A randomised study of prophylactic G-CSF following MRC UKALL XI intensification regimen in childhood ALL and T-NHL.

BACKGROUND: Despite the current widespread use of prophylactic G-CSF in children with solid tumours and leukaemia, its effectiveness has not been clearly demonstrated. This randomised study evaluates the role of G-CSF given after a 5-day intensification block in children with acute lymphoblastic leukaemia (ALL). PROCEDURE: Forty-six children with ALL or T-Cell non-Hodgkins lymphoma (NHL) treated on MRC ALL 97, UKALL XI or UKCCSG 9504 NHL protocols were randomised to receive granulocyte colony-stimulating factor following either the first or the second block of intensive chemotherapy in a cross-over study to determine if the prophylactic administration of G-CSF could reduce the rate of readmission to hospital for management of febrile neutropenia. RESULTS: There was a statistically significant difference in the rate of hospital admission in the group receiving prophylaxis, with 34 of 46 being admitted, compared to 42 of 46 patients in the control arm (74 vs. 91%; P=0.0386). There were no differences found in duration of hospital admission, haematological toxicity, neutrophil recovery or duration of supportive care between the two groups. There was no demonstrable cost benefit derived from the prophylactic administration of G-CSF. CONCLUSIONS: This study shows that the prophylactic administration of G-CSF following intensification chemotherapy for childhood ALL and T-NHL produces a significant reduction in the rate of readmission to hospital for the management of febrile neutropenia.

Transdermal fentanyl for pain relief in a paediatric palliative care population.

This multicentre, observational study examined the efficacy of the therapeutic transdermal fentanyl system (TTS-fentanyl) in children requiring opioids for pain in life-threatening disease. Forty-one children receiving oral morphine (median dose 60 mg/day) transferred to transdermal fentanyl (median dose 25 micrograms/h according with the manufacturer's dose conversion guidelines). Twenty-six children completed the 15-day treatment phase, seven died due to disease progression and eight were withdrawn because of adverse events, inadequate analgesia or a change to parenteral opioids. After 15 days, the median fentanyl dose was 75 micrograms/h (range 25-250). No serious adverse events were attributed to fentanyl. There was a trend toward improved side-effects and convenience with fentanyl. Twenty-three of 26 parents (three missing) and 25 of 26 investigators considered transdermal fentanyl to be better than previous treatment. For all records available (at 15 days or on withdrawal if earlier), 75% (27/36) reported that fentanyl treatment was 'good' or 'very good'. The findings suggest that transdermal fentanyl is both effective and acceptable for children and their families.

Response to influenza immunisation during treatment for cancer.

AIMS: To assess the annual risk of influenza infection in children with cancer and the immunogenicity of a trivalent split virus influenza vaccine in these children. METHODS: Eighty four children with cancer were tested for susceptibility to the circulating strains of influenza virus in autumn 1995 and 1996. Non-immunised children were reassessed the following spring for serological evidence of natural infection. Forty two patients received two doses of influenza vaccine. These children were receiving continuing chemotherapy for acute lymphoblastic leukaemia or were within six months of completing chemotherapy. RESULTS: Among the 84 children tested for influenza virus susceptibility only 8% of patients were fully protected (antibody titres >/= 40) against all three of the prevalent influenza virus strains; 33% were susceptible to all three viruses. Evidence of acquired natural infection was seen in 30% of unimmunised patients. Among immunised susceptible patients, 66% made some protective response to the vaccine and 55% showed protective antibody titres to all three viral strains following vaccination. Older age was associated with increased response to the H1N1 and H3N2 vaccine components, but total white cell count or neutrophil count at immunisation, type of cancer, or length of time on treatment for acute lymphoblastic leukaemia did not affect response. CONCLUSIONS: Most children with cancer studied were at risk of influenza infection. A significant response to immunisation was seen, supporting annual influenza vaccination for children being treated for cancer.

Presenting a case for involving children with a terminal illness in clinical trials.

Today's approaches to the treatment of childhood malignancies are the result of past clinical trials. In order to improve survival it is essential we continue to seek benefit from clinical trials. However, entry of terminally ill children into a phase I or phase II clinical trial, involving a novel, potentially therapeutic, agent is highly contentious. This article will argue in favour of a child's active and full participation in the decision to enter into a phase I or phase II clinical trial. A formal study of the role of children in clinical trials, especially phase I and phase II trials, is urgently required if standards of best practice are to be laid down and subsequently measured.

Sentence comprehension in Alzheimer's disease.

We asked 22 patients with Alzheimer's disease (AD) to respond to simple probes of sentences where we manipulated grammatical factors, semantic factors, and cognitive resource demands associated with a sentence. The results demonstrated limitations in the cognitive resources needed to appreciate atypical syntactic-thematic mapping relations and difficulty processing selection restrictions associated with a verb. By comparison, comprehension in AD was not influenced by the active or passive voice of a sentence. These findings are consistent with the hypothesis that impaired sentence comprehension in AD is multifactorial in nature, including difficulty processing cognitive resource and semantic aspects of sentences.

Semantic memory in Alzheimer's disease: representativeness, ontologic category, and material.

Alzheimer's disease (AD) patients with semantic memory difficulty and AD patients with relatively preserved semantic memory named pictures and judged the category membership of words and pictures of natural kinds and manufactured artifacts that varied in their representativeness. Only semantically impaired patients were insensitive to representativeness in their category judgments. AD subgroup judgments did not differ for natural kinds compared to manufactured artifacts nor for words compared to pictures. AD subgroup differences could not be explained by dementia severity, memory, reading, and visuoperception. The similarity process for relating coordinate members of a taxonomic category contributes to the normal appreciation of word and picture meaning, and this process is compromised in AD patients with semantic difficulty.

Constraints on the cerebral basis for semantic processing from neuroimaging studies of Alzheimer's disease.

OBJECTIVE: Functional activation studies of semantic processing in healthy adults have yielded conflicting results. The purpose was to evaluate the relative role of the brain regions implicated in semantic processing with converging evidence from imaging studies of patients with impaired semantic processing. METHODS: Semantic memory was assessed in patients with Alzheimer's disease using two measures, and these performance patterns were related to profiles of reduced cerebral functioning obtained with high resolution single photon emission computed tomography (SPECT). Patients with frontotemporal degeneration were similarly evaluated as a control group. RESULTS: Reduced relative cerebral perfusion was seen in parietal and posterior temporal brain regions of patients with Alzheimer's disease but not patients with frontotemporal degeneration. Impairments on semantically guided category membership decision tasks were also seen in patients with Alzheimer's disease but not those with frontotemporal degeneration. Performance on the semantic measures correlated with relative cerebral perfusion in inferior parietal and superior temporal regions of the left hemisphere only in Alzheimer's disease. Relative perfusion was significantly lower in these regions in patients with Alzheimer's disease with semantic difficulty compared with patients with Alzheimer's disease with relatively preserved semantic processing. CONCLUSION: These findings provide converging evidence to support the contribution of superior temporal and inferior parietal regions of the left hemisphere to semantic processing.

Calcium phosphate particle induction of metalloproteinase and mitogenesis: effect of particle sizes.

Calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals [hydroxyapatite (HA), octacalcium phosphate, tricalcium phosphate] are common in osteoarthritis knee effusions, and are often associated with low-grade synovial proliferation and inflammation. Calcium-containing crystals including HA, are known to have a number of biologic effects on culture cells such induction of mitogenesis, stimulation of Prostaglandin E2 (PGE2) production via the phospholipase A2/cyclo-oxygenase pathway, activation of phospholipase C and inositol phospholipid hydrolysis, induction of metalloproteinase synthesis and induction of proto-oncogenes (c-fos and c-myc). While endocytosis of HA particles is prerequisite of the mitogenic effect of calcium-containing crystals in fibroblasts, it is not known whether endocytosis is required for crystal-induced metalloproteinase synthesis. In the present series of experiments, we examine the effect of three different sizes (106, 46, and 17 microns mean diameters) well-characterized spherical HA particles on the induction of mitogenesis and metalloproteinase synthesis on human fibroblasts. We showed that endocytosis is required for HA particles to induce synthesis of metalloproteinases.

Abdominal aortic aneurysms. The old and the new.

Abdominal aortic aneurysms are more frequently diagnosed while they are asymptomatic, by ultrasound scanning or computerized tomography (CT). Large aneurysms should be treated. Open surgical repair is well proven but is a major procedure with some risk and a slow convalescence. New endoluminal techniques, inserting grafts through the femoral artery involve minimal trauma and risk, with rapid recovery, but long term success has yet to be confirmed. At present, we consider that endoluminal grafts should be reserved for patients at high risk, but with increasing experience they could be used in more than 50% of cases.

Structures of the extracellular domain of the type I tumor necrosis factor receptor.

BACKGROUND: Tumor necrosis factor (TNF) is a powerful cytokine that is involved in immune and pro-inflammatory responses. Two TNF receptors that belong to the cysteine-rich low affinity nerve growth factor receptor family (TNF-R1 and TNF-R2) are the sole mediators of TNF signalling. Signalling is thought to occur when a trimer of TNF binds to the extracellular domains of two or three receptor molecules, which permits aggregation and activation of the cytoplasmic domains. The complex is then internalized within an endocytic vesicle, whereupon it dissociates at low pH. Structure of the soluble extracellular domain of the receptor (sTNF-R1) both in the unliganded and TNF-bound state have previously been determined. In both instances, the fourth subdomain of the receptor was found to be partly disordered. In the unliganded state at pH 7.5, the extracellular domain forms two distinct types of dimer, parallel and antiparallel; the antiparallel dimer occludes the TNF-binding. RESULTS: We have determined the structure of sTNF-R1 in two crystal forms in high salt at pH 3.7. The orthorhombic crystals diffract to 1.85 ånd the entire polypeptide is well ordered. In contrast, the C-terminal 32 residues are disordered in the hexagonal crystals. In the orthorhombic form, these residues exhibit a topology and disulphide connectivity that differs from the other three cysteine-rich domains in the molecule. In both forms, the interface is considerably more extensive than that used in complex formation with LTalpha. This 'low pH' dimer is different from both of the dimers observed in crystals grown at pH 7.5. CONCLUSIONS: The occurrence of the antiparallel dimers in both low pH crystal forms suggest that they are not an artefact of crystal packing. Such dimers may form in the low pH environment of the endosome. Because the dimer contact surface occludes the TNF-binding site, formation of this dimer would dissociate the TNF-receptor complex within the endosome. Three of the four cysteine-rich domains of TNF-R1 are constructed from two distinct structural modules, termed A1 and B2. The fourth subdomain comprises an A1 module followed by an unusual C2 module. Although the orientation of these modules with respect to each other is sensitive to crystal packing, ligand binding, pH and ionic strength, the modules are structurally well conserved between and within the known sTNF-R1 structures.

Clinical and vascular laboratory determinants for outcome after infrainguinal atherectomy.

Three surgeons performed 180 atherectomy procedures in 161 patients using the Transluminal Extraction Catheter in 144 and the Auth Rotablator in 36. The primary patency rate was 55% at 1 year and 46% at 2 years, and failure was caused by stenosis in 28 (15.6%) and occlusion in 61 (33.7%) limbs. Multivariate Cox regression analysis showed significantly better outcome if the indication was claudication, the lesion was short or there was associated stenting. Vascular laboratory surveillance was performed in 93 limbs in 83 patients. Cox regression analysis in this subgroup also showed a significant relationship between outcome and the maximum peak systolic velocity from a duplex scan at the last study performed. Receiver operating characteristics curves showed that a raised maximum peak systolic velocity best predicted late failure (sensitivity 84%, specificity 66% for > 200 cm/s; sensitivity 72%, specificity 84% for > 250 cm/s); the velocity ratio at the stenosis to that in the segment above or the resting ankle/brachial pressure index were less predictive. For 50 procedures studied in the vascular laboratory which remained successful to the end of the study, maximum peak systolic velocities were > 250 cm/s from the first postoperative study, suggesting residual stenosis in 6%, or increased to become > 250 cm/s by the last study, suggesting recurrent stenoses in 12%. For 43 procedures which were studied and later failed, velocities were > 250 cm/s from the first test in 26% or increased to > 250 cm/s by the last test before failure in 40%. Vascular laboratory surveillance helps to predict outcome after atherectomy. Failure may be a result of residual disease from the time of the procedure or from restenosis. The apparent high incidence of clinically manifest or developing stenoses raises doubts as to the benefit of atherectomy over balloon dilatation alone.

Category-specific difficulty naming with verbs in Alzheimer's disease.

We studied 20 patients with Alzheimer's disease (AD) on a picture-naming task consisting of frequency-matched pairs of nouns and verbs that were homophonic and homographic (e.g., paint). Intragroup comparisons revealed that verb naming is significantly more difficult for patients with AD than noun naming. An error analysis demonstrated that patients with AD produce significantly more semantic and descriptive errors for verbs than nouns. We correlated verb naming and noun naming with measures of grammatical comprehension, lexical retrieval, and visuoperceptual processing, but there were no selective effects for verbs compared with nouns. Differences in the mental representation of concepts underlying verbs and nouns may account, in part, for the relative difficulty naming with verbs in AD.

Language comprehension profiles in Alzheimer's disease, multi-infarct dementia, and frontotemporal degeneration.

We assessed language functioning in 116 age-, education-, and severity-matched patients with the clinical diagnosis of Alzheimer's disease (AD), multi-infarct dementia (MID) due to small-vessel ischemic disease, or a frontotemporal form of degeneration (FD). Assessments of comprehension revealed that patients with AD are significantly impaired in their judgments of single word and picture meaning, whereas patients with FD had sentence comprehension difficulty due to impaired processing of grammatical phrase structure. Patients with MID did not differ from control subjects in their comprehension performance. Traditional aphasiologic measures did not distinguish between AD, MID, and FD. Selective patterns of comprehension difficulty in patients with different forms of dementia emphasize that language deficits cannot be explained entirely by the compromised memory associated with a progressive neurodegenerative illness.

Seeing double: crystal structures of the type I TNF receptor.

The crystal structure of the extracellular domain of the type I tumor necrosis factor receptor (sTNF-R1) has been determined to 2.25 A at pH 7.5. We have also solved the structure of sTNF-R1 at pH 3.7. sTNF-R1 is an elongated molecule consisting of a linear combination of four cysteine-rich motifs. Interestingly, the crystal structure reveals two distinct dimers of the receptor. One dimer is formed by a parallel arrangement of receptors, the other by an antiparallel arrangement of receptors. In the parallel arrangement of the receptors, the tumor necrosis factor (TNF) binding face of the receptor is completely exposed to solvent. However, in the antiparallel arrangement, the TNF binding face is intimately involved in the dimer interactions. Details of these recognition surfaces are discussed. Both these dimer interactions bury substantial surface area, comprise polar and apolar contact surfaces and have complimentary recognition surfaces. Thus these interactions are typical of genuine protein-protein interactions, rather than crystal packing contacts. These dimers may function to inhibit signal transduction in the absence of TNF or in the case of the parallel dimer, promote clustering of TNF/TNF receptor complexes on the cell surface.

Crystallographic evidence for dimerization of unliganded tumor necrosis factor receptor.

Activation of the cell surface receptors for tumor necrosis factor (TNF) is effected by the aggregation of cytoplasmic domains that occurs when the extracellular domains of two or three receptors bind to trimeric TNF alpha or TNF beta. The structure of the type I TNF receptor extracellular domain (sTNF-R1), crystallized in the absence of TNF, has now been determined at 2.25-A resolution. The receptor itself is an elongated molecule comprising four disulfide-rich domains in a nearly linear array. Contrary to expectations, the unliganded domains are found to associate into dimers of two distinct types, in which monomers are related by local two-fold axes of symmetry. In one case, the receptors are antiparallel to each other and associate through an interface that overlaps the TNF binding site. If intact receptors were capable of such an association, their cytoplasmic domains would be separated by over 100 A. This interaction could inhibit signaling in the absence of TNF. Parallel dimers are also observed in which the dimer interface is well separated from the TNF binding site. Associations among TNF-bound parallel dimers could cause receptor clustering. Both dimers bury substantial areas of protein surface and are formed by polar and non-polar interactions.

Infrainguinal atherectomy using the transluminal endarterectomy catheter: patency rates and clinical success for 144 procedures.

PURPOSE: To determine if atherectomy using the transluminal endarterectomy catheter (TEC) is an effective endoluminal therapy for infrainguinal occlusive disease. METHODS: Three surgeons used the TEC for 144 infrainguinal atherectomy procedures in 133 patients. The indications were severe claudication in 83, critical ischemia in 56, and graft stenosis in 5 limbs. The pathology was stenosis in 36 and occlusion in 105 limbs. Balloon dilation was also performed in 109 and stenting in 17 limbs. RESULTS: There was initial technical and anatomic success in 124 (86%) procedures. There were 67 technically successful procedures at mean follow-up of 19 months, although 3 of these limbs with gangrene and extensive distal disease required major amputation. There were 26 failures due to stenosis leading to further intervention and 51 due to occlusion. Twenty of these cases were managed conservatively, 21 were treated with repeat endovascular intervention, 31 with bypass grafting, and 5 with amputation. Repeat intervention in 52 limbs resulted in 36 with patent arteries, 10 that are occluded, and 6 that required amputation. Thirteen of the 14 amputations were for limbs with critical ischemia, but 1 was in a patient with claudication. Life-table analysis showed that the primary patency rate was 51%, the assisted primary patency rate was 61%, and the secondary patency rate was 75% at 15 months. The clinical success rate was 49%, and the salvage rate for limbs with critical ischemia was 78% at 12 months. Univariate log-rank testing showing no significant differences according to the clinical presentation of pathology, but results were worse for lesions > 5 cm long due to more frequent immediate failures. However, multivariate Cox regression analysis showed that results were significantly worse for critical ischemia than for claudication, stenosis compared to occlusions, for limbs with poor runoff, for operations performed by percutaneous rather than an open approach, and for those performed more recently. CONCLUSIONS: TEC atherectomy may have a place in selected patients, but the optimal circumstances for its use and long-term efficacy require further study.

Perioperative stroke after carotid endarterectomy. Etiological risk factors and management.

291 patients were subjected to carotid endarterectomy from January 1985 to June 1992 in two Australian medical institutions. Of the 291 patients, perioperative stroke occurred in 22 (6.3%) after 347 operations (moderate 17 and severe 5). The 22 patients were studied with Doppler scan, angiography, reexploration and CT. Reexploration showed that 12 of 14 patients had thrombosis in the internal carotid artery at operation. The etiological factors for perioperative strokes included thrombosis at the operative sites in 14 patients (64%), cerebral embolism after operation in 4, clamping ischemia in 2, intracerebral hemorrhage in 1 and unknown cause in 1. Six patients (27%) recovered completely in 4 weeks, 10 (45%) had mild residual neurological deficits, 5 (23%) had moderate neurological deficits and 1 died 3 days after operation. Only 6 patients had permanent neurological deficits (6/347, 17%).

Two crystal forms of the extracellular domain of type I tumor necrosis factor receptor.

The soluble extracellular domain of human type I tumor necrosis factor receptor (sTNFrI) is a 161 residue polypeptide found in serum and urine. This domain tightly binds tumor necrosis factors (TNF) alpha and beta and, as part of the whole receptor, initiates the powerful biological effects of TNF. The extracellular domain, typical of other TNF receptor superfamily members, comprises four cysteine-rich motifs. We have obtained two crystal forms of the sTNFrI. One crystal form is grown at pH 3.7 with MgSO4 as the precipitant. These crystals are orthorhombic, space group P2(1)2(1)2(1), with cell dimensions a = 78.5 A, b = 85.5 A and c = 67.5 A. A data set to 2.0 resolution has been collected for these crystals. Tetragonal crystals, space group P4(1)2(1)2 (or P4(3)2(1)2), with unit cell dimensions a = 69.0 A and c = 185.5 A are obtained using methylpentanediol as precipitant at pH 8.5. Data to 2.8 A have been measured from these crystals. It appears that both unit cells may contain two molecules in the asymmetric unit. These crystal structures of sTNFrI may reveal possible conformational differences between receptor localized on the cell surface (high pH), the receptor in the endosomal compartments (low pH) and the receptor in a complex with tumor necrosis factor beta. An accurate structure of the receptor and an understanding of its mechanism will provide a basis for rational drug design.