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Dopamine regulates normal functions such as movement, reinforcement learning, and cognition, and its dysfunction has been implicated in multiple psychiatric and neurological disorders. Dopamine acts through D1- (D1R and D5R) and D2-class (D2R, D3R, and D4R) receptors and activates both G protein- and β-arrestin-dependent signaling pathways. Current dopamine receptor-based therapies are used to ameliorate motor deficits in Parkinson's disease or as antipsychotic medications for schizophrenia. These drugs show efficacy for ameliorating only some symptoms caused by dopamine dysfunction and are plagued by debilitating side effects. Studies in primates and rodents have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing motor side effects such as dyskinesias, and can be efficacious at enhancing cognitive function compared to balanced agonists. Several structure-activity relationship (SAR) studies have embarked on discovering β-arrestin-biased dopamine agonists, focused on D2 partial agonists, noncatechol D1 agonists, and mixed D1/D2R dopamine receptor agonists. Here, we describe an SAR study to identify novel D1R β-arrestin-biased ligands using A-86929, a high-affinity D1R catechol agonist, as a core scaffold to identify chemical motifs responsible for β-arrestin-biased activity at both D1 and D2Rs. Most of the A-86929 analogs screened were G protein-biased, but none of them were exclusively arrestin-biased. Additionally, various small-fragment molecular probes displayed weak bias toward the β-arrestin pathway. Continued in-depth SFSR (structure-functional selectivity relationship) studies informed by structure determination, molecular modeling, and mutagenesis studies will facilitate the discovery of potent and efficacious arrestin-biased dopamine receptor ligands.

Transverse patella fractures with loss of knee extensor mechanism function are a common orthopaedic injury requiring operative fixation. Current accepted surgical options for noncomminuted transverse fractures include open reduction with tension band wiring. Although these procedures result in good clinical outcomes and fracture healing, symptomatic hardware from the historically used metal implants is very common. The purpose of this Technical Note is to describe a technique for treatment of transverse patellar fractures using cannulated compression screws with tensioned high-resistance suture tape functioning as the tension band. This technique provides effective, reproducible fracture fixation while minimizing symptomatic hardware, failure, and reoperation., Technique Video Video 1 Operative technique for patellar fracture fixation with cannulated compression screws and FiberTape Cerclage. The procedure is performed in a left knee. The patient is placed in the supine position on a radiolucent operating table. A midline longitudinal incision 6 to 10 cm in length is made sharply, centered over the patella. A Weber clamp is used to anatomically reduce the fracture. Once reduction is confirmed, two 1.35-mm guidewires are passed in parallel from distal to proximal through the C-ring Drill Guide spanning the fracture. The C-Ring Drill Guide is used to measure screw length. It is crucial to subtract 4 mm from the measured length to prevent prominent hardware. Predrilling with a 2.6-mm cannulated drill bit is performed over the guidewires, leaving the guidewires intact. The 4.0-mm partially threaded, blunt tip cannulated screws are then placed over the guidewires from distal to proximal to compress the fracture. The screw heads should be buried into the distal cortex, and the blunt screw tips are left short of the proximal cortex to decrease suture irritation. Fluoroscopy is used to confirm reduction and appropriate screw placement. The guide pins are left in place. The cannulated screwdriver is placed over the lateral guide pin and engages the screw head. The guide pin is removed while the screwdriver is left in place. The Suture Passing Wire is then passed into the cannulated screwdriver and through the cannulated screw. The screwdriver is removed, leaving the looped end of the suture passing wire at the distal end of the lateral screw. The leading end of the FiberTape cerclage suture is placed into the loop and shuttled through the lateral screw, from distal to proximal. That leading end of the suture is then brought over the anterior surface of the patella and advanced again through the medial screw, using the previously described technique. The suture is advanced so that only 4 to 5 cm of tail, together with the card, remains at the distal end of the lateral screw. This tail and card is then brought anteriorly to the superior medial aspect of the patella where the leading end of the cerclage suture remains. The FiberTape cerclage is then assembled as follows: The leading end of the tape is loaded through the suture shuttle (#1 on the card). The card is held at the bullseye (#2 on the card) and the cerclage suture is shuttled through the pre-tied racking hitch knot by pulling on the opposite loop (#3 on the card). The shuttle suture and card can be discarded. The knot is adjusted so that it sits at the superior medial aspect of the patella. The cerclage is first tightened by hand to remove slack. The leading end of the FiberTape is cut to reveal 2 FiberTape limbs. The 2 limbs are then loaded into the tensioner, which is used to tension the tapes with up to 80 pound-force of force. One half-hitch knot is tied and again tensioned to 80 pound-force with the tensioner. Two additional alternating half-hitches are tied to complete the repair. The remaining tails are cut and the knot is buried in the soft tissue. Final fluoroscopic images confirm reduction. Retinacular tears are repaired and the peritenon and subcutaneous tissue are closed. The skin is sutured and dressing is applied.

[Image: see text] Loss of dopamine neurons is central to the manifestation of Parkinson’s disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson’s disease, can restore normal movement yet cause side-effects such as dyskinesias upon prolonged administration. Dopamine D1 and D2 receptors activate G-protein- and arrestin-dependent signaling pathways that regulate various dopamine-dependent functions including locomotion. Studies have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing dyskinesias. However, simultaneous activation of both D1 and D2Rs is required for robust locomotor activity. Thus, it is desirable to develop ligands targeting both D1 and D2Rs and their functional selectivity. Here, we report structure–functional–selectivity relationship (SFSR) studies of novel apomorphine analogs to identify structural motifs responsible for biased activity at both D1 and D2Rs.

Dopamine regulates normal functions such as movement, reinforcement learning, and cognition, and its dysfunction has been implicated in multiple psychiatric and neurological disorders. Dopamine acts through the D1- (D1R and D5R) and D2-class (D2R, D3R and D4R) of seven transmembrane receptors, and activates both G-protein- and β-arrestin-dependent signaling pathways, to mediate its physiological effects. Current dopamine receptor-based therapies are used to ameliorate motor deficits in Parkinson’s disease, or as antipsychotic medications for schizophrenia. These drugs show efficacy for ameliorating only some symptoms caused by dopamine dysfunction and are plagued by debilitating side-effects. Studies in primates and rodents have shown that shifting the balance of dopamine receptor signaling towards the arrestin pathway can be beneficial for inducing normal movement, while reducing motor side-effects such as dyskinesias, and can be efficacious at enhancing cognitive function compared to balanced agonists. Several structure-activity-relationship (SAR) studies have embarked on discovering β-arrestin-biased dopamine agonists, focused on D2 partial agonists, non-catechol D1 agonists, and mixed D1/D2R dopamine receptor agonists. Here, we describe an SAR study to identify novel D1R β-arrestin biased ligands using A-86929, a high-affinity D1R catechol agonist, as a core scaffold. Previously described and novel analogs of A-86929 were synthesized and screened in vitro for structure-functional-selectivity relationships (SFSR) studies to identify chemical motifs responsible for β-arrestin biased activity at both D1 and D2Rs. Most of the A-86929 analogs screened were G protein biased but none of them were exclusively arrestin-biased. Additionally, various catechol aryl fragments were designed and synthesized. Other compounds surveyed included hydroxyl and chloro analogs of dopamine to test for hydrogen bonding and ionic interactions. Some of these small molecular probes displayed weak bias towards the β-arrestin pathway. Continued in-depth SFSR studies informed by structure determination, molecular modeling, and mutagenesis studies will facilitate discovery of potent and efficacious arrestin-biased dopamine receptor ligands.

Surfactant administration incorporates liquid bolus instillation via endotracheal tube catheter and use of a mechanical ventilator. Aerosolized surfactant has generated interest and conflicting data related to dose requirements and efficacy. We hypothesized that aerosolized surfactant with a novel breath-actuated vibrating mesh nebulizer would have similar efficacy and safety as instilled surfactant. Juvenile rabbits (1.50 ± 0.20 kg, n = 17) were sedated, anesthetized, intubated, and surfactant was depleted via lung lavage on mechanical ventilation. Subjects were randomized to receive standard dose liquid instillation via catheter (n = 5), low dose surfactant (n = 5) and standard dose surfactant (n = 5) via aerosol, and descriptive controls (no treatment, n = 2). Peridosing events, disease severity and gas exchange, were recorded every 30 min for 3 h following surfactant administration. Direct-Instillation group had higher incidence for peridosing events than aerosol. Standard dose liquid and aerosol groups had greater PaO2 from pre-treatment baseline following surfactant (p &lt, 0.05) with greater ventilation efficiency with aerosol (p &lt, 0.05). Our study showed similar improvement in oxygenation response with greater ventilation efficiency with aerosol than liquid bolus administration at the same dose with fewer peridosing events. Breath-synchronized aerosol via nebulizer has potential as a safe, effective, and economical alternative to bolus liquid surfactant instillation.

The human pegivirus type 1 (HPgV-1)-as known as hepatitis G virus and GB virus C-is a common single-stranded RNA flavivirus. Because few studies have demonstrated an association between HPgV-1 infection and disease, screening for HPgV-1 is not performed routinely. Nonetheless, a beneficial impact of HPgV-1 infection on HIV disease progression has been reported in multiple studies. Given the burden of HIV in Asia and the complex interactions between viral co-infections and the host, we provide a comprehensive overview of the existing data from Asia on HPgV-1 infection, including the prevalence and circulating genotypes in all Asian countries with data reported. This review highlights the research conducted thus far and emphasizes the need for additional studies on HPgV-1 across the Asian continent.

Individuals expose personally identifying information to access a website or qualify for a loan, undermining privacy and security. Firms share proprietary information in dealmaking negotiations; if the deal fails, the negotiating partner may use that information to compete. Regulators that comply with public transparency and oversight requirements can risk subjecting algorithmic governance tools to gaming that destroys their efficacy. Litigants might have to reveal trade secrets in court proceedings to prove a claim or defense. Such “verification dilemmas,” or costly choices between opportunities that require the verification of some fact, and risks of exposing sensitive information in order to perform verification, appear across the legal landscape. Yet, existing legal responses to them are imperfect. Legal responses often depend on ex post litigation remedies that are prohibitively expensive for those most in need, or that fail to address abuses of information entirely. Zero-knowledge proofs (ZKPs)—a class of cryptographic protocols that allow one party to verify a fact or characteristic of secret information without revealing the actual secret—can help solve these verification dilemmas. ZKPs have recently demonstrated their mettle, for example, by providing the privacy backbone for the blockchain. Yet they have received scant notice in the legal literature. This Article fills that gap by providing the first deep dive into ZKPs’ broad relevance for law. It explains ZKPs’ conceptual power and technical operation to a legal audience. It then demonstrates how, and that, ZKPs can be applied as a governance tool to transform verification dilemmas in multiple legal contexts. Finally, the Article surfaces, and provides a framework to address, the policy issues implicated by the potential substitution of ZKP governance tools in place of existing law and practice.

Supplemental Digital Content is available in the text., Objectives: Effective treatment options for surfactant therapy in acute respiratory distress syndrome and coronavirus disease 2019 have not been established. To conduct preclinical studies in vitro and in vivo to evaluate efficiency, particle size, dosing, safety, and efficacy of inhaled surfactant using a breath-synchronized, nebulized delivery system in an established acute respiratory distress syndrome model. Design: Preclinical study. Setting: Research laboratory. Subjects: Anesthetized pigs. Intervention: In vitro analysis included particle size distribution and inhaled dose during simulated ventilation using a novel breath-synchronized nebulizer. Physiologic effects of inhaled aerosolized surfactant (treatment) were compared with aerosolized normal saline (control) in an adult porcine model (weight of 34.3 ± 0.6 kg) of severe acute respiratory distress syndrome (Pao2/Fio2

The cortex plays an important role in regulating motivation and cognition, and does so by regulating multiple subcortical brain circuits. Glutamatergic pyramidal neurons in the prefrontal cortex (PFC) are topographically organized in different subregions such as the prelimbic, infralimbic (IL), and orbitofrontal and project to topographically-organized subcortical target regions. Dopamine D1 and D2 receptors are expressed on glutamatergic pyramidal neurons in the PFC. However, it is unclear whether D1 and D2 receptor-expressing pyramidal neurons in the PFC are also topographically organized. We used a retrograde adeno-associated virus (AAVRG)-based approach to illuminate the topographical organization of D1 and D2 receptor-expressing neurons, projecting to distinct striatal and midbrain subregions. Our experiments reveal that AAVRG injection in the nucleus accumbens (NAcc) or dorsal striatum (dSTR) of D1Cre mice labeled distinct neuronal subpopulations in medial orbitofrontal or prelimbic PFC, respectively. However, AAVRG injection in NAcc or dSTR of D2Cre mice labeled medial orbitofrontal, but not medial prelimbic PFC, respectively. Additionally, D2R+ but not D1R+ PFC neurons were labeled on injection of AAVRG in substantia nigra pars compacta (SNpc). Thus, our data are the first to highlight a unique dopamine receptor-specific topographical pattern in the PFC, which could have profound implications for corticostriatal signaling in the basal ganglia.

Background: Nonerosive gastroesophageal reflux disease (NERD) patients frequently show features of the irritable bowel syndrome (IBS). Aims: To investigate the prevalence and intensity of bowel symptoms and their relationship to esophageal acid exposure in NERD patients. Methods: Bowel and reflux symptoms and IBS status were assessed in NERD patients (normal upper endoscopy; esophageal pH 5% of the time on 24-h pH monitoring; n = 326), in relation to nonpatient controls. Bowel symptoms were scored on the 3 scales: diarrhea, constipation, and pain/gas symptoms. Results: NERD and age were independently associated with bowel symptoms. NERD patients scored significantly higher than controls on all bowel scales. In a multivariate analysis, the scores on the pain/gas scale were independently associated with NERD. In NERD patients, reflux symptoms independently predicted the bowel symptoms while acid exposure did not. Forty-nine percent of the NERD patients and 18% of the controls met the criteria for IBS [IBS(+)NERD]. IBS(+) NERD patients scored significantly higher than those not meeting IBS criteria [IBS(-)] on all bowel scales. Yet IBS( -) patients scored significantly higher than controls on the scales of constipation and pain/gas. IBS( + )NERD patients scored higher than IBS( - ) also on the GERD symptoms scale. Conclusions: (1) NERD patients scored significantly higher than controls on all the bowel scales; (2) Bowel symptoms were associated with reflux symptom scores, but not with acid exposure. (3) The presence of IBS features in a large proportion of NERD patients reflects a high prevalence of visceral hypersensitivity that may aggravate acid reflux symptoms.

Research is at the point where we might have to confront the possibility of what computer scientists call “strong AI” in the coming years. A strong AI could be intelligent by most reasonable definitions of the word, and possibly have a subjective experience. It stands to reason that we must seriously consider whether such a machine should have its will recognized, protected, and enabled. That is to say, such a sufficiently advanced machine might be said to carry responsibilities, and rights, on its own, as a legal person.This question is wrapped up in significant philosophical and technical questions of acceptability and feasibility. The novelty of this Essay is that it provides a positive reason to grant such rights with a basis in technical law, along with a concrete definition and justification for personhood. The organizing principle this Essay arrives at is: Personhood exists to protect conscious individuals from suffering and allow them exercise their wills, subject to their intelligence.This Essay examines several documents across a variety of fields, as well as historical records. Examples such as corporate law, personhood law, slavery law, and standing law demonstrate that the story of person-hood is a history of grappling with what is fully conscious, and how to allow these consciousness’s to exercise their will and avoid pain. However, because law was made by and for humans, by examining the law surrounding animal welfare and humans in a vegetative state, one finds that the law privileges humanity. Hence, our laws imply that a computer, if it is intelligent enough, should be considered conscious; however, our laws as they are would arbitrarily not provide it personhood simply because it is not made of flesh and blood.

Background Electromagnetic fields, such as those generated by cellular phones and metal detectors, may interfere with normal pacemaker function. However, it remains unclear whether the wireless capsule endoscope interacts with implanted pacemakers. This prospective study evaluated potential interactions between the M2A video capsule (Given Imaging, Yoknam, Israel) and implanted pacemakers. Methods A total of 100 consecutive patients (70 men, 30 women) with an implanted pacemaker (95 on bipolar mode) were studied. The testing was performed with a functional testing device (Test Cap) for the Given Diagnostic System that reproduces the effect of the video capsule by transmitting at exactly the same frequency. During continuous electrocardiographic monitoring and recording, 100 tests were carried out without changing the pacemaker settings. Those with a positive result were retested 1 week later. Results The 100 pacemakers evaluated in the study population included the following: 70 dual chamber (11 DDD, 56 DDDR, 3 VDD) and 30 ventricular inhibited (12 VVI, 18 VVIR). In 4 of the 100 patients, pacemaker interference (noise-mode function forcing a synchronous mode) was registered during the Test Cap operation. Three patients had a dual-chamber pacemaker, and one had a single-chamber pacemaker. The interference was reproducible in all cases 1 week later. None of the implanted pacemakers tested was affected by oversensing. Conclusions Electromagnetic interferences with pacemakers from the M2A video capsule can occur, but this is without clinical significance. No potentially dangerous pacemaker inhibition was observed.

Patients suffering from the irritable bowel syndrome (IBS) tend to have extraintestinal symptoms. The purposes of this study were to compare the nature and severity of these symptoms in IBS patients in relation to patients with inflammatory bowel disease (IBD) and to nonpatients and to clarify the relationship between intestinal and extraintestinal symptoms. A consecutive group of male patients and a control group of age-matched male subjects were studied. Symptoms were graded for severity using a validated, self-administered inventory. There were 53 IBS patients, 55 IBD patients (32 Crohn's disease), and 56 controls. IBS patients scored significantly higher than IBD patients on constipation, dyspepsia, and reflux scales. Musculoskeletal symptoms, neurasthenia, and sleep scores were similar in IBS and IBD patients, and both groups scored significantly higher than the controls. The scores of urinary, thoracic, and oral symptoms were similar in IBD patients and in controls. However, IBS patients scored significantly higher than both groups on all these scales. Reflux symptoms were the most powerful predictors of extraintestinal symptoms, both in IBS and in IBD. Diarrhea was predictive of extraintestinal symptoms only in IBD. In conclusion, IBS patients experienced extraintestinal symptoms to the same extent, or even more than patients with IBD. However, the relationship between intestinal and extraintestinal symptoms differed in the two conditions.

We wanted to identify features of prognostic significance in patients admitted to hospital because of acute upper gastrointestinal (UGI) hemorrhage.A prospective, longitudinal study of 321 consecutive cases admitted during 1988-91 was carried out. The relative risk of mortality associated with each of the background, laboratory, and endoscopic features and the hospital course was calculated. Multiple stepwise logistic regression was used to define factors independently associated with mortality. Two models were evaluated, the first based on the data at presentation (history, physical findings, initial laboratory data) and the second based on the first, plus the endoscopic and follow-up data.The overall mortality was 7.8%. At presentation the features associated with a significantly (p0.05) increased risk of mortality were (adjusted odds ratios in parentheses) ageor = 75 years (11.2), a history of cancer (12.1), blood in the gastric aspirate (9.6), and a systolic blood pressureor = 90 mm Hg (6.4). The overall predictors of mortality were ageor = 75 years (12.7), blood in the gastric aspirate (18.9), serum creatinine levelor = 150 mumol/l (14.8), increased serum aminotransferase level (20.2), and persistent or recurrent bleeding (57.3).In patients admitted to hospital because of UGI hemorrhage the prognosis depends on age, underlying diseases, hemodynamic status, and the persistence or recurrence of bleeding. The causes of bleeding were not relevant to the prognosis.

OBFECTIVES: Narcotic bowel syndrome (NBS) is characterized by a paradoxical increase in abdominal pain associated with continued or escalating dosages of narcotics. This study evaluated the clinical and psychosocial features of patients with NBS and the response to detoxification treatment.For 2 years, 39 patients seen by the GI consult service at the University of North Carolina at Chapel Hill (UNC) with presumed NBS were placed on a detoxification program. Clinical, psychosocial, health status, and outcome data were obtained before and after detoxification. Our aims were to: (i) clinically characterize patients with presumed NBS, (ii) assess the clinical response and adverse effects to detoxification, (iii) identify clinical and psychosocial predictors of treatment response, and (iv) determine the clinical outcome at 3 months after detoxification and the time frame for patients who revert back to narcotics.Of the 39 patients detoxified, 89.7% met predefined criteria. Patients were mostly well educated (14.5 ± 2.3 years of school), female (92.3%), and with a variety of diagnoses (21% irritable bowel syndrome IBS/functional, 37% inflammatory bowel disease and other structural, 29% fibromyalgia and other functional somatic, or orthopedic, and 13% postoperative or other). They reported high health-care use (15.3 ± 10.1 MD visits/6 months; 6.5 ± 6.1 hospitalizations/2 years, 6.4 ± 2.0 surgeries/lifetime), and 82.1% were jobless. Despite high dosages of narcotics (total intravenous (IV) morphine equivalent 75.3 ± 78.0 mg/day), pain scores were rated severe (52.9 ± 28.8 visual analog scale (VAS); 257.1 ± 139.6 functional bowel disorder severity index (FBDSI); 17.2 ± 10.2 (McGill Pain and greater than labor or postoperative pain). Multiple symptoms were reported (n = 17.8 ± 9.2) and rated as moderate to severe. Psychosocial scores showed high catastrophizing (19.9 ± 8.6); poor daily function (Short Form-36 (SF-36) physical 28.3 ± 7.7, mental 34.3 ± 11.0; worse than tetraplegia); 28.2% were clinically depressed and 33.3% anxious (Hospital Anxiety and Depression Scale (HADS)). Detoxification was successfully completed by 89.7%; after detoxification, abdominal pain was reduced by 35% (P0.03) and nonabdominal pain by 42% (P0.01) on VAS, and catastrophizing significantly improved (P0.01). Responder status was met in 56.4% with 48.7% achieving a ≥ 30% reduction in pain. By 3 months after detoxification, 45.8% had returned to using narcotics. For those who remained off narcotics at 3 months, the VAS abdominal pain score was 75% lower than pretreatment when compared with those who went back on narcotics (24% lower). Successful detoxification and a good clinical response was associated with low abuse potential (Current Opioid Misuse Measure (COMM) score9).Despite severe pain, poor coping, and poor health status, almost all patients with NBS undergoing detoxification were able to stop using narcotics and have significant improvement in pain and coping. However, almost ½ reverted to narcotic use at 3 months. Those who stayed off narcotics showed greater improvement in pain scores. This study provides a rationale for treating patients with NBS by detoxification in order to improve their clinical status. Further work is needed to understand the reasons for the high recidivism rate.

Hemorrhage from the upper gastrointestinal (UGI) tract is defined as primary when it is the cause of admission to hospital and as secondary when it complicates the course of patients admitted to hospital for other causes. The objective of this study was to compare the background features, course, and outcome of patients with primary and secondary bleeding.All patients who underwent upper endoscopy because of acute UGI bleeding during 1988-91 in a tertiary care university hospital were studied longitudinally. The background features of primary bleeders (n = 321) were compared with those of secondary bleeders (n = 125). From the primary bleeders, a group was matched to the secondary bleeders by age, sex, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and liver disease. The laboratory and endoscopic findings, hospital course, and mortality were compared in the two groups.Secondary bleeders were on the average 5 years older than primary bleeders and were significantly more likely to have ischemic heart disease, chronic lung disease, and chronic renal failure. Use of corticosteroids, H2 blockers, antacids, and anticoagulants in this group was significantly more prevalent, whereas the use of NSAIDs was similar in the two groups. The case-control analysis showed a similar distribution of the causes of bleeding in the two groups. However, rebleeding, endoscopic hemostasis, and complications were more frequent in secondary bleeders. The mortality in secondary bleeders was 28%, compared with 10% in matched primary bleeders, for a relative risk of 3.8 (p = 0.0002).Secondary hemorrhage is associated with an increased mortality, which is related to the underlying diseases and not to a difference in the causes of bleeding.

Non-esophageal symptoms are highly prevalent in non-erosive reflux disease (NERD). However, their prevalence in erosive esophagitis (ErE) is unclear. The aims of this study were to compare patients with pH-positive NERD and ErE in terms of non-esophageal symptoms and to investigate whether such symptoms can differentiate between these two conditions.A prospective observational study of ErE and pH-positive NERD patients matched for age and gender with a nested case-control analysis. Symptoms were scored on validated scales. The association between the scale scores and diagnosis was evaluated in a random group comprising 67% of the total (group A) and was validated on the rest (group B).124 ErE and 248 pH-positive NERD patients were studied. In group A, pH-positive NERD patients scored higher than ErE patients on all symptom scales. Scores on chest, constipation, sleep and urinary symptoms scales were significantly associated with diagnosis. A composite weighted score on these scales was 41.5% sensitive and 86.0% specificity in the differentiation of ErE from pH-positive NERD patients. When applied to group B, the sensitivity and specificity of this score were 48.8% and 70.3%, respectively.Digestive and non-digestive symptoms occurred with a significant higher prevalence in pH-positive NERD compared with ErE patients. However a composite score on scales of constipation, chest, sleep and urinary symptoms was not enough sensitive and specific to differentiate these two conditions.

OBJECTIVES: Treatment with pancreatic enzymes fails to completely correct malabsorption and gastrointestinal symptoms in patients with cystic fibrosis (CF). The aim of the present study was to examine the small intestine of patients with CF without overt evidence of gastrointestinal disease using capsule endoscopy (CE). METHODS: Patients with CF received the agile patency capsule and, depending on the result of that procedure, then underwent standard CE using the PillCam SB capsule (Given Imaging, Yokneam, Israel). A stool specimen was taken on the same day as the CE for determination of the calprotectin level. RESULTS: Forty-two patients with CF ages 10 to 36 years were included; 29 had pancreatic insufficiency. One patient failed to excrete the patency capsule after 36 hours and was withdrawn from the study. Pulmonary function was mild to moderate with FEV1 68.5% +/- 16% predicted. Review of the CE videos showed that most of the patients had varying degrees of diffuse areas of inflammatory findings in the small bowel including edema, erythema, mucosal breaks, and frank ulcerations. There were no adverse events. Fecal calprotectin levels were markedly high in patients with pancreatic insufficiency, 258 microg/g (normal

A decrease in the incidence of hospital admissions for acute non-variceal upper GI bleeding (AUGIB) has been reported in regions with a low prevalence of Helicobacter pylori (HP) infection.To investigate trends in hospital admissions for AUGIB in Israel, where the prevalence of HP infection is intermediate.We have searched the National Hospital Discharge Database of the Israeli Ministry of Health, where all admissions to acute care hospitals for the period January 1, 1996 through December 31, 2007 are compiled. Using a validated strategy, we identified all admissions for AUGIB according to ICD-9-CM codes. Incidence rates were calculated and adjusted to reflect the age and gender distribution of the Israeli population.The overall rates of hospital admissions for AUGIB decreased significantly from 29.3 to 16.8 cases/10(5)population/year (p0.0001). The decreases were similar in both genders. This decrease was due to decreased rates of bleeding from duodenal ulcers (from 13.6 to 5 cases/10(5)population/year) and gastric ulcers (from 4.3 to 2.4 cases/10(5)population/year). The rates of bleeding from other causes remained unchanged. The rates of surgical interventions bleeding control decreased significantly (overall from 11 to 4%). The in-hospital mortality rate varied between 7.6 and 7%, did not change significantly in both genders but increased significantly with age during the study period.A decline in the overall incidence of AUGIB during the study period was due to a significant decrease in the rate of bleeding peptic ulcers.

The transport of folic acid was investigated in organcultured endoscopic biopsy specimens of intestinal mucosa from normal subjects. In the proximal small intestine at pH 5.5 and 6.5, [ 3 H]folic acid accumulated to concentrations 2.64- and 2.17-fold higher than those of the medium, respectively, but at pH 7.5 the concentration was same as that of the medium. Saturability of initial rates of uptake was demonstrable with respect to luminal concentrations of [H + ] and folic acid. Two proton-dependent transport mechanisms were evident: (a) a carrier with a low affinity for H + and a low capacity for folic acid, and (b) a high-affinity, high-capacity carrier (K m , 635 and 54.6 nmol/L [H + ]; V max , 0.066 and 2.583 pmol folic acid/μL intracellular water per 10 minutes, respectively). Kinetic studies of folic acid uptake at pH 5.5 and 7.5 revealed a difference in K m for folic acid (15.76 and 34.38 μmol/L, respectively) with no change in V max . In the colon, folic acid did not accumulate against a concentration gradient, and the initial rate of uptake was not affected by luminal pH. The accumulation of folic acid in colonic mucosa was significantly higher at pH 5.5 than at 7.5 and showed significant regional variation, with optimal uptake in the sigmoid colon. Methotrexate inhibited folic acid uptake competitively both in the proximal small intestine and in the cecum (inhibition constant 6.9 and 54 μmol/L, respectively, at pH 5.5). These data indicate the presence of a proton-dependent, active transport of folic acid in the proximal small intestine at pH 5.0–6.5. At pH 7.5 and in the mucosa of the colon, uptake of folic acid proceeds by facilitated diffusion through a low-affinity carrier.

Attempts to spin high-molecular-weight liquid crystalline polyarylates frequently lead to decreases in strength rather than increases as a result of draw resonance in spinning and formation of thick–thin yarns. This phenomenon is attributed to the onset of highly non-Newtonian elongational flow behavior for these polymers. However, the use of small spinneret capillaries, (≤ 6 mils diameter) maintained at temperatures below the melting point of the polymer but above the freezing point, and selection of copolymers which have relatively low heats of fusion (≤ 10 J/g) can eliminate draw resonance and produce relatively high-strength fibers (up to about 14 dN/tex) without heat strengthening. With critical selection of polymer composition (i.e., copolymers containing phenylhydroquinoneterephthalate as the major component and 1,4 hydroxybenzoic acid plus, optionally, a small amount of another monomer as minor components), spinning of high-molecular-weight polymers can be effected above the melting point of the polymers without draw resonance. Tensile strengths as high as 18 dN/tex (as-spun) have been obtained in this way. A mechanism for these effects is proposed.

Oral administration of nonsteroidal antiinflammatory drugs induces gastroduodenal mucosal damage in experimental animals as well as in humans. The aim of the present study was to evaluate the effect of rectally administered nonsteroidal antiinflammatory drugs on gastric mucosal damage, as well as on mucosal prostaglandin E2 synthesis. Fasting male rats were treated intrarectally with 0.5 ml 1% NaHCO3 solution containing several concentrations of either indomethacin, aspirin, ibuprofen, diclofenac, ketoprofen, or sulindac and concomitantly received 1 ml of 150 mM HCL intragastrically. Control rats received intrarectally the vehicle only. After 4 h, lesions in the secretory part of the stomach were scored and mucosal prostaglandin E2 synthesis was determined by the ex vivo prostaglandin generation technique. Dose-dependent mucosal damage was observed in indomethacin- and diclofenac-treated rats. Ketoprofen damage did not show dose dependency. In sulindac- and aspirin-treated rats, as well as in controls, no damage was detected. All drugs induced a significant and comparable degree of inhibition of prostaglandin E2 synthesis. There was no correlation between the severity of the mucosal damage and the inhibition of prostaglandin E2 synthesis. The ulcerogenicity of rectally administered nonsteroidal antiinflammatory drugs is therefore not directly related to the degree of inhibition of prostaglandin E2 synthesis and is probably related to the specific chemical and pharmacokinetic properties of each individual drug.

Purpose: A subnormal status of vitamin C has been associated with an increased risk for several malignant diseases and may play a causative role in their development. The aim of the present study was to investigate whether this occurs also in neoplasms of the colon. METHODS: We have studied dietary intake and status of vitamin C in a consecutive group of patients with adenomatous colonic polyps (n=31) and compared it with that of patients with no such history and a normal colonic mucosa, as confirmed by colonoscopy (n=54). RESULTS: Dietary intake of this vitamin, as assessed by the dietary recall method, was similar in the two groups, as were the levels of vitamin C in plasma and leukocytes. There were no significant differences in intake of dietary fiber, fat, vitamin A, or calcium between the two groups. Lack of association between vitamin C intake or status and colonic polyps persisted after adjustment for potential confounders. CONCLUSION: We conclude that in this population, a deficient status of vitamin C is not an important factor in colonic neoplasia.

Patients suffering from the irritable bowel syndrome (IBS) tend to have extraintestinal symptoms. The purposes of this study were to compare the nature and severity of these symptoms in IBS patients in relation to patients with inflammatory bowel disease (IBD) and to nonpatients and to clarify the relationship between intestinal and extraintestinal symptoms. A consecutive group of male patients and a control group of age-matched male subjects were studied. Symptoms were graded for severity using a validated, self-administered inventory. There were 53 IBS patients, 55 IBD patients (32 Crohn's disease), and 56 controls. IBS patients scored significantly higher than IBD patients on constipation, dyspepsia, and reflux scales. Musculoskeletal symptoms, neurasthenia, and sleep scores were similar in IBS and IBD patients, and both groups scored significantly higher than the controls. The scores of urinary, thoracic, and oral symptoms were similar in IBD patients and in controls. However, IBS patients scored significantly higher than both groups on all these scales. Reflux symptoms were the most powerful predictors of extraintestinal symptoms, both in IBS and in IBD. Diarrhea was predictive of extraintestinal symptoms only in IBD. In conclusion, IBS patients experienced extraintestinal symptoms to the same extent, or even more than patients with IBD. However, the relationship between intestinal and extraintestinal symptoms differed in the two conditions.

The irritable bowel syndrome is characterized by abdominal pain, altered bowel habits and various other digestive symptoms. Emotional factors are important in some patients. I describe here a metaphor which links the altered motility of the digestive system to the emotional contents it may embody. A metaphor of a river is used to evoke both a smooth, coordinated flow through the normal digestive tract and a normal flow in the management of the patient's emotions. The possibility that some blockage has occurred in the river, resulting in perturbation of the normal flow is then suggested to the patient. This is followed by a suggestion for the patient to clear the blockage. This approach may lead patients to work on the emotional components of their symptoms, resulting in their subsequent resolution. I have used this approach with several patients and it proved very effective. This paper demonstrates the use of this metaphor in one of the patients.

A 58-year-old woman developed chronic, severe symptoms of heartburn, epigastric pain, and regurgitation that persisted for 2 years. She underwent a thorough evaluation and no organic cause was identified. Therefore, a diagnosis of dyspepsia was made. Her symptoms were refractory to pharmacological treatment. Upon further probing, the patient reported that the onset of her symptoms coincided with the death of her son of cancer 2 years earlier. She blamed herself for the death of her son and admitted to a need for self-punishment. A brief course of treatment using metaphors and hypnosis resulted in a complete resolution of her symptoms, which did not recur during a follow-up of 12 years. This is the first published report of the treatment of dyspepsia using hypnotic methods.

A method of sedation of patients undergoing upper gastrointestinal endoscopy is described. This technique employs a variety of elements, including “pacing and leading,” metaphors, use of physiological reactions to deepen the relaxation, imagery, and post hypnotic suggestions. It is a simple and effective method which does not require any preparation. It spares the need for a pharmacological sedation and obviates the possible hazards of such a sedation. The author has successfully used this technique to sedate more than 200 patients undergoing upper gastrointestinal endoscopy. The duration of examinations performed this way compares with that using conventional pharmacological sedation. However, unlike the case of pharmacological sedation, no further monitoring is needed after the completion of the examination and the patients can leave the clinic immediately to resume their activities.

The risk of death in patients presenting with upper gastrointestinal (UGI) hemorrhage increases with age. Our aims were to define the background characteristics, causes, course, and outcome in patients agedor = 80 years admitted to hospital because of acute UGI bleeding (n = 115) in relation to patients aged 60-69 years admitted for the same reason (n = 133).A prospective, longitudinal study with a nested case-control analysis was carried out.In the elderly patients there was a female preponderance and a significantly higher prevalence of atherosclerotic cardiovascular disease. By contrast, use of tobacco and alcohol, diabetes mellitus, and chronic liver disease were significantly commoner in the controls. The use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, anticoagulants, and corticosteroids was similar in the two groups. Esophagitis was the cause of bleeding in 21.1% of the elderly, as compared with 3.3% in the controls. The relative risk of developing esophagitis in the elderly was increased and was independent of gender, smoking, alcohol consumption, use of NSAIDs, aspirin, or corticosteroids, diabetes mellitus, atherosclerotic cardiovascular disease and liver disease. (Adjusted odds ratio, 18.1; P = 0.0002). The rates of persistent or recurrent bleeding and emergency surgery to control bleeding were similar. However, the mortality in the elderly was higher (13 versus 6.1%; P = 0.09).Ageor = 80 years is an independent determinant of esophagitis, a major cause of UGI bleeding in the elderly.

Background: Glutamine is the most abundant amino acid in the body. It has a key role in nitrogen metabolism and is a major source of energy for the enterocyte and many other cells. Glutamine is also essential for tumor growth, and marked changes in organ glutamine metabolism are characteristic in cancer patients. Methods: We have investigated the catabolism of glutamine in a classic premalignant condition: the colonic adenomatous polyp. The content of glutamine and activity of two catabolic enzymes, glutamine transferase and phosphate-dependent glutaminase, were studied in normal colon and in polyp mucosa. Results: Free glutamine content and activity of glutaminase were significantly lower in polyps than in their adjacent mucosa. Glutamine transferase activity was significantly lower in polyp mucosa than in normal colon controls. Conclusions: Adenomatous polyps might behave as a glutamine trap, channeling glutamine to protein and nucleic acid synthesis. These changes in glutamine catabolism could play a r...

Objectives. To identify clinical, laboratory and endoscopic features of prognostic implication in patients who suffer an upper gastrointestinal haemorrhage whilst hospitalized for other causes. Design/setting. A prospective longitudinal study of 125 consecutive cases (89 males, 36 females) seen during 1988–1991 in a tertiary care university hospital. Main outcome measures. The crude and adjusted relative risk of mortality associated with each of the various clinical, laboratory and endoscopic variables. Results. The rates of endoscopic haemostasis, persistent or recurrent bleeding and surgery to control bleeding were 48, 37 and 12%, respectively; the overall mortality was 28%. A significantly increased risk of mortality was associated with shock prior to onset of bleeding, sepsis, renal failure, cirrhosis, encephalopathy, presence of red blood in the nasogastric aspirate or per rectum, thrombocytopenia, hypoalbuminaemia, elevation of serum bilirubin, aminotransferases or urea levels, endoscopic evidence of active bleeding, the application of endoscopic haemostasis, rebleeding, transfusion of ≥ 6 units of blood, surgical treatment or any subsequent complication. Use of nonsteroidal anti-inflammatory drugs (27%) was associated with a decreased mortality risk (odds ratio 0.2; P = 0.03). A multivariate analysis showed that the features at presentation which were independently associated with an increased risk of mortality were: a history of cirrhosis, sepsis, shock prior to onset of bleeding, hypoalbuminaemia and elevated serum aminotransferases. Conclusion. The prognosis of secondary upper gastrointestinal haemorrhage depends on the underlying diseases and on the general condition of the patient, rather than on the actual cause of bleeding.

Proof CONTROL ID: 1019563 CURRENT CATEGORY: Neurogastroenterology and Motility PRESENTATION TYPE: AGA Institute Oral or Poster PRESENTER: Douglas Drossman PRESENTER (E-MAIL ONLY): drossman@med.unc.edu

(esophageal aperistalsis and hypotonic LES). Nine patients (60%) had endoscopic esophagitis, whereas all fifteen showed gastroesophageal reflux at the 24h pH-MII recording. Analyzing the type of reflux, 2 patients showed a pure acid reflux, five (33%) a non-acid reflux and the other eight (53%) had a mixed reflux, both acid and non acid. Regarding lung involvement, images of interstitial pneumonia were detected in 6 out 15 (40%). The proximal extent of liquid refluxate into the esophagus was documented in three patients, all of them with interstitial pneumonia (p>0.05 by Fisher's exact test) Conclusions: the majority of SSc patients showed both acid and non acid GERD, and these findings might help for better tailoring medical treatment. Patients with proximal extent of liquid refluxate seem to be at risk of pulmonary involvement. These preliminary data need to be confirmed in a larger cohort of SSc patients.