Search PubMed⌕ Search

Biomedical subjects

A Alexander

Publications and source records attributed to A Alexander.

At least 19 recordsLinked to original sources
PubMed2006

Prognostic significance of serial magnetic resonance spectroscopies over the course of radiation therapy for patients with malignant glioma.

BACKGROUND: The standard treatment of high grade gliomas (HGG) involves maximal neuro-surgical debulking, followed by post-operative radiotherapy, with or without concurrent chemotherapy, depending on histologic grade. Despite this aggressive strategy, there are few long-term survivors. Proton magnetic resonance spectroscopy (MRS) is a non-invasive imaging method that can monitor metabolic changes in brain tumours. To date there is little data concerning the prognostic significance of the evolving spectral alterations during a course of radiotherapy. MATERIALS: We report herein a prospective study of patients with HGGs undergoing post-operative radiotherapy. Fourteen consecutively eligible patients with a confirmed histologic diagnosis of malignant glioma and completion of all required MRS imaging were included in this study. All patients had MRS imaging prior to radiotherapy, at week 4 of radiotherapy, and 2 months post-treatment. T1 and T2 weighted images as well as post-gadolinium multi-voxel proton MRS images were obtained. Normalized (tumour metabolite/normal brain metabolite) levels of choline, NAA, creatine, lipid and lactate were calculated. Kaplan-Meier (KM) curves of progression-free and overall survival were constructed based on the evolving patterns of metabolite changes over the course of the images. RESULTS: The mean tumour choline/NAA ratio decreased over the course of therapy, with a reduction observed between the baseline and post-radiotherapy studies (1.91 vs. 1.29, P=0.049). A similar decrease was identified with the mean normalized choline ratio, with a highly significant difference observed between the baseline and post-radiation images (1.61 vs. 0.96, P=0.001). Patients who exhibited more than 40% decrease in normalized choline between the week 4 and post-radiotherapy studies were associated with unfavourable survival (logrank test, P=0.003) and disease progression (logrank test, P=0.012). The Lactate/NAA ratio at the 4th week of radiotherapy and the change in normalized choline/creatine between baseline and week 4 of radiotherapy were also predictive of outcome suggesting the possibility of adaptive, response-based radiation treatment. Patients with two or more poor prognostic MRS indices had a significantly shorter progression-free survival compared with those with zero or one poor indices, with 15% and 68% at 1 year, respectively (logrank test, P=0.045). CONCLUSION: The evolving pattern of spectral changes over the course of radiotherapy, in particular those associated with choline-containing compounds, appears to be prognostic of tumour response and outcome. Based on our data, a decision point may exist in the mid course of radical radiotherapy, at which time consideration of the choline levels could indicate the extent of radiotherapeutic response, thus allowing for individualized treatment modification.

Brain Neoplasms↗
PubMed2005

Enhancement of radiation sensitivity with BH3I-1 in non-small cell lung cancer.

BACKGROUND: Anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, are frequently over-expressed in human malignancies, and this is correlated with resistance to chemotherapeutic drugs and gamma- radiation. Recently identified small organic molecules capable of inhibiting Bcl-2 and/or Bcl-xL function, may enhance radiation sensitivity of cancer cells in which they are over expressed. We examined whether specific blockade of the BH3-domain binding to Bcl-xL could sensitize cancer cells to gamma- radiation. METHODS: Human non-small-cell lung cancer H460 cells with wild-type p53 and H1792 cells with mutant p53 were exposed to various doses of radiation and/or BH3I-1 and for different points of time to BH3I-1 treatment. XTT and clonogenic survival assays were used to evaluate the growth-inhibitory effects of the antagonist BH3I-1, ionizing radiation or both. Western blot analysis was used to examine the cellular effect of the expression of Bcl-xL, Bax, and p53. Apoptosis and cell cycle distribution were analyzed by confocal microscopy with Hoechst 33258 staining and cytochrome c, and flow cytometry, respectively. RESULTS: BH3I-1 appeared to induce a dose- and time-dependent apoptosis in H460 and H1792 cells, regardless of p53 status. After 2 days of BH3I-1 treatment, the cells that remained attached were exposed to ionizing radiation. Followed by clonogenic assay, BH3I-1 treatment enhanced the radiation sensitivity of H1792 surviving cells with mutant p53, but not in H460 cells with wild-type p53. A transient time-dependent cell cycle blockade at G2-M phase was identified for H1792 cells without subsequent modification of cell cycle distribution. CONCLUSION: These findings suggest a potential role for the small molecule inhibitor as a novel radiation sensitizer in non-small cell lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed2004

On compensation of mismatched recording conditions in the Bayesian approach for forensic automatic speaker recognition.

This paper deals with a procedure to compensate for mismatched recording conditions in forensic speaker recognition, using a statistical score normalization. Bayesian interpretation of the evidence in forensic automatic speaker recognition depends on three sets of recordings in order to perform forensic casework: reference (R) and control (C) recordings of the suspect, and a potential population database (P), as well as a questioned recording (QR) . The requirement of similar recording conditions between suspect control database (C) and the questioned recording (QR) is often not satisfied in real forensic cases. The aim of this paper is to investigate a procedure of normalization of scores, which is based on an adaptation of the Test-normalization (T-norm) [2] technique used in the speaker verification domain, to compensate for the mismatch. Polyphone IPSC-02 database and ASPIC (an automatic speaker recognition system developed by EPFL and IPS-UNIL in Lausanne, Switzerland) were used in order to test the normalization procedure. Experimental results for three different recording condition scenarios are presented using Tippett plots and the effect of the compensation on the evaluation of the strength of the evidence is discussed.

Bayes Theorem↗
PubMed2004

The effect of mismatched recording conditions on human and automatic speaker recognition in forensic applications.

In this paper, we analyse mismatched technical conditions in training and testing phases of speaker recognition and their effect on forensic human and automatic speaker recognition. We use perceptual tests performed by non-experts and compare their performance with that of a baseline automatic speaker recognition system. The degradation of the accuracy of human recognition in mismatched recording conditions is contrasted with that of the automatic system under similar recording conditions. The conditions considered are of public switched telephone network (PSTN) and global system for mobile communications (GSM) transmission and background noise. The perceptual cues that the human subjects use to perceive differences in voices are studied along with their importance in different conditions. We discuss the possibility of increasing the accuracy of automatic systems using the perceptual cues that remain robust to mismatched conditions. We estimate the strength of evidence for both humans and automatic systems, calculating likelihood ratios using the perceptual scores for humans and the log-likelihood scores for automatic systems.

Bayes Theorem↗
PubMed2003

Sampling and characterization of pharmaceutical powders and granular blends.

We use a variety of experimental results to illustrate issues and challenges involved in the sampling and characterization of pharmaceutical mixtures. Accurate and reliable characterization of granular mixtures is hindered by both the complexity of granular systems and the lack of validated and reliable sampling technology and techniques. Both sampling tools and sampling protocols are critically important for accurate characterization. Using cohesive and free-flowing powders and four thief probe designs, we reveal a large potential for extremely misleading results as well as severe disturbance of the granular bed. We also discuss results from several experiments designed to test the validity of various sampling protocols by varying parameters such as sampling location and frequency of sampling. These experiments illustrate the importance of effective sampling procedures to achieve the best and most efficient results.

Powders↗
PubMed2003

Effects of age, education and gender on verbal fluency.

The objective was to study the effects of age, education and gender on verbal fluency in cognitively unimpaired, older individuals. The methods used were as follows: cognitively unimpaired elderly (55-84 years) subjects (n=153), were administered category (animal) (CF) and letter (/pa/) (LF) fluency tasks, in their native language of Malayalam. Results and conclusions were (1) Level of education, but not age or gender, significantly influence LF. (2) Level of education (directly) and in the elderly subjects, age (inversely) affect CF. (3) Age, but not education, has a differential effect on the tasks of verbal fluency, influencing CF more than LF.

Age Factors↗
PubMed2001

Obstetric and diabetic care for pregnancy in diabetic women: 10 years outcome analysis, 1985-1995.

AIM: Ten-year outcome analysis of all pregnancies in diabetic women in a population of 1.5 million people. METHODS: Ascertainment of patients through the regional obstetrical computer, and by direct contact with each obstetrical unit. Retrospective assessment of early miscarriage of pregnancy from hospital records. Data are presented for the six smallest obstetrical units, the four smaller district hospitals, two larger teaching hospitals and for the regional referral centre. RESULTS: Nine hundred and eighty-six fetal outcomes were identified, 753 in mothers treated with insulin before the pregnancy, 131 in mothers in whom insulin was started for the first time during the pregnancy and 102 in mothers treated by diet only. Overall perinatal mortality rates were 35.8 per 1000 for those mothers booked and delivered at a local maternity unit, 28.9 per 1000 for those booked and delivered at the regional centre, but 75.0 per 1000 for those who had booked locally but were transferred to the centre mid-pregnancy. Information on blood glucose control before and during pregnancy was relatively poorly documented. For the available data at the regional centre, only 160 of the 416 mothers had an identifiable preconception HbA1c measurement (mean 7.9%, range 3.3-16.8%): at booking 360 of these mothers had a mean HbA1c of 7.5% and by the third trimester mean HbA1c was 6.3% (range 3.3-13.2%). CONCLUSIONS: The outcome of pregnancy in a diabetic mother in Northern Ireland remains a higher risk than for the general population. There is evidence that results in the regional centre are better, but problems arise when transfers occur mid-pregnancy. Measurement and recording of blood glucose control at all stages before and during pregnancy is incomplete. Diabet. Med. 18, 546-553 (2001)

Abortion, Spontaneous↗
PubMed2000

Gamma heavy chain disease in man: independent structural abnormalities and reduced transcription of a functionally rearranged lambda L-chain gene result in the absence of L-chains.

Human Ig heavy chain diseases of the alpha and gamma classes are characterized by the absence of light chain production as well as the disease-defining abnormalities in the heavy chain protein. Prior studies have suggested concomitant structural defects in productively rearranged L-chain genes as the reason for the absent L-chain proteins. We have found that the single rearranged lambda L-chain gene in the OMM heavy chain disease (HCD) cell line has a mutation in the splice donor site at the 3' end of the J exon, resulting in direct splicing of the 3' end of the leader to the acceptor site of the constant region. The cells contain an mRNA consisting of the leader-coding region joined directly to the constant region. The V-region exon is skipped and the shortened mRNA is translated into a truncated protein containing no V-region amino acids. We have also noted that, in contrast to most normal and neoplastic Ig-producing cells, the OMM cells produce an excess of heavy to light chain mRNA as well as protein. The excess is independent of the structural gene abnormality and is due to a low level of L-chain transcription, which can be increased by fusing the HCD cell to the murine myeloma cell line NS-1 or transfecting the defective OMM L-chain gene into a murine plasma cell. The latter data suggest that the OMM cells either lack a transcription factor present in mature plasma cells or have a functional repressor of L-chain transcription.

Amino Acid Sequence↗
PubMed2000

A questionnaire survey about doctor-patient communication, compliance and locus of control among south Indian people with epilepsy.

To date, very few studies have investigated patients' views on the information they receive from the doctor concerning epilepsy and its management. Little information is available about the influence of doctor-patient communication and locus of control on the compliance of persons with epilepsy. We investigated, through a questionnaire-interview design, among patients attending the epilepsy clinic of a tertiary referral center in South India, their views about the provision of information by the doctor, and their compliance and locus of control. We also determined the interrelation between doctor-patient communication, compliance and locus of control. Our subjects comprised 200 adult persons with epilepsy, 113 males and 87 females, mean age 30.5 (range 18-67) years. Over one-third of the subjects received from the doctor insufficient information about epilepsy and its treatment. There was a significant positive correlation between effective doctor-patient communication and compliance. A majority of our patients had an external locus of control, which negatively influenced the compliance. Even in a comprehensive epilepsy clinic of a model tertiary referral center in a developing country, a significant proportion of patients do not receive optimal information about epilepsy from the doctor. Knowledge about their disease will encourage people with epilepsy to make informed choices, and achieve better compliance and personal control of their problems. Educating primary and secondary care physicians about the importance of doctor-patient communication in the management of epilepsy and educating the public about the positive aspects of life in epilepsy cannot be overemphasized.

Adolescent↗
PubMed2000

The National Demonstration Hospitals Program.

Fifty-five public hospitals in all Australian States and Territories participated in the first two phases of National Demonstration Hospitals Program (NDHP). The program was established in 1994 as part of a commitment by the then Department of Health and Family Services to reduce waiting times and improve health outcomes for patients. The program uses a collaborative approach to assist public hospitals to improve service delivery and patient care outcomes. Key results from Phases 1 and 2 of the NDHP have confirmed that identification of industry best practice, collaboration, knowledge sharing and innovation are key elements required to achieve positive health care reforms.

Australia↗
PubMed1999

Narrow-band collisional activation technique for ion trap mass spectrometers.

Narrow-bandwidth signals were applied to the end caps of an ion trap mass spectrometer to excite ions during collisional activation. Excitation waveforms were created from a single-frequency component and a random noise component using a multiplier circuit. Tandem and higher order mass spectrometry experiments (MS3) can be performed without optimization of the supplemental frequency applied to the end cap electrodes. The usefulness of this method of ion excitation is demonstrated using singly and multiply protonated peptide ions as well as sodium-cationized carbohydrates.

Amino Acid Sequence↗
PubMed1999

Immunology of type 1 diabetes. Intervention and prevention strategies.

Type 1 diabetes is the outcome of a progressive and selective destruction of insulin-producing cells in the pancreatic islets of Langerhans. The precise cause and mechanism(s) that trigger the insulin-producing cell destruction are still unclear, although it is well accepted that an autoimmune process plays a central role in diabetes development among genetically susceptible children. Additionally, certain viral infections, especially those caused by Coxsackievirus B, have been associated with the onset of type 1 diabetes. Possible gene therapy-based prevention and intervention strategies are discussed, based on the most accepted models of type 1 diabetes pathogenesis.

Autoimmune Diseases↗
PubMed1999

Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4.

During immune responses, antigen-presenting cells (APCs) process antigens and present peptide epitopes complexed with human leukocyte antigen (HLA) molecules. CD4 cells recognize these naturally processed and presented epitopes (NPPEs) bound to HLA class II molecules. Epitope identification is important for developing diagnostic and therapeutic tools for immune-mediated diseases and providing insight into their etiology, but current approaches overlook effects of natural processing on epitope selection. We have developed a technique to identify NPPEs using mass spectrometry (MS) after antigen is targeted onto APCs using a lectin-based antigen delivery system (ADS). We applied the technique to identify NPPEs of the intracellular domain of the type 1 diabetes mellitus-associated (type 1 DM-associated) autoantigen insulinoma-associated-2 (IA-2ic), presented by HLA-DR4 (0401). IA-2ic-derived NPPEs eluted from HLA-DR4 constitute 6 sets of peptides nested around distinct core regions. Synthetic peptides based on these regions bind HLA-DR4 and elicit primary T-cell proliferation frequently in HLA-DR4-positive type 1 DM patients, but rarely in non-HLA-DR4 patients, and in none of the HLA-DR4 nondiabetic controls we tested. This flexible, direct approach identifies an HLA allele-specific map of NPPEs for any antigen, presented by any HLA class II molecule. This method should enable a greater understanding of epitope selection and lead to the generation of sensitive and specific reagents for detecting autoreactive T cells.

Adolescent↗
PubMed1999

Overcoming language barriers for non-English speaking patients.

Although some of the resources or services listed may seem expensive, it is cheaper to use these than to face a malpractice suit for failure to provide patients with limited English access to services equal to those provided to English speakers. The University of California at San Francisco (UCSF), one of the top three ranking research hospitals in the U.S., had a suit filed against it by the American Civil Liberties Union (ACLU) claiming failure to provide adequate translation services for the patient population. The university is now a participant in a statewide effort to provide access to well-trained translator services to the patient population. This effort and the development of an in-house interpreter services department has contributed to a competitive edge for UCSF in the area of patient services and satisfaction as well as attracting more Medicaid patients, which increases their revenues.

Audiovisual Aids↗
PubMed1998

Endocytosis and intracellular sorting of receptor tyrosine kinases.

Binding of the peptide growth factors (GF) on their surface receptors triggers rapid endocytosis of ligand-receptor complexes via clathrin-coated pits. Internalized receptors pass through the endosomal compartment where they are efficiently sorted to the lysosomal degradation pathway. Accelerated internalization and degradation of GF receptors leads to dramatic down-regulation of the receptors. Hence, we discuss the pathways, molecular mechanisms and the biological role of the GF-induced receptor endocytosis and lysosomal targeting. The endocytosis of epidermal growth factor (EGF) receptor is employed as a model system to describe the role of clathrin, clathrin adaptors and other proteins in the recruitment of receptors into coated pits and in the endosomal sorting process.

Endocytosis↗
PubMed1997

Effect of late modulation of nitric oxide production on murine lupus.

MRL/MpJ-Faslpr (MRL-lpr) and New Zealand Black/ White (NZB/W) mice develop spontaneous autoimmune disease characterized by autoantibody production and glomerulonephritis that progresses in parallel with increasing systemic nitric oxide (NO) production. A previously published study from our laboratory indicated that oral administration of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (NMMA) before the onset of clinical disease significantly decreased renal and joint pathology in MRL-lpr mice. To characterize the effect of late modulation of NO production in murine SLE, we administered oral NMMA and/or restricted dietary arginine after disease onset in two murine models of SLE. When receiving combined NMMA and arginine restriction, MRL-lpr mice had reduced joint pathology scores and NZB/W mice had lower renal pathology scores than control mice. These results indicate that modulating NO production after the onset of disease diminishes disease severity in two models of SLE, although not as effectively as treating before disease onset.

Animals↗
PubMed1997

Preoperative staging of irradiated rectal cancers using digital rectal examination, computed tomography, endorectal ultrasound, and magnetic resonance imaging does not accurately predict T0,N0 pathology.

PURPOSE: The postradiation preoperative staging results of 25 patients with rectal cancer who were found to have Stage T0,N0 lesions after surgery were examined. Our aim was to assess the ability of preoperative staging following radiation therapy to predict the absence of disease. METHODS: From 1983 to 1994, 25 patients treated with preoperative radiation therapy for biopsy-proven rectal cancer were found to have no pathologic evidence of disease in the resected specimen (T0,N0). The preoperative postradiation disease staging results of these patients were compared with the postoperative pathologic findings. Each patient received 4,500 to 5,580 cGy during a five-week to six-week period, and four patients had preoperative chemotherapy. Surgical resection was performed six to eight weeks after completion of radiation therapy. All 25 patients were staged by digital rectal examination before surgery. In addition, 13 patients were assessed using computed tomography, 6 by endorectal ultrasound, and 1 by magnetic resonance imaging. RESULTS: Most irradiated lesions were overstaged by radiologic assessment and physical examination. No technique could reliably distinguish between postradiation fibrosis and residual cancer. The negative predictive value for digital rectal examination was 24 percent. Computed tomography accurately staged 23 percent of lesions, and endorectal ultrasound predicted 17 percent of lesions correctly. The single patient evaluated by magnetic resonance imaging was overstaged and thought to have a T2 lesion. CONCLUSIONS: Our ability to assess local eradication of rectal cancer following radiation therapy remains poor. Conventional imaging and clinical examination techniques are unable to safely predict which patients do not require surgical excision following curative radiation therapy for rectal cancer.

Adenocarcinoma↗