Biomedical subjects

E Major

Publications and source records attributed to E Major.

At least 19 recordsLinked to original sources

PubMed2005

Molecular evaluation of BK polyomavirus nephropathy.

Understanding at a molecular level, the immunologic response of polyomavirus nephropathy (PVN), a critical cause of kidney graft loss, could lead to new targets for treatment and diagnosis. We undertook a transcriptional evaluation of kidney allograft biopsies from recipients with PVN or acute rejection (AR), as well as from recipients with stable allograft function (SF). In both the PVN and AR groups, Banff histologic scores and immunohistochemical analysis of inflammatory infiltrates were similar. Despite their different etiologies, the transcriptional profiles of PVN and AR were remarkably similar. However, transcription of genes previously linked to AR including CD8 (65.9 +/- 18.8) and related molecules IFN-gamma(55.1 +/- 17.0), CXCR3 (49.9 +/- 12.8) and perforin (153.8 +/- 50.4) were significantly higher in PVN compared to AR (30.9 +/- 2.0, 14.0 +/- 7.3, 12.1 +/- 7.3 and 15.6 +/- 3.8-fold, respectively; p < 0.01). Importantly, transcription of molecules associated with graft fibrosis including matrix collagens, TGFbeta, MMP2 and 9, as well as markers of epithelial-mesenchymal transformation (EMT) were significantly higher in PVN than AR. Thus, renal allografts with PVN transcribe proinflammatory genes equal in character and larger in magnitude to that seen during acute cellular rejection. BK infection creates a transcriptional microenvironment that promotes graft fibrosis. These findings provide new insights into the intrarenal inflammation of BK infection that promotes graft loss.

Adult↗

PubMed2001

Convection-enhanced intraparenchymal delivery (CEID) of cytosine arabinoside (AraC) for the treatment of HIV-related progressive multifocal leukoencephalopathy (PML).

AIDS-related PML continues to be a relatively common and rapidly fatal infection in patients with AIDS, and no effective therapy has been established to alleviate the effects of this disease. Through the years, isolated reports and small case studies have shown somewhat encouraging results using cytosine arabinoside (AraC) in the treatment of PML. The optimism behind the use AraC for this disease began to fade with ACTG trial 243, which suggested that AraC had no benefit in patients with HIV-related PML. In this article, we provide evidence that suggests that the failure of AraC in the ACTG trial may have been due to insufficient delivery of the drug through traditional intravenous and intrathecal routes. Furthermore, we provide evidence that convection-enhanced intraparenchymal delivery of AraC may prove to be a safe and effective means of treating this infection, and we outline a clinical trial that we have recently undertaken to test this hypothesis.

AIDS-Related Opportunistic Infections↗

PubMed2000

Population requirement for adult critical-care beds: a prospective quantitative and qualitative study.

BACKGROUND: The provision of adult critical-care facilities is not based on a rational or scientific assessment of need. We aimed to define the numbers of adult critical-care beds required for a population of 500000. METHODS: In five hospitals in Wales, UK, we classified patients who might be suitable for critical care in intensive-care or high-dependency units. On every 12th day for 1 calendar year, we counted the numbers of such patients admitted in a defined geographical population. A panel of ten intensivists made consensus decisions about whether individual patients were in the appropriate unit. The data were used to predict the numbers of beds and units required for the population. FINDINGS: 4058 patients were suitable for critical care, of whom 3028 lived in the study area. 56.4% were in general wards, 22.3% in high-dependency units, and 21.3% in intensive-care units. The mean risk of death was 22.0% and the in-hospital death rate 17.3%. According to the masked consensus, 41.3% of patients required high-dependency beds and 21.5% intensive-care beds. Mean risk of death increased from general wards (14.7%) to high-dependency units (19.2%) to intensive care (37.0%). Based on the consensus decisions, the average daily requirement of intensive-care beds was 21 and of high-dependency beds 43; to meet needs 95% of times required 30 and 55 beds, respectively, in a single critical-care unit. INTERPRETATION: We estimated, scientifically, numbers of adult critical-care beds required to meet population needs. Studies are necessary periodically to track changes in admissions requiring critical care.

APACHE↗

PubMed2000

Evaluating the neck for percutaneous dilatational tracheostomy.

PURPOSE: The aims of this article are to study how variations in the anatomy of the neck may influence the success of percutaneous dilatational tracheostomy (PDT). PATIENTS AND METHODS: Four hundred and ninety-seven patients were included in this study. Patients with a short neck and altered tracheal anatomy were evaluated on the basis of difficulty with PDT, use of long shank tracheostomy tubes, and need for open surgical tracheostomy. RESULTS: 33 (6.6%) patients had an apparently reduced cricoid ring to sternum distance and a deeply lying trachea. Nine of these patients were referred for open surgical tracheostomy. A further five patients had altered tracheal anatomy secondary to disease or surgery. Two of these patients were also referred for open surgical tracheostomy. Thus, unfavourable neck anatomy was responsible for 2.2% (11/497) of patients being referred for open surgical tracheostomy. CONCLUSION: Variations in the anatomy of the neck can make PDT both difficult and hazardous. Patients with a deeply lying trachea may need a long shank tube. Open surgical tracheostomy is indicated in some patients with a deeply lying trachea and conditions producing secondary deformity of the trachea. All patients should have a detailed history and thorough clinical examination of the neck and thorax prior to PDT. The selective use of chest radiography, MRI, and ultrasound assessment prior to PDT can assist in the identification of patients unsuitable for this technique.

Adolescent↗

PubMed2000

Percutaneous dilatational tracheostomy: haemorrhagic complications and the vascular anatomy of the anterior neck. A review based on 497 cases.

In a series of 497 PDT procedures done in the intensive therapy unit at Morriston Hospital between 1992 and 1999, PDT was abandoned because of bleeding in 6 patients and was noted to be a problem in a further 18 cases (overall incidence 4.8%). In all cases, haemorrhage was successfully arrested. Surgical tracheostomy was necessary in 6 of these 24 cases. The source of bleeding in 4 of these patients was attributed to the inferior thyroid vein (2 cases), high brachiocephalic vein, and possibly an aberrant anterior jugular communicating vein, respectively. In one patient, the vessel presumed injured could not be identified and in another patient, bleeding was related to multi-system disease. We conclude that the risk of bleeding, although low, can be minimised if the operator maintains a high index of suspicion for aberrant vascular anatomy and investigates possible abnormalities with diagnostic ultrasound. Injury to vessels low in the neck can be reduced by not fully extending the neck and siting the stoma at the upper tracheal rings. The possibility of developing a tracheoarterial fistula is reduced if the stoma is situated above the 4th tracheal ring and fibreoptic endoscopy is used to confirm correct tracheostomy tube placement.

Adult↗

PubMed1999

Nonproductive human immunodeficiency virus type 1 infection of human fetal astrocytes: independence from CD4 and major chemokine receptors.

Human immunodeficiency virus type 1 (HIV-1) infection of the brain is associated with neurological manifestations both in adults and in children. The primary target for HIV-1 infection in the brain is the microglia, but astrocytes can also be infected. We tested 26 primary HIV-1 isolates for their capacity to infect human fetal astrocytes in culture. Eight of these isolates, independent of their biological phenotype and chemokine receptor usage, were able to infect astrocytes. Although no sustained viral replication could be demonstrated, the virus was recovered by coculture with receptive cells such as macrophages or on stimulation with interleukin-1beta. To gain knowledge into the molecular events that regulate attachment and penetration of HIV-1 in astrocytes, we investigated the expression of several chemokine receptors. Fluorocytometry and calcium-mobilization assay did not provide evidence of expression of any of the major HIV-1 coreceptors, including CXCR4, CCR5, CCR3, and CCR2b, as well as the CD4 molecule on the cell surface of human fetal astrocytes. However, mRNA transcripts for CXCR4, CCR5, Bonzo/STRL33/TYMSTR, and APJ were detected by RT-PCR. Furthermore, infection of astrocytes by HIV-1 isolates with different chemokine receptor usage was not inhibited by the chemokines SDF-1beta, RANTES, MIP-1beta, or MCP-1 or by antibodies directed against the third variable region or the CD4 binding site of gp120. These data show that astrocytes can be infected by primary HIV-1 isolates via a mechanism independent of CD4 or major chemokine receptors. Furthermore, astrocytes are potential carriers of latent HIV-1 and on activation may be implicated in spreading the infection to other neighbouring cells, such as microglia or macrophages.

Adult↗

PubMed1999

Protection from Lyme neuroborreliosis in nonhuman primates with a multiantigenic vaccine.

In an effort to develop an effective and safe vaccine for lyme disease, rhesus macaques were injected with a multiantigenic preparation of Borrelia burgdorferi, strain N40. One month later animals were boosted before intradermal challenge with infectious B. burgdorferi. Challenges were performed at 1 and again at 5 months after the booster vaccination. Vaccinated and control nonvaccinated animals were monitored for development of systemic infection by measurement of serum anti-spirochetal antibodies by ELISA and Western blotting, and neurological involvement was monitored by testing of cerebrospinal fluid (CSF) and PCR analysis of central nervous system (CNS) tissue obtained at necropsy. Two control nonhuman primates (NHPs), given saline injections instead of vaccine and then challenged with B. burgdorferi, developed CSF pleocytosis, PCR positivity of the brain, and high levels of specific anti-B. burgdorferi antibody in the serum and CSF. Necropsy studies revealed widespread invasion of the CNS of one of these animals by the spirochete. In contrast, none of the four vaccinated animals developed evidence of invasion of the CNS after either of two challenge inoculations with infectious B. burgdorferi. In addition to resisting infection, no vaccinated animal demonstrated any untoward consequence of vaccination. These data demonstrate that a multiantigenic vaccine is effective in preventing systemic infection and lyme neuroboreliosis in NHPs and suggest that a successful vaccine could be developed in humans which would prevent lyme disease.

Animals↗

PubMed1999

Percutaneous dilatational tracheostomy under ultrasound guidance.

Diagnostic ultrasound may be used to assess the suitability of patients for percutaneous dilatational tracheostomy (PDT) in the intensive care unit (ICU). It may identify patients unsuitable for PDT, prevent puncture of aberrant vessels, estimate the distance from the surface of the skin to the trachea, and ensure accurate placement of the needle in the trachea. We conclude that diagnostic ultrasound permits careful evaluation of patients for whom PDT is being considered, and adds to the safety of the procedure.

Aged↗

PubMed1998

Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team.

BACKGROUND: Progressive multifocal leukoencephalopathy affects about 4 percent of patients with the acquired immunodeficiency syndrome (AIDS), and survival after the diagnosis of leukoencephalopathy averages only about three months. There have been anecdotal reports of improvement but no controlled trials of therapy with antiretroviral treatment plus intravenous or intrathecal cytarabine. METHODS: In this multicenter trial, 57 patients with human immunodeficiency virus (HIV) infection and biopsy-confirmed progressive multifocal leukoencephalopathy were randomly assigned to receive one of three treatments: antiretroviral therapy alone, antiretroviral therapy plus intravenous cytarabine, or antiretroviral therapy plus intrathecal cytarabine. After a lead-in period of 1 to 2 weeks, active treatment was given for 24 weeks. For most patients, antiretroviral therapy consisted of zidovudine plus either didanosine or stavudine. RESULTS: At the time of the last analysis, 14 patients in each treatment group had died, and there were no significant differences in survival among the three groups (P=0.85 by the log-rank test). The median survival times (11, 8, and 15 weeks, respectively) were similar to those in previous studies. Only seven patients completed the 24 weeks of treatment. Anemia and thrombocytopenia were more frequent in patients who received antiretroviral therapy in combination with intravenous cytarabine than in the other groups. CONCLUSIONS: Cytarabine administered either intravenously or intrathecally does not improve the prognosis of HIV-infected patients with progressive multifocal leukoencephalopathy who are treated with the antiretroviral agents we used, nor does high-dose antiretroviral therapy alone appear to improve survival over that reported in untreated patients.

AIDS-Related Opportunistic Infections↗

PubMed1998

Pneumopericardium: an unusual cause for cardiac arrest.

A 1-year-old boy breathing via a T-piece system and recovering from meningococcal septicaemia in the intensive care unit suffered a severe bout of coughing and developed bilateral pneumothoraces and tension pneumopericardium resulting in electromechanical dissociation and asystole. Conventional cardiopulmonary resuscitation and adrenaline boluses were unsuccessful. Administration of 20 ml.kg-1 of colloid and 3 mmol.kg-1 of sodium bicarbonate solutions produced instantaneous return of cardiac, output. The deleterious effects of cardiac tamponade appeared to decrease with increasing cardiac filling pressures. The patient was managed conservatively and he made a full recovery with no signs of residual neurological deficit.

Bacteremia↗

PubMed1997

Organ donation in the UK: a survey by a British Transplantation Society working party.

BACKGROUND: During the past few years the number of organ donors in the UK has declined after a slow but steady increase during the 1980s. Concern about the decline led to a survey by the British Transplantation Society. The report of this survey highlighted a number of reasons for the decline and this manuscript presents and discuss the main items in the report. METHODS: Comprehensive information relating to organ donation was obtained by a combination of structured interviews during visits to intensive care units (ICUs) and neurosurgical units, the use of detailed questionnaires sent to all UK ICUs, and from the register held by the United Kingdom Transplant Support Service Authority. RESULTS: The information obtained highlighted a number of reasons for the decline in organ donor numbers and these are presented and discussed. The pool of potential donors is shrinking as death rates from road traffic accidents and intracranial haemorrhage decrease. Also the increasing use of modern imaging techniques has improved predictive ability in patients with severe brain damage with the result that more patients whose prognosis is assessed as hopeless are not treated by ventilation. Inadequacies both in intensive care unit bed provision and the resourcing of the transplant co-ordinator service were also thought to be important. CONCLUSIONS: Eight recommendations have been made, covering ICU bed provision, neurosurgical provision, transplant surgical staffing, the transplant co-ordinator network, reimbursement to donor units, asystolic donation, live donor transplantation, and interventional ventilation.

Brain Diseases↗

PubMed1995

p53 dependent growth suppression by the c-Abl nuclear tyrosine kinase.

Growth suppression by the Rb and p53 tumor suppressor proteins is mediated through effects on cell cycle regulatory proteins at the G1/S transition. Because overexpression of c-Abl induces G1 arrest in fibroblasts, we reasoned that c-Abl may also affect cell cycle proteins which regulate G1. We used fibroblasts containing disruptions of the Rb or p53 genes to genetically test the role of these proteins in c-Abl growth suppression. We find that c-Abl requires p53 but not Rb to suppress growth. c-Abl binds p53 in vitro and enhances p53 dependent transcription from a promoter containing p53 DNA binding sites. An Abl mutant which no longer binds p53 does not enhance p53 transcriptional activity and fails to suppress growth. These findings provide a novel link between a growth inhibitory tyrosine kinase and the p53 tumor suppressor protein.

Animals↗

PubMed1995

Inoculation of nonhuman primates with the N40 strain of Borrelia burgdorferi leads to a model of Lyme neuroborreliosis faithful to the human disease.

We injected rhesus macaques with a highly infective strain of Borrelia burgdorferi to assess whether experimentally inoculated nonhuman primates (NHPs) could serve as models of human Lyme neuroborreliosis (LNB). The animals developed biopsy-confirmed erythema migrans in the area of the inoculations. ELISA testing of sera revealed strong antibody reactivity to B burgdorferi antigens, and Western blotting showed that 16-, 22-, 31-, 34-, and 41-kd proteins of the spirochete were major antigens recognized by antibody. Culture and polymerase chain reaction (PCR) testing of serial CSF specimens revealed that chronic infection of the CNS occurred in all NHPs injected. CSF pleocytosis occurred concurrently with CNS infection. Brain MRI revealed intense meningeal inflammation in one NHP as manifested by gadolinium uptake by the dura at the base of the temporal lobes. All animals had measurable antibody in the CSF after invasion. These studies are the first to demonstrate that experimental LNB in NHPs is a reliable model faithful to the human disease, with spirochetal invasion of the subarachnoid space. This also is the first report of CSF samples positive by culture in experimental LNB. Inflammation in the CNS as manifested by CSF pleocytosis and MRI findings was also correlated with the presence of spirochetal DNA detected by PCR. These data support the hypothesis that the pathogenesis of LNB is associated with direct spirochetal invasion, and provide evidence that CNS involvement is more common than heretofore thought.

Animals↗

PubMed1994

[The role of modern imaging methods in the determination of childhood obesity].

Authors compare on the basis of their examinations carried out with modern imaging methods the ultrasound and computer tomography techniques in order to determine the fatty layer of the body surface and the visceral fatty quantities. Ultrasound is well usable and documentable to determine the fatty layer of the body surface, because it is not invasive. Computer tomography is more precise but it is a methodology involving x-ray burden. With this method, first of all the visceral fat quantity can be examined. Its application is indicated only in cardiovascular endangered obese children.

Adipose Tissue↗

PubMed1994

Intensive Care Society's Acute Physiology and Chronic Health Evaluation (APACHE II) study in Britain and Ireland: a prospective, multicenter, cohort study comparing two methods for predicting outcome for adult intensive care patients.

OBJECTIVE: To compare the ability of two methods--Acute Physiology and Chronic Health Evaluation (APACHE II) and Mortality Prediction Model (MPM)--to predict hospital outcome for a large group of intensive care patients from Britain and Ireland. DESIGN: Prospective, multicenter, cohort study. SETTING: Twenty-six general intensive care units in Britain and Ireland. PATIENTS: A total of 8,724 patients admitted to the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Probabilities of hospital death for patients were estimated by applying APACHE II and MPM. Predicted risks of hospital death were compared with observed outcomes using four methods of assessing the overall goodness of fit. APACHE II performed better than MPM; the calibration curve for APACHE II lay closer to the line of perfect predictive ability. Lemeshow-Hosmer chi-square statistics were 81 and 57 for APACHE II, and 2515 and 1737 for MPM. The overall correct classification rate for APACHE II was 79%, and this classification rate was 74% for MPM, applying a decision criterion of 50%. The area under the receiver operating characteristic curve was 0.83 with APACHE II and 0.74 with MPM. Even after modifications to the MPM for the assessment of coma, the performance of APACHE II was superior. CONCLUSIONS: APACHE II demonstrated a higher degree of overall goodness of fit, which was superior to MPM for groups of intensive care patients from Britain and Ireland.

Adult↗

PubMed1994

Munchausen's syndrome. A case presenting as asthma requiring ventilation.

We present a variant of Munchausen's syndrome not previously described in which acute severe asthma is the presenting complaint. The clinical presentation is so extreme that the patient has received artificial ventilation on several occasions despite having had normal arterial blood gas values. The patient appears to be able to mimic the signs of severe respiratory distress by means of a protracted Valsalva manoeuvre, and all signs of acute asthma instantaneously disappear with sedation. Because of the chronic 'asthma', and the frequent dramatic acute episodes, the patient successfully claims invalidity benefit, and has done so for many years.

Acute Disease↗

PubMed1994

Temporal patterns of human immunodeficiency virus type 1 transcripts in human fetal astrocytes.

Human immunodeficiency virus type 1 (HIV-1) infection of the developing central nervous system results in a dementing process in children, termed HIV-1-associated encephalopathy. Infection of astroglial elements of the pediatric nervous system has been demonstrated and suggests that direct infection of some astrocytes may contribute to the neurologic deficit. In this model, HIV-1 establishes a persistent state of infection in astrocytes, which can be reactivated by the cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta). To better understand the natural history of viral persistence in astroglial cells, we characterized infection at the transcriptional level. The most abundant viral transcript during the establishment of persistence was the subgenomic multiply spliced 2-kb message, similar to mononuclear cell models of HIV-1 latency. Following reactivation with TNF-alpha or IL-1 beta the multiply spliced 2-kb message remained the most abundant viral transcript, in contrast to infected mononuclear cells in which reactivation leads to the reemergence of the 9- and 4-kb transcripts. Further characterization of the persistent 2-kb transcript by PCR amplification of in vitro-synthesized viral cDNA showed that, in the absence of cytokine stimulation, the most abundant multiply spliced transcripts were the Nef- and Rev-specific messages. However, following cytokine stimulation, double- and triple-spliced Tat-, Rev-, and Nef-specific messages could be identified. Immunohistochemical staining demonstrated that, during viral persistence, astrocytes expressed Nef protein but few or no viral structural proteins. These results demonstrate that viral persistence in astrocytes at the transcriptional level is fundamentally different from that seen in mononuclear cells and could account for the virtual absence of astroglial expression of viral structural antigens in vivo.

Astrocytes↗

PubMed1994

A rabbit model of Lyme neuroborreliosis: characterization by PCR, serology, and sequencing of the OspA gene from the brain.

To test whether rabbits can serve as a model for Lyme neuroborreliosis (LNB), we injected New Zealand white rabbits with Borrelia burgdorferi. We obtained samples of blood and CSF for culture, polymerase chain reaction/hybridization (PCR/H), serology, and Western blot. We then sacrificed the rabbits 2 to 3 months after infection and removed organs for culture and PCR/H analysis. The rabbits developed an antibody response, characterized by ELISA and Western blot analysis, consistent with a systemic infection. PCR/H and blood cultures were negative, but PCR/H analysis of CSF in one rabbit was positive. Positive PCR/H analysis of organs from the rabbits was consistent with widespread dissemination of the organism. The most consistently infected organ was the CNS. To determine whether antigenic variation occurred at the genetic level, we compared the sequences of the OspA gene of both the infecting strain and the brain PCR product. The differences between the two were minimal, indicating that variation in the OspA gene did not occur during in vivo infection in the rabbit. Thus, rabbits, after intradermal inoculation with B burgdorferi, develop a chronic systemic infection in which the CNS is a consistent target. These data indicate that rabbits may be an excellent model of LNB.

Animals↗