Is the NICE process flawed?
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
D Sherlock
Publications and source records attributed to D Sherlock.
Time-lapse 3-D seismic imaging of shallow subsurface contaminant flow.
This paper presents a physical modelling study outlining a technique whereby buoyant contaminant flow within water-saturated unconsolidated sand was remotely monitored utilizing the time-lapse 3-D (TL3-D) seismic response. The controlled temperature and pressure conditions, along with the high level of acquisition repeatability attainable using sandbox physical models, allow the TL3-D seismic response to pore fluid movement to be distinguished from all other effects. TL3-D seismic techniques are currently being developed to monitor hydrocarbon reserves within producing reservoirs in an endeavour to improve overall recovery. However, in many ways, sandbox models under atmospheric conditions more accurately simulate the shallow subsurface than petroleum reservoirs. For this reason, perhaps the greatest application for analogue sandbox modelling is to improve our understanding of shallow groundwater and environmental flow mechanisms. Two fluid flow simulations were conducted whereby air and kerosene were injected into separate water-saturated unconsolidated sand models. In both experiments, a base 3-D seismic volume was recorded and compared with six later monitor surveys recorded while the injection program was conducted. Normal incidence amplitude and P-wave velocity information were extracted from the TL3-D seismic data to provide visualization of contaminant migration. Reflection amplitudes displayed qualitative areal distribution of fluids when a suitable impedance contrast existed between pore fluids. TL3-D seismic reflection tomography can potentially monitor the change in areal distribution of fluid contaminants over time, indicating flow patterns. However, other research and this current work have not established a quantifiable relationship between either normal reflection amplitudes and attenuation and fluid saturation. Generally, different pore fluids will have unique seismic velocities due to differences in compressibility and density. The predictable relationships that exist between P-wave velocity and fluid saturation can allow a quantitative assessment of contaminant migration.
Forecasting↗
Sonographic diagnosis and follow-up of idiopathic hepatic artery aneurysm, an unusual cause of obstructive jaundice.
Hepatic artery aneurysms are rare. We report an idiopathic hepatic artery aneurysm causing obstructive jaundice in a case in which the common hepatic artery arose from the superior mesenteric artery. The diagnosis of hepatic artery aneurysm was suggested by gray-scale sonography, which showed that the common bile duct and intrahepatic biliary radicles were dilated with no obvious intraluminal abnormality and showed no evidence of a mass in the head of the pancreas. A papillotomy of the papilla duodeni major was performed to relieve the cholestasis. Repeat sonography 2 weeks later showed dilatation of the common bile duct and a cyst-like lesion at the porta hepatis impressing the anterior part of the common bile duct. Doppler sonography confirmed pulsatile flow within the cyst-like lesion. Helical CT showed a well-circumscribed lesion with a density similar to that of the abdominal aorta, and mesenteric angiography showed a 3-cm, smooth aneurysm arising from the common hepatic artery, which originated from the superior mesenteric artery. The aneurysm was successfully treated with transcatheter embolization.
Aneurysm↗
Functional and compositional studies of arteries stored in University of Wisconsin solution compared with Krebs-Bülbring buffer.
Endothelium-dependent and -independent vasorelaxation in ring segments of rabbit thoracic aorta is reduced and noradrenaline-induced vasoconstriction unaltered after prolonged storage in University of Wisconsin solution (UW) compared to arteries stored in extracellular-type solutions such as Krebs-Bülbring buffer (KBB). The aims of the present study were to determine whether angiotensin-II-induced vasoconstriction, alterations in myosin light chains, protein synthetic capacity, and subcellular structures are altered after 8 days of UW storage at 4 degrees C. The present study showed reduced contractility to angiotensin II, following 8 days of cold storage in UW, that was not reversed in the presence of a nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (100 microM). Measurements of contractile protein ratios in the same tissues after cold storage in UW or KBB did not show any significant alterations in smooth muscle myosin light chains or protein synthetic capacity (reflected by total RNA). It is concluded that reductions in vasoconstriction in UW-stored tissue are unlikely to be due to increased release of nitric oxide nor reduced availability of myosin light chains for phosphorylation and vasoconstriction.
Angiotensin II↗
Paradoxical cholinergic and purinergic vascular reactivity of rabbit thoracic aorta cold-stored in University of Wisconsin solution.
Endothelial dysfunction has been reported in donor blood vessels destined for organ transplantation following cold-storage preservation with University of Wisconsin solution (UW). This was investigated in the present work. Segments of rabbit thoracic aorta were mounted on isometric fine-wire myographs at 37 degrees C and gassed with 95% O2/5% CO2. Concentration-dependent vasodilatations to acetylcholine and adenosine-5'-triphosphate (ATP) were obtained in freshly-harvested rabbit aortic rings, with and without the endothelium, and after 8 days of cold-storage, at 4 degrees C, in either UW, Krebs-Bülbring buffer (KBB) or saline. The action of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) (100 microM) was evaluated upon the concentration-response curves to determine whether nitric oxide (NO) exerted any modulatory actions. Endothelium-dependent, NO-mediated responses to acetylcholine were unaltered after eight days of storage in UW, reduced after storage in KBB and absent after removal of the vascular endothelium, saline storage or after testing in the presence of L-NAME, suggesting improved NO-mediated endothelial function with the use of UW. Structural preservation was also confirmed using scanning electron microscopy. In contrast, endothelium-dependent responses to ATP were unchanged after eight days of storage in KBB but were reduced after storage in UW and saline, suggesting purinergic (ATP) endothelial dysfunction after storage in UW. L-NAME markedly reduced vasodilatation to ATP in freshly harvested rings and after eight days of storage in KBB. This reduction was statistically significant (P < 0.05, Student's two tailed, unpaired t-test) at -log (M) ATP concentrations of 5.5, 5.0, 4.5, 4.0 and 3.5. NO-dependent vasodilatation to ATP was not attenuated by L-NAME in UW-stored rings. Eight days' UW-storage of rabbit thoracic aortic rings appeared to have differential and paradoxical effects upon NO-dependent vasodilatation to acetylcholine and ATP. Morphological observations using electron microscopy suggested that UW preserved the vascular endothelium and this was verified by retained vascular reactivity of endothelium-dependent vasodilatations to acetylcholine. UW-storage however, significantly reduced endothelium-dependent relaxation to ATP thereby suggesting that P2Y-purinoceptors, which are located on the vascular endothelium, may be more susceptible to biodegradation than cholinergic receptors and may be responsible for endothelial dysfunction following transplantation.
Acetylcholine↗
Use of hepatic imaging techniques in the management of colorectal cancer: a survey of current practice among surgeons in the northwest of England.
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Colorectal Neoplasms↗
Cold-storage of rabbit thoracic aorta in University of Wisconsin solution reduces endothelium-independent vasodilation.
Optimum preservation conditions for storage of donor livers and blood vessels are essential for successful transplantation. The blood vessels are used as vascular conduits to facilitate anastomosis of the liver to the recipient's systemic vasculature. Failure of some transplants has been ascribed to thrombosis of these vascular conduits possibly because of alterations in vascular reactivity owing to inadequate storage techniques. To restrict data variability previously associated with studies using a heterogeneous sample of vessels from man, this study investigated changes in vascular reactivity in segments of rabbit thoracic aorta from male, age-matched, New Zealand White rabbits stored at 4 degrees C in either University of Wisconsin solution (UW; Du Pont Pharmaceuticals, UK) or Krebs-Bülbring buffer (KB). Percent vasodilation to acetylcholine remained significantly greater in UW than in KB at -log (M) concentrations of 7.0 (UW = 47.05 +/- 4.26 compared with KB = 13.20 +/- 7.20%; P < 0.001), 6.5 (UW = 66.82 +/- 4.83 compared with KB = 26.60 +/- 9.48%; P < 0.01), and 6.0 (UW = 83.68 +/- 5.26 compared with KB = 31.20 +/- 9.83%; P < 0.001). This was not significantly different to relaxation in unstored arteries and suggested improved endothelial function and structure, confirmed by electron microscopy. Percent vasodilation to sodium nitroprusside was significantly lower in UW than in unstored (D0) arteries at -log (M) concentrations of 7.5 (D0 = 28.27 +/- 4.02 compared with UW = 15.21 +/- 1.82%; P < 0.01), 7.3 (D0 = 52.58 +/- 5.05 compared with UW = 29.23 +/- 1.94%; P < 0.01), 7.0 (D0 = 69.70 +/- 4.85 compared with UW = 49.72 +/- 2.49%; P < 0.05), and 6.4 (D0 = 93.16 +/- 2.93 compared with UW = 71.29 +/- 5.20%; P < 0.05). Percent vasodilation was also lower in UW- compared with KB-stored arteries at -log (M) sodium nitroprusside concentrations of 7.0 (UW = 49.72 +/- 2.49 compared with KB = 64.11 +/- 5.03%; P < 0.05) and 6.4 (UW = 71.29 +/- 5.20 compared with KB = 96.91 +/- 5.96; P < 0.05). Electron microscopy confirmed that this was not a result of degradation of smooth muscle structure. The nitric oxide synthase inhibitor L-NG-nitro-L-arginine methyl ester (100 microM) did not significantly modulate sodium nitroprusside-induced vasodilation in unstored arteries, when endothelial function was maximum, or in UW-stored arteries, suggesting that the reduced responses in UW-stored arteries were not because of increased synthesis of nitric oxide. This reduced relaxation to sodium nitroprusside was therefore nitric oxide-independent and not a result of competition between sodium nitroprusside and endothelial 'nitric oxide donation' for cGMP. In summary, cold-storage preservation with UW reduced endothelium-independent vascular relaxation by mechanisms other than competition with NO; this requires further evaluation.
Acetylcholine↗
Cytochemical characteristics of neurons in the trigeminal mesencephalic nucleus of hatchling chicks.
The goal of the present study was to identify cytochemical markers characteristic of muscle afferents in hatchling chicks. To this end, we stained neurons in the trigeminal mesencephalic nucleus with a variety of markers that label subsets of neurons in avian dorsal root ganglia. We found that trigeminal mesencephalic neurons are surprisingly heterogeneous in their cytochemical make-up, expressing, to varying degrees, substance P, cholecystokinin, carbonic anhydrase, calbindin D-28k, parvalbumin, and S-100 beta. Calbindin D28k and S-100 beta appeared to be expressed equally in medial and lateral divisions of the trigeminal mesencephalic nucleus. In contrast, substance P- and cholecystokinin-immunoreactive neurons were more abundant in the medial division, whereas carbonic anhydrase activity and parvalbumin immunoreactivity were stronger in the lateral division. We were unable to detect met-enkephalin, neuropeptide Y, calcitonin gene-related peptide, vasoactive intestinal peptide, somatostatin, gamma-aminobutyric acid, or tyrosine hydroxylase in the trigeminal mesencephalic nucleus. Moreover, these neurons did not appear to bind the lectin Dolichos biflorus agglutinin. The heterogeneity of expression of markers among trigeminal mesencephalic nucleus neurons, especially between neurons in the medial and lateral divisions, suggests that these neurons are functionally diverse.
Animals↗
Primary treatment of hepatocellular carcinoma by arterial chemoembolization.
Two hundred and ninety-one patients with hepatocellular carcinoma were treated by chemoembolization (CE), using ethiodized oil, doxorubicin, and a gelatin sponge. Patients with thrombosis of either the portal vein or a main branch were excluded. The mortality rate in the first 2 months after treatment was 7% in noncirrhotic patients, 2.8% in patients with class A cirrhosis, 8% in patients with class B cirrhosis, and 37% in patients with class C cirrhosis. The tumor diameter remained the same in 55.3% of patients, was reduced by up to 50% in 20% of the patients, was reduced by more than 50% in 7.3% of the patients, and almost completely disappeared in 1.8% of the patients. The diameter of the tumor increased in 15.6% of patients. Forty-three patients underwent a resection or transplantation after chemoembolization. Histologic examination of the specimens revealed significant necrosis of the tumor. The long-term survival rate at 2 years was 49% for class A cirrhotics, 29% for class B cirrhotics, and 9% for class C cirrhotics. Complications included cholecystitis (10%), vasculitis (14%), renal decompensation (13%), an increase in ascites (14%), and jaundice (12%). Chemoembolization is an effective and safe initial treatment for hepatocellular carcinoma. It is effective in producing tumor necrosis and reducing the size of the tumor. Improvement in survival was noted when patients who underwent chemoembolization were compared with an historical series of untreated patients, and resection and transplantation are kept as options.
Adolescent↗
Options for elective treatment of portal hypertension in cirrhotic patients in the transplantation era.
We review herein our experience in the management of bleeding esophageal varices in cirrhotic patients and consider our findings in light of the dramatic changes in the treatment of cirrhosis resulting from the more widespread use of orthotopic liver transplantation (OLT). It does not seem realistic, at present, to propose OLT as the only effective treatment of variceal bleeding for a variety of reasons, and there remains a large group of patients who are noncompliant or unsuitable for liver transplantation. We propose that initial bleeding be controlled by endoscopic sclerotherapy, thereby allowing careful evaluation to be made electively. Grade A patients appear to be managed best by a reduced-size portacaval shunt (RPS) with prospects of good survival and few complications. Grade B patients can be managed by either sclerotherapy, RPS, or OLT, depending upon individual circumstances. Grade C patients are best managed by liver transplantation, again with excellent survival. In those grade C patients not deemed suitable for OLT (especially alcoholic patients), long-term endoscopic sclerotherapy is the best option. Changes in patient status may sometimes require revision of the treatment decision.
Adolescent↗
Human hepatic preservation using Marshall's solution and University of Wisconsin solution in a controlled, prospective trial.
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Adenosine↗
Gallbladder conduit vs end-to-end anastomosis of the common bile duct in orthotopic liver transplantation.
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Bile Ducts↗
Orthotopic liver transplantation in a patient with thrombosis of the hepatic portal and superior mesenteric veins.
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Female↗
The role of serotonin in the canine secretory response to cholera toxin in vivo.
This study was initiated to evaluate the role of serotonin in cholera toxin-induced jejunal secretion of water and electrolytes. Chronic Thiry-Vella loops, constructed in six dogs, were perfused with an isosmotic neutral perfusate containing [14C]polyethylene glycol as the recovery marker. Fluxes of water, sodium, chloride and potassium were calculated and immunoreactive serotonin levels were measured in blood and effluent perfusates. Intraluminal application of 20 micrograms of cholera toxin induced secretion; fluxes of water (basal, 32.3 +/- 11.1; 6 hr, -541 +/- 35 microliter/min), sodium (basal, 9.0 +/- 2.8; 6 hr, -78.3 +/- 5.6 microEq/min), chloride (basal, 3.8 +/- 1.5; 6 hr, -65.7 +/- 4.0 muEq/min) and potassium (basal, 0.10 +/- 0.08; 6 hr, -2.80 +/- 0.18 muEq/min) were all significantly different from basal. Serum electrolytes remained normal, except that potassium fell from 4.9 +/- 0.5 to 3.9 +/- 0.2 mEq/l. Although circulating serotonin levels did not change from base line (180.9 +/- 29.3 ng/ml), effluent concentrations increased significantly from 68.2 +/- 4.6 to 81.1 +/- 5.0 ng/ml (at 3 hr) and jejunal outputs increased from 136.6 +/- 10.2 to 205.1 +/- 10.1 ng/min (at 6 hr). In a separate set of experiments, verapamil was infused i.v. (12.5 micrograms/kg/min) during the 4th hr in four dogs exposed to cholera toxin. The lower dose of toxin (5 micrograms) induced secretion which was unaffected by the calcium channel blocker. In another series of studies, ketanserin (a 5-HT2 receptor blocker) was infused i.v. at 33 micrograms/kg/min during the 4th hr in four additional dogs exposed to the lower dose of cholera toxin. This potent serotonin antagonist failed to inhibit cholera toxin-induced jejunal secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Verapamil reversal of serotonin-induced jejunal secretion of water and electrolytes in awake dogs.
Intestinal handling of water and electrolytes was monitored in 5 conscious dogs with chronic 25-cm Thiry-Vella loops of proximal jejunum using a neutral isosmotic perfusate containing [14C]polyethylene glycol as a recovery marker. Under basal conditions the animals absorbed water, Na+, and Cl-, and there was minimal nonsignificant secretion of K+. Intravenous serotonin infusion (30 micrograms/kg X min) increased circulating hormone levels to 937 +/- 131 ng/ml and induced significant secretion of water (-150 +/- 52 microliter/min), Na+ (-22.8 +/- 8.4 microEq/min), Cl- (-23.5 +/- 6.0 microEq/min), and K+ (-1.79 +/- 0.34 microEq/min). Simultaneous infusion of verapamil, a calcium channel blocker, at 8.3 micrograms/kg X min, reversed the intestinal secretion to absorption of all these parameters (144 +/- 32 microliter/min, 15.1 +/- 5.1 microEq/min, 10.3 +/- 3.0 microEq/min, and 0.12 +/- 0.23 microEq/min, respectively). This was accompanied by a significant improvement in the clinical appearance of the animals, decreased visible agitation, and cessation of defecation. Cessation of verapamil infusion (leaving the serotonin infusion unopposed) resulted in prompt return to the secretory state. Serum electrolytes did not change significantly, with the exception of potassium, which fell from 5.1 +/- 0.2 to 4.1 +/- 0.1 mg/dl. In control experiments (no serotonin), verapamil had an insignificant stimulatory effect on the absorption of water, Na+, and Cl- whereas the effect on K+ was significant (-0.2 +/- 0.2 to +0.4 +/- 0.1 microEq/min; p less than 0.05). These data support the role of calcium in modulating the effects of serotonin, and they suggest a new promising technology for the management of serotonin-induced intestinal secretion such as that seen in the carcinoid syndrome.
Animals↗
Verapamil inhibition of the intestinal effects of substance P.
The undecapeptide substance P (SP) is contained in enterochromaffin cells and circulates in high concentrations in patients with carcinoid syndrome. We have previously reported that elevated SP levels, simulating those reported in patients with carcinoid syndrome, induce profound changes in intestinal water and electrolyte secretion, motility, and blood flow in a canine model. The purpose of this study was to attempt to block the effects of circulating carcinoid levels of SP on intestinal secretion and motility with the calcium channel blocker verapamil. In five dogs a chronic proximal jejunal Thiry-Vella loop was constructed, and after a 2-week recovery the loops were perfused with an isotonic test solution containing 14C-polyethylene glycol as a volume marker. Motor activity was measured by changes in intraluminal pressure and a motility index was calculated with computer-assisted planimetry and expressed as square millimeters per 5 minutes. After a 30-minute baseline period, SP was infused at 50 ng/kg/min for 90 minutes. SP circulating levels rose from a baseline of 6.2 +/- 1.3 pg/ml to a peak of 93.3 +/- 3.1 pg/ml during this infusion. Thirty minutes after the start of this SP infusion, a simultaneous infusion of verapamil (5.0 micrograms/kg/min) was begun at a separate site. During SP infusion there was a significant secretory response of water (-48 +/- 12 microliters/min), Na+ (-7.7 +/- 2.5 microEq/min), Cl- (-8.8 +/- 2.7 microEq/min) and K+ (-0.57 +/- 0.14 microEq/min), and hypermotility (motility index: 1479 +/- 138 mm2/5 min). When verapamil was added a reversal of secretion to net absorption was observed (water: + 116.9 +/- 15.6 microliter/min; Na+: + 13.8 +/- 2.1 microEq/min; Cl-: + 5.5 +/- 2 microEq/min; K+: + 0.38 +/- 0.9 microEq/min) (p less than 0.05). In addition, there was a reduction in motility (motility index: 853 +/- 92 mm2/5 min; p less than 0.05). These results confirm that SP has profound effects on both intestinal motility and secretion and that calcium channel blockade reduces these effects significantly.
Animals↗
Cholecystitis associated with myelomatosis.
A case of myeloma presenting as acute cholecystitis unresponsive to conventional management is reported. The impairment of the immunological response is a well-known aspect of myeloma, although this usually takes the form of recurrent respiratory infections. It is unusual for acute on chronic cholecystitis, a predominantly Gram-negative infection, to present in this way.
Adult↗
Bugs and faces in the two visual fields: the analytic/holistic processing dichotomy and task sequencing.
We report three experiments employing outline face and bug stimuli. Subjects either attended to the spatial relationships between and otherwise independent of the individual feature elements (holistic processing condition), or instead attended (with the same stimuli) to the shape of certain discrete feature elements (analytic condition). They were timed in performing discriminatory manual responses to laterally presented targets and nontargets. A left visual field superiority generally occurred under conditions of holistic processing both for faces and bugs, and a right field superiority when analytic processing was required; effects were rather more apparent in the second of a pair of sequential tasks, when the more difficult of the two tasks came first, for the more difficult of the two tasks, and with target rather than, nontarget stimuli. We conclude that those aspects of a stimulus to which a subject is set to attend can determine lateral asymmetries, as well as the actual stimuli themselves, that an analytic/holistic processing distinction is supported, rather than one based on verbal/visuospatial processing, and that task difficulty and order are important variables to be controlled and studied in this context in future research.
Adult↗