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Biomedical subjects

J Lees

Publications and source records attributed to J Lees.

At least 19 recordsLinked to original sources
PubMed2001

Multiple subpial transection in Landau-Kleffner syndrome.

We have considered multiple subpial transection (MST) as a treatment option for Landau-Kleffner syndrome (LKS) for the past 6 years. The effect of this technique on language and cognitive ability, behaviour, seizures, and EEG abnormalities is analysed here. Five children (4 males, 1 female; aged 5.5 to 10 years) underwent MST with sufficiently detailed pre- and postoperative data for analysis. Behaviour and seizure frequency improved dramatically after surgery in all children. Improvement in language also occurred in all children, although none improved to an age-appropriate level. All five had electrical status epilepticus in sleep (ESES) before surgery, which was eliminated by the procedure. One child has had an extension of his MST due to the recurrence of ESES and accompanying clinical deterioration with good effect. An attempt is made to set the effect of MST against the natural history of the condition. MST is an important treatment modality in LKS, although the timing of this intervention and its effect on final language outcome remains to be defined.

Cerebral Cortex↗
PubMed1999

Human fibroblasts transduced with CD80 or CD86 efficiently trans-costimulate CD4+ and CD8+ T lymphocytes in HLA-restricted reactions: implications for immune augmentation cancer therapy and autoimmunity.

Augmenting immunogenicity by genetically modifying tumor cells to express costimulatory molecules has proven to be a promising therapeutic strategy in murine tumor models and is currently under investigation in human clinical trials for metastatic cancer. However, there are significant technical and logistic problems associated with implementing strategies requiring direct gene modification of primary tumor cells. In an effort to circumvent these problems, we are developing a strategy in which the costimulatory signal required for tumor-specific T lymphocyte activation is provided by a genetically modified human fibroblast (trans-costimulation). We have evaluated the efficiency of CD80- and CD86-mediated trans-costimulation in the activation of human CD8+ and CD4+ T lymphocytes in MHC class I- and class II-restricted lymphoproliferation reactions. Our studies demonstrate that the efficiency of CD80- or CD86-mediated trans-costimulation of purified human CD8+ and CD4+ T lymphocytes is comparable to cis-costimulation under defined conditions. Moreover, a dose-response relationship consistent with the predicted two-hit kinetics of the reaction was evident in trans-costimulation reactions in which the ratio of target cells expressing either signal 1 or signal 2 was varied incrementally from 1:10 to 10:1. Importantly, the level of cell-surface CD86 required for trans-costimulation is equivalent to that constitutively expressed by human peripheral blood monocytes. These results may have significant implications for the clinical implementation of this type of cancer immunotherapy and also raise questions about the possibility of trans-costimulating autoreactive T lymphocytes in vivo.

3T3 Cells↗
PubMed1999

p53 gene status and chemosensitivity of childhood acute lymphoblastic leukemia cells to adriamycin.

The role of p53 as a determinant of sensitivity of ten childhood acute lymphoblastic leukemia (ALL) cell lines to Adriamycin (ADR) was investigated. ADR-sensitive cell lines were found to have wild-type (wt) p53, whereas resistant cell lines contained point mutations in the gene. The basal level of wt p53 protein in sensitive cells was lower than that of mutant p53 in resistant cells, however, after ADR treatment a 6- to 20-fold dose-dependent increase in wt p53 was observed, whereas mutant p53 increased only twofold. The percentage of apoptotic cells in ADR-sensitive lines with wt p53 ranged from 43 to 93% following ADR treatment, whereas that in resistant lines with mutant p53 was only 8-13%. The ratio of constitutive levels of Bax/Bcl-2 was significantly higher in cells containing wt p53 than in cells with mutant p53. These results suggest that p53 gene status and the ability of p53 to induce apoptosis may be determinants of sensitivity to ADR in childhood ALL cells.

Antineoplastic Agents↗
PubMed1999

Incidence of weight loss in head and neck cancer patients on commencing radiotherapy treatment at a regional oncology centre.

The aim of this prospective study was to investigate the incidence of weight loss in head and neck cancer patients on commencing radiotherapy treatment at a regional oncology centre. Of the 100 patients included in the study, 33% presented with carcinoma of the larynx. Fifty-seven per cent of patients had lost weight on commencing treatment. A mean weight loss of 6.5 kg, equating to approximately 10% of body weight, was reported. A significant number of patients experienced a dry and/or sore mouth, had difficulty masticating and swallowing food, had altered taste perception, were missing meals or had symptoms of uncontrollable nausea and constipation. Since radiotherapy treatment may further limit oral intake, it is essential that dietetic intervention is addressed for all head and neck cancer patients and incorporated into the treatment plan on diagnosis before definitive management commences.

Adult↗
PubMed1999

Antiemetic activity of the NK1 receptor antagonist GR205171 in the treatment of established postoperative nausea and vomiting after major gynaecological surgery.

In this double-blind, randomized, parallel group study, we have investigated the antiemetic activity of the potent and selective NK1 receptor antagonist GR205171 25 mg i.v. compared with placebo in the treatment of established postoperative nausea and vomiting (PONV) in patients after major gynaecological surgery performed under general anaesthesia. The incidence of PONV in the study population was 65%. Thirty-six patients were treated with placebo or GR205171 (18 patients per group). GR205171 produced greater control of PONV than placebo over the 24-h assessment period. The stimuli for emesis after PONV are multifactorial and the efficacy of GR205171 in this study supports the broad spectrum potential for NK1 receptor antagonists in the management of postoperative emesis. GR205171 was well tolerated and no adverse events were reported that would preclude the further development of this agent.

Adolescent↗
PubMed1998

A multicenter, double-blind comparison of i.v. and oral administration of ondansetron plus dexamethasone for acute cisplatin-induced emesis. Ondansetron Acute Emesis Study Group.

A total of 530 patients were treated in this multicenter, double-blind, double-dummy, parallel group study to compare the anti-emetic efficacy and safety of a once daily ondansetron oral regimen with a once daily i.v. dosing regimen over a 24 h period, administered to patients prior to receiving cisplatin (50 mg/m2 or greater) chemotherapy. Patients were randomized to receive a single dose of ondansetron plus dexamethasone given either orally (ondansetron 24 mg and dexamethasone 12 mg, n=262) or i.v. (ondansetron 8 mg and dexamethasone 20 mg, n=268). Complete control of emesis (i.e. no emetic episodes, no rescue and no premature withdrawal) was achieved for 85% of patients (224 of 262) in the oral group and 83% (223 of 268) in the i.v. group. No nausea was reported in 70% of patients in the oral group and 68% in the i.v. group. There were no statistically significant differences between the two groups for any of the assessments of efficacy, which included time to first emetic episode, number of emetic episodes and the worst grade of nausea occurring over the 24 h study period. Once daily ondansetron oral and i.v., in combination with dexamethasone, was well tolerated in this study. In conclusion, once daily oral ondansetron 24 mg plus dexamethasone is equally effective in the control of emesis and nausea induced by highly emetogenic chemotherapy as once daily ondansetron 8 mg i.v. plus dexamethasone.

Administration, Oral↗
PubMed1997

Total parenteral nutrition for patients receiving antineoplastic therapy at a regional oncology unit: a two-year study.

The aim of this prospective study was to establish the exact role parenteral nutrition has in the provision of nutritional support to patients receiving antineoplastic therapy. The diagnosis, reasons for implementation, method of delivery and duration of nutritional support were determined. The outcome of nutritional support was established by the percentage change in weight and alteration in body mass index during the period of nutritional support. The results indicate that parenteral nutrition can successfully maintain the body weight of patients who are unable to receive enteral nutrition whilst receiving antineoplastic treatment. However, it is recommended that the provision of parenteral nutrition is evaluated at regular intervals and alternative feeding methods via the enteral feeding route are accessed as soon as possible.

Adult↗
PubMed1997

Nasogastric and percutaneous endoscopic gastrostomy feeding in head and neck cancer patients receiving radiotherapy treatment at a regional oncology unit: a two year study.

The aim of this prospective two year study was to compare the outcome of two methods of nutritional support, namely nasogastric [NG] and percutaneous endoscopic gastrostomy [PEG] feeding implemented for head and neck cancer patients unable to maintain their nutritional status whilst receiving radiotherapy treatment at a regional oncology unit. The nutritional requirements of the 100 patients included in the study were calculated and an enteral feeding regime implemented to ensure the nutritional requirements of each individual patient were met. Any changes in the weight and body mass index [BMI] of each patient during the study period were documented. The method of delivery, composition of feed and duration of nutritional support of each feeding method were determined. The feeding methods were found to be equally effective at maintaining body weight. Patients with NG tubes in situ were more frequently prescribed a standard 1 kcal/ml feed administered via an enteral feeding pump, whereas patients with PEG tubes in situ were more frequently prescribed a high energy 1.5 Kcal/ ml feed administered by the bolus method. A number of advantages are associated with PEG feeding including greater mobility, cosmesis and quality of life. Evidence indicates the outcome of radiotherapy treatment is not as favourable if interrupted, therefore, it is essential PEG tubes are sited prior to commencing treatment, illustrating the necessity for dietetic intervention for every patient to be addressed and incorporated into the treatment plan on diagnosis of head and neck cancer before definitive management commences.

Adult↗
PubMed1997

Pathological and genetic correlates of apoptosis in the progression of colorectal neoplasia.

PURPOSE: Apoptosis is commonly observed in a variety of human tumors, and some of the genetic events which control this process have been identified in vitro. The aim of this study was to determine the frequency of apoptosis in colorectal neoplasms and to examine its relationship to a number of pathological parameters, to the presence of mutations in the p53 tumor suppressor gene, and to overexpression of the bcl-2 oncoprotein. METHODS: A total of 109 colorectal neoplasms (26 adenomas 83 carcinomas) were examined. An in situ end-labelling assay was used to detect apoptosis in paraffin-embedded tumor sections, and scores were determined by light microscopy. The p53 and bcl-2 status were determined by immunohistochemistry. RESULTS: Apoptotic frequency increased with tumor progression. Normal mucosa contained significantly fewer apoptotic cells than adenomas or carcinomas. Similarly adenomas showed less apoptosis than carcinomas, and the frequency of apoptosis increased with Dukes' stage. Overall, changes in apoptotic frequency were inversely related to the level of bcl-2 expression, but were not related to the p53 status of the tumors. CONCLUSIONS: The frequency of apoptosis in colorectal neoplasia appears to increase in the course of tumor progression in association with a decline in bcl-2 expression, but is not influenced by p53 gene mutations.

Adenocarcinoma↗
PubMed1997

Detection of apoptosis in colorectal carcinoma by light microscopy and in situ end labelling.

OBJECTIVE: An in situ end labelling reaction (ISEL) was recently described for the detection of apoptotic cells in histologic sections. We compared the efficiency and reproducibility of this assay with those of routine light microscopy using hematoxylin and eosin (H&E) in the quantitation of apoptotic cells in colorectal cancer. STUDY DESIGN: Paraffin-embedded archival tissues from 15 colorectal carcinomas were used in the study. ISEL was performed using terminal deoxynucleotidyl transferase, biotinylated deoxyuridine triphosphate and streptavidin-alkaline phosphatase. RESULTS: Apoptotic indices determined by the two assays showed a strong positive correlation (Pearson coefficient 0.82), with the ISEL assay detecting twice the number of apoptotic cells as that seen with H&E staining. Both assays showed significant interobserver and intraobserver variation, while the ISEL assay also showed considerable interassay variability and was less cost-effective than H&E in the detection of apoptotic cells. CONCLUSION: In the light microscopic quantitation of apoptosis in colorectal tumors, the ISEL assay offered no greater reproducibility, and was less cost-effective, than routine H&E staining.

Apoptosis↗
PubMed1996

Retrieval of human antibodies from phage-display libraries using enzymatic cleavage.

A combinatorial human IgG1, kappa gene library of 2 x 10(7) clones was constructed from a pericolic lymph node using the phagemid vector pComb3H. Fabs with binding activity against tetanus toxoid (TT) and keyhole limpet hemocyanin (KLH) were isolated from this library, and one such TT binding Fab was used to further evaluate a new phagemid vector for the display of recombinant antibody fragments (MCO1). This vector was designed to incorporate a cleavage site for the enzyme Genenase I, a myc peptide tag, and an amber codon between the heavy chain cloning site and the truncated M13 phage gene III. When MCO1 phage displaying an anti-TT Fab were bound to TT on a solid substrate, elution with Genenase I at concentrations of 5-10 micrograms/ml proved as effective as acid elution in releasing bound phage. Furthermore, enzymatic elution with Genenase I was comparable to acid elution in the enrichment of a TT binding Fab from the pericolic library subcloned into the vector MCO1. Importantly, the use of enzymatic or acid elutions resulted in the retrieval of different anti-TT Fabs from this same library. We conclude that panning of phage-displayed combinatorial antibody libraries can be successfully performed using enzymatic elution, and that this offers a useful alternative to currently available phage elution techniques.

Aged↗
PubMed1996

Biological properties of renal oncocytoma cells in culture.

This paper sought to determine biological properties of oncocytoma cells, both in vivo and in vitro, which may serve as useful diagnostic indicators. Cell lines were grown in short-term culture from two renal oncocytomas following enzymatic dissociation, characterised by immunohistochemistry and electron microscopy, and further studied for abnormal p53 or retinoblastoma genes. Cells in culture were shown to maintain the morphological attributes of the primary lesion, including the overproduction of mitochondria. Despite the absence of vimentin staining in the primary tumour, cells in culture were shown to express this intermediate filament. Immunohistochemistry for P53 protein demonstrated an overexpression in one of the tumours, suggesting that mutation had occurred. Restriction fragment length polymorphisms of the retinoblastoma and the p53 genes were not demonstrated. Mutation of the p53 gene does occur in oncocytomas. The maintenance of the phenotype of oncocytoma cells in culture suggests that in vitro studies may be useful in the identification of unique properties of the tumour.

Adenoma, Oxyphilic↗
PubMed1993

Interleukin-6 and tumor necrosis factor in cerebrospinal fluid: changes during pyrogen fever.

Several peptides (cytokines), viz., interleukin-1 (IL-1), interferon-alpha (IFN-alpha), interleukin-6 (IL-6), tumor necrosis factor (TNF), are formed in response to conditions causing tissue inflammation or damage and are implicated in reactive changes of the host, including fever, while IL-1 has been considered an important mediator of fever, the other cytokines, specifically IL-6 and TNF, have recently acquired prominence. The present study extends earlier research on IL-1 and addresses the question of the role of IL-6 and TNF in the genesis of fever. Experiments were conducted in the conscious cat, and IL-6 and TNF were assayed concomitantly in cerebrospinal fluid (CSF) from the third ventricle using specific bioassays. In the absence of fever, IL-6 was usually below the threshold of the assay (4-32 pg/ml), while TNF appeared measurable (424 +/- 57 pg/ml) in most experiments. A single intravenous injection of endotoxin (bolus) or continuous infusion of IL-1 at doses eliciting a sustained fever increased CSF levels of IL-6, but had no effect on concentrations of TNF. Intracerebroventricular injection of a pyrogenic dose of endotoxin led to an elevation of TNF and IL-6 and, in either case, the effect was manifest during the latent period before the fever. In addition, by the same route, IL-1 caused a rise in IL-6. We conclude that brain is intrinsically capable of producing both IL-6 and TNF depending on the site of challenge. However, since IL-6 CSF levels are elevated regardless of the site of pyrogen injection, IL-6 lends itself better to a role in the pathogenesis of fever.

Animals↗
PubMed1993

Eicosanoids in third ventricular cerebrospinal fluid of fetal and newborn sheep.

A method to serially sample cerebrospinal fluid (CSF) from the third ventricle of chronically catheterized fetal and newborn sheep was developed. Either sampling cannulas of preset lengths ("fixed-probe" technique) or a single cannula that could be positioned at the desired depth ("roving-probe" technique) was used. The roving probe proved superior because free CSF flow was obtained in seven of ten animals after surgery compared with two of nine animals implanted with a fixed probe. CSF (5 animals) and plasma (7 animals) was collected serially from 2 wk before to 2 wk after birth, including the time around labor. Prostaglandin E2 (PGE2) levels (means +/- SE) were significantly higher in CSF (366 +/- 120 pg/ml; n = 5) and plasma (520 +/- 69 pg/ml; n = 7) before the day of delivery than in the same animals after birth. During labor, CSF and plasma PGE2 levels increased significantly to 1,428 +/- 643 pg/ml in CSF and to 2,015 +/- 414 pg/ml in plasma. However, by 1 h after birth, PGE2 had fallen to 366 +/- 165 pg/ml in CSF and to 338 +/- 106 pg/ml in plasma; levels similar to those observed in the fetus before labor. PGE2 continued to decrease precipitously and, at 24 h of age, levels were significantly less than those observed in the fetus. PGE2 levels were near the limit of detection of the assay in CSF (< 5 pg/ml) and were 49 +/- 10 pg/ml in plasma. In contrast, CSF thromboxane B2 (n = 2) and total peptidoleukotriene content (n = 4) showed little change during labor or after birth.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Interleukin-1 receptor antagonist: effectiveness against interleukin-1 fever.

Conscious cats were used to examine the effectiveness of the interleukin-1 receptor antagonist against the fever induced by interleukin-1 and endotoxin. Although inactive by itself, the antagonist (three 1-micrograms bolus injections at 10-min intervals), injected into the third ventricle, attenuated the febrile response to a subsequent intracerebroventricular bolus of interleukin-1. The rise in prostaglandin E2 levels in cerebrospinal fluid, which is a characteristic feature of fever, was curtailed as well. The interleukin-1 antagonist had little or no inhibitory effect on the response to an intracerebroventricular bolus of endotoxin, even though a higher dose was employed (2-micrograms bolus injections given three times at 10-min intervals and six times at 30-min intervals, respectively, before and after endotoxin administration). At either dosage, the intracerebroventricular antagonist was completely ineffective against an intravenous bolus injection of interleukin-1 or endotoxin and both fever and prostaglandin E2 elevation developed unabated. We conclude that brain receptors mediating the pyrogenic action of centrally injected interleukin-1 are susceptible to the antagonist. The same receptors, however, are seemingly not activated by systemic pyrogens. Our findings are consistent with the concept of circulating interleukin-1 acting outside the blood-brain barrier in the normal sequence of fever.

Animals↗
PubMed1991

Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells.

Fever induced by endogenous as well as exogenous pyrogens is often prevented by cyclooxygenase inhibitors; endogenous pyrogens stimulate prostaglandin E2 (PGE2) in or near the thermoregulatory centers of the brain. The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), are two pyrogens which stimulate brain PGE2 formation during fever and also increase PGE2 synthesis in human mononuclear cells in vitro. In the present study, we examined whether interleukin-6 (IL-6) stimulates PGE2 formation in a manner similar to IL-1 and TNF. Both glycosylated and non-glycosylated forms of recombinant human IL-6 were tested. Following intravenous injection into rabbits, the glycosylated IL-6 was more pyrogenic than the non-glycosylated form and there was no evidence of synergy in the production of fever when IL-6 and IL-1 were given simultaneously. IL-6 fever was blocked by prior administration of the cyclooxygenase inhibitor ibuprofen. IL-6 was also pyrogenic in the cat by either the systemic or the intraventricular route. However, in both species, IL-6 was less effective than IL-1 beta. When given intraventricularly to cats, IL-6 produced an increase in PGE2 levels of the cerebrospinal fluid in parallel with the rise in body temperature. In the latter respect, IL-6 imitated IL-1 beta; however, IL-6 from 0.15-15 micrograms/ml did not increase mononuclear cell PGE2 production in vitro whereas IL-1 beta induced 20-30-fold increases in PGE2 at 100 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Leukotrienes in brain: natural occurrence and induced changes.

Peptidoleukotrienes (SP-LTs) (both total product and individual LTC4 and LTE4 and LTB4 were measured by radioimmunoassay in cerebrospinal fluid (CSF) collected from the third ventricle of conscious cats. Total SP-LT was expressed as LTE4 after treating samples with crude gamma-glutamyltranspeptidase. Prostaglandin (PG) E2 and thromboxane (TX) B2, the stable metabolite of TXA2, were also assayed in part of the experiments. Under basal conditions, SP-LT and LTC4 were consistently measurable (respectively, 327 +/- 14 and 244 +/- 41 pg/ml), while native LTE4 was below the threshold of the assay (60-280 pg/ml) in most cases. LTB4 was barely detectable (30 +/- 2 pg/ml) or not detectable at all. PGE2 was normally less abundant than TXB2 (31 +/- 4 vs 281 +/- 47 pg/ml). Intracerebroventricular (i.c.v.) administration of arachidonic acid (40 microgram) caused a 4-fold increase in SP-LT levels which was relatively small and transient compared to PGE2 (76-fold) and TXB2 (23-fold), while there was no change in either native LTE4 or LTB4. A similar response was obtained with platelet-activating factor (PAF, 1 microgram i.c.v.), though SP-LT elevation (4-fold) was more persistent. A further rise in SP-LT (9-fold) was noted when PAF administration was preceded by indomethacin (500 microgram i.c.v.), whereas PAF effect was reversed by pretreatment with either the PAF antagonist, BN52021 (1 microgram i.c.v.), or the 5-lipoxygenase inhibitors, U-60,257 (75 micrograms i.c.v.) and L-651,392 (10 mg/kg p.o.). PAF was also effective in causing a 3-fold rise in LTC4. Unlike PAF, pyrogens (endotoxin i.c.v. or i.v.; interleukin-1 i.v.) at doses above threshold for fever had no effect on LT levels in CSF, both in the absence and presence of indomethacin pretreatment. We conclude that SP-LTs are a normal constituent of CSF, LTC4, being the major species. The response to PAF accords with a pathogenetic role of the compounds in inflammatory processes and the reactive changes to injury. No evidence was obtained for the involvement of SP-LTs in the central mechanism of fever.

Administration, Oral↗