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Biomedical subjects

R Gallagher

Publications and source records attributed to R Gallagher.

At least 19 recordsLinked to original sources
PubMed2002

Controlling the physical behavior and biological performance of liposome formulations through use of surface grafted poly(ethylene glycol).

The presence of poly(ethylene glycol) (PEG) at the surface of a liposomal carrier has been clearly shown to extend the circulation lifetime of the vehicle. To this point, the extended circulation lifetime that the polymer affords has been attributed to the reduction or prevention of protein adsorption. However, there is little evidence that the presence of PEG at the surface of a vehicle actually reduces total serum protein binding. In this review we examine all aspects of PEG in order to gain a better understanding of how the polymer fulfills its biological role. The physical and chemical properties of the polymer are explored and compared to properties of other hydrophilic polymers. An evidence based assessment of several in vitro protein binding studies as well as in vivo pharmacokinetics studies involving PEG is included. The ability of PEG to prevent the self-aggregation of liposomes is considered as a possible means by which it extends circulation longevity. Also, a "dysopsonization" phenomenon where PEG actually promotes binding of certain proteins that then mask the vehicle is discussed.

Adsorption↗
PubMed2002

Effect of intestinal microflora on the urinary metabolic profile of rats: a (1)H-nuclear magnetic resonance spectroscopy study.

1. Analysis of urine by (1)H-nuclear magnetic resonance (NMR) spectroscopy is used to detect biochemical disturbances predictive of toxicological changes. Recent studies, using (1)H-NMR spectroscopy have suggested that Alderley Park rats can be classified as hippuric acid (HA) or m-(hydroxyphenyl)propionic acid (m-HPPA) excretors. Evidence exists for the role of intestinal microflora in the excretion of aromatic phenolic compounds including HA and m-HPPA. 2. We sought to investigate whether intestinal microflora contribute to the difference in excretion. Urinary HA and m-HPPA levels were monitored to characterize excretion over time. The effect of intestinal microflora on the (1)H-NMR spectrum was also investigated using antibiotics to sterilize the intestine. Finally, the levels of m-HPPA and phenylpropionic acid (a precursor for HA) were analysed in the caecum and colon (entire tissue, including contents). 3. Characterization confirmed the presence of HA and m-HPPA excretors; enquiries revealed that the rats were obtained from two floors within a barriered breeding unit. Housing the rats from the two floors together for 21 days resulted in comparable levels of HA and m-HPPA excretion demonstrating that the profiles are not stable. 4. Following antibiotic treatment, HA and m-HPPA excretion decreased, indicating that intestinal microflora contribute to the excretion of these compounds. Finally, m-HPPA levels were higher in the colon of rats that excreted m-HPPA whilst PPA was increased in the caecum and colon of rats that excreted HA. 5. These results demonstrate that the observed difference in HA/m-HPPA excretion is due to differences in the intestinal microflora.

Animals↗
PubMed2001

Lineage restriction of the RARalpha gene expression in myeloid differentiation.

To better understand the role of retinoids in myelopoiesis, expression of the retinoid receptor genes (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) were examined during differentiation of factor-dependent cell-Paterson (FDCP)-mixA4 murine progenitor cells. The major receptor expressed in undifferentiated A4 cells was RARalpha (primarily the RARalpha1 isoform). Following induction of myelomonocytic differentiation with granulocyte and granulocyte-macrophage colony-stimulating factors, a dramatic increase in RARalpha expression (particularly the RARalpha2 isoform) was seen. In contrast, expression of both RARalpha isoforms was rapidly extinguished upon induction of erythroid differentiation with erythropoeitin (EPO). A modest induction of RXRalpha expression was seen, particularly during differentiation in the myelomonocytic lineage. Low expression levels of RARgamma2 and RXRbeta remained unchanged, irrespective of differentiation pathway. Consistent with the gene expression patterns, RARalpha agonists and antagonists stimulated myelomonocytic and erythroid differentiation of FDCP-mixA4 cells, respectively. Taken together, these results suggest that erythropoiesis and granulopoiesis require diminished and enhanced RARalpha activities, respectively, which at physiological all-trans-retinoic acid (RA) concentrations may be accomplished by reciprocal effects of EPO and myelomonocytic growth factors on its expression. This hypothesis is corroborated by data showing that RA, which positively regulates RARalpha2 expression, can exert inhibitory effects on erythroid differentiation.

Bone Marrow↗
PubMed2001

The chemopotentiation of cisplatin by the novel bioreductive drug AQ4N.

AQ4N is a bioreductive drug that can significantly enhance the anti-tumour effect of radiation and cyclophosphamide. The aim of this study was to examine the ability of AQ4N to potentiate the anti-tumour effect of cisplatin and to compare it to the chemopotentiation effect of tirapazamine. In the T50/80 murine tumour model, AQ4N (50-100 mg/kg) was administered 30 min, 2.5 or 6 h prior to cisplatin (4 mg/kg or 8 mg/kg); this produced an anti-tumour effect that was approximately 1.5 to 2 times greater than that achieved by a single 4 or 8 mg/kg dose of cisplatin. Tirapazamine (25 mg/kg) administered 2.5 h prior to cisplatin (4 mg/kg) resulted in a small increase in anti-tumour efficacy. AQ4N was also successful in enhancing the anti-tumour effect of cisplatin in the SCCVII and RIF-1 murine tumour models. This resulted in an increased cell kill of greater than 3 logs in both models; this was a greater cell kill than that observed for tirapazamine with cisplatin. Combination of cisplatin with AQ4N or tirapazamine resulted in no additional bone marrow toxicity compared to cisplatin administered alone. In conclusion, AQ4N has the potential to improve the clinical efficacy of cisplatin.

Animals↗
PubMed2001

Using a trade-show format to educate the public about death and survey public knowledge and needs about issues surrounding death and dying.

A public education event on death and dying, based on the design of a commercial trade show, was held to raise the profile of palliative care in the community. Attendees answered a questionnaire designed to assess their knowledge on issues about dying and their anticipated needs if they were to face a terminal illness. Healthcare providers knew significantly more about dying, but there were persistent misconceptions that morphine shortens life, causes addiction, and develops tolerance. The questionnaire revealed confusion about treatment choices available to patients and euthanasia. The anticipated needs questions revealed that increasing age leads to less concern about physical needs, and independence/control. Further public forums on death and dying will be held with attention to education on the identified issues and inclusion of wider education and cultural groups.

Adult↗
PubMed2001

Autologous fibrin sealant reduces pain after tonsillectomy.

OBJECTIVES/HYPOTHESIS: Pain is a major cause of morbidity after tonsillectomy. Although various efforts have been made to reduce pain, the use of oral analgesics, which can have adverse side effects, remains the standard of care. It is hypothesized that fibrin sealant, used to achieve hemostasis and enhance healing in many surgical procedures, might help decrease pain after this operation. STUDY DESIGN: A prospective, randomized, blinded study was performed on 20 children aged 5 to 17 years who were undergoing tonsillectomy, to evaluate the efficacy of FIBRIN SEALANT in reducing postoperative pain. METHODS: All patients pre-donated 40 mL of blood from which autologous concentrated fibrinogen was prepared by cryoprecipitation. In the fibrin sealant group, fibrinogen and topical bovine thrombin were sprayed onto the surgical site to form fibrin sealant at the conclusion of tonsillectomy. The 10 patients in the control group (C) received no fibrin sealant. Patients rated their level of pain immediately after surgery and at regular intervals for 3 days after surgery using the Wong-Baker Faces Pain Rating Scale (1-6). Emesis, postoperative bleeding, medications, and adverse events were also evaluated. RESULTS: At 7.00 P.M. on postoperative day (POD) 0, the mean +/- SD fibrin sealant group pain score (2.9+/-0.41 units) was significantly lower than for the C group (4.1+/-0.43 units; P < or = .05). There was also a trend in favor of less pain in the fibrin sealant group at 7:00 P.M. on POD 1, with a mean of 3.5+/-0.43 units versus 2.4+/-0.48 units for C (P = .15). The odds of a patient in C experiencing emesis were 8.16 times higher, (P < or = .05) than for patients in the fibrin sealant group. CONCLUSIONS: Fibrin sealant significantly reduced pain the evening after pediatric tonsillectomy and also decreased the chance of experiencing emesis. Thus fibrin sealant may be clinically useful as an adjunct to tonsillectomy.

Administration, Topical↗
PubMed2001

The diagnosis and neuropsychological assessment of adult attention deficit/hyperactivity disorder. Scientific study and practical guidelines.

The recognition of attention deficit/hyperactivity disorder (ADHD) in adults is a well documented, but relatively new development. Investigations of the disorder have indicated that disturbances in behavior and adjustment are common. These disturbances may be linked to poorly developed executive functions. This paper reviews the neuropsychological studies that have compared persons with ADHD to normal controls and to psychiatric controls. The review indicates that persons with ADHD share many neuropsychological characteristics with other persons with serious psychiatric conditions, although those with ADHD may have a particular profile of slowed performance in tasks of sustained attention and set shifting, and their use of working memory may be particularly impaired. The implications of research for clinical assessment are discussed. We contend that a neuropsychological orientation is necessary for making the diagnosis and gaining a full understanding of adult ADHD. A model for clinical assessment is proposed which utilizes a neuropsychological orientation and the targeted administration of neuropsychological instruments. The careful use of neuropsychological measures is warranted in providing an elaborate picture of a person's functioning, although the use of neuropsychological tests is not necessary to make the diagnosis.

Adult↗
PubMed2001

Nanomechanical properties of hydrated carious human dentin.

Most restorative materials are bonded to caries-affected dentin that has altered structure. We tested the hypothesis that hydrated dentin of the transparent zone did not have increased hardness or elastic modulus. Nanoindentation by modified AFM was used to determine site-specific elastic modulus and hardness for components of hydrated dentin from 8 carious and non-carious human teeth. Indentations in intertubular dentin were made at intervals from pulp through the affected layers (subtransparent, transparent, and discolored zones). The values of intertubular dentin increased slightly from near the pulp into the transparent zone, then remained constant or decreased slightly through transparent dentin (E, 18.3 GPa; H, 0.8 GPa; confirming the hypothesis), and decreased markedly through the discolored region. Peritubular dentin values were unaltered in transparent dentin, and intratubular mineral had values between those of normal peritubular and intertubular dentin. Superficial areas contained distorted tubules without peritubular dentin or intratubular mineral.

Analysis of Variance↗
PubMed2001

The effect of TGF-beta 2 on dentin apposition and hardness in transgenic mice.

Transforming growth factor beta, TGF-beta, is expressed during tooth formation and can induce pre-odontoblast differentiation and formation of functional odontoblast-like cells in vitro. In addition, exogenous TGF-beta can increase reparative dentin formation, presumably by acting on odontoblasts. In this study, we examined the tooth phenotype of transgenic mice, in which TGF-beta 2 expression is directed by the osteocalcin promoter. Previous studies have shown that these mice have a bone phenotype that resembles that of human osteoporosis, including the existence of spontaneous fractures. Microhardness testing of the enamel and dentin showed no differences in the molars of these transgenic mice as compared with those of their wild-type littermates. Consistent with the increase in bone mineral apposition rate previously reported in these mice, the dentin apposition rate appeared to be increased in the TGF-beta 2-overexpressing mice. Thus, in teeth, as in bone, TGF-beta 2 appears to stimulate the synthesis and deposition of matrix. Further studies are needed to understand the effect of TGF-beta 2 on distinct mineralized tissues (bone, dentin, and cementum) and to determine whether exogenous TGF-beta 2 may be useful for tooth repair.

Animals↗
PubMed2001

Consultation to administrators.

Mental health specialists can contribute to improvements in children's school experience when they work with administrators to incorporate up-to-date mental health knowledge into educational practice. Effective consultation is not simply a knowledge dissemination exercise. The impact of the consultant's input is determined by how responsive the consultation process is to the needs and assets of faculty, students, and the broader community.

Administrative Personnel↗
PubMed2000

Simultaneous PML/RARalpha and AML1/ETO expression with t(15;17) at onset and relapse with only t(8;21) in an acute promyelocytic leukemia patient.

We report a patient with acute promyelocytic leukemia with the common translocation (15;17) and PML-RARAalpha fusion gene. In relapse, blasts showed typical FAB M2 morphologic features, and the karyotype was 45,X, -Y,t(8;21). A reexamination of the leukemic cells at diagnosis revealed that an AML1-ETO fusion gene was also present at that time without cytogenetic evidence of t(8;21). In relapse, only t(8;21) was detected. Two different clones were identified by cytogenetic standard techniques. The association of two common translocations supervening in the same time in the same cells could not be established.

Adult↗
PubMed2000

Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine.

The ability of the bioreductive drugs AQ4N and tirapazamine to enhance the anti-tumour effect of cyclophosphamide was assessed in three murine tumour models. In male BDF mice implanted with the T50/80 mammary carcinoma, AQ4N (50-150 mg kg(-1)) in combination with cyclophosphamide (100 mg kg(-1)) produced an effect equivalent to a single 200 mg kg 1 dose of cyclophosphamide. Tirapazamine (25 mg kg(-1)) in combination with cyclophosphamide (100 mg kg(-1)) produced an effect equivalent to a single 150 mg kg(-1) dose of cyclophosphamide. In C3H mice implanted with the SCCVII or RIF-1 tumours, enhancement of tumour cell killing was found with both drugs in combination with cyclophosphamide (50-200 mg kg(-1)); AQ4N (50-200 mg kg(-1)) produced a more effective combination than tirapazamine (12.5-50 mg kg(-1)). Unlike tirapazamine, which showed a significant increase in toxicity to bone marrow cells, the combination of AQ4N (100 mg kg(-1)) 6 h prior to cyclophosphamide (100 mg k(-1)) resulted in no additional toxicity towards bone marrow cells compared to that caused by cyclophosphamide alone. In conclusion, AQ4N gave a superior anti-tumour effect compared to tirapazamine when administered with a single dose of cyclophosphamide (100 mg kg(-1)).

Animals↗
PubMed2000

Childhood cancer in the offspring of male sawmill workers occupationally exposed to chlorophenate fungicides.

The objective of this study was to determine whether paternal occupational exposure to chlorophenol fungicides and their dioxin contaminants is associated with childhood cancer in the offspring of sawmill workers. We used data from 23,829 British Columbian sawmill workers employed for at least 1 continuous year between 1950 and 1985 in 11 sawmills that used chlorophenates. Probabilistic linkage of the sawmill worker cohort to the provincial marriage and birth files produced an offspring cohort of 19,674 children born at least 1 year after the initiation of employment in the period 1952-1988. We then linked the offspring cohort to the British Columbia Cancer Registry. We included all malignancies in cases younger than 20 years of age that appeared on the cancer registry between 1969 and 1993. We calculated standardized incidence ratios (SIRs) using the British Columbia population as a reference. A nested case-control analysis assessed the effects of paternal cumulative exposure and windows of exposure on the risk of developing cancer in the offspring. We identified 40 cases of cancer during 259,919 person-years of follow-up. The all-cancer SIR was 1.0 [95% confidence interval (CI), 0.7-1.4]; the SIR for leukemia was 1.0 (CI, 0.5-1.8); and the SIR for brain cancer was 1.3 (CI, 0.6-2.5). The nested case-control analysis showed slightly increased risks in the highest categories of chlorophenol exposure, although none was statistically significant. Our analyses provide little evidence to support a relationship between the risk of childhood cancer and paternal occupational exposure to chlorophenate fungicides in British Columbian sawmills.

Adolescent↗
PubMed2000

Hypofrontality and negative symptoms in patients with dementia of Alzheimer type.

OBJECTIVE: The purpose of the current study was to examine the relation between regional cerebral blood flow (rCBF) and negative symptoms (NS) in patients with dementia of Alzheimer type (DAT). BACKGROUND: Negative symptoms in neuropsychiatric disorders were associated with altered rCBF in frontal cortex. METHODS: Twenty-five subjects with a diagnosis of DAT were administered the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom Scale, the Hamilton Rating Scale for Depression, and the Mini-Mental State Examination. The subjects were divided into two groups by means of a median split with regard to NS severity (high NS group, N = 12; low NS group, N = 13). Each patient underwent a single photon emission tomography scan using 99mTc-HMPAO at rest. Cortical and subcortical regions of interest were symmetrically defined in each hemisphere. Cortical-to-cerebellar perfusion ratios were established quantitatively using ADAC software. RESULTS: High NS group subjects had a significantly lower rCBF than low NS group subjects in the frontal cortex and cingulate gyrus (MANOVA: p = 0.022) as a result of differences in the dorsolateral prefrontal cortex bilaterally (right: F = 12.12, p = 0.002; left: F = 6.55, p = 0.02) and in the frontal cortex, mainly in the right hemisphere (right: F = 6.33, p = 0.02; left: F = 3.26, p = 0.08). For all the subjects (N = 25), there were negative correlations between the SANS total score and rCBF, most prominently in the dorsolateral prefrontal cortex bilaterally (right: r = -0.48, p <0.01; left: r = -0.49, p = 0.01). No significant correlation was found between rCBF in any of the regions of interest and either the Mini-Mental State Examination or the Hamilton Rating Scale for Depression scores. CONCLUSIONS: This study indicates that decreased perfusion in the frontal cortex is associated with NS severity but not with measures of cognitive impairment or depressive symptoms in DAT patients. These results support the hypothesis that the frontal lobes may be involved in the cause of NS in DAT, and they underscore the importance of NS evaluation in neuroimaging studies.

Aged↗
PubMed2000

Drug delivery by the intravaginal route.

The human vagina represents a potential, accessible space that offers a valuable route for drug delivery through the use of specifically designed carrier systems for both local and systemic applications. Intravaginal drug delivery is particularly appropriate for drugs associated with women's health issues but may also have applications in general drug delivery within the female population. A range of drug delivery platforms suitable for intravaginal administration are discussed in this review, including hydrogels, vaginal tablets, pessaries/suppositories, particulate systems, and intravaginal rings. Drug release mechanisms and absorption pathways are reviewed with respect to a range of therapeutic and prophylactic indications for intravaginal delivery.

Absorption↗