Patrick A. McKee

The Clinical Validity of Normal Compression Ultrasonography in Outpatients Suspected of Having Deep Venous Thrombosis

Clinical trials have shown that, because the symptoms and signs of deep venous thrombosis are highly nonspecific, objective testing is required for patients suspected of having the condition [1-9]. Ultrasonography is the most commonly used test in the United States [10-13]; it is highly sensitive and specific for proximal venous thrombosis (thrombosis of the popliteal or more proximal veins) [10-14]. A recent report described a simplified ultrasonography technique in which imaging is limited to the deep veins at the groin and popliteal fossa [14]. These anatomic areas are evaluated by using the single criterion of vein compressibility [14]. This simplified compression ultrasonography technique is highly sensitive and specific for proximal venous thrombosis in outpatients suspected of having deep venous thrombosis [14]. Although imaging with the simplified technique is limited to the groin and popliteal fossa, it is very sensitive because thrombosis isolated to the iliac vein or superficial femoral vein is rare in symptomatic patients [15]. However, thrombosis confined to the deep veins of the calf is not rare, occurring in up to 13% of symptomatic patients [4-6]. Ultrasonography done by using compression, either alone or with color Doppler capacity, does not uniformly visualize the deep veins of the calf and has limited sensitivity (40% to 70%) for thrombosis of the calf veins [10-13, 16]. Therefore, serial testing is required to identify patients who develop extension of thrombosis into the popliteal vein or more proximal veins [6-917, 18], for whom treatment is required [19-21]. A clinical outcome study has shown that it is safe to withhold anticoagulation in symptomatic outpatients in whom the results of simplified compression ultrasonography are normal on initial testing and two repeated tests [17]. More than 500 000 patients are referred for testing each year in the United States [22]; 80% of these patients (400 000) will have a normal result on the first test and will need repeated testing [17]. Cost analysis shows that a single repeated test compared with two repeated tests results in substantial savings-

Phase II Trial of Single Agent Val-boroPro (Talabostat) Inhibiting Fibroblast Activation Protein in Patients with Metastatic Colorectal Cancer

260 per patient (in 1990 U.S. dollars) [23]. Therefore, more than

Predictions of coronary artery stenosis by artificial neural network

100 million could be saved yearly in the United States if the use of two repeated tests were replaced by the use of one repeated test. However, the safety of this approach is uncertain because it has not been evaluated by clinical trials. Of the patients with normal initial ultrasonography results who then have abnormal results on repeated testing, half have abnormal results the day after presentation and half have abnormal results on day 7 [17]. Patients whose results are abnormal the day after presentation may have detectable thrombosis on the initial test if the popliteal vein is imaged beyond the popliteal fossa to its most distal point (that is, to the trifurcation of the calf veins) because compression ultrasonography is sensitive for thrombi that barely extend out of the calf veins into the popliteal vein [24]. Repeated testing could then be limited to a single test done 5 to 7 days after the first test [16, 23]. We performed a prospective cohort study of outpatients suspected of having first-episode deep venous thrombosis. This was done to test the safety of withholding anticoagulation in patients who 1) have normal results on simplified compression ultrasonography that was done at presentation and that completely imaged the popliteal vein to its most distal point and 2) have a normal result on a single repeated test done 5 to 7 days after the first test. We used long-term follow-up to test the validity of this approach because inadequate management of proximal venous thrombosis results in clinically evident venous thromboembolic events that can be measured objectively [19-21]. Methods Patients and Study Protocol The study sample consisted of consecutive outpatients who were suspected of having first-episode deep venous thrombosis and were referred by their physicians to the noninvasive vascular laboratory of University Hospital or Veterans Administration Medical Center in Oklahoma City, Oklahoma, between December 1993 and 31 December 1995. Each patient was seen by a consultant physician who obtained a clinical history, performed a physical examination, and evaluated the patients eligibility for the study. Eligible patients who gave informed consent were then managed according to the study protocol (Figure 1). Patients were ineligible if compression ultrasonography could not be done because of physical or technical limitations, if the patients were unable to return for repeated testing in 5 to 7 days, if long-term follow-up was not possible because of geographic inaccessibility, if the patients had received therapeutic doses of heparin for more than 24 hours before their referral, or if the patients were pregnant. The institutional review board approved the study protocol. Figure 1. Study protocol and outcomes. Objective Testing for Venous Thrombosis at Study Entry Real-time B-mode ultrasonography was performed immediately after the clinical assessment. The simplified compression technique described by Lensing and colleagues [14] was used, with a minor modification as described below. Ultrasonography was performed by using an Acuson 128 scanner (Acuson Corp., Mountain View, California) equipped with a 7.5-MHz linear-array transducer. Both the common femoral and popliteal veins were imaged in gray scale and were assessed for compressibility [14]. The common femoral vein was imaged from the inguinal line to its bifurcation into the superficial femoral vein and profunda femoris. The popliteal vein was imaged from the proximal popliteal fossa to a point 10 cm distal from the mid-patella. This point was chosen to provide a reproducible method with which to approximate the most distal popliteal vein because the calf-vein trifurcation is often difficult to identify by ultrasonography. Vein anatomy in the popliteal fossa, as well as the formation of the popliteal vein itself, greatly varies; the classic trifurcation pattern is found in only a minority of patients [25-27]. Compressibility of the veins was assessed only in the transverse plane [14]. The results were categorized as normal if all imaged venous segments were fully compressible, as abnormal if a noncompressible segment was identified, or as inadequate for interpretation. If the result of initial compression ultrasonography was normal, anticoagulation was withheld and testing was repeated 5 to 7 days later. Anticoagulation was withheld from all patients whose results remained normal on compression ultrasonography (the normal cohort), regardless of their symptoms. If the result of initial or repeated testing was abnormal (the abnormal cohort), venography was done to confirm the extent of thrombosis. The venographic results were categorized as normal, positive for proximal venous thrombosis (thrombosis of the popliteal, femoral, or iliac vein with or without thrombosis of the calf vein), positive for isolated thrombosis of the calf vein, or inadequate for interpretation. The diagnostic criterion for the presence of deep venous thrombosis was an intraluminal filling defect that was constant on all films [28]. If the venogram was abnormal or inadequate for interpretation, anticoagulation was given unless contraindicated. If the venogram was normal, anticoagulation was not given and the abnormal ultrasonography result was considered falsely abnormal. Long-Term Follow-up All patients were instructed to immediately return to our clinic or emergency department if they had symptoms or signs of venous thrombosis or pulmonary embolism. They were also assessed routinely at 3 months either in the clinic or by telephone. At this follow-up assessment, an interval history was taken that addressed general health, specific symptoms (including leg pain, tenderness and swelling, chest pain, dyspnea, hemoptysis, and syncope), hospitalization, and use of anticoagulants. For all patients who died, the cause of death was determined either from autopsy or by independent clinical review. The primary outcome measure was a diagnosis of venous thrombosis or pulmonary embolism during follow-up confirmed by objective testing. The 3-month follow-up period was chosen because inadequate management of proximal venous thrombosis results in a high rate of recurrent venous thromboembolism during the subsequent 3 months [19-21]. All patients in either cohort who returned during 3-month follow-up with clinically suspected deep venous thrombosis underwent objective testing with impedance plethysmography, which was performed serially according to published protocols [7-929, 30]. Serial impedance plethysmography is highly sensitive and specific for proximal venous thrombosis in symptomatic patients [7-9]. Venography was indicated in patients with abnormal results on impedance plethysmography. If venography could not be done or the results of venography were inadequate, deep venous thrombosis was diagnosed if impedance plethysmography yielded abnormal results in the absence of conditions known to produce false-positive results [7-9, 29-31]. Patients suspected of having pulmonary embolism underwent objective testing with lung scanning and, if indicated, pulmonary angiography, according to published protocols and diagnostic criteria [32-34]. Methodologic Issues and Avoidance of Bias Care was taken to avoid bias. Selection bias was avoided by entering consecutive patients into the study. Bias during the initial testing period was avoided by defining criteria for normal and abnormal ultrasonography results a priori; by prohibiting venography or other objective leg testing in patients with normal ultrasonography results; and by withholding anticoagulation from all patients with normal ultrasonography results, regardless of their symptoms. Diagnostic suspicion bias [35] was avoided by objectively testing all patients who re

Rate of inpatient weight restoration predicts outcome in anorexia nervosa.

Purpose: Fibroblast Activation Protein (FAP) is a tumor fibroblast protease that has been shown to potentiate colorectal cancer growth. The clinical impact of FAP inhibition was tested using Val-boroPro (Talabostat), the first clinical inhibitor of FAP enzymatic activity, in a phase II study of patients with metastatic colorectal cancer. Methods: Patients with metastatic colorectal cancer who had previously received systemic chemotherapies were treated with single agent Val-boroPro 200 μg p.o. BID continuously. Eligibility included measurable disease, performance status of 0 to 2, and adequate organ function. Laboratory correlates evaluated the pharmacodynamic effects of Val-boroPro on FAP enzymatic function in the peripheral blood. Results: Twenty-eight patients (median age 62; 12 males, 16 females) were enrolled in this study. There were no objective responses. Six of 28 (21%) patients had stable disease for a median of 25 weeks (range 11-38 weeks). Laboratory analysis demonstrated significant, although incomplete inhibition of FAP enzymatic activity in the peripheral blood. Conclusion: This phase II trial of Val-boroPro demonstrated minimal clinical activity in patients with previously treated metastatic colorectal cancer. However it provides the initial proof-of-concept that physiologic inhibition of FAP activity can be accomplished in patients with colorectal cancer, and lays the groundwork for future studies targeting the tumor stroma.

Evidence that α2-antiplasmin becomes covalently ligated to plasma fibrinogen in the circulation: a new role for plasma factor XIII in fibrinolysis regulation

Data from angiography patient records comprised 14 input variables of a neural network. Outcomes (coronary artery stenosis or none) formed both supervisory and output variables. The network was trained by backpropagation on 332 records, optimized on 331 subsequent records, and tested on final 100 records. If 0.40 was chosen as the output distinguishing stenosis from no stenosis, 81 patients who had stenosis would have been identified, while 9 of 19 patients who did not have stenosis might have been spared angiography. The results demonstrated that artificial neural networks could identify some patients who do not need coronary angiography.

Attention-deficit hyperactivity symptoms and disorder in eating disorder inpatients.

OBJECTIVE To examine weight restoration parameters during inpatient treatment as predictors of outcome in anorexia nervosa (AN). METHOD Adolescent and adult females admitted for inpatient eating disorder treatment were recruited for an ongoing longitudinal study. This analysis examined several weight restoration parameters as predictors of clinical deterioration after discharge among participants with AN. RESULTS Rate of weight gain was the only restoration parameter that predicted year 1 outcome. Clinical deterioration occurred significantly less often among participants who gained >or=0.8 kg/week (12/41, 29%) than those below this threshold (20/38, 53%) (chi(2) = 4.37, df = 1, p = .037) and remained significant after adjustment for potential confounders. DISCUSSION Weight gain rate during inpatient treatment for AN was a significant predictor of short-term clinical outcome after discharge. It is unclear whether weight gain rate exerts a causal effect or is rather a marker for readiness to tolerate weight restoration and engage in the recovery process.

Neural network predictions of significant coronary artery stenosis in men

Summary.  Background: Plasma alpha2‐antiplasmin (α2AP) is a rapid and effective inhibitor of the fibrinolytic enzyme plasmin. Congenital α2AP deficiency results in a severe hemorrhagic disorder due to accelerated fibrinolysis. It is well established that in the presence of thrombin‐activated factor XIII (FXIIIa), α2AP becomes covalently ligated to the distal α chains of fibrin or fibrinogen at lysine 303 (two potential sites per molecule). Some time ago we showed that α2AP is covalently linked to plasma fibrinogen . That singular observation led to our hypothesis that native plasma factor XIII (FXIII), which is known to catalyze covalent cross‐linking of fibrinogen in the presence of calcium ions, can also incorporate α2AP into fibrinogen in the circulation. Results and Conclusions: We now provide evidence that FXIII incorporates I125‐labelled α2AP into the Aα‐chain sites on fibrinogen or fibrin. We also measured the content of α2AP in isolated plasma fibrinogen fractions by ELISA and found that substantial amounts were present (1.2–1.8 moles per mole fibrinogen). We propose that α2AP becomes ligated to fibrinogen while in the circulation through the action of FXIII, and that its immediate presence in plasma fibrinogen contributes to regulation of in vivo fibrinolysis.

Enhancement of fibrinolysis by inhibiting enzymatic cleavage of precursor α2-antiplasmin

OBJECTIVE The objective of this study was to determine the prevalence of attention-deficit hyperactivity disorder (ADHD) symptoms and a DSM-IV ADHD diagnosis in women admitted for treatment of an eating disorder. METHOD One hundred eighty-nine inpatient women with an eating disorder were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and ADHD interview from the Multi-international Psychiatric Interview (MINI). RESULTS Twenty-one percent of the sample reported at least six current ADHD symptoms, but the estimated prevalence rate for a diagnosis of ADHD in this population was only 5.8% (95% CI: 2.6%-9.5%). Most current ADHD inattentive symptoms appeared after childhood suggesting late-onset non-ADHD origins. Current inattention symptoms in those without a diagnosis of ADHD correlated with higher BMI (p < .0001), symptoms of bulimia nervosa and current level of depression symptoms (p = .025). DISCUSSION Although current ADHD symptoms were commonly endorsed in this population, clinicians should carefully examine for childhood symptom-onset of ADHD.

Noncovalent Interaction of α2-Antiplasmin with Fibrin(ogen): Localization of α2-Antiplasmin-Binding Sites

OBJECTIVE A neural network system was designed to predict whether coronary arteriography on a given patient would reveal any occurrence of significant coronary stenosis (>50%), a degree of stenosis which often leads to coronary intervention. METHODOLOGY A dataset of 2004 records from male cardiology patients was derived from a national cardiac catheterization database. The catheterizations selected for analysis from the database were first-time and elective, and they were precipitated by chest pain. Eleven patient variables were used as inputs in an artificial neural network system. The network was trained on the earliest 902 records in the dataset. The next 902 records formed a cross-validation file, which was used to optimize the training. A third file composed of the next 100 records facilitated the choice of a cutoff number between 0 and 1. The cutoff number was applied to the last 100 records, which comprised a test file. RESULTS When a cutoff of 0.25 was compared to the network outputs of all 100 records in the test file, 12 of 46 (specificity=26%) patients without significant stenosis had outputs<or=0.25, but all patients with significant stenosis had outputs>0.25 (sensitivity=100%). Therefore, the network identified a fraction of the patients in the test file who did not have significant coronary artery stenosis, while at the same time the network identified all of the patients in the test file who had significant stenosis capable of causing chest pain. CONCLUSION Artificial neural networks may be helpful in reducing unnecessary cardiac catheterizations.

Crosslinking of α2‐Antiplasmin to Fibrin

Summary.  Background and objective: Resistance of thrombi to plasmin digestion depends primarily on the amount of α2‐antiplasmin (α2AP) incorporated within fibrin. Circulating prolyl‐specific serine proteinase, antiplasmin‐cleaving enzyme (APCE), a homologue of fibroblast activation protein (FAP), cleaves precursor Met‐α2AP between ‐Pro12‐Asn13‐ to yield Asn‐α2AP, which is crosslinked to fibrin approximately 13× more rapidly than Met‐α2AP and confers resistance to plasmin. We reasoned that an APCE inhibitor might decrease conversion of Met‐α2AP to Asn‐α2AP and thereby enhance endogenous fibrinolysis. Methods and results: We designed and synthesized several APCE inhibitors and assessed each vs. plasma dipeptidyl peptidase IV (DPPIV) and prolyl oligopeptidase (POP), which have amino acid sequence similarity with APCE. Acetyl‐Arg‐(8‐amino‐3,6‐dioxaoctanoic acid)‐d‐Ala‐l‐boroPro selectively inhibited APCE vs. DPPIV, with an apparent Ki of 5.7 nm vs. 6.1 μm, indicating that an approximately 1000‐fold greater inhibitor concentration is required for DPPIV than for APCE. An apparent Ki of 7.4 nm was found for POP inhibition, which is similar to 5.7 nm for APCE; however, the potential problem of overlapping FAP/APCE and POP inhibition was negated by our finding that normal human plasma lacks POP activity. The inhibitor construct caused a dose‐dependent decrease of APCE‐mediated Met‐α2AP cleavage, which ultimately shortened plasminogen activator‐induced plasma clot lysis times. Incubation of the inhibitor with human plasma for 22 h did not lessen its APCE inhibitory activity, with its IC50 value in plasma remaining comparable to that in phosphate buffer. Conclusion: These data establish that inhibition of APCE might represent a therapeutic approach for enhancing thrombolytic activity.