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Following significant effort over the past several years by AFRL and NASA, the X-56A flight vehicle has proven to be a useful platform for exploring controllers and distributed actuation on a flexible, swept flying-wing. The program sought to advance the state of the art in airworthiness for vehicles encountering flutter, leading to relaxed design constraints that could drastically decrease structural weight and improve aircraft performance. Specifically, the vehicle was designed to encounter different forms of flutter: body-freedom flutter, and wing-bending torsion flutter, making it an ideal candidate for identifying dynamic actuation challenges. Flight testing led to fundamental observations by controller designers about the actuation needs for such a vehicle. Namely, the small inherent actuator deadband led to significant constant-amplitude limit cycle oscillations of the system during post-flutter controlled flight. This work captures these observations by exploring theoretical changes in the actuators via a nonlinear simulation tuned with flight testing data and shows that a 60% reduction in actuator deadband can improve ride quality by nearly 50%. The results are combined into a set of actuation challenges for the adaptive structures community at large, including precise actuation for a large number of cycles over multiple timescales, with a relevant baseline described by original actuation system.

The aim of this study was to obtain real-world, US, observational data on the effect of baseline resistance-associated substitutions (RASs) on achieving sustained virologic response (SVR) in hepatitis C (HCV) patients treated with direct-acting antiviral (DAA) regimens; the need for long-term follow-up in post-SVR patients. It is uncertain if the presence of RASs limits efficacy to DAAs. Once SVR is achieved, society guidelines recommend long-term surveillance for hepatocellular carcinoma in certain patients. Real-world data are limited on these topics. Adult patients treated with DAAs at community hepatitis clinics between January 2015 and April 2017 were included in this study. Baseline resistance testing was performed before treatment. Per guidelines, post-SVR long-term monitoring was required in patients with F3 to F4 fibrosis before treatment or with elevated ALT levels (>19 U/L females; >30 U/L males). A total of 875 chronic, mostly GT1a (60%) HCV patients were treated with an approved DAA regimen. Average baseline AST and ALT were 75 and 67 U/L, respectively, and 47% had F3 to F4 fibrosis at baseline. SVR was achieved in 863 (98.6%) patients despite a high presence of baseline RASs (61%). Long-term monitoring was required post-SVR in 539 patients (62%). In a real-life, US cohort of HCV-infected patients, nearly all patients achieved SVR with available DAA regimens regardless of baseline RASs. Approximately two-thirds of these patients required long-term follow-up, despite viral eradication.

Epidemiological studies indicate that light-moderate alcohol (ethanol) consumers tend to have reduced risks of cognitive impairment and progression to dementia during aging. Exploring possible mechanisms, we previously found that moderate ethanol preconditioning (MEP, 20-30 mM) of rat brain cultures for several days instigated neuroprotection against β-amyloid peptides. Our biochemical evidence implicated the NMDA receptor (NMDAR) as a potential neuroprotective “sensor”, specifically via synaptic NMDAR signaling. It remains unclear how ethanol modulates the receptor and its downstream targets to engender neuroprotection. Here we confirm with deconvolution microscopy that MEP of rat mixed cerebellar cultures robustly increases synaptic NMDAR localization. Phospho-activation of the non-receptor tyrosine kinases Src and Pyk2, known to be linked to synaptic NMDAR, is also demonstrated. Additionally, the preconditioning enhances levels of an antioxidant protein, peroxiredoxin 2 (Prx2), reported to be downstream of synaptic NMDAR signaling, and NMDAR antagonism with memantine (earlier found to abrogate MEP neuroprotection) blocks the Prx2 elevations. To further link Prx2 with antioxidant-based neuroprotection, we circumvented the ethanol preconditioning-NMDAR pathway by pharmacologically increasing Prx2 with the naturally-occurring cruciferous compound, 3H-1,2-dithiole-3-thione (D3T). Thus, D3T pretreatment elevated Prx2 expression to a similar extent as MEP, while concomitantly preventing β-amyloid neurotoxicity; D3T also protected the cultures from hydrogen peroxide toxicity. The findings support a mechanism that couples synaptic NMDAR signaling, Prx2 expression and augmented antioxidant defenses in ethanol preconditioning-induced neuroprotection. That this mechanism can be emulated by a cruciferous vegetable constituent suggests that such naturally-occurring “neutraceuticals” may be useful in therapy for oxidative stress-related dementias.

Preconditioning brain cultures with moderate concentrations of ethanol (EtOH) or trans-resveratrol (RES), key red wine constituents, can prevent amyloid-β (Aβ) neurotoxicity. Past studies have indicated that moderate EtOH activates synaptic N-methyl-D-aspartate receptors (NMDAR) that, in part, signal via protein kinase C (PKC) to increase protective antioxidant proteins such as peroxiredoxin-2 (Prx2). RES preconditioning also is reported to involve NMDAR and PKC. However, although moderate, the EtOH and RES concentrations used have been noticeably above circulating levels from two glasses of wine, a daily intake linked to reduced risk of cognitive decline among older social drinkers. Given their mechanistic parallels, we speculated that subprotective EtOH and RES concentrations in a combinatorial preconditioning paradigm might elicit synergistic neuroprotection. To examine this notion, rat cerebellar cultures were pretreated with 10 mM EtOH (circulating concentration after ~ 2 drinks), 5 μM RES, EtOH + RES combinatorially, or media alone (controls). After 3 days, media were removed, and fresh media aliquots containing Aβ25-35 (25 μM) were added. Assessing apoptosis 24 h later with Hoescht 33342, neurodegeneration did not differ from controls in cultures separately preconditioned with 10 mM EtOH or 5 μM RES. However, apoptosis was prevented in combinatorially preconditioned cultures. Also, immunoblotting revealed elevated Prx2 levels due to combinatorial pretreatment that correlated with subsequent neuroprotection, whereas Prx2 was unchanged in separately pretreated cultures. Although the protective mechanisms require clarification, synergistically upregulated NMDAR-PKC-Prx2 (and other antioxidant proteins) is a reasonable component. These findings imply that EtOH + RES antioxidant synergy could be involved in neurobenefits attributed to low-moderate wine consumption.

The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization. However, little is known about the endogenous ligands that engage ErbB4, the neural processes that activate them or their direct downstream targets. Here we demonstrate, in cultured neurons and in acute slices, that the NMDA receptor is both effector and target of neuregulin 2 (NRG2)/ErbB4 signalling in cortical interneurons. Interneurons co-express ErbB4 and NRG2, and pro-NRG2 accumulates on cell bodies atop subsurface cisternae. NMDA receptor activation rapidly triggers shedding of the signalling-competent NRG2 extracellular domain. In turn, NRG2 promotes ErbB4 association with GluN2B-containing NMDA receptors, followed by rapid internalization of surface receptors and potent downregulation of NMDA but not AMPA receptor currents. These effects occur selectively in ErbB4-positive interneurons and not in ErbB4-negative pyramidal neurons. Our findings reveal an intimate reciprocal relationship between ErbB4 and NMDA receptors with possible implications for the modulation of cortical microcircuits associated with cognitive deficits in psychiatric disorders., The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization but little is known about the endogenous ligands that engage ErbB4 and the downstream targets. Here the authors describe the existence of a cell-autonomous bidirectional pathway that links NMDA receptor activity with NRG signalling in GABAergic interneurons.

Nonvariceal upper gastrointestinal bleeding remains a challenging problem with a significant morbidity and mortality. In recent years endoscopic techniques have evolved, resulting in improved primary hemostasis and a reduction in the risk of rebleeding. Combination endoscopic therapy followed by high-dose proton pump inhibitor shows improved outcomes. Innovative endoscopic therapies hold promise but are as yet unproved. An aging population with significant medical comorbidities has a major influence on the overall outcome from upper gastrointestinal bleeding.

Background and study aims It is still difficult to differentiate reliably between benign and malignant biliary tract lesions. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has added to the diagnostic power of EUS for other gastrointestinal tumors. A retrospective analysis of experience with FNA sampling of bile duct lesions was therefore carried out. Patients and methods All EUS-FNA procedures for bile duct masses or strictures were analyzed at our tertiary referral center from May 2000 through October 2002. Data for EUS findings, the results of EUS-FNA, and tissue sampling at surgery were included. EUS-FNA procedures were carried out using a 22-gauge needle. An experienced cytopathologist was present during FNA in all but three cases. Clinical follow-up details were recorded when available for patients in whom a suitable diagnostic gold standard was not available for comparison. Results A total of 35 patients underwent EUS-FNA of bile duct lesions during the study period. There were no complications. Data for EUS-FNA of bile duct masses or strictures and tissue obtained at surgery were available for 23 patients. If positive cytology at surgical pathology is taken as the gold standard, EUS-FNA has a diagnostic yield for cancer of 100 % (if atypia/inconclusive findings in the FNA sample are regarded as benign). Eleven patients had a definite malignancy on surgical pathology. Of these 11 patients, five had a finding of malignancy on EUS-FNA, giving a sensitivity of 45 % (if FNA cytology reported as atypia/inconclusive is regarded as benign). Twelve patients had findings of no malignancy from tissue obtained at surgery. Of these 12 patients, nine had benign pathology and three had atypia/inconclusive findings in the EUS-FNA sample (specificity of 100 % if atypia/inconclusive findings are considered benign). A further 12 patients did not have surgical specimens for comparison with EUS-FNA results. Four patients had definite findings of malignancy on EUS-FNA alone, and one patient had FNA findings suspicious for malignancy. Seven patients had negative or equivocal EUS-FNA results. These 12 patients are described but excluded from further analysis, as a gold standard was not available for comparison. However, clinical follow-up data were available for eight of these 12 patients, and in each case the follow-up findings were compatible with previous benign or malignant EUS-FNA findings. Conclusions The practice of EUS-FNA has improved the diagnostic yield of EUS. These results suggest that it is a safe and useful procedure for investigating biliary masses or strictures that have hitherto caused considerable diagnostic confusion, especially in patients with negative brush cytology findings. The possibility of false-negative findings remains, but core biopsy needles may improve the situation. The results of further studies are awaited.

It may be tempting for the endoscopist performing endoscopic retrograde cholangiopancreatography (ERCP) to ignore the basic principles underpinning good radiological technique. However, while a thorough understanding of the physics behind X-ray production and image formation is not necessary, knowledge of basic radiology and its application to ERCP is an advantage when imaging the pancreatic and biliary systems. The endoscopist must also aware of the safety issues involved in dealing with ionizing radiation. In this article, we have covered the important radiological principles and safety issues as applied to ERCP, identified common problems encountered by ERCPists, and endeavored to provide guidance in order to overcome these.

Pseudocysts complicate acute pancreatitis in less than 5% of cases and chronic pancreatitis in 20% to 40% of cases. A pseudocyst is a localized collection of pancreatic fluid surrounded by a wall of granulation tissue and collagen. It takes 4 to 6 weeks for a fluid collection to mature and become a true pseudocyst. Unlike other cystic lesions of the pancreas from which they should be differentiated, pseudocysts lack an epithelial layer. Patients with pseudocysts present with a range of symptoms and signs. Pseudocysts are imaged using transabdominal ultrasound, CT, endoscopic ultrasound (EUS), and MRI. EUS confers an advantage over other imaging modalities in that certain EUS features are suggestive of pseudocysts over other cystic lesions. The diagnostic accuracy of EUS has improved further with the use of EUS-guided fine-needle aspiration. Therapeutic options include watchful observation or intervention. In our opinion, if acute pseudocysts are uncomplicated, asymptomatic, and do not appear to be enlarging on serial imaging, it is preferable to withhold intervention because many of these cysts resolve spontaneously. However, one needs to beware of the possibility of complications such as infection in unresolved pseudocysts. Pseudocysts associated with chronic pancreatitis are less likely to resolve spontaneously and are drained by intervention more frequently. Of the three interventional options, namely endoscopic, percutaneous, and surgical drainage, endoscopic drainage should be the treatment of choice if certain criteria are met. Preinterventional endoscopic retrograde cholangiopancreatography is mandatory to define ductal anatomy. If there is communication between the pseudocyst and the pancreatic duct, a transpapillary approach is preferred. Use of EUS should increase the number of cases in which pseudocysts can be drained endoscopically. Surgery should be reserved for cases in which there is a concern about malignancy or when there is glandular disruption.

The majority of benign biliary strictures are secondary to iatrogenic injury at surgery, sclerosing cholangitis, or chronic pancreatitis. There are several more uncommon causes of benign strictures of the bile ducts. These include recurrent pyogenic cholangitis, Mirizzi's syndrome, retroperitoneal fibrosis, and biliary varices. There are even rarer causes such as tuberculous involvement of the biliary tree, other infections such as schistosomiasis, common bile duct webs, and rare vascular anomalies. Management of the underlying cause of biliary strictures is warranted but radiological, endoscopic, or surgical intervention is often necessary for the strictures per se. The etiology, presentation, investigation, and management of uncommon biliary strictures are detailed in this article.

BACKGROUND: Serum amylase and lipase levels are widely used as markers of pancreatic inflammation. However, it would seem that mild elevations of amylase and lipase rarely predict significant pancreatic pathology. Pancreatic imaging tests are expensive. The gold standard, endoscopic retrograde cholangiopancreatography, carries risk of morbidity and mortality.OBJECTIVE: To determine whether extensive investigation of patients with mild, nonspecific abdominal symptoms and mild elevations of amylase and/or lipase results in a significant diagnostic yield.METHODS: Outpatient evaluations were retrospectively analyzed over 12 months. Inclusion criteria were nonspecific abdominal pain, and mild elevations (less than three times the upper limit of normal) of serum amylase or lipase, or both. Exclusion criteria included a history of chronic pancreatitis, elevation of liver tests and acute pain syndromes.RESULTS: Nineteen patients over the study period met the criteria. Of the nineteen patients, 58% had elevation of lipase alone, 21% amylase alone and 21% had elevations of both. In addition, 89.5% of the patients had nonspecific abdominal pain. After imaging with one or more of ultrasound, computed tomography, magnetic resonance cholangiopancreatography, endoscopic ultrasound and endoscopic retrograde cholangiopancreatography, small bowel follow through or hepatobiliary scanning, 78.9% patients were thought to have a normal pancreas. Of the remaining patients, 15.8% had mild or equivocal changes of chronic pancreatitis, and one patient was found to have a pancreatic tail pseudocyst. The average cost of investigation was US$2,255, taking only direct procedural costs into account. No patient was found to have malignancy.CONCLUSIONS: The majority of patients with nonspecific abdominal pain and isolated elevations of amylase and/or lipase (less than three times the upper limit of normal) had no identifiable pancreatic pathology. The diagnostic yield in patients with mild elevations of lipase alone was particularly poor. The cost effectiveness and risk-benefit ratio of extensive investigation of this group of patients warrants further study.

ErbB4 signaling in the central nervous system is implicated in neuropsychiatric disorders and epilepsy. In cortical tissue, ErbB4 associates with excitatory synapses located on inhibitory interneurons. However, biochemical and histological data described herein demonstrate that the vast majority of ErbB4 is extrasynaptic and detergent-soluble. To explore the function of this receptor population, we used unbiased proteomics, in combination with electrophysiological, biochemical, and cell biological techniques, to identify a clinically relevant ErbB4-interacting protein, the GABAA receptor α1 subunit (GABAR α1). We show that ErbB4 and GABAR α1 are robustly coexpressed in hippocampal interneurons, and that ErbB4-null mice have diminished cortical GABAR α1 expression. Moreover, we characterize a Neuregulin-mediated ErbB4 signaling modality, independent of receptor tyrosine kinase activity, that couples ErbB4 to decreased postsynaptic GABAR currents on inhibitory interneurons. Consistent with an evolving understanding of GABAR trafficking, this pathway requires both clathrin-mediated endocytosis and protein kinase C to reduce GABAR inhibitory currents, surface GABAR α1 expression, and colocalization with the inhibitory postsynaptic protein gephyrin. Our results reveal a function of ErbB4, independent of its tyrosine kinase activity, that modulates postsynaptic inhibitory control of hippocampal interneurons and may provide a novel pharmacological target in the treatment of neuropsychiatric disorders and epilepsy.

There is no question that chronic alcohol (ethanol) abuse, a leading worldwide problem, causes neuronal dysfunction and brain damage. However, various epidemiologic studies in recent years have indicated that in comparisons with abstainers or never-drinkers, light/moderate alcohol consumers have lower risks of age-dependent cognitive decline and/or dementia, including Alzheimer's disease (AD). Such reduced risks have been variously attributed to favorable circulatory and/or cerebrovascular effects of moderate ethanol intake, but they could also involve ethanol "preconditioning" phenomena in brain glia and neurons. Here we summarize our experimental studies showing that moderate ethanol preconditioning (MEP; 20-30 mM ethanol) of rat brain cultures prevents neurodegeneration due to beta-amyloid, an important protein implicated in AD, and to other neuroinflammatory proteins such as gp120, the human immunodeficiency virus 1 envelope protein linked to AIDS dementia. The MEP neuroprotection is associated with suppression of neurotoxic protein-evoked initial increases in [Ca(+2)](i) and proinflammatory mediators--e.g., superoxide anion, arachidonic acid, and glutamate. Applying a sensor --transducer --effector model to MEP, we find that onset of neuroprotection correlates temporally with elevations in "effector" heat shock proteins (HSP70, HSP27, and phospho-HSP27). The effector status of HSPs is supported by the fact that inhibiting HSP elevations due to MEP largely restores gp120-induced superoxide potentiation and subsequent neurotoxicity. As upstream mediators, synaptic N-methyl-d-aspartate receptors may be initial prosurvival sensors of ethanol, and protein kinase C epsilon and focal adhesion kinase are likely transducers during MEP that are essential for protective HSP elevations. Regarding human consumption, we speculate that moderate ethanol intake might counter incipient cognitive deterioration during advanced aging or AD by exerting preconditioning-like suppression of ongoing neuroinflammation related to amyloidogenic protein accumulation.

In several epidemiological studies, moderate ethanol consumption has been associated with reduced risks of cognitive decline or Alzheimer's dementia. Of potential relevance is that brain cultures preconditioned with moderate ethanol concentrations are resistant to neurotoxic Alzheimer's amyloid-beta (Abeta) peptides. Using rat cerebellar mixed cultures we investigated whether certain membrane receptors were early 'sensors' in moderate ethanol preconditioning (MEP). In a 6-day MEP protocol (30 mM ethanol), neuroprotection from Abeta25-35 was undiminished by antagonism during the first 3 days of either adenosine A(1) or Galpha(i/o) protein-coupled receptors. However, similar cotreatment with memantine or DL-2-amino-5-phosphono-pentanoic acid (AP-5), antagonists of NMDA receptors (NMDAR), abolished neuroprotection, indicating key early involvement of this ionotropic glutamate receptor. Also in these cultures, directly activating NMDAR using subexcitotoxic NMDA preconditioning prevented Abeta neurotoxicity. By day 2 of MEP, we observed increased levels of NMDAR subunits NR1, NR2B, and NR2C that persisted through day 6. Interestingly, memantine co-exposure blocked elevations in the obligatory NR1 subunit. Furthermore, 2 days of MEP significantly increased two indicators of synaptic NMDAR localization, NR2B phospho-Tyr1472, and post-synaptic density 95 scaffolding protein. The results indicate that ethanol preconditioning-dependent neuroprotection is associated with early increases in NR subunits concomitant with enhancement of synaptic localization and activity of NMDAR.

There is debate about whether intraoperative cholangiography (IOC) should be performed routinely or selectively during laparoscopic cholecystectomy (LC) in patients with suspected choledocholithiasis. The timing of endoscopic retrograde cholangiopancreatography (ERCP) in these patients also is an issue. We reviewed the experience in our center, where a management algorithm limiting ERCP in relation to LC was adopted.We retrospectively reviewed every LC performed by one surgeon during 6 years and the related ERCPs.A total of 264 LCs were performed. In 30 patients, stones were cleared or excluded by preoperative ERCP. In the remaining 234 LCs, 31 of 34 IOCs were successfully performed. Two of 31 IOCs were positive for bile duct stones; stone removal was successful in each patient at subsequent ERCP. Only 10 of 201 patients who did not have IOC required postsurgical ERCP within 10 weeks of LC, 3 of whom had common bile duct stones at ERCP.For patients who underwent LC, we performed selective IOC with postoperative ERCP for positive studies. Review of our experience using this algorithm showed it to be a powerful tool in limiting unnecessary ERCPs. Our data suggest that routine preoperative ERCP cannot be justified. Selective IOC during LC misses relatively few cases of biliary stones; these can be managed quickly by experienced endoscopists.

Since the US Food and Drug Administration banned the use of dietary supplements containing ephedra in February 2004, numerous "ephedra-free" weight-loss products have appeared on the market. Many of these supplements contain compounds such as bitter orange that are similar in structure and action to ephedra. We describe a patient in whom ischemic colitis developed 1 week after initiation of a bitter orange-containing weight-loss supplement. The patient had no other predisposing factors, and discontinuation of the supplement led to immediate improvement and ultimate resolution of her symptoms. Both consumers and health care professionals should be aware of the potential harm that bitter orange-containing dietary supplements can cause and report such adverse events to the US Food and Drug Administration.

During upper gastrointestinal endoscopy, topical oropharyngeal anesthesia with lidocaine and/or benzocaine is used routinely by many endodscopists. Although such a practice is usually safe, there have been a number of reports of methemoglobinemia induced by topical anesthesia. Early treatment is extremely important as the development of methemoglobinemia is potentially fatal. Methemoglobinemia should be considered when oxygen desaturation occurs without another explanation. In this case series, we report 4 cases of methemoglobinemia that followed the liberal application of Cetacaine for ERCP. All patients recovered after appropriate treatment but these cases serve to highlight the potential problem, the importance of early recognition and treatment, and the most appropriate treatment options.

BACKGROUND: Standard treatment for acute cholecystitis is cholecystectomy, but some patients are at high risk for immediate surgery. Percutaneous cholecystostomy might be the procedure of choice in this group. We reviewed the experience of percutaneous cholecystostomy in a large tertiary center population. STUDY DESIGN: We performed a retrospective analysis of patients who underwent percutaneous cholecystostomy, and recorded indications for cholecystostomy, duration of tube placement, clinical outcome, death within 30 days of procedure, complications, bacteriology of aspirated bile, gallbladder contents, and performance of interval cholecystectomy. RESULTS: Forty-five patients (mean age 63 years) had cholecystostomy tubes placed from July 1999 to March 2002. All had confirmed or presumed acute cholecystitis. Mean duration of tube insertion was 54.3 days. Thirty-six patients improved clinically within 5 days. Nine patients died within 30 days; only one death was directly related to gallbladder sepsis. Nine patients subsequently had laparoscopic cholecystectomy, eight had open cholecystectomy, and two had cholecystoenterostomy. Cholecystectomy was planned in another five patients. Cholecystostomy tubes leaked in two patients, blocked in four, and dislodged in one. One patient developed a hemoperitoneum. Bile aspirated at cholecystostomy was culture positive in 12 patients, negative in 16, and not sent or recorded in 17. Twenty-two patients had gallstones, 10 had sludge, 9 had both, and 4 had neither. CONCLUSIONS: In experienced hands, percutaneous cholecystostomy is easy to perform, with low complication and high success rates. It is the procedure of choice in patients with acute cholecystitis unfit for emergency surgery. Patients often improve clinically, so that cholecystectomy can be done electively.

There is good evidence from faecal occult blood testing trials that detection and removal of non-advanced colorectal neoplasms can achieve a reduction in colorectal cancer mortality. Both colonoscopy and barium enema have potential advantages and disadvantages if implemented for population screening. The relative merits of each are discussed.

Background and study aims Patients attending for diagnostic oesophagogastroduodenoscopy (OGD) for dyspeptic symptoms are often receiving acid-suppression therapy that has not been discontinued prior to endoscopy, and this may reduce the diagnostic yield of endoscopy. The aim of this study was to compare the diagnostic yield of OGD in uncomplicated dyspepsia in patients receiving no medication, those receiving acid-suppression therapy, and those receiving nonsteroidal anti-inflammatory drugs (NSAIDs) at the time of endoscopy. Patients and methods A total of 6825 diagnostic OGDs performed in our unit between 1993 and 2001 were analysed. Patients were excluded if they had sinister symptoms, were receiving NSAIDs, or were undergoing repeat or surveillance endoscopy. Results A total of 4233 OGDs (62 %) fulfilled the criteria for uncomplicated dyspepsia. Of the patients examined in these procedures, 1367 (32 %) were receiving acid-suppression therapy. A total of 724 patients (53 % of those on therapy) were receiving proton-pump inhibitors (PPIs), 393 of whom (54 %) had positive endoscopic findings (oesophagitis 31 %, gastritis 16 %, duodenal ulcer/duodenitis 16 %). A total of 643 (47 % of the patients on therapy) were receiving H 2 -receptor antagonists, 443 of whom (69 % of this group) had positive endoscopic findings (oesophagitis 30 %, gastritis 21 %, duodenal ulcer/duodenitis 31 %). A total of 2866 patients were not receiving acid-suppression therapy, 1805 of whom (63 %) had endoscopic findings (oesophagitis 37 %, gastritis 14 %, duodenal ulcer/duodenitis 24 %). The endoscopic yield was significantly lowest in the PPI group, except for the diagnosis of oesophagitis. Overall, 17 carcinomas were detected in patients referred with simple dyspepsia, and in five of these cases the patients were receiving acid suppression. Conclusions The widespread use of acid suppression in the treatment of simple dyspepsia prior to endoscopy leads to a reduction in the endoscopic recognition of mucosal lesions caused by acid-peptic disease, but not to a high healing rate for these lesions, and it may mask malignancy.

The advanced fire supression technology (AFST) research and development program is being conducted by Olin Aerospace Research and Development program is being conducted by Olin Aerospace Company for WPAFB. The three phase program goal is to evaluate the effectiveness of gas generator technology in suppressing aircraft drybay and engine nacelle fires. This report presents the activities of phase 1, including an initital evaluation of non-filtered solid propellant gas generators, as well as select hybrid agents.

We read with great interest the commentary by Boland and Savides ( Gut 2001; 48 :449–50) on our paper “Flexible sigmoidoscopy and the changing distribution of colorectal cancer: implications for screening” ( Gut 2001; 48 :522–5). The authors make several important points about the changing pattern of distribution of colorectal cancer and the possible reasons for the changes we observed. Our data showed an increased percentage of colorectal cancers diagnosed …

Summary Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2 −/− /NPTXR −/− mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2 −/− /NPTXR −/− mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2 −/− /NPTXR −/− mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.

The pulse volume recorder has been used in studying 62 limbs to assess its accuracy in localization of arteriosclerotic lesions of the lower limbs, realising the limitations of clinical examination and simple pressure measurements. Its advantages over simple pressure measurements are illustrated. It was shown to be most accurate in locating isolated stenoses. The technique helps differentiate aorto-iliac from high superficial femoral artery obstruction. It can be used when severe medial sclerosis is present and is very helpful when distal pulses cannot be detected for technical reasons.

From the dawn of medical history to the present day the handling of the third stage of labor has been an esoteric problem attested by the voluminous literature and the manifold methods that have been devised for the most beneficent results. A few of these stratagems will serve to refresh the memory and generate smiles of sympathy in compliment to the infinite ingenuity of our forebears. Methods 1 adhered to by the ancients consisted in pulling on the umbilical cord, pressing on the belly, giving emetics, tickling the nose to provoke sneezing, encouraging the woman to blow hard into a gourd, bottle or closed fist, and removing the placenta by hand from the uterus or vagina. Then came the idea of moderate cord traction plus fundal pressure; in 1767 John Harvie of the Rotunda Hospital, Dublin, Ireland, proffered a scheme in which he advised guarding the uterus for fifteen to

To the Editor:— In an attempt to forestall any possible decline in the popularity which caudal anesthesia, both the single injection and the continuous injection variety, have attained, this statement weighing the advantages and disadvantages of each is presented. Differences of opinion as to the merits of single injection caudal and continuous caudal prevail among the advocates of caudal anesthesia. Each has its place, dependent on the facilities and training of the personnel. The following points are listed to enable an impartial comparison of the two: The indications, contraindications and preanesthetic preparation of the patient are the same for the two types of caudal anesthesia. The obstetrician or the trained assistant administering caudal anesthesia must be constantly on guard against complications. The single injection caudal anesthetic may be given by the obstetrician or the trained assistant just prior to the termination of the second stage of labor, while