Inflammation and altered metabolism impede efficacy of functional electrical stimulation in critically ill patients.

BACKGROUND: Critically ill patients suffer from acute muscle wasting, which is associated with significant physical functional impairment. We describe data from nested muscle biopsy studies from two trials of functional electrical stimulation (FES) that did not shown improvements in physical function. METHODS: Primary cohort: single-centre randomized controlled trial. Additional healthy volunteer data from patients undergoing elective hip arthroplasty. Validation cohort: Four-centre randomized controlled trial. INTERVENTION: FES cycling for 60-90min/day. ANALYSES: Skeletal muscle mRNA expression of 223 genes underwent hierarchal clustering for targeted analysis and validation. RESULTS: Positively enriched pathways between healthy volunteers and ICU participants were "stress response", "response to stimuli" and "protein metabolism", in keeping with published data. Positively enriched pathways between admission and day 7 ICU participants were "FOXO-mediated transcription" (admission = 0.48 ± 0.94, day 7 = - 0.47 ± 1.04 mean log2 fold change; P = 0.042), "Fatty acid metabolism" (admission = 0.50 ± 0.67, day 7 = 0.07 ± 1.65 mean log2 fold change; P = 0.042) and "Interleukin-1 processing" (admission = 0.88 ± 0.50, day 7 = 0.97 ± 0.76 mean log2 fold change; P = 0.054). Muscle mRNA expression of UCP3 (P = 0.030) and DGKD (P = 0.040) decreased in both cohorts with no between group differences. Changes in IL-18 were not observed in the validation cohort (P = 0.268). Targeted analyses related to intramuscular mitochondrial substrate oxidation, fatty acid oxidation and intramuscular inflammation showed PPARγ-C1α; (P < 0.001), SLC25A20 (P = 0.017) and UCP3 (P < 0.001) decreased between admission and day 7 in both arms. LPIN-1 (P < 0.001) and SPT1 (P = 0.044) decreased between admission and day 7. IL-18 (P = 0.011) and TNFRSF12A (P = 0.009) increased in both arms between admission and day 7. IL-1ß (P = 0.007), its receptor IL-1R1 (P = 0.005) and IL-6R (P = 0.001) decreased in both arms between admission and day 7. No between group differences were seen in any of these (all p > 0.05). CONCLUSIONS: Intramuscular inflammation and altered substrate utilization are persistent in skeletal muscle during first week of critical illness and are not improved by the application of Functional Electrical Stimulation-assisted exercise. Future trials of exercise to prevent muscle wasting and physical impairment are unlikely to be successful unless these processes are addressed by other means than exercise alone.

Associations between nutritional energy delivery, bioimpedance spectroscopy and functional outcomes in survivors of critical illness.

BACKGROUND: Patients who survive critical illness frequently develop muscle weakness that can impact on quality of life; nutrition is potentially a modifiable risk factor. The present study aimed to explore the associations between cumulative energy deficits (using indirect calorimetry and estimated requirements), nutritional and functional outcomes. METHODS: A prospective single-centre observational study of 60 intensive care unit (ICU) patients, who were mechanically ventilated for at least 48 h, was conducted. Cumulative energy deficit was determined from artificial nutrition delivery compared to targets. Measurements included: (i) at recruitment and ICU discharge, weight, fat-free mass (bioimpedance spectroscopy) and malnutrition (Subjective Global Assessment score B/C); (ii) at awakening and ICU discharge, physical function (Physical Function in Intensive Care Test-scored) and muscle strength (Medical Research Council sum-score (MRC-SS). ICU-acquired weakness was defined as a MRC-SS score of less than 48/60. RESULTS: The median (interquartile range) cumulative energy deficit compared to the estimated targets up to ICU day 12 was 3648 (2514-5650) kcal. Adjusting for body mass index, age and severity of illness, cumulative energy deficit (per 1000 kcal) was independently associated with greater odds of ICU-acquired weakness [odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.4-3.3, P = 0.001] and malnutrition (OR = 1.9, 95% CI = 1.1-3.2, P = 0.02). In similar multivariable linear models, cumulative energy deficit was associated with reductions in fat-free mass (-1.3 kg; 95% CI = -2.4 to -0.2, P = 0.02) and physical function scores (-0.6 points; 95% CI = -0.9 to -0.3, P = 0.001). CONCLUSIONS: Cumulative energy deficit from artificial nutrition support was associated with reduced functional outcomes and greater loss of fat-free mass in ventilated ICU patients.

A classification and regression tree to assist clinical decision making in airway management for patients with cervical spinal cord injury.

STUDY DESIGN: This was a prospective observational study. OBJECTIVES: To review airway management of patients with acute cervical spinal cord injury (CSCI) who are admitted to the intensive care unit (ICU) and to develop a classification and regression tree (CART) to direct clinical decision making in airway management. SETTING: This study was carried out in Australia. METHODS: All patients with CSCI who required intubation and mechanical ventilation and who were admitted to ICU in three tertiary hospitals in Melbourne between October 2004 and May 2009 and two other interstate hospitals between December 2004 and December 2005 were included. Airway management was recorded. RESULTS: A total of 114 patients were included. Tracheostomy insertion occurred in 68 patients (59.7%). Using CART analysis, it was found that the variables forced vital capacity, the volume of pulmonary secretion and gas exchange were predictive of airway management on 82.3% occasions with an 8.7% extubation failure rate. CONCLUSION: A CART can be useful in clinical decision making regarding airway management in CSCI.

The acute respiratory management of cervical spinal cord injury in the first 6 weeks after injury: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: Identify, evaluate, and synthesize evidence regarding the effectiveness of various treatment strategies for the respiratory management of acute tetraplegia. SETTING: Melbourne, Australia. METHODS: A search of multiple electronic databases (Medline, Cinahl, EMBASE, Cochrane Library, Web of Science, http://www.guideline.gov and http://www.icord.org/scire) was undertaken accompanied by the reference lists of all relevant articles identified. Methodological quality was assessed using the Newcastle-Ottawa Scale and the PEDro Scale. Descriptive analysis was performed. RESULTS: Twenty-one studies including 1263 patients were identified. The majority of the studies were case series (n = 13). A variety of interventions were used for the management of respiratory complications. Mortality (ARR = 0.4, 95% confidence interval (CI) 0.18, 0.61), the incidence of respiratory complications (ARR = 0.36, 95% CI (0.08, 0.58)), and requirement for a tracheostomy (ARR = 0.18, 95% CI (-0.05, 0.4)) were significantly reduced by using a respiratory protocol. A clinical pathway reduced duration of mechanical ventilation by 6 days 95% CI (-0.56, 12.56), intensive care unit length of stay by 6.8 days 95% CI (0.17-13.77) and costs. Intubation, mechanical ventilation, and tracheostomy are the mainstay of respiratory management for complete injuries above the level of C5. CONCLUSION: This review showed a clinical pathway with a structured respiratory protocol that includes a combination of treatment techniques provided regularly is effective in reducing respiratory complications and cost. The overall study quality was moderate and further studies using specific interventions that target respiratory complications are associated with specific regions of the cervical spine using more methodologically rigorous designs are required.

Electron microscope study of surface immunoglobulin-bearing human tonsil cells.

Surface immunoglobulin-bearing cells were selected from suspensions of human tonsil cells by the reverse immune cytoadherence technique. The method employed a hybrid antibody directed against Ig on lymphoid cells and against ferritin bound to sheep red blood cells (SRBC). Only 6% of the cells formed rosettes. When subjected to electron microscopy they were shown to consist of a morphologically heterogeneous population of cells. However, most cells in the center of rosettes showed ribosome-associated endoplasmic reticulum (RER) and polyribosomes. Usually these organelles were located in close proximity to membrane sites where a 400-600 A bridge was resolved between the lymphocyte and the ferritin particle on the SRBC. The bridge is postulated to consist at least in part of Ig. Only 50% of the plasma cells formed rosettes and bridges could not be resolved. The surface of the plasma cells within rosettes differed from that of plasma cells which had not reacted with ferritin-coated sheep erythrocytes. The incidence of plasma cells and gamma-globulin-bearing lymphoid cells was corroborated with the help of fluorescent antibody techniques.

Effect of splenectomy on the immune response of BALB/c mice bearing an immunoglobulin M plasmacytoma (TEPC-183).

Mice bearing TEPC-183, an immunoglobulin M(kappa)-secreting plasmacytoma, exhibit severe suppression of their immune responses to both thymus-dependent and thymus-independent antigens, 2,4-dinitrophenyl, and the type 3 pneumococcal polysaccharide SSS-III. This immunosuppression is not lifted by splenectomy of the tumor-bearing mice or prevented by removal of the spleen prior to tumor injection. On the contrary, splenectomy either before or after tumor implantation further accentuates the immunosuppressed state of tumor bearers and even depresses the immune response of normal mice. A secondary immune response of normal mice 34 to 51 days after splenectomy is still reduced. Thus, spleen cells may play a dual role. While splenectomy may remove a source of suppressor cells in tumor-bearing mice, it also eliminates a major source of antibody-producing cells and results in reduced immune responses of normal and TEPC-183-bearing mice. These findings have clinical relevance since splenectomy is used as a therapeutic and diagnostic procedure in neoplastic lymphoproliferative disorders.

ICAM-3 (CD50) cross-linking augments signaling in CD3-activated peripheral human T lymphocytes.

ICAM-3 is a pan-hematopoietic, constitutive adhesion molecule. ICAM-3 binds to LFA-1 on antigen-presenting cells (APC) stabilizing the T cell-APC interaction, facilitating signaling through the CD3/TCR complex. However, recent evidence using cultured and transformed T cells suggests ICAM-3 may also function in signaling. Because ICAM-3 is constitutively expressed on resting T cells, we postulated that signaling through ICAM-3 in resting T cells represents an important costimulatory mechanism in these cells. In purified resting human T cells, cross-linking both ICAM-3 and CD3 with plate-bound antibodies resulted in a marked increase in cell size (consistent with blastogenesis), synergistically increased surface expression of CD25 and CD69, and increased T cell metabolism. Similarly, concomitant ICAM-3 and CD3 stimulation significantly (P < 0.001) increased resting human T cell phosphatidylinositol hydrolysis and phospholipase C-gamma1 phosphorylation. These results indicate that ICAM-3 augments signaling through CD3, functioning as a costimulatory molecule for resting T cells in the initial activation step.

Phosphatidylinositol hydrolysis in freshly isolated human T lymphocytes.

Antigen receptor-mediated activation of T and B lymphocytes results in activation of phospholipase C-gamma isozymes with subsequent hydrolysis of membrane inositol phospholipids. As a method of screening autoimmune or immunodeficient patients for early receptor signaling defects, we have developed a rapid technique for studying phosphatidylinositol (PI) hydrolysis in cultured cells and fresh clinical specimens resulting from surface receptor crosslinking. Using staphylococcal alpha-toxin, we permeabilized freshly isolated, purified human T lymphocytes to facilitate incorporation of [3H]myoinositol into membrane phospholipids. Aggregation of surface antigen receptors (TCR-CD3 complex and CD28 on T cells) with specific antibodies produced extensive ATP and Mg(2+)-dependent hydrolysis of the membrane inositol phospholipids as measured by release of water soluble inositol phosphates. Anti-human CD3 antibody produced 18.5 +/- 1.6 net % PI hydrolysis and anti-human CD28 antibody produced 4.6 +/- 0.2 net % PI hydrolysis. Simultaneous anti CD3/CD28 crosslinking produced 30.8 +/- 1.2 net % PI hydrolysis, an increase over either stimulus alone (p = 0.0013 two tailed t test). Isotype matched control antibodies produced 11.6 +/- 0.4% PI hydrolysis. The tyrosine phosphatase inhibitor orthovanadate (Na3VO4) was used as a positive control because it induces maximal protein tyrosine kinase-dependent PI hydrolysis in permeabilized cells. Na3VO4 consistently induced hydrolysis of > 50% of the membrane inositol phospholipid pool. These data indicate that costimulation of T cells with antibodies to CD3 and CD28 is synergistic and reinforces the importance of CD28 as an accessory T cell stimulus. This easy technique allows quick evaluation of the integrity of the early signaling cascade in lymphocytes as a screen for autoimmune and immunodeficiency diseases.

Viloxazine HCl in the treatment of endogenous depression: a standard (imipramine) controlled clinical study.

In a four week, double-blind clinical trial, 20 patients with endogenous depression were randomly assigned to treatment with either viloxazine or imipramine. Statistically significant improvement was observed on the Hamilton Psychiatric Rating Scales for Depression and Anxiety for both treatment groups. There were no differences between the two treatment groups in the type, incidence, or severity of treatment emergent symptoms. No medication-related abnormalities in clinical laboratory values occurred in either treatment group.

The role of the corpus striatum in neuroleptic- and narcotic-induced catalepsy.

Lesion experiments (in the rat) were designed to elucidate the function of the corpus striatum in neuroleptic- and narcotic-induced catalepsy, respectively. Bilateral lesions of the corpus striatum were observed to attenuate neuroleptic (CPZ)-induced catalepsy. However, analogous lesions of the corpus striatum potentiated narcotic (morphine)-induced catalepsy. These results suggests that (a) the corpus striatum may be a primary site of action of neuroleptic drugs (such as CPZ) in the production of catalepsy, and (b) narcotic (morphine)-induced catalepsy may not be exclusively mediated by the corpus striatum.

Rapid tranquilization: a comparative study of thiothixene and haloperidol.

In a double-blind comparative clinical study, both thiothixene and haloperidol were found to be effective agents for rapid tranquilization of manic and schizophrenic patients. While no statistically significant difference in any of the psychopathological areas which may create a psychiatric emergency was found, results of this study provide further substantiation of the notion that thiothixene has favorable effects on anergia .

Primary systemic amyloidosis with a retroperitoneal mass.

A 73-year-old black woman presented with congestive heart failure, abdominal distension and ascites. A large retroperitoneal mass was demonstrated by gray-scale abdominal ultrasonography and confirmed by laparatomy and postmortem examination. This retroperitoneal mass consisted mainly of amyloid, as demonstrated by green birifringence with alkaline Congo red staining. Resistance of this staining pattern to permanganate treatment and the absence of inflammatory disease or malignancy at autopsy suggest the diagnosis of primary systemic amyloidosis. This is the first reported case of this disease manifesting as a retroperitoneal mass.

CD2 (OKT11) augments CD3-mediated intracellular signaling events in human T lymphocytes.

CD2 (LFA-2) is expressed on thymocytes, natural killer cells, and virtually all peripheral T cells. CD2 binds to its primary ligand CD58 (LFA-3) on antigen presenting cells (APC) and stabilizes the T cell-APC interaction; this stable interaction then optimizes Ag-specific T-cell activation. We assessed whether CD2-cross-linking by mAb augments the process of T-cell stimulation through the TCR/CD3 complex. Plate-bound anti-CD2 or anti-CD3 mAb alone had no measurable effect on any of the assessed activation parameters of resting T cells. However, concomitant signaling through both CD2 and CD3 by plate-bound antibodies resulted in marked increases in CD69 expression on the T-cell surface and T-cell-cellular metabolism, as assessed by the ability of the cell to reduce 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxylmethoxyphenyl)-2-( 4-sulphophenyl)- 2H-tetrazolium (MTS) to formazen. In addition, simultaneous cross-linking of CD2 and CD3 caused a significant (P < 0.001) increase in phosphatidylinositol hydrolysis in resting T cells compared to stimulation with anti-CD3 mAb alone and anti-CD3 mAb plus anti-CD2 isotype control antibody. These results indicate that CD2 augments signaling through CD3, and consequently functions as a costimulatory molecule for resting T cells in the initial activation step.

CD5 (OKT1) augments CD3-mediated intracellular signaling events in human T lymphocytes.

CD5 is expressed on thymocytes, all mature T cells, and a subset of mature B cells, and probably contributes to T-cell-B-cell adhesion. We assessed whether CD5-crosslinking by mAb augments T-cell stimulation. Plate-bound anti-CD5 or anti-CD3 mAb alone had no effect on any of the assessed activation parameters of resting T cells. However, concomitant signaling through both CD5 and CD3 by plate-bound antibodies resulted in marked increases in T-cell surface CD69 expression and T-cell metabolism, as assessed by the T cell's ability to reduce 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxylmethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) to formazen. In addition, simultaneous cross-linking of CD5 and CD3 caused a significant (p < 0.001) increase in phosphatidylinositol hydrolysis in resting T cells compared to stimulation with anti-CD3 mAb alone or anti-CD3 mAb plus anti-CD5 isotype control antibody. These results indicate that CD5 augments signaling through CD3 and consequently functions as a costimulatory molecule for resting T cells.

Activated T-lymphocytes express occludin, a component of tight junctions.

T-lymphocytes routinely traffic from the lymphoid and vascular compartments to the tissues during immune surveillance and inflammatory responses. This egress occurs without compromising endothelial barrier, which is maintained by tight junctions (zonula occludens). We report that T-lymphocytes up-regulate the expression of occludin, a major component of the tight junction in response to stimulation with phorbol ester (PMA) + calcium ionophore, CD3 antibody or T-cell receptor (TCR) antibody. Only activated T-lymphocytes express occludin; this adhesion molecule is nearly absent in resting T-lymphocytes. By immunofluorescence, occludin is seen in lymphocyte aggregates, but does not appear to mediate aggregation since only 50% of the cells in these clusters express occludin. Occludin is expressed between 8 and 24 h following stimulation, and persists for at least 48 h. These data indicate that activated T cells produce occludin which may regulate lymphocyte adhesion and trafficking.

Sickle cell disease and silent avascular necrosis of the hip.

We reviewed the prevalence of avascular necrosis (AVN) in a series of patients with sickle cell disease, using radiography and magnetic resonance imaging. We found AVN of at least one hip in 11 of 27 patients (41%). This is a significantly greater prevalence than reported. MRI was not as helpful in patients with sickle cell disease as it is in patients with AVN from other causes; it detected no more cases than radiography.

Clinical application of the Melbourne risk prediction tool in a high-risk upper abdominal surgical population: an observational cohort study.

OBJECTIVES: (1) To determine the ability of the Melbourne risk prediction tool to predict a pulmonary complication as defined by the Melbourne Group Scale in a medically defined high-risk upper abdominal surgery population during the postoperative period; (2) to identify the incidence of postoperative pulmonary complications; and (3) to examine the risk factors for postoperative pulmonary complications in this high-risk population. DESIGN: Observational cohort study. SETTING: Tertiary Australian referral centre. PARTICIPANTS AND METHODS: 50 individuals who underwent medically defined high-risk upper abdominal surgery. Presence of postoperative pulmonary complications was screened daily for seven days using the Melbourne Group Scale (Version 2). Postoperative pulmonary risk prediction was calculated according to the Melbourne risk prediction tool. OUTCOME MEASURES: (1) Melbourne risk prediction tool; and (2) the incidence of postoperative pulmonary complications. RESULTS: Sixty-six percent (33/50) underwent hepatobiliary or upper gastrointestinal surgery. Mean (SD) anaesthetic duration was 377.8 (165.5) minutes. The risk prediction tool classified 84% (42/50) as high risk. Overall postoperative pulmonary complication incidence was 42% (21/50). The tool was 91% sensitive and 21% specific with a 50% chance of correct classification. CONCLUSION: This is the first study to externally validate the Melbourne risk prediction tool in an independent medically defined high-risk population. There was a higher incidence of pulmonary complications postoperatively observed compared to that previously reported. Results demonstrated poor validity of the tool in a population already defined medically as high risk and when applied postoperatively. This observational study has identified several important points to consider in future trials.

Association of postoperative pulmonary complications with delayed mobilisation following major abdominal surgery: an observational cohort study.

OBJECTIVES: Previous Australian studies reported that postoperative pulmonary complications affect 13% of patients undergoing upper abdominal laparotomy. This study measured the incidence of postoperative pulmonary complications, risk factors for the diagnosis of postoperative pulmonary complications and barriers to physiotherapy mobilisation in a cohort of patients undergoing high-risk abdominal surgery. DESIGN: Prospective, observational cohort study. SETTING: Two surgical wards in a tertiary Australian hospital. PARTICIPANTS: Seventy-two patients undergoing high-risk abdominal surgery (participants in a larger trial evaluating a novel model of medical co-management). MAIN OUTCOME MEASURES: Incidence of, and risk factors for, postoperative pulmonary complications, barriers to mobilisation and length of stay. RESULTS: The incidence of postoperative pulmonary complications was 39%. Incision type and time to mobilise away from the bed were independently associated with a diagnosis of postoperative pulmonary complications. Patients were 3.0 (95% confidence interval 1.2 to 8.0) times more likely to develop a postoperative pulmonary complication for each postoperative day they did not mobilise away from the bed. Fifty-two percent of patients had a barrier to mobilisation away from the bed on the first postoperative day, with the most common barrier being hypotension, although cessation criteria were not defined objectively by physiotherapists. Development of a postoperative pulmonary complication increased median hospital length of stay (16 vs 13 days; P=0.046). CONCLUSIONS: This study demonstrated an association between delayed postoperative mobilisation and postoperative pulmonary complications. Randomised controlled trials are required to test the role of early mobilisation in preventing postoperative pulmonary complications in patients undergoing high-risk upper abdominal surgery.

Exercise intervention to improve exercise capacity and health related quality of life for patients with Non-small cell lung cancer: a systematic review.

CONTEXT: The role of exercise intervention for patients with Non-small cell lung cancer (NSCLC) has not been systematically reviewed to date. OBJECTIVE: To identify, evaluate and synthesize the evidence examining (1) the effect of exercise intervention on exercise capacity, health related quality of life (HRQoL), physical activity levels, cancer symptoms and mortality for patients with NSCLC; and (2) the safety and feasibility of exercise intervention for a population with NSCLC. DATA SOURCES: A systematic review of articles using the electronic databases MEDLINE (1950-2010), CINAHL (1982-2010), EMBASE (1980-2010), TRIP (1997-2010), Science Direct (1994-2010), PubMed (1949-2010), Cochrane Library (2010), Expanded Academic ASAP (1994-2010), Meditext Informit (1995-2010), PEDRO (1999-2010) and DARE (2010). Additional studies were identified by manually cross referencing all full text reports and personal files were searched. No publication date restrictions were imposed. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials (RCTs), case-control studies and case series assessing exercise intervention to improve exercise capacity, HRQoL, level of daily physical activity, cancer symptoms or mortality of patients with NSCLC were included. Only articles available in English and published in a peer reviewed journal were included. DATA EXTRACTION: A data collection form was developed by one reviewer and data extracted. Data extraction was cross checked by a second reviewer. RESULTS AND DATA SYNTHESIS: 16 studies on 13 unique patient groups totalling 675 patients with NSCLC met the inclusion criteria. The majority of studies were case series (n=9) and two RCTs were included. Studies exercising participants pre-operatively reported improvements in exercise capacity but no change in HRQoL immediately post exercise intervention. Studies exercising participants post-treatment (surgery, chemotherapy or radiotherapy) demonstrated improvements in exercise capacity but conflicting results with respect to the impact on HRQoL immediately post exercise intervention. Heterogeneity among studies was observed and a meta-analysis was deemed inappropriate. PRISMA guidelines were followed in reporting this systematic review. CONCLUSION: Exercise intervention for patients with NSCLC is safe before and after cancer treatment. Interventions pre-operatively or post-cancer treatment are associated with positive benefits on exercise capacity, symptoms and some domains of HRQoL. The majority of studies are small case series therefore results should be viewed with caution until larger RCTs are completed. Further research is required to establish the effect of exercise during and after cancer treatment and in the advanced stage of disease, the optimum type of exercise training and the optimum setting for delivery.