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.

Maculotoxin: a neurotoxin from the venom glands of the octopus Hapalochlaena maculosa identified as tetrodotoxin.

Maculotoxin, a potent neurotoxin isolated from the posterior salivary glands of the blue-ringed octopus. Hapalochlaena maculosa, has now been identified as tetrodotoxin. This is the first reported case in which tetrodotoxin has been found to occur in a venom.

Studies on the subunit structure of textilotoxin, a potent neurotoxin from the venom of the Australian common brown snake (Pseudonaja textilis).

Textilotoxin is a presynaptic neurotoxin from the venom of the Australian common brown snake, Pseudonaja textilis. It has the highest lethality and is structurally the most complex of any known snake venom neurotoxin. It was resolved into its five non-covalently linked subunits in a single step by reverse-phase HPLC. Two of the subunits were identical. The N-terminal amino-acid sequence and amino-acid composition of each subunit were determined. Subunit A was the only one found to possess phospholipase A activity. Separation of textilotoxin into its subunits was reversible and reformed textilotoxin had the same Mr and lethality in mice as the native toxin. Experiments with various unnatural combinations of subunits have led to interesting variations in lethality and Mr of the resulting complexes.

Differing actions of convulsant and nonconvulsant barbiturates: an electrophysiological study in the isolated spinal cord of the rat.

The effects of various pairs of convulsant and nonconvulsant barbiturates on mono- and polysynaptic activity were studied in the isolated spinal cord of the immature rat, using extracellular recording. The convulsant barbiturates, 5-ethyl-5-(3-methylbut-2'-enyl) barbituric acid (3M2B), 5-ethyl-5-(1,3-dimethylbut-1'-enyl) barbituric acid (1,3M1B) and (+)-5-(1,3-dimethylbutyl)-5-ethyl barbituric acid [(+) DMBB] all increased the monosynaptic reflex at concentrations between 5 and 50 microM with no change in polysynaptic activity. When the concentration was raised to between 100 and 300 microM, however, the convulsants all reduced the monosynaptic reflex, thus producing a biphasic dose-response relationship. The nonconvulsant barbiturates phenobarbital, 5-ethyl-5-(3-methylbut-1'-enyl) barbituric acid (3M1B), amylobarbital (3MB) and (-)-5-(1,3-dimethylbutyl)-5-ethyl barbituric acid [(-)DMBB] produced only a decrease in mono- and polysynaptic reflexes. At concentrations which enhanced the monosynaptic reflex, the responses of motoneurones to glycine and eledoisin-related peptide (an analogue of substance P) were reduced by (+)DMBB, while 1,3M1B and 3M2B had no significant effects upon any of the neurotransmitters tested. At concentrations which depressed the monosynaptic reflex, the convulsants all reduced the response to glycine whereas the nonconvulsant barbiturates all increased the response to GABA. With the exception of phenobarbital, both convulsant and nonconvulsant barbiturates produced a direct depolarisation of the presynaptic terminal membrane, with only the convulsants producing a depolarisation of the membrane of the motoneurone. Using another convulsant barbiturate, 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB), this direct depolarising action was found to be calcium-dependent.

Effects of a depressant/convulsant pair of glutarimides on neuronal activity in the isolated spinal cord of the immature rat.

The effect of depressant/convulsant pair of glutarimides on the isolated spinal cord of the immature rat was examined using extracellular recording. At concentrations of 300 microM the depressant beta-butyl-beta-methyl glutarimide enhanced the response of motoneurones and dorsal root fibres to gamma-aminobutyric acid (GABA) while the convulsant bemegride (beta-ethyl-beta-methyl glutarimide) decreased both responses to GABA. At this concentration both the convulsant and depressant reduced mono- and polysynaptic reflex activity. Neither the convulsant or depressant had prominent direct actions, with only a small hyperpolarization being produced by both glutarimides on dorsal root fibres. The overall depressant or convulsant properties of these glutarimides may be due in part therefore to a differential effect on the postsynaptic action of the inhibitory transmitter GABA. Furthermore, the depressant glutarimide reduced the excitatory effects of L-glutamate and the convulsant reduced the inhibitory effects of glycine on spinal neurones; thus, actions on these transmitters may also contribute to the overall effects of these glutarimides.

Strychnine-like action of the convulsant barbiturate, CHEB.

The effect of 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB) on the isolated spinal cord of the immature rat was examined using extracellular recording. At concentrations less than 20 microM CHEB increased the monosynaptic reflex (MSR) but depressed the reflex at greater concentrations (30-100 microM). At concentrations which enhanced the monosynaptic reflex, CHEB reduced the responses of motoneurones to glycine and to a lesser extent to those of L-glutamate. In the presence of strychnine (5 microM), which enhanced both mono- and polysynaptic reflexes, CHEB produced only slight enhancement of the monosynaptic reflex. At concentrations of 30-100 microM the responses to gamma-aminobutyric acid (GABA), glycine, L-glutamate and eledoisin-related peptide (ERP a substance P and analogue) were all reduced. At these concentrations CHEB directly depolarised the motoneurone membrane. Increases in [Mg2+]0, which reduced spontaneous activity, blocked the enhancement, by CHEB, of the monosynaptic reflex. The actions of CHEB in small doses may be due therefore to its ability to block the action of glycine and thus block tonic inhibition.

The effect of calcium ions on the responses to motoneurons to substance P and eledoisin-related peptide in the toad and rat spinal cord.

The effects of changes in the external calcium ion concentration [Ca2+]0 on segmental reflexes and the responses of motoneurons to bath applied agonists have been studied in the toad and rat spinal cords in vitro. Reducing [Ca2+]0 enhanced polysynaptic reflexes in the toad, with maximal discharges occurring at 0.3 mM. Monosynaptic reflexes in the rat were reduced by lowering [Ca2+]0. Responses of toad motoneurons to substance P and eledoisin-related peptide were enhanced by lowering [Ca2+]0, maximum responses occurring at 0.3 mM. Lowering [Ca2+]0 also enhanced responses to L-glutamate but the effect was smaller and less consistent. This effect of Ca2+ was abolished by the addition of tetrodotoxin to the bathing solution. Toad motoneuron responses to gamma-aminobutyrate and glycine were not affected by alterations in [Ca2+]0. Rat motoneuron responses to substance P and eledoisin-related peptide were also enhanced by reductions in [Ca2+]0 but the effect was more pronounced in younger (less than 5 days post partum) than older (5-10 days post partum) animals. These results are consistent with the idea that motoneuron responses to peptides in normal solutions result from activation of receptors on both motoneurons and interneurons: enhancement of the responses by lowering [Ca2+]0 results from the potentiation of the transynaptic component.

Reconstruction of the inferior vena cava with a polytetrafluoroethylene tube graft after resection for hypernephroma of the right kidney.

A 49-year-old man underwent right radical nephrectomy including reconstruction of the inferior vena cava for a hypernephroma. To our knowledge this is the first clinical report of prosthetic replacement of the inferior vena cava with graft patency demonstrated postoperatively.

Effect of chronic exposure to lead on GABA binding in developing rat brain.

The effect of chronic treatment with lead on the growth and the development of calcium-dependent GABA(B) (forebrain and cerebellum) and calcium-independent GABA(A) binding (forebrain), at 10, 21 and 84 days post-natally (PN), was studied in rats whose dams received either lead acetate (7 gl(?1), 18.5 mM) or sodium acetate (controls) in their drinking water from conception to weaning and normal animals given only water. The body and brain weight of lead treated pups was significantly less than that of normal and control pups. Chronic lead treatment produced receptor specific effects on binding at different times during development. In the forebrain GABA(A) binding was reduced at PN 10 (decreased affinity and density) but showed increased receptor density at PN 84. GABA(B) binding, while reduced during the developmental period (increased affinity and decreased density), appeared to have recovered at maturity. The development of cerebellar calcium-dependent binding was more variable in showing an increase in affinity in adult animals and decreased density at PN 10 and 84. There was no difference in normal and control binding except at PN 10 for both GABA(A) and GABA(B) binding. Chronic lead treatment affects calcium-dependent and calcium-independent binding differently suggesting that within the period of greatest vulnerability to the effects of lead, development in different receptor systems may be affected in quite different ways according to the role of calcium in their normal function.

An assessment of the Coulter counter model S.

An assessment of the Coulter model S automatic blood counter has been carried out. The standard deviations for the haemoglobin concentration, haematocrit, red cell count, and white cell count are, respectively, +/- 0.15 g/100 ml, +/- 0.45%, +/- 0.04 m/c mm, and +/- 0.47 thous/c mm. These results are clearly more accurate than careful manual estimates, performed for comparison on the same samples. Details of the comparisons are presented. A comparison is also made with routine daily estimations.;Carryover' from one sample to the next was found to be about 2%, and tests in the ranges likely to be found in practice showed good linearity for the haemoglobin estimation, haematocrit, red cell count, and white cell count. A brief account of instrument failures is given.The performance of the Coulter model S compares well with that of other automated equipment for which detailed evaluations are available.

Renal cell carcinoma extending into vena cava and right atrium.

We report on a patient who underwent complete removal of a renal cell carcinoma extending into the vena cava and the right atrium. A review of the literature confirms the rarity of vena caval obstructive symptoms. Emphasis is on preoperative diagnosis, thoracoabdominal exposure, and team approach. Survival rates warrant aggressive surgical treatment in these patients.

Cytologic diagnosis of prostatic carcinoma by fine-needle aspiration biopsy. Community hospital experience.

Transrectal fine-needle aspiration and transrectal or perineal core biopsies were simultaneously performed on 31 patients with suspected prostatic cancer over an eighteen-month period. Of the 29 aspirations that were adequate for cytologic diagnosis, there was histologic correlation in 24 (83%). The sensitivity of aspiration for the diagnosis for prostatic cancer was 92 per cent (11 of 12) compared with 85 per cent (11 of 13) for the core biopsy method. There were no apparent false negative or false positive diagnoses with the aspiration biopsy technique. Insufficient material was obtained by aspiration in 2 cases. A febrile urinary tract infection occurred in 1 patient after transrectal aspiration and core biopsy. Our results suggest that fine-needle aspiration may be utilized by the practicing urologist in conjunction with a pathologist trained in the interpretation of fine-needle aspirates as a safe, relatively inexpensive, and sensitive diagnostic procedure for suspected prostatic cancer.

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.

Involvement of adenosine in synaptic depression induced by a brief period of hypoxia in isolated spinal cord of neonatal rat.

The monosynaptic reflex (MSR), recorded extracellularly from the ventral root isolated, superfused spinal cords of neonatal rats (6-10 days post-partum), was rapidly depressed to 35-45% of control values by either cessation of superfusion (4 min stop-flow period) or by superfusion with anoxic medium (95% N2-5% CO2; 4 min). The depression was reversible, 85-115% recovery occurring after 15 min of restoration of flow or normoxic (95% O2-5% CO2) superfusion. 2-Chloroadenosine, a metabolically stable adenosine analogue, also reversibly inhibited the MSR, an effect which was antagonised by 10(-6) M 8-cyclopentyltheophylline (8-CPT). The depression of the MSR, caused by 4 min of hypoxia (either stop-flow or anoxic superfusion), was prevented by 10(-6) M 8-CPT. These results provide strong evidence for a critical involvement of adenosine in mediating early synaptic depression evoked by a brief period of hypoxia.

Acute effects of lead at central synapses in vitro.

The acute effects of lead in the rat CNS in vitro were studied on synaptic transmission in the isolated hemisected spinal cord from newborn rats and on the transport of exogenous GABA, acetylcholine and cis-3-aminocyclohexane carboxylic acid (ACHC) from slices of cerebral cortex from adult rats. Lead had quite variable effects on monosynaptic reflexes and synaptic potentials. When it occurred, the depression of synaptic transmission by lead (typically at 18.5 mumol/liters of added lead acetate) was reversible provided exposure times were less than 15 min; furthermore, depression could be antagonised by increasing the external calcium concentration. Lead had no effect on the postsynaptic responses of motoneurons to the putative transmitters L-glutamate, GABA and glycine or to eledoisin-related peptide. The effects of lead on uptake and release of exogenous GABA and ACHC were dependent on the perfusion buffer employed: minimal effects were seen in solutions buffered with either phosphate or carbonate. When Tris HCl was used as buffer, lead inhibited the uptake of GABA and potentiated the spontaneous release of GABA with an EC50 = 50 mumol/liters as added lead acetate. In Tris HCl buffer, lead acetate (100 mumol/liters) produced a two-fold enhancement in the spontaneous release of acetylcholine under conditions where choline and acetylcholine re-uptake was blocked by hemicholinium. The availability of free lead cations in solution is highly dependent on the concentrations of other ions (particularly phosphates) and the pH. Under the appropriate conditions, lead can inhibit CNS synaptic function acutely in a manner consistent with lead competing with calcium ions in transmitter release processes as has been established for acetylcholine release at peripheral synapses.

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.

Depolarizing actions of convulsant barbiturates on isolated rat dorsal root ganglion cells.

The actions of convulsant barbiturates were studied on dorsal root ganglion (DRG) cells in vitro using intracellular recording techniques. Only the convulsant barbiturates (+)-DMBB and CHEB produced a concentration-dependent depression in the responses to gamma-aminobutyric acid (GABA). All convulsant barbiturates were found to produce a direct depolarization of the DRG cell membrane which was accompanied by a decrease in the input resistance of the cell and a reduction in the orthodromic action potential. A sub-population of DRG cells were found to be refractory to these actions but there was no relationship between the cell type (A beta, A delta and C) and ability to respond to the convulsant barbiturates.

Effect of magnesium on depression of the monosynaptic reflex induced by 2-chloroadenosine or hypoxia in the isolated spinal cord of neonatal rats.

Superfusion of the isolated spinal cord of neonatal rats (4-9 days postpartum) with physiological medium containing 2-chloroadenosine (2-CA) or anoxic medium (equilibrated with 95% N2-5% CO2) depressed the evoked monosynaptic reflex (MSR) recorded extracellularly from a ventral spinal root. The effectiveness of 2-CA or anoxic medium in depressing the MSR was significantly reduced when the concentration of Mg2+ in the physiological medium was lowered from 1.25 X 10(-3) M to zero. The absence of Mg2+ resulted in a 7-fold shift to the right of the concentration-response curve to 2-CA and a reduction in the maximal depression of the MSR from 100% to 65 +/- 4% (mean +/- S.E.M.) of control. A 10 min exposure to anoxic medium containing 1.25 X 10(-3) M Mg2+ decreased the amplitude of the MSR to 23 +/- 6% of control, whilst in zero Mg2+ a decrease to only 50 +/- 5% of control was observed. These data provide further evidence that the response to adenosine, at the A1-receptor, is sensitive to Mg2+ ion concentration and suggest that there is an absolute requirement for Mg2+ in order to obtain full expression of the adenosine effect. Furthermore, the data are consistent with the hypothesis that adenosine is an important mediator of hypoxia-induced depression of the evoked MSR in the spinal cord, and suggest a potential role for Mg2+ during or after exposure to hypoxia in altering the actions of adenosine on neuronal activity or synaptic events.

A simple in vivo method for evaluating drug action at central and peripheral synapses.

A simple in vivo method for studying spinal reflexes and neuromuscular transmission in anaesthetized mice is described. The technique utilizes electromyographic recording from muscles of both hind limbs following stimulation of the sciatic nerve in one limb. Drug effects on the neuromuscular junction, on monosynaptic reflex transmission and on crossed polysynaptic reflexes can be assessed. In addition a method for distinguishing between drugs which affect neuromuscular transmission and those which affect nerve conduction is described using their different effects on reexcitation of motoneurons. Details of data collection and analysis using a laboratory microcomputer are presented. The effects of a variety of representative compounds which have been shown to affect central and peripheral neurotransmission in other systems have been evaluated. The actions of these drugs in this system are compared with those obtained using spinal animals and more sophisticated recording techniques. The results compare favourably with those obtained using more complex methods and the technique offers a simple and inexpensive way of evaluating drug action at these synapses.

The site of action of muscle relaxant purine nucleosides.

The effects of a series of purine nucleosides, including the novel marine natural product 1-methylisoguanosine, have been examined on muscle relaxation in conscious animals and on spinal reflexes and neuromuscular transmission in mice anaesthetized with sodium pentobarbitone. 1-Methylisoguanosine (5--15 mumol kg--1) and 2-chloroadenosine (1--5 mumol kg--1), both of which cause muscle relaxation in conscious animals, depressed both mono- and polysynaptic spinal reflexes but did not affect neuromuscular transmission. At much higher doses (300 mumol kg--1) both compounds did depress neuromuscular transmission. Adenosine and 1-methyladenosine did not produce muscle relaxation in conscious animals and only slightly depressed polysynaptic reflexes at the highest doses tested (300 mumol kg--1). Theophylline 50 mumol kg--1 enhanced polysynaptic reflexes and antagonized the depression of these reflexes by 1-methylisoguanosine. Neither adenosine nor 1-methylisoguanosine affected the development of tension by isolated diaphragm muscles in vitro. It is concluded that the muscle relaxant purine nucleosides 2-chloroadenosine and 1-methylisoguanosine produce their effects primarily by depressing activity in the central nervous system. Transmission at the neuromuscular junction is not affected at doses in the range of those producing muscle relaxation.