Concussion history associated with increased postural control deficits after subsequent injury.

OBJECTIVE: Postural control deficits have been extensively reported following sport-related concussions. Concussed athletes demonstrate these deficits as early as 24 h post-concussion and may persist for up to six months. Many of these prior studies have included mixed samples with prior injury history that may affect the postural control data. The purpose of this investigation was to evaluate the effect of concussion history on postural control 24-48 h following sport-related concussion in Division I athletes. APPROACH: Twenty-eight Division I athletes (seven athlete controls (CON), seven no history (SRC0), seven with a previous concussion (SRC1), and seven with 2-3 concussions (SRC3) participated in this study. All participants were assessed within 24-48 h post-subsequent SRC and performed three trials of quiet stance in the eyes closed (EC) conditions for 30 s each on a force platform (1000 Hz). The data were analyzed with root mean square (RMS) and mean excursion velocity (MEV) in the anteroposterior (AP) and mediolateral (ML) directions. Two 3 × 2 MANOVAs were run by direction for group comparisons. MAIN RESULTS: SRC2 had significantly greater RMS than CON, SRC0, and SRC1 in the AP direction and ML direction. SRC2 exhibited significantly greater AP and ML MEV than CON, SRC0, and SRC1. SIGNIFICANCE: These results demonstrate that having 2-3 prior concussions negatively affects the postural system after a subsequent head injury. Sports medicine staff should approach the recovery process with caution with those that have a prior history of concussion, due to the negative effects that history of concussion has on postural control strategies.

Immunological differences between primary and metastatic breast cancer.

Background: Little is known about how the immune microenvironment of breast cancer evolves during disease progression. Patients and methods: We compared tumor infiltrating lymphocyte (TIL) count, programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry and mRNA levels of 730 immune-related genes using Nanostring technology in primary and metastatic cancer samples. Results: TIL counts and PD-L1 positivity were significantly lower in metastases. Immune cell metagenes corresponding to CD8, T-helper, T-reg, Cytotoxic T, Dendritic and Mastoid cells, and expression of 13 of 29 immuno-oncology therapeutic targets in clinical development including PD1, PD-L1, and CTLA4 were significantly lower in metastases. There was also coordinated down regulation of chemoattractant ligand/receptor pairs (CCL19/CCR7, CXCL9/CXCR3, IL15/IL15R), interferon regulated genes (STAT1, IRF-1,-4,-7, IFI-27,-35), granzyme/granulysin, MHC class I and immune proteasome (PSMB-8,-9,-10) expression in metastases. Immunotherapy response predictive signatures were also lower. The expression of macrophage markers (CD163, CCL2/CCR2, CSF1/CSFR1, CXCR4/CXCL12), protumorigenic toll-like receptor pathway genes (CD14/TLR-1,-2,-4,-5,-6/MyD88), HLA-E, ecto-nuclease CD73/NT5E and inhibitory complement receptors (CD-59,-55,-46) remained high in metastases and represent potential therapeutic targets. Conclusions: Metastatic breast cancers are immunologically more inert than the corresponding primary tumors but some immune-oncology targets and macrophage and angiogenesis signatures show preserved expression and suggest therapeutic combinations for clinical testing.

Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors.

Background: Based on its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Therefore, identification of tumor types with increased HRD is important for the optimal use of this class of therapeutic agents. HRD levels can be estimated using various mutational signatures from next generation sequencing data and we used this approach to determine whether breast cancer brain metastases show altered levels of HRD scores relative to their corresponding primary tumor. Patients and methods: We used a previously published next generation sequencing dataset of 21 matched primary breast cancer/brain metastasis pairs to derive the various mutational signatures/HRD scores strongly associated with HRD. We also carried out the myChoice HRD analysis on an independent cohort of 17 breast cancer patients with matched primary/brain metastasis pairs. Results: All of the mutational signatures indicative of HRD showed a significant increase in the brain metastases relative to their matched primary tumor in the previously published whole exome sequencing dataset. In the independent validation cohort, the myChoice HRD assay showed an increased level in 87.5% of the brain metastases relative to the primary tumor, with 56% of brain metastases being HRD positive according to the myChoice criteria. Conclusions: The consistent observation that brain metastases of breast cancer tend to have higher HRD measures may raise the possibility that brain metastases may be more sensitive to PARP inhibitor treatment. This observation warrants further investigation to assess whether this increase is common to other metastatic sites as well, and whether clinical trials should adjust their strategy in the application of HRD measures for the prioritization of patients for PARP inhibitor therapy.

Comparison of immunophenotypes of primary breast carcinomas and multiple corresponding distant metastases: an autopsy study of 25 patients.

Phenotypical change in metastatic breast carcinoma has widely been accepted as an inherent biological feature rather than technical fault. We analyzed the immunohistochemical phenotype and histopathological features of 25 primary breast carcinomas and 90 corresponding distant metastases in 23 organs retrospectively. Histological slides were reviewed for prognostic and predictive factors. Overall, metastases were more similar to each other and often differed from the primary tumor. We created a 3-step grouping system based on the localization of metastases. Regions: tumors metastasizing to the abdominal region were likely to lose ER (p = 0.002); we detected loss of PR in metastases to the thorax (p = 0.039) and abdomen (p < 0.001). Organ systems: loss of ER and PR was observed in metastases to the gastrointestinal system (p = 0.026 and p = 0.001, respectively), in the respiratory system only the loss of PR was significant (p = 0.05). Individual organs: the primaries were likely to lose the hormone receptors in liver metastases (ER p = 0.026; PR p = 0.004). In lung metastases only loss of PR was apparent (p = 0.049). We did not observe significant change in HER2 status, regarding Ki67 change occurred only in bone metastases compared to the primary (p = 0.048). 7/25 patients' distant metastases had heterogeneous immunoprofiles. The later the metastasis was discovered the more likely it had a differing IHC profile compared to the primary tumor, patients who had longer OS had a higher chance to develop a discordant metastasis. Immunoprofile of metastases may differ from primary breast cancer and from each other, probably resulting in different response to therapy.

Primary systemic therapy in breast cancer--an update for gynecologic oncologists.

Primary systemic - or neoadjuvant - chemotherapy (PST) is the standard of care in locally advanced breast cancer and it has also become an option in primary operable disease for patients who are candidates for adjuvant systemic chemotherapy. There are several advantages of administering PST: tumor downstaging--improving the chance of breast conserving surgery; in vivo assessment of tumor sensitivity to the chosen therapeutic regimen; and, early control of micrometastatic disease. On the other hand, the rate of tumor response can be used as a surrogate prognostic marker and for rapid screening of efficiency of new drugs. PST initially referred to systemic chemotherapy, but in recent years endocrine--and now multiple targeted therapies--are available in most of the countries within the confines of clinical trials.

Anticoagulation monitoring during vascular surgery: accuracy of the Hemochron low range activated clotting time (ACT-LR).

BACKGROUND: Activated clotting time (ACT) is currently used to monitor high concentrations of heparin anticoagulation. A new instrument, the Hemochron Jr Signature device, has been specifically designed to measure ACT in low-range heparin plasma concentrations (ACT-LR). The purpose of this study was to compare ACT-LR with anti-Xa activity in patients receiving low-dose i.v. heparin during vascular surgery. METHODS: Thirty patients, undergoing arterial vascular surgery, were included in the study and received unfractionated heparin (initial dose 50 u kg(-1)). One hundred and thirty-two pairs of blood samples were simultaneously collected during surgery to determine ACT-LR and anti-Xa activity. Pearson correlation, Kappa test, ROC curve and a specific clinical interpretation of the correlation were performed. RESULTS: ACT-LR ranged from 68 to 380 s, anti-Xa activity from 0 to 1.45 u ml(-1). We observed a strong correlation between anti-Xa activity and ACT-LR (r(2)=0.87; P<0.0001). Accuracy of ACT-LR was good for anti-Xa activity up to 0.6 u ml(-1) (Kappa, 0.94; accuracy, 97%) and 0.8 u ml(-1) (Kappa, 0.79; accuracy, 90%), and poor for anti-Xa activity above 1 u ml(-1) (Kappa, 0.59). A clinical interpretation of the correlation graph found 98% of measured ACT-LR values to be accurate. CONCLUSION: Hemochron Jr Signature provides measurements of ACT-LR, which are accurate for monitoring heparin anticoagulation at anti-Xa activity below 0.8 u ml(-1).

Evaluation of the pharmacokinetic profile and analgesic efficacy of oral morphine after total hip arthroplasty.

BACKGROUND AND OBJECTIVE: Oral morphine may be useful for postoperative pain relief, but few studies have tested its use after in-hospital surgery. METHODS: We evaluated clinical efficacy and the pharmacokinetic parameters of oral morphine after total hip arthroplasty. We recruited 60 patients who had total hip arthroplasty under general anaesthesia. The patients were randomized to receive placebo, 10 mg morphine sulphate or 20 mg morphine sulphate orally every 4 h for 24 h. The oral administration was started 3 h after the morphine-loading dose in the Post Anaesthesia Care Unit and then patients used intravenous morphine patient-controlled analgesia for 24 h. Pain score at rest (scored by patients on a visual analogue scale), sedation, nausea, vomiting and urinary retention were monitored. In 11 additional total hip arthroplasty patients, we determined the pharmacokinetics of morphine and its metabolites after oral administration of 20 mg morphine sulphate every 4 h for 16 h. RESULTS: The amount of morphine administered via patient-controlled analgesia over 24 h was reduced in the 20-mg group compared with that in the placebo group (19.0 +/- 2.7 mg vs. 33.0 +/- 5.5 mg; P = 0.03). No significant morphine-sparing effect was observed in the 10-mg group. Pain scores and side-effects were similar in all groups. The pharmacokinetic study revealed a limited and slow absorption of morphine. CONCLUSION: Despite a limited absorption of oral morphine postoperatively, high doses of oral morphine have a significant analgesic effect after total hip arthroplasty.

Value of bispectral index monitoring during cardiopulmonary resuscitation.

A 67-yr-old man, undergoing pulmonary metastasis resection, experienced a postoperative cardiopulmonary arrest as a result of severe bleeding. Cardiopulmonary resuscitation (CPR) was initiated, then bispectral index (BIS) monitoring was used which reassured the medical team of the adequacy of the resuscitation.

Increased CD8(+) T cells associated with Chlamydia pneumoniae in symptomatic carotid plaque.

BACKGROUND AND PURPOSE: The presence of Chlamydia pneumoniae has been reported in carotid atheroma, but its causative effect in the activation of an atherosclerotic plaque to a prothrombotic state remains unproved. Antigen- mediated activation of T lymphocytes within plaque may represent a mechanism by which infection can result in plaque conversion. The goal of the present study was to characterize the T-cell subtype profile related to the presence of C pneumoniae in patients with symptomatic versus asymptomatic carotid atherosclerosis. METHODS: We studied 14 plaques (5 symptomatic and 9 asymptomatic) positive for C pneumoniae confirmed by polymerase chain reaction and 14 plaques (6 symptomatic and 8 asymptomatic) from age- and stenosis-matched patients negative for C pneumoniae by polymerase chain reaction. T-cell subpopulations of T-helper, T-cytotoxic, and T-memory lymphocytes were identified through indirect enzyme immunohistochemistry with anti-CD3+, anti-CD4+, anti-CD8+, and anti-CD45RO+ monoclonal antibodies, respectively. Results are expressed as the number of positive cells per millimeter squared. RESULTS: In the absence of C pneumoniae, symptomatic plaques had a modest but significant increase of CD3+ (89.6 versus 55.3, P=0.013), CD4+ (57.3 versus 32.7, P=0.01), and CD45RO+ (82.8 versus 43.7, P=0.007), but not CD8+ T cells (28.5 versus 25.5, P=0.245) compared with asymptomatic. However, in the presence of C pneumoniae, there was significant increase of all T-lymphocyte subtypes in symptomatic plaques, including CD8+ (76.8 versus 30.3, P=0.03), CD3+ (192.1 versus 80.4, P=0.004), CD4+ (111.9 versus 37.9, P=0.003), and CD45RO+ (120.2 versus 72.9, P=0.003) cells compared with asymptomatic plaques. With use of 2-way ANOVA, both the presence of chlamydia and symptoms were associated with significantly higher T-cell counts (P<0.005 for all subtypes). CONCLUSIONS: Although all patients with symptomatic disease show a modest elevation in the concentration of intraplaque lymphocytes, a preferential increase in CD8+ class I-restricted T cells is observed in symptomatic carotid plaque positive for C pneumoniae. These data provide incentive to further explore the role of Chlamydia in the modification of immune-mediated mechanisms in active atherosclerotic plaque.

Assessment of systematic use of intraoperative transesophageal echocardiography during cardiac surgery in adults: a prospective study of 203 patients.

OBJECTIVE: To determine the usefulness of systematic intraoperative transesophageal echocardiography in a cardiac surgical unit. DESIGN: Open prospective observational survey. SETTING: University Hospital. PARTICIPANTS: Consecutive adult patients (n = 203) undergoing elective or urgent cardiac operations. MEASUREMENTS AND MAIN RESULTS: Pre-cardiopulmonary bypass imaging yielded unsuspected findings in 26 patients (12.8%) and changed the planned surgery in 22 patients (10.8%). Transesophageal echocardiography modified the diagnosis in eight patients (17%) operated on for mitral valvulopathy, in seven patients (15.5%) with aortic valvular disease, in four patients (4.6%) with coronary artery disease, in five patients operated on for thoracic aorta diseases regardless of their localization (18.5%), and in two miscellaneous cases. On the basis of the data obtained from the transesophageal echocardiography carried out at the end of cardiopulmonary bypass, an immediate reintervention was required in five cases (2.5%). CONCLUSIONS: It is concluded that systematic intraoperative transesophageal echocardiography significantly affected decision making in this cardiac surgical unit. Its routine use in all cardiac surgical patients is recommended.

Effects of propofol and thiopental on coronary blood flow and myocardial performance in an isolated rabbit heart.

BACKGROUND: Some clinical and experimental studies suggest that propofol decreases myocardial contractility and relaxation, whereas others report preserved cardiac function. To investigate the effects of propofol on intrinsic contractility and relaxation, increasing concentrations of propofol were infused in isolated blood-perfused rabbit hearts. Equimolar concentrations of thiopental were infused as a reference group. METHODS: Coronary blood flow, left ventricular contractility and relaxation (as maximal positive and negative left ventricular pressure derivatives [dP/dtmax and dP/dtmin], respectively), and myocardial oxygen consumption (MvO2) were measured during infusion of 10-1,000 microM propofol in blood-perfused hearts. To determine whether the effects of propofol depend on the heart's perfusate, propofol also was infused in isolated buffer-perfused rabbit hearts. In addition, the effects of propofol solvent were investigated in blood- and buffer-perfused preparations. RESULTS: In blood-perfused preparations, coronary blood flow increased with propofol concentrations greater than 30 microM and with 300 and 1,000 microM thiopental. Left ventricular dP/dtmax and dP/dtmin remained unchanged with propofol and decreased with concentrations of thiopental equal to or greater than 30 microM. MvO2 increased with 1,000 microM propofol, whereas coronary venous oxygen tension and content remained unchanged. MvO2 decreased with thiopental associated with a significant increase in coronary venous oxygen tension and content. In six buffer-perfused hearts, basal coronary blood flow was much greater and MvO2 less than in blood-perfused hearts. Left ventricular dP/dtmax and dP/dtmin decreased with 30, 100, and 300 microM propofol. Propofol vehicle did not change coronary blood flow, myocardial performance, or MvO2 of blood- or buffer-perfused hearts. CONCLUSIONS: When compared to a reference drug such as thiopental, propofol did not depress the myocardial performance of blood-perfused rabbit hearts. The type of the perfusate (blood vs. buffer), however, had a major influence on the myocardial effects of propofol.

Activated macrophages depress the contractility of rabbit carotids via an L-arginine/nitric oxide-dependent effector mechanism. Connection with amplified cytokine release.

Inflammatory mediators released by macrophages (M phi) are believed to be involved in septic vasoplegia. To investigate the effect of M phi on vascular reactivity, excised rabbit carotids were exposed intraluminally either to peritoneal rabbit M phi, activated by 18 h of incubation with 1 microgram/ml lipopolysaccharide, or to the supernatants (SPN) derived from them. The contractile responses to phenylephrine (PE, 10(-6) M) were determined by measuring changes in diameter using an ultrasonic microdimensiometer 1, 2, and 3 h after the first control contraction. In control arteries (n = 12), PE-induced contractions were, respectively, 102.9 +/- 3.3%, 95.2 +/- 4.1%, and 89.7 +/- 3.8% of the first contraction, after 1, 2, and 3 h. Activated M phi significantly reduced PE-stimulated contractions after as little as 1 h of carotid exposure (percentage of controls at 1, 2, or 3 h: 74.1 +/- 5.6, 57.2 +/- 5.2, and 34.2 +/- 5.6, n = 10, P less than 0.001). The activated macrophage-derived SPN took longer to diminish carotid contractility than the M phi themselves, and became significant only after 2 h. The greater effect of M phi might be due to cooperation between M phi and vascular cells, as suggested by the amplified interleukin-1 release observed after M phi infusion. The presence of the endothelium partially protected carotid contractility from depression by activated M phi. Extraluminal addition of NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis prevented this depression in arteries with or without endothelium. No products of the oxidative pathway of L-arginine were detected in rabbit activated M phi. These results suggest that activation of this pathway in smooth muscle cells seems to be involved in vascular hypocontractility.

Aortic surgery: effect of clonidine on intraoperative catecholaminergic and circulatory stability.

Twenty-eight patients presenting for aortic surgery were randomly assigned in a double-blind, placebo-controlled protocol to receive placebo (n = 14) or clonidine (4.7 +/- 1.2 micrograms.kg-1 po; n = 14), in addition to flunitrazepam 120 min before induction of anesthesia. Plasma catecholamines (CA) and hemodynamic variables were determined at 7 stages during surgery. In the placebo group, plasma epinephrine (E) and norepinephrine (NE) had risen twofold at skin closure compared to baseline (E: from 109 +/- 51 pg.ml-1 to 294 +/- 161 pg.ml-1; NE: from 658 +/- 226 to 1150 +/- 494 pg.ml-1). Plasma CA were significantly lower in the clonidine group (P less than 0.001 and 0.01 vs placebo for NE and E respectively). In both groups, similar directional changes were observed for the circulatory variables, upon aortic clamping and declamping. In the clonidine group, however, mean arterial pressure was lower at most stages (P less than 0.05 vs placebo); moreover, stroke volume index was greater in the clonidine group (P less than 0.05) upon declamping. This improved stability in the clonidine group was achieved with a halving in the number of anesthetic/circulatory interventions (P less than 0.05 vs placebo). Provided intravascular volume is adequate, clonidine suppresses the increase in plasma catecholamines induced by aortic surgery and improves circulatory stability, with a reduced number of anesthetic, circulatory adjustments.

Anonymity, sex, and weight-preoccupation as variables on the eating disorders inventory with normal college students.

The Eating Disorders Inventory was administered to 595 nonclinical male and female undergraduate college students in response to observations at the counseling center that an increasing number of students were seeking assistance for problems associated with binge eating. The purpose of the study was to identify a group with bulimic characteristics, and since secrecy is associated with bulimia, to compare students' responses when anonymous vs name-identified. Statistical analyses of the eight subscales of the inventory showed no significant differences by anonymity vs identification, but significant differences by sex and by weight-preoccupation existed.