Treatment choices and outcomes of patients with manometrically diagnosed achalasia.

This prospective population-based study was designed to evaluate treatment choices in patients with new manometrically diagnosed achalasia and their outcomes. Patients referred to the esophageal function laboratory were enrolled after a new manometric diagnosis of achalasia. Patients completed an initial achalasia symptom score validated questionnaire on their symptom severity, duration, treatment pre-diagnosis and Medical Outcomes Study 36-item Short-Form (SF-36) survey. Treatment decisions were made by the referring physician and the patient. Follow-up questionnaires were completed every 3 months for 1 year. Patients who chose not to undergo treatment at 1-year follow-up completed another questionnaire after 5 years. Between January 2004 and January 2005, 83 of 124 eligible patients were enrolled. Heller myotomy was performed on 31 patients, three patients received botulinum toxin injections, and 25 patients received 29 pneumatic balloon dilatations. Twenty-four patients chose to receive no treatment. Following treatment, patients treated with surgery, dilatation and botulinum toxin had an average improvement in achalasia symptom score of 23 +/- 12.2, 17 +/- 10.9, and 9 +/- 14, respectively. Patients receiving no treatment had worsening symptoms with a symptom score change of -3.5 +/- 11.4. Surgery and dilatation resulted in significant improvement (P < 0.01) relative to no treatment. In univariate logistic regression, symptom severity score (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.00 to 1.08), sphincter tone (OR 1.04, 95% CI 1.00 to 1.09), difficulty swallowing liquids (OR 3.21, 95% 1.15 to 8.99), waking from sleep (OR 2.75, 95% 1.00 to 7.61), and weight loss (OR 5.99, 95% CI 1.93 to 18.58) were all significant in predicting that patients would select treatment. In the multivariate analysis, older age (OR 1.05, 95% CI 1.01 to 1.09) and weight loss (OR 3.91, 95% CI 1.02 to 15.2) were statistically significant for undergoing treatment. At 5 years, five (21%) of those who had initially declined treatment at 1 year ultimately chose a treatment. Patients who finally chose Heller myotomy had lower mental component dimension scores on the SF-36 at 1 year than those who did not. This study shows that almost one third of patients with manometrically diagnosed achalasia choose not to undergo treatment within 1 year of their diagnosis. Patients who are more symptomatic appear to be more likely to undergo treatment by univariate analysis. In multivariate analysis, increasing age and weight loss are predictive of those who will undergo treatment, with weight loss having the greatest influence. Patients who choose not to undergo treatment make lifestyle changes to maintain their quality of life, and only a minority of them ultimately undergo treatment.

Lung transplantation with donation after circulatory determination of death donors and the impact of ex vivo lung perfusion.

The growing demand for suitable lungs for transplantation drives the quest for alternative strategies to expand the donor pool. The aim of this study is to evaluate the outcomes of lung transplantation (LTx) with donation after circulatory determination of death (DCDD) and the impact of selective ex vivo lung perfusion (EVLP). From 2007 to 2013, 673 LTx were performed, with 62 (9.2%) of them using DCDDs (seven bridged cases). Cases bridged with mechanical ventilation/extracorporeal life support were excluded. From 55 DCDDs, 28 (51%) underwent EVLP. Outcomes for LTx using DCDDs and donation after neurological determination of death (DNDD) donors were similar, with 1 and 5-year survivals of 85% and 54% versus 86% and 62%, respectively (p = 0.43). Although comparison of survival curves between DCDD + EVLP versus DCDD-no EVLP showed no significant difference, DCDD + EVLP cases presented shorter hospital stay (median 18 vs. 23 days, p = 0.047) and a trend toward shorter length of mechanical ventilation (2 vs. 3 days, p = 0.059). DCDDs represent a valuable source of lungs for transplantation, providing similar results to DNDDs. EVLP seems an important technique in the armamentarium to safely increase lung utilization from DCDDs; however, further studies are necessary to better define the role of EVLP in this context.

Normothermic acellular ex vivo liver perfusion reduces liver and bile duct injury of pig livers retrieved after cardiac death.

We compared cold static with acellular normothermic ex vivo liver perfusion (NEVLP) as a novel preservation technique in a pig model of DCD liver injury. DCD livers (60 min warm ischemia) were cold stored for 4 h, or treated with 4 h cold storage plus 8 h NEVLP. First, the livers were reperfused with diluted blood as a model of transplantation. Liver injury was determined by ALT, oxygen extraction, histology, bile content analysis and hepatic artery (HA) angiography. Second, AST levels and bile production were assessed after DCD liver transplantation. Cold stored versus NEVLP grafts had higher ALT levels (350 ± 125 vs. 55 ± 35 U/L; p < 0.0001), decreased oxygen extraction (250 ± 65 mmHg vs. 410 ± 58 mmHg, p < 0.01) and increased hepatocyte necrosis (45% vs. 10%, p = 0.01). Levels of bilirubin, phospholipids and bile salts were fivefold decreased, while LDH was sixfold higher in cold stored versus NEVLP grafts. HA perfusion was decreased (twofold), and bile duct necrosis was increased (100% vs. 5%, p < 0.0001) in cold stored versus NEVLP livers. Following transplantation, mean serum AST level was higher in the cold stored versus NEVLP group (1809 ± 205 U/L vs. 524 ± 187 U/L, p < 0.05), with similar bile production (2.5 ± 1.2 cc/h vs. 2.8 ± 1.4 cc/h; p = 0.2). NEVLP improved HA perfusion and decreased markers of liver duct injury in DCD grafts.

Orbital myiasis complicating squamous cell carcinoma of eyelid.

Myiasis is infestation of the body by fly maggots. Immobile patients with skin wounds in exposed areas are at high risk of developing myiasis. We report a case of orbital myiasis from the species Chrysomya bezziana complicating squamous cell carcinoma of the eyelid. Magnetic resonance imaging of the orbit is useful for delineating the extent of the infestation and identifying residual maggots. In extensive orbital myiasis, exenteration is needed to prevent intracranial extension of tissue destruction.

Development and characterization of a series of soluble tetrameric and monomeric streptavidin muteins with differential biotin binding affinities.

The strong biotin-streptavidin interaction limits the application of streptavidin as a reversible affinity matrix for purification of biotinylated biomolecules. To address this concern, a series of single, double, and triple streptavidin muteins with different affinities to biotin were designed. The strategy involves mutating one to three strategically positioned residues (Ser-45, Thr-90, and Asp-128) that interact with biotin and other framework structure-maintaining residues of streptavidin. The muteins were produced in soluble forms via secretion from Bacillus subtilis. The impact of individual residues on the overall structure of streptavidin is reflected by the formation of monomeric streptavidin to different extents. Of the three targeted residues, Asp-128 has the most dramatic effect (Asp-128 > Thr-90 > Ser-45). Conversion of all three targeted residues to alanine results in a soluble biotin binding mutein that exists 100% in the monomeric state. Both wild-type and mutated (monomeric and tetrameric) streptavidin proteins were purified, and their kinetic parameters (on- and off-rates) were determined using a BIAcore biosensor with biotin-conjugated bovine serum albumin immobilized to the sensor chip. This series of muteins shows a wide spectrum of affinity toward biotin (K(d) from 10(-6) to 10(-11) m). Some of them have the potential to serve as reversible biotin binding agents.

Multiplicative interaction between narcotic agonisms expressed at spinal and supraspinal sites of antinociceptive action as revealed by concurrent intrathecal and intracerebroventricular injections of morphine.

In rats in which the fourth ventricular exits had been acutely occluded, morphine sulfate was injected concomitantly into the spinal subarachnoid space (0-10 micrograms/4 microliter) and into the third cerebral ventricle (0-50 micrograms/5 microliter). The combinations of intrathecal (i.t.) and intracerebroventricular (i.v.t.) dosages used were selected to yield particular ratios of supraspinal to spinal (SS:S) agonisms. Dose-response lines for both the tail-flick and hot plate responses were constructed for each SS:S ratio, with the abscissa representing i.v.t. morphine dosage. It was observed that the analgetic potency of morphine injected i.v.t. was profoundly potentiated by the concurrent administration of morphine i.t. Dose-response lines for i.v.t. morphine were shifted progressively to the left as the spinal dose of morphine was increased. At the optimal balance of spinal and supraspinal dosage (SS:S = 1:1), the ED50 values for i.v.t. morphine for the hot plate and tail-flick tests were reduced by factors of 45 and 29, respectively. A similar, but less profound, potentiation of the analgetic potency of morphine injected i.t. by concurrent administration of morphine i.v.t. was observed. Isobolographic analysis of the data revealed that the isobols were hyperbolas having extreme negative curvature of all effect levels. Inspection of the isobols indicated that, at all ratios of spinal to supraspinal agonism which could conceivably be obtained when morphine is given systemically, the spinal-supraspinal interaction is multiplicative. The results suggest that narcotic agonism at both spinal and supraspinal narcotic-sensitive sites is essential to the production of analgesia by systemically administered morphine and that neither site can logically be deemed the "primary" site of narcotic action.

Sites of antinociceptive action of systemically injected morphine: involvement of supraspinal loci as revealed by intracerebroventricular injection of naloxone.

Dose-response lines for the tail-flick and hot plate tests were obtained in rats which had received systemic injections of morphine (10-150 mg/kg i.p.) and intracerebroventricular (i.v.t.) injections of naloxone (3-20 micrograms). Diffusion studies indicated that the antagonist remained localized within supraspinal structures. Between the doses of 3 and 10 micrograms i.v.t. naloxone produced a dose-dependent rightward shifting of the morphine dose-response lines, the shift produced by the 10-micrograms dose being sufficient to abolish the analgetic action of morphine doses as large as 75 mg/kg. Higher doses of naloxone (e.g., 20 micrograms) produced no additional rightward shift, indicating an inability of i.v.t. naloxone to antagonize the analgesia produced by high systemic doses of morphine. These findings seem to suggest that analgesia produced by low to moderate systemic doses of morphine is mediated entirely by an action of the narcotic upon supraspinal structures. However, the results of an analogous study in which naloxone was injected into the spinal subarachnoid space indicated that analgesia produced by morphine given systemically in low to moderate doses is mediated exclusively by an action on the spinal cord. This apparent paradox can be resolved if one assumes that the total analgesia observed after a low to moderate systemic dose of morphine is a result of a multiplicative, rather than an additive, interaction of narcotic agonisms expressed at the spinal and supraspinal sites of action, respectively.

Systematic examination in the rat of brain sites sensitive to the direct application of morphine: observation of differential effects within the periaqueductal gray.

An extensive mapping of the rat brain (403 sites) ranging from AP +8 to AP -3 revealed that the region showing maximum sensitivity to the intracerebral administration of morphine in the elevation of the nociceptive threshold lay within the periaqueductal gray. Analysis of the distribution of responsive sites indicated that the most active sites, those having the shortest latency of effect, were located within the ventrolateral aspect of the caudal periaqueductal gray. These antinociceptive actions of morphine were observed to be both dose-dependent and reversible by the administration of naloxone. We observed that microinjections of morphine could produce changes in the pinch withdrawal response which were distributed in a crude somatotopic fashion. Injections into the rostral aspect of the periaqueductal gray yielded a block of the pinch response in the rostral portions of the body, whereas such injections into the caudal periaqueductal gray always yielded a whole body analgesia. In the rostral sites, transient ipsilateral blocks of the pinch response were occasionally seen. A pinch block limited to the hind paws alone was never observed. It is suggested that morphine acting through the periaqueductal gray may actuate a potent supraspinal modulatory system related to the transmission of information derived from behaviorally aversive stimuli.

Effects of brain lesions on the antinociceptive properties of morphine in rats.

1. Electrolytic lesions were made in various brain regions of the rat, and the effects of these lesions on nociceptive threshold and the antinociceptive actions of morphine were tested using a shock titration technique. 2. Lesions in the medial thalamus, the periaqueductal grey area, or the caudate nucleus, had no effect on the nociceptive threshold; whereas, lesions in the posterior hypothalamus resulted in a small but statistically significant increase in this threshold. 3. Morphine administered intraperitoneally to rats having histologically verified lesions in the posterior hypothalamus, the caudate nucleus or the periaqueductal grey area resulted in a 15-30% increase in the nociceptive threshold. This increase was similar to that observed in unoperated control rats. On the other hand, injections of morphine into animals having greater than 50% of the medial thalamus destroyed produced a highly significant increase of 95% in the threshold. This potentiation of the antinociceptive action of morphine was not observed in rats having less than 50% destruction of the medial thalamus.