Mechanism of immune dysfunction in sepsis: inducible nitric oxide-meditated alterations in p38 MAPK activation

BACKGROUND: After the onset of sepsis, there is a marked dysfunction in cell-mediated immunity that contributes to the morbidity and mortality seen in this condition. Although both nitric oxide (NO) from inducible NO synthase (iNOS) and the activation of p38 mitogen-activated protein kinase (p38 MAPK) appear to contribute to this immune dysfunction, the extent to which NO regulates p38 MAPK activity in sepsis remains unknown. METHODS: To examine this, we induced sepsis by cecal ligation and puncture (CLP) in iNOS knockout (iNOS -/-) or C57BL/6 control mice. Twenty-four hours after CLP or sham operation, splenic T cells and macrophages were isolated and then stimulated with monoclonal antibody against the T-cell marker CD3 (anti-CD3) or lipopolysaccharide. At 4 or 24 hours after stimulation, cytokine release was determined by enzyme-linked immunosorbent assay, and p38 MAPK phosphorylation (activation) was determined by immunoblotting with antibody specific to phosphorylated p38 MAPK. RESULTS: Splenic T-cell p38 MAPK activation and interleukin (IL)-10 release was increased by CLP, whereas Th1 cytokine (IL-2, interferon-gamma) release was depressed. iNOS gene deficiency inhibited p38 MAPK activation in splenic T cells taken from septic mice, and also suppressed IL-10 release in both sham and septic mice. Interestingly, although deficiency of iNOS restored IL-2 release after CLP, both sham and CLP T cells remained depressed in their ability to release interferon-gamma. Septic insult markedly suppressed C57BL/6 splenic macrophage release of proinflammatory agents tumor necrosis factor, IL-12, and IL-1, while augmenting the release of IL-10. However, although deficiency of iNOS concomitantly restored the ability to produce tumor necrosis factor while suppressing the rise in IL-10 release and p38 MAPK activation, it only partially restored IL-1 release and had no effect on IL-12 production seen after CLP. CONCLUSION: These data suggest that NO release from iNOS regulates aspects of sepsis-induced immune dysfunction by the activation of p38 MAPK.     

Adult-to-adult living donor liver transplantation at the Asan Medical Center,Korea

Between February 1997 and December 2001, 311 adult-to-adult living donor liver transplants (A-A LDLTs) were performed at the Asan Medical Center for patients above 20 years of age. Indications for A-A LDLT were: chronic hepatitis B (203), chronic hepatitis C (5), hepatocellular carcinoma (64), alcoholic cirrhosis (9), cryptogenic cirrhosis (4), secondary biliary cirrhosis (5), primary biliary cirrhosis (1), Wilson' s disease (2), autoimmune hepatitis (1), hepatic tuberculosis (1), cholangiocarcinoma (1), fulminant hepatic failure (14) and primary non-function of cadaveric liver graft (1). Of 311 A-A LDLTs, 36 were of medical high urgency, 20 were for acute and subacute hepatic failure, 15 were for hepato-renal syndrome and 1 was for primary non-function. Recipient age ranged from 27 to 64 years. Donor age ranged from 16 to 62 years. There was no donor mortality. Implanted liver grafts were categorized into seven types: 175 modified right lobe (MRL), 70 left lobe, 32 right lobe, 20 dual grafts, 10 left lobe plus caudate lobe, three extended right lobe and one posterior segment. In MRL, the tributaries of the middle hepatic vein were reconstructed by interpositioning a vein graft. Indication for dual graft implantation was the same as single graft A-A LDLT, and four of 20 were emergency cases. Of 20 dual grafts, 14 received two left lobes, four received a left lobe and a lateral segment, one received a right lobe and a left lobe and one received a lateral segment and a posterior segment. Graft volume ranged from 28% to 83% of the standard liver volume of the recipients. There were 33 (10.6%) in-hospital mortalities (< 4 months) among the 310 patients after 311 A-A LDLTs. Of the 36 patients receiving emergency transplants, 31 survived. These encouraging results justify the expansion of A-A LDLT in coping with increasing demands, even in urgent situations. We have aimed to introduce the establishment of the efficacy of A-A LDLT in various end-stage chronic and acute liver diseases, as well as new technical advances to overcome small graft-size syndrome by using dual-graft implantation and MRL, both of which were first developed in our department.     

Evaluation of postural stability after low-dose droperidol in outpatients undergoing gynaecological dilatation and curettage procedure

Background. Low-dose droperidol is suggested to be cost-effectivein preventing nausea and vomiting after ambulatory surgery.This clinical study evaluated patient postural stability usinga computerized force platform after an i.v. dose of droperidol0.625 mg in outpatients undergoing gynaecological dilatationand curettage procedures. Methods. After institutional approval and informed consent,120 females were randomly assigned to receive either 0.9% saline(placebo) or droperidol 0.625 mg i.v. before surgery. Anaesthesiawas induced with propofol 2–2.5 mg kg^–1and fentanyl 50–100 µg, and was maintainedwith intermittent boluses of propofol 25–50 mg andfentanyl 25–50 µg i.v. After operation, thePost-Anaesthesia Discharge Score (PADS), patient self-assessmentscores for pain, nausea, drowsiness and dizziness, and extrapyramidalsymptoms were recorded. Body sway velocity was measured whilethe patient was standing on a firm surface with eyes open thenclosed vs standing on a foam surface with eyes open then closed,at the time of arrival in the operation holding area (baseline),on achieving a PADS of 9 after surgery and on discharge home. Results. At the time of achieving a PADS of 9, body sway wassignificantly greater in the droperidol group than in the placebogroup (overall 61% vs 33% above baseline). There were no differencesbetween groups with respect to scores for pain, nausea, drowsinessand dizziness. Three patients (5%) in the droperidol group reportednervousness and restlessness postoperatively (not significant). Conclusion. Low-dose droperidol 0.625 mg i.v. for anti-emeticprophylaxis can cause balance disturbances in females aftergynaecological dilatation and curettage procedures. Br J Anaesth 2002; 88: 819–23     

Probable gas embolism during operative hysteroscopy caused by products of combustion

PURPOSE: Gas embolism is a rare but well documented entity during operative hysteroscopy, with an incidence of 10-50%. Catastrophic outcomes occur at a rate of three in 17,000 procedures. The purpose of this report is to present a non-fatal case of gas embolism probably caused by the gaseous products of combustion. CLINICAL FEATURES: A 50-yr-old woman with a history of menorrhagia was scheduled for hysteroscopy and endometrial ablation and polypectomy. Fifteen minutes into the procedure, with the patient in lithotomy position, 20 degree head down tilt, and breathing spontaneously, a sudden oxygen desaturation occurred from 97% to 87%. The patient's end-tidal carbon dioxide dropped from 46 mmHg to 27 mmHg. The patient's breathing pattern remained normal, respiratory rate remained 11-12 breaths x min(-1) but amplitude of the reservoir bag movement was increased. Cardiovascular variables remained stable. She responded rapidly to 100% oxygen and made an uneventful recovery. Having ruled out other possible causes, we concluded gas embolism was responsible for the fall in oxygen saturation and end-tidal CO(2). CONCLUSION: With all the precautions in place to minimize the likelihood of fluid overload and ambient air embolism occurring, we surmised that products of combustion were the cause of the gas embolism. During endometrial ablation, gaseous products of combustion, mainly carbon dioxide, accumulate. The gases may then contribute to the rise in uterine pressure that occurs as irrigation fluid enters the uterus and this rise in pressure in turn encourages passage of gas into the open venous sinuses.     

A new method of functional tendon transfer for the dysfunction of extensor hallucis longus

A surgical technique of functional tendon transfer for the treatment of extensor hallucis longus (EHL) rupture is described. By using the extensor digitorum longus tendon of the second toe, the patient regains active dorsiflexion of the big toe and the deformity of the toe is corrected.     

Impact of the Introduction of Laparoscopic Wedge Resection as a Surgical Option for Suspected Small/Medium-Sized Gastrointestinal Stromal Tumors of the Stomach on Perioperative and Oncologic Outcomes

Background  

The present study is designed to determine the feasibility and impact of the introduction of laparoscopic wedge resection as a surgical option for the treatment of suspected small/medium-sized (<7 cm) gastric gastrointestinal stromal tumors (GISTs).     

Potassium Bicarbonate Supplementation Lowers Bone Turnover and Calcium Excretion in Older Men and Women: A Randomized Dose‐Finding Trial

The acid load accompanying modern diets may have adverse effects on bone and muscle metabolism. Treatment with alkaline salts of potassium can neutralize the acid load, but the optimal amount of alkali is not established. Our objective was to determine the effectiveness of two doses of potassium bicarbonate (KHCO₃) compared with placebo on biochemical markers of bone turnover, and calcium and nitrogen (N) excretion. In this double‐blind, randomized, placebo‐controlled study, 244 men and women age 50 years and older were randomized to placebo or 1 mmol/kg or 1.5 mmol/kg of KHCO₃ daily for 3 months; 233 completed the study. The primary outcomes were changes in 24‐hour urinary N‐telopeptide (NTX) and N; changes in these measures were compared across the treatment groups. Exploratory outcomes included 24‐hour urinary calcium excretion, serum amino‐terminal propeptide of type I procollagen (P1NP), and muscle strength and function assessments. The median administered doses in the low‐dose and high‐dose groups were 81 mmol/day and 122 mmol/day, respectively. When compared with placebo, urinary NTX declined significantly in the low‐dose group (p = 0.012, after adjustment for baseline NTX, gender, and change in urine creatinine) and serum P1NP declined significantly in the low‐dose group (p = 0.004, adjusted for baseline P1NP and gender). Urinary calcium declined significantly in both KHCO₃ groups versus placebo (p < 0.001, adjusted for baseline urinary calcium, gender, and changes in urine creatinine and calcium intake). There was no significant effect of either dose of KHCO₃ on urinary N excretion or on the physical strength and function measures. KHCO₃ has favorable effects on bone turnover and calcium excretion and the lower dose appears to be the more effective dose. Long‐term trials to assess the effect of alkali on bone mass and fracture risk are needed. © 2015 American Society for Bone and Mineral Research.     

Effects of trypsinization and mineralization on intrasynovial tendon allograft healing to bone

The purpose of the current study was to develop a novel technology to enhance tendon‐to‐bone interface healing by trypsinizing and mineralizing (TM) an intrasynovial tendon allograft in a rabbit bone tunnel model. Eight rabbit flexor digitorum profundus (FDP) tendons were used to optimize the trypsinization process. An additional 24 FDP tendons were stratified into control and TM groups; in each group, 4 tendons were used for in vitro evaluation of TM and 8 were transplanted into proximal tibial bone tunnels in rabbits. The samples were evaluated histologically and with mechanical testing at postoperative week 8. Maximum failure strength and linear stiffness were not significantly different between the control and TM tendons. A thin fibrous band of scar tissue formed at the graft‐to‐bone interface in the control group. However, only the TM group showed obvious new bone formation inside the tendon graft and a visible fibrocartilage layer at the bone tunnel entrance. This study is the first to explore effects of TM on the intrasynovial allograft healing to a bone tunnel. TM showed beneficial effects on chondrogenesis, osteogenesis, and integration of the intrasynovial tendon graft, but mechanical strength was the same as the control tendons in this short‐term in vivo study. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:468–474, 2015.