Delivery of neurotrophic factors to the CNS using encapsulated cells: developing treatments for neurodegenerative diseases.
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Acrylic Resins↗
Biomedical subjects
A Lee
Publications and source records attributed to A Lee.
Synthesis and beta-lactamase-mediated activation of a cephalosporin-taxol prodrug.
BACKGROUND: Enzyme-activatable prodrugs in conjunction with antibody-enzyme fusion proteins may enhance the anti-tumor efficacy of antibodies and reduce the toxic side effects of conventional chemotherapeutics. Cephalosporins have proven to be highly versatile triggers for the enzymatic activation of such prodrugs. RESULTS: A cephem prodrug of taxol (PROTAX) was synthesized by substituting the C-3' position of cephalothin with 2'-(gamma-aminobutyryl) taxol. Hydrolysis of PROTAX by beta-lactamase rapidly released 2'-(gamma-aminobutyryl) taxol (kcat/K(M) = (1.4 +/- 0.1) x 10(5) s-1 M-1), which yielded taxol following intramolecular displacement. PROTAX is inactive in a microtubule assembly assay in vitro but has similar activity to taxol following prolonged activation with beta-lactamase. PROTAX is approximately 10-fold less toxic than taxol against SK-BR-3 breast tumor cells in vitro but has activity approaching that of taxol following prolonged activation with a fusion protein comprising beta-lactamase fused to a tumor-targeting antibody fragment. CONCLUSIONS: Tubulin polymerization activity is abolished and cytotoxicity is reduced in the PROTAX prodrug compared to taxol. Activation of PROTAX by beta-lactamase followed by self-immolation restores the activity of PROTAX to that of free taxol.
Animals↗
The follicle-stimulating hormone receptor gene is polymorphic in premature ovarian failure and normal controls.
OBJECTIVE: To examine the FSH receptor gene for detectable abnormalities in women with premature ovarian failure. DESIGN: Study of genomic DNA from controls and from patients with 46,XX premature ovarian failure (POF). SETTING: Clinics and laboratories of university gynecology and obstetrics departments. PATIENTS: Twenty-one women with 46,XX POF and 40 normal fertile controls. INTERVENTIONS: Deoxyribonucleic acid was analyzed in patients and controls by Southern blot analysis, polymerase chain reaction (PCR), and denaturing gradient gel electrophoresis. Southern blots were hybridized with the FSH receptor complementary DNA and other smaller DNA probes. Exons 1, 5 to 6, and 10 were amplified by PCR and electrophoresed on agarose gels. Polymerase chain reaction products from exons 1 and 10 were electrophoresed on denaturing gradient gels. MAIN OUTCOME MEASURES: Fragments obtained by Southern blot analysis and PCR were compared in patients and controls. Polymerase chain reaction fragments electrophoresed on denaturing gels also were compared in patients and controls. CONCLUSIONS: No FSH receptor gene deletions or other mutations were identified in women with POF. Southern blots containing PstI- and HindIII-digested DNA revealed restriction fragment length polymorphisms in both patients and controls. Denaturing gradient gel electrophoresis analysis of PCR fragments of exon 10 also demonstrated DNA sequence polymorphisms in both patients and controls. Follicle-stimulating hormone receptor gene deletions are not common in women with POF, although the gene is polymorphic. We cannot exclude point mutations in other regions of the FSH receptor gene in some patients with POF.
Adolescent↗
A graphic digital database of Drosophila embryogenesis.
Modern studies of the genetic control of development have increased the need for an accurate and comprehensive storage and display of gene expression data. This can be achieved in the form of an electronic graphic database of development. Here, we introduce the first steps towards a database of Drosophila embryogenesis. For each morphologically defined stage, a complete series of histological and/or optical sections are generated (optical sections are generated by laser confocal microscopy). Digitized sections are imported into a drawing program where they serve as templates to define the contours of organs and the position of individual cells. From these data, surface and point cloud models of all developmental stages are generated. Gene expression data can be entered by translating the expression domain of a given gene into the three-dimensional coordinate system of the database.
Analog-Digital Conversion↗
Three-dimensional ultrasound in diagnosing phocomelia.
Deformations of the extremities with limb reduction are rare congenital defects which affect one in 1692 live babies. Three-dimensional ultrasound can be of value in the prenatal diagnosis of such deformities. We present a case of upper phocomelia and congenital thrombocytopenia (TAR syndrome). Visualization of the upper extremities was achieved by three-dimensional ultrasound after surface and volume rendering. This new technique allows imaging not only of surfaces like the fetal skin, but also of internal structures like the fetal skeleton.
Adult↗
B-cell chronic lymphocytic leukemia followed by high grade T-cell lymphoma. An unusual variant of Richter's syndrome.
A 70-year-old woman with a 2-year history of B-cell chronic lymphocytic leukemia (CLL) developed headache, fever, chills, and weakness. Bone marrow examination revealed both CLL and large cell immunoblastic lymphoma (Richter's syndrome). As expected, the CLL was of B-cell lineage. The neoplasm expressed low-density monotypic IgM lambda, the pan-B-cell antigens CD19, CD20, and CDw75, and the CD5 and CD43 antigens. The large cell immunoblastic lymphoma was of T-cell lineage, positive for the CD45RB, CD3, CD45RO, and CD43 antigens, and negative for the CD20 and CDw75 antigens. Both neoplastic components were negative for Epstein-Barr virus RNA and latent membrane protein. Although 3% to 5% of patients with B-cell CLL may develop higher-grade lymphoma, usually the lymphoma is of B-cell lineage and often represents a histologic manifestation of clonal evolution. Less commonly, B-CLL patients may develop transformation to a higher grade tumor that resembles Hodgkin's disease. Both the usual form of Richter's syndrome and particularly the Hodgkin's variant of Richter's syndrome may be associated with Epstein-Barr virus. Patients with B-cell CLL rarely develop a higher grade lymphoma of T-cell lineage. To our knowledge, only one other example has been reported in the literature. Epstein-Barr virus was not associated with either neoplasm in this case.
Aged↗
Seroepidemiology of Helicobacter pylori infection in heart transplant recipients.
We analyzed serum samples obtained from 100 heart transplant recipients before and after transplantation for the presence of IgG antibodies to Helicobacter pylori. Enzyme-linked immunosorbent assay revealed that 35 patients were seropositive before the procedure. Seropositive patients were older than seronegative patients, but the two groups did not differ in terms of cardiac diagnosis, gender, survival, or the number of admissions or rejection episodes. In addition, seropositive patients did not have more-frequent episodes of gastritis, ulcer disease, or gastrointestinal bleeding. Over a mean serological follow-up of 3.4 years, only one of 65 seronegative patients seroconverted. Of the 35 seropositive patients, 14 became seronegative for H. pylori a median of 194 days (range, 47-2,657 days) after transplantation. Seroreverters, as compared with serofast patients, had received more intravenous and total antibiotics during follow-up (P = .01), were more likely to have received a combination of antibiotics active against H. pylori (P < .025), and had received more antirejection treatment (P = .01). The incidence of H. pylori infection is not increased after heart transplantation, and many seropositive patients serorevert after transplantation when antibacterial and immunosuppressive agents are administered.
Adult↗
Multiplex PCR of bcr-abl fusion transcripts in Philadelphia positive acute lymphoblastic leukemia.
We describe a multiplex PCR assay for the detection of bcr-abl fusion mRNA in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). The assay provides a quick method for screening p190 (e1:a2) and p210 (b2:a2 or b3:a2) bcr-abl mRNAs simultaneously. The assay proves to be highly sensitive with detection of as little as one positive bcr-abl-expressing cell in a background of 10(5) negative bcr-abl cells. Bone marrow and peripheral blood specimens from six patients were in total accordance when run by multiplex PCR and by the single primer PCR approach. The multiplex bcr-abl assay may prove to be highly useful for screening newly diagnosed patients with ALL for the bcr-abl fusion transcript and in following the course of disease during therapy.
Base Sequence↗
Review article: the development of atrophic gastritis--Helicobacter pylori and the effects of acid suppressive therapy.
Helicobacter pylori is uniquely adapted to survival in the strongly acidic gastric lumen. In vitro, both acid and certain acid suppressors affect bacterial growth. In vivo, there is little evidence that acid suppressors have any effect on bacterial survival. In contrast, decrease of acid secretion quickly leads to a spreading of the bacterial infection throughout the body and fundus of the stomach, which is accompanied by an increase of the associated gastritis. Helicobacter pylori gastritis may, in a substantial number of infected subjects, ultimately lead to atrophy and intestinal metaplasia, conditions with an increased risk for gastric cancer. This review summarizes the data on the interrelation between Helicobacter pylori, gastric acid secretion and development of atrophic gastritis.
Animals↗
Three dimensional ultrasound: abnormalities of the fetal face in surface and volume rendering mode.
OBJECTIVE: To evaluate three dimensional ultrasound in surface and volume rendering mode in fetal malformations of the face. SETTING: Day assessment unit in a university hospital. SUBJECTS: Four cases have been examined: two cases represented cleft lip, one case was a male with trisomy 13 (Patau syndrome) with proboscis, and one case represented a male fetus with unilateral anophthalmia. CONCLUSION: A new technique of three dimensional ultrasound visualisation in fetal malformation using surface and volume rendering is presented. The equipment consisted of a commercially available ultrasound machine, a built-in graphic workstation, and three dimensional software. Post-processing of data required approximately 10 minutes of calculation. The application of three dimensional ultrasound in complex malformations of the face appears to provide reasonable value for prenatal diagnosis and may become clinically useful in the near future.
Adult↗
Effects of two antibiotic regimens on course and persistence of experimental Chlamydia pneumoniae TWAR pneumonitis.
We studied the effects of two antibiotic regimens on the course of Chlamydia pneumoniae infection in the lungs of Swiss Webster mice. After intranasal challenge with isolates AR-388 (1.3 x 10(7) inclusion-forming units per mouse) and AR-39 (1.5 x 10(6) inclusion-forming units per mouse), groups of animals were treated with either doxycycline (10 mg/kg of body weight once a day for 3 days), azithromycin (10 mg/kg [single dose]), or saline. Responses were assessed by the isolation of organisms in cell culture, detection of TWAR DNA in lung tissues by PCR, and lung histology. Both regimens were effective in clearing infections induced by AR-388 (P = 0.02 and 0.007 for doxycycline and azithromycin, respectively) compared with controls. TWAR DNA was detected in 77 and 25% of culture-negative lungs 2 weeks after treatment of AR-388 and AR-39 infections, respectively. Histological changes showed interstitial pneumonitis and were similar over time for all groups. Single-dose azithromycin produced drug levels in lung tissues above the MICs for the test strains for a period three times longer than that of single-dose doxycycline. We concluded that short-term antibiotic regimens were successful for the treatment of experimental TWAR pneumonitis in mice. TWAR DNA was frequently recovered from lung tissues after apparently successful treatment.
Animals↗
Characterization of alpha 2A-adrenergic receptors in GT1 neurosecretory cells.
In this paper, we report the endogenous expression of functional alpha 2-adrenergic receptors (alpha 2-ARs) in the immortalized hypothalamic cell line, GT1. Membranes from GT1 cells exhibited high-affinity binding for the specific alpha 2-AR radioligand [3H]RX821002 (Kd = 0.2 +/- 0.03 nM, Bmax = 29.5 +/- 2.1 fmol/mg protein, n = 3). The Ki values for the adrenergic ligands, oxymetazoline (1.6 +/- 0.3 nM, n = 3) and prazosin (287 +/- 89 mM, n = 3), were consistent with the pharmacological properties of the A subtype of alpha 2-AR (alpha 2A-AR). The presence of mRNA encoding the alpha 2A-AR in GT1 cell extracts was confirmed by Northern blot analysis. alpha 2-ARs in GT1 cells were found to be coupled to the inhibition of adenylyl cyclase through the pertussis toxin-sensitive class of heterotrimeric G-proteins. A maximal dose of the alpha 2-AR agonist UK 14304 inhibited forskolin-stimulated cAMP production in GT1 cells by 53% (EC50 = 316 nM). Double labeling of rodent brain sections with antibodies specific for GnRH and the alpha 2A-AR indicated a large proportion of neurons labeled with the GnRH antibody also contained alpha 2A-AR-like immunoreactivity. In both GT1 cells and GnRH-immunopositive neurons in brain, clusters of alpha 2A-AR-like immunoreactivity were associated with cell bodies and occasionally with neuritic processes. Punctate alpha 2A-AR-like immunoreactivity was localized to intracellular compartments in GT1 cells as determined by confocal microscopy. Whole cell radioligand binding techniques were used to show that at least one third of the alpha 2-AR population in GT1 cells was intracellular. In view of these data, GT1 cells may serve as a representative system in which to study the biology of alpha 2A-ARs in relation to neuronal and neurosecretory functions.
Adrenergic alpha-Antagonists↗
The Medical Emergency Team.
The concept of a Medical Emergency Team was developed in order to rapidly identify and manage seriously ill patients at risk of cardiopulmonary arrest and other high-risk conditions. The aim of this study was to describe the utilization and outcome of Medical Emergency Team interventions over a one-year period at a teaching hospital in South Western Sydney. Data was collected prospectively using a standardized form. Cardiopulmonary resuscitation occurred in 148/522 (28%) calls. Alerting the team using the specific condition criteria occurred in 253/522 (48%) calls and on physiological/pathological abnormality criteria in 121/522 (23%) calls. Survival rate to hospital discharge following cardiopulmonary arrest was low (29%), compared with other medical emergencies (76%).
APACHE↗
The perioperative system: a new approach to managing elective surgery.
A Perioperative Service has recently been introduced at liverpool hospital, a 460-bed university teaching hospital. This provides a co-ordinated system for managing all elective surgical patients from the time an admission booked until hospital discharge. This paper describes the patient assessment, structure and staff requirements, benefits of and problems encountered with this service. The patient's preoperative preparation occurs before hospital admission. Where possible, patients are admitted on the day of procedure, either as a day-only patient, or a day-of-surgery patient. Patients are initially admitted to a specifically designed Perioperative Unit, adjacent to the Operating Theatre Suite. Patients do not enter the surgical wards until after their operation. Planning of the hospital discharge process commences at the time of booking for operation. Introduction of the Perioperative Service was staged process commencing in mid-1992. The hospital admits approximately 6,400 elective surgery cases each year. From July 1992 to December 1994, day-only patients were approximately 45% of these cases. Day-of surgery admission patients increased from 6% to 35% of all cases over the same period. Approximately 22% of elective surgical cases were seen in the Perioperative Clinic. As the Perioperative Service became fully operational, the average length of stay for elective surgical procedures fell. There has been a reduction in the areas of cancellations due to unavailability of beds, inappropriate preparation of patients, and non-attendance of patients for booked procedures. Patient acceptance is high. The existence of a perioperative system facilitates the planning and management of elective surgery with maximum quality and efficiency.
Ambulatory Surgical Procedures↗
Psychological consequences of the Kegworth air disaster.
BACKGROUND: The study sought to quantify psychiatric morbidity among survivors of a major air crash and to identify aetiological factors linked with post-traumatic stress disorder (PTSD). METHOD: Sixty-eight of the 79 survivors (86%) were assessed at a clinical interview within one year of the disaster. The majority also completed the General Health Questionnaire, the Impact of Events Scale (IES) and the Zung Anxiety and Depression Scales. RESULTS: Fifty-four of the study group (79%) met DSM-III-R criteria for a psychiatric disorder within one year of the disaster, of whom 27 (50%) had PTSD. Those who saw injured or dead people at the scene, or had sustained less severe injuries as measured by their Injury Severity Scores, or were under 35 years old, were significantly more likely to develop PTSD. CONCLUSIONS: High rates of psychiatric morbidity are found in survivors of transportation disasters. Further studies are needed to identify those at most risk and to evaluate the benefits of psychological intervention.
Adult↗
The pros and cons of generic medicines.
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Drugs, Generic↗
Helicobacter infections in laboratory animals: a model for gastric neoplasias?
Evidence is rapidly accumulating that Helicobacter pylori is a major risk factor for human gastric adenocarcinomas and all low-grade B-cell gastric lymphomas. Given this, there is a need to develop animal models with a view to discovering not only how carcinogenesis is initiated, but also how the process can be prevented. The lack of H. pylori animal models suitable for long-term studies means that alternatives are needed. The most productive models are likely to be the Helicobacter mustelae-infected ferret or the mouse infected with either Helicobacter felis or 'Helicobacter heilmannii'. The first evidence that helicobacter infection induces a chronic inflammation that progresses to gastric atrophy, the precursor lesion to gastric adenocarcinoma in humans, has come from the mouse model. The severity of inflammation is dependent on the type of mouse strain used, highlighting the importance of host factors in the development of gastritis. Carcinogenesis studies should only be done with mouse strains known to cause atrophy. The H. mustaelae-infected ferret appears very susceptible to the development of adenocarcinoma following ingestion of chemical carcinogens. Long-term infection of mice with H. felis results in the development of low-grade B-cell gastric lymphomas indistinguishable to those found in H. pylori-infected humans. Helicobacter-infected animals, rodents in particular are going to provide exciting opportunities to investigate not only important aspects of gastric cancer and lymphoma but also fundamental issues of carcinogenesis in general.
Animals↗
Expression of p53 and NDP-K/nm23 in gastric carcinomas--association with metastasis and clinicopathologic parameters.
To evaluate the role of p53 and NDP-K/nm23(nm23) protein as a prognostic factor and their relation to metastasis of cancer, we studied metastatic and nonmetastatic gastric carcinoma specimens by immunohistochemical staining. Among the 101 specimens examined, 37(36.6%) showed positivity in staining for p53 protein and 64(63.4%) showed no detectable p53 protein in tumor cells. p53 overexpression was correlated with depth of invasion, lymphatic invasion, lymph node metastasis and distant metastasis. Out of 101 specimens, 35 cases had no staining for nm23. 62 cases(61.4%) exhibited a cytoplasmic staining on most cells and 42 cases (41.6%) had nuclear staining. In 16 of 101 cases(15.8%), a mild to moderate membranous staining was observed in some cells. Cytoplasmic nm23 expression was negatively correlated with lymph node metastasis(P < 0.01) and distant metastasis(P < 0.01). The nuclear nm23 expression showed negative correlation with depth of invasion(P < 0.01), lymphatic invasion(P < 0.01), lymph node metastasis(P < 0.01), and distant metastasis(P < 0.04). The membranous nm23 expression revealed negative correlation with lymphatic invasion(P < 0.02), lymph node metastasis(P < 0.01) and distant metastasis(P < 0.02).
Adult↗