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Biomedical subjects

J Mills

Publications and source records attributed to J Mills.

At least 19 recordsLinked to original sources
PubMed2007

The autoclavable semirigid thoracoscope: the way forward in pleural disease?

Medical thoracoscopy is a valuable tool in the investigation and management of pleural disease. It has considerable advantages over conventional blind pleural biopsy and video-assisted thoracoscopic surgery. Despite this, the practice of this technique in the UK is limited. Most operators use the rigid thoracoscope, which may be an unfamiliar instrument to respiratory physicians. A semirigid thoracoscope is available but its use has not been possible in the UK as it requires sterilisation with ethylene oxide, which is not approved in this country. The present authors describe herein their experience with the first ever autoclavable semirigid thoracoscope. Medical thoracoscopy using the new instrument was performed in 56 patients between June 2004 and May 2006. All patients had been referred with a unilateral pleural effusion of unknown aetiology, where blind pleural aspiration had failed to yield an answer. Diagnostic samples were taken and talc poudrage performed where appropriate. The instrument was easy to handle and excellent views were obtained. Histologically adequate biopsy samples were obtained in 54 patients. The combination of clinical features, computed tomography findings and thoracoscopic biopsy enabled a definite diagnosis in 49 (90.7%) of these patients. There were no complications. The autoclavable semirigid thoracoscope has immense potential in the diagnosis and management of pleural disease. Its diagnostic yield in pleural disease is comparable to the conventional rigid thoracoscope. It is similar in design to the fibreoptic bronchoscope and respiratory physicians should be able to adapt to its use easily. It is also compatible with existing video processors and light sources available in most endoscopy suites. The fact that this instrument is autoclavable should open the field for its use in the UK as well as in other countries.

Adult↗
PubMed2006

Cerebrospinal fluid (CSF) leak and pseudomeningocele formation after posterior fossa tumor resection in children: a retrospective analysis.

OBJECTIVE: The purpose of this study was to determine the incidence of pseudomeningocele and cerebrospinal fluid (CSF) leak after posterior fossa tumor surgery and to analyze factors that may be associated with these conditions. In particular, we wished to determine if there was evidence to support the hypothesis that the use of tissue glue, dural grafts, or external ventricular drainage (EVD) prevented CSF from leaking outside the closed dura. MATERIALS AND METHODS: A retrospective chart review was carried out of posterior fossa tumor resections at British Columbia's Children's Hospital. Information was collected regarding tumor location, surgical approach, CSF diversion, dural grafting, and use of tissue glue. Multiple univariate analyses and step-wise logistic regression were performed to identify factors associated with pseudomeningocele formation or CSF leak. A pseudomeningocele was said to be present if it was noted in the clinical records or if a fluid collection was present superficial to the craniotomy flap on a postoperative CT or MR scan. RESULTS: Out of 174 posterior fossa operations, 53 pseudomeningoceles with or without CSF leak were identified along with five CSF leaks in the absence of pseudomeningocele (33%). None of the factors examined reached statistical significance, although there was a trend towards higher rates in patients with external CSF drainage (P=0.06631), dural graft usage (p=0.06492), and patients in whom tissue glue was used (p=0.06181). On logistic regression, only tissue glue use and external CSF drainage were associated with increased incidence of pseudomeningocele and/or CSF leak. CONCLUSION: In this retrospective study, the use of tissue glue, dural grafts, and external ventricular drainage was not associated with a reduced rate of clinically or radiologically diagnosed pseudomeningocele formation or postoperative CSF leak. The results of this study provide a basis for planning a randomized controlled trial to determine the effectiveness of tissue glue and/or dural grafting in preventing these complications.

Cerebrospinal Fluid Otorrhea↗
PubMed2006

Modern psychiatry in India: the British role in establishing an Asian system, 1858-1947.

Four broad phases can be traced in the development of modern psychiatry in India. After briefly considering the outline of each of these phases this article will focus its attention on the second and third. It will be argued through tracing the trends in patient admission, treatment regimes and the organisation of the asylum system in these years that the foundations of modern psychiatry were laid in India in the period 1858 to 1947 and that the modern psychiatric system in India as it is today, although it has evolved since Independence in 1947, continues in significant ways to be shaped by the colonial period.

Colonialism↗
PubMed2004

Sequence and structure relatedness of matrix protein of human respiratory syncytial virus with matrix proteins of other negative-sense RNA viruses.

Matrix proteins of viruses within the order Mononegavirales have similar functions and play important roles in virus assembly. Protein sequence alignment, phylogenetic tree derivation, hydropathy profiles and secondary structure prediction were performed on selected matrix protein sequences, using human respiratory syncytial virus matrix protein as the reference. No general conservation of primary, secondary or tertiary structure was found, except for a broad similarity in the hydropathy pattern correlating with the fact that all the proteins studied are membrane-associated. Interestingly, the matrix proteins of Ebola virus and human respiratory syncytial virus shared secondary structure homology.

Amino Acid Sequence↗
PubMed2003

Association of matrix protein of respiratory syncytial virus with the host cell membrane of infected cells.

The matrix protein of paramyxoviruses plays an important role in virus assembly through its interactions with cell membrane, virus envelope and virus nucleocapsid. In the present study, we investigated the possible association of respiratory syncytial virus (RSV) matrix (M) protein with the plasma membrane of infected cells. Using confocal microscopy we found that M was present at the cytoplasmic side of the plasma membrane. We used flotation gradients to purify membranes from RSV infected cells and treated them with cold Triton X-100 to obtain lipid rafts in the insoluble fraction. Western blot of the lipid raft fraction with specific antibodies showed that it contained M, as well as G (attachment) and N (nucleocapsid) proteins. We also found that RSV purified on sucrose gradients contained lipid raft markers. Together, our data suggest that RSV uses lipid rafts for assembly and budding.

Cell Line↗
PubMed2003

The matrix protein of Human respiratory syncytial virus localises to the nucleus of infected cells and inhibits transcription.

We studied the kinetics of localisation of matrix (M) protein of Human respiratory syncytial virus (RSV) in infected cells. M protein was detected in the nucleus early in infection, by confocal microscopy and by immunoblotting of nuclear fractions. We next tested the possibility that M protein may be involved in inhibition of host cell transcription. Nuclear extracts from RSV infected cells had less transcriptional activity in vitro when compared to nuclear extracts from mock infected cells. In addition, nuclear extracts from RSV infected cells inhibited the transcriptional activity of nuclear extracts from mock infected cells, suggesting that an inhibitory activity was transferred with nuclear extracts from RSV infected cells. Our data suggest that M protein may play a role early in the infection by inhibiting host cell transcription.

Binding Sites↗
PubMed2003

Multiple heparin binding domains of respiratory syncytial virus G mediate binding to mammalian cells.

Respiratory syncytial virus (RSV) G glycoprotein mediates cell attachment through surface glycosaminoglycans (GAGs). Feldman et al. [10] suggested that specific basic amino acids in residues 184-198 of G defined a critical heparin binding domain (HBD). To further define the G HBD we made a series of truncated G proteins expressed in Escherichia coli. G88 (G residues 143-231), bound to HEp-2 cells in a dose dependent manner and binding was inhibited >99% with heparin. Cell binding of G88 was unaltered by alanine substitution mutagenesis of all basic amino acids in Feldman's region 184-198. A G88 variant truncated beyond residue 198, G58, and G58 fully alanine substituted in the region 184-198, G58A6, bound to HEp-2 cells about half as well and 100-fold less well than G88, respectively. G88 and all alanine substitution mutants of G88 inhibited RSV plaque formation by 50% (ID(50)) at concentrations of approximately 50 nM; the ID(50) of G58 was approximately 425 nM while G58A6 had an ID(50) >1600 nM. These data show that the G HBD includes as much as residues 187-231, that there is redundancy beyond the previously described HBD, and that the cell-binding and virus infectivity-blocking functions of these recombinant G proteins were closely linked and required at least one HBD.

Amino Acid Sequence↗
PubMed2002

Benefit from endoscopic sinus surgery.

Benefit and satisfaction following endoscopic sinus surgery were assessed using the Glasgow Benefit Inventory (GBI) and a validated outcome satisfaction score. In total, 140 patients were invited to participate; 101 (71%) responded. ESS produces significant benefit as assessed by the GBI and satisfaction, and the benefit compares favourably with other otorhinolaryngological procedures. Greatest benefit was derived by patients undergoing surgery for polyp disease. Patients whose cardinal preoperative symptom was nasal obstruction or headache tended to report higher benefit. Co-existent asthma, allergic rhinitis or aspirin intolerance appeared not to result in a significant decrease in benefit after surgery, except in patients with non-polyp disease, who also have both aspirin intolerance and asthma. Also, for non-polyp disease, postoperative medication with nasal steroids or antihistamines does not appear to influence benefit.

Endoscopy↗
PubMed2002

Elevated fibrinogen in the healthy male relatives of patients with severe, premature coronary artery disease.

AIMS: To assess the possible role of certain coagulation factors and associated genetic polymorphisms in families in which coronary disease has occurred prematurely. METHODS AND RESULTS: One hundred and eighty-five healthy male relatives aged 65 or less were recruited following the identification of 125 patients with confirmed, premature coronary artery disease and compared to a control group of 185 healthy, age-matched volunteers. None of the control subjects had a personal or family history of coronary artery disease. The relatives and controls were similar in terms of conventional coronary artery disease risk factors. Fibrinogen levels were elevated in relatives compared with controls and remained higher after adjustment for significant correlates, 3.0 g.l(-1) (2.9-3.1) vs 2.8 g.l(-1) (2.8-2.9),P =0.004. Factor VII coagulant activity and von Willebrand factor antigen did not differ between the groups nor were there any differences in genotype frequency for the fibrinogen beta-455 G/A polymorphism or the factor VII promoter deletion/insertion and Arg-Gln coding polymorphisms. CONCLUSIONS: A significant increase in fibrinogen levels was demonstrated in the healthy, male, first-degree relatives of patients with severe coronary artery disease. Fibrinogen may be of particular importance in subjects who, other than their family history, appear to be at low risk in terms of conventional coronary artery disease risk factors.

Adolescent↗
PubMed2002

Respiratory syncytial virus matrix protein associates with nucleocapsids in infected cells.

Little is known about the functions of the matrix (M) protein of respiratory syncytial virus (RSV). By analogy with other negative-strand RNA viruses, the M protein should inhibit the viral polymerase prior to packaging and facilitate virion assembly. In this study, localization of the RSV M protein in infected cells and its association with the RSV nucleocapsid complex was investigated. RSV-infected cells were shown to contain characteristic cytoplasmic inclusions. Further analysis showed that these inclusions were localization sites of the M protein as well as the N, P, L and M2-1 proteins described previously. The M protein co-purified with viral ribonucleoproteins (RNPs) from RSV-infected cells. The transcriptase activity of purified RNPs was enhanced by treatment with antibodies to the M protein in a dose-dependent manner. These data suggest that the M protein is associated with RSV nucleocapsids and, like the matrix proteins of other negative-strand RNA viruses, can inhibit virus transcription.

Cell Line↗
PubMed2001

No association between CHRNA7 microsatellite markers and attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder of childhood that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD. First, nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers, and nonsmokers. Second, ADHD is a significant risk factor for early initiation of cigarette smoking in children and maternal cigarette smoking appears to be a risk factor for ADHD. Finally, animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity. The nicotinic system has previously been studied in schizophrenia where the neuronal nicotinic acetylcholine receptor alpha 7 subunit gene (CHRNA7) has been implicated in decreased P50 inhibition and attentional disturbances in patients with schizophrenia and in many of their nonschizophrenic relatives. Three known microsatellite markers (D15S165, D15S1043, and D15S1360) near the nicotinic acetylcholine alpha 7 receptor gene, CHRNA7, were studied in 206 ADHD parent-proband trios of children aged 5-16 with ADHD according to DSM-IV criteria. Children with known major medical or psychiatric conditions or mental retardation (IQ < 70) were excluded from the study. Markers D15S165 and D15S1360 were in linkage disequilibrium. The extended Transmission Disequilibrium Test analyses demonstrated no evidence that variation at the microsatellite markers D15S1360, D15S1043, and D15S165 influences susceptibility to ADHD. However, it remains possible that the CHRNA7 gene and other nicotinic system genes may be involved in conferring susceptibility to ADHD.

Adolescent↗
PubMed2001

Comparison of genotyping and phenotyping methods for determining susceptibility of HIV-1 to antiretroviral drugs.

OBJECTIVE(S): To compare antiretroviral resistance susceptibility testing of patient HIV-1 strains using genotype and phenotype methods. DESIGN: Eighteen plasma samples with viral load > 2000 HIV-1 RNA copies/ml were randomly selected for testing by both methods. Disease and treatment data were available for all patients. METHODS: Samples were analysed genotypically using a kit assay (HIV-1 Genotyping Systems, Applied Biosystems), performed by the Clinical Research Laboratory at Macfarlane Burnet Centre for Medical Research. Samples were analysed phenotypically using a rapid phenotypic assay (PhenoSenseTM HIV, ViroLogic), performed by the manufacturer. Results from both methods were interpreted using a defined protocol. Each susceptibility assay was performed and interpreted by individuals unaware of either the clinical data or the results of the other susceptibility assay. Concordance was defined categorically as either the presence of reduced susceptibility (> 2.5-fold change) in the phenotypic assay and resistance associated mutations in the genotypic assay, or the absence of these findings in both assays. RESULTS: Concordance between phenotypic and genotypic susceptibility testing was 81% for nucleoside reverse transcriptase inhibitors, 91% for non-nucleoside reverse transcriptase inhibitors and 90% for protease inhibitors. Complete concordance between phenotype and genotype for all 14 drugs evaluated was observed in three (17%) patient samples. CONCLUSIONS: Phenotypic and genotypic susceptibility appear to provide similar results. However, interpretation of genotypic results can be complicated, and both methods still require clinical validation.

Anti-HIV Agents↗
PubMed2001

nef-deleted HIV-1 inhibits phagocytosis by monocyte-derived macrophages in vitro but not by peripheral blood monocytes in vivo.

OBJECTIVE: HIV-1 infection impairs a number of macrophage effector functions, but the mechanism is unknown. We studied the role of HIV-1 Nef in modulating phagocytosis by human monocytes and monocyte-derived macrophages (MDM). DESIGN AND METHODS: Using a flow cytometric assay, phagocytosis of Mycobacterium avium complex (MAC) by monocytes in whole blood of Sydney Blood Bank Cohort (SBBC) members infected with a nef-deleted (Delta nef) strain of HIV-1 was compared with that of monocytes from uninfected or wild-type (WT) HIV-infected subjects. The specific impact of Nef on phagocytosis by MDM was determined by either infecting cells in vitro with Delta nef strains of HIV-1 or electroporating Nef into uninfected MDM. RESULTS: MAC phagocytic capacity of monocytes from SBBC members was equivalent to that of cells from uninfected individuals (P = 0.81); it was greater than that of cells from individuals infected with WT HIV-1 (P < 0.0001), irrespective of CD4 counts and HIV viral load. In contrast, in vitro infection of MDM with either Delta nef or WT strains of HIV-1 resulted in similar levels of HIV replication and equivalent impairment of phagocytosis via Fc gamma and complement receptors. Electroporation of Nef into MDM did not alter phagocytic capacity. CONCLUSIONS: This study provides evidence demonstrating the complex indirect effect of Nef on phagocytosis by peripheral blood monocytes (infrequently infected with HIV-1) in vivo. Conversely, the fact that MDM infected with either Delta nef or WT HIV-1 in vitro (high multiplicity of infection) show comparably impaired phagocytosis, indicates that HIV-1 infection of macrophages can directly impair function, independent of Nef.

CD4 Lymphocyte Count↗
PubMed2001

Mass spectrometric analysis of cyanogen bromide fragments of integral membrane proteins at the picomole level: application to rhodopsin.

Advances in time-of-flight mass spectrometry allow unit mass resolution of proteins and peptides up to about 6000 Da molecular weight. Identification of larger proteins and study of their posttranslational or experimental modifications by mass analysis is greatly enhanced by cleavage into smaller fragments. Most membrane proteins are difficult to mass analyze because of their high hydrophobicity, typical expression in low quantities, and because the detergents commonly used for solubilization may be deleterious to mass analysis. Cleavage with cyanogen bromide is beneficial for analysis of membrane proteins since the methionine cleavage sites are typically located in hydrophobic domains and cleavage at these points reduces the size of the hydrophobic fragments. Cyanogen bromide also gives high cleavage yields and introduces only volatile contaminants. Even after cleavage membrane proteins often contain fragments that are difficult to chromatograph. Matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) is capable of analyzing complex mixtures without chromatography. We present a MALDI MS method that quickly and reliably identifies the cyanogen bromide fragments and posttranslational modifications of reduced and alkylated bovine rhodopsin from as little as 30 pmol of rhodopsin in detergent-solubilized retinal rod disk membranes, using 1-5 pmol of digest per sample. The amino acid sequences of some of the peptides in the digest were confirmed by post source decomposition MS analysis of the same samples. The method appears to be general and applicable to the analysis of membrane proteins and the protein composition of membrane preparations.

Amino Acid Sequence↗
PubMed2001

Live attenuated HIV vaccines: predicting the tradeoff between efficacy and safety.

The utility of live attenuated vaccines for controlling HIV epidemics is being debated. Live attenuated HIV vaccines (LAHVs) could be extremely effective in protecting against infection with wild-type strains, but may not be completely safe as the attenuated strain could cause AIDS in some vaccinated individuals. We present a theoretical framework for evaluating the consequences of the tradeoff between vaccine efficacy (in terms of preventing new infections with wild-type strains) and safety (in terms of vaccine-induced AIDS deaths). We use our framework to predict, for Zimbabwe and Thailand, the epidemiological impact of 1,000 different (specified by efficacy and safety characteristics) LAHVs. We predict that paradoxically: (i) in Zimbabwe (where transmission is high) LAHVs would significantly decrease the AIDS death rate, but (ii) in Thailand (where transmission is low) exactly the same vaccines (in terms of efficacy and safety characteristics) would increase the AIDS death rate. Our results imply that a threshold transmission rate exists that determines whether any given LAHV has a beneficial or a detrimental impact. We also determine the vaccine perversity point, which is defined in terms of the fraction of vaccinated individuals who progress to AIDS as a result of the vaccine strain. Vaccination with any LAHV that causes more than 5% of vaccinated individuals to progress to AIDS in 25 years would, even 50 years later, lead to perversity (i.e., increase the annual AIDS death rate) in Thailand; these same vaccines would lead to decreases in the annual AIDS death rate in Zimbabwe.

AIDS Vaccines↗
PubMed2001

Clinical, manometric, and EMG characteristics of patients with fecal incontinence.

Fecal incontinence occurs frequently in both men and women. Yet, few studies on fecal incontinence have separated the evaluation and interpretation of data by gender. This study was designed to identify differences in the clinical, anorectal manometry, and electromyography (EMG) characteristics between male and female patients with fecal incontinence. We compared 53 incontinent males (mean age, 64 years) with 72 incontinent females (mean age, 61 years). Each patient underwent computerized anorectal manometry, and invasive (pudendal nerve conduction studies and concentric needle EMG) and noninvasive EMG (anal sensor surface electrode). An anal incontinence score (AIS) ranging from 0 to 6 was used to categorize patients. Male patients had higher incontinence scores at presentation (AIS greater than 4, 70% vs. 54%). Female patients had significantly lower resting pressure (40 vs. 53 mmHg, p < 0.05) and more women had sphincter asymmetry (36% vs. 25%, p < 0.05). Both groups had similar PNTMLs (2.41 vs. 2.47 ms). Difference was seen in the net strength of the sphincter (women 4.0 microV vs. men 8.0 microV, p < 0.05), as measured by noninvasive EMG. In conclusion, it is well known that there are differences in anorectal physiologic function between male and female patients with normal continence. Comparing male and female patients with fecal incontinence suggests that female patients tend to have worse sphincter function that men. Both groups had similar EMG alterations, suggesting a common neurogenic injury as etiology. Future studies are needed to address the sexes separately.

Adult↗