Weekend admission and mortality for gastrointestinal disorders across England and Wales.

BACKGROUND: Little has been reported on mortality following admissions at weekends for many gastrointestinal (GI) disorders. The aim was to establish whether GI disorders are susceptible to increased mortality following unscheduled admission on weekends compared with weekdays. METHODS: Record linkage was undertaken of national administrative inpatient and mortality data for people in England and Wales who were hospitalized as an emergency for one of 19 major GI disorders. RESULTS: The study included 2 254 701 people in England and 155 464 in Wales. For 11 general surgical and medical GI disorders there were little, or no, significant weekend effects on mortality at 30 days in either country. There were large consistent weekend effects in both countries for severe liver disease (England: 26·2 (95 per cent c.i. 21·1 to 31·6) per cent; Wales: 32·0 (12·4 to 55·1 per cent) and GI cancer (England: 21·8 (19·1 to 24·5) per cent; Wales: 25·0 (15·0 to 35·9) per cent), which were lower in patients managed by surgeons. Admission rates were lower at weekends than on weekdays, most strongly for severe liver disease (by 43·3 per cent in England and 51·4 per cent in Wales) and GI cancer (by 44·6 and 52·8 per cent respectively). Both mortality and the weekend mortality effect for GI cancer were lower for patients managed by surgeons. DISCUSSION: There is little, or no, evidence of a weekend mortality effect for most major general surgical or medical GI disorders, but large weekend effects for GI cancer and severe liver disease. Lower admission rates at weekends indicate more severe cases. The findings for severe liver disease may suggest a lack of specialist hepatological resources. For cancers, reduced availability of end-of-life care in the community at weekends may be the cause.

Tuberculous pancreatitis complicated by ruptured splenic artery pseudoaneurysm.

Tuberculosis involving the pancreas is rare. We report a patient with pancreatic tuberculosis complicated by haemorrhage from a splenic artery pseudoaneurysm. As far as we are aware, the development of a splenic artery pseudoaneurysm in association with a large caseating mass of tuberculous pancreatic lymph nodes has not been reported previously. We review the literature and discuss the varied presentations of tuberculosis involving the pancreas or the pancreatic bed and its draining lymph nodes.

Gastrointestinal bleeding in a pregnant woman: mucinous cystic neoplasm of pancreas mimicking gastrointestinal stromal tumor of stomach.

A 38-year-old woman presented in early pregnancy with anemia due to an ulcerated gastric tumor which had the typical clinical presentation and endoscopic appearance of a gastric leiomyoma or gastrointestinal stromal tumor. At surgery this was subsequently found to be a mucinous cystic tumor of pancreas. Review of the literature shows that both gastrointestinal hemorrhage and infiltration of stomach are infrequent complications of this tumor.

Seat belt injury causing delayed sigmoid colon fistula.

Seat belt use can decrease the mortality rate associated with road traffic accidents (RTA). However, there is an increased risk of bowel perforations among seat belt wearers, possibly as a result of improper use. A case is reported of a female passenger who presented with an abdominal wall fistula 2 weeks after a RTA.

Fear conditioning to discontinuous auditory cues requires perirhinal cortical function.

Pretraining lesions of rat perirhinal (PR) cortex impair fear conditioning to ultrasonic vocalizations (USVs) but have no effect on conditioning to continuous tones. This study attempted to deconstruct USVs into simpler stimulus features that cause fear conditioning to be PR-dependent. Rats were conditioned to one of three cues: a multicall 19-kHz USV, a 19-kHz discontinuous tone, and a 19-kHz continuous tone. The discontinuous tone duplicated the on/off pattern of the individual calls in the USV, but it lacked the characteristic frequency modulations. Well-localized neurotoxic PR lesions impaired conditioning to the USV, the discontinuous tone, and the training context. However, PR lesions had no effect on conditioning to the continuous tone. The authors suggest that the lesion effects on fear conditioning to both cues and contexts reflect the essential role of PR in binding stimulus elements together into unitary representations.

Auditory trace fear conditioning requires perirhinal cortex.

The hippocampus is well-known to be critical for trace fear conditioning, but nothing is known about the importance of perirhinal cortex (PR), which has reciprocal connections with hippocampus. PR damage severely impairs delay fear conditioning to ultrasonic vocalizations (USVs) and discontinuous tones (pips), but has no effect on delay conditioning to continuous tones. Here we demonstrate that trace auditory fear conditioning also critically depends on PR function. The trace interval between the CS offset and the US onset was 16s. Pre-training neurotoxic lesions were produced through multiple injections of N-methyl-D-aspartate along the full length of PR, which was directly visualized during the injections. Control animals received injections with phosphate-buffered saline. Three-dimensional reconstructions of the lesion volumes demonstrated that the neurotoxic damage was well-localized to PR and included most of its anterior-posterior extent. Automated video analysis quantified freezing behavior, which served as the conditional response. PR-damaged rats were profoundly impaired in trace conditioning to either of three different CSs (a USV, tone pips, and a continuous tone) as well as conditioning to the training context. Within both the lesion and control groups, the type of cue had no effect on the mean CR. The overall PR lesion effect size was 2.7 for cue conditioning and 3.9 for context conditioning. We suggest that the role of PR in trace fear conditioning may be distinct from some of its more perceptual functions. The results further define the essential circuitry underlying trace fear conditioning to auditory cues.

Immunohistochemical study of nuclear factor-kappaB activity and interleukin-8 abundance in oesophageal adenocarcinoma; a useful strategy for monitoring these biomarkers.

AIMS: To determine if immunohistochemistry (IHC) could be used to monitor nuclear factor-kappaB (NF-kappaB) activity in oesophageal adenocarcinoma and pre-malignant (Barrett's) oesophageal tissues, relative to normal oesophageal mucosa. The pro-inflammatory cytokine interleukin-8 (IL-8), a transcriptional target of NF-kappaB, was also studied to better understand NF-kappaB functionality; its RNA and protein levels were assessed in oesophageal tissues. METHODS: IHC was employed using an antibody against the nuclear localisation sequence (NLS) of the p65 subunit as well as an antibody against IL-8. To assess NF-kappaB function, changes in gene expression of NF-kappaB controlled genes (IL-8 and I-kappaB) were also assessed in the histological sequence using real-time PCR. More global expression changes were also studied using membrane arrays. RESULTS: IHC was effective at monitoring overall NF-kappaB activity and IL-8 abundance. This method also allowed NF-kappaB activity and IL-8 abundance to be pinpointed in specific cell types. There were significant increases in nuclear NF-kappaB activity and IL-8 abundance across the histological series. Gene expression analysis also showed consistent up-regulation of IL-8, confirming the IHC data and showing enhanced transcriptional NF-kappaB activity. I-kappaB (another NF-kappaB target) showed down-regulation in dysplastic and adenocarcinoma tissues. Down-regulation of I-kappaB gene expression may partly explain increased NF-kappaB activity. CONCLUSION: IHC, using antibodies against the NLS of p65, may be useful in monitoring overall NF-kappaB activity in oesophageal tissues. As IHC is amenable to high-throughput screening (whereas traditional electrophoretic mobility shift assay methods are not), this may lead to the development of a better screening tool for early cancer risk.

Fluorescence in situ hybridisation analysis of chromosomal aberrations in gastric tissue: the potential involvement of Helicobacter pylori.

In this series of experiments, a novel protocol was developed whereby gastric cells were collected using endoscopic cytology brush techniques, and prepared, such that interphase fluorescence in situ hybridization (FISH) could be performed. In total, 80 distinct histological samples from 37 patients were studied using four chromosome probes (over 32,000 cells analysed). Studies have previously identified abnormalities of these four chromosomes in upper GI tumours. Using premalignant tissues, we aimed to determine how early in Correa's pathway to gastric cancer these chromosome abnormalities occurred. Aneuploidy of chromosomes 4, 8, 20 and 17(p53) was detected in histologically normal gastric mucosa, as well as in gastritis, intestinal metaplasia, dysplasia and cancer samples. The levels of aneuploidy increased as disease severity increased. Amplification of chromosome 4 and chromosome 20, and deletion of chromosome 17(p53) were the more common findings. Hence, a role for these abnormalities may exist in the initiation of, and the progression to, gastric cancer. Helicobacter pylori infection was determined in premalignant tissue using histological analysis and PCR technology. Detection rates were comparable. PCR was used to subtype H. pylori for CagA status. The amplification of chromosome 4 in gastric tissue was significantly more prevalent in H. pylori-positive patients (n=7) compared to H. pylori-negative patients (n=11), possibly reflecting a role for chromosome 4 amplification in H. pylori-induced gastric cancer. The more virulent CagA strain of H. pylori was associated with increased disease pathology and chromosomal abnormalities, although numbers were small (CagA+ n=3, CagA- n=4). Finally, in vitro work demonstrated that the aneuploidy induced in a human cell line after exposure to the reactive oxygen species (ROS) hydrogen peroxide was similar to that already shown in the gastric cancer pathway, and may further strengthen the hypothesis that H. pylori causes gastric cancer progression via an ROS-mediated mechanism.

Endoscopic placement of fibrin sealant as a treatment for a long-standing Boerhaave's fistula.

A 64-year-old man suffered a spontaneous rupture of the esophagus (Boerhaave's syndrome) after an episode of severe retching. He underwent attempted primary repair of the esophageal defect, but unfortunately the repair failed with the development of a persistent esophago-bronchial fistula resistant to extended conservative management. Three hundred and nineteen days after the initial rupture, the fistula was successfully treated with endoscopic placement of fibrin glue. We believe this to be the first reported case of fibrin sealant being used in the treatment of a long-standing fistula resulting from Boerhaave's syndrome.

Umbilical hernia in adults: day case local anaesthetic repair.

INTRODUCTION: The waiting times for elective surgery of Umbilical hernia (UH) in adults are unacceptably long in some cases. During this period, irreducibility and strangulation are possible. We operate on adult patients under local anaesthesia (LA) as day cases to avoid this delay and describe our experience in this paper. AIMS: The aims of our study were to look at the age and sex distribution, body weight, type and amount of local anaesthetic used, morbidity, admission and readmission rates, and waiting times of adult patients operated on for UH under LA. MATERIALS AND METHODS: It was a retrospective study covering a 4 year period from July 1996 to June 2000 including all adult patients undergoing the above procedure under the care of a single consultant general surgeon. A standard Mayo repair using non absorbable material was used without a mesh or a drain. RESULTS: 32 patients with UH were operated on under LA, 23 males and 9 females with a median age of 51 years (range 20 to 86 years). The body weight ranged from 63 to 120 (median 87) kg. The average duration of the procedure was 30 (range 22-40) minutes. Sedation was needed in 4 patients. Two patients developed wound infections, one superficial and one deep. There was no mortality. The median period of follow-up was 24 (range 4-48) months and there was no recurrence. The median waiting time for the operation was 6 weeks. CONCLUSIONS: Day case local anaesthetic repair of UH in adults seems to be safe and feasible with an acceptable morbidity. Suture repair in the right patient has excellent results and the waiting times are acceptable.

Amygdala lesions block conditioned enhancement of the early component of the rat eyeblink reflex.

A tone conditioned stimulus (CS) previously paired with a grid shock unconditioned stimulus (US) can greatly enhance the early electromyographic (EMG) component (R1) of the rat eyeblink reflex. The hypothesis that the central nucleus of the amygdala (ACe) is an essential part of the circuitry mediating conditioned R1 enhancement was tested. After bilateral ACe lesions (L) or a sham operation (S), rats received paired presentations of the CS and US (P) or explicitly unpaired CS and US presentations (U), resulting in 4 groups: P/S, P/L, U/S, and U/L. ACe lesions completely prevented conditioned R1 enhancement, which was only exhibited in Group P/S. In the latter group, the "preextinction" conditioned enhancement effect was roughly a 2-fold increase in the R1 magnitude. Circuit-level mechanisms are discussed, and some advantages of the eyeblink EMG response in this general conditioning paradigm are considered.

Predominance of late-spiking neurons in layer VI of rat perirhinal cortex.

Recent work demonstrated the importance of perirhinal cortex (PR) in a variety of behavioral tasks and disease processes. Studies from our laboratory revealed that some layers of PR contain neurons with unusual properties. Here we report a detailed examination of the cellular neurobiology of layer VI of PR, using whole-cell recordings and biocytin cell fills in horizontal rat brain slices. The most striking finding is that an overwhelming majority ( approximately 86%) of neurons are late-spiking (LS) cells, which can delay the onset of their spike trains by several seconds or more relative to the onset of a depolarizing current step. LS neurons previously have been shown to exist only in very small numbers in a limited number of other cortical regions. Anatomical reconstructions have revealed that the LS neurons vary greatly in morphology, including both pyramidal and nonpyramidal cells. Another surprising physiological finding is the fact that single-spiking (SS) neurons are the second most common cell type ( approximately 7%). SS neurons issue only a single action potential even in response to extreme depolarization. They have been seen previously in the amygdala, but never in cortex. A third remarkable finding is that there are almost no regular spiking (RS) neurons, unlike all other cortical regions that have been studied. This unique abundance of LS neurons in layer VI, along with the presence of SS neurons and the absence of RS neurons, demonstrates that layer VI of PR is unlike any other cortical region that has been studied to date.

Amygdalar nmda receptors are critical for the expression of multiple conditioned fear responses.

There is conflicting evidence regarding the issue of whether NMDA receptors in the basolateral amygdalar complex (BLA) are critically involved in the expression of conditioned fear. This matter was addressed by infusing the rat BLA with d,l-2-amino-5-phosphonovaleric acid (APV), a competitive NMDA receptor antagonist. APV infusion into the BLA was reported to block the expression of conditioned fear when measured by freezing but not when measured by fear-potentiated startle response to a loud noise. To examine this issue further, here we used multiple indices of conditioned fear, including analgesia, 22 kHz ultrasonic vocalization (USV), defecation, and freezing. Rats with bilateral BLA cannula implants underwent fear conditioning consisting of 10 tone-footshock pairings. Before context and tone fear-retention tests, animals received intra-BLA infusions with APV (2.5 microg/side) or artificial CSF. Both tone and context tests demonstrated that the expression of conditioned freezing, USV, defecation, and analgesia were significantly impaired by intra-amygdalar infusions of APV. In a second set of experiments, intra-BLA infusions of APV markedly impaired the normal expression of postshock fear responses during training, as measured by freezing, USV, and defecation. Immediate postshock fear expression was predictive of subsequent fear retention to the tone and context when the animals were not infused. These results are consistent with the hypothesis that amygdalar NMDA receptors participate in normal synaptic transmission and therefore the overall functioning of the amygdala.

Endoscopic ultrasound in the staging of tumours of the oesophagus and gastro-oesophageal junction.

BACKGROUND: Modern management of upper gastro-intestinal cancer demands accurate pre-operative staging. In continental Europe and Japan, endoscopic ultrasound (EUS) is established as the investigation of choice for local staging of these cancers, but British experience with this technique is limited. METHODS: A retrospective review of the medical records of patients with oesophageal or gastro-oesophageal junction tumours during our first 3.5 years' experience with EUS was undertaken and the findings at EUS correlated with the pathology of the resected specimen. RESULTS: A total of 124 patients (86 males), with a mean age of 64.5 years, underwent EUS: 84 had adenocarcinoma and 26 squamous cell carcinoma. There were 3 failed EUS examinations, 42 patients did not have surgery for a variety of reasons, and 10 patients had pre-operative chemoradiotherapy. In the remaining 69 patients, correlation for T stage showed an accuracy of EUS of 80% and for N staging of 54% overall. Comparison of the initial 2 years with the final 18 months showed no change in the T staging accuracy but an improvement in the N staging accuracy from 50% to 60%. CONCLUSION: Once initial experience has been gained, EUS is an accurate procedure for T and N staging of tumours of the oesophagus and gastro-oesophageal junction. It should be included with other imaging modalities, such as CT scanning, in the pre-operative assessment of these tumours.

Prolonged synaptic integration in perirhinal cortical neurons.

Layer II/III of rat perirhinal cortex (PR) contains numerous late-spiking (LS) pyramidal neurons. When injected with a depolarizing current step, these LS cells typically delay spiking for one or more seconds from the onset of the current step and then sustain firing for the duration of the step. This pattern of delayed and sustained firing suggested a specific computational role for LS cells in temporal learning. This hypothesis predicts and requires that some layer II/III neurons should also exhibit delayed and sustained spiking in response to a train of excitatory synaptic inputs. Here we tested this prediction using visually guided, whole cell recordings from rat PR brain slices. Most LS cells (19 of 26) exhibited delayed spiking to synaptic stimulation (>1 s latency from the train onset), and the majority of these cells (13 of 19) also showed sustained firing that persisted for the duration of the synaptic train (5-10 s duration). Delayed and sustained firing in response to long synaptic trains has not been previously reported in vertebrate neurons. The data are consistent with our model that a circuit containing late spiking neurons can be used for encoding long time intervals during associative learning.

Morphology and physiology of neurons in the rat perirhinal-lateral amygdala area.

Neuronal structure-function relationships were studied in rat brain slices containing the perirhinal cortex (PR) and immediately adjacent lateral nucleus of the amygdala (ALa). Using video microscopy, whole-cell recordings were made from visually preselected neurons that were labeled with biocytin for subsequent anatomical reconstructions. Most cells were 1 of 4 primary neurophysiological types: fast-spiking (FS), regular-spiking (RS), late-spiking (LS), and burst-spiking (BS). Fast-spiking neurons (small somata) were found throughout PR; RS neurons (stellates and pyramids) were present from layer II/III through VI of PR; BS neurons (large pyramids with thick nonbifurcating apical dendrites) were found in layer Va of PR; and LS neurons (stellates, small pyramids, and cone cells) were encountered in layers II/III and VI of PR. One subpopulation of LS neurons (small pyramids) was found in layer II/III; another (cone cells) was found in clusters spanning layer VI through the lateral portion of ALa. Layer Va also contained large RS pyramidal neurons whose axons were seen traveling in the external capsule, but not entering the ALa. Conversely, the axons of large RS pyramidal neurons in layer Vb typically projected deep into the ALa. The four primary firing patterns were present in ALa, which also contained irregular-spiking, slow-charging, and single-spiking cells. Spontaneous synaptic currents differed markedly among cell types and layers. There was excellent agreement between somatic areas measured from video images of living neurons and somatic areas from the same neurons following fixation. Representative montages, which combined the cellular neuroanatomy and neurophysiology, suggested a circuit-level organization that helps elucidate information processing through the PR-ALa region.

Testing the fit of a quantal model of neurotransmission.

Many studies of synaptic transmission have assumed a parametric model to estimate the mean quantal content and size or the effect upon them of manipulations such as the induction of long-term potentiation. Classical tests of fit usually assume that model parameters have been selected independently of the data. Therefore, their use is problematic after parameters have been estimated. We hypothesized that Monte Carlo (MC) simulations of a quantal model could provide a table of parameter-independent critical values with which to test the fit after parameter estimation, emulating Lilliefors's tests. However, when we tested this hypothesis within a conventional quantal model, the empirical distributions of two conventional goodness-of-fit statistics were affected by the values of the quantal parameters, falsifying the hypothesis. Notably, the tests' critical values increased when the combined variances of the noise and quantal-size distributions were reduced, increasing the distinctness of quantal peaks. Our results support two conclusions. First, tests that use a predetermined critical value to assess the fit of a quantal model after parameter estimation may operate at a differing unknown level of significance for each experiment. Second, a MC test enables a valid assessment of the fit of a quantal model after parameter estimation.

Complex synaptic current waveforms evoked in hippocampal pyramidal neurons by extracellular stimulation of dentate gyrus.

Excitatory postsynaptic currents (EPSCs) evoked in hippocampal CA3 pyramidal neurons by extracellular stimulation of the dentate gyrus typically exhibit complex waveforms. They commonly have inflections or notches on the rising phase; the decay phase may exhibit notches or other obvious departures from a simple monoexponential decline; they often display considerable variability in the latency from stimulation to the peak current; and the rise times tend to be long. One hypothesis is that these complex EPSC waveforms might result from excitation via other CA3 pyramidal cells that were recruited antidromically or trans-synaptically by the stimulus due to the complex anatomy of this region. An alternative hypothesis is that EPSC complexity does not emerge from the functional anatomy but rather reflects an unusual physiological property, intrinsic to excitation-secretion coupling in mossy-fiber (mf) synaptic terminals, that causes asynchronous quantal release. We evaluated certain predictions of our anatomic hypothesis by adding a pharmacological agent to the normal bathing medium that should suppress di- or polysynaptic responses. For this purpose we used baclofen (3 microM), a selective agonist for the gamma-aminobutyric acid B receptor. The idea was that baclophen should discriminate against polysynaptic versus monosynaptic inputs by hyperpolarizing the cells, bringing them further from spike threshold and possibly also through inhibitory presynaptic actions. Whole cell recordings were done from visually preselected CA3 pyramidal neurons and EPSCs were evoked by fine bipolar electrodes positioned into the granule cell layer of the dentate. To the extent that the EPSC complexity reflects di- or polysynaptic responses, we predicted baclofen to reduce the number of notches on the rising and decay phases, reduce the variance in latency to peak of the EPSCs, decrease the amplitudes and rise times of the individual and averaged EPSCs, and increase the apparent failures in evoked EPSCs. All of these predictions were confirmed, in support of the hypothesis that these complex EPSC waveforms commonly reflect di- or polysynaptic responses. We also documented a distinctly different, intermittent, form of EPSC complexity, which also is predicted and easily explained by our anatomic hypothesis. In particular, the results were in accord with the suggestion that stimulation of the dentate gyrus might antidromically stimulate axon collaterals of CA3 neurons that make recurrent synapses onto the recorded cell. We conclude that the overall pattern of results is consistent with expectations based on the functional anatomy. The explanation does not demand a special type of intrinsic asynchronous mechanism for excitation-secretion coupling in the mf synapses.

Methods for whole-cell recording from visually preselected neurons of perirhinal cortex in brain slices from young and aging rats.

This manuscript describes methods for preparing, visualizing, and recording from healthy perirhinal cortex neurons in brain slices from young and aging rats. We focused on perirhinal cortex because of its role in learning, memory, and aging-related cognitive decline. Detailed accounts of our dissection procedures are reported. Procedures that reliably yielded healthy neurons from juvenile rats were not conducive to obtaining healthy, readily-patchable neurons from aging rats, suggesting a procedure-by-age interaction. Performing an intracardiac perfusion, using a temperature-controlled vibratome, matching osmolarity between the cutting and incubation saline, using a slow cutting speed, and incubating slices at a warm temperature for 30 min were important when working with older tissue. Excellent visualization of neurons at depths of up to 100 microm was achieved in slices from all ages (without tissue clearing) avoiding the need to record from surface neurons, which are more likely to have truncated processes. Whole-cell recordings typically remained stable for several hours in neurons prepared from rats at all ages. These procedures should benefit neuroscientists interested in applying visually-guided whole-cell patch-clamp techniques to brain slice experiments using aged tissue. These methods should also facilitate the application of fluorescent imaging technology to brain slices for studying aging-related changes.

Identification and characterization of rat orbicularis oculi motoneurons using confocal laser scanning microscopy.

The eyeblink reflex is one of the most extensively studied behaviors in mammals. The active downward force that causes lid closure is controlled by the orbicularis oculi (OO) muscle. To augment our studies on the neurophysiology and plasticity of the rat eyeblink circuit, here we present the first anatomical paper to focus exclusively on identifying and characterizing the OO motoneurons of the rat facial motor nucleus (FMN). One thousand and twenty-nine cells from four animals were retrogradely labeled by injecting the OO muscle with HRP and were imaged conventionally. One hundred and one cells from five animals were labeled by injecting the OO muscle with a 3000 mol. wt. fluorescent dextran and were imaged using confocal laser scanning microscopy (CLSM). The latter method resulted in little tissue shrinkage, bright labeling, and excellent resolution of the soma, dendrites, and axon. Furthermore, it is a histologically simple alternative to HRP for retrograde labeling from the neuromuscular junction. Both methods revealed that the OO motoneurons were distributed over the entire length of the FMN, that they were concentrated along the dorsal crest of the nucleus, and that they were less numerous in the extreme rostral and caudal regions. As measured using the CLSM method, cell body areas were highly variable, ranging from 317 to 1500 microm2, but there was no size gradient along the rostrocaudal extent of the FMN. The neurons exhibited seven primary dendrites on average, which gave rise to bifurcating and even trifurcating secondary dendrites. Using the HRP method, the estimated area of OO motoneurons ranged from 161 to 1381 microm2. The combined methods furnished a detailed characterization of the number, spatial distribution, and morphology of rat OO motoneurons. Moreover, these methods provide a useful way to analyze the circuitry that modulates the rat eyeblink.