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The mechanisms involved in the initiation of human labor are largely unknown. Understanding the molecular pathways is fundamental in both the development of effective therapeutic strategies and intervention to prevent preterm labor. Prostaglandins are bioactive lipids and members of the eicosanoids family, derived from arachidonic acid, which act in a paracrine or autocrine manner and function via binding to specific G-protein-coupled receptors, activating intracellular signaling and gene transcription. Prostaglandins have a central role in the maintenance of pregnancy and initiation of labor, with the change from uterine quiescence to a contractile state facilitated by differential expression of prostaglandin receptors within the myometrium and fetal membranes. Clinical evidence for the key role of prostaglandins in human parturition is evident from their successful exploitation as exogenous agents for the induction of labor and the role of prostaglandin synthase inhibitors as a preventative therapy for preterm labor. This review aims to focus on prostaglandin synthesis and metabolism and how differential regulation of prostaglandins and their receptors in gestational tissues interact in the initiation of labor.

Prostaglandins are bioactive lipids and important mediators of uterine relaxation as well as contraction during pregnancy and labour. E series prostaglandins may directly contract or relax myometrium in a dose-dependent manner, with the relaxatory effects mediated through the prostanoid receptors EP(2) and EP(4). The aim of this study was to evaluate the pharmacological effects of prostaglandin analogues on isolated pregnant rat uterine contractility, at 10(-15) to 10(-9) M concentrations. Uterine strips from rats at 19 days of gestation were set up in organ baths at 37 degrees C, bathed in Krebs buffer and gassed with 95% O(2)/5% CO(2). Spontaneous contractions were recorded via a force transducer. Concentration ranges of 10(-15)-10(-9) M of PGE(2), PGF(2alpha) and a range of prostaglandin analogues were applied non-cumulatively to the tissues. Spontaneous contractions were recorded for 12 min post dose. Amplitude, frequency, baseline tone and percent contractility over 10 min periods were analysed. PGE(2), butaprost, 9-keto fluprostenol, 11-keto fluprostenol, 9-keto fluprostenol isopropyl ester, AL8810 and 15(S)-15-methyl PGE(2) all caused a decrease in percent contractility (P

We report the case of a patient with chronic diarrhea due to infiltrative cancer to the colon from the breast. A 49-year-old woman with a history of metastatic breast cancer to the bones was admitted to hospital with 4 weeks of watery diarrhea. Computed tomography (CT) scan of the abdomen showed pancolitis. Colonoscopy showed patchy subepithelial hemorrhages, most prominently in the ascending colon and sigmoid colon, but no mass lesion. Random biopsies taken throughout the colon showed infiltrative adenocarcinoma of breast origin in multiple specimens. Infectious work-up was negative.

54 Background: Definitive treatment for localized EC involves surgery alone or tri-modality therapy (TMT-chemotherapy, radiation, and surgery). TMT is administered to pts with clinical T2 or higher and lymph node (LN) positive ECs. Standard staging includes Computerized Tomography (CT)/Positron Emission Tomography (PET) imaging and Endoscopic Ultrasound (EUS). We investigated whether performing an EUS altered treatment decision in localized EC pts where a combination of imaging and clinical symptoms suggested the need for TMT. Methods: We performed a retrospective review to identify pts with localized EC who had their staging work up and treatment at the Medical College of Wisconsin between 2003 and 2012. Relevant clinical information was collected through review of the electronic medical record. Results: We identified 65 pts; median age at diagnosis was 62 years, 49 (75%) were male, and 56 (86%) were Caucasian. Histology was adenocarcinoma in 48 (74%) pts with 21 (44%) having background Barrett’s esophagus. Common presenting symptoms included dysphagia (83%), weight loss (73%), and odynophagia (25%). Staging evaluation included CT, PET, and EUS in 100%, 98%, and 89% of pts respectively. EUS staging results are in the table below. Dysphagia was reported by 67% of T1, 80% of T2, 84% of T3, 50% of T4, and 100% of Tx pts; 70% of pts with dysphagia were node positive by EUS. PET positive primary tumors/LNs were found in 89%/29% of all pts and 89%/33% of pts with dysphagia. Of the pts with PET positive LNs, 68% had node positive disease on EUS. Eighteen (28%) pts had both dysphagia and PET positive LNs, none with T1-2N0 staging by EUS; 36 pts had dysphagia and PET negative LNs, 7 (19%) with T1-2N0 staging by EUS. Among those 7 pts, 4 underwent surgery (1 pt-pT3N1aMx; 3pts-pT1bN0Mx). Conclusions: Localized EC pts with both dysphagia and PET positive LNs are candidates for TMT even in the absence of EUS staging. The role of EUS in this population may be limited to investigating adjacent organ invasion or confirmation of LN involvement. With improving PET capabilities, the role of EUS in this pt population needs to be studied prospectively. [Table: see text]

Importance Pancreas divisum is an uncommon congenital anomaly that may result in chronic pancreatitis (chronic pancreatitis secondary to pancreas divisum [CPPD]) and intractable pain. We evaluated the role of the Frey procedure in the management of patients with pain related to CPPD as compared with patients with chronic pancreatitis secondary to alcohol (CPA) or idiopathic causes (ICP). Objective To review our experience with the Frey procedure for the management of chronic pancreatitis related to pancreas divisum. Design This was a 2-year institutional retrospective of patients undergoing the Frey procedure for chronic pancreatitis related–pain from April 2008 to June 2010. Setting Academic tertiary care referral center. Participants A consecutive sample of 14 patients undergoing the Frey procedure for chronic pancreatitis and disease-related intractable pain. We sought to examine the utility of the Frey procedure in patients with CPPD as compared with CPA and ICP. Intervention The Frey procedure. Main Outcomes and Measures Perioperative outcomes and postoperative narcotic requirement were compared among patient groups. Results Fourteen patients underwent the Frey procedure. The etiology of the disease was pancreas divisum in 6 patients, alcohol in 5, and idiopathic in 3. The most common indication for surgery was intractable pain, and all patients had undergone endoscopic retrograde cholangiopancreatography for attempted relief in the past. There were no statistically significant differences in median operative time (263 minutes), intraoperative blood loss (425 mL), median length of stay (9.5 days), or rate of morbidity (21%) between the 3 etiologies. Two-thirds of patients required less or no opioid at follow-up, although follow-up was significantly longer for CPPD and ICP than CPA (median, 249, 259, and 42 days, respectively; P Conclusions and Relevance In this series, outcomes for patients with CPPD treated with the Frey procedure were equivalent to those treated for CPA. Patients with pancreas divisum and a dilated pancreatic duct may be ideally suited for this surgical strategy. The potential advantage of this approach over minor duct sphincteroplasty and lateral pancreaticojejunostomy is the removal of the fibrotic tissue of the head of the pancreas, thought to be the epicenter of pain in this condition. The benefits over resection alone include a more extensive ductal drainage procedure.

transesophageal prosthesis). No perforations occurred. Endoscopic injection of steroids did not accelerate remediation compared to patients who did not receive injected steroids [median 24 (IQR 8, 38.5) weeks, mean 7.5 (+/-2.6) dilations vs. median 11 (IQR 2, 14) weeks, mean 3.8 (+/-2.3) dilations, p=0.16 and p=0.007]. Conclusions: 1. Radiation-induced strictures appear to have a delayed onset from time of injury. 2. Endoscopic dilation can achieve medium-term luminal remediation but has a high long-term recurrence rate. 3. Endoscopically injected steroids do not promote remediation of radiation strictures.

Eliminating the Residual Negative Pressure in the EUS-FNA Needle Before Withdrawal Enhances the FNA Cytology Yield A. Aziz Aadam*, Young OH, Sahibzada U. Latif, Abdul H. Khan, Mukund Venu, ADAM Schiro, Bryan C. Hunt, R. Nagarjun Rao, Vinod B. Shidham, Kulwinder S. Dua Division of Gastroenterology and Hepatology, Northwestern University, Chicago, IL; Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI; Department of Pathology, Medical College of Wisconsin, Milwaukee, WI; Department of Pathology, Wayne State University, Detroit, M

were divided into 4 quartiles of 25 procedures each. There was a non-significant trend towards increase in the diagnostic yield of the final cytopathology over the 4 quartiles. The diagnostic yield of ROSE as well as the agreement between ROSE and final cytopathology was similar across the 4 quartiles. There was a non-significant trend towards a decrease in the duration of procedure over time. The median number of passes remained the same over the time period. (Table 1). Conclusion: While echoendosonographer and cytopathologist performance improves over time with case volume, these data suggest that a multi-disciplinary team can deliver a high diagnostic yield from inception, provided that the individual team members have sufficient training and experience in other settings. Institutions wishing to establish a multi-disciplinary EUS-FNA program may see high performance early-on provided that team members are individually experienced.

The characteristics of carnosine (beta-alanyl-L-histidine) transport have been studied using purified brush-border membrane vesicles from mouse small intestine. Uptake curves did not exhibit any overshoot phenomena, and were similar under Na+, K+ or choline+ gradient conditions (extravesicular greater than intravesicular). However, uptake of histidine showed an overshoot phenomenon in the presence of a Na+-gradient. There was no detectable hydrolysis of carnosine during 15 min of incubation with membrane vesicles under conditions used for transport experiments. Analysis of intravesicular contents further showed the complete absence of the constituent free amino acids of carnosine, and indicates that intact carnosine is transported. Studies on the effect of concentration on peptide uptake revealed that transport occurred by a saturable process conforming to Michaelis-Menten kinetics with a Km of 9.6 +/- 1.4 mM and a Vmax of 2.9 +/- 0.2 nmol/mg protein per 0.4 min. Uptake of carnosine was inhibited by both di- and tripeptides with a maximum inhibition of 68% by glycyl-L-leucyltyrosine. These results clearly demonstrate that carnosine is transported intact by a carrier-mediated, Na+-independent process.

Systolic and diastolic time intervals in 14 cardiac patients with pulsus alternans revealed significant alternation of preinjection period (PEP), isovolumic contraction time (IVCT), left ventricular ejection time (LVET), ejection time index (ETI), PEP/LVET, and carotid dD/dt with better functional values in the strong beats. Cycle length, duration of electromechanical systole (EMS) and total diastole, i.e., isovolumic relaxation period (IRP) and diastolic filling period (DFP) occurred in 7 out of 8 patients. These diastolic intervals alternated reciprocally such that the IRP of the strong beats encroached upon the DFP of the next (weak) beats.

Rheumatoid heart lesions in several forms are encountered in patients with rheumatoid arthritis. The proposed incidence of this kind of heart disease is 27–34% of heart lesions in rheumatoid patients, and the involvement may assume any of the following forms: pericarditis, myocarditis, endocarditis with valvulitis, and coronary arteritis. Clinical features are nondiagnostic and include the presence of pericardial rub, chest pain, arrhythmias, murmurs, and signs of cardiac enlargement or failure (Table 3). Chest X-ray findings may reveal generalized cardiomegaly or selective unexplained atrial enlargement. Electrocardiographic findings are not specific for this entity and include ventricular enlargement or “strain” patterns and various conduction abnormalities. Proof positive of rheumatoid heart disease is the demonstration of cardiac granuloma histologically resembling a subcutaneous rheumatoid nodule. These granulomata are rare, and the common histologic findings are nonspecific. The clinical diagnosis of rheumatoid heart disease is therefore based on guilt by association and by exclusion of other common forms of heart disease.

This study characterizes the transport of [1-14C]glycyl-L-proline into purified brush border membrane vesicles prepared from human small intestine. Time-course uptake curves of glycyl-L-proline were similar under sodium thiocyanate or potassium thiocyanate gradient conditions (extravesicular greater than intravesicular) and did not show any overshoot phenomena. The transport of glycine and proline, however, was stimulated by the presence of sodium gradient. Measurement of peptide uptake with increasing medium osmolarity showed that glycyl-L-proline was transported into an osmotically reactive intravesicular space with insignificant binding to the surface of the vesicles. Only 2% of the glycyl-L-proline in the incubation media was hydrolyzed after 10 min of incubation. Also, there was no hydrolysis of peptide transported into the intravesicular space. The effects of increasing concentrations of glycyl-L-proline on uptake showed that uptake of the peptide was saturable and conformed to Michaelis-Menten kinetics with a Km of 4.1 +/- 0.5 mM and a Vmax of 1.53 +/- 0.07 nmol/mg protein X 0.5 min. Free amino acids did not inhibit the transport of glycyl-L-proline while dipeptides and tripeptides exerted appreciable inhibition (up to 60%). Our results show that human small intestinal brush border membrane vesicles transport glycyl-L-proline as an intact peptide by a carrier-mediated, Na+-independent process.

The amplitude and time relationships of the carotid derivative in normal individuals and unselected cardiac patients is investigated together with the effects of different contraction strengths in patients with pulsus alternans and subjects challenged with isoproterenol and propranolol. Data regarding the relationship between the preejection period (PEP) and the ratio of peak to total amplitude of the carotid displacement pulse derivative are presented. It is found that cardiac abnormality tends to reduce the rate of rise of the carotid displacement pulse. The results obtained show that the PEP is a somewhat more sensitive index of the changes studied than the carotid displacement derivative.

760 Background: Somatic and germline DDR gene alterations in PC have been postulated to positively predict response to DNA damaging cytotoxic agents. Due to the relatively high prevalence of germline DDR gene alterations, germline testing is recommended in all pts with PC. We examined whether somatic CGP can be used to reliably identify PC pts that merit germline testing. Methods: We retrospectively reviewed the electronic medical records of PC pts who underwent both somatic CGP (utilizing the Foundation One assay) and germline testing. DDR gene mutations were categorized as somatic-pathogenic, somatic-variant of uncertain significance (VUS), germline-pathogenic and germline-VUS. For somatic testing, DNA was extracted from formalin fixed paraffin embedded (FFPE) clinical specimens and CGP was done on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Germline genetic testing was performed on submitted blood or saliva samples, utilizing commercial assays; next generation or Sanger sequencing of all coding regions and adjacent intronic nucleotides were performed. Results: Ninety-three pts had somatic CGP data, 51 (55%) pts had both somatic CGP and germline data available. Among the 51 pts with both germline and somatic data available, DDR gene alterations that were somatic-pathogenic, germline-pathogenic, somatic-VUS and germline-VUS were present in 7 (13.7%), 7 (13.7%), 23 (45.1%) and 16 (31.4%) pts, respectively. Of the 7 pts with somatic-pathogenic alterations, 5 (71%) had a concordant germline alteration and of the 7 pts with germline-pathogenic alterations, 5 (71%) had a concordant somatic alteration. Of the 23 pts with somatic-VUSs, 12 (52%) had a concordant germline VUS and of the 16 pts with germline-VUSs, 12 (75%) had a concordant somatic VUS. Conclusions: Both somatic and germline DDR gene alterations are common in PC pts. Despite the relatively high concordance rate between somatic and germline pathogenic DDR gene alterations, somatic CGP will miss approximately one fourth of the germline DDR gene alterations.

To the Editor.— Cardiopulmonary resuscitation (CPR) training is conducted with the aid of a manikin using the guidelines of the American Heart Association.1The procedure entails mouth-to-mouth breathing and cardiac compression, performed either as a single-person or as a twoperson effort. The latter requires frequent switching of roles by the two "rescuers" from breathing to cardiac compression without allowing time to clean the manikin's oral surface. Thus, the contamination of manikins by saliva poses a potential threat of infection. In a previous report, the Center for Disease Control2indicated that the chances of transmitting hepatitis via manikins contaminated with hepatitis B surface antigenpositive saliva were remote. We address ourselves to the potential danger of bacterial infection during a CPR training session. The initial study consisted of 30 physicians and six instructors (six persons to a manikin). Cultures taken from the manikin lips at the conclusion of the CPR

• Survivors of myocardial infarction who have been discharged from the hospital face an increasing cumulative risk of suffering another infarction or death. β-Adrenergic blocking agents have undergone various trials to reduce these risks and prolong life. Although earlier trials have shown conflicting results, recent studies have conclusively demonstrated the beneficial role of this class of drugs in reducing the chances of recurrent infarction and death. These studies are briefly reviewed and appropriate conclusions as well as recommendations are made. ( Arch Intern Med 1983;143:1759-1762)

Nitrate administration is sometimes associated with mild hypotension, but serious side effects are uncommon. Recently, we have seen four patients who have demonstrated life-threatening hypotension and bradycardia after nitroglycerin administration. This observation, which has also been noted previously,3gives grounds for caution in the administration of nitroglycerin. The efficacy of nitrates is attributed to their vasodilator effects, especially their peripheral venodilating properties. A decrease in venous return and, to a certain extent, in arteriolar resistance usually causes hypotension of variable degrees. This hypotension leads to baroreceptor-mediated reflex stimulation of the vasomotor center. In turn, vascular tone and heart rate both increase, helping to support the blood pressure. Thus, for tachycardia to emerge in response to hypotension, it is necessary to have both an intact reflex mechanism and adequate sinus node function. Conditions that impair the baroreceptor reflex mechanism or sinus node function should lead to an inadequate increase in

• Aprindine hydrochloride has been extensively used in Europe for the management of ventricular and supraventricular arrhythmias. Success has been achieved even in those cases that have proven refractory to standard antiarrhythmic agents. In this report, we describe our experience with aprindine therapy in seven patients with ventricular tachycardia in whom standard antiarrhythmic agents had proven either ineffective or had caused intolerable side effects. Aprindine was effective in five cases, and it failed in two. Neurologic side effects, although common, were easily controlled with adjustment of the dose. Agranulocytosis, a rare but serious side effect, was encountered in one of our patients. Relevant literature on aprindine is reviewed. ( Arch Intern Med 1983;143:229-232)

An auscultatory search for a fourth heart sound (S 4 ) was performed by two independent "blind" auscultators who did not know the medical status of 196 consecutively examined subjects, ages 50 to 80 years. Phonocardiograms (PCGs) and other tracings taken after recording the results were measured by a third observer who was also "blind." Results of this investigation indicate that any tendency for rapid completion of atrial excitation and early onset of S 4 appears to determine the auscultatory audibility of the fourth heart sound. Conversely, a tendency to later completion of atrial excitation and a later onset of S 4 will make it auscultatorily inaudible, although recordable even at considerable amplitude by PCG. The relative amplitude and frequency of S 4 were not significantly related to its audibility. The presence or absence of disease was not significantly related to the presence or absence of S 4 by PCG or to its audibility when present.