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OBJECTIVES: a) To determine whether decreased sarcoplasmic calcium release channel (CRC) activity is a mechanism by which myocardial contractility is reduced in endotoxemia; b) to determine whether nitric oxide modulates CRC activity in endotoxemia; and c) to examine two nitric oxide signaling pathways in relation to CRC function in endotoxemia. DESIGN: Randomized, prospective using a rat model of endotoxemia. SETTING: Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Endotoxemia was induced by lipopolysaccharide administration. The effects of nitric oxide were studied using the highly selective inducible nitric oxide synthase inhibitor N-(3-(aminomethyl)benzyl)acetamidine dihydrochloride (1400W) and the specific guanylyl cyclase inhibitor 1-H (1, 2, 4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). MEASUREMENTS AND MAIN RESULTS: We assessed myocardial contractility, myocardial nitric oxide content, and guanosine-3′,5′ (cyclic) phosphate (cGMP) content. We determined CRC activity by calcium release and ryanodine binding assays. We followed these variables at four time points through the course of endotoxemia. We found that myocardial contractility and CRC activity were decreased in late but not in early endotoxemia. Furthermore, inducible nitric oxide synthase inhibition with 1400W restored contractility and CRC activity in late endotoxemia but paradoxically worsened these variables in early endotoxemia. Through the use of the guanylyl cyclase inhibitor ODQ, we demonstrate that nitric oxide acts through cGMP-mediated mechanisms in early and late endotoxemia. We investigated cGMP-independent pathways by assessing the oxidative status of the CRC. We found that in late endotoxemia, nitric oxide decreased the number of free thiols, demonstrating that nitric oxide also acts through cGMP-independent pathways. CONCLUSIONS: Nitric oxide has a dual effect on the CRC in endotoxemia. At low concentrations, as measured in early endotoxemia, nitric oxide stabilizes the CRC through cGMP-mediated mechanisms. In late endotoxemia, high nitric oxide concentrations decrease channel activity through both cGMP-dependent and cGMP-independent mechanisms. [ABSTRACT FROM AUTHOR]

Study Design: A large-scale retrospective case-control study., Objective: Examine diabetes as a risk factor for lumbar spinal stenosis (LSS) development and evaluate the impact of diabetes duration, glycemic control, and associated complications on this risk., Summary of Background Data: Diabetes mellitus, a multiorgan disorder impacting various connective tissues, induces histological changes in spinal structures, particularly the ligamentum flavum. While clinical studies suggest a higher incidence of LSS in diabetic patients, substantial epidemiological research on the likelihood of LSS diagnosis in individuals with diabetes is scarce., Materials and Methods: Using nationwide data, a total of 49,576 patients diagnosed with LSS based on International Classification of Diseases-10 codes were matched with controls of the same number based on age and sex. Employing a multivariable logistic regression model, the study assessed for the association between spinal stenosis and diabetes, while adjusting for confounders., Results: We found a higher likelihood of LSS diagnosis in diabetic patients [odds ratio (OR) 1.39, 95% CI: 1.36 - 1.43, P <0.001]. Those with hemoglobin A1c ≥7% and ≥1 diabetes-related complication also had an elevated likelihood (OR: 1.19, 95% CI: 1.08-1.31, P =0.001). Prolonged diabetes exposure increased the risk. Diabetes diagnosis reduced median survival by around 4.5 years for both stenosis and nonstenosis patients; spinal stenosis diagnosis alone minimally impacted survival. Relative to individuals diagnosed with diabetes mellitus at the age of 65 or older, the OR for developing LSS were 1.22 (95% CI: 1.18-1.27, P <0.001) when DM was diagnosed at 50 to 65 years old and 1.67 (95% CI: 1.56-1.79, P <0.001) for those under 50 years old. Multivariate analysis revealed a significantly increased risk of all-cause mortality in patients with DM and spinal stenosis (hazard ratio: 1.36, 95% CI: 1.29-1.44, P <0.001) and those with DM without stenosis (hazard ratio: 1.49, 95% CI: 1.41-1.57, P <0.001) compared with controls., Conclusions: Diabetic patients with prolonged disease, poor glycemic control, and diabetes-related complications face an elevated risk of developing LSS. Recognizing the reciprocal adverse relationship between these conditions is crucial in clinical practice and designing public health measures for managing both conditions., Level of Evidence: 4., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Eccrine squamous syringometaplasia (ESS) has been associated with several conditions including morphea, linear scleroderma, and burns. It is yet to be reported in lichen sclerosus et atrophicus (LSA). We describe a bullous LSA plaque on the forearm of a woman with pre-existing genital LSA and vitiligo. Besides the histopathological findings of bullous LSA, numerous small irregular squamoid structures were present in the mid and upper dermis always above the normal eccrine glands. The histopathology, periodic acid-Schiff stain, and positive immunostains for P63, low molecular weight keratins 8&18, epithelial membrane antigen, and carcinoembryonic antigen supported the diagnosis of ESS. The pathogenesis of ESS in LSA may be related to ischemia, inflammation, and fibrosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Undersized ring annuloplasty for ischemic mitral regurgitation (MR) is associated with variable results and >30% MR recurrence. We tested whether subvalvular repair by severing second-order mitral chordae can improve annuloplasty by reducing papillary muscle tethering., Methods and Results: Posterolateral myocardial infarction known to produce chronic remodeling and MR was created in 28 sheep. At 3 months, sheep were randomized to sham surgery versus isolated undersized annuloplasty versus isolated bileaflet chordal cutting versus the combined therapy (n=7 each). At baseline, chronic myocardial infarction (3 months), and euthanasia (6.6 months), we measured left ventricular (LV) volumes and ejection fraction, wall motion score index, MR regurgitation fraction and vena contracta, mitral annulus area, and posterior leaflet restriction angle (posterior leaflet to mitral annulus area) by 2-dimensional and 3-dimensional echocardiography. All groups were comparable at baseline and chronic myocardial infarction, with mild to moderate MR (MR vena contracta, 4.6±0.1 mm; MR regurgitation fraction, 24.2±2.9%) and mitral annulus dilatation (P<0.01). At euthanasia, MR progressed to moderate to severe in controls but decreased to trace with ring plus chordal cutting versus trace to mild with chordal cutting alone versus mild to moderate with ring alone (MR vena contracta, 5.9±1.1 mm in controls, 0.5±0.08 with both, 1.0±0.3 with chordal cutting alone, 2.0±0.4 with ring alone; P<0.01). In addition, LV end-systolic volume increased by 108% in controls versus 28% with ring plus chordal cutting, less than with each intervention alone (P<0.01). In multivariate analysis, LV end-systolic volume and mitral annulus area most strongly predicted MR (r(2)=0.82, P<0.01)., Conclusions: Comprehensive annular and subvalvular repair improves long-term reduction of both chronic ischemic MR and LV remodeling without decreasing global or segmental LV function at follow-up.

Background: one of the key targets in treating mitral regurgitation (MR) is reducing the otherwise progressive left ventricular (LV) remodeling that exacerbates MR and conveys adverse prognosis. We have previously demonstrated that severing 2 second-order chordae to the anterior mitral leaflet relieves tethering and ischemic MR acutely. The purpose of this study was to test whether this technique reduces the progression of LV remodeling in the chronic ischemic MR setting., Methods and Results: a posterolateral MI was created in 18 sheep by obtuse marginal branch ligation. After chronic remodeling and MR development at 3 months, 6 sheep were randomized to sham surgery (control group) and 12 to second-order chordal cutting (6 each to anterior leaflet [AntL] and bileaflet [BiL] chordal cutting, techniques that are in clinical application). At baseline, chronic infarction (3 months), and follow-up at a mean of 6.6 months post-myocardial infarction (MI) (euthanasia), we measured LV end-diastolic (EDV) and end-systolic volume (ESV), ejection fraction, wall motion score index, and posterior leaflet (PL) restriction angle relative to the annulus by 2D and 3D echocardiography. All measurements were comparable among groups at baseline and chronic MI. At euthanasia, AntL and BiL chordal cutting limited the progressive remodeling seen in controls. LVESV increased relative to chronic MI by 109±8.7% in controls versus 30.5±6.1% with chordal cutting (P<0.01) (LVESV in controls, 82.5±2.6 mL; in AntL, 60.6±5.1 mL; in BiL, 61.8±4.1 mL). LVEDV increased by 63±2.0% in controls versus 26±5.5% and 22±3.4% with chordal cutting (P<0.01). LV ejection fraction and wall motion score index were not significantly different at follow-up among the chordal cutting and control groups. MR progressively increased to moderate in controls but decreased to trace-mild with AntL and BiL chordal cutting (MR vena contracta in controls, 5.9±1.1 mm; in AntL, 2.6±0.1 mm; in BiL, 1.7±0.1 mm; P<0.01). BiL chordal cutting provided greater PL mobility (decreased PL restriction angle to 54.2±5.0° versus 83±3.2° with AntL chordal cutting; P<0.01)., Conclusions: reduced leaflet tethering by chordal cutting in the chronic post-MI setting substantially decreases the progression of LV remodeling with sustained reduction of MR over a chronic follow-up. These benefits have the potential to improve clinical outcomes.

Background: The goal of this study was to assess the clinical value of stress myocardial perfusion scintigraphy (MPS) in elderly patients (> or =75 years of age)., Methods and Results: We followed up 5200 elderly patients (41% exercise) after dual-isotope MPS over 2.8+/-1.7 years (362 cardiac deaths [CDs], 7.0%, 2.6%/y) and a subset with extended follow-up (684 patients for 6.2+/-2.9 years; 320 all-cause deaths). Survival modeling of CD revealed that both MPS-measured ischemia and fixed defect added incrementally to pre-MPS data in both adenosine and exercise stress patients. Modeling a subset with gated MPS (n=2472) revealed that ejection fraction and perfusion data added incrementally to each other, further enhancing risk stratification. Unadjusted, annualized post-normal MPS CD rate was 1.3% but <1% in patients with normal rest ECG, exercise stress, or age of 75 to 84 years and was 2.3% to 3.7% in patients > or =85 years of age or undergoing pharmacological stress. However, compared with age-matched US population CD rates (75 to 84 years of age, 1.5%; > or =85 years, 4.8%), normal MPS CD rates were approximately one-third lower than the baseline risk of US individuals (both P<0.05). Modeling of all-cause death in 684 patients with extended follow-up revealed that after risk adjustment, an interaction between early treatment and ischemia was present; increasing ischemia was associated with increasing survival with early revascularization, whereas in the setting of little or no ischemia, medical therapy had improved outcomes., Conclusions: Stress MPS effectively stratifies CD risk in elderly patients and may identify optimal post-MPS therapy. CD rates after normal MPS are low in all subsets in relative terms compared with the age-matched US population.

Background: We have advocated the use of a 5-category "normal," "probably normal," "equivocal," "probably abnormal," and "definitely abnormal" approach to final interpretation of myocardial perfusion single-photon emission computed tomography (SPECT). The prognostic value of expressing levels of certainty compared with a dichotomous normal/abnormal classification or categories for summed stress scores is unclear., Methods and Results: Myocardial perfusion SPECT (MPS) was visually assessed using a standard semiquantitative approach, yielding summed scores that were used for preliminary interpretation using 5 levels of certainty. The interpreter was permitted to then shift the level of certainty in the final interpretation by 1 degree, based on nonperfusion MPS variables and available clinical information. To examine the prognostic value of expressing levels of clinical certainty, we evaluated 20 740 unique consecutive patients who underwent rest Tl-201/stress Tc-99m sestamibi MPS (34.3% vasodilator stress), of whom 845 (4.4%) were lost to follow-up and 1695 were excluded from prognostic analysis due to an early revascularization (<60 days after MPS). The remaining 18 200 patients (59.1% men; age, 65+/-13 years) were followed up for cardiac death for a mean of 2.7+/-1.7 years. During the follow-up, a total of 591 cardiac death events occurred. By univariable analysis, there were substantial differences in the distribution of follow-up cardiac death by the category of clinical MPS certainty. The clinical certainty was found to be an independent multivariable predictor of cardiac death in the study population and better identified patients at increased risk of cardiac death than the approaches based solely on the standard categories of summed perfusion scores or based solely on categories of segmental perfusion scores., Conclusions: The use of multicategory reporting of MPS results incorporating nonperfusion MPS results and clinical information enhances risk stratification compared with both a dichotomous normal/abnormal approach or approaches based solely on segmental categories of perfusion scores. Whether this enhanced risk stratification based on the clinical certainty of the MPS interpretation leads to a more effective therapeutic regimen, tailored to the individual patient's need, requires further prospective evaluation.

Objective: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. Principal treatment options for ADHD today include the psychostimulants, mainly methylphenidate (MPH). However, approximately 30% to 50% of children and adults with ADHD either do not respond to or do not tolerate treatment with stimulants. In this 8-week open-label, MPH-controlled, parallel group design study, we investigate the efficacy of reboxetine, a new selective norepinephrine reuptake inhibitor, in the treatment of boys with ADHD with a history of intolerance to MPH therapy., Method: Twenty-seven outpatient boys, aged 6 to 16 years, diagnosed with ADHD, participated in the study. Those with a history of intolerance to MPH therapy were assigned to treatment with reboxetine (2-8 mg/d), and the rest were assigned to treatment with MPH (10-20 mg/d) as the control group. The primary outcome measure for this study was the change in rating scores on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ADHD Scale (DAS) that was assessed at baseline and at 8 weeks., Results: At the end of 8 weeks, both reboxetine and MPH treatment regimens resulted in significant improvement in ADHD symptoms. The change in the reduction in the total DAS score and the DAS subscale scores between the reboxetine group and the MPH group was not statistically significant in any of the scores., Conclusions: Although preliminary, results of this study indicate that the use of reboxetine, a new selective norepinephrine reuptake inhibitor, in the treatment of ADHD could increase treatment options available for children who have shown intolerance or who are unresponsive to MPH.

Background: Guidelines for the use of antiretroviral agents for HIV-1 infection recommend combining at least three agents. The toxicity, cost, and complexity of such regimens warrant the search for other options., Methods: MONARK is a prospective, open-label, randomized, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir monotherapy with a standard lopinavir/ritonavir plus zidovudine and lamivudine regimen as an initial treatment regimen in HIV-infected patients with HIV-RNA levels less than 100,000 copies/ml. The primary endpoint was the proportion of patients with HIV-1-RNA levels below 400 copies/ml at week 24 and below 50 copies/ml at week 48., Results: Eight-three and 53 patients were randomly assigned and exposed in the monotherapy and triple-drug groups, respectively. At week 48, by an intent-to-treat analysis, 53 of 83 patients (64%) in the monotherapy group and 40 of 53 patients (75%) in the triple-drug group achieved the primary endpoint (P = 0.19). The on-treatment analysis indicates that 80 and 95% of patients reached the primary endpoint in the monotherapy and triple-drug groups, respectively (P = 0.02). In the monotherapy arm, protease inhibitor-associated resistance mutations were seen in three of the 21 patients qualifying for genotypic resistance testing, with a modest impact on lopinavir susceptibility. None of the serious reported adverse events were considered to be related to study treatment., Conclusion: Our results suggest that lopinavir/ritonavir monotherapy demonstrates lower rates of virological suppression when compared with lopinavir/ritonavir triple therapy and therefore should not be considered as a preferred treatment option for widespread use in antiretroviral-naive patients.

Introduction: Non-ossifying fibroma (NOF) is the most common fibrous bone lesion in children and young adults. This benign lesion is not a true neoplasm but is considered a developmental defect. Clinically, the lesion is asymptomatic and has a predilection for the long bones, particularly the femur and the tibia. NOF that ossify can show increased uptake on bone scintigraphy. Although the radiographic and histopathological findings of NOF have been well described, the scintigraphic findings of the abnormality have only been incidentally mentioned in the literature., Aim: To document the scintigraphic features of NOF in a group of military recruits undergoing bone scintigraphy for suspected stress fractures. Features to differentiate co-existent NOF and stress fractures lesions are discussed., Materials and Methods: Eighty-three military recruits, 67 male and 16 female, aged 18 to 22 years (mean, 19.4 years), who underwent Tc-methylene diphosphonate bone scans for suspected stress fractures or because of pain of the lower limbs had 91 focal lesions on bone scan which on further evaluation demonstrated characteristic radiographic findings of NOF. We evaluated the anatomical site of the lesions, documented the intensity of uptake on bone scan and compared the findings with the radiographic description of the lesions. Comparison with the characteristic scintigraphic pattern of co-existent stress fracture lesions and with previously reported data was performed., Results: A total of 91 NOF lesions were detected. Overall, 89% of NOF were located about the knee. Anatomic distribution of NOF lesions was as follows: 43 (47.3%, R=25, L=18) were located in the postero-medial aspect of the distal femur, 18 (19.8%, R=12, L=6) in the postero-medial aspect of the proximal tibia, 11 (12%, R=5, L=6) in the postero-lateral aspect of the distal femur, 10 (11%, R=4, L=6) in the postero-lateral aspect of the distal tibia, 4 (4.4%, R=2, L=2) in the postero-lateral aspect of the proximal tibia, 3 (3.3%, L=3) in the antero-central aspect of proximal tibia, 1 (1.1%, L=1) in the antero-lateral aspect of distal femur, 1 (1.1%, L=1) in the medial-central aspect of the proximal tibia. In this series NOF lesions were not found in the fibula. Eighty five of 91 (93.4%) of all NOF were located at the metaphysis of the long bones, 2/91 (2.2%) were located at the meta-diaphyseal region of the long bones and only 4/91 (4.4%) of the lesions were located at the diaphysis. All the NOF showed variable degrees of focal increased tracer uptake on bone scan. The bone scan appearance of the focal lesions was: faint uptake in 29 (31.9%), mild uptake in 27 (29.7%), moderate uptake in 28 (30.7%) and intensely increased uptake in seven (7.7%). The radiographic description of the NOF was: lucent NOF three (3.3%), mixed sclerotic and lucent 68 (74.7%) and sclerotic in 20 (22%). Most of the NOF which demonstrated moderate or intensely increased tracer uptake had mixed lucent and sclerotic radiographic appearance (healing). Most of the sclerotic lesions (healed) showed faint uptake. Co-existent stress fractures were predominantly located in the diaphysis of the long bones, characteristically in the postero-medial aspect of the mid-third of the tibia or femur., Conclusions: Military recruits undergoing bone scan for suspected stress fracture might have incidental findings which require further evaluation. Focal lesions on bone scan located about the knee in the lateral aspect of the distal femur or lateral aspect of the proximal tibia in the metaphyseal region of these bones are not compatible with the characteristic scintigraphic features of stress fracture. Such a finding should raise the suspicion for other bony lesions such as NOF, which is commonly located in this region. During the healing phase of the NOF which commonly occur in the age range of this group, the lesion shows mild-to-moderate increased tracer uptake on bone scan. Plain film radiography is usually diagnostic and patients are followed up conservatively. Some NOF lesions are still indistinguishable from stress fracture or splints on bone scan.

While a growing literature has addressed the psychological consequences of torture and refugee trauma, most studies have focused on homogeneous samples drawn from a single region. Thus, relatively little research has attempted to identify demographic or experiential factors that might help explain different levels of distress in these individuals. We measured depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms in a convenience sample of refugees and survivors of torture seeking treatment in a torture treatment program (N = 325). We found 81.1% of patients had clinically significant anxiety, 84.5% had clinically significant depressive symptoms, and 45.7% had significant PTSD symptoms. Regression analyses revealed that anxiety and depressive symptom were significant higher among women (beta = .08, p = 0.02 and beta = .22, p = 0.0001 for anxiety and depression respectively) and those who reported death threats as part of their traumatic experiences (beta = .10, p = 0.033 and beta = .12, p = 0.036 respectively). Symptoms of PTSD were also predicted by death threats (beta = .22, p = 0.03), but were also influenced by the experience of rape (beta = .33, p < 0.001), family torture experiences (beta = .23, p = 0.022), religion (beta = .21, p = 0.03), and age (beta = -.18, p = 0.004). The clinical implications of these results are discussed.

Purpose: To describe the appearance of gelatinous-like keratopathy in a corneal graft., Methods: A 42-year-old healthy white man underwent phacoemulsification and placement of a posterior chamber intraocular lens. After the procedure, he developed pseudophakic bullous keratopathy and underwent 2 subsequent corneal transplantations because of failure of the primary corneal graft., Results: Over 14 months after the second transplantation, a flower-like gelatinous keratopathy appeared in the corneal transplant. The patient underwent superficial keratectomy, removal of the continuous suture, topical application of nitomycin C, and placement of therapeutic contact lens until reepithelialization. The condition did not recur in a follow-up of 6 months. Histologically, hyperplastic epithelium, subepithelial fibrosis, and hyaline material were noted., Conclusion: Secondary gelatinous-like keratopathy may rarely affect corneal grafts causing a decrease in visual acuity. It may be a rare pathologic response to chronic pathophysiologic stress. Superficial keratectomy and application of topical mitomycin C with careful follow-up of the corneal graft may improve the visual outcome.

Background: The prognostic importance of various hemodynamic responses to adenosine infusion in patients undergoing adenosine stress myocardial perfusion stress (MPS) has not been defined., Methods and Results: We identified 3444 unique patients (53.5% women, mean age 74.0+/-8.4 years) who underwent adenosine (with no additional exercise) stress myocardial perfusion single photon emission computed tomography (MPS) and were followed up for 2.0+/-0.8 years. Multivariable Cox proportional hazards analysis was used to assess the prognostic value of hemodynamic variables in predicting cardiac death (CD). Two hundred twenty-four CDs (6.5%) occurred during follow-up. By multivariable analysis, higher rest heart rate (HR) and to a lesser extent lower peak HR were markers of CD. When added to the multivariable model in place of peak and rest HR, the peak/rest HR ratio was an independent predictor of CD. Peak/rest HR ratio additionally risk-stratified patients within each MPS category. A significant interaction was found between gender and peak systolic blood pressure (SBP), in which there was an increased risk associated with a low peak SBP (<90 mm Hg at end of adenosine infusion) in men but not in women., Conclusions: Patients undergoing adenosine stress MPS with high rest HR and low peak/rest HR ratio have increased risk of CD, as do male patients with a low peak SBP. Assessment of the hemodynamic response to adenosine adds incremental prognostic value to MPS results and enhances identification of patients at risk for CD.

Background: The relationship between the amount of inducible ischemia present on stress myocardial perfusion single photon emission computed tomography (myocardial perfusion stress [MPS]) and the presence of a short-term survival benefit with early revascularization versus medical therapy is not clearly defined., Methods and Results: A total of 10 627 consecutive patients who underwent exercise or adenosine MPS and had no prior myocardial infarction or revascularization were followed up (90.6% complete; mean: 1.9+/-0.6 years). Cardiac death occurred in 146 patients (1.4%). Treatment received within 60 days after MPS defined subgroups undergoing revascularization (671 patients, 2.8% mortality) or medical therapy (MT) (9956 patients, 1.3% mortality; P=0.0004). To adjust for nonrandomization of treatment, a propensity score was developed using logistic regression to model the decision to refer to revascularization. This model (chi2=1822, c index=0.94, P<10-7) identified inducible ischemia and anginal symptoms as the most powerful predictors (83%, 6% of overall chi2) and was incorporated into survival models. On the basis of the Cox proportional hazards model predicting cardiac death (chi2=539, P<0.0001), patients undergoing MT demonstrated a survival advantage over patients undergoing revascularization in the setting of no or mild ischemia, whereas patients undergoing revascularization had an increasing survival benefit over patients undergoing MT when moderate to severe ischemia was present. Furthermore, increasing survival benefit for revascularization over MT was noted in higher risk patients (elderly, adenosine stress, and women, especially those with diabetes)., Conclusions: Revascularization compared with MT had greater survival benefit (absolute and relative) in patients with moderate to large amounts of inducible ischemia. These findings have significant consequences for future approaches to post-single photon emission computed tomography patient management if confirmed by prospective evaluations.

While protease-activated receptors (PARs) play a traditional role in vascular biology, they emerge with surprisingly new assignments in tumor biology. PAR1 expression correlates with the invasion properties of breast carcinoma, whereas human PAR1 antisense reduces their ability to migrate through Matrigel. Part of the molecular mechanism of PAR1 invasion involves the formation of focal contact complexes on PAR1 activation. PAR1 induces angiogenesis in animal models in vivo and exhibits an oncogenic phenotype of enhanced ductal complexity when overexpressed in mouse mammary glands.

Background: The incremental value and cost-effectiveness of stress single photon emission computed tomography (SPECT) is of unclear added value over clinical and exercise treadmill testing data in patients with normal resting ECGs, a patient subset known to be at relatively lower risk., Methods and Results: We identified 3058 consecutive patients who underwent exercise dual isotope SPECT, who on follow-up (mean, 1.6+/-0.5 years; 3.6% lost to follow-up) were found to have 70 hard events (2.3% hard-event rate). Survival analysis used a Cox proportional hazards model, and cost-effectiveness was determined by the cost per hard event identified by strategies with versus without the use of SPECT. In this cohort, a normal study was associated with an exceedingly low hard-event rate (0.4% per year) that increased significantly as a function of the SPECT result. After adjusting for pre-SPECT information, exercise stress SPECT yielded incremental value for the prediction of hard events (chi2 52 to 85, P<0.001) and significantly stratified patients. In patients with intermediate to high likelihood of coronary artery disease after exercise treadmill testing, a cost-effectiveness ratio of $25 134 per hard event identified and a cost of $5417 per reclassification of patient risk were found. Subset analyses revealed similar prognostic, and cost results were present in men, women, and patients with and without prior histories of coronary artery disease., Conclusions: Stress SPECT yields incremental prognostic value and enhanced risk stratification in patients with normal resting ECGs in a cost-effective manner. These findings are opposite those of previous studies examining anatomic end points in this same population and thus, if confirmed, have significant implications for patient management.

Background: In experimental animals, a reduction in renal mass leads to glomerulosclerosis of the residual parenchyma and eventual renal failure. In humans, however, data on the influence of nephrectomy or agenesis on future functional parameters and hypertension are as yet controversial., Objective: To evaluate blood-pressure patterns in children with a solitary kidney as a result of either unilateral renal agenesis (URA) or uninephrectomy (UNX) and correlate them to the increase in size of the remaining kidney., Methods: Twenty-eight children with a solitary kidney were divided into two groups: the URA group, with 18 subjects (13 male and five female, with a mean age of 9.6 +/- 3.9 years), and the UNX group, which contained 10 subjects (four male and six female, with a mean age of 14.0 +/- 2.7 years). The mean time since nephrectomy was 8.7 years. Each study group was assigned an age-, weight- and height-matched control group. In all subjects, ambulatory blood pressure monitoring was performed using the SpaceLabs model no. 90207. Daytime and night-time were defined as 0800-2200 h and 2200-0800 h, respectively. Urinalysis, serum creatinine and urea results were recorded for all the study group participants. The size of the remaining kidney was determined by ultrasound examination. The percentage increase in kidney size, as calculated from standard kidney-length-against-age nomograms was correlated to the percentage deviation from normal blood pressure values., Results: The mean 24 h, daytime and night-time systolic blood pressure (SBP) readings were significantly higher in children in the URA group than in those in the corresponding control group (111.4 +/- 7.5 mmHg versus 106.9 +/- 6.7 mmHg, P < 0.004; 115.2 +/- 3.1 mmHg versus 110.7 +/- 3.4 mmHg, P < 0.004; and 105.2 +/- 2.6 mmHg versus 101.2 +/- 1.8 mmHg, P < 0.002, respectively). Daytime heart rate was found to be significantly reduced (84.4 +/- 5.2 versus 87.8 +/- 8.2 beats/min, P < 0.04). In the UNX group, 24 h mean, systolic and diastolic blood pressure (DBP), as well as heart rate, did not differ from control values. Daytime systolic and diastolic blood pressures were higher than those of the controls (119.8 +/- 4.0 mmHg versus 115.5 +/- 3.8 mmHg, P < 0.02; and 72.7 +/- 4.0 mmHg versus 70.0 +/- 11.0 mmHg, P < 0.02, respectively). Nocturnal dipping was present in all groups and was of equal magnitude in the corresponding control groups. The mean 24 h diastolic blood pressure load was significantly greater in URA patients than in controls (19.6 versus 10.8%, respectively, P < 0.01). In the UNX group, the blood pressure loads were similar to those of controls. The percentage increase in length of the remaining kidney was found to correlate positively with the percentage delta increase in both systolic and diastolic blood pressure., Conclusions: Compared with the age-, height- and weight-matched controls, the children with a solitary kidney caused by URA had an elevated mean 24 h SBP. In contrast, those with UNX had mean 24 h blood pressure values similar to those of their controls. A rise in SBP was, however, seen in both groups during the daytime hours. Thus, the presence of a solitary kidney, for whatever reason, may be pathogenetically linked to a raised blood pressure, and this linkage may be more pronounced in URA. The delta increase in size of the remaining kidney may serve as a prognostic indicator of blood pressure elevation.

Purpose: To describe a corneal co-infection with the fungus Scedosporium apiospermum and Acanthamoeba that result in spontaneous corneal perforation., Methods: A 27-year-old man presented due to severe ocular pain in his left eye caused by a corneal ulcer. The patient was injured 7 days before presentation by metallic thread contaminated by sewage. Corneal scrapping and deep stromal biopsy were obtained and stained for microscopic evaluation with periodic acid-Schiff, Giemsa, and Gomori's methenamine silver stains. Samples were sent for aerobic and anaerobic bacterial and fungal cultures., Results: Corneal biopsy and corneal scrapping showed viable Acanthamoeba cysts in the corneal stroma and S. apiospermum micelle, respectively. The fungal culture was sensitive to ketoconazole, miconazole, econasole, and traconazole. Devastating corneal perforation occurred despite aggressive antifungal and antiamoebic topical and systemic treatment initiated after diagnosis. The corneal button showed a necrotic tissue devoid of inflammatory cells and microorganisms., Conclusion: S. apiospermum and Acanthamoeba may co-infect immune privilege sites, such as the cornea, in immunocompetent hosts. Compromised corneal surface, e.g., after trauma by sewage-contaminated objects, may increase the susceptibility for such devastating coinfection. Prevention may be possible by use of protective eyewear by high-risk individuals. Treatment should be initiated promptly with broad-spectrum antimicrobial agents after ocular injury by sewage-contaminated objects. Repeated corneal cultures and biopsies, if the cultures are negative, are warranted. Corticosteroids should be withheld until the causative agents are identified and targeted treatment is initiated.

Purpose: To describe unilateral deep marginal corneal infiltrates and chronic anterior uveitis in a young patient with sinus histiocytosis and massive lymphadenopathy., Methods: A 20-year-old man with a painless enlargement of his cervical lymph nodes was followed for five years after debulking of these nodes on the right side for right chronic anterior uveitis and deep marginal corneal infiltrates., Results: Histological sections of cervical lymph node confirmed the diagnosis of sinus histiocytosis with the typical emperipolesis. The uveitis partially responded to topical corticosteroid treatment but tended to recur upon its withdrawal. The marginal corneal infiltrates resolved gradually over a period of five years., Conclusions: Marginal corneal infiltrates and uveitis may presumably be associated with sinus histiocytosis. Patients with sinus histiocytosis should also be screened for rare ocular involvement, such as uveitis and corneal infiltrates.

Background: The incremental prognostic value of rest-redistribution (201)Tl compared with stress and rest perfusion abnormalities has not been defined., Methods and Results: We identified 458 patients who underwent rest (201)Tl /stress (exercise or adenosine) (99m)Tc sestamibi single-photon emission computed tomography (SPECT) and had late (18 to 24 hours) (201)Tl imaging, were not revascularized within 60 days of SPECT, and were followed up at >1 year. SPECT images were visually analyzed with the use of a 20-segment model on a scale of 0 to 4. Thirty-seven cardiac deaths (CDs) and 17 nonfatal myocardial infarctions occurred. Univariate Cox proportional hazards analysis showed that the presence of a large amount of rest (201)Tl reversibility (rest-late summed difference score [SDS] of >8) was a significant predictor of CD (chi(2) = 5.77, P = 0.02) and CD or myocardial infarction (chi(2) = 5.3, P = 0.02). The CD rate was 9.3% y(-1) in patients with rest-late SDS of >8 compared with 3.6% y(-1) in patients with a mild/moderate amount of rest reversibility (rest-late SDS 3 to 8) and 3.4% y(-1) in patients with no rest reversibility (rest-late SDS <3) (P = 0.029). Kaplan-Meier survival analysis demonstrated significantly lower cumulative survival rates in patients with rest-late SDS of >8 (P = 0.01). Multivariate Cox proportional hazards analysis demonstrated that the presence of a large amount of resting reversibility was an independent and incremental predictor of CD after adjustment for stress and rest perfusion information. Multivariate logistic regression analysis demonstrated that resting reversibility was not an independent predictor of referral to coronary angiography and revascularization., Conclusions: The identification of a large amount of resting (201)Tl reversibility is an independent predictor of CD over stress and rest perfusion abnormalities.

To evaluate possible predicting factors for endometrial cancer in postmenopausal breast cancer patients with tamoxifen treatment, we compared various clinical features between 12 postmenopausal breast cancer tamoxifen-treated patients with endometrial cancer and a control group of 261 otherwise similar patients without this endometrial pathology. These comparisons were based on a long-term prospective follow-up. Several clinical factors such as longer duration of breast disease, older patient age, lower frequency of chemotherapy administration, and higher frequency of postmenopausal bleeding were found among the tamoxifen-treated patients with endometrial cancers, and were significantly different when compared to the control group. Only eight (66.7%) had postmenopausal bleeding, and a preoperative diagnosis of endometrial cancer was made in only six (50.0%). When considering postmenopausal bleeding as a marker for endometrial cancer in the study patients, sensitivity was 67% and specificity was 98%.

Background: The incremental prognostic value of post-stress left ventricular ejection fraction (EF) and volume over perfusion has not been investigated., Methods and Results: We identified 1680 consecutive patients who underwent rest Tl-201/stress Tc-99m sestamibi gated single photon emission computed tomography (SPECT) and who were followed-up for 569+/-106 days. Receiver-operator characteristics analysis defined an EF<45%, an end-systolic volume (ESV) >70 mL, and an end-diastolic volume >120 mL as optimal thresholds, yielding moderate sensitivity and high specificity in the prediction of cardiac death. Patients with an EF> or = 45% had mortality rates <1%/year, despite severe perfusion abnormalities, whereas patients with an EF<45% had high mortality rates, even with only mild/moderate perfusion abnormalities (9.2%/year; P<0.00001). Similarly, an ESV< or = 70 mL was related to a low cardiac death rate (<1.2%/year), even for patients with severe perfusion abnormalities, whereas patients with an ESV>70 mL and only mild/moderate perfusion abnormalities had high death rates (8.2%/year; P<0.00001). Patients with an EF<45% and an ESV< or = 70 mL had low cardiac death rates (1.7%/year); those with an EF<45% but an ESV>70 mL had high death rates (7.9%/year; P<0.02). Multivariate Cox proportional hazards regression showed that perfusion variables and ESV were independent predictors of overall coronary events, whereas EF and ESV demonstrated incremental prognostic values over prescan and perfusion information in predicting cardiac death and cardiac death or myocardial infarction., Conclusions: Post-stress EF and ESV by gated-SPECT have incremental prognostic values over prescan and perfusion information in predicting cardiac death, and they provide clinically useful risk stratification.

Background: The incremental prognostic value of stress single photon emission computed tomography (SPECT) for the prediction of cardiac death as an individual end point and the implications for risk stratification are undefined., Methods and Results: We identified 5183 consecutive patients who underwent stress/rest SPECT and were followed up for the occurrence of cardiac death or myocardial infarction. Over a mean follow up of 642+/-226 days, 119 cardiac deaths and 158 myocardial infarctions occurred (3.0% cardiac death rate, 2.3% myocardial infarction rate). Patients with normal scans were at low risk (< or =0.5%/y), and rates of both outcomes increased significantly with worsening scan abnormalities. Patients who underwent exercise stress and had mildly abnormal scans had low rates of cardiac death but higher rates of myocardial infarction (0.7%/y versus 2.6%/y; P<.05). After adjustment for prescan information, scan results provided incremental prognostic value toward the prediction of cardiac death. The identification of patients at intermediate risk of nonfatal myocardial infarction and low risk for cardiac death by SPECT may result in significant cost savings when applied to a clinical testing strategy., Conclusions: Myocardial perfusion SPECT yields incremental prognostic information toward the identification of cardiac death. Patients with mildly abnormal scans after exercise stress are at low risk for cardiac death but intermediate risk for nonfatal myocardial infarction and thus may benefit from a noninvasive strategy and may not require invasive management.

Various endometrial lesions were more frequent among asymptomatic postmenopausal breast cancer patients who were treated with tamoxifen for > 48 consecutive months (30.8%) when compared with similar patients who were treated for 6-24 months or for 25-48 months (20.8% and 12.5%, respectively). However, this difference was not statistically significant. There were also no significant differences in the frequency of the various endometrial lesions between these three groups, although endometrial polyps were more frequently found among those treated for > 48 months. Overall, 20.7% of the 164 tamoxifen-treated patients in the study had an endometrial pathology. It can be concluded that there is a slight tendency among those postmenopausal patients who have been treated for > 48 consecutive months to have a higher frequency of endometrial lesions.

Background: We evaluated the incremental prognostic value, the role in risk stratification, and the impact on patient management of myocardial perfusion single-photon emission computed tomography (SPECT) in a population of patients without prior myocardial infarction, catheterization, or revascularization., Methods and Results: We examined 2200 consecutive patients who at the time of their dual-isotope SPECT had not undergone catheterization, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty and had no known history of previous myocardial infarction. Follow-up was performed at a mean of 566 +/- 142 days (97% complete) for hard events (cardiac death and myocardial infarction) and for referral to cardiac catheterization or revascularization within 60 days after nuclear testing. Examination of clinical, exercise, and nuclear models by use of pre-exercise tolerance test (ETT), post-ETT, and nuclear information using a stepwise Cox proportional hazards model and receiver-operating characteristic curve analysis revealed that nuclear testing added incremental prognostic value after inclusion of the most predictive clinical and exercise variables (global chi2 = 12 for clinical variables; 31 for clinical + exercise variables; 169 for nuclear variables; gain in chi2, P < .0001 for all; receiver-operating characteristic areas: 0.66 +/- 0.04 for clinical, 0.73 +/- 0.04 for clinical + exercise variables, 0.87 +/- 0.03 for nuclear variables, P = .03 for gain in area with exercise variables; P < .001 for increase with nuclear variables). Multiple logistic regression analysis revealed that scan information contributed 95% of the information regarding referral to catheterization with further additional information provided by presenting symptoms and exercise-induced ischemia. Referral rates to early catheterization and revascularization paralleled the hard event rates in all scan categories - very low referral rates in patients with normal scans and significant increases in referral rates as a function of worsening scan results. Even after stratification by clinical and exercise variables such as the Duke treadmill score, pre- and post-ETT likelihood of coronary artery disease, presenting symptoms, sex, and age, the nuclear scan results further risk-stratified the patient subgroups, thus demonstrating clinical incremental value., Conclusions: In a patient population with no evidence of previous coronary artery disease at overall low risk (1.8% hard event rate), myocardial perfusion SPECT adds incremental prognostic information and risk-stratifies patients even after clinical and exercise information is known. It appears that referring physicians use this test in an appropriate manner in selecting patients to be referred to catheterization or revascularization.

In order to assess endometrial reaction to the combined treatment of tamoxifen and progestogens in asymptomatic postmenopausal breast cancer patients, we evaluated all such patients by vaginal ultrasonography and by histological examination of endometrial samplings. All patients were initially treated with tamoxifen, and progestogens were then added when metastases became evident. Of 12 patients included in the study, eight (66.66%) showed evidence of strong endometrial stromal decidualization, while three (25%) had decidual reactions in endometrial polyps. Overall, 11 (91.66%) of the patients had decidual reactions, and all were treated with progestogens for > or = 3 consecutive months. One patient, treated with progestogens for 1 months, had an inactive endometrium. All but three had thickened endometria (> 10 mm) on ultrasonographic evaluation. These data show that postmenopausal breast cancer patients who received progestogens for < or = 3 months, and who concomitantly took tamoxifen, had a uniform decidual reaction in all uteri.

We studied the staining pattern of HMB-45 antibody in 29 compound Spitz nevi (SNs) of the epithelioid cell variety, 17 of which showed extension of nevus cells into the reticular dermis (i.e., "deep"); 20 ordinary compound nevi (CNs), all with a deep dermal component; and 22 primary cutaneous invasive malignant melanomas (MMs) (excluding the desmoplastic and spindle cell types), 12 of which extended into Clark level IV or V. Of the 29 SNs, eight (28%) stained negatively; five (17%), including two deep SNs, stained in the epidermal component only; and 16 (55%), including 10 deep SNs, stained in both the epidermal and dermal components. Of the latter 10 deep SNs, eight stained in the upper dermis only, and in the remaining two lesions, a smaller number of positively stained nevus cells were detectable in the lower dermis as well; these two SNs were not atypical histologically. Of the 20 CNs, four (20%) stained negatively, two (10%) stained in the epidermal component only, and 14 (70%) stained in the epidermal component and the upper dermis only. Of the 22 MMs, one stained negatively, and 21 (95%) stained positively in both the epidermal and dermal components. The pattern was variable in frequency of both staining and distribution, but showed no stratification. We conclude that the majority of our positively stained deep compound SNs showed a stratified pattern of HMB-45 staining, similar to ordinary CNs and different from MMs, and that this pattern might be used as an adjunct in the histopathologic differential diagnosis of compound SN and MM, in the proper clinicopathological context.

In this report we describe a modified, sensitive MLR test that appears to detect fine antigenic disparities between HLA-identical siblings confirmed as such by serology and the standard MLR test. In a group of 40 consecutive allogeneic bone marrow transplants, reactivity detected by the modified MLR test correlated with the development of rejection of matched marrow grafts and onset of acute graft vs. host disease (aGVHD). Thus, 13/15 positively reacting patient/donor pairs developed one of these complications (P < 0.001), while only 2/25 developed aGVHD in the negatively reacting group. This test may be useful for selecting the most compatible donor when several potential donors are available.

We have investigated the actions of acetylcholine in the absence and presence of the beta-agonist isoproterenol in cardiac Purkinje fibers. beta-Agonists, like isoproterenol, increase the magnitude of the pacemaker current (If) in cardiac myocytes by shifting its activation voltage more positive on the voltage axis. We find that acetylcholine has no effect on If in the absence of isoproterenol. However, if If is first increased by beta-agonist stimulation, acetylcholine can then return If to control levels. This effect on If is exerted through muscarinic receptors since atropine prevents this action of acetylcholine. Functionally, this action of acetylcholine can guarantee the maintenance of ventricular pacemakers when there is high parasympathetic tone but can also prevent extra ventricular beats when sympathetic and parasympathetic tone are both high.

A 36-year-old woman required laparotomy early in the puerperium after a normal delivery because of the presence of a large abdominal cyst. At laparotomy, a large mucinous cystadenoma was found attached to the root of the ileal mesentery; the ovaries were normal. This is the third case of mesenteric cyst published in association with pregnancy, but the first with a mucinous pattern. Pathologic aspects, possible complications, and treatment are discussed.

In adult strain 13 guinea pigs, two lines of evidence show that there are natural autoreactive thymocytes that can react with myelin basic protein (BP) or the encephalitogenic nonapeptide (EP). An autoradiographic binding assay revealed antigen-specific receptors for 125I-BP on thymocytes. A 3H-thymidine antigen-specific proliferation assay demonstrated that normal thymocytes were activated by EP- or BP-pulsed macrophages. Soluble BP suppressed the activation of thymocytes by macrophage-associated BP. The mode of presentation of BP or EP, whether macrophage-associated or soluble, may be critical in maintaining self-tolerance and preventing an autoimmune attack on the central nervous system.

We have previously described the protective effect of a lipoidal splenic factor (SF) against lethal endotoxemia in mice. Since this protective effect is also accompanied by significant antithrombotic changes, and since burn injury causes thrombosis and consumptive coagulopathy, it was postulated that SF decreased the severity of the burn wound. Swiss white mice were anesthetized with pentobarbital sodium and then burned on a depilated area of the lower back with a 2-cm diameter stainless steel weight at 95 degrees for 10 sec. SF (10 mg/kg) (n = 20) or an equal volume of saline (controls) (n = 13) was administered within 1 hour after thermal injury. Severity of burn injury was assessed by examination of hematoxylin and eosin-stained biopsies obtained 24 hours postburn by a grading scale of 0 (normal) to 4 (severe) depending on the degree of epidermal loss, coagulation necrosis, and inflammatory cell infiltrate. Average degree of burn severity was 1.10 +/- 0.20 for SF recipients and 2.85 +/- 0.27 for the controls (p less than 0.001).