Human mesenchymal stromal cells modulate T‐cell responses through TNF‐α‐mediated activation of NF‐κB

Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF‐κB) in human MSCs. This pathway is activated by TNF‐α that is generated following TCR stimulation of T cells. Inhibition of NF‐κB through silencing of IκB kinase β or the TNF‐α receptor abolishes the immunosuppressive capacity of MSCs. Our data also indicate that MSC‐associated NF‐κB activation primarily leads to inhibition of T‐cell proliferation with little effect on expression of the activation markers CD69 and CD25. Thus, our data support the hypothesis that the TNF‐α/NF‐κB signalling pathway is required for the initial priming of immunosuppressive function in human MSCs. Interestingly, drugs that interfere with NF‐κB activation significantly antagonise the immunoregulatory effect of MSCs, which could have important implications for immunosuppression regimens in the clinic.     

The claw paw mutation reveals a role for Lgi4 in peripheral nerve development

Peripheral nerve development results from multiple cellular interactions between axons, Schwann cells and the surrounding mesenchymal tissue. The delayed axonal sorting and hypomyelination throughout the peripheral nervous system of claw paw (clp) mutant mice suggest that the clp gene product is critical for these interactions. Here we identify the clp mutation as a 225-bp insertion in the Lgi4 gene. Lgi4 encodes a secreted and glycosylated leucine-rich repeat protein and is expressed in Schwann cells. The clp mutation affects Lgi4 mRNA splicing, resulting in a mutant protein that is retained in the cell. Additionally, siRNA-mediated downregulation of Lgi4 in wild-type neuron-Schwann cell cocultures inhibits myelination, whereas exogenous Lgi4 restores myelination in clp/clp cultures. Thus, the abnormalities observed in clp mice are attributable to the loss of Lgi4 function, and they identify Lgi4 as a new component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation.     

TMD before and after correction of dentofacial deformities by orthodontic and orthognathic treatment

The aims of the study were to investigate the alteration of temporomandibular disorders (TMD) after correction of dentofacial deformities by orthodontic treatment in conjunction with orthognathic surgery; and to compare the frequency of TMD in patients with dentofacial deformities with an age and gender matched control group. TMD were evaluated in 121 consecutive patients (treatment group), referred for orthognathic surgery, by a questionnaire and a clinical examination. 18 months after treatment, 81% of the patients completed a follow-up examination. The control group comprised 56 age and gender matched subjects, of whom 68% presented for follow-up examination. TMD were diagnosed according to research diagnostic criteria for TMD. At baseline examination, the treatment group had a higher frequency of myofascial pain (P = .035) and arthralgia (P = .040) than the control group. At follow-up, the frequencies of myofascial pain, arthralgia and disc displacement had decreased in the treatment group (P = .050, P = .004, P = .041, respectively). The frequency of TMD was comparable in the two groups at follow-up. Patients with dentofacial deformities, corrected by orthodontic treatment in conjunction with orthognathic surgery, seem to have a positive treatment outcome in respect of TMD pain.     

Hemodynamic predictors for weaning patients from ventricular assist devices (VADs)

In order to find hemodynamic parameters that can accurately predict whether patients can be successfully weaned from ventricular assist devices (VADs), we studied data from 17 patients supported with Pierce-Donachy VADs [11 left VAD (LVAD); 6 right VAD (RVAD)] following cardiogenic shock for periods from 1.3 to 22 days (mean 5.4). Myocardial recovery was determined by daily measurements of "pump on pump off" parameters, and the data from the 8 LVAD patients and 3 RVAD patients whose hearts recovered were compared to the data from those whose did not. In this study, daily pump on pump off hemodynamic measurements were found to be predictive of success for weaning patients from VADs. In particular, the most significant predictors were: increases in mixed venous oxygen saturation, cardiac index, mean arterial pressure and ventricular ejection fraction, as well as decreases in atrial pressures. An index for measuring hemodynamic function with the VAD off is proposed, as are models of recovery. Seventy percent of the patients weaned from VADs survived, indicating that patients appropriately weaned from VAD support have a reasonable chance for survival.     

RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions

Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities and premature death. It was recently proposed that autonomic dysfunction is triggered by oxidation‐mediated inactivation of neuronal nicotinic acetylcholine receptors (nAChRs), impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure. We investigated whether the receptor for advanced glycation end products (RAGE) and its role in the generation of reactive oxygen species (ROS) could be contributing to the events that initiate sympathetic malfunction under high glucose conditions. Using biochemical, live imaging and electrophysiological tools we demonstrated that exposure of sympathetic neurons to high glucose increases RAGE expression and oxidative markers, and that incubation with RAGE ligands (e.g. AGEs, S100 and HMGB1) mimics both ROS elevation and nAChR inactivation. In contrast, co‐treatment with either antioxidants or an anti‐RAGE IgG prevented the inactivation of nAChRs. Lastly, a role for RAGE in this context was corroborated by the lack of sensitivity of sympathetic neurons from RAGE knock‐out mice to high glucose. These data define a pivotal role for RAGE in initiating the events associated with exposure of sympathetic neurons to high glucose, and strongly support RAGE signaling as a potential therapeutic target in the autonomic complications associated with diabetes.     

Use of computerized ICU documentation to capture ICU core measures

BACKGROUND: Intensive care unit (ICU) core measures that target the prevention of catheter-related bloodstream infections (CRBSIs) and ventilator-associated pneumonia (VAP) in ventilated ICU patients are underway across the United States. Implementation often requires additional personnel to educate providers and collect the data. We hypothesized that use of our current computerized ICU flowsheet could provide timely, accurate data on ICU core measures without additional personnel dedicated to data capture. METHODS: In a 10-bed, closed surgical ICU with existing protocols for deep vein thrombosis (DVT) prophylaxis, stress ulcer bleeding prophylaxis (SUP), ventilator weaning parameters, and glucose control, we created a reporting tool that would document daily weaning parameters, head of bed (HOB) at 30 degrees , glucose levels, DVT prophylaxis, and SUP. Our glucose protocol targeted <150 mg/dL, with all daily glucose values reported rather than just the morning value. The results from the previous 12 am to 11:59 pm were available to the rounding team at 7 am. We examined compliance at the start and after education of medical staff (March/April for HOB up, DVT, and SUP; May/June for glucose control). RESULTS: During 2005, compliance with all protocols improved. Percent compliance for DVT prophylaxis, SUP, and HOB up rose from as low as 32% at the start of the documentation process to consistently higher than the target level of 95%. Compliance for glucose control increased after intensive education of nursing and physicians with the mean glucose falling from 144 to 122 mg/dL. There was increased nursing workload for checking glucose levels in which the mean number of glucose checks rose from a low of 1.5 per patient to as high as 8.2 per patient per day. CRBSI and VAP rates did not decrease during this period compared with the prior year. Length of stay and mortality were unchanged. CONCLUSIONS: Reporting of ICU core measures to treating staff can be done accurately and promptly with a computerized system. Education was effective in improving compliance levels. No additional personnel were required to create reports, capture data, or improve compliance after initial development and testing. Although compliance with core measures met target levels at the end of the year, we did not observe improved outcomes in terms of CRBSI, VAP, mortality, or length of stay.     

A clinical calculator for predicting intraoperative blood loss and transfusion risk in spine tumor patients

BACKGROUND CONTEXTSurgery for vertebral column tumors is commonly associated with intraoperative blood loss (IOBL) exceeding 2 liters and the need for transfusion of allogeneic blood products. Transfusion of allogeneic blood, while necessary, is not benign, and has been associated with increased rates of wound complication, venous thromboembolism, delirium, and death.PURPOSETo develop a prediction tool capable of predicting IOBL and risk of requiring allogeneic transfusion in patients undergoing surgery for vertebral column tumors.STUDY DESIGN/SETTINGRetrospective, single-center study.PATIENT SAMPLEConsecutive series of 274 patients undergoing 350 unique operations for primary or metastatic spinal column tumors over a 46-month period at a comprehensive cancer centerOUTCOME MEASURESIOBL (in mL), use of intraoperative blood products, and intraoperative blood products transfused.METHODSWe identified IOBL and transfusions, along with demographic data, preoperative laboratory data, and surgical procedures performed. Independent predictors of IOBL and transfusion risk were identified using multivariable regression.RESULTSMean age at surgery was 57.0±13.6 years, 53.1% were male, and 67.1% were treated for metastatic lesions. Independent predictors of IOBL included en bloc resection (p<.001), surgical invasiveness (β=25.43 per point; p<0.001), and preoperative albumin (β=?244.86 per g/dL; p=0.011). Predictors of transfusion risk included preoperative hematocrit (odds ratio [OR]=0.88 per %; 95% confidence interval [CI, 0.84, 0.93]; p<0.001), preoperative MCHgb (OR=0.88 per pg; 95% CI [0.78, 1.00]; p=0.048), preoperative red cell distribution width (OR=1.32 per %; 95% CI [1.13, 1.55]; p<0.001), en bloc resection (OR=3.17; 95%CI [1.33, 7.54]; p=0.009), and surgical invasiveness (OR=1.08 per point; [1.06; 1.11]; p<0.001). The transfusion model showed a good fit of the data with an optimism-corrected area under the curve of 0.819. A freely available, web-based calculator was developed for the transfusion risk model (https://jhuspine3.shinyapps.io/TRUST/).CONCLUSIONSHere we present the first clinical calculator for intraoperative blood loss and transfusion risk in patients being treated for primary or metastatic vertebral column tumors. Surgical invasiveness and preoperative microcytic anemia most strongly predict transfusion risk. The resultant calculators may prove clinically useful for surgeons counseling patients about their individual risk of requiring allogeneic transfusion.     

Phytoestrogen and multiple vitamin/mineral effects on bone mineral density in early postmenopausal women: a pilot study

The purpose of the study was to assess the effect of a combination regimen of herbs, vitamins, and minerals on bone mineral density (BMD) in early postmenopausal women via a 2-year, single-blind, uncontrolled, prospective trial. BMD was measured by dual energy x-ray absorptiometry (DEXA) at baseline and at 6, 12, and 24 months. Results of lumbar spine, hip, and forearm densities did not differ significantly from historical controls derived from other recent trials using a similar patient population. Bone mineral losses are reported on an annualized basis over the 2 years for the 12 women who completed the trial: spine (-1.42% per year), hip (-0.43% per year), forearm (-1.42% per year). Six women were withdrawn from the trial by the investigators because of excessive losses of bone mineral, and 1 of these women was diagnosed with hyperparathyroidism. There were no metabolic diseases to explain the losses in the remaining 5 withdrawn subjects. Four of 21 subjects experienced adverse side effects, necessitating dropping out by 3 of these women. In conclusion, the combined treatment regimen of a menopause symptom-oriented herbal blend plus a high potency vitamin/mineral was unsuccessful in protecting women against the predictable acceleration of bone mineral losses associated with early postmenopause.