Effect of Bariatric Surgery on Plasma Cell-Free Mitochondrial DNA, Insulin Sensitivity and Metabolic Changes in Obese Patients.

While improvement of mitochondrial function after bariatric surgery has been demonstrated, there is limited evidence about the effects of bariatric surgery on circulatory cell-free (cf) mitochondrial DNA (mtDNA) and intracellular mtDNA abundance. Plasma and peripheral blood mononuclear (PBM) cells were isolated from healthy controls (HC) and bariatric surgery patients before surgery and 2 weeks, 3 months, and 6 months after surgery. At baseline, the plasma level of short cf-mtDNA (ND6, ~100 bp) fragments was significantly higher in obese patients compared to HC. But there was no significant variation in mean ND6 values post-surgery. A significant positive correlation was observed between preop plasma ND6 levels and HgbA1c, ND6 and HOMA-IR 2 weeks post-surgery, and mtDNA content 6 months post-surgery. Interestingly, plasma from both HC and obese groups at all time points post-surgery contains long (~8 kb) cf-mtDNA fragments, suggesting the presence of near-intact and/or whole mitochondrial genomes. No significant variation was observed in mtDNA content post-surgery compared to baseline data in both PBM and skeletal muscle samples. Overall, bariatric surgery improved insulin sensitivity and other metabolic parameters without significant changes in plasma short cf-mtDNA levels or cellular mtDNA content. Our study provides novel insights about possible molecular mechanisms underlying the metabolic effects of bariatric surgery and suggests the development of new generalized approaches to characterize cf-mtDNA.

Evaluation of High-Interval Education to Improve Outcomes for Bariatric Patients With Health Disparities.

A correlation of health disparities, socioeconomic barriers, and health literacy were hypothesized as causative factors of poor weight loss, weight regain, and loss to clinical follow-up in postbariatric patients. This study explored nurse practitioner-led interventions to address health disparities and improve outcomes. This pilot project evaluated 3-month weights of an intervention cohort as compared with a retrospective cohort. The intervention cohort received a weekly educational phone call from the clinical nurse practitioner. Quantitative data based on 3-month weights reveal an average excess body weight percentage lost at the 3-month postoperative clinical visit (36.54 ± 0.11, p = .2929) in the retrospective cohort ( n = 30) as compared with the intervention cohort ( n = 30; 33.46 ± 0.11, p = .2929). Participants responding to the barriers screening tool did not correspond with the actual needs represented by the population. Food access and transportation were leading factors affecting weight loss. This project revealed implications including the need for development of bariatric-specific social needs assessments, the need to explore telehealth as a modality to improve patient education, the need to modify education to overcome deficits in health literacy. Findings also validate the role of the nurse practitioner as a leader of multidisciplinary care teams.

Review of Outcomes of Low Verses Standard Pressure Pneumoperitoneum in Laparoscopic Surgery.

BACKGROUND: Carbon dioxide pneumoperitoneum during laparoscopy changes cardiorespiratory physiology and contributes to post-op pain. We studied outcomes before and after implementing low-pressure pneumoperitoneum QI project. METHODS: Forty-two patients were insufflated at standard pressures (15 mmHg) while 41 were insufflated using low (8-12 mmHg) during laparoscopic procedures. These variables were obtained from the patient chart: pain scores, intravenous morphine milligram equivalents (MME), peak inspiratory pressures (PIP), end-tidal CO2 (EtCO2), surgery duration, and patient demographics. The study was conducted after IRB approval. RESULTS: Low-pressure pneumoperitoneum is feasible and the surgeon can increase to 10-12 mmHg as needed. The mean post-op IV MME was significantly decreased in the low-pressure group (11.75 ± 10.41) compared to the standard pressure group (17.36 ± 18.1) (t-test, P = .047). Mean peak inspiratory pressures during insufflation were significantly higher for procedures conducted at standard pressure (31.40 ± 4.82) compared to the 8 mmHg (24.68 ± 4.19) and 12 mmHg (27.33± 3.85) low pressure groups (one-way ANOVA, P < .0001). During insufflation, there was a significant increase in the average EtCO2 in the standard pressure group (42.07 ± 5.60) compared to the 8 mmHg low pressure group (37.59 ± 5.05) (ANOVA, P = .0096). Constant flow insufflation was more likely to be performed at low pressure than demand mode (58% v. 33%). CONCLUSION: Low pressure pneumoperitoneum decreases PIP pressure and CO2 absorption evidenced by lower ETCO2 intra-operatively. Patients have significant improvement in postoperative pain evidenced by decreased narcotics needed. Low pressure pneumoperitoneum using a constant flow insufflator is safe and results in improved patient outcomes.

For the People and the Profession.

In 1982 Dean Warren delivered the presidential address "Not for the Profession… For the People" in which he identified substandard surgical residency programs graduating residents who were unable to pass American Board of Surgery exams. Drs. Warren and Shires as members of the independent ACGME began to close the substandard programs in order to improve surgical care for average Americans i.e. "for the people". By 2003 these changes dramatically reduced the failure rate for the ABS exams and trained good surgeons who could operate independently however the residents were on duty for every other or every third night. In 2003 the ACGME mandated duty hour restrictions in order improve resident wellness and improve the training environment for the profession. However, work hour restrictions reduced the time surgical residents spent in the hospital environment primarily when residents had more autonomy and had exposure to emergency cases which degraded readiness for independent practice. Surgical educators in the 2 decades after the work hour restrictions have improved techniques of training so graduates could not only pass the board exams but also be prepared for independent practice. Surgical residency training has improved by both the changes implemented by the independent ACGME in 1981 and by the work hour restrictions mandated in 2003. Five recommendations are made to ensure that Dr Warren's culture of excellence in surgical training continues in an environment that enhances wellbeing of the trainee i.e. "For the People and the Profession".

W. Dean Warren, MD, FACS, Father of Selective Shunts for Variceal Hemorrhage: Lessons Learned.

Dr Dean Warren was born in 1924 and died prematurely from cancer in 1989. He was a man of uncommon intelligence, wit, collegiality, integrity, honesty, and a true leader in American surgery. In 1966, he and his colleagues (Drs Zeppa and Fomon) presented a new concept for surgical shunts to control variceal hemorrhage while maintaining portal perfusion or hepatopetal blood flow. He termed this new shunt the distal splenorenal shunt (DSRS), which was the first selective shunt invented. The DSRS selective shunt was a brilliant improvement over the total shunt concept proposed by Nicolai Eck and was practiced worldwide during the 1980s. In a space of 2 decades, Dr Warren's pioneering work would show that the selective DSRS was superior to total shunts for treatment of portal hypertension, but that endoscopic sclerotherapy was a better first-line treatment for variceal hemorrhage than his own creation. His absolute adherence to the principles he espoused in his presidential address to the Society for Surgery of the Alimentary Tract in 1973 were employed in his research and treatment of patients. This paper details Dr Warren's extraordinary research accomplishments and sets a lesson for us that well-designed clinical trials including randomization are essential in the advancement of the care of surgical patients.

Plasma mitochondrial DNA is elevated in obese type 2 diabetes mellitus patients and correlates positively with insulin resistance.

Cells damaged by mechanical or infectious injury release proinflammatory mitochondrial DNA (mtDNA) fragments into the circulation. We evaluated the relation between plasma levels of mtDNA fragments in obese type 2 diabetes mellitus (T2DM) patients and measures of chronic inflammation and insulin resistance. In 10 obese T2DM patients and 12 healthy control (HC) subjects, we measured levels of plasma cell-free mtDNA with quantitative real-time polymerase chain reaction, and mtDNA damage in skeletal muscle with quantitative alkaline Southern blot. Also, markers of systemic inflammation and oxidative stress in skeletal muscle were measured. Plasma levels of mtDNA fragments, mtDNA damage in skeletal muscle and plasma tumor necrosis factor α levels were greater in obese T2DM patients than HC subjects. Also, the abundance of plasma mtDNA fragments in obese T2DM patients levels positively correlated with insulin resistance. To the best of our knowledge, this is the first published evidence that elevated level of plasma mtDNA fragments is associated with mtDNA damage and oxidative stress in skeletal muscle and correlates with insulin resistance in obese T2DM patients. Plasma mtDNA may be a useful biomarker for predicting and monitoring insulin resistance in obese patients.

Magnetoenterography for the Detection of Partial Mesenteric Ischemia.

BACKGROUND: Acute mesenteric ischemia represents a life-threatening gastrointestinal condition. A noninvasive diagnostic modality that identifies mesenteric ischemia patients early in the disease process will enable early surgical intervention. Previous studies have identified significant changes in the small-bowel electrical slow-wave parameters during intestinal ischemia caused by total occlusion of the superior mesenteric artery. The purpose of this study was to use noninvasive biomagnetic techniques to assess functional physiological changes in intestinal slow waves in response to partial mesenteric ischemia. METHODS: We induced progressive intestinal ischemia in normal porcine subjects (n = 10) by slowly increasing the occlusion of the superior mesenteric artery at the following percentages of baseline flow: 50%, 75%, 90%, and 100% while simultaneous transabdominal magnetoenterogram (MENG) and serosal electromyogram (EMG) recordings were being obtained. RESULTS: A statistically significant serosal EMG amplitude decrease was observed at 100% occlusion compared with baseline, whereas no significant change was observed for MENG amplitude at any progressive occlusion levels. MENG recordings showed significant changes in the frequency and percentage of power distributed in bradyenteric and normoenteric frequency ranges at 50%, 75%, 90%, and 100% vessel occlusions. In serosal EMG recordings, a similar percent power distribution (PPD) effect was observed at 75%, 90%, and 100% occlusion levels. Serosal EMG showed a statistically significant increase in tachyenteric PPD at 90% and 100% occlusion. We observed significant increase in tachyenteric PPD only at the 100% occlusion level in MENG recordings. CONCLUSIONS: Ischemic changes in the intestinal slow wave can be detected early and noninvasively even with partial vascular occlusion. Our results suggest that noninvasive MENG may be useful for clinical diagnosis of partial mesenteric ischemia.

Early Assessment of Burn Depth with Far Infrared Time-Lapse Thermography.

BACKGROUND: Diagnosing the extremes of superficial burns and full-thickness burns is straightforward. It is in the middle ground of partial-thickness burns where the diagnostic difficulties emerge; it can take up to 3 to 5 days for signs of healing to appear. We hypothesize that cooling partial-thickness burns and tracking the rate of rewarming will immediately reflect the condition of the burn: shallow partial-thickness burns that retain cell health and blood flow will rewarm rapidly, and deeper burns with damaged microvessels will rewarm slowly. STUDY DESIGN: We enrolled 16 patients with isolated, partial-thickness burns on their extremities who were diagnosed as indeterminate by our burn surgeon. Within 24 hours after presentation, room-temperature saline was poured over the burn as a cooling challenge. An infrared camera that was sensitive to body temperature produced false-color images showing pixel-by-pixel temperatures. A time-lapse recording from the infrared camera images taken as the burn rewarmed produced a time-temperature curve that reflected the kinetics of rewarming. The outcomes variable was whether or not the patient received a skin graft, which was determined 72 hours after presentation. RESULTS: The method correctly predicted whether or not the patient required a skin graft. CONCLUSIONS: Here we report a new technique that permits determination of wound viability much earlier than clinical examination. Due to the simplicity of the method, non-experts can successfully perform the technique on the first day of the burn and make the correct diagnosis and decision to graft or not to graft.

Comparative Analysis of Laparoscopic Fundoplication and Magnetic Sphincter Augmentation for the Treatment of Medically Refractory GERD.

We have recently introduced laparoscopic magnetic sphincter augmentation (MSA) combined with hiatal hernia repair for treatment of patients with medically refractory gastroesophageal reflux disease (GERD). MSA is a novel surgical approach to the treatment of severe GERD, in which magnetic beads are secured around the lower esophageal sphincter, augmenting the lower esophageal sphincter function as an anti-reflux barrier. We hypothesize that patients undergoing MSA will achieve GERD relief, equal to that obtained after laparoscopic Nissen fundoplication. The GERD Health Related Quality of Life (GERD HRQL) Questionnaire is a validated clinical tool that was used to quantify patient outcomes in terms of GERD-related symptoms both on and off proton pump inhibitors and after acute radiation syndrome. We retrospectively reviewed data from patients at our institution enrolled in a prospective institutional review board-approved database "Registry Outcomes Anti-Reflux Surgery" that applies objective and subjective information about patients undergoing anti-reflux surgery. Information from both the database and patient HRQL scores were used to compare the effectiveness of medical intervention with acute radiation syndrome (laparoscopic Nissen fundoplication and MSA) in decreasing GERD-related symptoms in patients. Results are expressed as mean ± SE, and single-factor ANOVA test was used to compare groups. We found that MSA and laparoscopic fundoplication both lead to a comparable decrease in HRQL score and an increase in patient satisfaction when compared with patient's preoperative symptoms with maximum proton pump inhibitor use. In addition, our study shows that MSA is a safe minimally invasive anti-reflux procedure without the negative side-effects, such as gas bloat, inability to belch, and inability to vomit, commonly associated with NF.

Heller myotomy versus Heller myotomy with Dor fundoplication for achalasia: long-term symptomatic follow-up of a prospective randomized controlled trial.

BACKGROUND: Our prior randomized controlled trial of Heller myotomy alone versus Heller plus Dor fundoplication for achalasia from 2000 to 2004 demonstrated comparable postoperative resolution of dysphagia but less gastroesophageal reflux after Heller plus Dor. Patient-reported outcomes are needed to determine whether the findings are sustained long-term. METHODS: We actively engaged participants from the prior randomized cohort, making up to six contact attempts per person using telephone, mail, and electronic messaging. We collected patient-reported measures of dysphagia and gastroesophageal reflux using the Dysphagia Score and the Gastroesophageal Reflux Disease-Health-Related Quality of Life (GERD-HRQL) instrument. Patient-reported re-interventions for dysphagia were verified by obtaining longitudinal medical records. RESULTS: Among living participants, 27/41 (66%) were contacted and all completed the follow-up study at a mean of 11.8 years postoperatively. Median Dysphagia Scores and GERD-HRQL scores were slightly worse for Heller than Heller plus Dor but were not statistically different (6 vs 3, p = 0.08 for dysphagia, 15 vs 13, p = 0.25 for reflux). Five patients in the Heller group and 6 in Heller plus Dor underwent re-intervention for dysphagia with most occurring more than five years postoperatively. One patient in each group underwent redo Heller myotomy and subsequent esophagectomy. Nearly all patients (96%) would undergo operation again. CONCLUSIONS: Long-term patient-reported outcomes after Heller alone and Heller plus Dor for achalasia are comparable, providing support for either procedure.

Characterization of Electrophysiological Propagation by Multichannel Sensors.

OBJECTIVE: The propagation of electrophysiological activity measured by multichannel devices could have significant clinical implications. Gastric slow waves normally propagate along longitudinal paths that are evident in recordings of serosal potentials and transcutaneous magnetic fields. We employed a realistic model of gastric slow wave activity to simulate the transabdominal magnetogastrogram (MGG) recorded in a multichannel biomagnetometer and to determine characteristics of electrophysiological propagation from MGG measurements. METHODS: Using MGG simulations of slow wave sources in a realistic abdomen (both superficial and deep sources) and in a horizontally-layered volume conductor, we compared two analytic methods (second-order blind identification, SOBI and surface current density, SCD) that allow quantitative characterization of slow wave propagation. We also evaluated the performance of the methods with simulated experimental noise. The methods were also validated in an experimental animal model. RESULTS: Mean square errors in position estimates were within 2 cm of the correct position, and average propagation velocities within 2 mm/s of the actual velocities. SOBI propagation analysis outperformed the SCD method for dipoles in the superficial and horizontal layer models with and without additive noise. The SCD method gave better estimates for deep sources, but did not handle additive noise as well as SOBI. CONCLUSION: SOBI-MGG and SCD-MGG were used to quantify slow wave propagation in a realistic abdomen model of gastric electrical activity. SIGNIFICANCE: These methods could be generalized to any propagating electrophysiological activity detected by multichannel sensor arrays.

Pharyngostomy.

A retrospective analysis of a prospective observational study of a cohort of patients who required prolonged foregut/midgut decompression/intraluminal stenting and/or enteral nutritional support was conducted. Those patients were intolerant of protracted nasogastric intubation. They also manifested hostile peritoneal cavities and therefore were not candidates for a laparoendoscopic gastrostomy or jejunostomy. Accordingly, they underwent insertion of a pharyngogastric or pharyngojejunal tube. With patients properly positioned and anesthetized and with attention to the anatomy of the superior carotid cervical triangle, those pharyngostomies and cannulations were performed safely and efficiently. The tubes remained indefinitely or were changed/removed ad libitum. Morbidity was nil and no mortality attributable to the procedure was observed. Pharyngostomy should be part of the armamentarium of all general surgeons.

Evaluation of Microvascular Perfusion and Resuscitation after Severe Injury.

Achieving adequate perfusion is a key goal of treatment in severe trauma; however, tissue perfusion has classically been measured by indirect means. Direct visualization of capillary flow has been applied in sepsis, but application of this technology to the trauma population has been limited. The purpose of this investigation was to compare the efficacy of standard indirect measures of perfusion to direct imaging of the sublingual microcirculatory flow during trauma resuscitation. Patients with injury severity scores >15 were serially examined using a handheld sidestream dark-field video microscope. In addition, measurements were also made from healthy volunteers. The De Backer score, a morphometric capillary density score, and total vessel density (TVD) as cumulative vessel area within the image, were calculated using Automated Vascular Analysis (AVA3.0) software. These indices were compared against clinical and laboratory parameters of organ function and systemic metabolic status as well as mortality. Twenty severely injured patients had lower TVD (X = 14.6 ± 0.22 vs 17.66 ± 0.51) and De Backer scores (X = 9.62 ± 0.16 vs 11.55 ± 0.37) compared with healthy controls. These scores best correlated with serum lactate (TVD R(2) = 0.525, De Backer R(2) = 0.576, P < 0.05). Mean arterial pressure, heart rate, oxygen saturation, pH, bicarbonate, base deficit, hematocrit, and coagulation parameters correlated poorly with both TVD and De Backer score. Direct measurement of sublingual microvascular perfusion is technically feasible in trauma patients, and seems to provide real-time assessment of microcirculatory perfusion. This study suggests that in severe trauma, many indirect measurements of perfusion do not correlate with microvascular perfusion. However, visualized perfusion deficiencies do reflect a shift toward anaerobic metabolism.

Bariatric surgery improves the circulating numbers and biological activity of late outgrowth endothelial progenitor cells.

BACKGROUND: Although the salutary effects of bariatric surgery as a treatment for excess weight and type 2 diabetes are established, there is scant evidence for effects on other contributors to cardiovascular diseases such as repair of endothelial dysfunction. This study evaluates outcomes of bariatric surgery on late outgrowth endothelial progenitor cells (LOEPCs), a cell phenotype essential for endothelial repair. METHODS: Patients with a body mass index >35 kg/m(2) and type 2 diabetes were enrolled into either medical or bariatric surgical arms. Primary outcomes included analysis of isolated LOEPCs from peripheral blood for growth, function, and mitochondrial respiration. Plasma was used for metabolic profiling. RESULTS: Medical arm patients showed no improvement in any of the parameters tested. Bariatric surgical arm patients showed a 24% reduction in body mass index as early as 3 months postintervention and resolution of type 2 diabetes at 24 months postintervention (HbA1c 31% reduction; fasting glucose 29% reduction). Bariatric surgery increased the numbers of LOEPCs 8-fold and increased LOEPC network formation 3-fold at 24 months postintervention. The increased numbers and activity of LOEPCs in the bariatric surgical arm correlated with improvements in body mass index, insulin, and triglyceride levels only at 24 month postintervention. LOEPC mitochondrial respiration displayed a trend toward improvement compared with baseline as evidenced by an increase (36%) at 24 months in the bariatric arm. CONCLUSION: Bariatric surgery increases LOEPC levels and activity, which correlates with weight loss and improved metabolic profile at 24 months postintervention.

microRNA-29 negatively regulates EMT regulator N-myc interactor in breast cancer.

BACKGROUND: N-Myc Interactor is an inducible protein whose expression is compromised in advanced stage breast cancer. Downregulation of NMI, a gatekeeper of epithelial phenotype, in breast tumors promotes mesenchymal, invasive and metastatic phenotype of the cancer cells. Thus the mechanisms that regulate expression of NMI are of potential interest for understanding the etiology of breast tumor progression and metastasis. METHOD: Web based prediction algorithms were used to identify miRNAs that potentially target the NMI transcript. Luciferase reporter assays and western blot analysis were used to confirm the ability of miR-29 to target NMI. Quantitive-RT-PCRs were used to examine levels of miR29 and NMI from cell line and patient specimen derived RNA. The functional impact of miR-29 on EMT phenotype was evaluated using transwell migration as well as monitoring 3D matrigel growth morphology. Anti-miRs were used to examine effects of reducing miR-29 levels from cells. Western blots were used to examine changes in GSK3ß phosphorylation status. The impact on molecular attributes of EMT was evaluated using immunocytochemistry, qRT-PCRs as well as Western blot analyses. RESULTS: Invasive, mesenchymal-like breast cancer cell lines showed increased levels of miR-29. Introduction of miR-29 into breast cancer cells (with robust level of NMI) resulted in decreased NMI expression and increased invasion, whereas treatment of cells with high miR-29 and low NMI levels with miR-29 antagonists increased NMI expression and decreased invasion. Assessment of 2D and 3D growth morphologies revealed an EMT promoting effect of miR-29. Analysis of mRNA of NMI and miR-29 from patient derived breast cancer tumors showed a strong, inverse relationship between the expression of NMI and the miR-29. Our studies also revealed that in the absence of NMI, miR-29 expression is upregulated due to unrestricted Wnt/ß-catenin signaling resulting from inactivation of GSK3ß. CONCLUSION: Aberrant miR-29 expression may account for reduced NMI expression in breast tumors and mesenchymal phenotype of cancer cells that promotes invasive growth. Reduction in NMI levels has a feed-forward impact on miR-29 levels.