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.

Giant synaptic potential hypothesis for epileptiform activity.

According to one hypothesis, the paroxysmal depolarizing shift observed in the penicillin model of epilepsy results from a giant excitatory postsynaptic potential. This hypothesis has recently been questioned, primarily because it has never been subjected to rigorous experimental examination. Four quantitative predictions were derived from this hypothesis and tested in CA3 pyramidal neurons of the hippocampus. The four critical predictions concern the behavior of the paroxysmal depolarizing shift under current- and voltage-clamp conditions as a function of membrane potential. The experiments confirmed all four predictions.

Differential conditioning of associative synaptic enhancement in hippocampal brain slices.

An electrophysiological stimulation paradigm similar to one that produces Pavlovian conditioning was applied to synaptic inputs to pyramidal neurons of hippocampal brain slices. Persistent synaptic enhancement was induced in one of two weak synaptic inputs by pairing high-frequency electrical stimulation of the weak input with stimulation of a third, stronger input to the same region. Forward (temporally overlapping) but not backward (temporally separate) pairings caused this enhancement. Thus hippocampal synapses in vitro can undergo the conditional and selective type of associative modification that could provide the substrate for some of the mnemonic functions in which the hippocampus is thought to participate.

Long-term synaptic potentiation in the superior cervical ganglion.

Brief tetanic stimulation of the preganglionic nerves to the superior cervical ganglion enhances the postganglionic response to single preganglionic stimuli for 1 to 3 hours. This long-term potentiation of transmission through the ganglion is apparently not attributable to a persistent muscarinic action of the preganglionic neurotransmitter, acetylcholine, since neither the magnitude nor the time course of the phenomenon is reduced by atropine. The decay of long-term potentiation can be described by a first-order kinetic process with a mean time constant of 80 minutes. We conclude that long-term potentiation, once considered a unique property of the hippocampus, is in fact a more general feature of synaptic function. This form of synaptic memory may significantly influence information processing and control in other regions of the nervous system, including autonomic ganglia.

Long-term synaptic potentiation.

Long-term synaptic potentiation (LTP) is a leading candidate for a synaptic mechanism of rapid learning in mammals. LTP is a persistent increase in synaptic efficacy that can be quickly induced. The biophysical process that controls one type of LTP is formally similar to a synaptic memory mechanism postulated decades ago by the psychologist Donald Hebb. A key aspect of the modification process involves the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. This ionophore allows calcium influx only if the endogenous ligand glutamate binds to the NMDA receptor and if the voltage across the associated channel is also sufficiently depolarized to relieve a magnesium block. According to one popular hypothesis, the resulting increase in the intracellular calcium concentration activates protein kinases that enhance the postsynaptic conductance. Further biophysical and molecular understanding of the modification process should facilitate detailed explorations of the mnemonic functions of LTP.

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.

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.

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.

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.

The effects of SB 206284A, a novel neuronal calcium-channel antagonist, in models of cerebral ischemia.

The effects of SB 206284A, 1-[7-(4-benzyloxyphenoxy)heptyl] piperidine hydrochloride, have been investigated in vitro on calcium and sodium currents in rat-cultured dorsal root ganglion (DRG) neurones and potassium-mediated calcium influx in rat synaptosomes. Cardiovascular hemodynamic effects in both anesthetized and conscious rats, and neuroprotective activity in in vivo cerebral ischemia models were also investigated. In the rat DRG cells, SB 206284A caused almost complete block of the sustained inward Ca2+ current (IC50 = 2.4 microM), suggesting that the compound is an effective blocker of slowly inactivating, high-voltage calcium current. SB 206284A reduced locomotor hyperactivity in the gerbil bilateral carotid artery occlusion model without affecting ischemia-induced damage in the hippocampal CA1 region. In the rat middle cerebral artery occlusion model, SB 206284A reduced lesion volume in the posterior forebrain, and in the rat photochemical cortical lesion model, lesion volume was reduced even when treatment was delayed until 4 hours after occlusion. At neuroprotective doses, SB 206284A had no cardiovascular effects. These findings show that SB 206284A is a novel calcium channel antagonist that shows neuroprotective properties.

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.

SB 201823-A, a neuronal Ca2+ antagonist is neuroprotective in two models of cerebral ischaemia.

We have characterised the Ca2+ channel blocking properties of a new non-peptide Ca2+ channel antagonist, SB 201823-A, in cultures of rat sensory neurones. The IC50 for SB 201823-A against total Ca2+ current in sensory neurones was 4.9 microM. SB 201823-A showed little selectivity for sub-types of neuronal Ca2+ channel but was selective for Ca2+ channels over Na+ and K+ channels. Efficacy against other types of cation channel such as agonist gated channels was not assessed. SB 201823-A was neuroprotective in vivo when administered post-ischaemia in one focal and one global model of neuronal ischaemia. In the rat photothrombotic focal lesion model, SB 201823-A administered i.p. 10 min post-ischaemia resulted in a dramatic reduction in lesion volume. In the gerbil bilateral carotid artery occlusion global model, SB 201823-A dosed i.p. 30 min post-occlusion resulted in both histological and functional improvements when compared to vehicle treated animals. These data suggest that such novel neuronal Ca2+ channel antagonists may have potential in ameliorating both the pathological and functional consequences of stroke in man.

Reversible inhibitors of the gastric (H+/K+)-ATPase. 4. Identification of an inhibitor with an intermediate duration of action.

3-Acyl-4-(arylamino)quinolines were previously identified as gastric (H+/K+)-ATPase inhibitors, and clinical efficacy has been demonstrated for compound 3 (SK&F 96067). In the present study the further structure-activity relationship of this series is developed. Only a limited range of substituents are tolerated on the N-aryl ring or the 6- and 7-positions of the quinoline, and although hydroxylated derivatives were identified possessing markedly greater affinity for the enzyme, none of these proved to have adequate potency after oral dosing. In contrast, the 8-position of the quinoline ring proved suitable for a wide variety of substituents, allowing modification of physicochemical properties while retaining primary activity. This led to the identification of compound 4 (SK&F 97574), which combines good oral potency with a somewhat longer duration of action than 3 (though much shorter than covalent inhibitors such as omeprazole). This compound was selected for further development and evaluation in man.

Reversible inhibitors of the gastric (H+/K+)-ATPase. 5. Substituted 2,4-diaminoquinazolines and thienopyrimidines.

Quinazolines bearing a secondary 4-(arylamino) substituent demonstrate an SAR for inhibition of the gastric (H+/K+)-ATPase different from the previously described 3-acylquinolines, suggesting that, although these compounds are also K(+)-competitive, they probably bind to the enzyme in a different orientation. Compounds bearing a tertiary 4-(arylamino) substituent, however, in particular 4-(N-methylarylamino), appear to possess an SAR quite similar to the 3-acylquinolines. We show that this arises from the effect of the N-methylation, which is to orientate the 4-(arylamino) substituent syn to C5, analogous to the 3-acylquinolines. Compounds possessing both a 4-(N-methylarylamino) substituent and a 2-(arylamino) substituent proved to be very potent, K(+)-competitive inhibitors of K(+)-stimulated ATPase activity with Ki values down to 12 nM. Some compounds also proved to be effective inhibitors of stimulated acid secretion in both the rat and dog when dosed intravenously. However, although a number of these demonstrated activity after oral administration in the dog, the level and variability precluded further evaluation.

Reversible inhibitors of the gastric (H+/K+)-ATPase. 2. 1-Arylpyrrolo[3,2-c]quinolines: effect of the 4-substituent.

Further work on compounds 1 has identified the 4-position as a site where substantial modifications are tolerated, leading to analogues which are more potent and less toxic than those described previously. The best compound in the series is 13a (SK&F 96356), which is a potent inhibitor of gastric acid secretion in both the pentagastrin-stimulated rat and the histamine-stimulated dog. This compound shows reversible, K(+)-competitive binding to the enzyme. Because of its fluorescent properties, it is also proving useful in vitro as a probe of the structure and function of the (H+/K+)-ATPase.

Reversible inhibitors of the gastric (H+/K+)-ATPase. 1. 1-Aryl-4-methylpyrrolo[3,2-c]quinolines as conformationally restrained analogues of 4-(arylamino)quinolines.

The 4-(arylamino)quinoline 4, previously described as an antiulcer compound, is shown to be an inhibitor of the gastric (H+/K+)-ATPase. It is postulated that 1-arylpyrrolo[3,2-c]quinolines 6 act as conformationally restrained analogues of 4. A series of derivatives of 6 has been prepared and shown to be potent inhibitors of the target enzyme in vitro. Substitution in the ortho position of the aryl ring is important for activity. Unsaturation in the 5-membered ring makes little difference, but introduction of heteroatoms into the same ring markedly reduces activity. In more detailed kinetic experiments, 15c and 4 both show reversible, K(+)-competitive binding to the enzyme, with submicromolar Ki values. The compounds appear to act at the lumenal face of the enzyme and to require protonation for activity. Several compounds in the series are shown to be potent inhibitors of pentagastrin-stimulated acid secretion in the rat.

Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists.

A rational approach to the design of centrally acting agents is presented, based initially upon a comparison of the physicochemical properties of three typical histamine H2 receptor antagonists which do not readily cross the blood-brain barrier with those of the three brain-penetrating drugs clonidine (6), mepyramine (7) and imipramine (8). A good correlation was found between the logarithms of the equilibrium brain/blood concentration ratios in the rat and the partition parameter, delta log P, defined as log P (1-octanol/water)-log P (cyclohexane/water), which suggests that brain penetration might be improved by reducing overall hydrogen-bonding ability. This model has been employed as a guide in the design of novel brain-penetrating H2 antagonists by the systematic structural modification of representatives of different structural types of H2 antagonists. Although marked increases in brain penetration amongst congeners of cimetidine (1), ranitidine (9), and tiotidine (10) were achieved, no compound was found with an acceptable combination of H2 antagonist activity (-log KB in the guinea pig atrium greater than 7.0) and brain penetration (steady-state brain/blood concentration ratio greater than 1.0). Conversely, structural modification of N-[[(piperidinyl-methyl)phenoxy]propy]acetamide (30) led to several potent, novel compounds which readily cross the blood-brain barrier. One of these, zolantidine (SK&F 95282, 41), whose -log KB is 7.46 and steady-state brain/blood ratio is 1.4, has been identified for use in studying histaminergic H2 receptor mechanisms in brain. Comparison of delta log P values with the logarithms of the brain/blood ratios for 20 structurally diverse compounds for which data became available confirms a highly significant correlation and supports the general validity of this model.