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Biomedical subjects

M Gordon

Publications and source records attributed to M Gordon.

At least 109 records · Page 6Linked to original sources
PubMed1997

The peripheral flicker effect: desensitization of the luminance pathway by static and modulated light.

Previous studies have shown that luminance flicker, presented peripheral to a foveal test target, increases thresholds for target detection: the peripheral flicker (PF) effect. These studies have also shown that thresholds are elevated more for luminance targets, relative to chromatic targets. In the present study we examined the specificity of the PF effect on the luminance mechanism and assessed the contribution of modulated stray-light to the test field, as well as longer range spatial interactions. We found that the presence of a foveal luminance pedestal, as well as PF, caused a notch to appear in the spectral sensitivity function around 570 nm. This result confirms the hypothesis that the PF effect decreases the sensitivity of the luminance pathway. To assess the contribution of stray-light to the PF effect, we modulated a luminance pedestal without the presence of PF in order to simulate the stray-light effect in isolation. A decrease in sensitivity for wavelengths around 570 nm occurred with modulated stray-light, suggesting that modulated stray-light contributes substantially to this effect. We then minimized the modulated stray-light by phase-reversing a checkerboard pattern in the periphery. A significant, though smaller, threshold elevation to mid-spectrum stimuli was obtained, suggesting that long range spatial effects are also active in the PF effect. We conclude that the PF effect causes a desensitization of foveal luminance pathways via local and more long range spatial interactions. Our results are consistent with previous data which suggest that the PF effect is due to selective adaptation of cells in the magnocellular pathway (M-cells). Our data imply that local network adaptation may be a property of the magnocellular pathway.

Color Perception↗
PubMed1997

Apical expression of functional asialoglycoprotein receptor in the human intestinal cell line HT-29.

BACKGROUND & AIMS: The asialoglycoprotein receptor localizes to the basolateral membrane of hepatocytes and to the apical membrane of enterocytes. The aim of this study was to examine HT-29 cells as a polarized cell model for studying apically localized endogenous asialoglycoprotein receptor. METHODS: Subunits H1 and H2 (human) were detected by Western blot and immunoprecipitated using subunit-specific antisera against hepatic receptor peptides. Receptor function was assessed by uptake of iodinated asialo-orosomucoid, immunoglobulin (Ig) A1, and haptocorrin. Immunocytochemistry was analyzed by standard light and confocal microscopy. RESULTS: Receptor content of the minor subunit, H2, was predominant. HT-29 cells mediated specific uptake and degradation of 125I-asialo-orosomucoid. A high-affinity (0.6 x 10(-9) mmol/L) and a low-affinity binding site were present. The specific ligand binding capacity of the apical surface was approximately twice that of the basolateral surface. Immunocytochemistry revealed a predominant apical membrane location of the minor receptor subunit, with some intracellular receptor. The apical H2 subunit was preferentially labeled with amino acid precursors compared with basolaterally located subunit. Human IgA1 bound specifically to HT-29 cells with a molar ratio of 0.26 compared with asialo-orosomucoid; porcine haptocorrin bound with a molar ratio of 1.35. CONCLUSIONS: HT-29 cells produce a functional apically located asialoglycoprotein receptor and provide a model for receptor trafficking in the enterocyte.

Asialoglycoprotein Receptor↗
PubMed1997

A systematic review of the evidence for hypodermoclysis to treat dehydration in older people.

BACKGROUND: The purpose of the study was to evaluate the evidence supporting the use of hypodermoclysis (i.e., subcutaneous infusion of fluids) to treat dehydrated elderly patients, and to discuss clinical applications of this mode of therapy in the long-term care setting. METHOD: Articles reporting the use of hypodermoclysis were identified using a systematic MEDLINE search between January 1966 and May 1996. Articles were included in our sample if they contained original patient data that evaluated either the efficacy or adverse effects associated with the use of subcutaneous infusions to treat dehydration in adults, whether hyaluronidase was required to facilitate the absorption of subcutaneous fluid, or if potassium could be added to the solution. RESULTS: Eighteen articles met the inclusion criteria. Since we hypothesized that adverse effects associated with hypodermoclysis may have been related largely to the use of nonelectrolyte or hypertonic solutions, the studies were evaluated according to the type of fluid administered. Six hundred and eighty-five patients were described in 13 studies evaluating the efficacy and toxicity of subcutaneously administered fluid. Four studies evaluated hypodermoclysis using electrolyte-containing solutions in 25 patients. Two of these were randomized control trials (RCT) that compared hypodermoclysis to intravenous therapy. Both reported similar absorption of fluids. In the single RCT that evaluated adverse effects, 4 of 17 patients receiving hypodermoclysis reported minor side effects similar to those reported with intravenous therapy. Adverse effects were more severe when electrolyte-free or hypertonic solutions were evaluated. Of the 639 patients who may have received electrolyte-free solutions, 16 patients (2.5%) reported adverse effects, 8 of which were severe. Both patients reported to have received hypertonic solutions noted adverse effects, one of which was severe. The use of hyaluronidase to facilitate absorption was evaluated in 74 patients. These studies suggest that hyaluronidase improves the speed of fluid absorption but may not change the patient's comfort level. A single case report of 350 subcutaneous infusions in 67 patients investigated the administration of up to 34 mmol/L of potassium chloride (KCl) by hypodermoclysis. The only adverse reaction observed was discomfort at the infusion site. CONCLUSIONS: Hypodermoclysis can be used to most safely provide fluids when electrolyte-containing fluids are administered. Hypodermoclysis may have fallen into disuse because of reports of severe adverse reactions related to infusions of electrolyte-free or hypertonic solutions that would likely be considered inappropriate today. Whether or not hyaluronidase is required to promote subcutaneous fluid absorption remains unresolved. Limited evidence suggests that potassium chloride may, with caution, be safely added to subcutaneous infusions. The majority of the available studies evaluating hypodermoclysis are of poor quality. Because of the tremendous potential benefits of administering fluid subcutaneously, there is a need for good quality studies to evaluate the efficacy of hypodermoclysis.

Aged↗
PubMed1997

Salmon calcitonin nasal spray in the prevention of corticosteroid-induced osteoporosis.

The objectives were to determine the efficacy and safety of nasal salmon calcitonin 200 IU daily in the prevention of corticosteroid-induced osteoporosis. A minimized, double-blind, placebo-controlled trial was carried out in corticosteroid-treated patients with polymyalgia rheumatica. The setting was a tertiary care university-affiliated hospital and a total of 31 patients were enrolled. The primary outcome measure was the percentage change in bone mineral density of the lumbar spine in the two treatment groups from baseline to 1 yr of follow-up. The mean +/- S.D. bone mineral density of the lumbar spine in the calcitonin-treated group decreased by 1.29 +/- 6.76% and in the placebo group by 4.95 +/- 3.50% after 12 months. The observed difference of 3.65 +/- 2.10% between groups is statistically significant (P < 0.05). Nasal salmon calcitonin prevented loss of bone in the lumbar spine as measured by dual-energy X-ray absorptiometry.

Absorptiometry, Photon↗
PubMed1997

Multicenter, randomized, prospective trial of early tracheostomy.

OBJECTIVES: Determine the effect of early (days 3-5) or late (days 10-14) tracheostomy on intensive care unit length of stay (ICU LOS), frequency of pneumonia, and mortality, and evidence of short-term or long-term pharyngeal, laryngeal, or tracheal injury in head trauma, non-head trauma, and critically ill nontrauma patients. STUDY DESIGN: Randomized, prospective. SETTING: Five Level I trauma centers. METHODS: Data were obtained prospectively and included Acute Physiology and Chronic Health Evaluation III score (AIII), Glasgow Coma Scale score, Emergency Room Trauma Score, Injury Severity Score, Acute Injury Score, type of endotracheal tube or tracheostomy, level of positive end-expiratory pressure, and peak inspiratory pressure. Patients were to undergo laryngoscopy for detection of injury according to the Lindholm criteria at the time of endotracheal tube or tracheostomy removal and be reevaluated at 3 to 5 months after discharge. RESULTS: One hundred fifty-seven patients were entered, 127 to early randomization (3-5 days) and 28 to late randomization (10-14 days); however, only 112 patients with early and 14 with late randomization had completed data forms for the primary study goals. An additional 22 patients from the early entry groups were rerandomized late. Early randomization data: the AIII score was higher (p < 0.05) in the head trauma tracheostomy (65 +/- 4) than in the nontracheostomy group (51 +/- 4) and in the nontrauma tracheostomy (92 +/- 6) than in the nontracheostomy group (68 +/- 7), but was equivalent in the non-head trauma group. Glasgow Coma Scale score, Emergency Room Trauma Score, Injury Severity Score, Acute Injury Score, positive end-expiratory pressure, and peak inspiratory pressure were not significantly different in any of the groups. There were no significant differences in ICU LOS, frequency of pneumonia, or death in any of the groups after either early or late tracheostomy compared with continued endotracheal intubation. Only 83 patients underwent postextubation laryngoscopy. There were no significant differences between the groups; however, there were trends to more vocal cord ulceration and subglottic inflammation in the continued intubation group. No patient was seen in this study with late vocal cord or laryngeal stenosis; there were no tracheal-innominate artery fistulae. Seven of the patients with abnormal findings at extubation had normal 3- to 5-month postextubation laryngoscopy. CONCLUSION: Physician bias limited patient entry into the study. Although there were higher AIII scores in the head trauma early tracheostomy patients, there were no differences in the primary end points of ICU LOS, pneumonia, or death in any of the groups studied. Long-term endoscopic follow-up was poor, but no known late tracheal stenosis was seen.

APACHE↗
PubMed1997

Social support and adverse pregnancy outcome in a high-risk population.

Low birth weight is a significant health problem in the United States, particularly among poor women. By combining traditional predictors of birth weight with social support indicators, we were able to substantially improve the discrimination between the highest birth weight quartile from the lowest among high-risk gravidae receiving first time prenatal care at the Albany, New York, County Department of Health. The impact of traditional predictors and social support indicators varied considerably between African-American and white women. Providers of care to poor women can utilize this information to maximize the likelihood of a good birth outcome.

Adolescent↗
PubMed1997

Seasonal prevalence of vitamin D deficiency in institutionalized older adults.

OBJECTIVE: To determine the prevalence and seasonal variation of vitamin D deficiency among older residents of long-term care facilities. DESIGN: Cross-sectional survey with 6-month follow-up. SETTING: Three long-term care facilities in Toronto. PATIENTS: Persons more than 65 years old, medically stable, who had resided in the facility for at least 6 months and had no conditions known to interfere with vitamin D metabolism. MEASUREMENTS: Information regarding demographics, past health, and medication use was collected. Mental and functional status were assessed by questionnaire. Venous blood samples were analyzed for alkaline phosphatase, calcium profile, albumin, intact parathyroid hormone, 25 hydroxyvitamin D (25OHD), and vitamin D binding protein in September 1994 and March 1995. In a subgroup of patients, bone specific alkaline phosphatase was measured, and dietary intake of vitamin D was assessed. RESULTS: A total of 155 subjects completed the study. The mean age of the subjects was 83.2 years (SD 7.1), and 47% were female. The mean 25OHD level in the March sample (39.9 nmol/L, SD 19.7) was significantly lower than the mean 25OHD level in the September sample (44.9 nmol/L, SD 16.9) (P = .001). The prevalence of vitamin D deficiency in the osteomalacic range (25OHD < 25 nmol/L) increased from 9% in the fall sample to 18% after the winter (chi 2 = 4.65, P = .03). The prevalence of borderline deficiency or hypovitaminosis D (25OHD < 40 nmol/L) increased from 38% in the fall sample to 60% in the spring sample (chi 2 = 14.9, P < .001). Dependence in transfers was associated with an increased risk of hypovitaminosis D, odds ratio 2.08 (95% confidence interval 1.08-4.01), dependence in ambulation 2.57 (1.26-5.23), and regular use of a wheelchair 2.17 (1.09-4.31). When entered into a forward conditional logistic regression model, only dependence in ambulation remained significant, with an adjusted odds ratio of 2.57 (95% CI: 1.26-5.18). CONCLUSIONS: Vitamin D deficiency and borderline vitamin D status are common among older residents of long-term care facilities in Canada. Even though this population has limited outdoor exposure, seasonal variation in the prevalence of deficiency remains significant. Evaluation of interventions to improve the status of vitamin D nutrition in this population is needed.

Aged↗
PubMed1997

Factors influencing the false positive and negative rates of BCR-ABL fluorescence in situ hybridization.

BCR-ABL fluorescence in situ hybridization has a useful role to play in experimental and clinical investigations of chronic myeloid leukaemia. However, the interpretation of results is complicated by variability in the false positive rate (FPR) and false negative rate (FNR). We therefore examined the effects on FNR and FPR of three factors, namely, the criteria used for defining a fusion signal, nucleus size, and the genomic position of the ABL breakpoint. We established two different criteria for BCR-ABL positivity: by criterion A cells were scored as positive when BCR and ABL signals were overlapping or touching and by criterion B cells were positive if they satisfied criterion A or if the signals were separated by up to one signal diameter. We measured nucleus size and Philadelphia (Ph) positivity in 573 cells from normal persons and 787 cells from the Ph+ SD-1 cell line and related results to FNRs and FPRs. We also assessed the FNR in Ph+ CFU-GM colonies from five patients with different ABL breakpoints. We showed that each of these factors influenced the FNR and FPR. The less strict criterion (B) for Ph positivity increased the FPR but reduced the FNR, the FPR increased as the nucleus size decreased, and the FNR was greatest in CML cells with a 5' ABL breakpoint. We conclude that these factors should be considered when evaluating the results of FISH studies to detect the BCR-ABL fusion gene and that analogous factors may influence results of FISH studies directed at other fusion genes.

Chromosome Breakage↗
PubMed1997

Burn management. Initial assessment, management, and stabilization.

Burn statistics today reflect a downward trend in occurrence, and many burn injuries are preventable. The outcomes of the injury are greatly influenced by the care received at the scene of the accident and in the emergency department. Initial burn wound assessment and fluid resuscitation, as well as management of associated injuries, pain, and anxiety are critical elements of care and require monitoring by experienced burn team staff members.

Adolescent↗
PubMed1997

Immunohistochemistry of unclassified sex cord-stromal tumors of the testis with a predominance of spindle cells.

Unclassified sex cord-stromal tumors (SCSTs) of the testis comprised predominantly of spindle cells can be difficult to classify. To achieve better definition of these tumors, we examined the histologic, histochemical, and ultrastructural features of four unclassified SCSTs with spindle-cell features, and compared their immunohistochemical features with those of 24 other SCSTs of the testis and ovary. Three of the spindle-cell tumors were composed of relatively short spindled cells with prominent nuclear grooves and intermixed epithelioid cells. All of the three were located adjacent to the rete testis. The fourth case consisted of elongate spindle cells that were reminiscent of smooth muscle. In all of the four cases, reticulin enveloped aggregates of cells of various sizes but not individual cells. Ultrastructural analysis of two of the spindle-cell tumors revealed desmosomes, numerous thin filaments, and focal dense-bodies. Immunohistochemically, all of the four tumors were reactive for S-100 protein and smooth muscle actin. Staining for S-100 protein and smooth muscle actin was also observed in three of six granulosa cell tumors and both juvenile granulosa cell tumors. Although variable staining for S-100 protein was found in 5 of the 12 other SCSTs (4 Leydig cell, 6 Sertoli-Leydig cell, and 2 unclassifiable ovarian SCSTs), reactivity for smooth muscle actin was present in only 1 Sertoli-Leydig cell tumor. In contrast, all of the four ovarian fibromas/thecomas were reactive for smooth muscle actin but failed to stain for S-100 protein. Taken together, the histologic, histochemical, immunohistochemical, and ultrastructural features of the spindle-cell tumors are similar to those of granulosa cell tumors. Reactivity for S-100 protein and smooth muscle actin is characteristic of these tumors. These tumors should be distinguished from other unclassified SCSTs.

Actins↗
PubMed1997

Curdlan sulfate (CRDS) in a 21-day intravenous tolerance study in human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infected patients: indication of anti-CMV activity with low toxicity.

This study evaluated tolerance (and possible efficacy) for 21 days of i.v. administration at three dose levels of curdlan sulfate (CRDS) (a semisynthetic sulfated polysaccharide), administered over 30 minutes, in HIV and CMV (in some cases) infected individuals with CD4 levels < 500 cells/mm3. Half of the subjects were previously treated with reverse transcriptase inhibitors (RTI) (which were continued during the CRDS administration) and half the patients had no prior RTI treatment. Evaluation of other sulfated polysaccharides in HIV had been discontinued due to side effects and lack of activity. Three groups of HIV patients (also including subsets with CMV infection) were treated separately with 50 mg/70 Kg, 100 mg/70 Kg and 200 mg/70 Kg of CRDS infused i.v. over thirty minutes daily for 21 days. In each dose group, half of the patients selected were being treated with a RTI and half were on no RTI. Patients were monitored for CD4 cell levels, viral load in some cases, and safety parameters in blood. Samples of urine and semen were additionally taken for CMV by culture and for PCR assay in subsets of participants. CRDS in this 21 day study was well-tolerated and produced few reportable side effects. Systematic decreases in platelets and increases in p24 antigen previously seen with dextran sulfate were not observed in this study with CRDS. In the 21 patients testing positive for CMV at the start of the study, 12 were CMV negative at the end of 21 days. In an untreated historical control group, 0/36 went from CMV positive to negative over a period of 13-15 years. The anti-CMV activity of CRDS in this study, therefore, had a p value < 0.001, based on these historical controls. The marked temporary increases in CD4 levels seen in the single dose and the seven-day CRDS studies on HIV patients were also seen for 21 days in the current study (p = 0.0001). Treatment with CRDS seems promising against CMV in HIV infected patients, even with once daily dosing of this two-hour half-life drug. CRDS was well tolerated and its lack of toxicity makes it an attractive candidate for CMV-infected HIV patients. Multiple daily dosing, or the continuous infusion of CRDS, could lead to increased effectiveness against both HIV and CMV, especially in combination with other agents. Given the toxicity of existing anti-CMV agents, and considering the emerging importance of CMV in atherosclerotic disease, further studies on CRDS are warranted.

AIDS-Related Opportunistic Infections↗
PubMed1997

Fluoride therapy in prevention of rheumatoid arthritis induced bone loss.

OBJECTIVE: To determine the efficacy of sodium fluoride (40 mg/day) in preventing rheumatoid arthritis (RA) induced bone loss, which may lead to osteoporosis. METHODS: We conducted an 18 month, randomized, double blind, placebo controlled trial in 38 patients with RA. The primary outcome measure was the difference in the percentage change between groups in lumbar spine bone mineral density (BMD) from baseline values after 18 months of therapy. The secondary outcome measures were the differences in the percentage change between groups in femoral neck, Ward's triangle, trochanter, and total body BMD from baseline after 18 months of therapy. RESULTS: There was a significant percentage difference (SD) between groups of 6.2% (7.3%) (p = 0.0005) in lumbar spine BMD after 18 months of treatment in favor of the fluoride group. The fluoride group experienced a 5.2% (8.4%) (p = 0.0125) increase, whereas the placebo group showed a 1.0% (4.8%) (p = 0.8015) decrease in lumbar spine BMD after treatment. No significant differences were found for the femoral neck, Ward's triangle, trochanter, and total body BMD in terms of the percentage changes from baseline within each treatment group or in the differences in the degree of change between groups after therapy. Lumbar spine BMD increased in about 80% of patients treated with fluoride (responders) compared to 44% of patients treated with placebo. CONCLUSION: The results showed that fluoride therapy was well tolerated and increased vertebral bone mass in patients with RA.

Administration, Oral↗
PubMed1997

Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997.

PURPOSE: This article reviews long-term follow-up data from three phase II studies conducted by the Cytokine Working Group from 1989 to 1995 that evaluated various recombinant interleukin-2 (rIL-2) -based regimens in patients with metastatic renal cell cancer. Response rates, long-term response duration, and toxicity are compared. PATIENTS AND METHODS: The Cytokine Working Group studies reviewed here investigated the safety and efficacy of two high-dose intravenous rIL-2-based regimens and two moderate-dose outpatient subcutaneous rIL-2-based regimens in patients with progressive metastatic renal cell cancer. A randomized phase II study, initiated in 1989, investigated the safety and efficacy of high-dose intravenous rIL-2 alone and high-dose intravenous rIL-2 plus recombinant interferon-alpha (rIFN-alpha). A second phase II study, initiated in 1992, tested the safety and efficacy of moderate-dose subcutaneous rIL-2 plus subcutaneous rIFN-alpha in the outpatient setting. The third trial, initiated in 1995, investigated a regimen consisting of the previous subcutaneous rIL-2 plus rIFN-alpha regimen alternating with intravenous bolus 5-fluorouracil (5-FU) plus subcutaneous rIFN-alpha. Median follow-up for these studies is 72 months, 48 months, and 24 months, respectively. RESULTS: The overall response rates observed with each of these regimens were similar (17% with high-dose rIL-2 alone, 11% with high-dose rIL-2/rIFN-alpha, 17% with outpatient subcutaneous rIL-2/rIFN-alpha, and 16% with outpatient rIL-2/rIFN-alpha, plus 5-FU/rIFN-alpha). However, the high-dose rIL-2 regimen produced a 7% complete response rate, compared with 0%, 4%, and 4%, respectively, with each of the other regimens. Median response duration was also much longer with high-dose intravenous rIL-2 alone (53 months), compared with 7 months, 12 months, and 9 months, respectively, with each of the other regimens. CONCLUSION: Complete response rate and response duration appear to favor the high-dose intravenous rIL-2 regimen. This will require verification in a randomized study comparing the best high-dose arm (rIL-2 alone) with the best outpatient regimen (rIL-2/IFN-alpha). The Cytokine Working Group is currently conducting such a study.

Adult↗
PubMed1997

Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies.

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.

Adult↗
PubMed1996

Beta-secretase processing of the beta-amyloid precursor protein in transgenic mice is efficient in neurons but inefficient in astrocytes.

Alzheimer's disease is characterized by the extracellular deposition of beta-amyloid peptide (Abeta) in cerebral plaques and evidence is accumulating that amyloid is neurotoxic. Abeta is derived from the beta-amyloid precursor protein (APP). Proteolytic processing of APP by the enzyme, beta-secretase, produces the N terminus of Abeta, and releases a secreted ectodomain of APP (beta-s-APP). To develop animal models for measuring beta-secretase activity in specific brain cells in vivo, we have targeted the expression of the full-length human APP to either neurons or astrocytes in transgenic mice using the neuron- specific enolase (NSE) promoter or a modified glial fibrillary acidic protein (GFAP) gene, respectively. The APP cDNAs expressed were mutated (KM to NL at 670/671) to encode amino acid substitutions that enhance amyloidogenic processing in vitro. Western analyses revealed abundant production of beta-s-APP in the brains of NSE-APP mice and enzyme-linked immunosorbent assay analyses showed production of Abeta in fetal primary mixed brain cultures and brain homogenates from these transgenic animals. Because the NSE promoter drives expression primarily in neurons, this provides in vivo evidence that the beta-secretase cleavage necessary for generation of beta-s-APP and Abeta is efficiently performed in neurons. In contrast, only little beta-s-APP was detected in brain homogenates of GFAP-APP mice, indicating that astrocytes show very little beta-secretase activity in vivo. This provides strong in vivo evidence that the major source of Abeta in brain is from neurons and not from astrocytes.

Amyloid Precursor Protein Secretases↗