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The transcription factor and oncoprotein MYC is a potent driver of many human cancers and can regulate numerous biological activities that contribute to tumorigenesis. How a single transcription factor can regulate such a diverse set of biological programmes is central to the understanding of MYC function in cancer. In this Perspective, we highlight how multiple proteins that interact with MYC enable MYC to regulate several central control points of gene transcription. These include promoter binding, epigenetic modifications, initiation, elongation and post-transcriptional processes. Evidence shows that a combination of multiple protein interactions enables MYC to function as a potent oncoprotein, working together in a 'coalition model', as presented here. Moreover, as MYC depends on its protein interactome for function, we discuss recent research that emphasizes an unprecedented opportunity to target protein interactors to directly impede MYC oncogenesis.

By identifying MYC protein-protein interactors, we aim to gain a deeper mechanistic understanding of MYC as a regulator of gene transcription and potent oncoprotein. This information can then be used to devise strategies for disrupting critical MYC protein-protein interactions to inhibit MYC-driven tumorigenesis. In this chapter, we discuss four techniques to identify and validate MYC-interacting partners. First, we highlight BioID, a powerful discovery method used to identify high-confidence proximal interactors in living cells. We also discuss bioinformatic prioritization strategies for the BioID-derived MYC-proximal complexes. Next, we discuss how protein interactions can be validated using techniques such as in vivo-in vitro pull-down assays and the proximity ligation assay (PLA). We conclude with an overview of biolayer interferometry (BLI), a quantitative method used to characterize direct interactions between two proteins in vitro. Overall, we highlight the principles of each assay and provide methodology necessary to conduct these experiments and adapt them to the study of interactors of additional proteins of interest.

Objective:Meta-analyses report moderate effects across cognitive remediation (CR) trials in schizophrenia. However, individual responses are variable, with some participants showing no appreciable gain in cognitive performance. Furthermore, reasons for heterogeneous outcome are undetermined. We examine the extent to which CR outcome is attributable to near learning—direct gains in trained cognitive tasks—while also exploring factors influencing far transfer of gains during training to external cognitive measures.Method:Thirty-seven schizophrenia outpatients were classified as CR responders and non-responders according to change in MATRICS Consensus Cognitive Battery composite score following 20 sessions of computer-based training. Metrics of near learning during training, as well as baseline demographic, clinical, cognitive, and electroencephalographic (EEG) measures, were examined as predictors of responder status.Results:Significant post-training improvement in cognitive composite score (Cohen’s d = .41) was observed across the sample, with n = 21 and n = 16 classified as responders and non-responders, respectively. Near learning was evidenced by significant improvement on each training exercise with practice; however, learning did not directly predict responder status. Group-wise comparison of responders and non-responders identified two factors favoring responders: higher EEG individual alpha frequency (IAF) and lower antipsychotic dosing. Tested in moderation analyses, IAF interacted with learning to predict improvement in cognitive outcome.Conclusion:CR outcome in schizophrenia is not directly explained by learning during training and appears to depend on latent factors influencing far transfer of trained abilities. Further understanding of factors influencing transfer of learning is needed to optimize CR efficacy.

Leukemia is broadly divided into acute and chronic lymphocytic and myeloid types based on the proportion of blasts, morphology of cells, and expression of specific antigens on neoplastic cells. Classifying leukemia in horses can be challenging if blasts predominate and since few antibodies to identify cell types are available. The objective of this study was to describe in detail the clinical and pathologic features of acute leukemia in horses. Twelve horses ranging from 0.2 to 25.9 years of age were diagnosed with acute leukemia. Six cases were classified as acute lymphocytic leukemia (ALL) based on predominance of blasts, lack of granulocytic or monocytic differentiation, and detection of CD3, CD20, and/or CD79a antigens by immunohistochemistry. Six other cases were classified as acute myeloid leukemia (AML) with myelomonocytic ( n = 4), basophilic ( n = 1), and eosinophilic ( n = 1) differentiation based on > 20% bone marrow blasts and partial leukocytic differentiation. Reactivity with antibodies to Iba-1/AIF-1, CD172a, and CD163 was determined for all cases of AML. Eleven horses had thrombocytopenia, 10 had neutropenia, 8 had anemia, all had blasts on blood films, and none had leukocytosis. Ten horses had increased serum acute phase proteins. Bone marrow cellularity ranged from 30% to 100%, and the proportion of blasts ranged from 80% to 100% and 30% to 60% in ALL and AML, respectively. Horses were severely ill at diagnosis and euthanized within days or weeks. Unique features of acute leukemia in horses compared to other species were variable lymphocyte antigen expression (ALL) and frequent inflammation (ALL and AML).

Objective—To evaluate influence of electrode position on cardioversion energy (CE; energy delivered in the shock at which cardioversion was achieved) during transvenous electrical cardioversion (TVEC) in horses with atrial fibrillation. Animals—37 horses with atrial fibrillation (41 cardioversion events). Procedures—Records were reviewed to identify horses that underwent TVEC for treatment of atrial fibrillation. Signalment and CE were recorded. Electrode positions in the right atrium and pulmonary artery were identified on intraoperative radiographs. An orthogonal coordinate space was created, and electrode y- and z-axis coordinates and shadow lengths were determined. Trigonometric modeling was used to estimate x-axis electrode positions that resulted in observed shadows. Postmortem casts of catheterized horses were used to assess electrode paths and anatomic relationships. Model assumptions were tested by use of these and a theoretical data set. Relationships between signalment, electrode position, and CE were assessed via multivariate analysis. Results—Sex and y-axis differences between electrode positions were significant predictors of CE. Population stratification based on examination of residuals improved model strength; populations differed in z-axis variables and in CE. Decreasing distance between electrodes and pulmonary artery electrode positions ventral to the right atrium were associated with increased CE. Agreement between estimated and actual x-axis coordinates was poor. Conclusions and Clinical Relevance—Optimal electrode positioning can reduce the energy requirement for successful TVEC and may eventually support application of TVEC under short-term IV anesthesia and potentially increase chances of treatment response. Further investigation into these relationships is warranted.

Liver kinase B1 (LKB1) is a tumor-suppressing protein that is involved in the regulation of muscle metabolism and growth by phosphorylating and activating AMP-activated protein kinase (AMPK) family members. Here we report the development of a myopathic phenotype in skeletal and cardiac muscle-specific LKB1 knockout (mLKB1-KO) mice. The myopathic phenotype becomes overtly apparent at 30–50 wk of age and is characterized by decreased body weight and a proportional reduction in fast-twitch skeletal muscle weight. The ability to ambulate is compromised with an often complete loss of hindlimb function. Skeletal muscle atrophy is associated with a 50–75% reduction in mammalian target of rapamycin pathway phosphorylation, as well as lower peroxisome proliferator-activated receptor-α coactivator-1 content and cAMP response element binding protein phosphorylation (43 and 40% lower in mLKB1-KO mice, respectively). Maximum in situ specific force production is not affected, but fatigue is exaggerated, and relaxation kinetics are slowed in the myopathic mice. The increased fatigue is associated with a 30–78% decrease in mitochondrial protein content, a shift away from type IIA/D toward type IIB muscle fibers, and a tendency ( P = 0.07) for decreased capillarity in mLKB1-KO muscles. Hearts from myopathic mLKB1-KO mice exhibit grossly dilated atria, suggesting cardiac insufficiency and heart failure, which likely contributes to the phenotype. These findings indicate that LKB1 plays a critical role in the maintenance of both skeletal and cardiac function.

Ciprofloxacin is a fluoroquinolone antimicrobial used extensively in human medicine. It is available in oral and i.v. preparations and is used widely in human medicine for the treatment of urinary, lower respiratory tract, skin, bone and joint infections (Lettieri et al. 1992). It is not labelled for use in horses and there have been no published studies reporting its therapeutic use in this species. This report describes a possible association of oral ciprofloxacin administration with the development of colitis in 4 Standardbred horses.

Background: Transvenous electrical cardioversion (TVEC) has been developed for treatment of atrial fibrillation (AF) in horses. The relationship among patient variables, treatment response, and outcome in a typical referral population has not been evaluated. Hypothesis: Patient variables such as age, sex, weight, and duration of arrhythmia affect prognosis for response to treatment and the energy level at which cardioversion occurs. Animals: TVEC was applied to 72 episodes of lone AF in 63 client-owned performance horses, with the majority (54) being Standardbred racehorses. Methods: Catheterization of the right atrium (RA) and pulmonary artery (PA) through the jugular vein was used for electrode placement before horses were placed under general anesthesia. Biphasic, truncated exponential shock waves were delivered at incremental energy levels until cardioversion was achieved or a maximum single-energy level of 300 J was reached (cumulative energy 50–1,960 J). A multivariate model was constructed to evaluate influence of patient factors on cardioversion energy. Results: Cardioversion was achieved in 71 of 72 episodes (62 of 63 horses) at a mean energy of 165.43 ± 8.75 J. Cardioversion energy was higher for females than for males, and for interaction terms, weight was negatively related to energy in females and positively related in males. Age was positively related to cardioversion energy in females. No relationship was identified between duration of arrhythmia before treatment and prognosis for response or cardioversion energy. Conclusions and Clinical Importance: TVEC is highly effective in the treatment of lone AF in horses. Although age and sex influence cardioversion energy level, duration of arrhythmia does not.

Objective—To describe management of anesthesia for transvenous electrical cardioversion (TVEC) in horses and report perianesthetic complications. Design—Retrospective case series. Animals—62 horses with atrial fibrillation and without underlying cardiac disease and 60 horses without atrial fibrillation. Procedures—Medical records of horses with atrial fibrillation anesthetized for TVEC were reviewed, as were records of horses without atrial fibrillation anesthetized for magnetic resonance imaging (MRI). The TVEC group horses were compared with MRI group horses for incidence of intraoperative bradycardia and use of inotropic drugs. Data obtained included patient signalment, weight, duration of anesthesia, heart rate and arterial blood pressure during anesthesia, anesthetic drugs administered, mode of ventilation, perioperative complications, and quality of recovery. Results—The TVEC group horses were > 1 year of age and were predominantly Standardbreds. The TVEC group horses underwent a total of 76 anesthetic episodes. For 40 (52.6%) anesthetic episodes, horses received xylazine only for premedication, and for 26 (34.2%) anesthetic episodes, horses received xylazine and butorphanol. Induction of anesthesia consisted of ketamine administration in various combinations with diazepam and guaifenesin for 74 (97.4%) anesthetic episodes and ketamine alone for 2 (2.6%). Bradycardia in horses was encountered during 15 of 76 (19.7%) anesthetic episodes. Minor signs of possible postanesthetic myopathy occurred following 6 (7.9%) anesthetic episodes. No significant difference was found between TVEC and MRI group horses regarding incidence of bradycardia and inotropic drug administration. Conclusions and Clinical Relevance—Short-duration anesthesia for TVEC of atrial fibrillation in horses without underlying cardiac disease was a safe procedure.

Electrical cardioversion of atrial fibrillation is a well-established technique for restoration of sinus rhythm in humans. While transthoracic cardioversion is more commonly used, transvenous electrical cardioversion (TVEC) has been reported as having higher efficacy at substantially lower energy levels. In horses, treatment of atrial fibrillation has essentially been limited to the administration of quinidine salts either orally or intravenously. TVEC provides an alternative to quinidine salts, especially for those animals in which quinidine is neither effective nor tolerated. The present report details this technique in horses, discusses possible complications of the procedure, and provides guidance for successful outcome. Still and video images are used to illustrate details with regard to TVEC techniques in horses. Please view supplemental material for the videos.

A 2-week-old Toggenburg kid was evaluated for persistent diarrhea and poor body condition. The herd had high morbidity and mortality associated with diarrhea in neonatal kids. Lactose intolerance was diagnosed on the basis of results of a lactose tolerance test and glucose absorption test. Clinically normal herdmates were used as control animals. The kid responded to lactase supplementation. Cryptosporidium organisms were detected in feces of several affected kids during episodes of acute diarrhea. Lactose intolerance was presumed to have developed secondary to intestinal cryptosporidiosis.

To assess evidence for genetic contributions to atrial fibrillation (AF) in the Standardbred horse.Equine referrals to the Ontario Veterinary College Health Sciences Centre (OVCHSC) for 1985-2009, and age and gait matched breed registry controls.Breeds presenting ≥ 5 times annually were tabulated (admission year and diagnosis; total 40,039; AF 396; no AF 39,643), and breed and year effects examined. Heritability and inbreeding coefficients were determined for Standardbred AF cases and racing contemporaries, and odds ratios for AF were calculated for frequently occurring sires.Year and breed effects on diagnosis were highly significant (Chi-Square 212.85, p0.0001, and 304.25, p0.0001, respectively). Year effect on diagnosis by breed was significant from 1997, and due to Standardbred admissions each year. Quarterhorses were significantly less likely to present with AF (OR 0.0578-0.6048), Standardbreds were more likely (OR 4.3874-10.9006). Heritability of AF on the underlying scale (h²(u)) was estimated at 29.6 ± 3.9% and on the observed binomial scale (h²(o)), at 9.6%. For horses born in 1994 or later, h²(u) was 31.1 ± 4.3% and h²(o), 10.1%. Of 22 first generation sires appearing ≥ 10 times in the case/control file, seven pacing and one trotting sire produced affected horses more frequently than expected (OR 2.66-66.32). Inbreeding was not a factor.There is genetic liability to AF in Standardbred horses, likely due to more than single genes with simple Mendelian inheritance. Genomic studies are required.

Objective : To study the responsiveness of peripheral blood mononuclear cells to lipopolysaccharide (LPS) after severe trauma and its regulatory mechanisms. Materials and Methods : The release of proinflammatory reacting cytokines (tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, interferon (IFN)-γ) into whole blood from 12 patients on day 1, 5, 10, and 14 after severe trauma (Injury Severity Score, 39.3 ± 2.8 points) and 10 healthy volunteers was studied after stimulation with LPS, concanavalin A, phorbol myristate acetate (PMA), and the addition of recombinant IFN-γ. Main Results : Trauma caused a significant reduction of LPS and concanavalin A induced release of inflammation activating cytokines into whole blood, including IFN-γ. However, the diminished release of proinflammatory cytokines could be increased with recombinant IFN-γ or even attenuated after stimulation of peripheral blood mononuclear cells with the protein kinase C activator PMA. Conclusions : Trauma leads to reduced responsiveness of blood monocytes to LPS and a decreased secretion of proinflammatory reacting lymphokines. Because activation of the protein kinase C pathway with PMA or the addition of IFN-γ significantly increased cytokine response, endotoxin tolerance is not caused by inhibition of protein synthesis, but to disturbances in the signal transduction pathway and its regulating mediators.

Norplant's long duration of action may result in users being less motivated than non-users to return for reproductive health care appointments. This study determined compliance with scheduled return appointments among adolescents using Norplant and those using other methods of contraception.We retrospectively reviewed the records of all teenagers (ageor = 18 years) who received Norplant between June 1991 and August 1993, as well as those of a comparison group of adolescents, matched for age and race, using other methods of contraception. Subjects receiving Norplant were given appointments for a two-week and an annual examination. Comparison subjects were given only an appointment for an annual examination. Norplant users not returning within 5 weeks or any subject not presenting within 12 months for an annual examination, were considered non-compliant.Eighty-eight adolescents received Norplant during the study period and the records of 85 were available for review. Only 48 of the 85 Norplant users returned for scheduled two-week check-up, while 18 of 43 subjects who had Norplant at least 12 months were compliant with annual examinations. The compliance rate with annual examinations among the 89 subjects not using Norplant was 38%, not dissimilar from that of the Norplant group.These data demonstrate that compliance with return appointments for reproductive health care among adolescent Norplant users is poor but not significantly worse than that of non-users of Norplant. Strategies promoting the benefits of return visits need to be improved for adolescents receiving contraception.Although the long-term protection from pregnancy conferred by Norplant use makes this a potentially effective method for adolescents, there are concerns that teenagers with implants will not be motivated to return for routine reproductive health examinations. To assess this possibility, compliance with scheduled return clinic appointments among 85 Norplant acceptors aged 18 years and younger and 89 age- and race-matched controls was compared through retrospective review of records at a community-based family planning clinic in North Carolina. Only 14 Norplant acceptors returned to have the insertion site examined within five weeks of insertion; another seven appeared for the initial examination after a reminder was mailed, yielding a 25% compliance rate. In terms of the annual examination, 18 of the 43 subjects who had used Norplant for at least 12 months and 34 of the 89 controls were compliant. There was no significant difference in this compliance rate between cases (41.9%) and users of other methods (38.2%). Among cases, the records showed that appointment compliance after Norplant insertion was not significantly lower than it had been among these women when they were using other methods. Only three Norplant acceptors discontinued the method, indicating a high degree of user satisfaction. Although these findings indicate that Norplant use does not increase the risk of poor compliance with reproductive health care, they indicate a need to convince teenagers of the benefits of such care, especially for the detection of sexually transmitted diseases.

Case Description—4 racehorses were examined because of markedly abnormal behavior following administration of fluphenazine decanoate. Clinical Findings—Clinical signs included restlessness, agitation, profuse sweating, hypermetria, aimless circling, intense pawing and striking with the thoracic limbs, and rhythmic swinging of the head and neck alternating with episodes of severe stupor. Fluphenazine was detected in serum or plasma from all 4 horses. The dose of fluphenazine decanoate administered to 3 of the 4 horses was within the range (25 to 50 mg) routinely administered to adult humans. Treatment and Outcome—In 2 horses, there was no response to IV administration of diphenhydramine hydrochloride, but the abnormal behavior in these 2 horses appeared to resolve following administration of benztropine mesylate, and both horses returned to racing. The other 2 horses responded to diphenhydramine administration. One returned to racing. The other was euthanized because of severe neurologic signs, respiratory failure, and acute renal failure. Clinical Relevance—Findings indicate that adverse extrapyramidal effects may occur in horses given fluphenazine decanoate. These effects appear to be unpredictable and may be severe and life threatening. Use of fluphenazine decanoate as an anxiolytic in performance horses is not permitted in many racing and horse show jurisdictions, and analytic procedures are now available to detect the presence of fluphenazine in serum or plasma.

Objective—To determine clinical signs, diagnostic findings, outcome, and prognostic factors in dogs treated surgically for massive hepatocellular carcinoma (HCC) and compare survival times of surgically and conservatively treated dogs. Design—Retrospective study. Animals—48 dogs. Procedure—Medical records were examined for clinical signs, diagnostic and surgical findings, and postoperative outcome. Dogs were allocated into surgery and nonsurgery groups depending on whether curative- intent liver lobectomy was performed. Data from the surgical and nonsurgical groups were analyzed to identify prognostic factors and determine and compare rates of tumor control and survival time. Results—42 dogs were treated surgically, and 6 were managed conservatively. In the surgery group, intraoperative mortality rate was 4.8% with no local recurrence, metastatic rate was 4.8%, and median survival time was > 1,460 days (range, 1 to 1,460 days). High alanine aminotransferase and aspartate aminotransferase activities were associated with poor prognosis. Median survival time for the nonsurgery group was 270 days (range, 0 to 415 days), which was significantly less than that of surgically treated dogs. Conclusions and Clinical Relevance—Liver lobectomy is recommended for dogs with massive HCC because tumor-related mortality rate was 15.4 times higher in dogs in the nonsurgery group, compared with the surgery group. Tumor control was excellent after surgical resection with no local recurrence and a low metastatic rate. Prognostic factors were identified, but their clinical relevance was uncertain because only 9.5% of dogs in the surgery group died as a result of their disease. (J Am Vet Med Assoc 2004;225:1225–1230)

Objective—To identify and characterize motilin receptors in equine duodenum, jejunum, cecum, and large colon and to determine whether erythromycin lactobionate competes with porcine motilin for binding to these receptors. Sample Population—Specimens of various segments of the intestinal tracts of 4 adult horses euthanatized for reasons unrelated to gastrointestinal tract disease. Procedure—Cellular membranes were prepared from smooth muscle tissues of the duodenum, jejunum, pelvic flexure, and cecum. Affinity and distribution of motilin binding on membrane preparations were determined by use of 125I-labeled synthetic porcine motilin. Displacement studies were used to investigate competition between 125I-labeled synthetic porcine motilin and erythromycin lactobionate for binding to motilin receptors in various segments of bowel. Results—Affinity of 125I-labeled synthetic porcine motilin for the equine motilin receptor was estimated to be 6.1nM. A significantly higher number of motilin receptors was found in the duodenum than in the pelvic flexure and cecum. The jejunum had a significantly higher number of motilin receptors than the cecum. Erythromycin lactobionate displacement of 125I-labeled porcine motilin from the equine motilin receptor did not differ significantly among various segments of bowel. Conclusions and Clinical Relevance—Motilin receptors were found in the duodenum, jejunum, pelvic flexure, and cecum of horses. The highest number of motilin receptors was in the duodenum, and it decreased in more distal segments of bowel. Erythromycin lactobionate competed with motilin binding in the equine gastrointestinal tract. This suggests that 1 of the prokinetic actions of erythromycin in horses is likely to be secondary to binding on motilin receptors. (Am J Vet Res 2002;63:1545–1550)

Purpose The localization and site of action of photosensitizers in the eye may be important for photodynamic therapy for fundus disorders but remain poorly understood for most agents. We investigated the intraocular localization of xanthene, phthalocyanine, and chlorin photosensitizers by using fluorescence microscopy and digital fundus fluorescence angiography. Methods Rose bengal (40 mg/kg), aluminum phthalocyanine tetrasulfonate (CASPc) (5 mg/kg), or chlorin e6 (2 mg/kg) was intravenously administered to albino rabbits. The eyes were enucleated and examined by means of fluorescence microscopy 5, 20, 60, and 120 minutes and 24 hours after dye injection. In vivo digital fundus fluorescence angiography with use of rose bengal (2–4 mg/kg), CASPc (2 mg/kg), and chlorin e6 (2 mg/kg) was performed. Results For all agents studied pathologically, there was moderate fluorescence from the choroid and retinal pigment epithelium 5 minutes after dye injection. Mild fluorescence detected from the photoreceptor outer segments at 5 minutes was increased at 20 minutes. Angiographic studies with use of rose bengal, CASPc, and chlorin e6 revealed differences in the pattern and rate of photosensitizer accumulation. Conclusions Rose bengal, CASPc, and chlorin e6 accumulate rapidly in the choroid and retinal pigment epithelium and less rapidly in the outer retina. Differences in ocular localization of these photosensitizers were demonstrated. The significance of these findings for potential photodynamic therapy with these agents requires further investigation.

Purpose: To study the efficacy of liposomal benzoporphyrin derivative (BPD) (Verteporfin) for the angiographic visualization and photodynamic therapy (PDT) of experimental iris neovascularization. Methods: Experimental iris neovascularization was induced in eight cynomolgus monkey eyes by occluding all the branch retinal veins with a dye-yellow (577-nm) laser. Iris angiography was done with sodium fluorescein, indocyanine green (ICG), and Liposomal BPD to compare the visualization of normal and neovascular vessels by these three dyes. PDT was performed using an intravenous infusion of liposomal BPD (0.375-0.75 mg/kg), followed by irradiation with 689-nm light from a diode laser/slit-lamp delivery system using 600 mW/cm 2 irradiance and 150 J/cm 2 fluence. The effect of treatment was followed by iris photography and angiography, and the findings were confirmed by histopathology using light and electron microscopy. Results: Iris fluorescein angiography (FA) showed superficial tortuous and leaky new vessels. Liposomal BPD and ICG angiography of the same eye demonstrated deeper dilated and tortuous iris vessels, with minimal dye leakage. PDT of the iris with irradiation, performed within 20 minutes of the start of dye infusion (0.75 mg/kg), resulted in angiographic and histologic occlusion of iris vessels examined at 24 hours. Three to nine days after PDT, histopathologic examination showed regression of the iris neovascular membrane, with some open vessels. Conclusions: Liposomal BPD and ICG provided angiographic visualization of deeper normal and neovascular iris vessels. PDT using liposomal BPD leads to effective early closure to experimental iris neovascularization.

Background : Excessive release of proinflammatory cytokines has been involved in pathogenesis of acute respiratory distress syndrome. Design : Since injured patients with chest trauma reveal a high risk for posttraumatic acute respiratory distress syndrome, local and systemic release of proinflammatory cytokines and their naturally occurring inhibitors were determined in the early posttraumatic period. Materials and Methods : Proinflammatory and anti-inflammatory mediators were measured in plasma and bronchoalveolar lavage fluid (BALF) from 16 patients with multiple injuries including severe chest injury (Injury Severity Score of 34.4 ± 2.3 points) and compared with healthy volunteers (n = 17). Results : Tumor necrosis factor-α was detectable neither in plasma nor in BALF. Interleukin-1β and interleukin-8 were significantly increased in BALF from injured patients, while plasma levels were similar in both groups. Soluble tumor necrosis factor receptors p55 and p75 and interleukin-lra were markedly elevated in plasma (p ≤ 0.01) and BALF (p ≤ 0.001) from injured patients compared with controls. Conclusion : Highly increased concentrations of proinflammatory cytokines in BALF, but not in circulation, indicate a strong local inflammatory response early after multiple injuries combined with chest injury rather than severe systemic inflammation. In contrast, anti-inflammatory mechanisms seem to be activated locally and systemically.

Congestive heart failure (CHF) is accompanied by increased sympathetic nervous activity. Previous studies have demonstrated that plasma norepinephrine (NE), a marker of sympathetic nervous activity, is elevated in CHF due to increased NE spillover into the circulation and decreased NE clearance. In this study we compared the clearance of NE and isoproterenol (ISO) in eight CHF subjects (plasma NE 601 +/- 133 pg/ml), and in nine controls (plasma NE 285 +/- 53 pg/ml) by using steady-state infusions of tritiated NE ([3H]NE) and tritiated ISO ([3H]ISO). Because ISO is not a substrate of neuronal reuptake but is removed from the circulation in a way that is similar to NE after neuronal reuptake blockade with desipramine, ISO clearance may permit a gross estimation of non-neuronal uptake of circulating NE. The NE clearance was lower in CHF than in the control group (CHF 1.25 +/- 0.13, controls 2.04 +/- 0.22 l.min-1.m-2; P = 0.009). The ISO clearance was reduced similarly in CHF (CHF 0.90 +/- 0.09, controls 1.59 +/- 0.12 l.min-1.m-2; P less than 0.001). Because the ratio of ISO to NE clearance was similar in both groups, our findings suggest that a low cardiac output in CHF decreases the availability of circulating catecholamines to tissue elimination sites.

We carried out a case-control study to investigate the association between the risk of developing cystic ovaries and the concentrations of Se in the blood of dairy cows. Cows were from dairy herds in the vicinity of Ithaca, NY. One hundred and thirty-two cystic ovary cases were identified; a similar number of herdmates who did not have cystic ovaries were selected as controls. Whole blood samples were collected from cystic cows and controls in which Se concentrations were determined. Milk samples also were collected and analyzed for concentrations of progesterone. Multivariate logistic regression analysis was used to identify the role of Se in the risk of developing cystic ovaries while controlling for other possible risk factors. Mean Se in blood concentration for cows with cystic ovaries (141 ng/ml) was similar to that of control cows without cystic ovaries (136 ng/ml). The concentration of progesterone in milk was significantly higher in controls than in cows with cystic ovaries. In the multivariate logistic regression analysis, cows with concentrations of Se in blood greater than 169 ng/ml had twice the risk of developing cystic ovaries compared with cows that had Se levels less than 108 ng/ml.

Neck contracture after burn injury can result in severe functional as well as aesthetic deformities. Contracture can recur even after wide and complete release and full-thickness skin grafting. Recurrence is partly due to the inherent difficulties in both early postoperative immobilization and the required long-term splinting. When adjacent tissues are also burned, adequate local tissue for reconstruction may not be available; therefore, free-tissue transfer may be necessary. The large surface area that is required after adequate release may be provided by tissue expansion before free-tissue transfer. In the case presented the use of tissue-expanded radial forearm free flap for the reconstruction of a recurrent neck contracture is described.

Early tangential excision sometimes results in considerable blood loss, prolonged operative time, and partial loss of the graft secondary to hematoma formation. Previous reports document positive hemostatic effects and improved skin fixation with fibrin "glue." The commercial preparation used in Europe, however, has not been approved by the United States Food and Drug Administration because of the high risk of hepatitis and human immunodeficiency virus transmission. Using a method developed at the University of Virginia, we applied single-donor fibrin glue as an adjunct in early excision and grafting in 16 patients (26 hands). The overall graft take was 99%. In all patients, better adherence of the split-thickness graft to the recipient bed, during and immediately after application, was noted. We have observed no negative effects with regard to infection or healing. We recommend the use of single-donor fibrin glue to reduce operative blood loss, improve survival and ease of graft application, and possibly to accelerate healing.

Reconstruction of the burned penile urethra has received scant attention in the surgical literature. Techniques used in repairing congenital hypospadias may not be applicable in this situation. We describe a dartos musculocutaneous island flap used to reconstruct the distal burned penile urethra in a 13-year-old boy who sustained burns to 85% of his total body surface area. Reconstruction was completed in one surgical procedure, and at two-year follow-up good results were demonstrated.

Conventional treatment of equine atrial fibrillation (AF) involves administration of quinidine salts. Most uncomplicated cases respond to treatment, but pharmacologic cardioversion involves a range of adverse effects, and some horses are unable to tolerate medication. A study was undertaken to develop transvenous electrical cardioversion (TVEC) as an alternative treatment. Safety issues and catheter placement techniques with catheter-integrated cardioversion electrodes were investigated, and responses to shock application were evaluated. After the premortem catheterization of elective-euthanasia horses, no tissue abnormalities were detected at postmortem examination. To evaluate the response to the application of shocks and appropriate electrode positions, an electrical cardioversion of research horses in chronic AF was then attempted. After catheterization of the right atrium (RA) and pulmonary artery through the right jugular vein, horses were placed under general anesthesia. Biphasic, truncated exponential shock waves were delivered at incremental energies until cardioversion was achieved or until a maximum energy of 300 J was reached. Five treatment events were applied to 3 horses, with cardioversion achieved in one of the treatment events. No adverse effects of cardioversion attempts or general anesthesia were observed. The procedure was then applied to 8 client-owned horses, with cardioversion achieved in 7. No adverse responses to appropriately delivered shocks were observed. No antiarrhythmic medications were administered to any horse at any stage. Catheter design and placement technique evolved throughout the study, with combined ultrasonography and pressure guidance proving most effective in achieving appropriate electrode placement. Results suggest TVEC, as applied in the present study, is a safe, effective, and realistic therapeutic option for equine AF.

Primary cardiovascular manifestations of SSc include pericardial disease, myocardial disease, conduction abnormalities, and cardiac arrhythmias. Significant cardiac abnormalities are present in more than half of SSc patients at autopsy. As the frequency of subclinical cardiac involvement is now appreciated and noninvasive cardiac diagnostic modalities continue to improve, the ability to detect early asymptomatic involvement in SSc has improved. Two-dimensional echocardiography, radionucleotide imaging, and ambulatory ECG allow recurrent serial testing with virtually no morbidity. The current treatment of cardiac involvement in SSc is emperic and primarily directed at symptomatology. Large prospective randomized trials are needed to determine if preventive therapy is effective. With the advent of new immunological and cardiotropic agents and a better understanding of the primary disease process, our ability to alter the pathogenesis and final outcome of cardiac involvement in SSc should improve.

SUMMARY This article is a collective review of all the prospective clinical studies that assessed the therapeutic value of antibiotics in minor soft tissue lacerations. This review critically evaluates each study that tests the hypothesis that antibiotic treatment reduces the incidence of infection. Even though the design of each of the studies was scientifically inadequate, important factors were identified that influenced the incidence of infection. On the basis of this collective review as well as other studies, indications for antibiotic therapy of minor soft tissue lacerations have been identified. Future clinical studies must be designed to test more precisely the validity of these recommendations.

Treatment of burn injuries of the head and neck can be divided into acute and chronic stages. The acute phase consists of physiologic resuscitation of the patient and early care of the burn wound. The chronic stage begins from completion of wound coverage until the wound has matured. A major advance in the care of the patient with head and neck burns has been the realization that clinical application of exercise, traction, and pressure can reduce the development of contractures and hypertrophic scarring. Once the burn scars mature, the residual scar deformity can be improved by reconstructive surgical procedures.

The public expects firefighters not only to extinguish fires in burning structures but also to search out and assist victims whose lives are in immediate danger. Because of this expectation, many fire departments require firefighters to be certified as emergency medical technicians. Fire victims may suffer from chemical and electrical burns as well as thermal injury. Associated life-threatening problems include inadequate ventilation, impaired circulation, and extensive bleeding. High levels of carbon monoxide and other toxic gases may also pose a danger to life. This article describes the firefighter's assessment of the burn victim and discusses the emergency diagnosis and treatment of conditions that threaten the lives of victims of structural fires

Ambulatory patients with large sacral ulcers can represent extremely challenging coverage problems. Technical options become fewer when sacral ulcers are coupled with radiation dermatitis. Latissimus dorsi free flap transfer, with direct anastomoses to sacral vessels, is described in 2 patients.

A case report of a cystic preauricular mass that changed in size and position with jaw movement is presented. This tumor proved to be a ganglion of the temporomandibular joint (TM) cyst, which is relatively rare. When a preauricular mass retrudes into the masseter muscle in jaw opening, pathological conditions associated with the TMJ should be considered. Ganglion cysts of the TMJ are a benign pathological entity which can mimic parotid tumors. Temporomandibular joint radiography and perhaps ultrasonography of the region are useful in the preoperative evaluation of preauricular masses. The TMJ ganglion cyst can be successfully treated by direct excision and repair of the joint capsule. This approach avoids the potential morbidity of a superficial parotidectomy.

At the University of Virginia Hospital we have developed a new technique of urethroplasty utilizing a full-thickness flap of bladder wall. Tubing and transfer of the flap may be completed in two stages. The bladder flap is approximately 28 X 4 cm in size. Strictures have not occurred with this technique, but special care is needed in placing the tube to avoid kinking of the new urethra at the angle where the penile urethra passes anterior to the pubic bone. In conjunction with modern methods of phalloplasty, a two-stage reconstruction of the entire phallus, including a functioning urethra, can be performed by combining the bladder wall flap with a modern (axial vessel) abdominal or groin skin flap. This will allow a patient to have satisfactory intercourse and permit orthostatic micturition with a minimum number of operative procedures.

A new hemostatic scalpel has been developed to control bleeding between the cut edges of wound tissue. The scalpel blade resembles conventional scalpel blades, except that it can be heated and its temperature controlled within narrow limits. Cutting is accomplished by the blade's sharp edges, and hemostasis results from the direct transfer of heat from the blade to the tissue. This experimental study has demonstrated that the hemostatic effect of the scalpel is associated with damage to the tissue's defenses against infection and impaired wound healing.

Early tangential excision and immediate grafting of the burn-injured patient has been shown to be effective. Along with the use of this technique, however, comes the potential for significant blood loss, prolonged operative time, and partial loss of graft due to underlying hematoma formation. Based on experience using a pooled fibrinogen preparation, European and Japanese surgeons have provided evidence for the positive hemostatic and skin transplant fixation effects of fibrin glue. This commercial preparation, however, has not been approved by the U.S. Food and Drug Administration for use in the United States because of high risk of hepatitis and HIV transmission. Using a method of preparing highly concentrated fibrinogen utilizing standard blood bank techniques developed at the University of Virginia, we have applied single-donor fibrin glue as an adjunct in the early excision and grafting of 26 patients. Since we have been using fibrin glue, we have noted a marked reduction in operative blood loss and time involved in obtaining hemostasis. Additionally, we have found the application of the grafts to be facilitated by the "stickiness" of the recipient bed. In follow-up, grafts applied utilizing the fibrin glue technique have proceeded to uncomplicated wound healing with an overall 98% graft take.

Oral administration of 6-chloro-Δ6-dehydro-17-acetoxyprogesterone (CAP) and 6-α-methyl-17-α-acetoxyprogesterone (MAP) over a period of either 14 or 17 days, successfully induced estrus of lactating and non-lactating anestrous ewes. CAP was found to be more effective than MAP, at the concentrations employed (2.5 mg CAP to 40 mg MAP daily). The effectiveness of CAP and PMS in promoting predictable and early-cycling estrus in anestrous ewes was not enhanced by treatment with estradiol-17-β. Conception and lambing percentages were higher from the hormone-treated non-lactating ewes than from the hormone-treated lactating ewes.

Summary A cutting forceps and suture removal scissors have been specially designed for removal of percutaneous sutures. Our clinical experience with these instruments indicate that they facilitate removal of percutaneous sutures in the surgical patient.

The purpose of this study was to measure the degree of pain elicited by either staple implantation and by removal in human subjects. Included in the study were conventional rectangular staples and the new arcuate staples. The pain associated with staple implantation was significantly greater than that associated with staple removal. The configuration of the staple did not influence the magnitude of pain associated with either staple implantation or staple removal.

Using a reproducible technique for determining the blood loss from skin graft donor sites, the hemostatic effect of topical application of dilute solutions of phenylephrine and thrombin was evaluated. Both drugs decreased blood loss from donor sites significantly, but phenylephrine proved the more effective hemostatic agent. Topical treatment of donor sites with this vasoactive agent was not associated with any systemic pressor effects or cardiac irregularities. Its low cost compared to that of thrombin is an additional advantage.

The purpose of this study was to identify a skin wound cleanser that could be used safely to cleanse lacerations of the periorbital region. The irritation and toxicity to the eye of the commercially available skin wound cleansers were quantitated using numerical values and weights for the ocular lesions in experimental animals. Shur Clens ® did not elicit lesions in experimental animals or in a series of 20 patients with periorbital lacerations. On the basis of this study, Shur Clens ® is recommended as a safe skin wound cleanser for periorbital lacerations.

The reliability and accuracy of pulse oximetry as a monitoring device in deep superficial and full-thickness circumferential burns of the upper extremity were evaluated clinically. Pulse oximetry was correlated with the laser Doppler flowmeter experimentally in healthy volunteers. By continuously monitoring oxygen saturation levels, the pulse oximeter detected extremity hypoxia before it resulted in an adverse outcome. Extremities exhibiting oxygen saturation above 95% were treated with early excision and skin grafting without escharotomy. Extremities with O2 saturations of less than 95% underwent immediate escharotomy with return to normal saturation levels. The pulse oximeter is easy to use by nursing personnel; is noninvasive and accurate; and displays the oxygen saturation level within seconds.