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Biomedical subjects

S Heath

Publications and source records attributed to S Heath.

At least 19 recordsLinked to original sources
PubMed2003

Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM.

BACKGROUND: X linked hyper-IgM (XHIM) is a primary immunodeficiency caused by mutations in the tumour necrosis factor superfamily 5 gene, TNFSF5, also known as the CD40 ligand (CD40L) gene. Patients often present with recurrent infections, and confirmation of a diagnosis of XHIM enables appropriate therapeutic interventions, including replacement immunoglobulin, antibiotics, and bone marrow transplantation. AIM: To review and optimise the institution's diagnostic strategy for XHIM. METHOD: Samples from 65 boys were referred to this centre for further investigation of suspected XHIM. The results, which included a flow cytometric whole blood assay for CD40L expression followed by mutation analysis in selected patients, were reviewed. RESULTS: Twenty one patients failed to express CD40L and TNFSF5 mutations were found in 20 of these patients. In contrast, no TNFSF5 mutations were found in 16 patients with weak expression of CD40L. Interestingly, one quarter of patients with confirmed XHIM who had TNFSF5 mutations had low concentrations of IgG, IgA, and IgM. Most of the remaining patients with XHIM had the classic pattern of normal or raised IgM with low concentrations of IgA and IgG. CONCLUSIONS: This study demonstrates the usefulness of the whole blood staining method as a rapid screen to select patients for subsequent TNFSF5 mutation analysis, and shows the benefits of a unified protein/genetic diagnostic strategy.

Adolescent↗
PubMed2001

Protein assays for diagnosis of Wiskott-Aldrich syndrome and X-linked thrombocytopenia.

Mutations in the gene encoding the Wiskott-Aldrich syndrome protein (WASp) give rise to Wiskott-Aldrich syndrome (WAS), a condition that exhibits a wide spectrum of clinical severity. Patients may develop mild thrombocytopenia or suffer from a wide range of associated disorders including eczema, immune dysfunction, autoimmune disease and malignancy. The clinical diagnosis of Wiskott-Aldrich syndrome (WAS) can be difficult and is usually supported by the detection of WASp gene mutations using genetic analysis. Recently, protein-based assays have been used to demonstrate the absence of WASp in patients known to have WASp gene mutations. We have now reversed this approach and report on the use of immunoblot assays to rapidly diagnose WAS in 13 patients. There was a complete absence of WASp in 10 out of 13 patients and an abnormal protein form was detected in the remaining three patients. In all cases, subsequent genetic analysis confirmed the presence of a WASp gene mutation. We believe that protein-based assays should be employed as the first line of investigation in the diagnosis of WAS spectrum disorders.

Aged↗
PubMed2001

In-vitro susceptibility of hydatid cysts of Echinococcus granulosus to nitric oxide and the effect of the laminated layer on nitric oxide production.

Murine hydatid cysts of Echinococcus granulosus were incubated in vitro in the presence of nitric oxide produced from S-nitroso-N-acetylpenicillamine (SNAP) or interferon-gamma activated peritoneal macrophages. In both situations, evidence of cyst damage and death was observed by microscopy in over 77% of cysts after 3 days, indicating that intact hydatid cysts could be susceptible to a Th1 driven macrophage attack. A crude extract of the laminated layer from cysts was found to be able to reduce the production of nitric oxide from activated macrophages in vitro and in vivo and this may have been due to phagocytosis of laminated layer fragments by the macrophages. The results indicate that, although cysts may be susceptible to the effects of nitric oxide, the laminated layer may be involved in downregulating nitric oxide production.

Animals↗
PubMed2001

A novel approach to search for identity by descent in small samples of patients and controls from the same mendelian breeding unit: a pilot study on myopia.

Autosomal dominant high myopia, a genetic disorder already mapped to region 18p11.31, is common in Carloforte (Sardinia, Italy), an isolated village of 8,000 inhabitants descending from a founder group of 300 in the early 1700s. Fifteen myopic propositi and 36 normal controls were selected for not having ancestors in common at least up to the grandparental generation, although still descendants of the original founders. All subjects were genotyped for 14 markers located on autosome 18 at a resolution of about 10 cM. Allelic distributions were found to be similar at all tested loci in propositi and controls, except for the candidate marker D18S63 known to segregate in close linkage association with high myopia. In particular, the frequency of allele 85 among the propositi was almost double that of the controls (Fisher's exact test, p = 0.037). The association is more striking when the frequency of the genotype 85/85 in the two groups is compared (Fisher's exact test, p = 0.005). This conclusion was further evaluated through a bootstrap analysis by computing the overall probability of the observed data under the null hypothesis (i.e. no difference between the two groups in frequency distributions for the chromosome 18 markers). Again, marker D18S63 was found to have a sample probability lower than 0.004, which is significant at the 0.05 level after correcting for simultaneous testing of multiple loci. The study demonstrates the efficiency of our novel strategy to detect identity by descent (IBD) in small numbers of patients and controls when they are both part of well-defined Mendelian breeding units (MBUs). The iterative application of our strategy in separate MBUs is expected to become the method of choice to evaluate the ever-growing number of reported associations between candidate genes and multifactorial traits and diseases.

Adult↗
PubMed2001

Capacity building for health promotion and chronic disease prevention--Nova Scotia's experience.

The purpose of this paper is to report on the capacity building efforts that took place during the dissemination research phase of Heart Health Nova Scotia (HHNS). HHNS, a health promotion research team, is funded by Health Canada and the Nova Scotia Department of Health. It is located in Halifax, Nova Scotia, a province of 937,000 people situated on the east coast of Canada. It has been a member of the Canadian Heart Health Initiative since its inception in 1989. The first phase of the program, Demonstration, was successfully completed in December 1995 (Heart Health Nova Scotia, 1995). In 1996, HHNS entered its second phase, Dissemination Research, which was conducted between April 1996 and March 2001 in the Western Health Region of Nova Scotia. This was completed in collaboration with organizations, community groups, and government agencies who joined HHNS to form the Heart Health Partnership (HHP) (Heart Health Nova Scotia, 2001). The main aim of this phase of the initiative was to build and research organizational capacity for health promotion and chronic disease prevention.

Diffusion of Innovation↗
PubMed2000

Monitoring Piscirickettsia salmonis by denaturant gel electrophoresis and competitive PCR.

Reported strains of Piscirickettsia salmonis, a pathogen of salmonid fishes, were analyzed by amplifying part of the internal transcribed spacer (ITS) of the ribosomal RNA (rRNA) operon followed by denaturing gradient gel electrophoresis (DGGE) of the amplicons. All amplified fragments differing in sequence were distinguished by migration during DGGE. A simpler format, constant denaturant gel electrophoresis (CDGE), allowed the same diagnostic distinctions among strains. Sampling during 1997 and 1998 of salmonids from 5 different sites on and near Chiloé Island in southern Chile displaying piscirickettsiosis revealed only P. salmonis resembling LF-89, the type strain first isolated in 1989. These observations are encouraging for control strategies, which might otherwise be compromised by unpredictable shifts of P. salmonis types in salmon farms. A competitive PCR assay offered insight about the power of PCR for quantification and about specific tissue invasiveness by this intracellular pathogen. This approach revealed that the PCR could amplify approximately 1 to 10 P. salmonis genome equivalents against a background of > 99.9% salmonid DNA. It also raised the possibility that the salmonid brain is an important site for P. salmonis survival, with its bacterial load in 1 individual having been about 100 times the loads observed in liver and kidney. Pathogen detection by competitive PCR in a surface seawater sample from a netpen in use indicated a density of about 3000 to 4000 P. salmonis cells (or their DNA remnants) 1(-1). Such quantitative estimates should aid decisions about disease prevention and management as, for example, choice of netpen sites following fallow periods and certification of ova, which are known conduits of infection.

Animals↗
PubMed2000

Treatment of separation anxiety in dogs with clomipramine: results from a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial.

The efficacy and tolerability of clomipramine in the treatment of separation anxiety in dogs was tested in a prospective, randomized, double-blind, placebo-controlled, parallel-group, international multicenter clinical trial. For a diagnosis of separation anxiety, dogs had to exhibit at least one of the following signs in the absence of their owner: destruction, defecation, urination and/or vocalization, as well as the behaviour suggestive of "hyper-attachment" to their owner. A total of 95 dogs were randomized to receive one of the three treatments for 2-3 months: "standard-dose" clomipramine (1 to <2 mg/kg, PO, q. 12 h); "low-dose" clomipramine (0.5 to <1 mg/kg, PO, q. 12 h); and placebo (PO, q. 12 h). All dogs received behavioural therapy. Dogs were examined at four time points (days 0, 28, 56 and 84) after the initiation of therapy. Improvement in each dog's behaviour at days 28, 56 and 84 was evaluated in comparison to its behaviour at day 0.The results showed that, compared to placebo, dogs receiving standard-dose clomipramine were rated improved at least three times faster for the signs destruction, defecation and urination. At most time points, more dogs in the standard-dose clomipramine group were rated improved for the signs destruction, defecation and urination, and in an owner's global assessment of the dog's overall behaviour (p<0.05 at certain time points). However, there were no statistically significant differences at any time point between the standard dose and the placebo groups in the sign vocalization. The low-dose clomipramine group produced no statistically significant effect when compared with placebo. Mild and transient vomiting was noted as a side effect of clomipramine in a small number of dogs.It is concluded that addition of standard-dose (1 to <2 mg/kg, PO, q. 12 h) clomipramine to conventional behavioural therapy for 2-3 months ameliorated the signs of separation anxiety in dogs.

Journal Article↗
PubMed1999

Transgene expression and repression in transgenic rats bearing the phosphoenolpyruvate carboxykinase-simian virus 40 T antigen or the phosphoenolpyruvate carboxykinase-transforming growth factor-alpha constructs.

Transgenic Sprague-Dawley rats expressing either human transforming growth factor-alpha (TGFalpha) or simian virus 40 large and small T antigen (TAg), each under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter, were developed as an approach to the study of the promotion of hepatocarcinogenesis in the presence of a transgene regulatable by diet and/or hormones. Five lines of PEPCK-TGFalpha transgenic rats were established, each genetic line containing from one to several copies of the transgene per haploid genome. Two PEPCK-TAg transgenic founder rats were obtained, each with multiple copies of the transgene. Expression of the transgene was undetectable in the TGFalpha transgenic rats and could not be induced when the animals were placed on a high-protein, low-carbohydrate diet. The transgene was found to be highly methylated in all of these lines. No pathological alterations in the liver and intestine were observed at any time (up to 2 years) during the lives of these rats. One line of transgenic rats expressing the PEPCK-TAg transgene developed pancreatic islet cell hyperplasias and carcinomas, with few normal islets evident in the pancreas. This transgene is integrated as a hypomethylated tandem array of 10 to 12 copies on chromosome 8q11. Expression of large T antigen is highest in pancreatic neoplasms, but is also detectable in the normal brain, kidney, and liver. Mortality is most rapid in males, starting at 5 months of age and reaching 100% by 8 months. Morphologically, islet cell differentiation in the tumors ranges from poor to well differentiated, with regions of necrosis and fibrosis. Spontaneous metastasis of TAg-positive tumor cells to regional lymph nodes was observed. These studies indicate the importance of DNA methylation in the repression of specific transgenes in the rat. However, the expression of the PEPCK-TAg induces neoplastic transformation in islet cells, probably late in neuroendocrine cell differentiation. T antigen expression during neoplastic development may result in a pervasive change in the islet cell growth properties with selection of a transformed phenotype as a possible requirement for cell viability.

Animals↗
PubMed1999

Helminth parasites of the wild rabbit Oryctolagus cuniculus near Malham Tarn, Yorkshire, UK.

Between 1992 and 1996, 95 rabbits from the immediate locality of Malham Tarn, North Yorkshire, UK were examined for the presence of helminth parasites. All the examinations took place in late September or October. Three species of nematodes, Graphidium strigosum, Passalurus ambiguus and Trichostrongylus retortaeformis and two species of cestodes, Taenia pisiformis and Cittotaenia pectinata were identified. There were no associations between helminth species richness and year of sampling, host weight or sex. A logistic model was fitted to the prevalence data from these helminths as was an over-dispersed Poisson model to the worm burden data. Graphidium strigosum was the most frequently identified species with an average prevalence of 78%. The mean prevalence and intensity of Graphidium infection were significantly effected by sampling year. The lower than normal rainfall recorded at the Tarn during the years 1995 and 1996 may have be one reason for this pattern. The worm burden of G. strigosum was significantly positively associated with rabbit body weight. The intensity of infection with P. ambiguus was significantly higher in female rabbits. There was a significant non-linear relationship between P. ambiguus worm burden and rabbit weight (P = 0.002) with worm burdens being highest in the 1000 g to 1499 g weight cohort. Trichostrongylus retortaeformis was only identified in 1994 and male rabbits harboured significantly higher worm burdens than females (48 vs. 7, P = 0.022). Over the five years, the average Taenia pisiformis prevalence was 31% and there was a significant positive association between worm burden and rabbit weight (P = 0.001). Cittotaenia pectinata had a prevalence of 37% over the whole study period with no interactions between prevalence or intensity and body weight, year of sampling or rabbit sex. All five helminths showed an overdispersed distribution with k values less than 1.

Animals↗
PubMed1998

The mechanism of thioacetamide-induced apoptosis in the L37 albumin-SV40 T-antigen transgenic rat hepatocyte-derived cell line occurs without DNA fragmentation.

The hepatotoxicant thioacetamide (TH) has classically been used as a model to study hepatic necrosis; however, recent studies have shown that TH can also induce apoptosis. In this report we demonstrate that 2.68+/-0.54% of the albumin-SV40 T-antigen transgenic rat hepatocytes undergo TH-induced apoptosis, a level comparable to other in vivo models of liver apoptosis. In addition, TH could induce apoptosis and necrosis in the L37 albumin-SV40 T-antigen transgenic rat liver-derived cell line. Examination of dying L37 cells treated with 100 mM TH by electron microscopy revealed distinct morphological characteristics that could be attributed to apoptosis. Quantitation of apoptosis by FACS analysis 24 h after treatment with 100 mM TH revealed that 81.3+/-1.6% of the cells were undergoing apoptosis. In contrast, when L37 cells were treated with 250 mM TH, cells exhibited characteristics consistent with necrotic cell death. DNA fragmentation ladders were produced by growth factor withdrawal-induced apoptosis; however, in 100 mM TH-induced apoptosis, DNA fragmentation ladders were not observed. Analysis of endonuclease activity in L37 cells revealed that the enzymes were not inactivated in the presence of 100 mM TH. The data presented in this report indicate that the L37 cell line could be used to study the mechanism of TH-induced apoptosis that was not mediated through a mechanism requiring DNA fragmentation.

Albumins↗
PubMed1997

Differential behavioral responses to dopaminergic stimulation of nucleus accumbens subregions in the rat.

The following experiments investigated the behavioral response to local microinfusion of dopamine (DA) and selective DA agonists into the core and shell subregions of the nucleus accumbens. Rats were implanted with chronic indwelling cannulae aimed at these subregions. Two experiments were conducted. In experiment 1, the response to DA (0, 2, 5, 10 microg/0.5 microl/side), the D-1 agonist SKF-82598 (0, 0.1, 1.0 microg), the D-2/3 agonist quinpirole (0, 1, 5, 15 microg) and the D-3 preferring agonist pramipexole (0.1, 1.0, 10.0 microg) was examined in photocell activity cages. Locomotor (horizontal) and rearing (vertical) activities were measured. DA and SKF-82958 induced relatively greater increases in activity following stimulation of the shell as compared with the core. Quinpirole induced a dose-dependent suppression of activity after infusion into both sites, although the core was more sensitive to the suppressive effect than the shell. Pramipexole induced time-dependent, biphasic effects that were small in magnitude and did not differentiate between site. In experiment 2, an observation procedure was used to record behaviors (locomotion, rearing, feeding, drinking). Dopamine (0, 2, 10 microg) elicited greater increases in rearing and feeding behavior in the shell than in the core. SKF-82958 (0, 0.75 microg) enhanced locomotion and rearing to a similar extent in both subregions in this test, whereas a mixture of a low dose (0.25 microg) of the D-1 and D-2 agonists selectively induced behavioral activation in the shell. In contrast to the results in the activity cage test, quinpirole (0, 1, 5 microg) increased motor activity at the lower dose when infused into the shell but not into the core. No alterations in feeding were observed following infusion of selective agonists, and no changes in drinking were found with any of the treatments. In summary, the shell appears to be relatively more sensitive to the motor activating effects of DA agonists than the core. Moreover, circuits associated with shell may be preferentially involved in feeding.

Animals↗
PubMed1996

Pseudomeningocele/CSF fistula in a patient with lumbar spinal implants treated with epidural blood patch and a brief course of closed subarachnoid drainage. A case report.

STUDY DESIGN: This case report illustrates the development of a cerebrospinal fluid fistula and pseudomeningocele in a patient after lumbar discectomy and fusion with instrumentation. OBJECTIVE: The patient is treated successfully with a combined treatment protocol of epidural blood patch and brief course of spinal drainage. SUMMARY OF BACKGROUND DATA: Many surgeons advocate a trial of cerebrospinal fluid diversion for postoperative cerebrospinal fluid fistula. This treatment may be problematic in patients with spinal implants because a trial of cerebrospinal fluid diversion may not obliterate the extradural anatomic dead space that is created by instrumentation procedures and increases the rist of infection. A few case reports indicate that epidural blood patch also may be an effective management technique. A combined treatment protocol that may offer some advantages to either treatment alone is described METHODS: The patient was brought to the radiology department, and a lumbar spinal drain was placed at the L2-L3 interspace under fluoroscopic guidance with the patient in the prone position. A Tuohy needle was inserted into the pseudomeningocele, and the collection was drained. Thirty milliters of blood drawn from an antecubital vein was injected into the epidural space over the laminectomy site. Spinal drainage was continued for 4 days. RESULTS: The treatment protocol resulted in resolution of cerebrospinal fluid leakage in the patient. This result was confirmed by myelogram. CONCLUSIONS: Postoperative pseudomeningocele and cerebrospinal fluid fistula in patients with spinal instrumentation can be treated successfully with epidural blood patch and a brief course (4 days) of spinal drainage. This combined treatment protocol may have some advantages to treatment with 7 days of cerebrospinal fluid diversion or to percutaneous epidural blood patch alone.

Adult↗
PubMed1996

Cancer rehabilitation for children: a model with potential.

The dramatic improvements in the treatment of children's cancers has lead to the identification of a growing need for the development of comprehensive rehabilitation programmes. These programmes should include help in learning to live with cancer, and maximize levels of independence for the child with cancer and their family. In this paper, the author will demonstrate the potential for childhood cancer rehabilitation, highlighting factors already in place and those areas that could benefit from development.

Activities of Daily Living↗
PubMed1995

The effects of calcitonin on serum calcium levels in immature brown trout, Salmo trutta.

Salmon calcitonin was administered intraperitoneally (0.1, 10, 1000 ng/100 g of fish) to freshwater-adapted, immature, female brown trout, Salmo trutta, and changes in serum calcium levels were determined. The lowest dose (0.1 ng) had an effect similar to injection of saline (control), but the higher doses produced hypercalcemia. These latter effects were associated with increased serum levels of calcitonin. Maintaining immature brown trout in waters containing 20 and 50 mM calcium chloride resulted in a significant lowering of serum calcitonin with time although serum calcium levels remained stable. The extent of the decrease in serum calcitonin increased with the higher levels of environmental calcium.

Aging↗