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Biomedical subjects

P Clarke

Publications and source records attributed to P Clarke.

At least 37 records · Page 2Linked to original sources
PubMed2005

Mechanisms of reovirus-induced cell death and tissue injury: role of apoptosis and virus-induced perturbation of host-cell signaling and transcription factor activation.

Reoviruses have provided insight into the roles played by specific viral genes and the proteins they encode in virus-induced cell death and tissue injury. Apoptosis is a major mechanism of cell death induced by reoviruses. Reovirus-induced apoptosis involves both death-receptor and mitochondrial cell death pathways. Reovirus infection is associated with selective activation of mitogen activated protein kinase (MAPK) cascades including JNK/SAPK. Infection also perturbs transcription factor signaling resulting in the activation of c-Jun and initial activation followed by strain-specific inhibition of NF-kappaB. Infection results in changes in the expression of genes encoding proteins involved in cell cycle regulation, apoptosis, and DNA damage and repair processes. Apoptosis is a major mechanism of reovirus-induced injury to key target organs including the CNS and heart. Inhibition of apoptosis through the use of caspase or calpain inhibitors, minocycline, or in caspase 3(-/-) mice all reduce virus-associated tissue injury and enhance survival of infected animals. Reoviruses induce apoptotic cell death (oncolysis) in a wide variety of cancer cells and tumors. The capacity of reoviruses to grow efficiently in transformed cells is enhanced by the presence of an activated Ras signaling pathway likely through mechanisms involving inhibition of antiviral PKR signaling and activation of Ras/RalGEF/p38 pathways. The potential of reovirus-induced oncolysis in therapy of human cancers is currently being investigated in phase I/II clinical trials.

Animals↗
PubMed2005

Neonatal symptoms following maternal paroxetine treatment: serotonin toxicity or paroxetine discontinuation syndrome?

We report a case of neonatal symptoms of irritability, increased tonus and convulsions after in-utero exposure to paroxetine 30 mg/day. The infant's symptoms commenced on the first day after birth and persisted for 10 days. Paroxetine levels were undetectable on day 6. Extensive investigations excluded infective and metabolic causes. Serotonin toxicity due to paroxetine seems the most likely mechanism, though an important differential diagnosis is a paroxetine discontinuation (withdrawal) syndrome. Differentiating between these two syndromes in the neonate presents a dilemma for clinicians. Irrespective of the mechanism, we recommend that all neonates exposed to antidepressants, particularly serotonin reuptake inhibitors (SSRIs), during the last trimester should be followed-up closely for adverse symptoms commencing in the first 10 days after birth. The possibility of such symptoms needs to be discussed with women who are considering starting or continuing antidepressant treatment in pregnancy. All neonatal adverse drug events should be reported to a pharmacovigilance centre. Further research is warranted.

Adult↗
PubMed2004

Antimicrobial susceptibility of invasive isolates of Streptococcus pneumoniae in Ireland.

Between January 1999 and June 2002, 646 invasive isolates of Streptococcus pneumoniae were collected in Ireland. MICs of penicillin, ciprofloxacin, cefotaxime, moxifloxacin and linezolid were determined by Etest methodology. Eighty-seven (13.5%) isolates showed intermediate resistance to penicillin, while seven (1.1%) showed high-level resistance. Eighty-seven (13.5%) isolates were resistant to erythromycin, but all isolates were susceptible to cefotaxime, moxifloxacin and linezolid. The prevalence of pneumococcal isolates non-susceptible to penicillin in Ireland is worryingly high, but currently there are alternative agents available to treat invasive infection.

Adolescent↗
PubMed2004

Employment status, employment conditions, and limiting illness: prospective evidence from the British household panel survey 1991-2001.

OBJECTIVES: To assess the relation of the incidence of, and recovery from, limiting illness to employment status, occupational social class, and income over time in an initially healthy sample of working age men and women. METHODS: Cox proportional hazards models. RESULTS: There were large differences in the risk of limiting illness according to occupational social class, with men and women in the least favourable employment conditions nearly four times more likely to become ill than those in the most favourable. Unemployment and economic inactivity also had a powerful effect on illness incidence. Limiting illness was not a permanent state for most participants in the study. Employment status was also related to recovery. CONCLUSIONS: Having secure employment in favourable working conditions greatly reduces the risk of healthy people developing limiting illness. Secure employment increases the likelihood of recovery. These findings have considerable implications for both health inequality and economic policies.

Adult↗
PubMed2003

Reovirus-induced apoptosis: A minireview.

Reoviruses infect a variety of mammalian hosts and serve as an important experimental system for studying the mechanisms of virus-induced injury. Reovirus infection induces apoptosis in cultured cells in vitro and in target tissues in vivo, including the heart and central nervous system (CNS). In epithelial cells, reovirus-induced apoptosis involves the release of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) from infected cells and the activation of TRAIL-associated death receptors (DRs) DR4 and DR5. DR activation is followed by activation of caspase 8, cleavage of Bid, and the subsequent release of pro-apoptotic mitochondrial factors. By contrast, in neurons, reovirus-induced apoptosis involves a wider array of DRs, including TNFR and Fas, and the mitochondria appear to play a less critical role. These results show that reoviruses induce apoptotic pathways in a cell and tissue specific manner. In vivo there is an excellent correlation between the location of viral infection, the presence of tissue injury and apoptosis, indicating that apoptosis is a critical mechanism by which disease is triggered in the host. These studies suggest that inhibition of apoptosis may provide a novel strategy for limiting virus-induced tissue damage following infection.

Animals↗
PubMed2003

Parenteral nutrition solution retrieved by lumbar puncture following left saphenous vein catheterization.

Two extremely preterm infants had silastic lines inserted via the left great saphenous vein for intravenous feeding. Clinical deterioration approximately 10 days later led to lumbar puncture as part of a sepsis screen. Parenteral nutrition solution was recovered in the cerebrospinal fluid and heralded potentially life-threatening catheter malposition. The cases illustrate another percutaneous central line-associated morbidity, which is avoidable by careful verification of line position. All previously reported cases of this unusual complication are reviewed and we describe its likely mechanism. We postulate that the phenomenon is a complication peculiar to percutaneous catheterization of the left lower limb.

Australia↗
PubMed2003

The impact of diabetes-related complications on healthcare costs: results from the United Kingdom Prospective Diabetes Study (UKPDS Study No. 65).

AIMS: To develop a model for estimating the immediate and long-term healthcare costs associated with seven diabetes-related complications in patients with Type 2 diabetes participating in the UK Prospective Diabetes Study (UKPDS). METHODS: The costs associated with some major complications were estimated using data on 5102 UKPDS patients (mean age 52.4 years at diagnosis). In-patient and out-patient costs were estimated using multiple regression analysis based on costs calculated from the length of admission multiplied by the average specialty cost and a survey of 3488 UKPDS patients' healthcare usage conducted in 1996-1997. RESULTS: Using the model, the estimate of the cost of first complications were as follows: amputation pound 8459 (95% confidence interval pound 5295, pound 13 200); non-fatal myocardial infarction pound 4070 ( pound 3580, pound 4722); fatal myocardial infarction pound 1152 ( pound 941, pound 1396); fatal stroke pound 3383 ( pound 1935, pound 5431); non-fatal stroke pound 2367 ( pound 1599, pound 3274); ischaemic heart disease pound 1959 ( pound 1467, pound 2541); heart failure pound 2221 ( pound 1690, pound 2896); cataract extraction pound 1553 ( pound 1320, pound 1855); and blindness in one eye pound 872 ( pound 526, pound 1299). The annual average in-patient cost of events in subsequent years ranged from pound 631 ( pound 403, pound 896) for heart failure to pound 105 ( pound 80, pound 142) for cataract extraction. Non-in-patient costs for macrovascular complications were pound 315 ( pound 247, pound 394) and for microvascular complications were pound 273 ( pound 215, pound 343) in the year of the event. In each subsequent year the costs were, respectively, pound 258 ( pound 228, pound 297) and pound 204 ( pound 181, pound 255). CONCLUSIONS: These results provide estimates of the immediate and long-term healthcare costs associated with seven diabetes-related complications.

Ambulatory Care↗
PubMed2003

A postnatal fasting plasma glucose is useful in determining which women with gestational diabetes should undergo a postnatal oral glucose tolerance test.

AIMS: It is recommended that women with gestational diabetes (GDM) should have a 6-week postnatal oral glucose tolerance test (OGTT). As this test may be unpleasant, time-consuming and has resource implications, we evaluated whether the 6-week postnatal fasting glucose could be used to determine which women should undergo an OGTT. METHODS: All women with GDM, diagnosed according to the World Health Organization criteria, who were delivered at the Princess Anne Hospital, Southampton between May 2000 and May 2002, were recommended to have an OGTT. The results of the fasting plasma glucose concentration were assessed in relation to the 2-h glucose value. RESULTS: One-hundred and fifty-two women with GDM were delivered. Thirty (19.7%) women refused an OGTT or failed to attend. In the 122 OGTTs, three (2.4%; 95% confidence interval 0.8, 7) women had diabetes, three had impaired glucose tolerance and four had impaired fasting glycaemia. No woman with a normal test had fasting glucose of > or =6.0 mmol/l. Fasting glucose was correlated with the 2-h glucose (r=0.62, P<0.0001). Only 10 (8.1%) of the OGTTs would have been performed if only women with fasting glucose of > or =6.0 mmol/l underwent the test. The sensitivity and specificity of this approach for the diagnosis of postnatal diabetes is 100% and 94%, respectively. Linear regression methods indicate that it would miss fewer than three in 10 000 cases. CONCLUSIONS: In our population, a 6-week postnatal fasting plasma glucose is useful in determining which women with gestational diabetes should undergo an OGTT. Consequently we now perform OGTT only in women whose postnatal fasting plasma glucose is > or =6.0 mmol/l.

Blood Glucose↗
PubMed2003

Effect of a fourth Haemophilus influenzae type b immunisation in preterm infants who received dexamethasone for chronic lung disease.

AIM: To assess whether a fourth Hib polysaccharide-tetanus protein conjugate vaccine (PRP-T) would improve antibody response in preterm infants previously treated with dexamethasone for chronic lung disease. METHODS: In a pilot study 12 infants born at less than 30 weeks gestation who had received corticosteroids were given a supplementary Hib dose six weeks after completion of the primary immunisation course. Serum samples obtained before and at eight weeks following the fourth Hib dose were analysed for total level and avidity of anti-PRP antibody. RESULTS: There was no significant increase in the geometric mean titre (GMT) of anti-PRP antibody resulting from the fourth Hib immunisation (GMT: pre 2.35 micro g/ml, post 2.24 micro g/ml, p = 0.79). A subgroup of six infants had subprotective antibody levels (<1.0 micro g/ml) after the primary immunisation course, which remained subprotective following the extra Hib immunisation. Despite the poor response in total antibody level, the study group showed a significant rise in PRP specific IgG avidity following the fourth immunisation (GMAI: pre 0.076, post 0.138, p = 0.043). CONCLUSION: An additional Hib immunisation given to recently steroid treated preterm infants six weeks after completion of the primary schedule did not augment primary immunogenicity. However, increasing avidity may imply successful priming and long term immunity to Hib.

Antibodies, Viral↗