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Biomedical subjects

J Jackson

Publications and source records attributed to J Jackson.

At least 37 records · Page 2Linked to original sources
PubMed2003

Neoadjuvant tamoxifen and aromatase inhibitors: comparisons and clinical outcomes.

Neoadjuvant hormonal therapy for oestrogen receptor (ER) and/or progesterone receptor (PgR) positive large operable or locally advanced breast cancer is effective and a safe alternative to chemotherapy in postmenopausal women. A randomised trial has demonstrated that the response rate and the incidence and degree of downstaging with the aromatase inhibitor letrozole is significantly greater than with tamoxifen [J. Clin. Oncol. 19 (2001) 3808]. Tumours at all levels of ER appear to respond better to letrozole than tamoxifen but at low levels of ER responses are seen only with letrozole and not with tamoxifen. Patients most likely to benefit from neoadjuvant therapy and those who achieve the greatest reduction in tumour volume are those patients with tumours that express very high levels of ER (ALLRED category score 8). Both letrozole and anastrozole appear effective in both erbB2 positive and negative breast cancers. Three months of treatment is adequate to determine if a tumour will respond. Following breast-conserving surgery and radiotherapy, local recurrence rates appear satisfactory.

Anastrozole↗
PubMed2003

Effectiveness of dietary advice given by community dietitians to men with elevated blood cholesterol in a clinical setting: a pilot study.

OBJECTIVE: To compare the effect of two types of dietary advice given by community dietitians on subsequent dietary intake in Scottish men, over 8 weeks. DESIGN: A parallel design intervention study was employed. Twenty-five men with elevated blood cholesterol levels were randomly assigned to Group 1 (advice to reduce dietary fat only) or Group 2 (advice to reduce dietary fat and sugar). RESULTS: Neither group significantly reduced fat intakes, yet both groups self-rated their fat intake as being lower at the end than at the start of the study. Group 2 reduced per cent energy from sugar and increased per cent energy from starch without significantly changing per cent energy from total carbohydrate. No significant change in blood cholesterol levels were observed. CONCLUSIONS: Advice to reduce dietary fat was not effective in this group of subjects. Advice to reduce both fat and sugar resulted in a decrease in sugar intake only. Both groups wrongly rated their fat intake to be lower at the end of the study. This may be a barrier to further dietary advice.

Adult↗
PubMed2003

Anti-transglutaminase antibodies and the serological diagnosis of coeliac disease.

Tissue transglutaminase (tTG) has recently been identified as the antigenic target recognised by anti-endomysial antibodies in patients with coeliac disease. In this study, an enzyme-linked immunosorbent assay (ELISA) is used to measure IgA, IgG and IgM antibodies to tTG in patients with coeliac disease and a variety of other inflammatory disorders; and is compared to the standard immunofluorescence test used to detect endomysial antibodies (EMA). In the samples tested, 3% control sera (n=146), 83% EMA-positive sera (n=29), 9% patients with Graves' disease (n=94), 12% antimitochondrial antibody-positive sera (n=53), 11% rheumatoid arthritis patients (n=53) and 22% systemic lupus erythematosus (SLE) patients (n=46) were positive for anti-tTG antibodies. In contrast, none of the controls, 1% of patients with Graves' disease, 2% antimitochondrial antibody-positive sera, 2% rheumatoid arthritis patients and none of the SLE patients were positive for EMA. Measurement of IgG or IgM antibodies to tTG was much less reliable than IgA anti-tTG antibody for the serological diagnosis of coeliac disease. The addition of calcium to the coating buffer improved the assay characteristics of the anti-tTG ELISA. However, the IgA anti-tTG ELISA, with and without calcium, performed less well than the standard EMA test used for the serological diagnosis of coeliac disease. In particular, the anti-tTG ELISA gave a higher rate of non-specific positive reactions.

Antibodies↗
PubMed2003

The therapeutic potential of aromatase inhibitors.

The third generation aromatase inhibitors are both remarkably potent and specific endocrine agents inhibiting aromatase activity and reducing circulating oestrogen levels in postmenopausal women to levels never previously seen. Their therapeutic potential is consequently much greater than the earlier prototype drugs. Their excellent side-effect profile also allows for potential wider indications in the treatment of oestrogen-related diseases, including breast cancer. It still remains to determine whether their potent endocrine effects translate into increased therapeutic benefit. In advanced breast cancer, aromatase inhibitors have been shown to have improved efficacy and toxicity profiles when compared with progestins, aminoglutethimide and tamoxifen. Aromatase inhibitors have also been used in the neoadjuvant setting, where they have been shown to achieve higher response rates than tamoxifen and to be more successful at downstaging tumours. Early results comparing an aromatase inhibitor with tamoxifen in the adjuvant setting in early breast cancer show anastrozole to be superior to tamoxifen in terms of both disease-free survival and a lower incidence of new contralateral tumours. There was also a more favourable side-effect profile, which has implications for potential future prophylactic treatment. Additionally, since aromatase inhibitors have different mechanisms of action, unlike antioestrogens, they may be particularly useful as chemopreventive agents if oestrogens are themselves genotoxic. Aromatase inhibitors have been used to date almost exclusively in postmenopausal women. The potential of combining them with luteinising hormone-releasing hormone analogues allows the possibility of treating premenopausal women with either oestrogen receptor-positive breast cancer or benign conditions such as cyclical breast pain, fibroadenomata, recurrent cystic disease or endometriosis. There is also the potential for their use in men with conditions such as gynaecomastia or prostate cancer. These new generation aromatase inhibitors may well have an increasing role in the future management of a number of conditions in addition to breast cancer.

Animals↗
PubMed2003

Safety issues surrounding the use of aromatase inhibitors in breast cancer.

Third generation aromatase inhibitors (AIs) are now established therapy in advanced oestrogen receptor (ER)-positive breast cancer. As the use of AIs expands to include adjuvant treatment of early breast cancer and breast cancer prevention, tolerability and effects on other organs such as bone will become as important as the antitumour properties of the drugs. In direct comparisons with tamoxifen, AIs have a better toxicity profile with fewer patients stopping therapy because of drug-related side effects. There is a lower incidence of thromboembolic events and vaginal bleeding compared with tamoxifen. Although published information about the side effects of AIs is scarce, it is likely that they will have adverse effects on bone and possibly also on lipid metabolism. Subprotocols of ongoing adjuvant trials are investigating these effects. It is likely that the choice of which third generation AI to use will be largely determined by its tolerability and safety profile, since it is likely that the currently available drugs have similar efficacy.

Anastrozole↗
PubMed2002

Construction and analysis of a microsatellite-based database of European wheat varieties.

A database of 502 recent European wheat varieties, mainly of winter type, was constructed using 19 wheat microsatellites and one secalin-specific marker. All datapoints were generated in at least two laboratories using different techniques for fragment analysis. An overall level of >99.5% accuracy was achieved. The 199 alleles detected allowed discrimination between all of the varieties except duplicates, and varieties derived from identical parents. Approximately 25% of the varieties showed some heterogeneities, with the highest level of heterogeneity in south-eastern European material. The highest genetic diversity and the highest number of rare alleles were found in varieties from southern Europe. The relative allele frequencies varied for most microsatellites in different geographical regions.

DNA Fingerprinting↗
PubMed2002

Tumour necrosis factor blocking agents: a new therapeutic modality for inflammatory disorders.

Development of anti-tumour necrosis factor-alpha (anti-TNF alpha) treatment offers the potential to alter radically the course of inflammatory diseases such as rheumatoid arthritis and Crohn's disease using modalities directed against a specific inflammatory mediator. Controlled randomised trials in these diseases demonstrate clinical benefit associated with significant improvement in patients with severe active joint and intestinal disease, often when conventional therapies are unsuccessful. To date, anti-TNF alpha therapy has been well tolerated and shows a favourable safety profile. This review considers the nature of this therapy and current evidence of its clinical benefit and adverse effects.

Antibodies, Monoclonal↗
PubMed2002

Polyarteritis nodosa presenting as a pyrexia of unknown origin.

A case of an 18 year old woman is reported who presented with a pyrexia of unknown origin having returned from a trip to India. She initially had constitutional symptoms only, which rapidly progressed to a multisystem disorder. The difficulty in making the diagnosis of polyarteritis nodosa, especially with the possible differential diagnosis of infection after her recent travel, is discussed. The discussion reviews the condition of polyarteritis nodosa and analyses the diagnostic difficulties in this case.

Adolescent↗
PubMed2001

Neurotensin analog selective for hypothermia over antinociception and exhibiting atypical neuroleptic-like properties.

Neurotensin (NT) is a tridecapeptide neurotransmitter in the central nervous system. It has been implicated in the therapeutic effects of neuroleptics. Central activity of NT can only be demonstrated by direct injection into the brain, since it is readily degraded by peptidases in the periphery. We have developed many NT(8-13) analogs that are resistant to peptidase degradation and can cross the blood-brain barrier (BBB). In this study, we report on one of these analogs, NT77L. NT77L induced hypothermia (ED(50)=6.5 mg/kg, i.p.) but induced analgesia only at the highest dose examined (20 mg/kg, i.p.). Like the atypical neuroleptic clozapine, NT77L blocked the climbing behavior in rats induced by the dopamine agonist apomorphine (600 microg/kg) with an ED(50) of 5.6 mg/kg (i.p.), without affecting the licking and the sniffing behaviors. By itself NT77L did not cause catalepsy, but it moderately reversed haloperidol-induced catalepsy with an ED(50) of 6.0 mg/kg (i.p.). Haloperidol alone did not lower body temperature, but it potentiated the body temperature lowering effect of NT77L. In studies using in vivo microdialysis NT77L showed similar effects on dopamine turnover to those of clozapine, and significantly different from those of haloperidol in the striatum. In the prefrontal cortex, NT77L significantly increased serotonergic transmission as evidenced by increased 5-hydroxyindole acetic acid:5-hydroxytryptamine (5-HIAA:5-HT) ratio. Thus, NT77L selectively caused hypothermia, over antinociception, while exhibiting atypical neuroleptic-like effects.

Analgesics↗
PubMed2001

Altering behavioral responses and dopamine transporter protein with antisense peptide nucleic acids.

The dopamine transporter (DAT) plays a role in locomotion and is an obligatory target for amphetamines. We designed and synthesized an antisense peptide nucleic acid (PNA) to rat DAT to examine the effect of this antisense molecule on locomotion and on responsiveness to amphetamines. Rats were injected intraperitoneally daily for 9 days with either saline, an antisense DAT PNA, a scrambled DAT PNA, or a mismatch DAT PNA. On days 7 and 9 after initial motility measurements were taken, the animals were challenged with 10 mg/kg of amphetamine and scored for motility. On day 7, there was no significant difference between the baseline levels of activity of any of the groups or their responses to amphetamine. On day 9, the antisense PNA-treated rats showed a statistically significant increase in their resting motility (P < 0.01). When these rats were challenged with amphetamine, motility of the saline-, scrambled PNA-, and mismatch PNA-treated animals showed increases of 31-, 36-, and 20-fold, respectively, while the antisense PNA-treated animals showed increases of only 3.4-fold (P < 0.01). ELISA results revealed a 32% decrease in striatal DAT in antisense PNA-treated rats compared with the saline, scrambled PNA, and mismatch PNA controls (P < 0.001). These results extend our previous findings that brain proteins can be knocked down in a specific manner by antisense molecules administered extracranially. Additionally, these results suggest some novel approaches for the treatment of diseases dependent upon the function of the dopamine transporter.

Animals↗
PubMed2001

Intraperitoneal injection of antisense peptide nucleic acids targeted to the mu receptor decreases response to morphine and receptor protein levels in rat brain.

To determine the effectiveness of peptide nucleic acids (PNAs) in vivo, we designed and synthesized PNAs antisense to the mu receptor, the molecular target of morphine for inducing antinociception. Responsiveness of rats to morphine and the levels of mu receptor expression after treatment was measured. We delivered intraperitoneal injections of antisense PNAs targeted to the mu receptor (AS-MOR), mismatch PNAs (AS-MOR MM), antisense PNAs targeted to the neurotensin receptor subtype 1 (AS-NTR1), or saline and then challenged the rats with 5 mg/kg morphine (intraperitonally) or neurotensin directly into the periaqueductal gray region of the brain. To avoid tolerance, separate groups of animals were tested at 24, 48, and 72 h post-PNA treatment. Only animals treated with the AS-MOR showed a reduction in their antinociceptive response to morphine. The lack of effect of morphine on the AS-MOR rats was profound at 24 and 48 h, but animals tested at 72 h were similar to control groups. At 24 h the AS-MOR rats had a significant 55% decrease in the levels of mu receptor in their periaqueductal gray region, while AS-MOR MM rats showed no significant change. Lastly, the AS-MOR rats continued to show a normal antinociceptive response to neurotensin. This study, therefore, provides additional support for the use of PNAs to target proteins within brain by systemically administered PNAs.

Analgesics, Opioid↗
PubMed2001

Pathologic changes in grossly normal menisci in dogs with rupture of the cranial cruciate ligament.

OBJECTIVE: To determine whether histopathologic changes are detectable in grossly normal medial menisci from dogs with rupture of the cranial cruciate ligament (CCL). DESIGN: Case series. SAMPLE POPULATION: 40 medial menisci from dogs with rupture of the CCL and 20 medial menisci from control dogs without stifle joint disease. PROCEDURE: Data evaluated included age, duration of clinical signs, and whether rupture of the CCL was complete or incomplete. Three groups (n = 20/group) were also compared on the basis of 5 histologic criteria; group-1 menisci appeared grossly normal and were obtained from dogs with naturally occurring rupture of the CCL, group-2 menisci were grossly abnormal and were also obtained from dogs with naturally occurring CCL ruptures, and group-3 menisci were collected at postmortem from dogs without stifle joint disease that were of similar age and weight as dogs in groups 1 and 2. RESULTS: Group-2 menisci were significantly different from group-1 and -3 menisci in all histologic criteria. Group-1 menisci were significantly different from control menisci in only 1 of the 5 histologic criteria (cartilage differentiation). Dogs that were > or =3 years old had significantly more surface cellularity than did dogs that were < 3 years old. A significant difference was not detected between groups 1 and 2 with regard to completeness of rupture. CONCLUSIONS AND CLINICAL RELEVANCE: Histologic changes in meniscal cartilage correlate with gross appearance of the cartilage at time of surgery for rupture of the CCL. On the basis of minimal histologic changes, routine removal of grossly normal menisci does not appear to be warranted.

Age Factors↗
PubMed2001

Introducing safety syringes into a UK dental school--a controlled study.

AIM: How an appropriate safety syringe was chosen, how the change-over to it was achieved and what outcome measures were used to measure the effectiveness of this change. INTRODUCTION: One third of all reported sharps injuries in dental practice are due to the use of non disposable dental syringes with most injuries being sustained during removal and disposal of the disposable needle from the non-disposable syringe. METHOD: After evaluation of all available disposable safety syringes they were introduced into a dental school after appropriate education of all staff and students. Risk management provided data on all reported needle-stick injuries in the dental school and a control unit using non disposable syringes for a period of two years. RESULTS: Avoidable needle stick injuries reduced from an average of 11.8 to 0 injuries per 1,000,000 hours worked per year as compared with a control unit who reduced their frequency from 26 to 20 injuries per 1,000,000 hours worked. The cost of safety syringes is comparable to non-disposable syringes but the reduction in cost of management of needle stick injuries including the psychological effects are significant. CONCLUSION: Education plays a vitally important role in the effective implementation of the change to safety syringes which is advocated for all dentists.

Accidents, Occupational↗
PubMed2001

Karyotype, phenotype and parental origin in 19 cases of triploidy.

The parental origin of triploidy in 19 cases was examined by inheritance of DNA microsatellites and by methylation patterns of SNRPN or PW71 (where parents' blood was unavailable). The fetal and placental morphology on these cases was reviewed. The phenotype of the fetuses with non-mosaic triploidy was assessed in relation to the two types described by McFadden and Kalousek. Of the diandric fetuses three of the six showed mild-to-moderate symmetrical growth retardation and the other three had growth characteristics in accordance with their gestational ages. This study would suggest the fetal triploid 'Type 1' definition be modified to 'well grown to moderate symmetrical IUGR' to allow for such variation. In the digynic fetuses (McFadden/Kalousek Type 2) there were poor growth characteristics with IUGR being more severe and asymmetrical. The diandric fetuses were as common as digynic fetuses in this series. The ratio of diandric to digynic specimens was 11:8 but if only fetal specimens (not embryos or mosaic children) were included the ratio was 6:5. Many diandric conceptions end as partial moles but later in gestation diandric fetuses may be well grown. It is proposed that there may be a survival barrier for diandric fetuses early in gestation (possibly based on the proportion of vascularised placental villi), although once this is passed the diandric fetuses are comparatively more viable and better grown than digynic fetuses. In the XXY triploid fetuses, 5/6 had hypoplastic or ambiguous external genitalia (two were recorded as of female phenotype) as has been reported previously. In these, the gonadal histology was testicular in all the diandrics but in the single digynic XXY case, sex reversal was complete with normal uterus and Fallopian tubes and the gonads were histologically ovaries. Two triploid/diploid mosaics were proven to be due to digyny. The probable cause is delayed incorporation of the second polar body into a blastomere and there was evidence of identical alleles from the same sperm being present in both diploid and triploid cells. In one of these triploid/diploid mosaics in which there was a termination of pregnancy (TOP) after prenatal karyotyping the diploid cell line had trisomy 16 which was not evident in the triploid line. This trisomy was probably of post-zygotic origin and we suggest the fetus was rescued by the prominence of the triploid line.

Abortion, Spontaneous↗
PubMed2001

Site specificity of the Arabidopsis METI DNA methyltransferase demonstrated through hypermethylation of the superman locus.

Plants with low levels of DNA methylation show a range of developmental abnormalities including homeotic transformation of floral organs. Two independent DNA METHYLTRANSFERASEI (METI) antisense transformants with low levels of DNA methylation had flowers with increased numbers of stamens which resembled flowers seen on the loss-of-function superman (sup) mutant plants and on transgenic plants that ectopically express APETALA3 (AP3). These METI antisense plants have both increased and decreased methylation in and around the sup gene, compared with untransformed controls. DNA from the antisense plants was demethylated at least 4 kb upstream of the sup gene, while there was dense methylation around the start of transcription and within the coding region of this gene; these regions were unmethylated in control DNA. Methylation within the sup gene was correlated with an absence of SUP transcripts. The pattern and density of methylation was heterogeneous among different DNA molecules from the same plant, with some molecules being completely unmethylated. Methylcytosine occurred in asymmetric sites and in symmetric CpA/TpG but rarely in CpG dinucleotides in the antisense plants. In contrast, segregants lacking the METI antisense construct and epimutants with a hypermethylated allele of sup (clark kent 3), both of which have active METI genes, showed a higher frequency of methylation of CpG dinucleotides and of asymmetric cytosines. We conclude that METI is the predominant CpG methyltransferase and directly or indirectly affects asymmetric methylation.

Arabidopsis↗
PubMed2001

Enumeration of bone marrow 'homing' haemopoietic stem cells from G-CSF-mobilised normal donors and influence on engraftment following allogeneic transplantation.

Expression of the chemokine receptor CXCR4 on human haemopoietic stem cells (HSC) may play a crucial role in localising these cells to the bone marrow. To evaluate whether CXCR4 expression is clinically relevant we have enumerated CXCR4-positive HSC used for allogeneic transplantation and sought any relationship with the rate of subsequent haemopoietic reconstitution. CD34-positive progenitor cells were isolated from peripheral blood stem cell (PBSC) collections from 16 normal donors. The proportion of cells co-expressing CXCR4 was enumerated and the times to recipient haemopoietic reconstitution measured. The median frequency of CD34-positive cells co-expressing CXCR4 was 41% (range 16% to 76%) and the median number of CXCR4 CD34 double-positive cells infused at transplantation was 2.5 x 10(6) cells/kg (range 0.8-10.3). Patients receiving >2.5 x 10(6) CXCR4 CD34 double-positive cells/kg demonstrated a significant shortening of time to platelet engraftment compared to the recipients of the lower cell doses (10 days vs 14.5 days, respectively, P = 0.02) with all but one of the recipients of the higher cell doses achieving platelet engraftment by day 11. Co-expression of CXCR4 on CD34-positive progenitor cells may be an important determinant of post-transplant engraftment and in our hands transplantation of a minimum of 2.5 x 10(6) CXCR4 CD34 double-positive cells/kg ensured rapid post-transplant platelet recovery.

Adult↗
PubMed2001

Flow cytometric measurement of intracellular migration inhibition factor and tumour necrosis factor alpha in the mucosa of patients with coeliac disease.

There is increasing evidence that proinflammatory cytokines contribute to many of the small intestinal features in coeliac disease. The aim of the study was to investigate the expression of two proinflammatory cytokines, migration inhibition factor (MIF) and tumour necrosis factor alpha (TNF-alpha) in duodenal biopsy specimens from patients with coeliac disease on a gluten-free diet and normal control subjects. A flow cytometric system was used to analyse intracellular protein levels of MIF and TNF-alpha in freshly isolated cells from duodenal biopsies taken from 12 patients with treated coeliac disease and 10 healthy control subjects. From the biopsy specimens, single cell suspensions of the epithelium and lamina propria were prepared using EDTA/DTT and enzymes. Intracellular cytokine expression was studied in intraepithelial lymphocytes (IELs), lamina propria T cells (LP T) and intestinal epithelial cells using different surface labelling antibodies. MIF protein was constitutively expressed in IELs, LP T cells and epithelial cells from normal intestinal mucosa. In contrast, although TNF-alpha was found in LP T cells, this cytokine was virtually undetectable in either IELs or epithelial cells. In coeliac disease, intracellular levels of MIF were significantly higher in epithelial cells compared with control subjects (P = 0.005). Raised levels of TNF-alpha were found in epithelial cells (P = 0.03) as well as IELs (P = 0.045) from coeliac patients compared with controls. The findings from this study show up-regulated expression of MIF and TNF-alpha in IELs and epithelial cells of histologically normal mucosa in patients with coeliac disease. Increased expression of proinflammatory cytokines in cells occupying the epithelial layer could help explain the rapidity with which the coeliac mucosa may respond to gluten challenge.

Adolescent↗