Biomedical subjects
M Berridge
Publications and source records attributed to M Berridge.
Neuroimaging of vessel amyloid in Alzheimer's disease.
Despite extensive recent advances in understanding Alzheimer's disease (AD) we are unable to noninvasively establish a definite diagnosis during life and cannot monitor the cerebral deposition of amyloid beta protein (A beta) in living patients. We evaluated the use of 10H3, a monoclonal antibody Fab targeting A beta protein 1-28 labeled with Tc-99m. Six subjects with probable AD were studied using single-photon emission computed tomography (SPECT) at times from 0-24 hours following injection. Curves of radioactivity in blood demonstrate a half-life of the injected Fab of 2-3 hours. Images show uptake around the head in the scalp or bone marrow in all subjects. There is no evidence of cerebral uptake of the antibody. Scalp biopsies in all six patients demonstrate diffuse staining with 10H3 of the scalp, a pattern indistinguishable from that found in controls. Evidence of amyloid deposition in the scalp in AD is not seen with other anti-A beta antibodies, suggesting that 10H3 is cross-reacting with another protein. Further studies with anti-A beta antibodies will require longer-lived radionuclides to detect cerebral uptake at later times after injection to allow for complete clearance from the blood. Alternately, imaging using labeled A beta itself may provide a means for noninvasive targeting of cerebral amyloid.
Imaging the hierarchical Ca2+ signalling system in HeLa cells.
1. Confocal microscopy was used to investigate hormone-induced subcellular Ca2+ release signals from the endoplasmic reticulum (ER) in a prototype non-excitable cell line (HeLa cells). 2. Histamine application evoked two types of elementary Ca2+ signals: (i) Ca2+ blips arising from single ER Ca2+ release channels (amplitude, 30 nM; lateral spreading, 1.3 microns); (ii) Ca2+ puffs resulting from the concerted activation of several Ca2+ blips (amplitude, 170 nM; spreading, 4 microns). 3. Ca2+ waves in the HeLa cells arose from a variable number of initiation sites, but for individual cells, the number and subcellular location of the initiation sites were constant. The kinetics and amplitude of global Ca2+ signals were directly proportional to the number of initiation sites recruited. 4. Reduction of the feedback inherent in intracellular Ca2+ release caused saltatoric Ca2+ waves, revealing the two principal steps underlying wave propagation: diffusion and regeneration. Threshold stimulation evoked abortive Ca2+ waves, caused by the limited recruitment of Ca2+ puffs. 5. The hierarchy of Ca2+ signalling events, from fundamental levels (blips) to intermediate levels (puffs) to Ca2+ waves, is a prototype for Ca2+ signal transduction for non-excitable cells, and is also analogous to the Ca2+ quarks, Ca2+ sparks and Ca2+ waves in cardiac muscle cells.
Multiple, coordinated Ca2+ -release events underlie the inositol trisphosphate-induced local Ca2+ spikes in mouse pancreatic acinar cells.
Ca2+ wave initiation and non-propagating Ca2+ spikes occur as a result of localized Ca2+ release from the more sensitive intracellular Ca2+ stores. Using high spatial and temporal Ca2+ -imaging techniques we have investigated inositol 1,4,5 triphosphate (InsP3)-induced local Ca2+ spiking, which occurs at the site of Ca2+ wave initiation in pancreatic acinar cells. The spatial and temporal organization of a single spike suggested discrete hot spots of Ca2+ release. Further analysis of long trains of Ca2+ spikes demonstrated that these hot spots showed regenerative Ca2+ -release events which were consistently active from spike to spike. Regions adjacent to these hot spots also showed regenerative Ca2+ -release events of similar amplitude but with a much lower frequency of occurrence. We conclude that the InsP3-induced non-propagating Ca2+ spikes can be devolved into smaller components of release. Our results are consistent with a model of coordinated activity of pacemaker hot spots of Ca2+ release that recruit and entrain active Ca2+ -release events from surrounding regions.
On the generality of the "sit and reach" test: an analysis of flexibility data for an aging population.
Head rotation, shoulder extension and rotation, ankle plantar and dorsiflexion, hip flexion, and sit and reach (SR) scores were examined in 41 women and 39 men, aged 45-75 years. The SR gave more reproducible data than the other measurements (intraclass test/retest correlation over 8 months, r = .83). SR scores were independent of standing height (r2 = .068) but were greater in women (p less than .002). The flexibility at all joints was less than reported for young adults. There were age-related decreases of flexibility scores for the head and shoulder joints (p less than .01), with a parallel trend (p less than .05) for ankle plantar flexion and SR scores (the last only after inclusion of an age-gender interaction term). A principal components analysis identified three factors (tentatively identified as general trunk, ankle, and shoulder flexibility) accounting for 55.9% of total variance. SR scores had a moderate correlation with the first factor (r = .61) but only weak correlations with the second and third. Although the SR test is the most reliable simple instrument, it provides only limited information about the flexibility at other joints in an older population.
Ion channels, intracellular calcium, and exocytosis: control of hormone secretion in cultured bovine pituitary lactotrophs.
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Simultaneous double-isotope autoradiographic measurement of local cerebral glucose metabolic rate and acid-base status in rat brain.
We developed a double-isotope autoradiographic method for the simultaneous measurement of the local cerebral metabolic rate for glucose (1CMRG) and index of regional acid-base status (rABI) in single brain slices using [2-14C]deoxy-D-glucose (DG) and 5,5-dimethyl-[2-14C]oxazolidine-2,4,dione (DMO). After iv isotope administration, paper chromatography separates plasma DMO from DG activity using a methanol-methylene chloride solvent system. Initial tissue autoradiograms depict regional DMO plus DG and DG metabolite distribution. After 14 days in a well-ventilated hood, 97.5 +/- 0.5% of all DMO is lost from tissue sections by sublimation, and a second autoradiogram depicts DG plus DG metabolite distribution. Retention of brain lipids does not alter beta-particle self-absorption, avoiding problems associated with isotope extraction with solvents. Autoradiograms are digitized and converted to isotope-content images. The second autoradiogram is used for 1CMRG computation. After subtracting the second regional isotope-content value from the first, the DMO content is obtained and used to compute rABI. Application of this method to normal animals yields expected values for 1CMRG and rABI. This method is amenable to whole-slice digitization and creation of functional images of 1CMRG and ABI followed by pixel-by-pixel correlations of the two variables, making this a potentially valuable tool for the investigation of the relationships between glucose metabolism and brain acid-base balance.
Mood, depressive illness and gait patterns.
This study measures the ground force patterns of 87 normal, older adults. It tests the hypothesis that there is a relation between a subject's mood as measured by the Beck Inventory, and the ground reaction forces as measured by a force plate during normal gait. Results showed that the push-off force in the posterior and downward directions was correlated with the expression of mood state. Lower mood individuals demonstrated a smaller push-off force and these ground force patterns of low mood state subjects resembled the patterns found in a previous study of clinically depressed patients. It is suggested that gait measurement could provide a sensitive index of level of depression in a clinical population.
Exercise compliance of elderly volunteers.
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Influence of exercise and of lifestyle education upon attitudes to exercise of older people.
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Tissue acid-base balance and oxygen metabolism in human cerebral infarction studied with positron emission tomography.
Nine patients who had suffered strokes were examined between 10 and 34 days after onset using positron emission tomography. DMO labeled with carbon 11 was used to evaluate brain acid-base balance, and the oxygen-15 inhalation technique was used to measure regional cerebral blood flow, the oxygen extraction fraction, and cerebral metabolic rate for oxygen. [11C]DMO concentration and oxygen metabolism variables were measured in the infarcted area and in the symmetrical region in the contralateral cerebral hemisphere. [11C]DMO concentration was found to be unchanged or slightly increased in five cases and markedly increased in four cases. The apparent increase in tissue pH can be explained by the presence of a large extracellular fluid space with a pH nearly identical to that of brain plasma, or by an increase in intracellular pH, or by both phenomena. The change in [11C]DMO concentration in the infarcted area relative to that in the normal tissue was independent of the change in blood flow. Cerebral metabolic rate for oxygen was decreased in all cases. The increase in [11C]DMO concentration in the infarcted area was linearly correlated with the decrease in the oxygen extraction fraction in the same region; that is, it was correlated with the occurrence of perfusion in excess of metabolic demand. The overabundant local perfusion could play a role in the decreased H+ content.
11C-labelled phosgene: an improved procedure and synthesis device.
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Synthesis and in vivo characteristics of [2-11 C]5,5-dimethyloxazolidine-2,4-dione (DMO).
No-carrier-added [2-11 C]5,5-dimethyloxazolidine-2,4-dione (DMO) has been prepared rapidly and in good radiochemical yield. The synthesis involves in situ conversion of phosgene to diethyl carbonate which reacts with 2-hydroxy-2-methylpropionamide to yield labeled DMO. HPLC purification provided up to 1.85 GBq (50 mCi) of pure [11C]-DMO for injection. The product's in vivo distribution was examined in mice and rabbits. The results are encouraging for further application to in vivo measurement of intracellular pH using positron tomography.
Gait patterns of depressed patients and normal subjects.
The authors compared the gait patterns of 15 patients with affective disorders with those of 15 normal control subjects. The procedure involved a frame-by-frame analysis of a film of each subject walking at normal speed. Angle measurements were made of the hip and knee at their maximum extension during a single gait cycle (one stride). The results generally support the hypothesis that depressed patients walk with a lifting motion of the leg, whereas normal control subjects propel themselves forward.
Preliminary report: brain blood flow using PET in patients with posttraumatic stress disorder and substance-abuse histories.
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Second messenger dualism in neuromodulation and memory.
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