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Background: Endovascular repair of the thoracic aorta has become an increasingly utilized therapy. Although the short-term mortality advantage over open surgery is well documented, late mortality and the impact of presenting pathology on long-term outcomes remain poorly reported.Methods and Results: A database was built from 5 prospective studies and a single institutional series. Rates of perioperative adverse events were calculated, as were midterm death and reintervention rates. Multivariate analysis was performed with the use of logistic regression modeling. Kaplan-Meier survival curves were drawn for midterm outcomes. The database contained 1010 patients: 670 patients with thoracic aortic aneurysm, 195 with chronic type B aortic dissection, and 114 with acute type B aortic dissection. Lower elective mortality was observed in patients with chronic dissections (3%) compared with patients with aneurysms (5%). Multivariate analysis identified age, mode of admission, American Society of Anesthesiologists grade, and pathology as independent predictors of 30-day death (P < 0.05). In the midterm, the all-cause mortality rate was 8, 4.9, and 3.2 deaths per 100 patient-years for thoracic aortic aneurysm, acute type B aortic dissection, and chronic type B aortic dissection, respectively. The rates of aortic-related death were 0.6, 1.2, and 0.4 deaths per 100 patient-years for thoracic aortic aneurysm, acute type B aortic dissection, and chronic type B aortic dissection, respectively.Conclusions: This study indicated that the midterm outcomes of endovascular repair of the thoracic aorta are defined by presenting pathology, associated comorbidities, and mode of admission. Nonaortic mortality is high in the midterm for patients with thoracic aortic aneurysm, and managing modifiable risk factors appears vital. Endovascular repair of the thoracic aorta results in excellent midterm protection from aortic-related mortality, regardless of presenting pathology. [ABSTRACT FROM AUTHOR]

Background: Invasive exercise right heart catheterization is a gold standard in diagnosing heart failure with preserved ejection fraction (HFpEF). Body positions during the test influence hemodynamics. However, the discrepancy in HFpEF diagnosis between exercise testing in supine versus upright position is unknown., Methods: We conducted a 2-center prospective study enrolling patients referred for exercise right heart catheterization for HFpEF. We performed a Supright protocol integrating submaximal supine bicycle ergometry (20 W) followed by maximal upright bicycle ergometry with a breath-by-breath oxygen analyzer. HFpEF hemodynamic criteria specific to testing positions were applied. Patients were considered to have concordant HFpEF if they met criteria in both positions or discordant HFpEF if they met criteria only in the supine position., Results: Of 36 patients who met HFpEF criteria in supine position, 18 (50%) did not meet criteria in upright position (discordant HFpEF). Discordant HFpEF had less atrial fibrillation (0% versus 55%; P <0.001), lower left atrial volume (60±14 versus 77±21 mL; P =0.010), and lower H 2 FPEF score (2.1±1.3 versus 5.1±2.3; P <0.001). In supine position, pulmonary arterial wedge pressure was lower in discordant HFpEF at rest (15±4 versus 19±7 mm Hg; P =0.040). In upright position, pulmonary arterial wedge pressure was lower in discordant HFpEF both at rest (8±4 versus 14±6 mm Hg; P =0.002) and at peak exercise (14±4 versus 27±7 mm Hg; P <0.001). Pulmonary arterial wedge pressure/cardiac output slope was lower in discordant HFpEF (1.6±1.7 versus 3.6±2.9; P <0.001). Maximal workload (46±18 versus 49±24 W; P =0.59) or peak oxygen consumption (11.4±2.8 versus 12.9±3.4 mL/[kg·min]; P =0.15) was similar between groups., Conclusions: Half of patients who met HFpEF criteria in the supine position did not meet the criteria in the upright position. Patients with a discordant HFpEF phenotype had less structural and hemodynamic abnormalities compared with those with concordant HFpEF. A Supright exercise right heart catheterization approach is feasible and merits further investigation to determine the clinical implications of discordant exercise hemodynamic findings in supine and upright positions., Competing Interests: Dr Fudim was supported by the National Institutes of Health, Bodyport, Sardocor, and Doris Duke. He is a consultant/has ownership interesting in Abbott, Alleviant, AxonTherapies, and Daxor. Dr Caravita is a consultant to Alleviant. Dr Senni reports consultancy fees from Novartis, Merck, Vifor Pharma, Abbott, Boehringer Ingelheim, Bioventrix, Servier, and Novo Nordisk. Dr Vachiéry is holder of the Johnson & Johnson Chair for Pulmonary Hypertension at his institution. The other authors report no conflicts.

Background: Despite the Joining Forces initiative and recently published veteran care competencies, nursing students and graduates are often unprepared to care for veterans who have unique service-connected illnesses and injuries., Purpose: The purpose was to evaluate identified content gaps in prelicensure nursing textbooks with the veteran care competencies knowledge, skills, and attitude (KSA) domains., Methods: A secondary qualitative analysis was conducted of veteran content in prelicensure nursing textbooks., Results: The skills and attitude domains of veteran care competencies were poorly addressed in nursing textbooks. Overall, the knowledge domain was adequately covered; however, most had limited connection with veterans and veteran care. Competency-focused recommendations for expanding and enhancing veteran content, KSAs, and teaching strategies are offered., Conclusions: Prelicensure textbooks met the knowledge domain for each veteran competency. Overcoming content gaps needed to achieve requisite skills and attitudes requires interaction with veterans through clinical immersion experiences in various care settings., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Many older adults (65+) present to the Emergency Department (ED) with chest pain, but do not have otherwise clear clinical indication of whether they should be admitted or discharged. This uncertainty leads to decisions that are highly variable-in addition to already being costly-which could have adverse consequences, since older adults are particularly vulnerable from hospitalization., Objective: The objective of this study was to determine whether admitting versus discharging an older adult presenting to the ED with chest pain reduces risk of mortality and readmission., Study Design: Electronic health records were curated from an academic hospital system between January 1, 2014, and September 27, 2018. Average effects of admission on 30-day readmission and mortality were estimated using a new causal inference approach based on a latent-variable model of the admission process. Additional analyses assessed moderators and robustness of estimates., Subjects: Older patients (n=3090) presenting to University of Wisconsin Hospital ED., Measures: Readmission and mortality within 25, 30, and 35 days of discharge from the ED for discharged patients or the hospital for admitted patients RESULTS:: For older chest pain patients, admission is estimated to lower the 30-day risk of readmission by 42.8% (95% confidence interval: 41.0%-44.6%) but increase the 30-day risk of mortality by 0.8% (95% confidence interval: 0.4%-1.2%). Individuals with higher hierarchical conditional category scores or diabetes with complications have both lower 30-day risk of readmission and higher 30-day risk of mortality compared with their counterparts (P≤0.02)., Conclusions: Our findings suggest ED admission may prevent readmission at the cost of increasing mortality risk for older chest pain patients, especially those with comorbidity. Additional studies are needed to validate these findings.

Purpose of Review: Cannabis use for medical purposes has become increasingly common, including as treatment for mental health disorders such as anxiety. Unfortunately, the evidence examining its use in mental health has been slow to evolve, but is emerging. Given the widespread use of cannabis, it is important for both clinicians and those who suffer with anxiety to understand the effects of cannabis on symptoms of anxiety. In this review, we present recent, available evidence from animal models, clinical trials, and survey studies and evaluate the contribution of these studies to the current understanding of the role of cannabis in treating anxiety., Recent Findings: In reviewing recent evidence, we observed significant inconsistencies across findings from preclinical studies. Large-scale surveys suggest that cannabis may be effective in reducing anxiety, however, these results stand in contrast to equivocal findings from clinical trials., Summary: The literature evaluating the efficacy of cannabis in anxiety disorders is in its infancy. The survey data is generally positive. Although, while some animal studies posit cannabis constituents to have anxiolytic effects, others suggest the opposite or null results. Few new clinical trials have been conducted recently, and the extant trials have significant flaws in methodology. Although anecdotal evidence from survey studies, and a small signal found in animal studies and single-dose clinical trials provide early support that cannabis may be effective for alleviating anxiety, ultimately, the current evidence is equivocal. More high-quality clinical trials must be published before sound conclusions regarding the efficacy of cannabis for treating anxiety can be drawn.

Background: We have shown that glucagon-like peptide-1 (GLP-1[7-36] amide) stimulates myocardial glucose uptake in dilated cardiomyopathy (DCM) independent of an insulinotropic effect. The cellular mechanisms of GLP-1-induced myocardial glucose uptake are unknown., Methods and Results: Myocardial substrates and glucoregulatory hormones were measured in conscious, chronically instrumented dogs at control (n=6), DCM (n=9) and DCM after treatment with a 48-hour infusion of GLP-1 (7-36) amide (n=9) or vehicle (n=6). GLP-1 receptors and cellular pathways implicated in myocardial glucose uptake were measured in sarcolemmal membranes harvested from the 4 groups. GLP-1 stimulated myocardial glucose uptake (DCM: 20+/-7 nmol/min/g; DCM+GLP-1: 61+/-12 nmol/min/g; P=0.001) independent of increased plasma insulin levels. The GLP-1 receptors were upregulated in the sarcolemmal membranes (control: 98+/-2 density units; DCM: 256+/-58 density units; P=0.046) and were expressed in their activated (65 kDa) form in DCM. The GLP-1-induced increases in myocardial glucose uptake did not involve adenylyl cyclase or Akt activation but was associated with marked increases in p38alpha MAP kinase activity (DCM+vehicle: 97+/-22 pmol ATP/mg/min; DCM+GLP-1: 170+/-36 pmol ATP/mg/min; P=0.051), induction of nitric oxide synthase 2 (DCM+vehicle: 151+/-13 density units; DCM+GLP-1: 306+/-12 density units; P=0.001), and GLUT-1 translocation (DCM+vehicle: 21+/-3% membrane bound; DCM+GLP-1: 39+/-3% membrane bound; P=0.005). The effects of GLP-1 on myocardial glucose uptake were blocked by pretreatment with the p38alpha MAP kinase inhibitor or the nonspecific nitric oxide synthase inhibitor nitro-l-arginine., Conclusions: GLP-1 stimulates myocardial glucose uptake through a non-Akt-1-dependent mechanism by activating cellular pathways that have been identified in mediating chronic hibernation and the late phase of ischemic preconditioning.

Purpose of Review: Myocardial glucose uptake and metabolism are essential for maintaining myocardial energetics under circumstances of stress, such as myocardial ischemia or hypertrophy. We will discuss new information as to the mechanisms of altered glucose uptake as a consequence of impaired insulin action as well as emerging alternative cellular signaling mechanisms that lead to increased noninsulin dependent glucose uptake and metabolism. We will also review provocative clinical data that demonstrate the limitations of tight glycemic control as a mechanism to confer myocardial protection in patients with type 2 diabetes and discuss potential mechanistic explanations for the paradoxical results., Recent Findings: New studies have shed important light on the distal mechanisms involved in insulin-mediated Glut 4 translocation. There are also important new insights into the role of AMP kinase and hypoxia-induced factor-1alpha in mediating myocardial glucose uptake while conferring cardioprotection., Summary: The importance of understanding the link between glucose uptake and cardioprotection is underscored by recent clinical trials that have failed to demonstrate a benefit between tight glycemic control and reduced cardiovascular events. These data underscore the need for additional agents that affect both outcomes.

Background: Factors thought to influence the decision for limb salvage include injury severity, physiologic reserve of the patient, and characteristics of the patient and their support system., Methods: Eligible patients were between the ages of 16 and 69 with Gustilo type IIIB and IIIC tibial fractures, dysvascular limbs resulting from trauma, type IIIB ankle fractures, or severe open midfoot or hindfoot injuries. Data collected at enrollment relevant to the decision-making process included injury characteristics and its treatment, and the nature and severity of other injuries. Logistic regression and stepwise modeling were used to determine the effect of each covariate on the variable salvage/ amputation., Results: Of 527 patients included in the analysis, 408 left the hospital with a salvaged limb. Of the 119 amputations performed, 55 were immediate and 64 were delayed. The multivariate analysis confirmed the bivariate analysis: all injury characteristics remained significant predictors of limb status with the exception of bone loss; and soft tissue injury and absence of plantar sensation were the most important factors in accounting for model validity., Conclusion: Soft tissue injury severity has the greatest impact on decision making regarding limb salvage versus amputation.

Objective: To determine if low level, persistent, HIV-1 replication within specific immune cells contributes to HIV-1-specific immune responsiveness., Design: We analyzed 59 HIV-1-infected subjects on stable highly active antiretroviral therapy (HAART) therapy (not including zidovudine) with suppressed plasma viremia (< 400 copies/ml) for phenotypic and lymphoproliferative correlates of immune function., Methods: Peripheral blood mononuclear cells were collected for immunophenotyping, lymphoproliferative assays, and simultaneous immunophenotyping/ultrasensitive in situ hybridization. Plasma was collected for plasma viral load as determined by the Ultra Sensitive Roche Amplicor RT-PCR. Descriptive statistics (mean and SD, median, first and third quartiles) were determined for all variables in two groups defined as having persistent viral replication present or absent. The two-sided Wilcoxon test (continuity correction, 0.5) was used to compare lymphocyte phenotypes, lymphoproliferative assay responses, intracellular gag-pol mRNA, lowest CD4 counts and CD4% of these two groups., Results: HIV-1 replication in CD4, CD45RO memory T lymphocytes persists in spite of undetectable plasma viral load. Patients (n = 24) with persistent intracellular expression of HIV-1 mRNA (> 0.3%) showed significant in vitro proliferative responses to HIV-1 p24 (stimulation index > or = 10) compared to patients (n = 35) without persistent intracellular replication. The group with persistent HIV-1 replication in cells showed no significant response to the recall antigen tetanus toxoid but a trend toward higher responses to pathogen antigens. There were no differences between the groups in the prevalence of AIDS or occurrences of opportunistic infections; however, the high viral persistence group was more HAART experienced (P < 0.05)., Conclusions: These results suggest that HIV-1-specific immune responses correlate with evidence of ongoing HIV-1 replication.

Objective: To develop a model to predict transmission of HIV-1 from men to women., Design: HIV-1 in seminal plasma, and endocervical CCR5 receptors were correlated with epidemiological studies of HIV-1 transmission to develop a probabilistic model., Settings: Semen samples were collected from patient subjects in Seattle Washington, Chapel Hill, North Carolina, and St. Gallen, Switzerland. Endocervical biopsy specimens were obtained from women in Chicago, Illinois., Participants: Eighty-six men (not receiving antiretroviral therapy) in whom CD4 cell count and semen volume were available, and 24 women in whom the number of endocervical CCR5 receptors were determined., Main Outcome Measures: Prediction of transmission of HIV-1 from men to women per episode of vaginal intercourse based on the absolute burden of HIV (volume x HIV RNA copies/ml seminal plasma)., Results: The model suggests efficient heterosexual transmission of HIV-1 when semen viral burden is high. When semen contains 100 000 copies of non-syncytium-inducing (NSI) HIV RNA the probability of HIV-1 transmission is 1 per 100 episodes of intercourse; conversely, with 1000 copies NSI HIV RNA in semen, transmission probability is 3 per 10 000 episodes of intercourse., Conclusions: This model links biological and epidemiological data related to heterosexual HIV-1 transmission. The model can be used to estimate transmission of HIV from men with high semen viral burden from inflammation, or reduced burden after antiretroviral therapy. The results offer a biological explanation for the magnitude of the HIV epidemic in places where earlier studies have shown men have high semen viral burden, such as in sub-Saharan Africa. The model can be used to develop and test HIV-1 prevention strategies.

Lower extremity amputations are occasionally required after high-voltage electric and deep thermal burns. The extensive loss of skin and soft tissue after these injuries may make it difficult to fashion below-knee amputation that will readily tolerate a prosthesis. We have found an osteocutaneous pedicle fillet flap of the foot useful in the salvage of below-knee amputation after severe burn injury. Three patients have undergone this procedure after burn injury, 1 with burn secondary to high-voltage electric injury and 2 after deep thermal burns. All became ambulatory with artificial prostheses. There were no postoperative infections and no need for further revisions. The osteocutaneous pedicle fillet flap of the foot has proven to be a reliable form of below-knee stump coverage in patients with extensive soft tissue necrosis after burn injury.

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder that may result from different mutations in the apolipoprotein B (apoB) gene or chromosome 2. However, linkage of FHBL to the apoB gene was ruled out in 2 kindreds reported to date, and the genetic and metabolic bases for FHBL remain unknown. One of the reported kindreds is our 40-member F kindred, in which we found linkage of FHBL to a novel susceptibility region on chromosome 3p21. 1-2. In addition to having low apoB levels, some, but not all, of the affected subjects in the F kindred also had low levels of high density lipoprotein (HDL) cholesterol and apoA-I. Our aim was to define the metabolic bases of the disorder in the F kindred. Therefore, we studied the in vivo kinetics of apoB and apoA-I and very low density lipoprotein (VLDL) triglycerides in 4 affected subjects and 5 normolipidemic relatives. Deuterated leucine and deuterated glycerol were used to label the apolipoproteins and triglycerides, respectively. Compartmental modeling was used to obtain the kinetic parameters. Affected subjects had (1) normal fractional catabolic rates (FCRs) for VLDL apoB, (2) increased FCRs for low density lipoprotein (LDL) apoB (0.050+/-0.009 versus 0. 030+/-0.006 pools per hour for normal subjects, P=0.005), and (3) decreased production rates of VLDL apoB (11.4+/-1.7 versus 25.6+/-4. 9 mg. kg(-1). d(-1), P=0.003), LDL apoB (7.8+/-1.3 versus 12.7+/-3.7 mg. kg(-1). d(-1), P=0.04), and VLDL triglycerides (8.2+/-4.5 versus 19.6+/-10.8 58 micromol. kg(-1). h(-1), P=0.09). These data differ from those obtained in previously studied FHBL heterozygotes bearing apoB-2 and apoB-9, 2 very short truncations of apoB. Low HDL cholesterol and apoA-I levels were caused by higher apoA-I FCRs (0. 035+/-0.005 versus 0.018+/-0.005 pools per hour in controls, P<0.01) without significant decrease in apoA-I production rates (18.7+/-2.7 versus 22.8+/-5.6 mg. kg(-1). d(-1)). In conclusion, decreased secretion of apoB-containing lipoproteins and hypercatabolism of LDL account for low apoB and cholesterol levels in this novel form of FHBL.

Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder characterized by low levels of apolipoprotein (apo) B and low-density lipoprotein (LDL) cholesterol. Decreased production rates of apoB have been demonstrated in vivo in FHBL heterozygotes. In the present study, we wished to investigate whether the transport of triglycerides was similarly affected in these subjects. Therefore, we studied the in vivo kinetics of very-low-density lipoprotein (VLDL) triglycerides and VLDL apoB-100 simultaneously in 7 FHBL heterozygotes from 2 well-characterized kindreds and 7 healthy normolipidemic subjects. In both kindreds, hypobetalipoproteinemia is caused by mutations in the 5' portion of the apoB gene specifying short truncations of apoB undetectable in plasma. A bolus injection of deuterated palmitate and a primed constant infusion of deuterated leucine were given simultaneously, and their incorporation into VLDL triglycerides and VLDL apoB, respectively, were determined by gas chromatography-mass spectrometry. Kinetic parameters were calculated by using compartmental modeling. VLDL apoB fractional catabolic rates (FCRs) in FHBL heterozygotes and controls were similar (11. 6+/-3.9 and 10.9+/-2.4 pools per day, respectively, P=0.72). On the other hand, FHBL heterozygotes had a 75% decrease in VLDL apoB production rates compared with normal subjects (5.8+/-1.8 versus 23.4+/-7.1 mg/kg per day, P<0.001). The decreased production rates of VLDL apoB accounts for the very low concentrations of plasma apoB found in heterozygotes from these kindreds (24% of normal). Mean VLDL triglyceride FCRs in FHBL subjects and controls were not significantly different (1.06+/-0.74 versus 0.89+/-0.50 pools per hour, respectively, P=0.61). There was a good correlation between VLDL apoB FCR and VLDL triglyceride FCR in the 2 groups (r=0.84, P<0. 001). VLDL triglyceride production rates were decreased by 60% in FHBL heterozygotes compared with controls (9.3+/-6.0 versus 23.0+/-9. 6 micromol/kg per hour, P=0.008). Thus, the hepatic secretion of VLDL triglycerides is reduced in FHBL heterozygotes but to a lesser extent than the decrease in apoB-100 secretion. This is probably achieved by the secretion of VLDL particles enriched with triglycerides.

Objectives: Dendritic cells (DC) are potential first target cells in sexually transmitted HIV-1 infection. They are also considered to be central in the activation of naive T cells, which thereupon can become permissive for HIV-1. In addition, activated DC express effector molecules, which likely contribute to the direction of T helper (Th1/Th2)-specific immune responses., Methods: The capacity of cytokine and chemokine production in in vitro DC infected and uninfected with HIV-1 was assessed by enzyme-linked immunosorbent assay (ELISA) and by in situ immunocytochemical detection at the single cell level. Fluorescent in situ 5'-nuclease assay (FISNA) was used for quantitative evaluation of HIV-1 gag-positive cells., Results: Macrophage-tropic HIV-1 effectively infected 20-40% of in vitro cultured DC. However, this activity alone did not induce detectable cytokine or chemokine protein expression in DC. In contrast, lipopolysaccharide (LPS) stimulation of these HIV-1-infected DC resulted in a significantly increased level of cells producing tumour necrosis factor alpha (TNF-alpha) and interleukin (IL) 1beta but reduced frequencies of cells producing IL-1 receptor antagonist (IL-1ra) compared with the LPS-stimulated but uninfected DC cultures (P < 0.05). Furthermore, an extensive production of the beta-chemokines [RANTES, macrophage inflammatory proteins (MIP) 1alpha and 1beta] was detected in DC in response to both LPS and HIV-1 plus LPS., Conclusions: These findings indicate that HIV-1 infected DC may have an increased proinflammatory activity. Elevated production of cytokines such as TNF-alpha and IL-1beta and reduced IL-1ra may contribute to enhanced replication of HIV-1 in bystander T cells. Gram-negative bacterial infection and gut-associated bacterial translocation in HIV-1-infected individuals may also result in endotoxin-mediated reactivation of HIV-1 in bystander CD4 CD45RO T cells caused by the increased production of proinflammatory cytokines in DC.

Objective: We examined the effect of an HIV-1-specific immune-based therapy on cell-associated HIV-1 DNA and RNA., Design: Five HIV-1-infected subjects receiving HIV-1 immunogen plus HAART were compared with three HIV-1-infected subjects who received incomplete Freund's adjuvant (IFA) plus HAART., Methods: Cell-associated HIV-1 RNA or DNA in lymphocytes and monocytes was determined using a dual immunophenotyping/in situ hybridization assay with or without in situ PCR amplification., Results: Cell-associated HIV-1 RNA in CD4 cells correlated with plasma RNA overall. CD4, HIV-1 gag-pol messenger (m)RNA+ cells decreased in the immunogen plus HAART group compared with the IFA plus HAART group. Decreases in HIV-1 DNA+ CD4 cells were observed in the immunogen plus HAART compared with the IFA plus HAART group. Decreases in HIV-1 gag-pol mRNA+ monocytes were observed in the immunogen plus HAART group compared with the IFA plus HAART group. Consistent with the findings in CD4 cells, decreases in HIV-1 DNA+ monocytes were observed in the immunogen plus HAART group compared with the IFA plus HAART group., Conclusions: These preliminary observations support the rationale for examining the combination of immune-based therapies and antiretroviral drugs for effective HIV-1 control.

Background: Residual HIV-1-infected cells are poorly eliminated from lymphoid tissue (LT) reservoirs by effector cytotoxic T lymphocytes (eCTL) despite antiretroviral therapy. Perforin and granzyme A (grA) constitute major effector molecules within eCTL granules that induce apoptosis and lysis of virally infected cells., Objective: Expression of perforin and grA was studied at the single cell level in LT and blood from 16 patients infected with HIV-1 (stage A1-C) who were not taking antiretroviral therapy., Method: Immunohistochemical analysis by in situ imaging of cells from blood and LT., Results: Quantitative in situ imaging showed that perforin-expressing CD8 T cells comprised 0.3-1.5% of total cells within the LT from recent HIV-1 seroconverters, while grA was found in 2.1-7.2% of total cells. However, despite high-level grA upregulation (1.5-4.5% of total cells) compared with that in non-infected individuals (0.4-0.9%), perforin expression remained low (< 0.1% of total cells) (P < 0.02) in LT from patients with chronic HIV-1 infection (stage A2-C). This contrasted with findings in peripheral blood mononuclear cells (PBMC) from the same HIV-1 infected cohort where perforin was detected in 13-31% of all PBMC, which was 10- to 100-fold higher than in lymphoid tissue (P < 0.001); grA was found in 14-32% of total PBMC. Two-colour staining showed that granular expression of perforin and grA was restricted to CD8 T cells in over 90% of total cells in both LT and blood., Conclusions: These findings indicate that cytotoxic perforin expression is impaired at local sites of HIV replication within lymphoid tissue. Since perforin is required together with grA for granule-mediated cytolysis, the low perforin expression in the LT may limit the ability of eCTL to eliminate HIV-1 infected cells in lymphoid tissue.

Alcohol fed to rabbits in a liquid formula at 30% of calories increased plasma cholesterol by 36% in the absence of dietary cholesterol and by 40% in the presence of a 0.5% cholesterol diet. The increase was caused almost entirely by VLDL, IDL, and LDL. Cholesterol feeding decreased the fractional catabolic rate for VLDL and LDL apoprotein by 80% and 57%, respectively, and increased the production rate of VLDL and LDL apoprotein by 75% and 15%, respectively. Alcohol feeding had no effect on VLDL apoprotein production but increased LDL production rate by 55%. The efficiency of intestinal cholesterol absorption was increased by alcohol. In the presence of dietary cholesterol, percent cholesterol absorption rose from 34.4+/-2.6% to 44.9+/-2.5% and in the absence of dietary cholesterol, from 84.3+/-1.4% to 88.9+/-1.0%. Increased cholesterol absorption and increased LDL production rate may be important mechanisms for exacerbation by alcohol of hypercholesterolemia in the cholesterol-fed rabbit model.

Objective: To evaluate immune reconstitution within HIV-infected lymphoid tissue during highly active antiretroviral therapy (HAART)., Design and Methods: In situ cellular responses were studied in sequential tonsillar biopsies in three asymptomatic HIV-infected (CD4 cells greater than 400 x 10(6)/l) antiretroviral treatment-naive volunteers enrolled in a clinical trial to determine the early effect of HAART. Computerized image analysis was used to study immunohistochemically stained sequential tonsil sections for the patterns of local cytokine production, chemokine receptor expression and cellular distribution. Replicate quantitative assessments of samples before and after 4 weeks of therapy were used for the evaluation of drug effects and compared with four uninfected controls. Tonsillar HIV proviral-DNA was determined by fluorescent in situ 5'-nuclease assay., Results: HIV-infected tonsil tissue was characterized by extensive pro-inflammatory and type 1 cytokine expression. A five- to 15-fold elevation of interleukin (IL)-1 alpha, IL-12, IL-2 and interferon (IFN)-gamma protein expression was found compared with controls, and each encompassed a mean of at least 4.5% of the tissue compartment. This was reduced by 20-90% in all individuals after 4 weeks of HAART. In contrast, type 2 cytokine expression (IL-4, IL-10), plus tumour necrosis factor (TNF)-alpha, remained low throughout the study. HAART reduced, by 40%, the expression of HIV co-receptors, CCR5 and CXCR4, which initially were elevated four to six times over the control values. In addition, the myelomonocytic inflammatory proteins, CD68 and calprotectin, diminished by 26-83% after therapy. The HIV RNA was reduced to undetectable levels in plasma by HAART. However, a large pool of tonsil cells (2-7%), remained HIV DNA positive after 4 weeks of therapy., Conclusions: Although immune activation may be the direct consequence of HIV replication, HAART-associated reconstitution begins with a reduction in inflammatory cytokine production which precedes the elimination of local proviral reservoirs.

Objective: To determine if long-term (7 days) infusion of insulin can ameliorate altered protein kinetics in skeletal muscle of severely burned patients and to investigate the hypothesis that changes in protein kinetics during insulin infusion are associated with an increased rate of transmembrane amino acid transport from plasma into the intracellular free amino acid pool., Summary Background Data: In critically ill patients, vigorous nutritional support alone may often fail to entirely curtail muscle catabolism; insulin stimulates muscle protein synthesis in normal volunteers., Methods: Nine patients with severe burns were studied once during enteral feeding alone (control period), and once after 7 days of high-dose insulin. The order of treatment with insulin was randomized. Data were derived from a model based on a primed-continuous infusion of L-[15N]phenylalanine, sampling of blood from the femoral artery and vein, and biopsies of the vastus lateralis muscle., Results: Net leg muscle protein balance was significantly (p < 0.05) negative during the control period. Exogenous insulin eliminated this negative balance by stimulating protein synthesis approximately 350% (p < 0.01). This was made possible in part by a sixfold increase in the inward transport of amino acids from blood (p < 0.01). There was also a significant increase in leg muscle protein breakdown. The new rates of synthesis, breakdown, and inward transport during insulin were in balance, such that there was no difference in the intracellular phenylalanine concentration from the control period. The fractional synthetic rate of protein in the wound was also stimulated by insulin by approximately 50%, but the response was variable and did not reach significance., Conclusions: Exogenous insulin may be useful in promoting muscle protein synthesis in severely catabolic patients.

Ninety-two-kilodalton type IV collagenase (MMP-9) is present in aortic aneurysms and may be important to the pathogenesis of this disease. Alteration in expression of MMP-9 or its inhibitor, the tissue inhibitor of metalloproteinase type 1 (TIMP-1), could increase degradation of extracellular matrix and lead to aneurysm formation. The purpose of this study was (1) to measure tissue levels of MMP-9 and TIMP-1 mRNA in aneurysmal (AAA), atherosclerotic occlusive (AOD), and normal (NL) human infrarenal aorta; (2) to test for their expression by cultured AAA and NL vascular smooth muscle cells (VSMCs); and (3) to locate in situ the cells responsible for mRNA production within AAA, AOD, and NL aortic wall. Total RNA extracted from AAA (n = 8), AOD (n = 8), and NL (n = 7) tissue was subjected to Northern analysis. Signals for MMP-9 and TIMP-1 were normalized to alpha-tubulin. Mean values +/- SEM were compared by ANOVA. NL and AAA VSMCs were cultured, passaged, and grown to confluence before RNA extraction and Northern analysis. In situ hybridization with digoxigenin-labeled RNA probes localized cells responsible for MMP-9 and TIMP-1 mRNA expression within sections of AAA (n = 5), AOD (n = 2), and NL (n = 2) aorta. MMP-9 mRNA levels were significantly greater in AAA (0.855 +/- 0.180) than NL (0.046 +/- 0.23) (P < .02), but differences between AOD (0.406 +/- 0.196) and AAA or AOD and NL were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: The purpose of the study was to define the outcome following retrograde nailing of the femoral shaft., Design: Retrospective clinical study., Materials and Methods: Seventeen retrograde intramedullary nailings of the femur were performed in 16 patients for management of complex orthopedic trauma. Thirteen patients were followed for an average of 22.8 months (range from 9 to 72 months). The indications for retrograde nailing were an ipsilateral femoral neck and shaft fracture in eight cases, knee disarticulation or long above knee amputation associated with a femoral shaft fracture in five cases, traumatic arthrotomy of the knee ipsilateral to a shaft fracture in two cases, one case of a shaft fracture ipsilateral to an acetabular fracture that required an extensile exposure, and one case of a femoral nonunion with a knee contracture. In fourteen of the seventeen cases the femur fracture was open including two grade III C injuries., Measurements and Main Results: Two patients died in the early postoperative period due to the severity of the initial trauma and one patient was lost to follow-up. The results were generally poor and postoperative complications were common. There were five nonunions in the group, one which required revision to an above knee amputation for an infected nonunion following a grade III open femur fracture. The average range of motion of the knee was 3 degrees to 110 degrees, and two patients had an extensor lag of 5 degrees or more. Six patients underwent removal of hardware through a second arthrotomy with no significant loss of knee function related to the second procedure., Conclusions: The authors concluded that the high complication rate and poor results were related to the severity of the initial injury. An intercondylar starting can be used in properly selected cases with minimal effect on knee function.

Background: The decreased incidence of coronary artery disease observed in postmenopausal women given estrogen (E2) replacement demonstrates an atheroprotective effect of E2 that is generally believed to be mediated by indirect, E2-induced changes in cardiovascular risk factor profiles. We hypothesized that the atheroprotective effect of E2 may be in part mediated by a direct effect of E2 on vascular smooth muscle cells (VSMCs). Therefore, a series of experiments was performed to determine whether human VSMCs contain a competent E2 receptor, a ligand-activated transcription factor known to mediate E2-induced effects in nonvascular cells., Methods and Results: Ribonuclease protection assays, with a probe derived from the human E2 receptor, were used to demonstrate E2-receptor mRNA in human saphenous vein VSMCs. To show that VSMCs contain E2-receptor protein as well as message, immunoblotting and immunofluorescence studies with a monoclonal anti-E2-receptor antibody were performed, and E2-receptor protein was detected by both methods. Transient transfection assays using a specific E2-responsive reporter system were used next to determine whether the VSMC E2 receptor is capable of E2-induced transcriptional transactivation. Initial studies using mammary artery-derived VSMCs resulted in a 2.4-fold increase in reporter activity in response to 10(-7) mol/L E2. Subsequent studies using saphenous vein VSMCs demonstrated increasing levels of reporter activation as the concentration of E2 was increased from 10(-9) mol/L (1.3-fold increase; SEM, 0.07; P = .05, n = 3) to 10(-7) mol/L (1.6-fold increase; SEM, 0.04; P = .002, n = 6). The specificity of the E2-induced transactivation of the reporter gene was shown by dose-dependent inhibition of transactivation by the pure E2 antagonist ICI 164,384 and by enhancement of the transactivation by simultaneous overexpression of the E2 receptor., Conclusions: We have demonstrated for the first time that human VSMCs express E2-receptor mRNA and protein and that the E2 receptor in VSMCs is capable of estrogen-dependent gene activation. These data suggest a mechanism by which estrogen may directly alter VSMC function.

A study of cranial vault lengthening using a custom expandable fixation-distraction (craniotatic) appliance was performed in the young-adult rabbit model. Ten 24-week-old rabbits underwent circumferential suturectomy plus expansion (expanded group), 10 underwent circumferential suturectomy without expansion (sham control group), and 10 served as normal controls. The appliance was lengthened at a rate of 2.5 mm per week for 5 weeks. Serial lateral cephalometry, comparative dry-skull anthropometric measurements, and histologic examinations were performed. The expanded group demonstrated a significantly longer skull, cranial vault, anterior cranial base, posterior face, and orbit as compared with the control groups (p less than 0.05). Callus bone filled the distracted suturectomy and united the frontofacial complex to the posterior cranium. In conclusion, skull lengthening by distraction osteogenesis is possible in the rabbit model and offers a new technique for future investigation in the treatment of coronal synostosis.

Pulmonary tumor embolism is a common finding at autopsy but is generally perceived as a difficult diagnosis to make ante mortem. After a retrospective review of 164 reported cases of pulmonary tumor embolism, we identified a typical profile of clinical, laboratory, and imaging features that may permit confident clinical diagnosis in most patients with this condition. The clinical features include a documented or suspected underlying malignancy, acute to subacute onset of dyspnea, and signs of cor pulmonale. Supportive laboratory features are hypoxemia or increased alveolar-arterial oxygen gradient, and invasive or noninvasive evidence of pulmonary artery hypertension. Typical imaging findings are normal chest radiographs; multiple, subsegmental, peripheral perfusion defects on ventilation-perfusion lung scans; and delayed filling with or without subsegmental filling defects but without a thrombus on pulmonary angiogram. Radiolabeled monoclonal antibody imaging and pulmonary microvascular cytology sampling techniques are promising diagnostic tests for early diagnosis of pulmonary tumor embolism.

Plasma fibrinogen is known to be elevated in pregnancy and with certain disease processes. This report establishes norms at 2-week intervals throughout pregnancy. A calculated slope by trimester reveals a more rapid elevation during the first trimester. A thrombin clottable method that is rapid and accurate is evaluated.

Uterine tumors resembling ovarian sex-cord tumors are of uncertain histogenesis. We report such a neoplasm in which epithelial features observed by light microscopy were confirmed by electron microscopy and in which foam cells resembling those present in the stroma of hyperplastic endometria and in carcinoma represented a conspicuous intrinsic component. The lesion is interpreted as arising from endometrial stroma or multipotential uterine mesenchyme that has differentiated toward endometrial stroma and epithelium. The relationship of these uterine tumors to ovarian sex-cord stromal tumors and plexiform tumorlets is discussed.

It has been hypothesized that myotonic dystrophy is caused by a generalized disorder of membrane aminergic and petidergic receptors. A single uncontrolled study has suggested that the affective symptomatology and muscular disability of this disorder might be improved by tricyclic antidepressant treatment. In the present study, 12 adult patients with myotonic dystrophy (age range 18-55 yr) were treated with imipramine and placebo in a double-blind crossover paradigm. Both grip and percussion myotonia were significantly improved by imipramine treatment independent of change in depressive symptomatology. Serum drug levels revealed nonlinear elimination kinetics for imipramine in this patient population.