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Biomedical subjects

Peter G Smith

Publications and source records attributed to Peter G Smith.

At least 19 recordsLinked to original sources
PubMed2007

Low-cost rapid detection of rifampicin resistant tuberculosis using bacteriophage in Kampala, Uganda.

BACKGROUND: Resistance to anti-tuberculosis drugs is a serious public health problem. Multi-drug resistant tuberculosis (MDR-TB), defined as resistance to at least rifampicin and isoniazid, has been reported in all regions of the world. Current phenotypic methods of assessing drug susceptibility of M. tuberculosis are slow. Rapid molecular methods to detect resistance to rifampicin have been developed but they are not affordable in some high prevalence countries such as those in sub Saharan Africa. A simple multi-well plate assay using mycobacteriophage D29 has been developed to test M. tuberculosis isolates for resistance to rifampicin. The purpose of this study was to investigate the performance of this technology in Kampala, Uganda. METHODS: In a blinded study 149 M. tuberculosis isolates were tested for resistance to rifampicin by the phage assay and results compared to those from routine phenotypic testing in BACTEC 460. Three concentrations of drug were used 2, 4 and 10 microg/ml. Isolates found resistant by either assay were subjected to sequence analysis of a 81 bp fragment of the rpoB gene to identify mutations predictive of resistance. Four isolates with discrepant phage and BACTEC results were tested in a second phenotypic assay to determine minimal inhibitory concentrations. RESULTS: Initial analysis suggested a sensitivity and specificity of 100% and 96.5% respectively for the phage assay used at 4 and 10 microg/ml when compared to the BACTEC 460. However, further analysis revealed 4 false negative results from the BACTEC 460 and the phage assay proved the more sensitive and specific of the two tests. Of the 39 isolates found resistant by the phage assay 38 (97.4%) were found to have mutations predictive of resistance in the 81 bp region of the rpoB gene. When used at 2 mug/ml false resistant results were observed from the phage assay. The cost of reagents for testing each isolate was estimated to be 1.3 US dollars when testing a batch of 20 isolates on a single 96 well plate. Results were obtained in 48 hours. CONCLUSION: The phage assay can be used for screening of isolates for resistance to rifampicin, with high sensitivity and specificity in Uganda. The test may be useful in poorly resourced laboratories as a rapid screen to differentiate between rifampicin susceptible and potential MDR-TB cases.

Antibiotics, Antitubercular↗
PubMed2006

Sympathetic hyperinnervation and inflammatory cell NGF synthesis following myocardial infarction in rats.

Sympathetic hyperinnervation occurs in human ventricular tissue after myocardial infarction and may contribute to arrhythmias. Aberrant sympathetic sprouting is associated with elevated nerve growth factor (NGF) in many contexts, including ventricular hyperinnervation. However, it is unclear whether cardiomyocytes or other cell types are responsible for increased NGF synthesis. In this study, left coronary arteries were ligated and ventricular tissue examined in rats 1-28 days post-infarction. Infarct and peri-infarct tissue was essentially devoid of sensory and parasympathetic nerves at all time points. However, areas of increased sympathetic nerve density were observed in the peri-infarct zone between post-ligation days 4-14. Hyperinnervation occurred in regions containing accumulations of macrophages and myofibroblasts. To assess whether these inflammatory cells synthesize NGF, sections were processed for NGF in situ hybridization and immunohistochemistry. Both macrophage1 antigen-positive macrophages and alpha-smooth muscle actin-immunoreactive myofibroblasts expressed NGF in areas where they were closely proximate to sympathetic nerves. To investigate whether NGF produced by peri-infarct cells induces sympathetic outgrowth, we co-cultured adult sympathetic ganglia with peri-infarct explants. Neurite outgrowth from sympathetic ganglia was significantly greater at post-ligation days 7-14 as compared to control tissue. Addition of an NGF function-blocking antibody prevented the increased neurite outgrowth induced by peri-infarct tissue. These findings provide evidence that inflammatory cell NGF synthesis plays a causal role in sympathetic hyperinnervation following myocardial infarction.

Analysis of Variance↗
PubMed2006

Chapter 28: Studies to assess the long-term efficacy and effectiveness of HPV vaccination in developed and developing countries.

We review studies of the implementation of human papillomavirus (HPV) vaccination programmes in developed and developing countries. The review spans the period from establishment of long-term vaccine efficacy follow-up studies, operational research on issues of vaccine preparedness, and relevant predictive modelling studies during the pre-licensure phase to plans of phase IV effectiveness trials, forms of epidemiological surveillance, and further operational research in the post-licensure phase. Much of the research is already ongoing. Depending on the results of the planned immuno bridging studies among HIV-negative and HIV-positive women, further phase III and/or phase IV trials may be warranted.

Developed Countries↗
PubMed2006

Risk factors for variant Creutzfeldt-Jakob disease: a case-control study.

OBJECTIVE: To investigate the potential risk factors for variant Creutzfeldt-Jakob disease (VCJD) in the United Kingdom. METHODS: Definite and probable vCJD cases (n = 136) were residing in Great Britain at disease onset, and were referred between May 1995 and November 2003. Control subjects (n = 922) were recruited between 2002 and 2003, from 100 randomly selected geographical clusters sampled to represent the geographical distribution of vCJD. RESULTS: Reported frequent consumption of beef and beef products thought likely to contain mechanically recovered or head meat, or both, including burgers and meat pies, was associated with increased risk for vCJD, as was reported frequent chicken consumption. Surgical operations were generally similarly reported for cases and control subjects, with the exception of a small group of minor operations, possibly attributable to underreporting in control subjects. Cases and control subjects had similar reported occupational histories and exposure to animals. INTERPRETATION: These findings are consistent with dietary exposure to contaminated beef products being the main route of infection of vCJD, but recall bias cannot be excluded. There was no convincing evidence of increased risk through medical, surgical, or occupational exposure or exposure to animals.

Adolescent↗
PubMed2006

A guide for diagnostic evaluations.

Accurate diagnostic tests have a key role in patient management and the control of most infectious diseases. Unfortunately, in many developing countries, clinical care is often critically compromised by the lack of regulatory controls on the quality of these tests. The information available on the performance of a diagnostic test can be biased or flawed because of failings in the design of the studies which assessed the performance characteristics of the test. As a result, diagnostic tests are sold and used in much of the developing world without evidence of effectiveness. Misdiagnosis leading to failure to treat a serious infection or wasting expensive treatment on people who are not infected remains a serious obstacle to health.

Communicable Disease Control↗
PubMed2006

A guide for diagnostic evaluations.

Accurate diagnostic tests have a key role in patient management and the control of most infectious diseases. Unfortunately, in many developing countries, clinical care is often critically compromised by the lack of regulatory controls on the quality of these tests. The information available on the performance of a diagnostic test can be biased or flawed because of failings in the design of the studies which assessed the performance characteristics of the test. As a result, diagnostic tests are sold and used in much of the developing world without evidence of effectiveness. Misdiagnosis leading to failure to treat a serious infection or wasting expensive treatment on people who are not infected remains a serious obstacle to health.

Communicable Diseases↗
PubMed2006

Cerebrospinal fluid cytology to aid the diagnosis of cerebellopontine angle tumors.

OBJECTIVE: To determine if cerebrospinal fluid (CSF) cytology can be useful in the workup of patients with internal auditory canal/cerebellopontine angle (IAC/CPA) tumors and facial paralysis to diagnose metastatic disease before surgical intervention. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Patients who presented with or developed facial paralysis and IAC/CPA tumors. OUTCOME MEASURE: Lumbar puncture and CSF cytological analysis. RESULTS: Seven patients presented with or developed high-grade facial paralysis (greater than House-Brackmann Grade II). In the first patient, excision of the tumor revealed adenocarcinoma. All subsequent patients were evaluated with CSF cytological analysis. In five of these patients, cytological CSF analysis revealed malignant cells, suggesting a diagnosis of a metastatic lesion rather than acoustic neuroma. Primary neoplasms were identified in all but one of these patients. A sixth patient had metastatic breast cancer, but negative CSF cytology and a stable CPA tumor after radiation treatment. Two patients who were being conservatively followed up for their IAC/CPA tumor developed a nonprogressive but persistent mild Grade II facial weakness and underwent CSF analysis which tested negative. One patient had surgical resection with pathologic findings consistent with a typical acoustic schwannoma, and the other patient has been conservatively followed up without change. CONCLUSION: Our experience suggests that patients presenting with IAC/CPA tumors and progressive facial paralysis of House-Brackmann Grade III or greater should have a CSF cytological examination before surgical intervention to evaluate for a malignant process.

Adenocarcinoma↗
PubMed2005

Estrogen alters trkA and p75 neurotrophin receptor expression within sympathetic neurons.

Survival and growth of sympathetic neurons is regulated by nerve growth factor acting through trkA and p75NTR receptors. Sympathetic neurons are also affected by gonadal steroid hormones, particularly estrogen. To determine if estrogen may influence sympathetic neurons via altered neurotrophin receptor expression, we investigated effects of acute or chronic estrogen administration on levels of trkA and p75NTR proteins, numbers of immunoreactive neurons, and numbers of neurons expressing trkA, p75NTR, and estrogen receptor-alpha transcripts. Superior cervical ganglia from ovariectomized or estradiol-treated rats were processed for in situ hybridization or immunohistochemistry, and percentages of stained neurons quantitated or processed for Western blot analysis. In ovariectomized rats, approximately 50% of sympathetic neurons expressed trkA mRNA and protein. Acute estrogen administration did not affect trkA transcript expression, but reduced trkA protein significantly. Chronic treatment did not alter neuronal trkA expression. Approximately 70% of sympathetic neurons in ovariectomized rats expressed p75NTR transcripts and about 50% showed p75NTR immunoreactivity. Acute estrogen did not affect p75NTR expression. However, chronic estrogen reduced p75NTR mRNA and protein expression significantly. Fifty to sixty percent of sympathetic neurons in ovariectomized rats displayed estrogen receptor-alpha mRNA. After acute estrogen administration, estrogen receptor-alpha transcript expression increased by 35%, although this was not maintained chronically. These findings indicate that estrogen can influence sympathetic neuronal neurotrophin receptor expression as well as estrogen receptor-alpha. Reduced trkA expression after acute estrogen may transiently predispose neurons to degenerative events, while diminished p75NTR expression by chronic estrogen administration may exert long-term effects on survival or axonal outgrowth in sympathetic neurons.

Animals↗
PubMed2005

Efficient infection and persistence of a herpesvirus saimiri-based gene delivery vector into human tumor xenografts and multicellular spheroid cultures.

Herpesvirus saimiri (HVS) has the ability to infect a variety of human cell lines and establish a persistent infection by virtue of episomal maintenance. Moreover, the viral episome provides sustained expression of a heterologous transgene. HVS-based vectors can also persist for a long term in tumor xenografts generated from HVS-infected human carcinoma cell lines. The viral episome remains latent within the xenograft allowing long-term transgene expression. These properties, in addition to its ability to incorporate large amounts of heterologous DNA, make HVS an attractive potential gene delivery vector. Here we report on the further evaluation of such HVS-based vectors. We demonstrate for the first time that HVS can efficiently infect solid tumor xenografts derived from a variety of human carcinoma cells via direct intratumoral injections. Furthermore, HVS can efficiently infect spheroid cultures, a three-dimensional cell culture system that closely resembles a tumor. Upon infection of both the tumor xenografts and spheroid cultures, HVS-based vectors can establish a persistent episomal infection within the tumor xenograft allowing expression of a heterologous transgene. These results suggest that HVS-based vectors may be suitable for cancer gene therapy applications.

Animals↗
PubMed2005

Antiretroviral treatment in resource-poor settings: public health research priorities.

Many countries in Africa are planning to provide highly active antiretroviral therapy (HAART) to millions of people with acquired immune deficiency syndrome. This will be a highly complex therapy programme. Physician-based models of care adapted from industrialized countries will not succeed in providing treatment to the majority of those who need it in resource-constrained settings. A high priority is to identify care models for Africa that will increase coverage of HAART safely and effectively: key issues are (i) whether nursing staff or non-clinically qualified staff can take the major role in the treatment programme and reduce the workload of physicians, (ii) whether treatment and monitoring can be delivered through peripheral health centres or through home visits and achieve better adherence and be more cost-effective than delivery at hospitals and (iii) which clinical algorithms used by nursing or non-clinically qualified staff will be effective for screening, diagnosing and managing treatment-related side-effects and medical problems being incurred. Many current ART support programmes are making little or no investment in research, but answering important questions on delivery of HAART will be essential if HAART programmes are to be successful in African nations with a high burden of human immunodeficiency virus infection.

Africa↗
PubMed2004

Rate of first recorded diagnosis of autism and other pervasive developmental disorders in United Kingdom general practice, 1988 to 2001.

BACKGROUND: There has been concern that the incidence of autism and other pervasive developmental disorders (PDDs) is increasing. Previous studies have been smaller, restricted to autism (excluding other pervasive developmental disorders such as Asperger's syndrome), included boys only, or have not been based on a national sample. We investigated time trends in the rates of diagnosis of pervasive developmental disorders. METHODS: We analysed the rates of first diagnosis of pervasive developmental disorders among people registered with a practice contributing to the United Kingdom General Practice Research Database during the period 1988 to 2001. We included 1410 cases from over 14 million person-years of observation. The main outcome measures were rates of diagnosis of pervasive developmental disorders by year of diagnosis, year of birth, gender and geographical region. RESULTS: The rate increased progressively from 0.40/10,000 person-years (95% CI 0.30 to 0.54) in 1991 to 2.98/10,000 (95% CI 2.56 to 3.47) in 2001. A similar change occurred in the age standardised incidence ratios, from 35 (95% CI: 26-47) in 1991 to 365 (95% CI: 314-425) in 2001. The temporal increase was not limited to children born during specific years nor to children diagnosed in a specific time period. The rate of diagnosis of PDDs other than autism rose from zero for the period 1988-1992 to 1.06/10,000 person-years in 2001. The rate of diagnosis of autism also increased but to a lesser extent. There was marked geographical variation in rates, with standardised incidence ratios varying from 66 for Wales to 141 for the South East of England. CONCLUSIONS: Better ascertainment of diagnosis is likely to have contributed to the observed temporal increase in rates of diagnosis of PDD, but we cannot exclude a real increase.

Asperger Syndrome↗
PubMed2004

Resistance-modifying agents. 11.(1) Pyrimido[5,4-d]pyrimidine modulators of antitumor drug activity. Synthesis and structure-activity relationships for nucleoside transport inhibition and binding to alpha1-acid glycoprotein.

The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of (3)H-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4'-methoxybenzylamino, 3',4'-dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.

Animals↗
PubMed2004

The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT-dependent apoptosis in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Advances in the treatment of this disease will require the identification of novel therapeutic targets. We previously defined an expression signature of outcome in DLBCL and found that the phosphodiesterase PDE4B was overexpressed in fatal/refractory tumors. Phosphodiesterase 4B (PDE4B) inactivates the second messenger cyclic adenosine 3',5' monophosphate (cAMP) and abrogates its inhibitory effects in B lymphocytes. Hence, DLBCLs that express high PDE4B levels may be resistant to cAMP-induced apoptosis, contributing to their less favorable outcome. Herein, we confirmed the risk-related expression of PDE4B in an independent series of primary DLBCLs and defined the enzyme's role in modulating cAMP-induced apoptosis in parental DLBCL cell lines or those reconstituted with wild-type or mutant PDE4B. The cAMP-mediated apoptosis of DLBCLs was largely independent of the previously described cAMP effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), but associated with inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The central role of AKT in this process was confirmed by expressing constitutively active mutants of this kinase in DLBCL cells. Our findings highlight the important role of cAMP signaling in DLBCL and suggest that clinically relevant PDE4 and PI3K/AKT inhibitors might be useful in the treatment of DLBCL and additional B-lymphoid malignancies with increased PDE4B expression.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

Estrogen selectively increases sensory nociceptor innervation of arterioles in the female rat.

Differences exist in vascular function and disease susceptibility in males and females, and estrogen is apparently a primary factor. One mechanism by which estrogen may influence vascular function is by affecting vasomotor innervation. We have shown previously that estrogen increases calcitonin gene-related peptide (CGRP)-immunoreactive sensory innervation of the rat mammary gland, but it is not known if this occurs in other tissues. The objective of this study was to determine if estrogen modulates CGRP-immunoreactive innervation of vascular and non-vascular tissues. Ovariectomized adult virgin female rats were implanted with pellets containing 17beta-estradiol or placebo. After 7 days, innervation was examined in the external ear, jejunal mesenteric arterioles, superficial epigastric, femoral, and uterine arteries, and foot skin. Immunofluorescence microscopy of the external ear pinna revealed increased CGRP-immunoreactive sensory innervation in estrogen-treated rats, and this was attributable specifically to increased innervation of arterioles. Tyrosine hydroxylase-immunoreactive innervation was unchanged. Total nerve density, revealed by the pan-neuronal marker PGP 9.5, was also greater after estrogen treatment, implying structural proliferation of nociceptor vasodilator fibers. Mesenteric arteriolar CGRP-immunoreactive nerve density was also selectively increased by estrogen treatment. However, estrogen did not affect CGRP-immunoreactive nerve density of superficial epigastric, femoral, or uterine arteries, or foot skin. Therefore, estrogen increases sensory innervation of arterioles, but not of large arteries or skin. We conclude that sensory nociceptor vasodilatory innervation of arterioles is selectively enriched by estrogen, which may influence cardiovascular function in health and disease.

Animals↗