Sparse Deconvolution and Causality Analysis of Inflammatory Markers During Cardiac Surgery.

Major bodily trauma such as cardiac surgery elicits (in response to tissue injury and other exogenous surgical factors) a whole-body inflammation response during which specialized signaling proteins called cytokines are synthesized and invoke multiple defense mechanisms. Many proinflammatory and anti-inflammatory cytokines such as interleukins (IL) and tumor necrosis factor (TNF) are produced to initiate bodily repair. Due to the adverse health consequences, including mortality, of a maladaptive cytokine response, understanding their complex dynamics using system-theoretic modeling and analysis may pave the way for controlling the inflammatory response which may eventually improve medical outcomes for patients. To this end, we use clinical data from ten patients undergoing coronary arterial bypass graft surgery to study the response of four cytokines (IL6, IL8, IL10, TNFα) and the neuroendocrine hormone cortisol. We perform deconvolution to obtain the secretory pulses underlying their pulsatile production and analyze causal interactions, mathematically uncovering some interactive relationships found in previous experimental studies.Clinical relevance- This work is a first step towards a mechanistic inference of the inflammatory response to surgery that could eventually help control the inflammatory response and could inform medical interventions to improve patient outcomes.

Myasthenia gravis induced or exacerbated by immune checkpoint inhibitors: a rising concern.

Immune checkpoint inhibitors can cause immune side effects, with myasthenia gravis (MG) being relatively rare. With this review, we present 66-year-old man with melanoma treated with pembrolizumab who developed MG. With immuno-oncology (IO) single agent usage, 42 cases reported new-onset MG and 9 cases reported exacerbation of pre-existing MG. Among the patients who had new-onset MG after administration of programmed cell death protein 1 (PD-1) inhibitors, 14 patients (38.8%) developed severe respiratory failure and required intubation and 10 patients (27.02%) died. Among the patients with exacerbation of pre-existing MG after receiving PD-1 inhibitors, 1 patient (11.1%) required intubation, and no death was reported. Combination IO therapy-induced MG was reported in seven cases, with at least two cases complicated by respiratory failure and one death. Our observations suggest a possible difference in the severity of the disease and outcome among different IO therapy options.

Effects of pentoxifylline and alendronate on fracture healing in ovariectomy-induced osteoporosis in rats.

Osteoporosis is determined by decreased bone strength that increases the threat of fractures. The aim of this study was to evaluate the effects of pentoxifylline (PTX) and alendronate (ALN), on the stereological parameters, and gene expression in callus of fracture in an experimental rat model of ovariectomy-induced osteoporosis (OVX). The OVX was induced in 90 female rats. Fourteen weeks later, a complete fracture on the right femur was made. Rats were divided into five groups: 1) control: no treatment; 2) sham: received daily distilled water; 3) daily 3.00 mg kg-1 ALN subcutaneously (SC); 4) daily 200 mg kg-1 PTX (SC) and 5) daily PTX (SC) + ALN (same doses). The osteoclast count was significantly lower in all treatment groups, at 21 and 56 days post-surgery, compared to the control and sham groups. The PTX significantly increased total callus volume at 21 and 56 days post-surgery, compared to the other groups. The PTX+ALN treatment significantly increased both cortical bone volume on day 21, and osteocyte and osteoblast numbers on day 56, compared to the control and sham groups. It can be concluded that PTX and ALN have antiresorptive effects, in OVX rats. Also, PTX has increased the extracellular matrix on both 21 and 56 days after surgery, compared to the other groups. PTX+ALN elevated cortical bone volume on day 21, and osteocyte and osteoblast numbers compared to the control and sham groups on day 56.

Evaluation of the Effects of Photobiomodulation on Partial Osteotomy in Streptozotocin-Induced Diabetes in Rats.

OBJECTIVE: We examined the effects of photobiomodulation (PBM) on stereological parameters, and gene expression of Runt-related transcription factor 2 (RUNX2), osteocalcin, and receptor activator of nuclear factor kappa-B ligand (RANKL) in repairing tissue of tibial bone defect in streptozotocin (STZ)-induced type 1 diabetes mellitus (TIDM) in rats during catabolic response of fracture healing. BACKGROUND DATA: There were conflicting results regarding the efficacy of PBM on bone healing process in healthy and diabetic animals. MATERIALS AND METHODS: Forty-eight rats have been distributed into four groups: group 1 (healthy control, no TIDM and no PBM), group 2 (healthy test, no TIDM and PBM), group 3 (diabetic control, TIDM and no PBM), and group 4 (diabetic test, no TIDM and PBM). TIDM was induced in the groups 3 and 4. A partial bone defect in tibia was made in all groups. The bone defects of groups second and fourth were irradiated by a laser (890 nm, 80 Hz, 1.5 J/cm2). Thirty days after the surgery, all bone defects were extracted and were submitted to stereological examination and real-time polymerase chain reaction (RT-PCR). RESULTS: PBM significantly increased volumes of total callus, total bone, bone marrow, trabecular bone, and cortical bone, and the numbers of osteocytes and osteoblasts of callus in TIDM rats compared to those of callus in diabetic control. In addition, TIDM increased RUNX2, and osteocalcin in callus of tibial bone defect compared to healthy group. PBM significantly decreased osteocalcin gene expression in TIDM rats. CONCLUSIONS: PBM significantly increased many stereological parameters of bone repair in an STZ-induced TIDM during catabolic response of fracture healing. Further RT-PCR test demonstrated that bone repair was modulated in diabetic rats during catabolic response of fracture healing by significant increase in mRNA expression of RUNX2, and osteocalcin compared to healthy control rats. PBM also decreased osteocalcin mRNA expression in TIDM rats.

Combined effects of photobiomodulation and alendronate on viability of osteoporotic bone marrow-derived mesenchymal stem cells.

Osteoporotic bone marrow mesenchymal stem cells (BMMSCs) are involved in the pathogenesis of osteoporosis (OP). Photobiomodulation (PBM) has positive effects on healthy BMMSCs. The goal of current experiment was to evaluate the combined influence of photobiomodulation PBM and alendronate (ALN) incubation on ovariectomized induced osteoporosis(OVX)- BMMSC viability in vitro. 15 female adult Wistar rats were distributed into the 2 groups: (1) 3 healthy (sham)control rats, (2) 12 OVX- rats. All OVX rats underwent ovariectomy. After 3.5 months sham and OVX rats were euthanized and their MSC harvested and cultured in a complete osteogenic incubation medium (OM). As the next step, in sham and OVX groups flowcytometry and osteogenic differentiation assays were performed. OVX- rats were divided into (2) OVX-control, (3) OVX- PBM (HeNe laser, 623.8 nm, 1.2 J/cm2, one time), (4) OVX-ALN (10-8 M, three times incubations), and (5) OVX-PBM + ALN, Finally BMMSC viability of all five groups were evaluated using MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide) assay. Based on our observations, PBM significantly increased optical density of OVX-BMMSCs (2.15 ±â€¯0.11) compared to control -OVX-BMMSCs (1.55 ±â€¯0.10) and healthy -BMMSCs (1.65 ±â€¯0.10)(LSD test, both p < 0.05). Further, we found that both ALN, and ALN + PBM significantly increased optical densities of OVX-BMMSCs (24 h:2.40 ±â€¯0.03;48 h:2.06 ±â€¯0.00[ALN],both p < 0.01) and 1.88 ±â€¯0.05[ALN + PBM], p < 0.05 compared to control -OVX-BMMSCs (24 h: 1.46 ±â€¯0.01; 48 h: 1.83 ±â€¯0.00 and 1.57 ±â€¯0.08). It was concluded that PBM significantly increased cell viability of OVX-BMMSCs compared to control -OVX-BMMSCs and healthy -BMMSCs.

Effect of in vivo low-level laser therapy on bone marrow-derived mesenchymal stem cells in ovariectomy-induced osteoporosis of rats.

Postmenopausal osteoporosis (PMOP) is considered by decreased bone strength that escalates the threat of fractures. Positive effects of photobiomodulation (PBM) with pulse wave have been demonstrated in cell culture and animal models. The aim of this study was to assess the in vivo effects of PBM on viability and calcium ion release of ovariectomy induced osteoporosis (OVX) - bone marrow derived mesenchymal stem cells (BMMSCs). MATERIAL AND METHODS: 18 female rats were distributed into the following groups: 1) control healthy, 2) LASER-healthy (890nm, 80Hz, 1.5J/cm2, three days weekly, 60days), 3) control OVX, 4) LASER-OVX, 5) Alendronate (Alen.)-OVX [0.5mg/kg, 5days per week, 60days], and 6) Alen.+LASER-OVX. Ovariectomy was done on rats of groups 3, 4, 5 and 6. After that all rats were euthanized and their MSC harvested and cultured in complete osteogenic medium. In all groups, BMMSC viability, and calcium colorimetric assay were performed. RESULTS: We observed a significant increase in optical density (OD) of BMMSCs viability in LASER healthy group compared to control-OVX, Alen.-OVX, LASER-OVX, LASER+Alen.-OVX, groups. LASER+Alen.-OVX group displayed a significant escalation in OD of BMMSCs viability compared to LASER-OVX, Alen.-OVX, and control-OVX groups. There were a significant increase in calcium ion release of LASER-healthy group compared to control healthy, control-OVX, Alen.-OVX, LASER-OVX, and LASER+Alen.-OVX groups. LASER+Alen.-OVX group displayed a significant escalation in calcium ion release compared to LASER-OVX, Alen.-OVX, and control-OVX groups. CONCLUSION: Pulse wave (PW) PBM significantly stimulated viability and cell proliferation of healthy BMMSCs compared to those of control-OVX, OVX-alendronate, OVX-LASER, and LASER+alendronate-OVX. In addition stimulatory effect of LASER+alendronate on viability and cell proliferation of OVX-BMMSCs compared to those of control-OVX, alendronate-OVX, and LASER-OVX groups were found.

Pseudomonas aeruginosa exotoxin T induces potent cytotoxicity against a variety of murine and human cancer cell lines.

In patients with malignancy, the major barrier to achieving complete response is emergence of resistance to current chemotherapeutic agents. One of the major mechanisms by which tumour cells become resistant to therapies is by altering cellular drug targets through mutations and/or deletions. Resistance by this mechanism is achieved more easily if the drug has limited cellular targets and/or processes. We hypothesized that as Pseudomonas aeruginosa exotoxin T (ExoT) targets six proteins that are required for cancer cell survival and proliferation, it is highly unlikely for cancer cells to develop resistance to this toxin. We assessed ExoT's cytotoxicity against multiple invasive and highly resistant tumour cell lines in order to evaluate its potential as a chemotherapeutic agent. Our data demonstrated that ExoT induced potent cytotoxicity in all tumour cell lines that we examined. Collectively, our data highlighted the potential of ExoT as a possible chemotherapeutic candidate for the treatment of cancer.

Changing pattern of infective endocarditis in Iran: A 16 years survey.

OBJECTIVES: To investigate the changes in characteristics of patients with infective endocarditis in Iran and comparing the results with the changing profiles of Infection Endocarditis (IE) in other countries. METHODOLOGY: We studied all patients with definite or possible IE seen at four referral teaching hospitals in Iran from Jan. 1995 to Dec. 2010. The data was analyzed both collectively and separately in two consecutive eight-year periods, i.e. 1995-2003 and 2004-2010. RESULTS: A total of 286 episodes of IE, 172 males and 114 females, were reviewed from which 162 ones were in the first eight-year time period and 124 episodes in the second one. Mean age of the patients was significantly increased in the second eight-year period (24.2±11 vs 39.4±15 years old, p value = 0.01). Increase in the episodes caused by Staphylococcus aureus was significant (40.7% vs 22.8%, p value = 0.01). The mean size of the vegetation was noticeably higher among IDUs than non-IDUs (1.53±0.1cm vs 0.76±0.2cm, p value < 0.001). As well as extra cardiac complications, mortality rate was noticeably higher among the patients with vegetation size ≥ 1cm (34.4% vs 16.3%, p value = 0.003). There was not a significant difference regarding the mortality rate between the conservatively and surgically treated patients (20.7% vs 22.9%, p value = 0.07). CONCLUSION: The most important changing characteristic of IE which influences the outcome of the disease seems to be vegetation size which can account for as the outcome predictor.