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Biomedical subjects

M Madden

Publications and source records attributed to M Madden.

At least 19 recordsLinked to original sources

Double-blind randomised trial comparing 5-fluorouracil plus leucovorin to placebo for metastatic colorectal carcinoma.

OBJECTIVE: Previous randomised trials of chemotherapy for metastatic colorectal cancer have not concealed the allocation of treatment from participants. Most of these unblinded trials showed improved survival with chemotherapy. This trial used a double-blind design to test the hypothesis that there is no difference between the effect of 5-fluorouracil plus leucovorin and the effect of placebo on the survival of subjects with metastatic colorectal cancer. PATIENTS AND METHODS: In one hospital, 147 subjects with metastatic colorectal cancer were studied from 1989 to 2001. 73 were allocated chemotherapy with 5-fluorouracil plus leucovorin. 74 were allocated placebo. The primary end point was survival after randomization. Secondary end points were performance score, quality of life, serum level of carcinoembryonic antigen (CEA) and toxicity of treatment. RESULTS: One hundred and forty-two patients were followed up until death. The median survival time in the chemotherapy group was 8.7 months (95% confidence interval (CI) 6.9-11.0 months) compared to 6.7 months in the placebo group (95% CI 5.3-7.9 months). Chemotherapy did not affect performance status but slowed the rise of CEA and caused appreciable toxicity. CONCLUSIONS: In this double-blind trial, chemotherapy with 5-fluorouracil plus leucovorin did not improve survival, did not impair performance, but caused appreciable toxicity.

Antineoplastic Combined Chemotherapy Protocols↗

Complete maternal deprivation affects social, but not spatial, learning in adult rats.

The effects of maternal deprivation on learning of social and spatial tasks were investigated in female adult rats. Pups were reared artificially and received "lickinglike" tactile stimulation (AR animals) or were reared with their mothers (MR animals). In adulthood, subjects were tested on paradigms of spatial learning and on paradigms involving learning of social cues. Results showed that maternal deprivation did not affect performance on spatial learning, but it did impair performance on the three social learning tasks. The AR animals made no distinction between a new and a previously presented juvenile conspecific. AR animals also responded less rapidly than MR animals at test for maternal behavior 2 weeks after a postpartum experience with pups. Finally, AR animals did not develop a preference for a food previously eaten by a familiar conspecific whereas MR animals did. This study indicates that animals reared without mother and siblings show no deficits in spatial tasks while showing consistent deficits in learning involving social interactions.

Animals↗

Hybridization screening of very short PCR products for paleoepidemiological studies of Chagas' disease.

Single strands of very short PCR products can be covalently immobilized to a slide and then easily detected by probe hybridization. In this work, the PCR product was a 70-nucleotide segment of ancient DNA, representing a portion of repeat mini-circle DNA from the kinetoplast of Trypanosoma cruzi, the infectious agent of Chagas' disease (American Trypanosomiasis). The target segment was initially established to be present in soft tissue samples taken from four "naturally" mummified Andean bodies using PCR followed by cloning and sequencing. Hybridization screening of the covalently immobilized PCR products positively identified products from 25 of 27 specimens of different tissues from these four mummies. The method appears to be ideal for the purpose of screening a large number of specimens when the target PCR product is very short.

Animals↗

Laparoscopic transcystic sphincter of Oddi manometry is not affected by carbon dioxide pneumoperitoneum.

Sphincter of Oddi (SO) dysfunction as a potential cause of chronic acalculous cholecystitis (CAC) has not been studied in cases for which intraoperative SO manometry was used during laparoscopic cholecystectomy. In this study, we evaluated the effects of carbon dioxide pneumoperitoneum on laparoscopic transcystic SO manometry. In 27 patients with CAC, transcystic SO manometry had been attempted during laparoscopic cholecystectomy. The mean age of the patients was 46 years (range, 22-71). Complete manometric data sets were obtained in 18 patients. The mean SO pressure, phasic SO pressure, and phasic frequency were 35.4 +/- 29.1 mm/Hg versus 30.8 +/- 23.8 mm/Hg, 104.8 +/- 63.0 mm/Hg versus 73.6 +/- 34.6 mm/Hg, and 2.1 +/- 1.8 contractions/min versus 2.8 +/- 3.4 contractions/min with and without pneumoperitoneum, respectively. All differences were nonsignificant (P > 0.05). Two complications (7.4%) were observed: pancreatitis and jaundice. SO manometry is not affected by CO2 pneumoperitoneum. It may be used to study SO motility in patients with CAC.

Adult↗

Experimental investigation into the incineration of wool scouring sludges in a novel rotating fluidised bed.

The main purpose of this research was to investigate the possibility of incineration of wool scouring sludges in a novel vertical axis rotating fluidized bed (RFB). A small-scale RFB was designed and constructed with an internal diameter (ID) of 200 mm and height of 50 mm to carry out the experiments. In phase one of the experiments, a cold test was conducted to investigate the fluidization performance of the RFB, which eventually led to the optimisation of the operating parameters, i.e., sand particle size, rotation speed and bed loading (bed thickness) which ensures complete fluidization and minimum particle elutriation. Sand particle size of 0.5 to 0.6 mm, rotation speed of 200 to 400 rpm and bed loading of 1 kg (equivalent to bed thickness of 27 mm) were found optimal. These information generated were useful for the second phase of the experiments, which was the hot test, in investigating the possibility of incinerating wool scouring sludges in the RFB. Nine wool sludges from different process routes generated from the wool scouring industries were analysed for their compositions. Most of these sludges were highly moist, had high volatile matter and high ash content with low level of fixed carbon. These characteristics made incineration difficult. Hence, the effect of varying the moisture content, rotation speed and sludge feed rate on the incineration of the three selected sludges were studied in the hot test. With 5% support methane, all sludges with a maximum moisture up to 70% as-received could be successfully burned in the RFB at rotating speeds of 200 and 300 rpm. The combustion was found to be intense with a high efficiency due to the good turbulence and mixing in the RFB. The combustion gases produced, i.e., CO, CO(2) and NO(x) were reasonably low due to the high combustion intensity and efficiency. To study the dynamics of the bed and freeboard region in the RFB, the velocity flow field was simulated using a computational fluid dynamics (CFD) model to generate information of the flow pattern. The special advantages of swirling flow would benefit the gas combustion in the RFB. The experimental results obtained have suggested that the incineration was successful and the ash particles elutriated were fine due to the good mixing and turbulence in the RFB. This also reflects the RFB as an effective incinerator.

Animals↗

The inflammatory response within Dukes' B colorectal cancers: implications for progression of micrometastases and patient survival.

OBJECTIVES: The aim of this study was to determine the relationship between the inflammatory response in primary colorectal carcinomas, patient outcome, and the fate of bone marrow micrometastases. METHODS: The populations studied were a) 155 consecutive patients with Dukes' B colorectal cancer and follow-up for a mean of 5 yr, from the Mercy Hospital, Cork, and b) 260 consecutive patients with rectal carcinoma Dukes' B and follow-up for >10 yr, from St. Mark's Hospital, London. The primary tumor was assessed for the Jass and "Crohn's-like" lymphoid reactions. In 36 consecutive patients, bone marrow aspirates were examined for micrometastases before and > or = 6 months postoperatively. RESULTS: The relationship between prognosis and the inflammatory reactivity in the tumors was similar in both populations. In the Mercy group there were two deaths among 40 patients who had coexistent Jass and Crohn's-like infiltrates. This contrasted with 25 deaths among 58 patients in whom both infiltrates were absent (p < 0.005). Results were intermediate in cases in which either type of inflammatory reaction was present alone. In the St. Mark' s patients similar prognostic differences were sustained for up to 10 yr. Bone marrow micrometastases were present in 12/36 patients preoperatively and in 14/36 postoperatively. Seven of 12 patients with preoperative micrometastases were negative postoperatively, indicating clearance of tumor cells. Nine of 24 who tested negative preoperatively had micrometastases postoperatively. The clearance and presence of postoperative micrometastases was related to the immunological responses in the primary tumor. CONCLUSIONS: These results demonstrate an association between the inflammatory reaction, prognosis, and clearance of micrometastases, indicating a systemic antitumor reaction that confers a survival advantage.

Aged↗

Characterization of the gene encoding an extracellular laccase of Myceliophthora thermophila and analysis of the recombinant enzyme expressed in Aspergillus oryzae.

A genomic DNA segment encoding an extracellular laccase was isolated from the thermophilic fungus Myceliophthora thermophila, and the nucleotide sequence of this gene was determined. The deduced amino acid sequence of M. thermophila laccase (MtL) shows homology to laccases from diverse fungal genera. A vector containing the M. thermophila laccase coding region, under transcriptional control of an Aspergillus oryzae alpha-amylase gene promoter and terminator, was constructed for heterologous expression in A. oryzae. The recombinant laccase expressed in A. oryzae was purified to electrophoretic homogeneity by anion-exchange chromatography. Amino-terminal sequence data suggests that MtL is synthesized as a preproenzyme. The molecular mass was estimated to be approximately 100 to 140 kDa by gel filtration on Sephacryl S-300 and to be 85 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Carbohydrate analysis revealed that MtL contains 40 to 60% glycosylation. The laccase shows an absorbance spectrum that is typical of blue copper oxidases, with maxima at 276 and 589 nm, and contains 3.9 copper atoms per subunit. With syringaldazine as a substrate, MtL has optimal activity at pH 6.5 and retains nearly 100% of its activity when incubated at 60 degrees C for 20 min. This is the first report of the cloning and heterologous expression of a thermostable laccase.

Aspergillus oryzae↗

Micrometastases: marker of metastatic potential or evidence of residual disease?

BACKGROUND: Micrometastases within bone marrow have been shown to indicate a poor prognosis in patients with epithelial tumours. However, the degree to which micrometastases represent true residual disease or cell shedding and metastatic potential, is unclear. AIM: To explore whether micrometastases represent residual disease, bone marrow taken from carefully staged patients before and after (> 6 months) "curative" resection of a primary gastrointestinal cancer was studied prospectively. PATIENTS/METHODS: Seventy two consecutive patients were studied; the only exclusions were patients with known overt metastatic disease at the time of surgery. Micrometastatic cells were quantified per 10(5) marrow cells by flow cytometry after staining for contaminant cytokeratin-18 positive cells. RESULTS: Micrometastases were detected preoperatively in 22% (16/72) of all patients, comprising 11 (23%) of 48 with colorectal cancer, five (33%) of 15 with gastric adenocarcinoma and none (0%) of nine with oesophageal squamous cancer. Although fewer metastatic cells were detected in postoperative bone marrow, and clearance of marrow deposits was evident in most patients, the persistence of micrometastases in five of 16 patients after resection, without evidence of tumour recurrence, indicates a subset with true residual disease. Detection of micrometastases postoperatively (persistent or newly developed) was significantly associated with development of overt metastases during the subsequent 12-18 months of follow up (nine of 19 patients) when compared with patients testing negative for micrometastases (eight of 53; p < 0.01). CONCLUSIONS: Preoperative detection of micrometastases may reflect either transient shedding of cells, metastatic potential or residual disease, but postoperative micrometastases indicate minimal residual disease. Identification of these patients is important because they may benefit from adjuvant therapy.

Biomarkers, Tumor↗

Epithelial cell-conditioned media inhibits degranulation of the RBL-2H3 rat mast cell line.

The effect of epithelial cells on mast cell responses was investigated by examination of degranulation of the rat mast cell line RBL-2H3 after overnight culture in media conditioned by the BEAS-2B human bronchial epithelial cell line [epithelial cell-conditioned media (ECM)]. These studies indicate that BEAS-2B cells secrete an inhibitor(s) of immunoglobulin E and A-23187-mediated degranulation of the RBL-2H3 cell line. The inhibitory activities of ECM are recovered after filtration through a 3-kDa cutoff filter. Pharmacological inhibition of cyclooxygenase in the BEAS-2B cells before preparation of ECM has no effect on subsequent inhibition of mast cell degranulation by ECM. However, cycloheximide treatment of the BEAS-2B cells before the conditioning process does preclude development of mast cell inhibitor activity in ECM, suggesting that this activity depends on protein synthesis. The effects of ECM on mast cell function are reversible, demonstrating that these effects do not result from overt cytotoxicity. Finally, media conditioned by primary cultures of human respiratory epithelial cells, but not fibroblasts, influence RBL-2H3 degranulation in a manner similar to ECM, suggesting that secretion of mast cell inhibitors may be somewhat unique to epithelial cells.

Animals↗

Effects of cyclo-oxygenase inhibition on ozone-induced respiratory inflammation and lung function changes.

Inhalation of O3 causes airways neutrophilic inflammation accompanied by other changes including increased levels of cyclo-oxygenase products of arachidonic acid in bronchoalveolar lavage fluid (BALF). Ozone O3 exposure also causes decreased forced vital capacity (FVC) and forced expiratory volume after 1 s (FEV(1)), associated with cough and substernal pain on inspiration, and small increases in specific airway resistance (SRAW). The spirometric decrements are substantially blunted by pretreatment with indomethacin. Since the O3-induced decrement in FVC is due to involuntary inhibition of inspiration, a role for stimulation of nociceptive respiratory tract afferents has been suggested and cyclo-oxygenase products have been hypothesized to mediate this stimulation. However, the relation (if any) between the O3-induced neutrophilic airways inflammation and decreased inspiratory capacity remains unclear. We studied the effects of pharmacologic inhibition of O3-induced spirometric changes on the inflammatory changes. Each of ten healthy men was exposed twice (5-week interval) to 0.4 ppm O3 for 2 h, including 1 h of intermittent exercise (ventilation 601*min(-1)). One-and-a-half hours prior to and midway during each exposure the subject ingested 800 mg and 200 mg, respectively, of the non-steroidal anti-inflammatory drug ibuprofen (IBU), or placebo [PLA (sucrose)], in randomized, double-blind fashion. Spirometry and body plethysmography were performed prior to drug administration, and before and after O3 exposure. Immediately following postexposure testing, fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was performed. Neither IBU nor PLA administration changed pre-exposure lung function. O3 exposure (with PLA) caused a significant 17 percent mean decrement in FEV(1) (P <0.01) and a 56 percent increase in mean SRAW. Following IBU pretreatment, O3 exposure induced a significantly lesser mean decrement in FEV(1) (7 percent) but still a 50 percent increase in mean SRAW. IBU pretreatment significantly decreased post-O3 BAL levels of prostaglandin E2 (PGE2) by 60.4 percent (P <0.05) and thromboxane B(2) (TxB(2)) by 25.5 percent (P <0.05). Of the proteins, only interleukin-6 was significantly reduced (45 percent, P <0.05) by IBU as compared to PLA pretreatment. As expected, O3 exposure produced neutrophilia in BALF. There was, however, no effect of IBU on this finding. None of the major cell types in the BALF differed significantly between pretreatments. We found no association between post-exposure changes of BALF components and pulmonary function decrements. We conclude that IBU causes significant inhibition of O3-induced increases in respiratory tract PGE(2) and TxB(2) levels concomitant with a blunting of the spirometric response. This is consistent with the hypothesis that the products of AA metabolism mediate inhibition of inspiration. However, IBU did not alter the modest SRAW response to O3.

Adult↗

Arteriovenous malformations of the scalp.

We report twenty-four patients with cirsoid aneurysms of the scalp. For nine patients (38%), the lesions were related to trauma. Each of the patients presented with a pulsatile scalp swelling with a bruit. No focal neurological deficits were noted in any of the patients. Scalp malformations in all patients were confirmed by selective internal and external carotid angiography, with no intracerebral component revealed in any of the patients. Twenty-one patients had the lesions surgically excised, with good results. The remaining three refused surgical intervention. Meticulous surgical technique, which includes removal of the pericranial component of the malformation, was paramount.

Adolescent↗

A good man's fault: alcohol and Irish people at home and abroad.

Long-standing stereotypes portray Irish people as prone to use alcohol to excess. This review traces the historical origins of those stereotypes, and examines evidence drawn from a range of secondary sources in Ireland and Britain about alcohol consumption, attributed hospital admissions and mortality. The available data indicate that the 'problem' of Irish drinking and Irish attitudes to alcohol are not as straightforward as traditionally supposed. Far from the stereotypical image of the Irish embodied in the ubiquitous drunk male labourer, rates of abstinence from alcohol are higher in Ireland than in Britain. Amongst migrants, the Irish are no more likely to consume alcohol than the indigenous population. However, those Irish people who do drink alcohol do so at generally higher levels than their British born counterparts. Analysis of combined years' data from the General Household Survey indicates first that people of Irish birth or parentage are no more likely than the British born to use alcohol at all. However, if they make use of alcohol at all, members of the Irish groups were more likely than the British born to consume alcohol at levels greater than 14 or 21 units per week. Both the review and the data presented suggest that a more complex understanding of the dynamics and nature of Irish drinking needs to be developed.

Alcohol Drinking↗

[In vitro exposure of a human bronchial epithelial cell line with nitrogen dioxide induces enhanced transcription and liberation of pro-inflammatory cytokines].

Studies of in vivo inhalation of nitrogen dioxide (NO2) have demonstrated a transient pulmonary inflammation. This study was done to determine the contribution of airway epithelial cells to the release of inflammatory mediators following NO2 exposure. Confluent cultures of the human bronchial epithelial cell line BEAS-2B on Transwell-Col filters were exposed for 1 h to air or NO2 up to 1.5 ppm with the apical fluids removed with 5% CO2 at 37 degrees C. The cells were hydrated with Hanks' Balanced Salt Solution (HBSS) in the basolateral compartment. Sequential reverse transcription and quantitative cDNA amplification (RT-PCR) was used to measure inflammatory mediator mRNA abundance in BEAS-2B cultures. When compared to air-exposed cells, NO2 induced increases in IL-6 (23.4-fold) and IL-8 (30.9-fold) mRNA abundance. The NO2-dependent increases in mRNA expression reached a maximum between 0 and 1 h post exposure and returned to baseline levels within 24 h. IL-6 and IL-8 proteins as measured by enzyme-linked immunosorbent assays (ELISA) were also elevated in supernatants recovered from NO2-exposed BEAS-2B cells. These studies suggest that exposure to NO2 induces the synthesis and release of inflammatory mediators from airway epithelial cells that may participate in the pathogenesis of airway disease.

Bronchi↗

Possible role of Helicobacter pylori serology in reducing endoscopy workload.

We validated a commercial enzyme-linked immunosorbent assay (ELISA), Helico-G, in diagnosing H. pylori in 129 patients (mean age 50 years, range 15-86). We analysed the results of endoscopy against serology to see whether there was a possibility of adopting the strategy of not endoscoping dyspeptic subjects under the age of 45. H. pylori infection was considered present if either histology and/or culture were positive. The ELISA had a sensitivity of 88%, specificity of 72%, positive predictive value of 85%, negative predictive value of 77% and accuracy of 82% in detecting H. pylori. In a subgroup of 52 subjects aged 45 or less (mean age 35 years, range 15-45), 17 out of 25 patients with positive endoscopic findings were H. pylori seropositive while 16 out of 27 patients had normal endoscopic findings. Eighteen out of the 52 patients (35%) were H. pylori seronegative and normal endoscopically except for five patients (10%) who had mild to moderate oesophagitis and two who had non-erosive gastritis (4%). All patients with duodenal ulcer disease (7) were seropositive giving predictive values of positive and negative serology for a diagnosis of duodenal ulcer disease as 28% and 100%, respectively. Therefore adopting a strategy of endoscoping subjects under the age of 45 only if they were H. pylori seropositive would have saved 35% of endoscopies in this age group but missed oesophagitis in 10%. Negative serology would tend to exclude duodenal ulcer disease while positive serology discriminates poorly for it. Serology may be a useful adjunct in screening to reduce endoscopy workload provided that patients with gastro-oesophageal reflux symptoms are excluded.

Aged↗

Neck sprains after road traffic accidents: a modern epidemic.

This study was carried out to determine the incidence of soft tissue injuries of the cervical spine after road traffic accidents and to assess whether the incidence had changed with time. The results show that there has been a progressive increase since 1982 in the number of patients seen in accident and emergency departments with a neck sprain after road traffic accidents. The results suggest that the increase is not necessarily due to the introduction of seat belts, but that the relentless increasing epidemic may be due to other factors.

Accidents, Traffic↗