Biomedical subjects

Robert Shapiro

Publications and source records attributed to Robert Shapiro.

At least 37 records · Page 2Linked to original sources

PubMed2004

Structural and stereoisomer effects of model estrogen quinone-derived DNA adducts: N6-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyadenosine and N2-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyguanosine.

An extensive conformational analysis has been carried out for two diastereoisomeric pairs of model estrogen quinone-derived DNA adducts, N6-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyadenosine (2-OHE1-6(alpha,beta)-N6-dA) and N2-(2-hydroxyestron-6(alpha,beta)-yl)-2'-deoxyguanosine (2-OHE1-6(alpha,beta)-N2-dG), in a B-DNA duplex and at a primer-template junction in a pol alpha family DNA polymerase. In vitro primer extension studies in pol alpha [Terashima, I., et al. (1998) Biochemistry 37, 13807-13815] have shown that the adenine adducts can incorporate dT, together with a small proportion of the incorrect base dC opposite the lesion, and they block less strongly than the guanine adducts. We have carried out conformational searches with energy minimization for four DNA duplexes containing 2-OHE1-6alpha-N6-dA, 2-OHE1-6beta-N6-dA, 2-OHE1-6alpha-N2-dG, or 2-OHE1-6beta-N2-dG. Our searches revealed that the four-ring nonplanar 2-hydroxyestrone (2-OHE1) moiety strongly prefers to reside in the major groove of the adenine adducts or the minor groove of the guanine adducts in a B-DNA duplex, with stereochemistry-dependent orientational differences in each case. No low energy conformations involving intercalation of the 2-OHE1 moiety were located in the searches. This stems from the largely nonplanar, nonaromatic nature of the 2-OHE1 ring system and implies that the proclivity for such bulky, nonplanar adducts to reside at the DNA helix exterior is a plausible conformational feature of other structurally similar estrogen quinone-derived DNA adducts, independent of base sequence context. In addition, the adenine adduct isomers, located in the major groove, manifest serious disturbance to the Watson-Crick base pairs at and near the lesion site, suggesting repair susceptibility. Possible structures of these adducts in a pol alpha family polymerase were also investigated through molecular modeling. The results rationalized the experimental in vitro primer extension studies. In addition, poor accommodation of the beta-stereoisomers within the polymerase was noted, suggesting that these stereoisomers would be more prone to cause blockage. Stereochemistry-dependent differences in adduct orientation could be expected to produce different biochemical effects, as has been observed in adducts derived from polycyclic aromatic hydrocarbons.

DNA Adducts↗

PubMed2004

Measures of accuracy for active shoulder movements at 3 different speeds with kinesthetic and visual feedback.

STUDY DESIGN: Repeated-measures experiment. OBJECTIVE: To compare measures of end point accuracy (EPA) for 2 feedback conditions: (1) visual and kinesthetic feedback and (2) kinesthetic feedback alone, during shoulder movements, at 3 different speeds. BACKGROUND: Shoulder joint kinesthesia is typically reported with EPA measures, such as constant error. Reporting multiple measures of EPA, such as variable error and absolute error, could provide a more detailed description of performance. METHODS AND MEASURES: Subjects were seated with the shoulder abducted 90 degrees in the scapular plane and externally rotated 75 degrees, with the forearm placed in a custom shoulder wheel. Subjects internally rotated the shoulder 27 degrees to a target position at 48 degrees of shoulder external rotation for both conditions. Motion analysis was used to determine peak angular velocity and 3 EPA measures for shoulder movements. Each EPA measure was compared between the 2 feedback conditions and among the 3 speeds with a separate 2-way analysis of variance. RESULTS: Movements performed with kinesthetic feedback alone, measured by constant error (P<.01), variable error (P<.01), and absolute error (P<.01), were less accurate than movements performed with visual and kinesthetic feedback. Faster movements were less accurate when measured by constant error (P = .01) and absolute error (P<.01) than slower movements. Subjects tended to overshoot the target in the absence of visual feedback; however, movement speed played minimal role in the overshooting. CONCLUSIONS: Multiple measures of EPA, such as constant, variable, and absolute error during simple restricted shoulder movements may provide additional information regarding the evaluation of a motor performance or identify different central nervous system control mechanisms for joint kinesthesia.

Adult↗

PubMed2003

Selective abolition of pancreatic RNase binding to its inhibitor protein.

We have modified RNase inhibitor (RI) protein so that it no longer detectably binds pancreatic RNases but retains near-native affinity for human angiogenin (ANG). The K(i) value for RNase A is increased by a factor of >10(8), from 36 fM to >4 microM, and the selectivity factor for ANG is now >10(9). This dramatic change was achieved by remodeling the human RI loop segment Cys-408 -Leu-409 -Gly-410, which makes minor interactions with pancreatic RNase but does not contact ANG. The modifications selected were designed to sterically hinder docking of the undesired ligand. Three of the variants tested (C408W, G410W, and C408W/G410W) bind RNase A with almost the same avidity as WT RI. However, combination of the 408/410 double Trp replacement with deletion of the intervening residue, Leu-409, was sufficient to abolish inhibition of RNase A and human pancreatic RNase. The K(i) value for ANG with the deletion variant is 1.1 fM, only 2-fold higher than with WT RI. This variant may have potential utility both as an anticancer drug targeting ANG and as a tool for the investigation of the biological function of ANG. More generally, these findings demonstrate that a protein-protein interaction can be effectively and specifically disrupted by redesigning an interface region that makes no major energetic contribution to complex stability. This finding, in turn, may have implications for the development of small molecules that modulate protein-protein interactions.

Base Sequence↗

PubMed2003

Unexpected binding mode for 2'-phosphoadenosine-based nucleotide inhibitors in complex with human angiogenin revealed by heteronuclear NMR spectroscopy.

Human angiogenin (Ang) is a tumor-promoting RNase in the pancreatic RNase superfamily. Efforts to develop nucleotide-based inhibitors of Ang as potential anticancer drugs have been hampered by the lack of direct structural information on Ang-nucleotide complexes. Here, we have used heteronuclear NMR spectroscopy with (15)N- and (15)N/(13)C-labeled Ang to map the interactions of Ang with the phosphate ion, seven adenosine mononucleotides (the 2'-, 3'-, and 5'-monophosphates, the 2',5'- and 3',5'-diphosphates, the 5'-diphosphate, and the 2'-monophospho-5'-diphosphate), and the dinucleotide 2'-deoxyuridine 3'-pyrophosphate (P' --> 5') adenosine-2'-phosphate (dUppA-2'-p). The 2'-phosphate based derivatives, which bind more tightly than the corresponding 3'-phosphate isomers, induced characteristic large resonance perturbations of the backbone amide proton of Leu(115), the backbone (15)N of His(114), and the Gln(12) side-chain NH(2) group in the Ang active site. In contrast, adenosine derivatives with only 3'- or 5'-phosphates produced much less dramatic perturbations of Leu(115) and His(114) resonances, along with modest perturbations of additional residues both within and beyond the active site. Measurements of NOEs together with molecular docking analyses revealed the three-dimensional structures of the complexes of Ang with adenosine 2',5'-diphosphate and dUppA-2'-p; the binding modes of these inhibitors differ substantially from those predicted in earlier studies. Most notably, the 2'-phosphate rather than the 5'-phosphate occupies the P(1) catalytic subsite of Ang, and the side chain of His(114) has undergone a conformational transition that positions it outside P(1) and allows it to form stacking interactions with the adenine ring of the inhibitor. Strikingly, the 2'-deoxyuridine moiety of dUppA-2'-p makes only a few contacts with Ang, and these involve residues outside the B(1) subsite where the pyrimidine ring of substrates normally binds.

Adenine Nucleotides↗

PubMed2003

Identification of small-molecule inhibitors of human angiogenin and characterization of their binding interactions guided by computational docking.

Angiogenin (ANG) is a potent inducer of angiogenesis and an RNase A homologue whose ribonucleolytic activity is essential for its biological action. Recently, we reported the identification of small non-nucleotide inhibitors of the enzymatic activity of ANG by high-throughput screening (HTS) [Kao, R. Y. T., et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 10066-10071]. Two of the inhibitors that were obtained, National Cancer Institute compound NSC-65828 [8-amino-5-(4'-hydroxybiphenyl-4-ylazo)naphthalene-2-sulfonate] and ChemBridge compound C-181431 [4,4'-dicarboxy-3,3'-bis(naphthylamido)diphenylmethanone], were judged to be suitable for further development, and one of these (NSC-65828) was shown to possess antitumor activity in mice. Here we have used computational docking as a guide for the identification of available NSC-65828 and C-181431 analogues that bind more tightly to ANG, and for the characterization of inhibitor binding modes. Numerous analogues were found to have greater avidity than the HTS compounds or any small nucleotide inhibitors; four were considered to be of interest as potential leads (K(i) = 5-25 microM). Two of these analogues bind more tightly to ANG than to RNase A, and are the first small molecules shown to exhibit this selectivity. The predicted binding orientations of the HTS compounds and the new lead inhibitors were evaluated by determining the effects of ANG active site mutations on inhibitory potency. The results with ANG variants R5A, H8A, N68A, and des(121-123) are highly consistent with the docking models. Affinity changes observed with Q12A and Q117G reveal aspects of active site function that are not apparent from the free ANG crystal structure or from the modeled complexes. These findings should prove to be useful in the design of more effective and specific ANG antagonists.

Amino Acid Substitution↗

PubMed2003

Mutational analysis of the complex of human RNase inhibitor and human eosinophil-derived neurotoxin (RNase 2).

RNase inhibitor (RI) binds diverse proteins in the pancreatic RNase superfamily with extremely high avidity. Previous studies showed that tight binding of RNase A and angiogenin (Ang) is achieved primarily through interactions of hot spot residues in the 434-460 C-terminal segment of RI with the enzymatic active site; Asp435 of RI forms key hydrogen bonds with the catalytic lysine in both complexes, whereas the other contacts are largely distinctive. Here we have investigated the structural basis for recognition of a third ligand, eosinophil-derived neurotoxin (EDN), by single-site and multisite mutagenesis. Surprisingly, Ala replacement of Asp435 decreases affinity for EDN only by 14-fold, as compared to the several hundred-fold decreases with RNase A and Ang, and individual mutations of three other hot spot residues-Tyr434, Tyr437, and Ser460-have essentially no effect. Ala substitutions of nine additional residues, selected by examining a computational model of the RI.EDN complex, also have no marked impact. Overall, the losses in affinity for the single-residue variants examined account for only approximately 25% of the free energy of binding for the complex. However, multisite mutagenesis of RI reveals strong superadditivity of mutational effects, indicating that part of this shortfall reflects negative cooperativity. Replacement of Tyr434 together with Asp435 or Tyr437 increases K(i) by 540- and 290-fold, respectively. Thus, the C-terminal region of RI again plays an important role in ligand recognition, although probably smaller than for binding RNase A and Ang. Simultaneous substitutions of three neighboring tryptophans (261, 263, and 318) on RI attenuate affinity even more dramatically (by 4900-fold), indicating that the interactions of this RI region also contribute a considerable amount of the binding energy for the EDN complex. These findings highlight the potential importance of cooperativity in protein-protein interactions and the consequent limitations of single-site mutagenesis for assessing interface energetics.

Alanine↗

PubMed2003

Inhibition of mammalian ribonucleases by endogenous adenosine dinucleotides.

The most potent low molecular weight inhibitors of pancreatic RNase superfamily enzymes reported to date are synthetic derivatives of adenosine 5(')-pyrophosphate. Here we have investigated the effects of six natural nucleotides that also incorporate this moiety (NADP(+), NADPH, ATP, Ap(3)A, Ap(4)A, and Ap(5)A) on the activities of RNase A and two of its homologues, eosinophil-derived neurotoxin and angiogenin. With eosinophil-derived neurotoxin and angiogenin, Ap(5)A is comparable to the tightest binding inhibitors identified previously (K(i) values at pH 5.9 are 370 nM and 100 microM, respectively); it ranks among the strongest small antagonists of RNase A as well (K(i)=230 nM). The K(i) for NADPH with angiogenin is similar to that of Ap(5)A. These findings suggest that Ap(5)A and NADPH may serve as useful new leads for inhibitor design. Examination of inhibition under physiological conditions indicates that NADPH, ATP, and Ap(5)A may suppress intracellular RNase activity significantly in vivo.

Adenine Nucleotides↗

PubMed2003

Virtual screening to enrich hit lists from high-throughput screening: a case study on small-molecule inhibitors of angiogenin.

"Hit lists" generated by high-throughput screening (HTS) typically contain a large percentage of false positives, making follow-up assays necessary to distinguish active from inactive substances. Here we present a method for improving the accuracy of HTS hit lists by computationally based virtual screening (VS) of the corresponding chemical libraries and selecting hits by HTS/VS consensus. This approach was applied in a case study on the target-enzyme angiogenin, a potent inducer of angiogenesis. In conjunction with HTS of the National Cancer Institute Diversity Set and ChemBridge DIVERSet E (approximately 18,000 compounds total), VS was performed with two flexible library docking/scoring methods, DockVision/Ludi and GOLD. Analysis of the results reveals that dramatic enrichment of the HTS hit rate can be achieved by selecting compounds in consensus with one or both of the VS functions. For example, HTS hits ranked in the top 2% by GOLD included 42% of the true hits, but only 8% of the false positives; this represents a sixfold enrichment over the HTS hit rate. Notably, the HTS/VS method was effective in selecting out inhibitors with midmicromolar dissociation constants typical of leads commonly obtained in primary screens.

Binding Sites↗

PubMed2003

The crystal structure of human angiogenin in complex with an antitumor neutralizing antibody.

The murine monoclonal antibody 26-2F neutralizes the angiogenic and ribonucleolytic activities of human angiogenin (ANG) and is highly effective in preventing the establishment and metastatic dissemination of human tumors in athymic mice. Here we report a 2.0 A resolution crystal structure for the complex of ANG with the Fab fragment of 26-2F that reveals the detailed interactions between ANG and the complementarity-determining regions (CDRs) of the antibody. Surprisingly, Fab binding induces a dramatic conformational change in the cell binding region of ANG at the opposite end of the molecule from the combining site; crosslinking experiments indicate that this rearrangement also occurs in solution. The ANG-Fab complex structure should be invaluable for designing maximally humanized versions of 26-2F for potential clinical use.

Amino Acid Sequence↗

PubMed2003

Conformations of stereoisomeric base adducts to 4-hydroxyequilenin.

Exposure to estrogen through estrogen replacement therapy increases the risk of women developing cancer in hormone sensitive tissues. Premarin (Wyeth), which has been the most frequent choice for estrogen replacement therapy in the United States, contains the equine estrogens equilin and equilenin as major components. 4-Hydroxyequilenin (4-OHEN) is a phase I metabolite of both of these substances. This catechol estrogen autoxidizes to potent cytotoxic quinoids that can react with dG, dA, and dC to form unusual stereoisomeric cyclic adducts (Bolton, J. L., et al. (1998) Chem. Res. Toxicol. 11, 1113-1127). Like other bulky DNA adducts, these lesions may exhibit different susceptibilities to DNA repair and mutagenic potential, if not repaired in a structure-dependent manner. To ultimately gain insights into structure-function relationships, we computed conformations of stereoisomeric guanine, adenine, and cytosine base adducts using density functional theory. We find near mirror image conformations in stereoisomer adduct pairs for each modified base, suggesting opposite orientations with respect to the 5' --> 3' direction of the modified strand when the stereoisomer pairs are incorporated into duplex DNA. Such opposite orientations could cause stereoisomer pairs of lesions to respond differently to DNA replication and repair enzymes.

DNA Adducts↗

PubMed2003

High-speed video analysis of head-first and feet-first sliding techniques in collegiate baseball players.

OBJECTIVE: To determine the method of sliding that propels the baseball athlete to the desired base in the shortest amount of time. To assess the athlete's perception of the quickest, safest, and preferred sliding technique. DESIGN: A single occasion with repeated measures design was used. The independent variable was slide type, and the dependent variable was time. SETTING: The study was conducted in October 2000 at the University of Kentucky baseball complex. PARTICIPANTS: Twenty collegiate baseball players. INTERVENTIONS: High-speed video (to 1/200th of second) analysis of 20 collegiate baseball players performing 3 trials each of both head-first and feet-first sliding techniques. Additionally, each participant was asked to complete a sliding survey. MAIN OUTCOME MEASURES: The videotape of each slide performed was reviewed separately (using the same viewing equipment) by 2 of the study investigators. Slide type and time were recorded for each slide. RESULTS: There was no significant difference between head-first versus feet-first slide times (P = 0.357). The average time for feet-first slides was 3.67 seconds, while that for head-first was 3.65 seconds. Sixty-eight percent of the players felt that head-first slides were faster than feet-first slides. Seventy-four percent identified the feet-first slide as the technique they most used, while 90% of the athletes perceived the feet-first technique to be safer. CONCLUSIONS: On average, head-first and feet-first sliding techniques employed at the end aspect of base running propel the baseball player to the base in similar times. The head-first sliding technique is perceived to be faster and more dangerous.

Adult↗

PubMed2002

Guest-host crosstalk in an angiogenin-RNase A chimeric protein.

Angiogenin and ribonuclease A share 33% sequence identity but have distinct functions. Angiogenin is a potent inducer of angiogenesis that is only weakly ribonucleolytic, whereas ribonuclease A is a robust ribonuclease that is not angiogenic. A chimera ("ARH-I"), in which angiogenin residues 58-70 are replaced with residues 59-73 of ribonuclease A, has intermediate ribonucleolytic potency and no angiogenic activity. Here we report a crystal structure of ARH-I that reveals the molecular basis for these characteristics. The ribonuclease A-derived (guest) segment adopts a structure largely similar to that in ribonuclease A, and successfully converts this region from a cell-binding site to a purine-binding site. At the same time, its presence causes complex changes in the angiogenin-derived (host) portion that account for much of the increased ribonuclease activity of ARH-I. Guest-host interactions of this type probably occur more generally in protein chimeras, emphasizing the importance of direct structural information for understanding the functional behavior of such molecules.

Amino Acid Sequence↗

PubMed2002

A small-molecule inhibitor of the ribonucleolytic activity of human angiogenin that possesses antitumor activity.

The results of previous preclinical and clinical studies have identified angiogenin (ANG) as a potentially important target for anticancer therapy. Here we report the design and implementation of a high-throughput screening assay to identify small molecules that bind to the ribonucleolytic active site of ANG, which is critically involved in the induction of angiogenesis by this protein. Screening of 18,310 compounds from the National Cancer Institute (NCI) Diversity Set and ChemBridge DIVERSet yielded 15 hits that inhibit the enzymatic activity of ANG with K(i) values <100 microM. One of these, NCI compound 65828 [8-amino-5-(4'-hydroxybiphenyl-4-ylazo)naphthalene-2-sulfonate; K(i) = 81 microM], was selected for more detailed studies. Minor changes in ANG or ligand structure markedly reduced potency, demonstrating that inhibition reflects active-site rather than nonspecific binding; these observations are consistent with a computationally generated model of the ANG.65828 complex. Local treatment with modest doses of 65828 significantly delayed the formation of s.c. tumors from two distinct human cancer cell types in athymic mice. ANG is the likely target involved because (i) a 65828 analogue with much lower potency against the enzymatic activity of ANG failed to exert any antitumor effect, (ii) tumors from 65828-treated mice had fewer interior blood vessels than those from control mice, and (iii) 65828 appears to have no direct effect on the tumor cells. Our findings provide considerable support for the targeting of the enzymatic active site of ANG as a strategy for developing new anticancer drugs.

Amino Acid Substitution↗

PubMed2002

Crystallographic studies on the role of the C-terminal segment of human angiogenin in defining enzymatic potency.

Human angiogenin (Ang) is an RNase in the pancreatic RNase superfamily that induces angiogenesis. Its catalytic activity is comparatively weak, but nonetheless critical for biological activity. The crystal structure of Ang has shown that enzymatic potency is attenuated in part by the obstructive positioning of Gln117 within the B(1) pyrimidine binding pocket, and that the C-terminal segment of residues 117-123 must reorient for Ang to bind and cleave RNA. The native closed conformation appears to be stabilized by Gln117-Thr44 and Asp116-Ser118 hydrogen bonds, as well as hydrophobic packing of Ile119 and Phe120. Consistent with this view, Q117G, D116H, and I119A/F120A variants are 4-30-fold more active than Ang. Here we have determined crystal structures for these variants to examine the structural basis for the activity increases. In all three cases, the C-terminal segment remains obstructive, demonstrating that none of the residues that has been replaced is essential for maintaining the closed conformation. The Q117G structure shows no changes other than the loss of the side chain of residue 117, whereas those of D116H and I119A/F120A reveal C-terminal perturbations beyond the replacement site, suggesting that the native closed conformation has been destabilized. Thus, the interactions of Gln117 seem to be less important than those of residues 116, 119, and 120 for stabilization. In D116H, His116 does not replicate either of the hydrogen bonds of Asp116 with Ser118 and instead forms a water-mediated interaction with catalytic residue His114; residues 117-121 deviate significantly from their positions in Ang. In I119A/F120A, the segment of residues 117-123 has become highly mobile and all of the interactions thought to position Gln117 have been weakened or lost; the space occupied by Phe120 in Ang is partially filled by Arg101, which has moved several angstroms. A crystal structure was also determined for the deletion mutant des(121-123), which has 10-fold reduced activity toward large substrates. The structure is consistent with the earlier proposal that residues 121-123 form part of a peripheral substrate binding subsite, but also raises the possibility that changes in the position of another residue, Lys82, might be responsible for the decreased activity of this variant.

Crystallography↗

PubMed2002

Granular cell tumor of the trachea in a child.

Granular cell tumors are benign neoplasms found most commonly in the head and neck, particularly the tongue. They have, however, been described in all areas of the body. Their presentation in the trachea is exceedingly rare, with their presence in the pediatric trachea being an even rarer occurrence. We describe a case of a granular cell tumor of the trachea in a 10-year-old boy with a dramatic, almost lethal, presentation. This is followed by a review of the literature, including pathology and treatment options.

Anastomosis, Surgical↗

PubMed2002

Comments on 'concentration by evaporation and the prebiotic synthesis of cytosine'.

The claim by Nelson et al. (2001) that the reaction of cyanoacetaldehyde and urea provides 'an efficient prebiotic synthesis' of cytosine is disputed. The authors have not dealt with the important points presented in a criticism of this reaction (Shapiro, 1999): (1) The reactants undergo side reactions with common nucleophiles that appear to proceed more rapidly than cytosine formation, and (2) No reactions have been described thus far that would produce cytosine at a rate sufficient to compensate for its decomposition by deamination, and permit accumulation over extended periods of time. Instead, Nelson et al. have conducted 'drying-down' experiments, in an effort to simulate evaporations on the early Earth, but the design of these experiments is flawed. The initial reactant concentrations are much higher than might be expected in a natural setting, and potentially interfering substances such as glycine, cyanide and thiols have been excluded. 'Drying beaches and drying lagoons' have been invoked as sites for such a reaction but no effort has been made to describe the characteristics of such sites or to estimate their frequency with reference to the present Earth. In the absence of contradictory data, the conclusion put forward in Shapiro (1999) remains valid: 'It was quite unlikely that cytosine played a role in the origin of life'.

Cytosine↗

PubMed2002

Venous hemodynamics in living donor right lobe liver transplantation.

We evaluated the influence of portal and hepatic venous hemodynamics on the immediate and 3-month postoperative function of living donor right lobe grafts. Portal velocity was measured prospectively by ultrasound in 14 consecutive donor/recipient pairs. Velocity was converted to flow with the Moriyasu formula. Measurements were taken in donors in the operating room and in recipients at 1 hour after reperfusion and 3 months after transplant. Recipient liver function tests were measured postoperatively. Prereperfusion and postreperfusion liver biopsies were evaluated and correlated with the hemodynamic and biochemical results. There were 11 male (78.6%) and 3 female donors (mean age, 38.9 +/- 9.8 years) for 10 male (71.4%) and 4 female recipients (mean age, 49.3 +/- 14 years). The mean graft/recipient weight ratio was 1.22 +/- 0.3. The mean right portal vein pressure was 8 +/- 1.8 mm Hg in donors versus 13 +/- 4.7 mm Hg in recipients (P < .05). The mean peak flow velocity (Vmax) in the portal vein in donors was 47.6 +/- 12.8 cm/sec (normal, 44 cm/sec). One hour after graft reperfusion in the recipient, the mean portal Vmax was significantly higher at 94.7 +/- 28.4 cm/sec (P = .004), but by 3 months follow-up, mean portal Vmax had fallen to 58.8 +/- 37.8 (P = .01). Recipient portal vein Vmax highly correlated with portal flow (r = 0.7, P = .01). Increased recipient total bilirubin on postoperative day 2 correlated highly with higher recipient portal flow one hour after transplant (r = 0.6; P =.03). Portal vein velocity/flow dramatically increases after reperfusion, returning to baseline about 3 months after transplant. Evaluation of hepatic and portal venous flow is a relatively easy skill to acquire. Intraoperative ultrasound may enable the surgeon to predict graft dysfunction and possibly, may be used to implement pre-emptive therapies.

Adult↗

PubMed2002

Electromyographic comparison of standard and modified closed-chain isometric knee extension exercises.

The purpose of this study was to compare electromyographic (EMG) activity during open kinetic chain (OKC) and a modified closed kinetic chain (MCKC) knee extension exercises. Both OKC and closed kinetic chain (CKC) exercises provide benefits when devising conditioning programs; however, there are no exercises that combine the benefits of both exercises. Subjects performed maximum isometric knee extensions for both traditional OKC and MCKC knee extension exercises. Surface electrodes were placed on 8 lower-extremity muscles. One second of integrated EMG activity followed 95% maximal knee extension force. The following muscles demonstrated greater EMG activity during the MCKC vs. the OKC knee extension exercises: vastus medialis, medial hamstring, lateral hamstrings, and gluteus maximus. There was no difference between force output between the 2 conditions. This study demonstrates that modifications to traditional OKC exercises demonstrate some characteristics of CKC exercises, and therefore provide another avenue of rehabilitation or strengthening.

Adolescent↗