores (mHHS), Hip Disability and Osteoarthritis Outcome Score, Joint Replacement (HOOS JR), and modified Multiple Sclerosis Impact Scale (mMSIS) scores (with the MS cohort also evaluated based on the disease phenotype)); 3) physical therapy duration and return to function; 4) radiographic outcomes; and 5) complications. Patients and Methods: We reviewed our institution's database to identify MS patients who underwent THA between January 2008 and June 2016. A total of 34 MS patients (41 hips) were matched in a 1:2 ratio to a cohort of THA patients who did not have MS, based on age, body mass index (BMI), and Charlson/Deyo score. Patient records were reviewed for complications, and their functional outcomes and radiographs were reviewed at their most recent follow-up. Results: Compared with the matched cohort, MS patients had lower all-cause implant survivorship at eight years (91.5% (95% confidence interval (CI) 82.7 to 100) vs 98.7% (95% CI 96.2 to 100)) (p = 0.033), lower mHHS scores (66 vs 80, p < 0.001), and HOOS JR scores (79 vs 88, p = 0.009). Multiple sclerosis patients also required more physiotherapy (five weeks vs three weeks, p = 0.002) and took longer to return to baseline (seven weeks vs five weeks, p = 0.010) than the matched cohort. Furthermore, MS patients had more complications than the non-MS patients (six vs zero, p < 0.001). The worse outcomes of the MS group can potentially be explained by predisposition of these patients to mechanical complications and progression of their disease during the period of this study, as demonstrated by worsening of the mMSIS scores (2.9 vs 3.4; p = 0.008). Conclusion: MS patients had lower implant survivorship, lower functional outcome scores, and increased complication rates; in addition, MS patients took longer to return to their baseline functional level after THA. Cite this article: Bone Joint J 2018;100-B:875-81.

Vascular and metabolic effects of methacholine in relation to insulin action in muscle.

AIMS/HYPOTHESIS: Methacholine (MC) is a nitric oxide vasodilator, but unlike other vasodilators, it potentiates insulin-mediated glucose uptake by muscle. The present study aimed to resolve whether this action was the result of a vascular effect of MC leading to increased muscle perfusion or a direct effect of MC on the myocytes. We hypothesise that vascular-mediated insulin-stimulated glucose uptake responses to MC occur at lower doses than direct myocyte MC-mediated increases in glucose uptake. METHODS: The vascular and metabolic effects of this vasodilator were examined in rats in vivo using a novel local infusion technique, and in the pump-perfused rat hindlimb under conditions of constant flow. RESULTS: Local infusion of low-dose MC (0.3 micromol/l) into the epigastric artery of one leg (test) in vivo markedly increased femoral blood flow and decreased vascular resistance, without effects in the contra-lateral leg. Capillary recruitment, but not glucose uptake, was increased in the test leg. All increases caused by MC were confined to the test leg and blocked by local infusion into the test leg of N-nitro-L-arginine methyl ester (L-NAME), but not by infusion of N-nitro-D-arginine methyl ester (D-NAME). In the constant-flow pump-perfused rat hindlimb, infusion of 0.6 micromol/l MC vasodilated the pre-constriction effected by 70 nmol/l noradrenaline or 300 nmol/l serotonin, and this was blocked by 10 micromol/l L-NAME. 2-Deoxyglucose in muscle was increased by 30 micromol/l MC (p<0.05), but was unaffected by 3 micromol/l MC. All increases in 2-deoxyglucose uptake by 30 micromol/l MC were blocked by 10 micromol/l L-NAME. CONCLUSIONS/INTERPRETATION: MC has dose-dependent effects both on the vasculature and on muscle metabolism. At low dose (0.3-3 micromol/l), MC is a potent vasodilator in muscle, both in vivo and in vitro, without metabolic effects; at higher doses (> or =30 micromol/l) MC has a direct metabolic effect leading to increased glucose uptake. Both the vascular and metabolic effects are sensitive to L-NAME. The low-dose enhancement of insulin action in vivo by MC, which has been reported previously, thus seems to be attributable to vascular effects.

Structural analysis of a set of proteins resulting from a bacterial genomics project.

The targets of the Structural GenomiX (SGX) bacterial genomics project were proteins conserved in multiple prokaryotic organisms with no obvious sequence homolog in the Protein Data Bank of known structures. The outcome of this work was 80 structures, covering 60 unique sequences and 49 different genes. Experimental phase determination from proteins incorporating Se-Met was carried out for 45 structures with most of the remainder solved by molecular replacement using members of the experimentally phased set as search models. An automated tool was developed to deposit these structures in the Protein Data Bank, along with the associated X-ray diffraction data (including refined experimental phases) and experimentally confirmed sequences. BLAST comparisons of the SGX structures with structures that had appeared in the Protein Data Bank over the intervening 3.5 years since the SGX target list had been compiled identified homologs for 49 of the 60 unique sequences represented by the SGX structures. This result indicates that, for bacterial structures that are relatively easy to express, purify, and crystallize, the structural coverage of gene space is proceeding rapidly. More distant sequence-structure relationships between the SGX and PDB structures were investigated using PDB-BLAST and Combinatorial Extension (CE). Only one structure, SufD, has a truly unique topology compared to all folds in the PDB.

Nutritive blood flow affects microdialysis O/I ratio for [(14)C]ethanol and (3)H(2)O in perfused rat hindlimb.

Changes in the microdialysis outflow-to-inflow (O/I) ratio for [(14)C]ethanol and (3)H(2)O were determined in the perfused rat hindlimb after increases and decreases in nutritive flow mediated by the vasoconstrictors norepinephrine (NE) and serotonin (5-HT), respectively. Microdialysis probes (containing 10 mM [(14)C]ethanol and (3)H(2)O pumped at 1 or 2 microl/min) were inserted through the calf of the rat. Hindlimb perfusion flow rate was varied from 6 to 56 ml x min(-1) x 100 g(-1) in the presence of NE, 5-HT, or saline vehicle. The O/I ratios for both tracers were determined at each perfusion flow rate, as was perfusion pressure, oxygen uptake (a surrogate indicator of nutritive flow), and lactate release. Both tracers showed a decreased O/I ratio as hindlimb perfusion flow was increased, with [(14)C]ethanol being higher than (3)H(2)O. NE decreased the O/I ratio compared with vehicle, and 5-HT increased it for both tracers and both microdialysis flow rates. We conclude that the microdialysis O/I ratio, while able to detect changes in total flow, is also sensitive to changes in nutritive and nonnutritive flow, where the latter still extracts tracer, but less than the former.

The Everglades Nutrient Removal Project test cells: STA optimization--status of the research at the north site.

The Everglades is an oligotrophic ecosystem that is being adversely impacted by hydrologic changes and nutrient-rich runoff generated from urban and agricultural sources. The Stormwater Treatment Area (STA) Optimization Research and Monitoring program is mandated by the 1994 Everglades Forever Act and will assist the South Florida Water Management District in developing operational strategies that maximize performance of emergent macrophyte STAs. The primary objective of this research is to examine how hydrologic conditions may influence STA performance. The study was conducted in 0.2 ha, shallow, fully lined test cells located within the perimeter of the Everglades Nutrient Removal Project. Experiments were designed to examine the effect of increased and decreased hydraulic loading rate (HLR) on wetland performance and to determine, if possible, the HLR at which STA treatment fails to reduce outflow total phosphorus concentration to the interim target of 50 microg-P/L. To date, two HLR experiments have been completed at the north site. Preliminary data indicated at all HLRs tested that particulate phosphorus and dissolved organic phosphorus ratios remained virtually unchanged from inflow to outflow. The dissolved organic and particulate compounds within these test cells are extremely recalcitrant, and are not easily assimilated within the system. High HLRs may not result in detention times long enough to mineralize these forms into easily assimilated inorganic compounds, resulting in mean TP concentrations greater than 50 microg-P/L.

Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty.

BACKGROUND: Recent studies have shown that symptomatic venous thromboembolism after total hip arthroplasty most commonly develops after the patient is discharged from the hospital. Risk factors associated with these symptomatic thromboembolic events are not well defined. METHODS: Using administrative data from the California Medicare records for 1993 through 1996, we identified 297 patients 65 years of age or older who were rehospitalized for thromboembolism within three months after total hip arthroplasty. We compared demographic, surgical, and medical variables potentially associated with the development of thromboembolism in these patients and 592 unmatched controls. RESULTS: A total of 89.6 percent of patients with thromboembolism and 93.8 percent of control patients were treated with pneumatic compression, warfarin, enoxaparin, or unfractionated heparin, alone or in combination. In addition, 22.2 percent and 29.7 percent, respectively, received warfarin after discharge. A body-mass index (the weight in kilograms divided by the square of the height in meters) of 25 or greater was associated with rehospitalization for thromboembolism, with an odds ratio of 2.5 (95 percent confidence interval, 1.8 to 3.4). In a multivariate model, the only prophylactic regimens associated with a reduced risk of thromboembolism were pneumatic compression in patients with body-mass indexes of less than 25 (odds ratio, 0.3; 95 percent confidence interval, 0.2 to 0.6) and warfarin treatment after discharge (odds ratio, 0.6; 95 percent confidence interval, 0.4 to 1.0). CONCLUSIONS: In patients who underwent total hip arthroplasty, a body-mass index of 25 or greater was associated with subsequent hospitalization for thromboembolism. Pneumatic compression in patients with a body-mass index of less than 25 and prophylaxis with warfarin after discharge were independently protective against thromboembolism.

Interaction between metabolism and flow in tendon and muscle.

Blood vessels supplying the musculotendinous region of tendons, including interfibrillar connective tissue, represent a parallel vascular network to that supplying muscle fibers. Reciprocal control by vasomodulators and neural input determines relative flow in each network, and therefore relative supply of nutrients and hormones. Vessels supplying the tendon support fat cells and may function as a non-nutritive network within muscle groups to regulate resting muscle energy metabolism and to act as a flow reservoir for nutrient delivery in exercise.

Relationship of MTT reduction to stimulants of muscle metabolism.

MTT, a positively charged tetrazolium salt, is widely used as an indicator of cell viability and metabolism and has potential for histochemical identification of tissue regions of hypermetabolism. In the present study, MTT was infused in the constant-flow perfused rat hindlimb to assess the effect of various agents and particularly vasoconstrictors that increase muscle metabolism. Reduction of MTT to the insoluble formazan in muscles assessed at the end of experiments was linear over a 30 min period and production rates were greater in red fibre types than white fibre types. The vasoconstrictors, norepinephrine (100 nM) and angiotensin (10 nM) decreased MTT formazan production in all muscles but increased hindlimb oxygen uptake and lactate efflux. Veratridine, a Na(+) channel opener that increases hindlimb oxygen uptake and lactate efflux without increases in perfusion pressure, also decreased MTT formazan production. Membrane stabilizing doses (100 microM) of (+/-)-propranolol reversed the inhibitory effects of angiotensin and veratridine on MTT formazan production. Muscle contractions elicited by stimulation of the sciatic nerve, reversed the norepinephrine-mediated inhibitory effects on MTT formazan production, even though oxygen consumption and lactate efflux were further stimulated. Stimulation of hindlimb muscle oxygen uptake by pentachlorophenol, a mitochondrial uncoupler, was not associated with alterations in MTT formazan production. It is concluded that apart from muscle contractions MTT formazan production does not increase with increased muscle metabolism. Since the vasoconstrictors angiotensin and norepinephrine as well as veratridine activate Na(+) channels and the Na(+)/K(+) pump, energy required for Na(+) pumping may be required for MTT reduction. It is unlikely that vasoconstrictors that stimulate oxygen uptake do so by uncoupling respiration.

Nutritive and non-nutritive blood flow: rest and exercise.

There is growing evidence to support the notion of two vascular routes within, or closely associated with skeletal muscle. One route is in intimate contact with muscle cells (hence is known as 'nutritive') and the other functions as a vascular shunt (and has had the interesting misnomer of 'non-nutritive'). Recent findings suggest that the 'non-nutritive' route may, in part, be those vessels in closely associated (interlacing?) connective tissue that nourishes attached fat cells, and may form the basis of 'marbling' of muscle in obesity. In addition, embolism studies using various size microspheres indicate that the 'non-nutritive' vessels are likely to be capillaries fed by terminal arterioles that branch from the same transverse arterioles as those supplying terminal arterioles of the muscle capillaries (i.e. two vascular systems operating in parallel). The proportion of flow distributed between the two routes is tightly regulated and controls muscle metabolism and contraction by regulating hormone and substrate delivery as well as product removal. Because a high proportion of nutritive flow may elevate the set point for basal metabolism, a low proportion of nutritive flow in muscle at rest confers an evolutionary advantage, particularly when food is scarce. In addition, the proportion of flow that is carried by the non-nutritive routes at rest affords a flow reserve that can be switched to the nutritive route to amplify nutrient supply during exercise. Alternatively the non-nutritive route may allow flow to escape when active muscle contraction compresses its nutritive capillaries. Thus rhythmic oscillation of blood flow between the non-nutritive and nutritive networks may aid the muscle pump.

Structural genomics in the post-genomics era - the shapes of things to come.

The overwhelming success of the current genomic sequencing efforts has spawned analogous efforts in the structural biology community. These new research efforts, termed 'structural genomics', seek to create and execute high-throughput structure determination that would allow scientists to obtain hundreds to thousands of relevant macromolecular structures in a fraction of the time required today. Groups in academia, national laboratories and industry are launching such efforts, each examining a different set of model organisms and each with a different research model. This review will present the current structural genomics efforts and the data that have been derived from these efforts to date. The utility of these projects to pharmaceutical drug discovery efforts will also be presented.

Increased metabolism of infused 1-methylxanthine by working muscle.

Exogenous substrates for capillary endothelial enzymes have potential as markers for changes in capillary recruitment (albeit nutritive flow). The metabolism of infused 1-methylxanthine (1-MX) to 1-methylurate (1-MU) by capillary endothelial xanthine oxidase of the constant-flow perfused rat hindlimb was shown previously to decrease with oxygen uptake (VO2) when nutritive flow was decreased. In the present study, the metabolism of 1-MX was investigated under conditions when VO2 and nutritive flow are known to increase during muscle contraction. The constant-flow red blood cell-perfused rat hindlimb at 37 degrees C was used with sciatic nerve stimulation, and perfusate samples from whole hindlimb and working muscles taken for analysis of oxygen, lactate, 1-MX and 1-MU. Flow to muscle was assessed separately using fluorescent microspheres and was found to increase 2.3-fold to the working muscles while flow to the non-working leg muscles decreased to compensate. The activity of xanthine oxidase of whole muscle extracts was not altered by contraction. Samples from the vein draining the working muscles, and microsphere measurements of flow, indicated increased VO2 (5.5-fold to 249.2 +/- 43.1 micromol h-1 g-1, P < 0.001), and 1-MX conversion (2.5-fold to 1.87 +/- 0.25 micromol h-1 g-1, P < 0.01) (SEM are shown). It is concluded that as 1-MX metabolism parallels VO2, this substrate may be a useful indicator of changes in capillary (nutritive) surface area in muscle.

Outcome following acute myocardial infarction: are differences among physician specialties the result of quality of care or case mix?

BACKGROUND: Studies to determine whether care by cardiologists improves the survival of patients with acute myocardial infarction (MI) have produced conflicting results, and it is not known what accounts for differences in patient outcome by physician specialty. OBJECTIVES: To evaluate whether cardiologists provide more recommended therapies to elderly patients with acute MI and, if so, to determine whether variations in processes of care account for differences in patient outcome. DESIGN: Retrospective cohort study using medical chart data and administrative data files. SETTING: All nonfederal acute care hospitals in California. PATIENTS: A cohort of 7663 Medicare beneficiaries 65 years and older directly admitted to the hospital with a confirmed acute MI from April 1994 to July 1995 with complete data regarding potential contraindications to recommended therapies. MAIN OUTCOME MEASURES: Percentage of "good" and "ideal" candidates for a given acute MI therapy who actually received that therapy, percentage who received exercise stress testing or coronary angiography, percentage who underwent revascularization, and 1-year mortality, stratified by specialty of the attending physician. RESULTS: During hospitalization, good candidates for aspirin were more likely to receive aspirin if they were treated by cardiologists (87%) than by medical subspecialists (73%; P<.001), general internists (84%; P = .003), or family practitioners (81%; P<.001). Cardiologists were also more likely to treat good candidates with thrombolytic therapy (51%) than were medical subspecialists (29%; P<.001), general internists (40%; P<.001), or family practitioners (27%; P<.001). Patients of cardiologists were 2- to 4-fold more likely to undergo a revascularization procedure. Despite these differences in utilization, we found similar 30-day mortality rates across physician specialties. However, 1-year mortality rates were greater for patients treated by medical subspecialists (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.3), general internists (OR, 1.4; 95% CI, 1.3-1.6), and family practitioners (OR, 1.7; 95% CI, 1.4-1.9) than for those treated by cardiologists. Adjusting for differences in patient and hospital characteristics markedly reduced the ORs for those treated by medical subspecialists (OR, 1.2; 95% CI, 0.9-1.4), general internists (OR, 1.1; 95% CI, 1.0-1.3), and family practitioners (OR, 1.3; 95% CI, 1.1-1.6), whereas further adjustment for medication use and revascularization procedures had little effect. CONCLUSIONS: Differences in the use of recommended therapies by physician specialty are generally small and do not explain differences in patient outcome. In comparison, differences among patients treated by physicians of various specialties (case mix) have a large impact on patient outcome and may account for the residual survival advantage of patients treated by cardiologists. With the exception of the in-hospital use of aspirin, recommended MI therapies are markedly underused, regardless of the specialty of the physician.

Contribution of mitochondrial proton leak to respiration rate in working skeletal muscle and liver and to SMR.

Proton pumping across the mitochondrial inner membrane and proton leak back through the natural proton conductance pathway make up a futile cycle that dissipates redox energy. We measured respiration and average mitochondrial membrane potential in perfused rat hindquarter with maximal tetanic contraction of the left gastrocnemius-soleus-plantaris muscle group, and we estimate that the mitochondrial proton cycle accounted for 34% of the respiration rate of the preparation. Similar measurements in rat hepatocytes given substrates to cause a high rate of gluconeogenesis and ureagenesis showed that the proton cycle accounted for 22% of the respiration rate of these cells. Combining these in vitro values with literature values for the contribution of skeletal muscle and liver to standard metabolic rate (SMR), we calculate that the proton cycle in working muscle and liver may account for 15% of SMR in vivo. Although this value is less than the 20% of SMR we calculated previously using data from resting skeletal muscle and hepatocytes, it is still large, and we conclude that the futile proton cycle is a major contributor to SMR.

Vascular control of nutrient delivery by flow redistribution within muscle: implications for exercise and post-exercise muscle metabolism.

There is evidence for non-nutritive flow routes within, or associated with, skeletal muscle. Large capillary-like structures are possible candidates. The proportion of flow distributed between nutritive and non-nutritive routes appears to be tightly regulated and can control muscle metabolism and contraction by regulating delivery and product removal. The portion of flow that is carried by the non-nutritive routes at rest affords a flow reserve for amplifying nutrient delivery as muscle begins to work and may determine post-exercise metabolism. Inappropriate signals, however, may diminish nutritive flow to the detriment of muscle performance and post-exercise recovery. New technologies should allow the identification of the non-nutritive routes.

Class-directed structure determination: foundation for a protein structure initiative.

The recent sequencing of many complete genomes, combined with the development of methods that allow rapid structure determination for many proteins, has changed the way in which protein structure determinations can be approached. One-by-one determinations of individual protein structures will soon be augmented by class-directed structure analyses in which a group of proteins is targeted and structures of representative members are determined and used to represent the entire group. Such a shift in approach would be the foundation for a broad protein structure initiative targeting classes of proteins important for biotechnology and for a fundamental understanding of protein function.

Stimulation and inhibition of resting muscle thermogenesis by vasoconstrictors in perfused rat hind limb.

Angiotensin (AII) and serotonin (5-HT) are both vasoconstrictors of the constant-flow perfused rat hind limb that have opposite effects on thermogenesis, possibly the result of differing effects on vascular flow distribution between nutritive and non-nutritive pathways. In the present study interaction between the two opposing agents was examined with the expectation that the combined presence would show additive effects on pressure and mutually neutralizing effects on thermogenesis. Thus doses of AII and 5-HT that gave similar, but opposite, quantitative effects on thermogenesis were infused alone, in combination one after the other, or in combination with the order reversed, and the effects on perfusion pressure (PP) and thermogenesis (oxygen uptake, VO2) were compared. AII (3 nM) alone increased PP by 15+/-1 mmHg (1 mmHg = 133.3 Pa) and VO2 by 3.1-/+0.2 micromol.h(-1).g(-1), whereas 5-HT (1 microM) alone increased PP by 75+/-6 mmHg and inhibited VO2 by 3.9+/-0.2 micromol.h(-1).g(-1). When added in combination, the outcome depended on the order of addition. Following AII, infusion of 5-HT further increased PP by 160+/-11 mmHg and decreased VO2 by 6.3+/-0.2 micromol.h(-1)g(-1). Following 5-HT, infusion of AII further increased PP by 28+/-4 mmHg and increased VO2 by only 1.8+/-0.3 micromol.h(-1).g(-1). The prior presence of 5-HT (1 microM) shifted the AII dose-response curves for VO2 and pressure to the right and left, respectively. The prior infusion of AII increased the dose-dependent response to 5-HT in terms of both the inhibition of VO2 and the increase in PP. At low doses of 5-HT (10(-8)-10(-7) M), but not alpha-methyl serotonin (alphaMT), there was a marked vasodilatation-associated inhibition of AII-mediated increase in VO2. Overall the data show that the combined effect of AII and 5-HT differed from the simple addition of each separately. Since the order of addition appears to be critical in terms of thermogenic outcome, it is concluded that each vasoconstrictor exerts a specific hemodynamic action to affect access of the other to vascular receptor sites. These findings are consistent with the previously reported effects of these vasoconstrictors on substrate and insulin access to muscle of the perfused rat hind limb.

Microvascular regulation of muscle metabolism.

Nutrient and hormone delivery to skeletal muscle plays a major role in the regulation of metabolism of this tissue. Compromised perfusion, leading to the exclusion of single capillaries or groups of capillaries, can result from the inability of the cardiovascular system to maintain adequate total blood flow. Recent new data, however, indicate that nutrient delivery to skeletal muscle may not simply equate to total blood flow, but the partitioning between two circulatory systems, nutritive and non-nutritive, associated with each muscle. A number of hormones and neural mechanisms have now been identified that control the proportion of nutritive to non-nutritive flow. In addition, muscle metabolism and contractile performance have been shown to correlate with the extent of nutritive flow and inversely with non-nutritive flow, where the latter occurs in closely associated connective tissue. This review presents some of the evidence supporting the dual circulatory system model of muscle and the implications it may have in the management and treatment of patients subjected to shock, trauma, heart failure and long periods of immobilization.

Vessels supplying septa and tendons as functional shunts in perfused rat hindlimb.

An assessment was made of the relationship between vasoconstrictor-mediated changes in metabolism and the apparent flow in putative nonnutritive vessels of muscle located on tendon. Surgically isolated rat hindlimbs were perfused at constant flow while monitoring perfusion pressure and venous pO2. In addition exposed tibial tendon vessels of the biceps femoris muscle of the perfused leg were positioned either under a surface fluorometer probe to monitor signal strength when pulses of fluorescein isothiocyanate dextran were infused or over the objective lens of an inverted microscope for photography when pulses of India ink were infused. Measurements were conducted under steady state with vehicle, norepinephrine, or serotonin infused. Norepinephrine increased perfusion pressure and oxygen uptake (VO2), but decreased fluorescence signal from the tendon vessels. Photomicroscopy confirmed that the vessels had generally decreased in diameter. Serotonin also increased perfusion pressure but decreased VO2 and increased fluorescence signal from the tendon vessels. Photomicroscopy confirmed that serotonin infusion had led to a marked increase in diameter of the vessels. It is concluded that a reciprocal relationship exists between resting muscle metabolism as controlled by vasoconstrictors and flow-through muscle tendon vessels.