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Biomedical subjects

D Walsh

Publications and source records attributed to D Walsh.

At least 127 records · Page 7Linked to original sources
PubMed1998

The opioid-sparing effects of intravenous ketorolac as an adjuvant analgesic in cancer pain: application in bone metastases and the opioid bowel syndrome.

Side effects of morphine are common when given in titrated doses to control severe pain in advanced cancer. We report a case series of acutely ill cancer patients suffering from pain, complications of advanced disease, and opioid side effects. They were treated with intravenous (i.v.) ketorolac along with i.v. morphine using repeated dosing. Excellent pain relief with improvement in the opioid bowel syndrome was achieved. We found it possible to switch from IV ketorolac to oral ketorolac along with oral morphine for long-term pain control. Ketorolac can be well tolerated in high-dose, long-term use even in this frail patient population. An algorithm is presented for the suggested use of ketorolac as a morphine sparing agent. Potential methods for studying ketorolac further in this role are discussed.

Adult↗
PubMed1998

Examination of new and reported data of the DRD3/MscI polymorphism: no support for the proposed association with schizophrenia.

The dopamine D3 (DRD3) receptor gene has been implicated in the aetiology of schizophrenia as a candidate gene since it combines both the dopamine receptor and limbic hypotheses of the disease. Previous association studies of a DRD3/MscI polymorphism suggested an increased frequency of homozygosity at the DRD3 receptor gene in schizophrenia. Homozygosity appeared to be particularly frequent in male patients, individuals with family history of the disease and in good responders to neuroleptic treatment. Many studies have since examined this polymorphism and have altered or extended the original homozygosity hypothesis. In this study, we have investigated the distribution of the DRD3/MscI polymorphism in 198 Irish schizophrenic patients and 235 ethnically matched controls. Patients and controls showed-similar allele and genotype frequencies. Furthermore, linkage analysis using two microsatellite markers flanking the DRD3 gene was performed on 265 Irish schizophrenic families, with substantially negative results. Our findings, in combination with a review of previous studies do not support a role for the DRD3/MscI polymorphism in the pathogenesis of schizophrenia.

Alleles↗
PubMed1998

Hospital use by an ageing cohort: an investigation into the association between biological, behavioural and social risk markers and subsequent hospital utilization.

BACKGROUND: The aims of the study were to describe the pattern of hospital utilization (acute and mental health sectors) of the Paisley-Renfrew MIDSPAN cohort and assess the influence of biological, behavioural and social 'risk factors' (established at the time of screening) on subsequent hospital admissions. METHOD: A cohort analysis was carried out in Paisley and Renfrew, two post-industrial towns in West Central Scotland. This used a linked data set covering a 23 year follow-up period to combine original 'risk'-related data with subsequent routine hospital admissions data. The subjects were 8349 women and 7057 men, aged 45-64 in the early to mid-1970s, and representing approximately 80 per cent of the eligible population. The main outcome measures were patterns of hospital utilization (acute and mental health sectors), 'any acute hospital admission', 'a serious acute hospital admission' and 'death' (relative risks of each outcome were calculated for all risk factors). RESULTS: The following patterns of hospital utilization were found. Only 5 per cent experienced a mental health admission but mean stay was long (265 bed days per cohort member admitted). In contrast, 79 per cent experienced at least one acute hospital stay. The age-specific proportions of cohort members requiring admission increased over time but the growth in acute episodes was even higher (suggesting increasing rates of multiple admission). For non-survivors, 42 per cent of all acute episodes (55 per cent of bed days) took place during the 12 months before death. Analysis of risk factors (using Cox's proportional hazards model) of 'any admission' and 'a serious admission' showed forced expiratory volume (FEV1), age, sex, smoking status, blood pressure, blood sugar, body mass index, cholesterol and deprivation category to be important predictors. CONCLUSIONS: Despite the desirability of alternative settings of care for the chronically ill and dying, a high proportion of hospital bed days were required near the time of death. The absolute size of the demand for hospital services within the cohort was strikingly large and increasing over time. Strategies to address the tide of rising admissions will have to confront the increasing proportion of individuals requiring admission as well as the growth in multiple admissions. Those who were at higher risk of admission were the older members of the cohort (especially men), those with low FEV1, smokers, those who were underweight or obese, the small number with abnormal levels of blood sugar, those with high blood pressure and those who lived in the most deprived areas. Thus, programmes which affect these determinants of ill health may be useful in reducing age-specific admission rates.

Aged↗
PubMed1998

Effect of Helicobacter pylori eradication on the natural history of duodenal ulcer disease.

BACKGROUND: Duodenal ulcer disease is strongly associated with Helicobacter pylori infection of the gastric mucosa. Eradication of H pylori from the gastric mucosa in adults is associated with long term healing of ulcers. AIMS: To follow a cohort of children with duodenal ulcer disease for a minimum of two years after the eradication of H pylori. PATIENTS AND METHODS: Over a three year period, all children diagnosed with duodenal ulcer disease had their symptoms documented and their H pylori status evaluated. The histories of these children were carefully screened to determine previous symptoms and to document previous treatment regimens. RESULTS: Sixteen children were diagnosed with ulcers and 15 were available for treatment and long term follow up. The median age at which symptoms first occurred was 10.5 years (range, 6-14) and the median duration of symptoms was 24 months (range, 2-60). Ten of the children had been treated with H2 receptor antagonists for a median of 3.5 months (range, 1-60). Duodenal ulcers healed in all children after eradication of H pylori and all children have remained asymptomatic for a median of 37 months (range, 26-62). No child has required subsequent admission to hospital. CONCLUSION: Eradication of H pylori is very effective in the long term healing of duodenal ulcer disease. H pylori eradication should be the standard treatment for all infected children who present with duodenal ulcer disease.

Adolescent↗
PubMed1998

Benzonatate for opioid-resistant cough in advanced cancer.

Chronic cough is a distressing symptom experienced by approximately 37% of patients with advanced cancer. Palliation of chronic nonproductive cough should always first address the underlying cause but in some patients chronic, nonproductive cough persists and antitussive agents are required. Opioids are the gold standard cough suppressants, of which codeine is the most widely used; patients with an opioid-resistant cough often prove to be a therapeutic challenge. We report three patients with an opioid-resistant cough who achieved symptomatic relief with the peripherally acting nonopioid drug benzonatate.

Adenocarcinoma↗
PubMed1998

Colonoscopy under general anesthesia in children.

OBJECTIVE: In children, colonoscopy is usually performed using deep sedation that may be associated with significant risks. The purpose of this study was to evaluate the safety of colonoscopy performed under general anesthesia. METHODS: All patients undergoing colonoscopy during a 3-year period were reviewed for the study. One hundred and thirty-six procedures were performed. Colonoscopies were performed by a pediatric gastroenterologist. Anesthesia was administered by a pediatric anesthetist in a gastroenterology procedure room, adjacent to the operating recovery area. RESULTS: Three patients had significant abdominal pain and tenderness after the procedure, 1 of whom suffered a perforation of the sigmoid colon. This patient had severe ulcerative colitis. The gastrointestinal complication rate was no higher than reported in adult patients undergoing colonoscopy under sedation. No significant complications relating to the administration of anesthesia were encountered. CONCLUSION: We conclude that colonoscopy performed under general anesthesia in children is a very safe procedure. It is superior to the use of sedation because the child is not placed at risk of respiratory compromise. Furthermore, the procedure is less worrisome for children when performed under a general anesthetic.

Abdominal Pain↗
PubMed1998

Pharmacologic management of anorexia/cachexia.

Anorexia is a symptom seen in the majority of patients with cancer or the acquired immunodeficiency syndrome (AIDS) who experience involuntary weight loss. It is frequently not seen as a symptom requiring management in the same proactive manner as pain, nausea, or constipation. Progressive inanition or wasting is a fundamental component of the complex phenomenon known as the anorexia/cachexia syndrome (ACS) of malignancy or AIDS. Weight loss can be seen in the full spectrum of patient care settings: as a presenting complaint, defining condition, treatment-related toxicity, or as a hallmark of impending death. Primary pharmacologic management of ACS includes use of orexigenic agents (appetite stimulants), anticatabolic agents (antimetabolic and anticytokine), and anabolic agents (primarily hormonal). In addition to these specific categories of pharmacologic intervention, broad aspects of symptom management need to be addressed and are complementary. The available literature evaluating pharmacologic management of ACS in both malignancy and AIDS is reviewed.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Progressive cyclic nucleotide-induced conformational changes in the cGMP-dependent protein kinase studied by small angle X-ray scattering in solution.

Small angle scattering data from bovine lung type Ialpha cGMP-dependent protein kinase (PKG) in the absence of cGMP show the protein to have a highly asymmetric structure with a radius of gyration (Rg) of 45 A and a maximum linear dimension (dmax) of 165 A. The addition of cGMP induces a marked conformational change in PKG. The Rg and dmax increase 25-30%, and the protein's mass moves further away from the center of mass; this results in an even more asymmetric structure. Fourier transform infrared spectroscopy data suggest that the conformational change induced by cGMP binding is primarily due to a topographical movement of the structural domains of PKG rather than to secondary structural changes within one or more of the individual domains. Each monomer of the dimeric PKG contains one high and one low affinity cGMP-binding site. A prominent increase in the asymmetry of PKG occurs with binding to high affinity cGMP-binding sites alone, but the full domain movements require the binding to both sets of sites. These conformational changes occurring in PKG with the progressive binding of cGMP to both sets of cGMP-binding sites correlate with past data, which have indicated that cGMP binding to both sets of sites is required for the full activation of the enzyme. These results provide the first quantitative measurement of the overall PKG structure, as well as an assessment of the structural events that accompany the activation of a protein kinase upon binding a small molecular weight ligand.

Animals↗
PubMed1997

Air pollution exposure-DNA adduct dosimetry in humans and rodents: evidence for non-linearity at high doses.

The impact of air pollution exposure on the level of total DNA adducts in human white blood cells (WBCs) was evaluated in two populations in the Czech Republic and compared to the exposure-DNA adduct relationship in other populations in the US and China in human lung cells and rodent lung tissue. The human populations examined were exposed to respirable particles (< 2.5 microm) (PM2.5) in urban, rural, and occupational settings where the particles originated from coal and petroleum fuel combustion, coke production, and other coal-tar aerosols (e.g., used in aluminum production). These particles contain carcinogenic polycyclic aromatic hydrocarbons (PAHs) that are known to form DNA adducts through covalent binding. Personal exposure to PM2.5 and PAHs were measured prior to collection of blood samples for DNA adduct analysis by 32P-postlabeling. Coke oven workers (n = 76), in 10 job categories on the top and side of a coke oven in Ostrava, CZ, were studied and compared to a different population exposed to environmental levels of PAHs from air pollution in Teplice, CZ. Personal exposures to airborne particles ranged from < 1 to more than 15,000 microg/m3 and carcinogenic PAHs exposure ranged from < 5 to > 200,000 ng/m3. At low to moderate environmental exposures to carcinogenic PAHs, DNA adduct levels in the WBCs were significantly correlated with exposure. However, at the higher occupational levels found on the coke oven, the exposure-DNA adduct relationship became non-linear. Under these high exposure conditions, the relative DNA adduct level per unit of exposure (DNA-binding potency) was significantly lower than measured at environmental exposures. This finding is consistent with observations in lung cells from bronchoalveolar lavage of humans exposed to a wide range of PAH. This same high exposure-dose non-linearity was also observed in lung DNA from rats exposed by inhalation to a coal-tar pitch aerosol. DNA adduct levels in all these cases show evidence of a form of non-linearity at high doses that has been described by Lutz (W.K. Lutz, Dose-response relationship and low dose extrapolation in chemical carcinogenesis, Carcinogenesis, 11 (1990) 1243-1247) as a superlinear dose response. This superlinear response may be due to saturation of metabolic activation enzymes, induction of either DNA repair processes or detoxification enzymes, or other mechanisms. Regardless of the mechanism, this decrease in the DNA-binding potency at moderate to high doses of PAH has important implications for dose-response extrapolation in risk assessment.

Air Pollutants↗
PubMed1997

No association or linkage between the 5-HT2a/T102C polymorphism and schizophrenia in Irish families.

Recent findings of an association between schizophrenia and a T102C polymorphism at the 5-HT2a receptor gene (particularly with genotype 1-2 and 2-2 and allele 2) prompted us to investigate this marker in familial Irish schizophrenic patients, their relatives, and ethnically matched unrelated controls; 247 probands and 249 controls were included in this study. In contrast to some studies, we found no evidence of significant differences either in the frequency of the genotypes 1-2 and 2-2 or allele 2 between the schizophrenic patients and the controls. A transmission disequilibrium test, run on the full set of 265 families yielded no evidence to support linkage disequilibrium. Linkage analysis with both parametric and non-parametric methods yielded strongly negative results. Our findings are consistent with other recent association studies which argue against the involvement of the 5-HT2a/T102C polymorphism in predisposition to schizophrenia. The positive findings reported to date might have occurred by chance or the apparent conflict may be due to genetic heterogeneity between samples.

Disease Susceptibility↗
PubMed1997

The recovery of a B2 insertion in the lacI gene of a rat cell line containing a lambda/LIZ shuttle vector.

The bacterial lacI gene is in use as a reporter gene for mutation in transgenic mice, rats and in cell lines. During a mutagenesis study in which we used such a rat cell line, we recovered a mutant which features an insertion of a rat B2 repeated sequence element. This sequence element was inserted between positions 77 and 78 in the lacI gene. When the inserted sequence was compared to the published rat B2 sequences, two short deletions, possibly mediated by short repeat sequences, were revealed. This is the first demonstration of the recovery of a repeated sequence element into the lacI gene used in transgenic animals and cell lines, and confirms previous findings that such sequences indeed move around the genome.

Animals↗
PubMed1997

Chromosomal assignment of 311 sequences transcribed in human adult testis.

A total of 311 expressed sequence tags (ESTs) derived from human adult testis have been assigned to human chromosomes by Southern analysis of a monochromosome somatic cell hybrid panel. Over 70% of the ESTs show conservation to hamster and mouse DNA, and the overall distribution of transcripts correlates well with physical chromosome size and to a greater extent with male meiotic chromosome length. The notable exception is the X chromosome, for which the number of testis-derived ESTs is greatly underrepresented. This finding may reflect inactivation of the X chromosome during the meiotic phase of spermatogenesis and a consequent selection against large numbers of X-linked germ cell transcripts. Further analysis of the distribution of testis ESTs showed that the EST density remains significantly correlated with the recombination density of each autosome. Analysis of a comparable number (320) of brain EST autosome assignments showed no similar correlation. These data suggest a specific association between transcription in testis tissue and male meiotic recombination.

Adult↗
PubMed1997

Heat shock and the role of the HSPs during neural plate induction in early mammalian CNS and brain development.

We have investigated the early development expressional of the heat shock protein genes (hsps) and HSP synthesis and their role during neuroectoderm induction, differentiation and early CNS formation. The expression and kinetics of 90, 73/71, 47 and 27 HSPs on neuroectoderm differentiation was compared under normal and stressed conditions. The role of HSPs on neuroctoderm cell fate including thermotolerance and apoptosis using a whole in vitro embryo culture system was studied. Hsp expression appears closely linked in early mammalian development to critical differentiation and proliferation stages in early brain and heart formation. The hsps are developmentally activated around blastula stage and HSPs are constitutively expressed at high levels during neural tube closure and are heat shock responsive. Using both Northern analysis, confocal microscopy and whole mount in situ hybridisation we have identified the mRNA hsp transcripts and HSPs during organogenesis. HSPs were detected during neuroectoderm cell induction and differentiation with the hsp mRNA being tightly regulated during the cell cycle of neuroectoderm especially at early fore-, mid-, hindbrain and heart formation. The 'chaperone' functions of the HSPs are well known, recently during gastrulation the HSP47 and 27 have been shown to specifically bind and fold to nascent collagen and actin molecules respectively. This role is essential for the formation of the basement membrane, extra cellular matrix and neural crest migration during neural plate development. HSP function was observed by using anti-sense strategy, short '5 anti-sense cDNA' hsp oligonucleotides inhibited hsp expression during gastrulation in the whole embryo cultures. The developmental activation of the heat shock element (HSE) is essential to our understanding of the HSPs role in neuronal cell fate. Using specific polyclonal antibodies to HSF1 and 2 (Dr Nakai, Kyoto University) the expression of heat shock factors (HSFs) during neuroectoderm differentiation was examined. Using Western analysis, confocal microscopy and flow cytometry HSF1 and 2 were identified and studied under both normal and heat shocked conditions. During gastrulation higher levels of HSF1 and 2 were identified in the neuroectoderm layer especially in regions of the fore-, mid- and hindbrain. The heat shock response and activation of the HSPs 90, 70, 47 and 27 families have been correlated with HSF1 and 2. The HSF1 appears to be present in all early embryonic cells but appears not to bind to the HSE until early head fold stage at gastrulation when the presence of HSF2 is observed. During neuroectoderm differentiation the activation of HSF1 and 2 appears to correlate with high constitutive expression of many of the hsps specifically hsp90, 73, 71, 47 and 27 being tightly regulated by the cell cycle at neurulation.

Animals↗
PubMed1997

A prospective, within-patient, crossover study of continuous intravenous and subcutaneous morphine for chronic cancer pain.

The dose, efficacy, and side effects of continuous intravenous infusion (CIVI) of morphine were compared with continuous subcutaneous infusion (CSCI) of morphine in patients with chronic cancer pain. Eligible patients were referred to the Palliative Care Program and were receiving a stable dose of CIVI of morphine. The design was a within-patient, one-way crossover; in which each patient provided data before and after a switch from CIVI to CSCI of morphine. "Rescue" doses were 50% of the hourly dose given every 2 hours as needed. Morphine was infused intravenously (i.v.) and subcutaneously (s.c.) via a McGaw/AccuPro Volumetric Infusion Pump. After baseline data, including side effects and pain assessment, were obtained, patients were evaluated twice daily for toxicity and analgesic efficacy. Those who had a stable CIVI dose for 48 consecutive hr were crossed over to the CSCI at the same dose as the intravenous (i.v.) phase. A stable dose was defined as no dose change, four or less rescue doses in the previous 24 hr, and a pain rating of none or mild. CIVI was considered equal to CSCI if these criteria were maintained for 96 consecutive hr. Fifty-seven patients were entered, and 40 were evaluable (15 women and 25 men). The median age was 67 (range 30-83 years). All 40 participants, after maintaining a stable dose throughout the i.v. phase, crossed to the s.c. phase and remained on s.c. for at least 48 hr. Thirty-two patients maintained a stable dose throughout the i.v. and s.c. phases. The mean stable i.v. dose (day 2) was 5.05 mg/hr, and the mean stable s.c. dose (day 4) was 5.7 mg/hr (P = 0.01). The mean number of rescue doses on day 2 was 0.83 per 24 hr versus 0.80 per 24 hours on day 4 (P = 0.6). The mean categorical pain score on day 2 was 0.83, and on day 4, 0.85 (P = 0.7). The mean visual analogue scale (VAS) on day 2 was 22.9 mm versus 17.6 mm on day 4 (P = 0.1). The mean incidence of side effects on day 2 was 1.7, and on day 4, 2.0 (P = 0.2). No patient was withdrawn or had a dose reduction due to unacceptable toxicity. There were two reports of local toxicity (mild erythema) at the SC needle insertion point, which required a site change. All of our 40 patients had adequate pain control with CIVI and CSCI morphine. Of the eight participants who were not maintained on the same i.v. and s.c. dose, all had adequate pain control and a similar side-effect profile on a higher s.c. morphine dose. These data suggest that the i.v. and s.c. routes are equianalgesic for most patients when administered as a continuous infusion. Pain control and side-effect profiles are quite similar and acceptable. s.c. morphine is an excellent alternative to i.v. morphine in both inpatients and outpatients requiring parenteral morphine for pain.

Adult↗