Assessing the impact of an English national initiative for early cancer diagnosis in primary care.

BACKGROUND: The Cancer Networks Supporting Primary Care programme was a National Health Service (NHS) initiative in England between 2011 and 2013 that aimed to better understand and improve referral practices for suspected cancer. METHODS: A mixed methods evaluation using semi-structured interviews with purposefully sampled key stakeholders and an analysis of Cancer Waiting Times and Hospital Episode Statistics data for all 8179 practices in England were undertaken. We compared periods before (2009/10) and at the end (2012/13) of the initiative for practices taking up any one of four specified quality improvement initiatives expected to change referral practice in the short to medium term and those that did not. RESULTS: Overall, 38% of general practices were involved in at least one of four quality improvement activities (clinical audit, significant event analysis, use of risk assessment tools and development of practice plans). Against an overall 29% increase in urgent cancer referrals between 2009/10 and 2012/13, these practices had a significantly higher increase in referral rate, with reduced between-practice variation. There were no significant differences between the two groups in conversion, detection or emergency presentation rates. Key features of successful implementation at practice and network level reported by participants included leadership, organisational culture and physician involvement. Concurrent health service reforms created organisational uncertainty and limited the programme's effectiveness. CONCLUSIONS: Specific primary care initiatives promoted by cancer networks had an additional and positive impact on urgent referrals for suspected cancer. Successful engagement with the programmes depended on effective and well-supported leadership by cancer networks and their general practitioner (GP) leads.

Chronic high dose captopril decreases total heart rate variability and increases heart rate in C57BL/6J mice.

The effects of high dose captopril, within the therapeutic range, on autonomic activity are unknown in those with normal cardiovascular function. Thus the study aims were to assess the effects of high dose captopril on autonomic function in mice. Autonomic activity was measured using heart rate variability (HRV). ECG recordings were obtained from 18 Male C57BL/6J mice (20-25 g) subdivided into control (N=8) or mice receiving oral captopril (0.688 mg/ml captopril in the drinking water for 6 weeks, N=10). HRV results for linear and non-linear parameters were attenuated following chronic captopril for 6 weeks compared to control. Captopril was associated with a trend for an increase in average heart rate and approximate entropy (ApEn), a non-linear measure of HRV decreased significantly compared to control (p<0.05). In conclusion high dose captopril reduces total HRV and increases heart rate in normotensive mice with normal cardiac function.

[3H]GR113808 binding to serotonin 5-HT(4) receptors in the postmortem neocortex of Alzheimer disease: a clinicopathological study.

Abnormalities in neural transmission of serotonin (5-HT) may play a role in both cognitive and neuropsychiatric features of Alzheimer disease (AD). We measured 5-HT(4) receptors in the postmortem frontal and temporal cortex of 34 AD subjects and 15 controls by radioligand binding with [3H]GR113808. Receptor binding data was then correlated with prospectively assessed cognitive (Mini-Mental State Examination, MMSE) and behavioral (Present Behavioural Examination, PBE) data. [3H]GR113808 binding affinity (K(D)) and density (B(max)) in AD were unchanged compared to controls in both cortical regions, and did not correlate with MMSE or PBE data. The binding parameters were also not related to disease duration, senile plaque and neurofibrillary tangle counts, and neuroleptic medication. We conclude that unlike other 5-HT receptors, 5-HT(4) receptor binding affinity and density do not seem to be affected in the frontal and temporal cortex in AD and may not have a direct role in the clinical features of the disease.

Target detection in scientific visualization.

Three experiments were conducted to test participants' ability to detect targets in colored spatial displays using 7-level bipolar scales. Experiment 1 assessed the ability of participants to detect high or low targets using 12 scales whose poles either were directly opposed in color space or had a primary and an intermediate hue at each pole. Experiment 2 used 8 scales whose arms were orthogonal in color space. Experiment 3 examined the simultaneous detection of high and low targets. Although there are notable exceptions, scales that are close to or above the horizontal (red-green) axis in color space perform best. Of the scales with orthogonal arms, those that are oriented downward, toward the blues, in color space are least satisfactory. Scales that are asymmetrically effective are common, and applications requiring good detectability at both extremes must take this into account. The results are discussed in the context of the evolution of trichromatic color vision.

Immediate and sustained effects of smoking on autonomic arousal in human subjects.

The effects of smoking on sudomotor/autonomic activity were examined by measuring water transfer across the skin (sweat output) as an index of activity. Sweat output was measured in 14 subjects (11 male and 3 female) during the act of smoking and for about 60 min following this. Sweat output was measured in 5 (4 male, 1 female) controls over the same time period. Smoking had two effects on sweat output: In 12 subjects it caused an immediate increase in output; in 4 of these 12 the increase persisted for the duration of the recording period. In the other 2 subjects no increase was noted, but in no subject did smoking cause a decrease in sweat output. Mood state questionnaires were administered at the beginning and end of the experimental period. No clear association was found between scores on the mood questionnaires and the autonomic effects of smoking. In 2 subjects, transdermal blood flow was also measured during and after smoking. Smoking caused a decrease in blood flow in these subjects. These results are discussed in terms of the "arousal modulation" hypothesis of smoking.

Long-term potentiation saturation in chronic cerebral hypoperfusion.

Chronic reductions in cerebral blood flow (CBF) of between 25 and 50%, in the absence of cerebral infarction, lead to impairments in hippocampal in vitro long-term potentiation (LTP). This study set out to explore some of the properties of this impairment of LTP. LTP is an electrophysiological property known to occur in the hippocampus, a region known to be exquisitely sensitive to hypoxic or ischemic insults. Thus, assessing LTP is a novel way of assessing the effects of subtle ischemic insults. Five male Sprague-Dawley rats had arteriovenous fistulae created surgically in the neck to induce a state of chronic cerebral hypoperfusion (CCH) with the features described above. Five rats were used as age-matched controls. Twenty-six weeks after fistula formation, the animals were prepared for in vitro hippocampal recording in a submerged tissue bath. Extracellular field potentials were recorded at the Schaffer collateral-CA1 region, with a stimulus intensity that achieved a population spike amplitude of 1 mV. After tetanic stimulation, the frequency and magnitude of LTP was compared between control and fistula animals. All animals in both these groups demonstrated LTP in contradistinction to our previous work where LTP was impaired in fistula animals when a higher intensity of stimulation was used. This indicates that the structures that are associated with the initiation and maintenance of LTP (most probably the ischemia-sensitive CA1 pyramidal cells) are saturated as the stimulus intensity is increased. Thus, at this lower intensity of stimulation LTP is preserved in the fistula animals, but found to be impaired as the stimulus intensity is increased. Consequently, this study provides further information on this newly identified subtype of chronic cerebral ischemia which, in time, after further studies in humans, may help to redefine therapeutic indicators for the management of cerebral arteriovenous malformation and severe cerebrovascular disease.

Role of inhibition in chronic cerebral hypoperfusion.

Chronic reductions in cerebral blood flow (CBF) of between 25 and 50% maintained for 26 weeks impair neuronal function, through a mechanism which is not known, but which is now explored. Increased GABAergic synaptic inhibition may play a role, as inhibitory interneurons are known to be relatively resistant to acute ischaemic insults. The phenomenon of tetanus-induced longterm potentiation (LTP) was previously found to be impaired in this setting, and was thus examined in the in vitro rat hippocampus in the presence of bicuculline, a specific GABA(A) antagonist, to evaluate the role of inhibition in the impairment of LTP in chronic cerebral hypoperfusion (CCH). Nine Sprague-Dawley rats aged 8-10 weeks had arteriovenous fistulae (AVF) surgically constructed to reduce CBF to between 25 and 50%. Ten animals were used as age-matched controls. After a further 26 weeks, 400 mum hippocampal slices were prepared. Tetanic stimulation was used in order to attempt to induce LTP. In vitro extracellular field potentials from control and AVF slices with 5 x 10(-)6 M bicuculline exposure and subsequent tetanic stimulation were compared. There was no statistical difference between the responses of the two groups in either scenario (P > 0.05), although LTP was in general more difficult to induce (only occurring in 60% of control animals). Possible causes of this are discussed. It is concluded that increased GABAergic synaptic inhibition does not play a role in impairment of neuronal function seen after 26 weeks of non-infarctional CCH.

Using artificial neural networks to classify the activity of capsaicin and its analogues.

Back-propagation artificial neural networks (ANNs) were trained with parameters derived from different molecular structure representation methods, including topological indices, molecular connectivity, and novel physicochemical descriptors to model the structure--activity relationship of a large series of capsaicin analogues. The ANN QSAR model produced a high level of correlation between the experimental and predicted data. After optimization, using cross-validation and selective pruning techniques, the ANNs predicted the EC50 values of 101 capsaicin analogues, correctly classifying 34 of 41 inactive compounds and 58 of 60 active compounds. These results demonstrate the capability of ANNs for predicting the biological activity of drugs, when trained on an optimal set of input parameters derived from a combination of different molecular structure representations.

Chronic cerebral hypoperfusion inhibits calcium-induced long-term potentiation in rats.

BACKGROUND AND PURPOSE: Long-term potentiation (LTP) in the rat hippocampus induced by tetanic stimulation is impaired by chronic cerebral hypoperfusion. The effects of chronic cerebral hypoperfusion on other forms of LTP are unknown. Such data could help delineate the pathways of cellular alteration caused by chronic cerebral hypoperfusion. The in vitro phenomenon of calcium-induced LTP was thus examined in rat hippocampal CA1 cells that had undergone chronic hypoperfusion with a reduction in cerebral blood flow of between 25% and 50% maintained for 26 weeks. METHODS: Ten Sprague-Dawley rats had a cervical arteriovenous fistula surgically constructed, and an additional 10 animals were used as age-matched controls. Hippocampal slices were prepared after 26 weeks of hypoperfusion, and in vitro extracellular field potential recordings were taken from the Schäffer collateral CA1 region. Properties of LTP induced through transient exposure to a hypercalcemic solution were analyzed. RESULTS: LTP was impaired in animals with an arteriovenous fistula (P < .05). Control animals demonstrated potentiation lasting for the entire 2 hours of recording, whereas fistula animals showed only transient potentiation (< 60 minutes) before returning to baseline values. CONCLUSIONS: Calcium-induced LTP is impaired by chronic cerebral hypoperfusion. This form of LTP is different from that induced by tetanic stimulation. It is the most sensitive test available for in vitro detection of the changes induced in neuronal function by chronic noninfarctional reductions in cerebral blood flow of 25% to 50% and may indicate that the most basic cellular parameters involving calcium homeostasis and metabolism are being altered. The precise mechanisms remain to be elucidated, and several postulates are discussed.

Normal perfusion pressure breakthrough: the role of capillaries.

Excision of human cerebral arteriovenous malformations (AVMs) can be complicated by postoperative edema and hemorrhage in adjacent brain tissue, despite the complete excision of the malformation. Various theories have purported to explain the hemodynamic basis for this predisposition, including disordered autoregulation causing "normal perfusion pressure breakthrough" and obstruction of venous drainage leading to "occlusive hyperemia." This study did not evaluate the arterial or venous circulations in this scenario, but rather examined the capillaries in adjacent brain parenchyma for any structural deficiencies that would predispose the brain to the postoperative formation of edema and hemorrhage. Arteriovenous fistulas (AVFs) were created surgically in the necks of 10 male Sprague-Dawley rats, which caused chronic cerebral hypoperfusion with a reduction in cerebral blood flow of between 25% and 50%. Ten age-matched animals were used as controls. Twenty-six weeks after AVF formation the animals were killed and perfusion fixed. Their brain tissue was prepared for light microscopic studies by staining for glial fibrillary acidic protein or for transmission electron microscopy. In the CA1 pyramidal cell region of the hippocampus, it was found that in the animals with AVFs there was increased capillary density and absent astrocytic foot processes in some of these vessels. It was concluded that these vessels had developed as a result of neovascularization in response to chronic cerebral ischemia and that their anatomical configuration made them prone to mechanical weakness and instability following the increase in perfusion pressure that occurs in adjacent brain parenchyma after AVM excision. The authors believe that this study pinpoints a structural accompaniment to the hemodynamic changes that occur in brain tissue in the vicinity of cerebral AVMs that predispose these areas to the formation of edema and hemorrhage after AVM excision.

Chronic cerebral hypoperfusion: pathological and behavioral consequences.

OBJECTIVE: Although the effects of acute ischemic insults to the brain are well known, the effects related to chronic ischemia are poorly delineated. The pathological and behavioral changes induced by a chronic noninfarctional reduction in cerebral blood flow of 25 to 50% maintained for 6 months were assessed. METHODS: In each of 18 male Sprague-Dawley rats, an arteriovenous fistula was created in the neck via an anastomosis between the right external jugular vein and the right common carotid artery to induce cerebral hypoperfusion. Nineteen age-matched animals comprised a control group. Six months after surgery, the animals were examined using light and electron microscopic techniques, as well as via a battery of behavioral tests (motor, open field, and T-maze). RESULTS: Examination of the hippocampus by using light microscopy revealed disorganization of the CA1 sector with an increased number of astrocytes. Transmission electron microscopy of the CA1 region demonstrated neurons with increased lipofuscin pigment and central nucleoli and astrocytes with more numerous cytosolic mitochondria. Motor performance testing revealed no gross motor deficits, although open-field assessment demonstrated increased exploratory behavior in rats with fistulas. Finally, T-maze testing results suggested that errors in working memory were more common in rats undergoing chronic cerebral hypoperfusion (P < 0.05). CONCLUSIONS: These findings suggest that chronic reductions in cerebral blood flow of a magnitude previously thought to be harmless to neurons (i.e., reduced by 25-50%) do alter neuronal structure and affect whole animal behavior. Such a scenario may be responsible for a symptomatology secondary to arteriovenous steal and severe carotid stenoses. The mechanisms are still unknown.

Incidence of inguinal hernias following radical retropubic prostatectomy.

OBJECTIVES: During the last decade, the number of patients undergoing radical retropubic prostatectomy (RRP) has substantially increased. Over this same time period, we have noted that a significant number of these patients have developed postoperative inguinal hernias. We sought to identify the incidence of postoperative inguinal hernias after RRP and compared this with the stated 5% incidence in the general adult male population. METHODS: Ninety-two consecutive RRPs performed by three surgeons (I.J.S., N.L.C., S.W.D.) were retrospectively reviewed. The operative reports for each patient who subsequently underwent inguinal herniorrhaphy were analyzed to determine whether the hernias were direct or indirect. RESULTS: The overall incidence of postoperative inguinal hernias was 12% (11 of 92). All hernias were found within approximately 6 months of the prostatectomy. Ninety-one percent (10 of 11) of these hernias were indirect, and only 9% (1 of 11) were direct. CONCLUSIONS: We believe this to be the first report in the English literature describing postoperative inguinal hernias following retropubic prostatectomy. A significantly higher incidence (12%) of inguinal hernias was noted in the postprostatectomy population compared with the general adult male population (5%). This finding suggests that inguinal hernias can be a consequence of RRP. Urologists should be cognizant of this possibility in order to screen all patients carefully prior to surgery for subtle weakness in the inguinal canal, as well as to inform patients properly of the possibility of developing an inguinal hernia after surgery.

Chronic cerebral hypoperfusion in the rat: temporal delineation of effects and the in vitro ischemic threshold.

Acute reductions in cerebral blood flow of up to 50% do not affect neuronal function although it has been shown that reductions of a similar magnitude maintained for 26 weeks do induce neuronal changes. In vitro rat hippocampal LTP was evaluated after 10 weeks of cerebral hypoperfusion. An assessment was also made of the possible 'robustness' of hippocampal CA1 pyramidal neurons to combined in vitro hypoxic/ischemic insults because of previously shown differences in hemodynamic autoregulatory curves. No differences were found between controlled and chronically hypoperfused animals in either study. It is concluded that the changes in neuronal function induced by reductions in cerebral blood flow of less than 50% take time to develop and do not induce adaptive changes in affected neurons. The mechanism for these changes remains to be elucidated.

Chronic cerebral hypoperfusion and impaired neuronal function in rats.

BACKGROUND AND PURPOSE: Studies in acute cerebral ischemia have shown that reductions in cerebral blood flow of up to 50% do not lead to infarction or alterations in neuronal electric activity. Little is known about the effects of chronic reductions in cerebral blood flow. The purpose of this study was to evaluate neuronal electrophysiological function in brain that had been subjected to a chronic reduction of cerebral blood flow of less than 50%. Based on existing knowledge of thresholds of cerebral ischemia, neuronal electrophysiological function should be unaffected by hypoperfusion of this magnitude. METHODS: An arteriovenous fistula model in the rat was used to induce chronic cerebral hypoperfusion with reductions of cerebral blood flow of 25% to 50% as measured previously by 14C-labeled autoradiography. Using in vitro electrophysiological brain slice techniques, long-term potentiation in hippocampal CA1 neurons was examined extracellularly after 6 months of chronic noninfarctional cerebral hypoperfusion. Brains were also examined histologically at this time for evidence of cerebral infarction. RESULTS: There was no evidence of cerebral infarction. Long-term potentiation was produced in 9 of 12 control animals and only 2 of 8 hypoperfused animals. This difference was significant (P < .05) and demonstrated that long-term potentiation was impaired in animals with chronic hypoperfusion. CONCLUSIONS: Noninfarctional reductions in cerebral blood flow of up to 50% do impair neuronal function in chronic cerebral ischemia, a result quite distinct from that seen in acute ischemia. The threshold for neuronal dysfunction in chronic cerebral hypoperfusion is lower than that found in acute cerebral ischemia, suggesting that duration as well as severity of ischemic insult determines cellular viability. Chronic hypoperfusion may lead to a noninfarctional state with impaired neuronal function, a category of chronic cerebral ischemia not previously identified.

Judgments of change and proportion in graphical perception.

Subjects judged change and proportion when viewing graphs in two experiments. Change was judged more quickly and accurately with line and bar graphs than with pie charts or tiered bar graphs, and this difference was larger when the rate of change was smaller. Without a graduated scale, proportion was judged more quickly and accurately with pie charts and divided bar graphs than with line or bar graphs. Perception is direct when it requires simpler or fewer mental operations; we propose that perception of change is direct with line and bar graphs, whereas perception of proportion is direct with pie charts and divided bar graphs. The results are also consistent with the proximity compatibility principle. Suggestions for improving the design of graphical displays are given.

Frequency-dependent neuromuscular blockade by textilotoxin in vivo.

The effect of stimulation frequency on the timecourse of neuromuscular blockade, following the administration of textilotoxin (20 micrograms/kg) or beta-bungarotoxin (50 micrograms/kg), was examined in the interdigital muscles of the hindlimb in anaesthetized mice. While the time of death was variable, neuromuscular blockade of the interdigital muscles occurred at the same time as respiratory failure with both textilotoxin and beta-bungarotoxin only at stimulation rates of 0.5 Hz and above. Textilotoxin (50 micrograms/kg) produced an increase in the heart rate prior to death but no change in the shape of the electrocardiogram.

Protection of monkeys against the lethal effects of male funnel-web spider (Atrax robustus) venom by immunization with a toxoid.

A stable toxoid was prepared from robustoxin (the lethal polypeptide neurotoxin in the venom of the male funnel-web spider, Atrax robustus) by polymerization with glutaraldehyde. This material was non-toxic in new-born mice. Administration of the toxoid to three Macaca fascicularis monkeys (50-80 micrograms/kg s.c. at 14-day intervals for 8-12 weeks) produced no toxic effects; anti-robustoxin antibodies were detected in serum samples by immunodiffusion tests within 13-27 days. In vivo evidence of successful protection with the toxoid was obtained by challenging the monkeys with male A. robustus venom (50 micrograms/kg i.v.) under anaesthesia with pentobarbitone (one monkey), or with ketamine, halothane and nitrous oxide, 1-26 weeks after the last injection of the toxoid. Only minor respiratory, cardiovascular and skeletal motor disturbances were produced, and all monkeys recovered fully and uneventfully. Challenge with the same dose of venom in non-immunized or robustoxin N-terminal decapeptide ovalbumin conjugate-treated monkeys resulted in typical lethal neurotoxic effects, culminating in severe hypotension or death from circulatory and respiratory failure within 280 min.

An endogenous antitoxin to the lethal venom of the funnel web spider, Atrax robustus, in rabbit sera.

1. An endogenous antitoxin fraction was isolated from non-immune rabbit sera by affinity chromatography with robustoxin bound to the solid support. 2. Robustoxin is the sole lethal toxin in the venom of the male funnel web spider, Atrax robustus. 3. The fraction was found to contain IgG and IgM immunoglobulins. 4. This fraction prevented or reversed the lethal actions of the crude venom in newborn mice, in mouse phrenic nerve-hemidiaphragm preparations, and in anaesthetized monkeys. 5. The antitoxin fraction is of potential value in the therapy of human envenomation by A. robustus.

Visual psychophysics of simple graphical elements.

The accuracy with which graphical elements are judged was assessed in a psychophysical task that parallels the real-life use of graphs. The task is a variant of the Metfessel-Comrey constant-sum method, and an associated model based on Stevens's law is proposed. The stimuli were horizontal and vertical lines, bars, pie and disk slices, cylinders, boxes, and table entries (numbers). Stevens's law exponents were near unity for numbers and 1-dimensional elements but were also close to 1 for elements possessing 2 or 3 apparent dimensions--subjects accommodate extraneous dimensions that do not carry variation, changing the effective dimensionality of the stimulus. Judgment errors were small, with numbers yielding the best performance; elements such as bars and pie slices were judged almost as accurately; disk elements were judged least accurately, but the magnitude of the errors was not large.

Calcium-dependent actions of the convulsant barbiturate, CHEB, on transmitter release at the rat neuromuscular junction.

1. The effect of convulsant barbiturates on spontaneous and evoked acetylcholine release was studied at the rat neuromuscular junction in vitro. 2. The convulsant barbiturates (+)-5-(1,3-dimethylbutyl)-5-ethyl barbituric acid [(+)-DMBB], 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB), 5-ethyl-5-(3-methylbut-2'-enyl) barbituric acid (3M2B) and 5-ethyl-5-(1,3-dimethylbut-1'-enyl) barbituric acid (1,3M1B) all produced a concentration-dependent increase in miniature end-plate potential (MEPP) frequency. 3. With CHEB (100 microM) this increase in MEPP frequency was found to be dependent on the [Ca2+]o. CHEB in 0.5 mM [Ca2+]o did not alter MEPP amplitude, but in 1.3 and 2.5 mM [Ca2+]o CHEB significantly reduced the amplitude. 4. At a [Ca2+]o of 0.5 mM, CHEB produced an increase in both EPP amplitude and quantal content, while at 1.3 mM [Ca2+]o CHEB did not alter EPP amplitude or quantal content. 5. The plot of log quantal content vs log [Ca2+]o showed a parallel shift to the left in the presence of 100 microM CHEB. This change occurred without any alteration in the maximum quantal content. This suggests that the enhancement of transmitter release may be mediated by an effect on calcium fluxes in the pre-junctional nerve terminal.