Determination and importance of clinical and patient-based measures in outcome assessment of peripheral arterial occlusive disease.

Therapeutic effectiveness is the overall effect of an intervention on clinical and quality-of-life measures. Traditionally, in peripheral arterial disease, this has been evaluated in terms of clinical outcomes only. The lack of correlation between quality-of-life and clinical measures means that these cannot adequately describe overall patient benefit or adverse effects from an intervention. Therefore, patient-based measures such as changes in disease-specific questionnaire scores must be included in the evaluation of therapeutic effectiveness.

Comparative model building of interleukin-7 using interleukin-4 as a template: a structural hypothesis that displays atypical surface chemistry in helix D important for receptor activation.

Using a combination of theoretical sequence structure recognition predictions and experimental disulfide bond assignments, a three-dimensional (3D) model of human interleukin-7 (hIL-7) was constructed that predicts atypical surface chemistry in helix D that is important for receptor activation. A 3D model of hIL-7 was built using the X-ray crystal structure of interleukin-4 (IL-4) as a template (Walter MR et al., 1992, J Mol Biol. 224:1075-1085; Walter MR et al., 1992, J Biol Chem 267:20371-20376). Core secondary structures were constructed from sequences of hIL-7 predicted to form helices. The model was constructed by superimposing IL-7 helices onto the IL-4 template and connecting them together in an up-up down-down topology. The model was finished by incorporating the disulfide bond assignments (Cys3, Cys142), (Cys35, Cys130), and (Cys48, Cys93), which were determined by MALDI mass spectroscopy and site-directed mutagenesis (Cosenza L, Sweeney E, Murphy JR, 1997, J Biol Chem 272:32995-33000). Quality analysis of the hIL-7 model identified poor structural features in the carboxyl terminus that, when further studied using hydrophobic moment analysis, detected an atypical structural property in helix D, which contains Cys 130 and Cys142. This analysis demonstrated that helix D had a hydrophobic surface exposed to bulk solvent that accounted for the poor quality of the model, but was suggestive of a region in IL-7 that maybe important for protein interactions. Alanine (Ala) substitution scanning mutagenesis was performed to test if the predicted atypical surface chemistry of helix D in the hIL-7 model is important for receptor activation. This analysis resulted in the construction, purification, and characterization of four hIL-7 variants, hIL-7(K121A), hIL-7(L136A), hIL-7(K140A), and hIL-7(W143A), that displayed reduced or abrogated ability to stimulate a murine IL-7 dependent pre-B cell proliferation. The mutant hIL-7(W143A), which is biologically inactive and displaces [125I]-hIL-7, is the first reported IL-7R system antagonist.

Kininogens are antithrombotic proteins In vivo.

Kininogens have recently been shown to possess antiadhesive, anticoagulant, and profibrinolytic properties and can inhibit platelet activation at low thrombin concentrations. To test whether kininogens have antithrombotic properties in vivo, we devised a model of limited arterial injury confined to removal of the endothelium. Brown-Norway Katholiek strain rats with an absence of low- and high-molecular-weight kininogen due to a single point mutation, A163T, were compared in the thrombosis model to the wild-type animals, which were otherwise genetically identical. Despite an equivalent vascular injury, the mean time (+/-SEM) for a 90% decrease in flow measured by laser Doppler was 38.4+/-17 minutes in the kininogen-deficient rats compared with 194+/-29 minutes in the wild-type animals (P<0.002). The degree of vascular injury was the same. No evidence for disseminated intravascular coagulation (decrease in factor V, antithrombin, or fibrinogen) or excessive fibrinolysis (elevation of fibrinogen degradation products) was found in either group of animals. The results suggest that kininogens have antithrombotic properties at low concentrations of thrombin and that inhibitory peptides derived from kininogen may constitute a new antithrombotic strategy.

A Bayes-optimal sequence-structure theory that unifies protein sequence-structure recognition and alignment.

A rigorous Bayesian analysis is presented that unifies protein sequence-structure alignment and recognition. Given a sequence, explicit formulae are derived to select (1) its globally most probable core structure from a structure library; (2) its globally most probable alignment to a given core structure; (3) its most probable joint core structure and alignment chosen globally across the entire library; and (4) its most probable individual segments, secondary structure, and super-secondary structures across the entire library. The computations involved are NP-hard in the general case (3D-3D). Fast exact recursions for the restricted sequence singleton-only (1D-3D) case are given. Conclusions include: (a) the most probable joint core structure and alignment is not necessarily the most probable alignment of the most probable core structure, but rather maximizes the product of core and alignment probabilities; (b) use of a sequence-independent linear or affine gap penalty may result in the highest-probability threading not having the lowest score; (c) selecting the most probable core structure from the library (core structure selection or fold recognition only) involves comparing probabilities summed over all possible alignments of the sequence to the core, and not comparing individual optimal (or near-optimal) sequence-structure alignments; and (d) assuming uninformative priors, core structure selection is equivalent to comparing the ratio of two global means.

A homology identification method that combines protein sequence and structure information.

A new method is presented for identifying distantly related homologous proteins that are unrecognizable by conventional sequence comparison methods. The method combines information about functionally conserved sequence patterns with information about structure context. This information is encoded in stochastic discrete state-space models (DSMs) that comprise a new family of hidden Markov models. The new models are called sequence-pattern-embedded DSMs (pDSMs). This method can identify distantly related protein family members with a high sensitivity and specificity. The method is illustrated with trypsin-like serine proteases and globins. The strategy for building pDSMs is presented. The method has been validated using carefully constructed positive and negative control sets. In addition to the ability to recognize remote homologs, pDSM sequence analysis predicts secondary structures with higher sensitivity, specificity, and Q3 accuracy than DSM analysis, which omits information about conserved sequence patterns. The identification of trypsin-like serine proteases in new genomes is discussed.

Diagnostic and interventional angioscopy.

As an imaging modality, angioscopy provides a simple method for the careful evaluation and treatment of the lumen of native vessels and bypass grafts. When used as a diagnostic study, angioscopy can provide more accurate information regarding the flow surface than conventional tests, such as angiography or duplex imaging. It can significantly enhance the ability of the surgeon to detect flow surface problems. With the recent advance in endovascular tools, angioscopically guided luminal intervention has become an increasingly useful approach to many vascular problems. More precise treatment of endoluminal abnormalities and a reduction in incision length and soft-tissue dissection can result in decreased patient morbidity and extended patient benefit.

"Pancake kidney": a renal anomaly complicating aortic reconstruction.

Pancake kidney is a rare fusion anomaly of the kidneys characterized by the presence of a displaced, lobulated pelvic renal mass of dual parenchymatous system without intervening septum. The existence of this anomaly during aortic reconstruction presents a great technical challenge. The surgical management of a 51-year-old man with a 5.0 cm aortic aneurysm and a pancake kidney is described.

Carbon dioxide angioscopy.

Endovascular intervention has become an increasingly more popular method of diagnosing and treating vascular disease. Its expanding scope includes applications ranging from visualization of the peripheral vascular system to coronary artery interventions. This trend is primarily a result of the limitations of angiography, the current imaging standard, when compared to angioscopy. Multiple disease entities, including atherosclerotic plaque, embolic debris, and thrombus, can not be differentiated between based on angiographic appearance. Angioscopy is a more sensitive method of distinguishing between the above disease states by allowing direct visualization of the luminal surface. The significance of this distinction lies in the fact that the treatment options are notably different based upon the diagnosis. Yet another advantage of angioscopy is its therapeutic value in addition to its diagnostic abilities. Directed embolectomy, guide-wire or catheter placement, or pseudointimal resection are all possible through the angioscope at the time of diagnosis.

Venous outflow of the leg: anatomy and physiologic mechanism of the plantar venous plexus.

PURPOSE: Mechanisms of venous outflow from the leg and foot have not been clearly defined. The purpose of this study was to evaluate the anatomy and physiologic mechanism of the plantar venous plexus and its impact on venous drainage from the tibial veins. METHODS: Fifty phlebograms that contained complete foot and calf films were reviewed. On lateral films, the number of veins in the plantar venous plexus and its tibial outflow tract were counted. The length and diameter of the longest vein in the plantar venous system and the length of the foot arch were measured. The ratio of the length of the plantar venous plexus to the arch length was calculated. The presence or absence of valves within the plexus was recorded. Plantar venous plexus outflow was evaluated by an duplex ultrasonographic scan of the posterior tibial, anterior tibial, and peroneal veins during intermittent external pneumatic compression of the plantar surface of the foot. RESULTS: The plantar venous plexus was composed of one to four large veins (mean, 2.7 veins) within the plantar aspect of the foot. The diameter of these veins was 4.0 +/- 1.2 mm. The veins coursed diagonally from a lateral position in the forefoot to a medial position at the level of the ankle, spanning 75% of the foot arch. Prominent valves were recognized within the plantar veins in 22 of 50 patients. The plexus coalesced into an outflow tract of one to four veins (mean, 2.5 veins) that flowed exclusively into the posterior tibial venous system. Small accessory veins that drained the plantar surface of the forefoot flowed into either the posterior tibial or peroneal veins. This pattern of selective drainage of the plantar venous plexus was confirmed by duplex imaging. Mechanical compression of the plantar venous plexus produced a mean peak velocity in the posterior tibial veins of 123 +/- 71 cm/sec, in the anterior tibial veins of 24 +/- 14 cm/sec, and in the peroneal veins of 29 +/- 26 cm/sec. CONCLUSIONS: The plantar venous plexus is composed of multiple large-diameter veins that span the arch of the foot. Compression of the plantar venous plexus, such as that which occurs during ambulation, is capable of significantly increasing flow through the posterior tibial venous system into the popliteal vein. Its function may be integral to venous outflow from the calf and priming of the more proximal calf muscle pump.

Assessing health status in the elderly: the nutrition screening initiative.

The recent dramatic growth in the population aged 65 and over is projected to continue well into the 21st century. While improved health status of most aging Americans is also expected, such is not the case in certain vulnerable subgroups at risk for poor health. This includes older women; minority groups; those aged 85 and above; older persons with limited economic resources, those isolated from family and friends; and older persons with impaired physical, cognitive, or emotional status. These factors, plus the cost implications of caring for a rapidly aging population, provided the impetus for the development of the Nutrition Screening Initiative (NSI). Established in 1990, the goal of the NSI is to promote the incorporation of routine nutrition screening and nutritional care into America's health services delivery system. The NSI has devoted its activities toward increasing the awareness of nutritional factors as they relate to the older population.

The nutrition screening initiative: a 5-year perspective.

A history of the goals, activities, and accomplishments of the Nutrition Screening Initiative (NSI) is provided. A commentary on the development and intended use of the NSI's self-assessment and screening tools is given to facilitate selection of feeding devices for older Americans who need nutrition care. Additional questionnaires and interventions designed to address the needs identified through the NSI's standardized, interdisciplinary approach to the assessment of nutritional risk are described and their use encouraged. Legislative and public policy advocacy is summarized. A systemic approach to the assessment and maintenance of optimal nutritional health in the older population will have a profound effect on health care delivery systems.

Thrombolytic therapy for acute deep venous thrombosis: how much is enough?

Twenty-eight patients treated with thrombolytic therapy for acute deep venous thrombosis were monitored prospectively with non-invasive testing every 12-24h during treatment to evaluate thrombus response and whether duration of therapy was appropriate. Some 75% (21 of 28) of patients demonstrated improvement with lytic therapy with 36% (10 of 28) demonstrating complete lysis; 95% of responders (20 of 21) initiated lysis within 24h. Some 33% (7 of 21) of all responders and 64% (7 of 11) of those having partial lysis had treatment terminated during thrombus resolution but before maximal lysis. Non-invasive testing indicated that thrombolytic therapy for acute deep venous thrombosis is frequently terminated before maximal lysis of the thrombus. Monitoring thrombus response with venous duplex imaging should be part of the treatment strategy of deep venous thrombosis if thrombolytic therapy is used. This approach should increase efficacy and potentially reduce complications of thrombolytic therapy for acute deep venous thrombosis.

Reducing morbidity of thoracoabdominal aneurysm repair by preliminary axillofemoral bypass.

BACKGROUND: Thoracoabdominal aneurysm (TAA) repair continues to be associated with appreciable morbidity and mortality. To reduce the substantial cardiac afterload of thoracic aortic clamping, preserve visceral, renal, and lower-extremity perfusion, and reduce spinal cord ischemia, a right axillofemoral bypass was performed before TAA resection. PATIENTS AND METHODS: Fifteen patients undergoing repair of their TAA had a preliminary axillofemoral bypass with an 8- to 10-mm externally supported polytetrafluoroethylene graft. Nine underwent elective repair and 6 were operated on emergently. All but 2 patients (both had type IV aneurysms) had spinal fluid drainage and all had moderate hypothermia induced (31 degrees C to 32 degrees C). All visible intercostal arteries were reimplanted. RESULTS: Requirements for pharmacologic afterload reduction were minimal. Urine output was preserved during proximal aortic and intercostal anastomoses, and acidosis was minimal. Anticoagulation was not necessary unless the aortic bifurcation was replaced, and no patient had thrombotic complications. One (7%) patient died after repair of a ruptured aneurysm, and 1 (7%) developed paraplegia and required temporary dialysis. CONCLUSION: Preliminary axillofemoral bypass avoids the profound hemodynamic and physiologic derangement caused by clamping of the thoracic aorta, and effectively reduces the morbidity of TAA repair.

Modeling protein cores with Markov random fields.

A mathematical formalism is introduced that has general applicability to many protein structure models used in the various approaches to the "inverse protein folding problem." The inverse nature of the problem arises from the fact that one begins with a set of assumed tertiary structures and searches for those most compatible with a new sequence, rather than attempting to predict the structure directly from the new sequence. The formalism is based on the well-known theory of Markov random fields (MRFs). Our MRF formulation provides explicit representations for the relevant amino acid position environments and the physical topologies of the structural contacts. In particular, MRF models can readily be constructed for the secondary structure packing topologies found in protein domain cores, or other structural motifs, that are anticipated to be common among large sets of both homologous and nonhomologous proteins. MRF models are probabilistic and can exploit the statistical data from the limited number of proteins having known domain structures. The MRF approach leads to a new scoring function for comparing different threadings (placements) of a sequence through different structure models. The scoring function is very important, because comparing alternative structure models with each other is a key step in the inverse folding problem. Unlike previously published scoring functions, the one derived in this paper is based on a comprehensive probabilistic formulation of the threading problem.

A strategy of aggressive regional therapy for acute iliofemoral venous thrombosis with contemporary venous thrombectomy or catheter-directed thrombolysis.

PURPOSE: Occlusive iliofemoral venous thrombosis is associated with morbid short- and long-term consequences. Having been disappointed with standard anticoagulant therapy and systemic fibrinolysis, we embarked on an aggressive multidisciplinary regional approach to treat these patients, with the goals of therapy being (1) to eliminate iliofemoral venous thrombus, (2) to provide unobstructed venous drainage from the affected limb, and (3) to prevent recurrent thrombosis. METHODS: Twelve consecutive patients were treated for extensive iliofemoral venous thrombosis. Each had thrombus from their infrapopliteal veins through their iliofemoral system, and four had vena caval involvement. The conditions of 11 patients failed to improve when the patients were given anticoagulants, and prior systemic fibrinolysis failed in five patients. The treatment strategy includes catheter-directed thrombolysis with intrathrombus infusion of the plasminogen activator or operative thrombectomy or venous bypass with a permanent 4 mm arteriovenous fistula (AVF). RESULTS: Nine of 12 patients had a good or excellent clinical outcome (mean follow-up 25 months), which correlated with restored unobstructed venous drainage from the affected limb. Seven patients had catheter-directed lytic therapy attempted. In five patients the catheters were appropriately positioned, and lysis was successful. Five of the eight patients who underwent operations had successful procedures. Two of the three patients with poor operative outcomes had residual thrombus in their iliac veins or vena cava after thrombectomy (without bypass). The third patient, in whom anticoagulation was contraindicated, had an initially successful thrombectomy and AVF; however, vena caval thrombosis developed 2 months after operation. No patient had symptomatic pulmonary emboli, and routine posttreatment ventilation/perfusion lung scanning was not performed. CONCLUSIONS: An aggressive multidisciplinary regional approach to patients with obliterative iliofemoral venous thrombosis, designed to remove thrombus and provide unobstructed venous drainage, offers substantially better clinical outcome compared with systemic fibrinolysis and standard anticoagulation. Catheter-directed thrombolysis is successful if the catheter is appropriately positioned within the thrombus. Contemporary venous thrombectomy, which includes thrombus removal, completion phlebography, AVF, and cross-pubic bypass when necessary, is associated with high success rates. Failures can be anticipated and avoided in most patients.