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Biomedical subjects

P Russell

Publications and source records attributed to P Russell.

At least 19 recordsLinked to original sources

A biocompatible microdevice for core body temperature monitoring in the early diagnosis of infectious disease.

The early diagnosis of microbial infection is critical to the clinical instigation of effective post-exposure prophylaxis or therapy. However, diagnosis of infection is often attempted only when there are overt clinical signs, and for some of the serious human pathogens, this may jeopardize the efficacy of therapy. We have used a miniaturised sealed, implantable transponder incorporating a calibrated temperature sensor with an external receiver system, to monitor core body temperature (Tc) remotely. We have observed early changes in the diurnal rhythm of Tc, after infection of mice with bacterial pathogens. Changes in Tc preceded overt clinical signs by 3-10 h following challenge with Yersinia pestis, which causes acute infection, In contrast, changes in Tc were detected 11 days before clinical signs in mice exposed to Burkholderia pseudomallei, which causes a chronic syndrome. Significantly, mice pre-vaccinated against Y.pestis infection showed only slight and transient disruption to the diurnal rhythm for Tc, in the absence of clinical signs, when challenged with 10(6) median lethal doses of Y.pestis. This remote monitoring technology could be used to monitor changes in more than one physiological parameter and extrapolation of these data to the clinic would define the available therapeutic window in which diagnosis and post-exposure prophylaxis could be instigated, after a suspected exposure.

Animals↗

Emerging epidemic diseases of frogs in Britain are dependent on the source of ranavirus agent and the route of exposure.

A series of transmission studies was conducted to investigate the aetiology, or aetiologies, of emerging fatal epidemic disease syndromes affecting the common frog (Rana temporaria) in Britain. The syndromes, characterized by skin ulceration or systemic haemorrhages, were induced upon exposure to lesion homogenates or cultured ranavirus. The re-isolation of ranavirus from experimentally affected frogs fulfilled Koch's postulates. Aeromonas hydrophila, previously associated with similar lesions, was not significant to disease development. Unexpectedly, disease outcomes were influenced by both the source of agent and the route of exposure, indicating that different ranaviruses with different tissue tropisms and pathogeneses (possibly similar to quasi-species in RNA virus populations) are circulating in the British common frog population. Our findings confirm that ranavirus disease has emerged as an important cause of amphibian mortality in Britain.

Aeromonas hydrophila↗

Interaction of an optical soliton with a dispersive wave.

Scattering of a dispersive wave by optical solitons is studied experimentally in photonic crystal fibers in cases when the soliton and the dispersive wave have either identical or orthogonal polarization states. Observations of new resonant frequencies are reported. The experimental results are compared to numerical simulations and predictions from the recently derived wave vector matching conditions.

Journal Article↗

High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis.

BACKGROUND: Endometriosis is a common gynaecological disease and is frequently associated with recurrent and serious pelvic pain such as dysmenorrhoea and dyspareunia, but the mechanisms by which these symptoms are generated are not well understood. METHODS: Histological sections of endometrial tissue were prepared from endometrial curettings and hysterectomies performed on women with endometriosis (n=25 and n=10, respectively) and without endometriosis (n=47 and n=35, respectively). These were stained immunohistochemically for the highly specific polyclonal rabbit anti-protein gene product 9.5 (PGP9.5) and monoclonal mouse anti-neurofilament protein (NF) to demonstrate both myelinated and unmyelinated nerve fibres. RESULTS: Small nerve fibres were identified throughout the basal and functional layers of the endometrium in all endometriosis patients, but were not seen in the functional layer of the endometrium in any of the women without endometriosis (P<0.001). NF-immunoreactive nerve fibres were present in the basal layer in all endometriosis patients but not in non-endometriosis patients, with one exception (P<0.001). CONCLUSIONS: Small nerve fibres detected in the functional layer in all women with endometriosis may have important implications for understanding the generation of pain in these patients. The presence of nerve fibres in an endometrial biopsy may be a novel surrogate marker of clinical endometriosis.

Adult↗

Prognostic analysis of pre-transplant peripheral T-cell levels in patients receiving an autologous hematopoietic progenitor-cell transplant.

The purpose of this study was to evaluate pre-transplant T-cell status in autologous hematopoietic progenitor-cell transplantation (HPCT) recipients. Between 1999 and 2002 we prospectively enrolled 85 autologous HPCT recipients with solid tumors (N = 50) or hematological malignancies (n = 35). Patient diagnoses included breast cancer (N = 49), non-Hodgkin's lymphoma (N = 20), myeloma (N = 11), Hodgkin's disease (N = 3), germ-cell tumor (N = 1) and amyloidosis (N = 1). Levels of CD3, CD4, CD8, memory and naïve CD4, and CD8 T-cell subsets were analyzed before autologous HPCT. Autologous HPCT recipients presented with lower pre-transplant counts of CD3, CD4, but not CD8 T cells, as compared to healthy controls. Pre-transplant CD4 T-cell levels correlated with progression-free survival (PFS) (P = 0.002) and overall survival (OS) (P = 0.05), in patients with hematologic malignancies (P = 0.02) and breast cancer (P = 0.04). Specifically, pre-transplant memory CD4 + CD45RA - CD62L - T-cell levels correlated with PFS (P = 0.01). The prognostic effects of pre-transplant CD4 and CD4 + CD45RA - CD62L - T cells were independent of tumor diagnosis, tumor stage, tumor sensitivity, and, for breast cancer patients, Her2 / neu status. Our results suggest that pre-transplant CD4 T-cell status, specifically CD4 + CD45RA - CD62L - memory T cells, correlates with the outcome of autologous HPCT recipients. These observations suggest the feasibility of prospective identification of those patients at higher risk of relapse, based on their immune status.

Adult↗

Efficacy of the latest fluoroquinolones against experimental Yersinia pestis.

The efficacies of prophylactic and therapeutic gatifloxacin and moxifloxacin were assessed in a BALB/c mouse model of systemic and pneumonic plague and compared with ciprofloxacin. Mice were given 100 mg/kg of the antibiotic by oral administration twice daily for 7 days starting 1h prior to infection or following infection. All antibiotics offered full protection for up to 6h following systemic challenge, and for up to 30 h following an aerosol challenge. The efficacy of each of the antibiotics decreased when antibiotics were started 18 h following systemic challenge and 48 h following aerosol challenge. Fluoroquinolones may therefore be considered useful candidates for the treatment of bubonic and pneumonic plague.

Animals↗

Cerebellar metastases from prostatic carcinoma.

A 67-year-old man presented with worsening headaches and gait disturbance, and with minimal clinical signs. A brain MRI showed multiple solid cerebellar metastases. The pathological diagnosis of metastatic carcinoma of the prostate was further suggested by an elevation in prostate specific antigen, and was pathologically confirmed following the neurosurgical removal of the tumours. The rarity of this presentation, as documented in the clinical literature, is reviewed.

Adenocarcinoma↗

Passive protection against Burkholderia pseudomallei infection in mice by monoclonal antibodies against capsular polysaccharide, lipopolysaccharide or proteins.

Burkholderia pseudomallei, the aetiological agent of melioidosis, is endemic in south-east Asia and northern Australia, where it is an important cause of human disease. There is no vaccine available and antibiotic therapy is associated with high relapse rates. A panel of seven monoclonal antibodies (MAbs) that recognise capsular polysaccharide, lipopolysaccharide or proteins was produced and their ability to protect mice passively against experimental melioidosis was evaluated. The MAbs were capable of protecting mice against intra-peritoneal challenge with 10(4) cfu/250 MLD of a virulent strain of B. pseudomallei (NCTC 4845), when pooled, and four of the MAbs were individually protective. However, at a higher B. pseudomallei challenge level of 10(6) cfu none of the MAbs afforded protection and only the anti-exopolysaccharide MAbs produced a significantly delayed time to death.

Animals↗

High grade abnormalities following an 'inconclusive' smear.

OBJECTIVE: The National Health and Medical Research Council (NHMRC) recommends a report of 'inconclusive possible high grade epithelial abnormality', but many laboratories only report 'inconclusive' with reference to any possible high grade disease elsewhere in the report. This study was performed to determine possible reasons for cytological difficulties resulting in this category of report and to determine the rate of significant disease within this category. DESIGN: Retrospective record review. Clinical details were extracted without patient-identifying data. SETTING: Gynaecological Oncology Department, King George V/Royal Prince Alfred Hospital. POPULATION: Two hundred patients referred with the cytological abnormality. MATERIALS AND METHODS: An adequate colposcopic diagram documenting size, distribution and grade of lesion was required. All patients had colposcopy with management according to colposcopic and histological results as appropriate to their disease. OUTCOME MEASURES: Colposcopic features, topography and size of any lesion, histological results, treatments performed and subsequent review of untreated patients. RESULTS: Colposcopy found high-grade lesions in 43% and carcinoma in 1%. Histopathology found 49% and 4% respectively. Treatment was performed in 124 patients. Inflammation was found in 27%, a small lesion in 43% and endocervical disease in 21%. CONCLUSIONS: The high rate of endocervical disease, inflammation and small lesions may explain the cytological difficulties leading to an 'inconclusive' result. The authors believe that the term 'inconclusive' alone does not adequately convey the high level of risk faced by these patients.

Adolescent↗

A mutant of Burkholderia pseudomallei, auxotrophic in the branched chain amino acid biosynthetic pathway, is attenuated and protective in a murine model of melioidosis.

Using a transposon mutagenesis approach, we have identified a mutant of Burkholderia pseudomallei that is auxotrophic for branched chain amino acids. The transposon was shown to have interrupted the ilvI gene encoding the large subunit of the acetolactate synthase enzyme. Compared to the wild type, this mutant was significantly attenuated in a murine model of disease. Mice inoculated intraperitoneally with the auxotrophic mutant, 35 days prior to challenge, were protected against a challenge dose of 6,000 median lethal doses of wild-type B. pseudomallei.

Amino Acids, Branched-Chain↗

Purification and characterization of the 1.0 MDa CCR4-NOT complex identifies two novel components of the complex.

The CCR4-NOT complex is an evolutionarily conserved, transcriptional regulatory complex that is involved in controlling mRNA initiation, elongation and degradation. The CCR4-NOT proteins from Saccharomyces cerevisiae exist in two complexes, 1.9x10(6) Da and 1.0x10(6) Da (1.0 MDa) in size, and individual components of these complexes display such disparate functions as binding to and restricting TFIID functions, contacting SAGA and contributing to mRNA deadenylation. As a first step in characterizing the functional roles of the 1.0 MDa complex, we have purified it to near homogeneity. Mass spectrometric analysis was subsequently used to identify all the components of the complex. The 1.0 MDa complex was found to contain CCR4, CAF1, NOT1-5 and two new proteins, CAF40 and CAF130. CAF130 and CAF40 are two unique yeast proteins, with CAF40 displaying extensive homology to proteins from other eukaryotes. Immunoprecipitation and gel filtration experiments confirmed that CAF130 and CAF40 are components of both of the 1.9 MDa and 1.0 MDa CCR4-NOT complexes. Biochemical analysis indicated that the CAF40 and CAF130 proteins bind to the NOT1 protein and exist in a location separate from the two other subsets of proteins in the complex: the CCR4 and CAF1 proteins, and the NOT2, NOT4 and NOT5 proteins. Moreover, CAF40 was able to interact with human NOT1, suggesting that human CAF40 would also be a component of the recently identified human CCR4-NOT complex. Analysis of caf40 and caf130 deletions indicated that they elicited phenotypes shared by defects in other CCR4-NOT genes. The distinct location of CAF40 and CAF130 and the evolutionary conservation of CAF40 implicate them in novel roles in the function of the CCR4-NOT complex.

Binding Sites↗

Mus81-Eme1 are essential components of a Holliday junction resolvase.

Mus81, a fission yeast protein related to the XPF subunit of ERCC1-XPF nucleotide excision repair endonuclease, is essential for meiosis and important for coping with stalled replication forks. These processes require resolution of X-shaped DNA structures known as Holliday junctions. We report that Mus81 and an associated protein Eme1 are components of an endonuclease that resolves Holliday junctions into linear duplex products. Mus81 and Eme1 are required during meiosis at a late step of meiotic recombination. The mus81 meiotic defect is rescued by expression of a bacterial Holliday junction resolvase. These findings constitute strong evidence that Mus81 and Eme1 are subunits of a nuclear Holliday junction resolvase.

Amino Acid Sequence↗

Serine-345 is required for Rad3-dependent phosphorylation and function of checkpoint kinase Chk1 in fission yeast.

Genome integrity is monitored by a checkpoint that delays mitosis in response to DNA damage. This checkpoint is enforced by Chk1, a protein kinase that inhibits the mitotic inducer Cdc25. In fission yeast, Chk1 is regulated by a group of proteins that includes Rad3, a protein kinase related to human ATM and ATR. These kinases phosphorylate serine or threonine followed by glutamine (SQ/TQ). Fission yeast and human Chk1 proteins share two conserved SQ motifs at serine-345 and serine-367. Serine-345 of human Chk1 is phosphorylated in response to DNA damage. Here we report that Rad3 and ATM phosphorylate serine-345 of fission yeast Chk1. Mutation of serine-345 (chk1-S345A) abrogates Rad3-dependent phosphorylation of Chk1 in vivo. The chk1-S345A cells are sensitive to DNA damage and are checkpoint defective. In contrast, mutations of serine-367 and other SQ/TQ sites do not substantially impair the checkpoint or cause damage sensitivity. These findings attest to the importance of serine-345 phosphorylation for Chk1 function and strengthen evidence that transduction of the DNA damage checkpoint signal requires direct phosphorylation of Chk1 by Rad3.

Adenosine Triphosphatases↗