Biomedical subjects

J He

Publications and source records attributed to J He.

At least 37 records · Page 2Linked to original sources

PubMed2001

On and off pathways segregated at the auditory thalamus of the guinea pig.

ON and OFF auditory responses were examined on the medial geniculate body (MGB) of the guinea pig. Single-unit and multiunit recordings were performed on 13 anesthetized subjects while either noise-burst or pure-tone stimuli were applied to the ear contralateral to the recorded hemisphere. Of 2187 uneven-spaced samples, 1142 were ON neurons, 386 were OFF neurons, and 488 were ON-OFF neurons. Neither ON nor OFF neurons changed their response patterns when the stimulus was changed from a noise burst of 60 dB sound pressure level intensity (expressed in decibels per 20 mPa) to pure tones or noise bursts of other intensities. However, most of the ON-OFF neurons changed to either ON or OFF responses with some stimuli. OFF neurons formed clusters. With anatomical confirmation, we found that OFF neuron clusters are always segregated from ON neuron clusters and form OFF sheets in various divisions of the MGB. In the ventral division of the MGB (MGv), the neurons showed mainly ON responses in its core and OFF responses in its periphery or on its boundary with other divisions. The MGv was partially surrounded by an OFF sheet dorsolaterally at the caudal part and medioventrally at the rostral part and was almost completely surrounded by an OFF sheet at the central level rostrocaudally.

Acoustic Stimulation↗

PubMed2001

Molecular heterogeneity of oligodendrogliomas suggests alternative pathways in tumor progression.

OBJECTIVE: To identify different genetic molecular profiles in oligodendrogliomas and to evaluate their prognostic significance. METHODS: The main genetic alterations reported in glial tumors were investigated in 26 oligodendrogliomas (10 World Health Organization grade II and 16 World Health Organization grade III). Correlation between identified molecular changes and pathologic grade or clinical course was subsequently analyzed using univariate and multivariate statistical analyses. RESULTS: Loss of heterozygosity (LOH) on chromosome 1p, 19q, and 10; P16/CDKN2A homozygous deletion; EGFR (epidermal growth factor receptor) amplification; and TP53 and PTEN mutations were observed in 14 (54%), 15 (58%), 9 (35%), 7 (27%), 5 (19%), 1 (4%), and 0 cases. LOH 1p and 19q were tightly associated (p < 0.0001). A mutual exclusion was found between LOH 1p/19q and EGFR amplification (p = 0.01), P16/CDKN2A deletions (p = 0.001), or LOH on 10q (p = 0.03), suggesting the existence of distinct genetic subsets in oligodendrogliomas. On univariate analysis, age <50 years (p = 0.002) and LOH 1p (p = 0.01) were associated with a longer progression-free survival (PFS) whereas LOH 10q (p = 0.03) and EGFR amplification (p = 0.007) were associated with a worse PFS. In multivariate analyses, age <50 years (p = 0.001) and LOH 1p (p = 0.006) remained independent predictive factors for PFS. CONCLUSION: These results provide evidence for two alternative molecular pathways of progression in oligodendrogliomas. The first one is associated with loss of 1p and 19q and the second one with P16/CDKN2A deletion, 10q loss, and EGFR amplification. The findings confirm the value of loss of 1p as predictor of longer progression-free survival; in addition, the study demonstrates the unfavorable impact of 10q loss and EGFR amplification on the prognosis.

Adult↗

PubMed2001

Direct measurements of the enthalpy of solution of solid solute in supercritical fluids: study on the CO2-naphthalene system.

A setup for a calorimeter for simultaneously measuring the solubility and the solution enthalpy of solid solutes in supercritical fluids (SCFs) has been established. The enthalpy of solution of naphthalene in supercritical CO2 was measured at 308.15 K in the pressure range from 8.0-11.0 MPa. It was found that the enthalpy of solution (deltaH) was negative in the pressure range from 8.0 to 9.5 MPa, and the absolute value decreased with increasing pressure. In this pressure range, the dissolution of the solute was enthalpy driven. However, the deltaH became positive at pressures higher than 9.5 MPa, and the dissolution was entropy driven. Monte Carlo simulation was performed to analyze the local structural environment of the solvated naphthalene molecules in supercritical CO2 under the experimental conditions for the calorimetric measurements. By combining the enthalpy data and the simulation results, it can be deduced that the energy level of CO2 in the high compressible region is higher than that at higher pressures, which results in the large negative enthalpy of solution and the larger degree of solvent-solute clustering in the high compressible region.

Journal Article↗

PubMed2001

Disabled-2 mediates c-Fos suppression and the cell growth regulatory activity of retinoic acid in embryonic carcinoma cells.

F9 embryonic stem cell-like teratocarcinoma cells are widely used to study early embryonic development and cell differentiation. The cells can be induced by retinoic acid to undergo endodermal differentiation. The retinoic acid-induced differentiation accompanies cell growth suppression, and thus, F9 cells are also often used as a model for analysis of retinoic acid biological activity. We have recently shown that MAPK activation and c-Fos expression are uncoupled in F9 cells upon retinoic acid-induced endodermal differentiation. The expression of the candidate tumor suppressor Disabled-2 is induced and correlates with cell growth suppression in F9 cells. We were not able to establish stable Disabled-2 expression by cDNA transfection in F9 cells without induction of spontaneous cell differentiation. Transient transfection of Dab2 by adenoviral vector nevertheless suppresses Elk-1 phosphorylation, c-Fos expression, and cell growth. In PA-1, another teratocarcinoma cell line of human origin that has no or very low levels of Disabled-2, retinoic acid fails to induce Disabled-2, correlating with a lack of growth suppression, although PA-1 is responsive to retinoic acid in morphological change. Transfection and expression of Disabled-2 in PA-1 cells mimic the effects of retinoic acid on growth suppression; the Disabled-2-expressing cells reach a much lower saturation density, and serum-stimulated c-Fos expression is greatly suppressed and disassociated from MAPK activation. Thus, Dab2 is one of the principal genes induced by retinoic acid involved in cell growth suppression, and expression of Dab2 alone is sufficient for uncoupling of MAPK activation and c-Fos expression. Resistance to retinoic acid regulation in PA-1 cells likely results from defects in retinoic acid up-regulation of Dab2 expression.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Beyond butadiene II: thermal isomerization of the [2 + 2] photodimer of an all-trans tetraene, (R)-4,4abeta,5,6,10a-hexahydro-10abeta-methyl-2(3H)-methyleneanthracene, to a 16-membered [8 + 8] cycle.

Enthalpies of stabilization of polyenyl radicals of increasing order previously obtained by thermal geometrical isomerization are applied to the ethylene-cyclobutane paradigm. Progressively lower enthalpies of activation for thermal cyclodimerization and its reverse, cycloreversion, are predicted and realized. Photochemical dimerization at -75 degrees C of the optically pure tetraene of the title (1) at the semicyclic double bond produces in the main only one (4-axx) of the three allowed cyclobutanes (4), to which the tentative configuration anti-exo,exo is assigned. Equilibration among the three cyclobutanes (4), a slower rearrangement to a thermodynamically considerably more stable, [8 + 8] cyclohexadecahexaene (16), and a surprisingly slow fragmentation to 1 are studied kinetically between -42.3 and -8.2 degrees C. Cycloreversion of the dimer 16 to monomer 1 occurs in the range 60.4-86.6 degrees C (DeltaH = 31.7 kcal mol(-1), DeltaS = +10.8 cal mol(-1) K(-1)). The ratio of the rates of stereomutation and cycloreversion is significantly larger in these 1,2-dihexatrienylcyclobutanes than in two less strongly stabilized, previously published examples. The possible extension of Doubleday's calculational finding of entropic control of products from cyclobutane is considered.

Journal Article↗

PubMed2001

A novel zebrafish bHLH gene, neurogenin3, is expressed in the hypothalamus.

Many basic helix-loop-helix transcriptional factors play important roles in vertebrate neurogenesis. Among them, Neurogenins act as determination factors and initiate the expression of differentiation genes such as neuroD and other neurogenic genes. Here we describe a zebrafish cDNA (neurogenin3 or ngn3) encoding a novel member of the Neurogenin family closest to mouse Ngn3 and human NGN3. Using a zebrafish radiation hybrid panel, ngn3 was mapped to zebrafish linkage group 13 and the region displayed a conserved synteny with the region of human chromosome 10 containing NGN3. As judged by RT-PCR and whole-mount in situ hybridization, ngn3 expression in zebrafish started much later than other neurogenin genes, at only around 24 h post-fertilization (hpf) and with a higher level of expression on the left side of the anterio-ventral diencephalon. Later at 48 hpf, ngn3 expression was detected in a small number of cells in the tuberal hypothalamus. Unlike Ngn3 in the mouse, zebrafish ngn3 mRNAs were not detected in developing pancreas and spinal cord. Genomic Southern blot hybridization suggested that a closely related sequence is present in the zebrafish genome and the hypothetical gene might result from the recent genome duplication in certain teleost lineage and share the function of the common ancestor with the currently characterized ngn3.

Amino Acid Sequence↗

PubMed2001

Phosphorylation and cell cycle-dependent regulation of Na+/H+ exchanger regulatory factor-1 by Cdc2 kinase.

Na(+)/H(+) exchanger regulatory factor (NHERF)-1 is a PDZ domain-containing adaptor protein known to bind to various receptors, channels, cytoskeletal elements, and cytoplasmic signaling proteins. We report here that the phosphorylation state of NHERF-1 is profoundly regulated by the cell cycle: NHERF-1 in HeLa cells is hyperphosphorylated in mitosis phase and much less phosphorylated at other points of the cell cycle. This mitosis phase-dependent phosphorylation of NHERF-1 could be blocked by roscovitine, consistent with phosphorylation by cyclin-dependent kinases. In vitro studies with purified NHERF-1 fusion proteins and purified kinases revealed that NHERF-1 was robustly phosphorylated by the cyclin-dependent kinase Cdc2. In contrast, the NHERF-1 relative NHERF-2 was not phosphorylated at all by Cdc2. NHERF-1 possesses two serines (Ser(279) and Ser(301)) that conform to the SPX(K/R) motif preferred for phosphorylation by Cdc2. Mutation of either of these serines reduced Cdc2-mediated phosphorylation of NHERF-1 in vitro, and mutation of both residues together completely abolished Cdc2-mediated phosphorylation. When the S279A/S301A NHERF-1 mutant was expressed in cells, it failed to exhibit the mitosis phase-dependent phosphorylation observed with wild-type NHERF-1. Mutation of both Ser(279) and Ser(301) to aspartate, to mimic Cdc2 phosphorylation of NHERF-1, resulted in a NHERF-1 mutant with a markedly impaired ability to oligomerize in vitro. Similarly, endogenous NHERF-1 from lysates of mitosis phase HeLa cells exhibited a markedly reduced ability to oligomerize relative to endogenous NHERF-1 from lysates of interphase HeLa cells. Mitosis phase NHERF-1 furthermore exhibited the ability to associate with Pin1, a WW domain-containing peptidylprolyl isomerase that does not detectably bind to NHERF-1 in interphase lysates. The association of NHERF-1 with Pin1 facilitated dephosphorylation of NHERF-1, as shown in experiments in which cellular Pin1 activity was blocked by the selective inhibitor juglone. These data reveal that cellular NHERF-1 is phosphorylated during mitosis phase by Cdc2 at Ser(279) and Ser(301) and that this phosphorylation regulates NHERF-1 oligomerization and association with Pin1.

Amino Acid Sequence↗

PubMed2001

[Study on telomerase activity and its clinical value in human non small cell lung cancer].

OBJECTIVE: To investigate telomerase activity and its clinical value in human non small cell lung cancer. METHODS: Using the method of TRAP-PCR-ELISA, we measured telomerase activity in human non small cell lung cancerous, adjacent, lung benign lesion, and normal lung tissues. RESULTS: The positive rate of telomerase activity was 75%(27/36) in lung cancerous tissues; 6.25%(2/32) in adjacent tissues; 11.1%(1/9) in lung benign lesion tissues; and 0%(0/9) in normal lung tissues. There was no significant difference in telomerase activity among the pathological type, the degree of tissue differentiation, the size of tumor, lymph node metastasis, and clinical stage in the patients with lung cancer. CONCLUSION: The telomerase activity may become an important molecular marker in the diagnosis and differential diagnosis of human non small cell lung cancer.

Adult↗

PubMed2001

Finding and using local symmetry in identifying lower domain movements in hexon subunits of the herpes simplex virus type 1 B capsid.

A characteristic of virus assembly is the use of symmetry to construct a complex capsid from a limited number of different proteins. Many spherical viruses display not only icosahedral symmetry, but also local symmetries, which further increase the redundancy of their structural proteins. We have developed a computational procedure for evaluating the quality of these local symmetries that allows us to probe the extent of local structural variations among subunits. This type of analysis can also provide orientation parameters for carrying out non-icosahedral averaging of quasi-equivalent subunits during three-dimensional structural determination. We have used this procedure to analyze the three types of hexon (P, E and C) in the 8.5 A resolution map of the herpes simplex virus type 1 (HSV-1) B capsid, determined by electron cryomicroscopy. The comparison of the three hexons showed that they have good overall 6-fold symmetry and are almost identical throughout most of their lengths. The largest difference among the three lies near the inner surface in a region of about 34 A in thickness. In this region, the P hexon displays slightly lower 6-fold symmetry than the C and E hexons. More detailed analysis showed that parts of two of the P hexon subunits are displaced counterclockwise with respect to their expected 6-fold positions. The most highly displaced subunit interacts with a subunit from an adjacent P hexon (P'). Using the local 6-fold symmetry axis of the P hexon as a rotation axis, we examined the geometrical relationships among the local symmetry axes of the surrounding capsomeres. Deviations from exact symmetry are also found among these local symmetry axes. The relevance of these findings to the process of capsid assembly is considered.

Capsid↗

PubMed2001

Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder.

BACKGROUND: Aortic aneurysms cause significant mortality, and >20% relate to hereditary disorders. Familial aortic aneurysm (FAA) has been described in such conditions as the Marfan and Ehlers-Danlos type IV syndromes, due to defects in the fibrillin-1 and type III procollagen genes, respectively. Other gene defects that cause isolated aneurysms, however, have not thus far been described. METHODS AND RESULTS: We studied 3 families affected by FAA. No family met the diagnostic criteria for either Marfan or Ehlers-Danlos syndrome. Echocardiography defined involvement of both the thoracic and abdominal aorta. In family ANA, candidate gene analysis excluded linkage to loci associated with aneurysm formation, including fibrillin-1, fibrillin-2, and type III procollagen, and chromosome 3p24.2-p25. Genome-wide linkage analysis identified a 2.3-cM FAA locus (FAA1) on chromosome 11q23.3-q24 with a maximum multipoint logarithm of the odds score of 4.4. In family ANB, FAA was linked to fibrillin-1. In family ANF, however, FAA was not linked to any locus previously associated with aneurysm formation, including fibrillin-1 and FAA1. CONCLUSIONS: FAA disease is genetically heterogeneous. We have identified a novel FAA locus at chromosome 11q23.3-q24, a critical step toward elucidating 1 gene defect responsible for aortic dilatation. Future characterization of the FAA1 gene will enhance our ability to achieve presymptomatic diagnosis of aortic aneurysms and will define molecular mechanisms to target therapeutics.

Adolescent↗

PubMed2001

Disabled-2 exerts its tumor suppressor activity by uncoupling c-Fos expression and MAP kinase activation.

Disabled-2 (Dab2) is a putative tumor suppressor in breast and ovarian cancers. Its expression is lost in a majority of tumors, and homozygous deletions have been identified in a small percentage of tumors. Dab2 expression is absent or very low in the majority of breast and ovarian cancer cell lines, including MCF-7 and SK-Br-3 breast cancer cells. Transfection and expression of Dab2 in MCF-7 and SK-Br-3 cells suppress tumorigenicity. The cells reach a much lower saturation density and have reduced ability to form colonies on agar plates. In examining the signal transduction pathway of Dab2-transfected cells, we found that serum-stimulated c-Fos expression was greatly suppressed; however, the effects of Dab2 on MAPK family kinases were not as consistent. In MCF-7 and SK-Br-3 cells, although c-Fos expression was suppressed, the Erk1/2, JNK, and p38(MAPK) activities were unchanged or even increased. Serum-stimulated c-Fos expression is dependent on MAPK/Erk activity because the MEK inhibitor PD98059 suppresses Erk activity and c-Fos expression. Therefore, Dab2 appears to uncouple MAPK activation and c-fos transcription. Thus, we conclude that Dab2 re-expression suppresses tumorigenicity by reducing c-Fos expression at a site downstream of the activation of MAPK family kinases. Because Dab2 is frequently lost in cancer, the uncoupling of MAPK activation and c-Fos expression may be a favored target for inactivation in tumorigenicity.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Chromosomal location of murine disabled-2 gene and structural comparison with its human ortholog.

Disabled-2 (Dab2) is one of the two mammalian orthologs of the Drosophila Disabled. The three spliced forms, p96, p93, and p67 of murine Dab2 cDNAs were first isolated as phosphoproteins functioning in the macrophage CSF-1 signal transduction pathway. Subsequently, the involvement of Dab2 in ovarian cancer development has been investigated: Dab2 expression is lost or greatly diminished in breast and ovarian cancers, and gene deletions have been found. Regulation of Disabled-2 expression is also found to be important in development and physiological functions. Structural information of the murine Dab2 gene is essential for studies of transcription regulation and gene function in mouse models. In this study, the mouse Dab2 gene coding sequence was identified and sequenced from three lambda phage clones containing the gene. Two BAC clones of mouse genomic DNA were also used to identify the sequences of the non-coding first exon and promoter. The first exon is separated from the second exon by a large (15 kb) intron. The mouse gene is about 40 kb in size and consists of 15 exons, producing a 3.6 kb message. The translation initiation site resides in the middle of the second exon. The mouse Dab2 gene structure is very similar to that of its human ortholog in exon/intron sizes and promoter sequences. The chromosomal localization of mouse Dab2 was mapped by FISH to chromosome 15A2, a site of syntax with the human 5p12 where human Dab2 gene resides. The information on the mouse Dab2 gene structure and promoter will be invaluable in studies of the involvement of Dab2 gene in cancer, expression, physiological function, and development in mouse models.

Animals↗

PubMed2001

High-performance liquid chromatographic analysis for a non-chromophore-containing phosphatidyl inositol analog, 1-((1-O-octadecyl-2-O-methyl-sn-glycero)phospho)-1D-3-deoxy-myo-inositol, using indirect UV detection.

Phosphatidylinositide-3-kinase (PI3 kinase) is an important constituent of growth factor regulation. It is also involved in oncogene signaling pathways. An ether-containing phosphatidyl inositol(PI) analog, OMDPI, 1-[(1-O-octadecyl-2-O-methyl-sn-glycero)-phospho]-1D-3-deoxy-myo-inositol, is a potent inhibitor of this pathway and may be clinically useful in the treatment of a variety of neoplasms. OMDPI is currently being investigated as an anti-tumor agent by the National Cancer Institute, NIH. OMDPI, a non-chromophore-containing PI analog, is not directly adaptable to the commonly used UV detection of HPLC. This paper reports the development and validation of an HPLC assay for OMDPI based on indirect UV detection, in which a UV-absorbing ion-pair reagent (the probe), protriptyline, is added to the mobile phase to induce a signal for the compound. The method is sensitive (limit of detection <5 microl of 1 microg/ml or 5 ng), precise (R.S.D.<2.5%), linear (r2=0.9995) and accurate (error<0.7%). It is superior to refractive index detection and evaporative light scattering detection in either sensitivity or linearity and does not require special equipment.

Chromatography, High Pressure Liquid↗

PubMed2001

Diffusion MRI in ischemic stroke compared to pathologically verified infarction.

BACKGROUND: Diffusion MRI abnormality correlates with pathology in animal ischemic stroke models. A combined retrospective and prospective analysis of consecutive patients over a 3-year period who had a clinical diagnosis of probable new ischemic stroke, underwent diffusion MRI, and were later studied at autopsy was performed. METHODS: Inclusion criteria for the retrospective analysis were 1) symptom onset within 14 days of presentation, 2) diffusion MRI within 28 days of symptom onset, and 3) autopsy within 16 weeks of symptom onset. Patients with suspected further infarcts between MRI and autopsy were excluded. The locations of all areas of MRI abnormality were identified by a blinded neuroradiologist, and recent infarcts were identified by review of pathologic records and microscopic slides. RESULTS: Eleven patients were identified who fulfilled inclusion criteria, with 25 discrete pathologic infarcts. Diffusion MRI abnormality corresponded to pathologically verified infarction in 23 cases, was present in two locations where no pathologic infarct was identified, and was absent in two locations where an infarct was present at autopsy. In two cases, despite clinical suspicion of acute ischemic stroke, no MRI abnormality or pathologic infarct was found. The sensitivity and specificity of diffusion MRI were 88.5% (95% CI, 69.9% to 97.6%) and 96.6% (95% CI, 91.5% to 99.1%). Accuracy was 95.1% (95% CI, 90.2% to 98%). Three further patients who died during the course of the retrospective analysis were studied prospectively, and are described separately. CONCLUSIONS: These findings suggest high accuracy of diffusion MRI for detection of ischemic infarction compared with pathologic examination.

Adult↗

PubMed2001

Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study.

BACKGROUND: The incidence of congestive heart failure (CHF) has been increasing steadily in the United States during the past 2 decades. We studied risk factors for CHF and their corresponding attributable risk in the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. PARTICIPANTS AND METHODS: A total of 13 643 men and women without a history of CHF at baseline examination were included in this prospective cohort study. Risk factors were measured using standard methods between 1971 and 1975. Incidence of CHF was assessed using medical records and death certificates obtained between 1982 and 1984 and in 1986, 1987, and 1992. RESULTS: During average follow-up of 19 years, 1382 CHF cases were documented. Incidence of CHF was positively and significantly associated with male sex (relative risk [RR], 1.24; 95% confidence interval [CI], 1.10-1.39; P<.001; population attributable risk [PAR], 8.9%), less than a high school education (RR, 1.22; 95% CI, 1.04-1.42; P =.01; PAR, 8.9%), low physical activity (RR, 1.23; 95% CI, 1.09-1.38; P<.001; PAR, 9.2%), cigarette smoking (RR, 1.59; 95% CI, 1.39-1.83; P<.001; PAR, 17.1%), overweight (RR, 1.30; 95% CI, 1.12-1.52; P =.001; PAR, 8.0%), hypertension (RR, 1.40; 95% CI, 1.24-1.59; P<.001; PAR, 10.1%), diabetes (RR, 1.85; 95% CI, 1.51-2.28; P<.001; PAR, 3.1%), valvular heart disease (RR, 1.46; 95% CI, 1.17-1.82; P =.001; PAR, 2.2%), and coronary heart disease (RR, 8.11; 95% CI, 6.95-9.46; P<.001; PAR, 61.6%). CONCLUSIONS: Male sex, less education, physical inactivity, cigarette smoking, overweight, diabetes, hypertension, valvular heart disease, and coronary heart disease are all independent risk factors for CHF. More than 60% of the CHF that occurs in the US general population might be attributable to coronary heart disease.

Aged↗

PubMed2001

The in vitro fate of rabbit fetal brain cells after acute in vivo hypoxia.

In the investigation of ischemia-induced brain damage, traditional methods using histopathology estimate brain cell death at a time remote from ischemic insult. These observations fail to take into account endogenous repair processes or ongoing injury cascades like apoptosis. The cells that are injured but not killed initially are the population most amenable to rescue. The hypothesis was that in vivo uterine ischemia-reperfusion would result in more cell death and apoptosis in fetal brain cells cultured in vitro. Near-term, 29 d gestation, pregnant New Zealand White rabbits were subjected to repetitive uterine ischemia for a cumulative time of 40 min ischemia and 20 min reperfusion. Immediately after uterine ischemia, the fetal brains were removed and dissociated into a cell suspension. The ischemic group had more cell death than non-ischemic controls as assessed by Trypan Blue exclusion and propidium iodide (PI) uptake on a flow cytometer. Aliquots of cells were plated and cultured for 24 and 48 hr. The ischemic group had significantly more cell death (propidium iodide) than non-ischemic controls at 24 hr and significantly more apoptosis, as assessed by annexin-V binding in cells at 24 hr and caspase-3 activity at 48 hr. Fewer cells attached to the culture plates at 48 hr in the ischemia group. After uterine ischemia, certain fetal brain cells die immediately, and other cells undergo ongoing damage resulting in necrosis and apoptosis that is manifest later. This method offers insight into the fate of those cells and provides a tool for assessing interventions to decrease cell injury.

Acute Disease↗

PubMed2001

Comparison of glucose and lactate as substrates during NMDA-induced activation of hippocampal slices.

It has been postulated that lactate released from astrocytes may be the preferred metabolic substrate for neurons, particularly during intense neuronal activity (the astrocyte-neuron lactate shuttle hypothesis). We examined this hypothesis by exposing rat hippocampal slices to artificial cerebrospinal fluid containing either glucose or lactate and either N-methyl-D-aspartate, which activates neurons without stimulating astrocytic glucose uptake, or alpha-cyano-4-hydroxycinnamate, which blocks monocarboxylate transport across plasma and mitochondrial membranes. When exposed to N-methyl-D-aspartate, slices lost synaptic transmission and K+ homeostasis more slowly in glucose-containing artificial cerebrospinal fluid than in lactate-containing artificial cerebrospinal fluid. After N-methyl-D-aspartate exposure, slices recovered synaptic transmission more completely in glucose. These results suggest that hippocampal neurons can use glucose more effectively than lactate when energy demand is high. In experiments with alpha-cyano-4-hydroxycinnamate, 500 microM alpha-cyano-4-hydroxycinnamate caused loss of K+ homeostasis and synaptic transmission in hippocampal slices during normoxia. When 200 microM alpha-cyano-4-hydroxycinnamate was used, synaptic activity and intracellular pH in slices decreased significantly during normoxia. These results suggest that alpha-cyano-4-hydroxycinnamate may have blocked mitochondrial oxidative metabolism along with lactate transport. Thus, studies using alpha-cyano-4-hydroxycinnamate to demonstrate the presence of a lactate shuttle in the brain tissue may need reevaluation. Our findings, together with observations in the literature that (1) glucose is available to neurons during activation, (2) heightened energy demand rapidly activates glycolysis in neurons, and (3) activation of glycolysis suppresses lactate utilization, suggests that glucose is the primary substrate for neurons during neuronal activation and do not support the astrocyte-neuron lactate shuttle hypothesis.

Animals↗

PubMed2001

Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials.

Coffee drinking has been associated with increased serum cholesterol levels in some, but not all, studies. A Medline search of the English-language literature published prior to December 1998, a bibliography review, and consultations with experts were performed to identify 14 published trials of coffee consumption. Information was abstracted independently by two reviewers using a standardized protocol. With a random-effects model, treatment effects were estimated by pooling results from individual trials after weighting the results by the inverse of total variance. A dose-response relation between coffee consumption and both total cholesterol and LDL cholesterol was identified (p < 0.01). Increases in serum lipids were greater in studies of patients with hyperlipidemia and in trials of caffeinated or boiled coffee. Trials using filtered coffee demonstrated very little increase in serum cholesterol. Consumption of unfiltered, but not filtered, coffee increases serum levels of total and LDL cholesterol.

Adult↗