[Motility disorders of the esophagus]. / Motilitätsstörungen des Ösophagus.

Motility disorders of the esophagus comprise a heterogeneous spectrum of diseases. Primary malformations of the esophagus are now amenable to improved surgical and gastroenterological therapies; however, they often lead to persistent long-term esophageal dysmotility. Achalasia originates from impaired relaxation of the gastroesophageal sphincter apparatus. Systemic diseases may give rise to secondary disorders of esophageal motility. A number of visceral neuromuscular disorders show an esophageal manifestation but aganglionosis rarely extends into the esophagus. The growing group of myopathies includes metabolic and mitochondrial disorders with increasing levels of genetic characterization and incipient emergence of therapeutic strategies. Esophagitis with an infectious etiology causes severe dysmotility particularly in immunocompromised patients. Immunologically mediated inflammatory processes involving the esophagus are increasingly better understood. Finally, rare tumors and tumor-like lesions may impair esophageal motor function.

Effects of aging and vincamine derivatives on pericapillary microenvironment: stereological characterization of the cerebral capillary network.

Changes in the pericapillary microenvironment of adult (18-month-old) and senescent (27 1/2-month-old) Fischer-344 rats treated for 6 weeks with daily IP injections of brovincamine or apovincamine (0, 2.5, 5, 10 mg/kg) were correlated with spontaneous locomotor activity and [14C]-2-deoxyglucose uptake of the brain. The animals were tested for spontaneous locomotor activity in a tunnel maze. Twenty-four hr after behavioral testing and subsequently after a [14C]-2-deoxyglucose injection, brains were removed and capillaries stained with alkaline phosphatase reaction, being later measured with an optical-electronic image analysis technique. Results revealed an increase in intercapillary distance, as a sensitive parameter for capillary density, in the hippocampus (CA1) and in the parietal cortex (area 39) in association with aging. Capillary diameter in the parietal cortex was found to be increased age dependently. A similar age-related increase was also observed in the CA1 field but this age trend was not significant. Chronic treatment with the vincamines produced a dose-dependent reduction in intercapillary distance in senescent animals which approached the level of untreated adult control rats. Significant negative correlations were found between maze locomotion and intercapillary distance among senescent rats. Furthermore, intercapillary distance and local relative 2-deoxyglucose uptake tended to be negatively correlated in both age groups. These findings provide evidence for the working hypothesis that mean intercapillary distance can be considered as an indicator of neuronal activity in the pericapillary microenvironment.

The significance of glucose turnover in the brain in the pathogenetic mechanisms of Alzheimer's disease.

This paper presents a comprehensive survey of the pathogenesis and pathophysiology of Alzheimer's disease (AD). Two mechanisms are of etiological importance in the development of a degenerative dementing brain disease: 1. Lesions in the mitochondrial genome that are caused by free radicals. Primary degenerative AD is characterized by a tendency to acquire random lesions within mitochondrial DNA that are produced by free radicals. The consequence of these lesions is a decrease in glucose turnover and a decline in oxidative phosphorylation. Point mutations on chromosome 21 are hypothesized to increase the susceptibility of mitochondrial DNA to lesions created by free radicals. 2. Ischemic brain lesions as well as traumatic brain damage cause an increase in the release of excitotoxic amino acids (glutamate, aspartate, etc.). These neurotransmitters increase CA(+2) influx into the nerve cell and significantly lower energy production. From a pathogenetic point of view, AD is characterized by a decrease in glucose turnover in the brain. The progression of AD can be monitored by F18- deoxyglucose PET studies. This technique also allows the recognition of patients who are prone to develop AD. The actual development of a cognitive deficit is a threshold phenomenon that occurs if glucose turnover in the hippocampus or temporoparietal cortex drops below a critical level of about 40% of the level of age-matched controls. The low glucose turnover in AD causes a cholinergic deficit by decreasing the synthesis of AcCoA, which is used by choline acetyltransferase in the acetylation of choline to acetylcholine. The decrease in glucose turnover also reduces oxidative phosphorylation. The resulting decrease in ATP triggers the hyperphosphorylation of tau protein by activating protein kinase 40erk. The hyperphosphorylation leads to the development of paired helical filaments. The generation of beta amyloid and the loss of neuronal synapses are also caused by a decrease in oxidative phosphorylation, since beta amyloid precursor proteins are not inserted into the membranes of nerve cells in the absence of a sufficient amount of ATP. This results in the generation of intact beta amyloid molecules and leads to amyloidosis in the brains of patients with Alzheimer's disease.

Glycolytic enzymes from human autoptic brain cortex: normal aged and demented cases.

The activities of glycolytic enzymes were determined in human autoptic temporal lobes from patients with different forms of dementia. For some enzymes (hexokinase, phosphofructokinase and phosphoglycerate mutase) the effect seen in dementia can be regarded as an intensification of the normal ageing affect. For other enzymes (aldolase, phosphoglucose isomerase, triosephosphate isomerase and lactate dehydrogenase) no changes in enzyme activities corresponding to those found in dementia are observed in the normal ageing process. These effects are most pronounced in the non-vascular Alzheimer cases. With the exception of triosephosphate isomerase and lactate dehydrogenase, enzyme activity is also reduced in bronchopneumonia. The effects of dementia and bronchopneumonia on the activities of glycolytic enzymes in human autoptic brain tissue are often difficult to distinguish.

Stereological changes in the capillary network and nerve cells of the aging human brain.

Stereologic parameters of the capillaries and nerve cells of the brain cortex and putamen were investigated. Thirty-eight brains from subjects aged between 19 and 94 years were examined. All cases were free of metabolic, neurologic and psychiatric diseases. It is demonstrated that the capillary diameter remains unchanged during aging in both brain cortex and putamen. However, in the putamen the total capillary length per unit volume and the capillary volume fractions increase (approximately 60%) progressively with age. Consequently the mean inter-capillary distances in the putamen decrease (approximately 15%). These age-induced changes in the putamen indicate shrinking of subcortical brain structures. In contrast to those of the putamen, the morphometric data of the capillaries in the cortex remain unchanged during the aging process. Stereologic investigations of nerve cells in the brain cortex and putamen revealed that only in brains over 85 years of age can a significant decrease in nerve cell size be demonstrated. A correlation of all the data by a correspondence analytical procedure showed that only the surface/volume ratio of the capillaries correlates with the nerve cell size. This observation suggests a functional interaction between the nerve cells and the capillaries. From the data presented it becomes apparent that the shrinkage of the gyri in the aging brain is not a change in the volume of the cortex, but a decrease in the volume of subcortical structures.

Impaired succinic dehydrogenase activity of rat Purkinje cell mitochondria during aging.

The perikaryal Purkinje cell mitochondria positive to the copper ferrocyanide histochemical reaction for succinic dehydrogenase (SDH) have been investigated by means of semiautomatic morphometric methods in rats of 3, 12 and 24 months of age. The number of organelles/microm3 of Purkinje cell cytoplasm (Numeric density: Nv), the average mitochondrial volume (V) and the mitochondrial volume fraction (Volume density: Vv) were the ultrastructural parameters taken into account. Nv was significantly higher at 12 than at 3 and 24 months of age. V was significantly decreased at 12 and 24 months of age, but no difference was envisaged between adult and old rats. Vv was significantly decreased in old animals vs. the other age groups. In young and old rats, the percentage of organelles larger than 0.32 microm3 was 13.5 and 11%, respectively, while these enlarged mitochondria accounted for less than 1% in the adult group. Since SDH activity is of critical importance when energy demand is high, the marked decrease of Vv supports an impaired capacity of the old Purkinje cells to match actual energy supply at sustained transmission of the nervous impulse. However, the high percentage of enlarged organelles found in old rats may witness a morphofunctional compensatory response.

Age-dependent decrease in the activity of succinic dehydrogenase in rat CA1 pyramidal cells: a quantitative cytochemical study.

A computer-assisted morphometric study has been carried out on the ultrastructure of perikaryal CA1 pyramidal cell mitochondria positive to the copper ferricyanide cytochemical reaction for succinic dehydrogenase (SDH) in rats of 3, 12 and 23 months of age. The cytoplasmic volume fraction occupied by the positive mitochondria (Volume density: Vv), the number of organelles/micron 3 of CA1 pyramidal cell cytoplasm (Numerical density: Nv) and the average mitochondrial volume (V) were automatically calculated by means of computer-assisted morphometry. Vv was significantly decreased in 23-month-old animals versus the other age groups. Nv was unchanged between 3 and 12 months of age, but was decreased to a significant extent in old animals. V did not undergo significant changes in the three age groups taken into account. In the old animals the percent of organelles smaller than 0.16 micron 3 is above 20%, while in the young and adult groups the same size of mitochondria accounts for 7 and 3%, respectively. Thus, a reduction in the number of medium sized organelles appears to be responsible for the decrease in Vv due to age. Since SDH activity is known to support maximum rates of respiration, quantitative estimation of the active mitochondria provides information on the metabolic competence of the cells investigated when energy demand is high. In this context, our present findings document that a significant impairment in the efficiency to match actual energy provisions occurs in old CA1 pyramidal cells.

Histopathological criteria for intestinal neuronal dysplasia of the submucosal plexus (type B)

The aim of this study was to review critically the diagnostic features of intestinal neuronal dysplasia type B (IND B). Over a period of 5 years colonic mucosal biopsies of 773 children with symptoms of chronic constipation were examined. Four biopsies taken 2-10 cm above the pectinate line were cut in serial sections and histochemical lactate dehydrogenase, succinate dehydrogenase, (SDH) and acetylcholinesterase (AChE) reactions performed. Presence of giant ganglia of the submucosal plexus, being characterized by more than seven nerve cells, established the diagnosis of IND B. Giant ganglia were found to be age-independent changes, while hyperplasia of the submucosal plexus, increase of AChE activity in nerve fibres of the lamina propria and low SDH activity in nerve cells proved to be age-dependent findings which disappear during the maturation of the enteric nervous system. Using these criteria IND B was diagnosed in 209 children. In 64 of these patients a combination of IND B and aganglionosis (Hirschsprung's disease) was found. IND B seems to be related to premature expression of laminin A during embryogenesis, resulting in premature nerve cell differentiation in the myenteric and submucosal plexus, which in turn blocks neuroblast colonization of the rectum. IND B, hypoganglionosis and aganglionosis, which are often combined, may therefore be considered to be different manifestations of the same developmental abnormality.

Senile dementia: a threshold phenomenon of normal aging? A contribution to the functional reserve hypothesis of the brain.

Neurochemical investigations with normal aging brains show that in the first 70 years of life no major changes of the glycolytic pathway can be observed. Only in the following decades does a significant decrease of brain metabolic turnover occur. Changes in nerve cell size, one of the most relevant parameters in evaluating a diffuse nerve cell atrophy, appear in the brain cortex not earlier than between 85 and 94 years of age; a 21% nerve cell shrinkage is the mean. The results demonstrate that a significant decrease in turnover of the glycolytic pathway is followed by a significant but moderate shrinkage of the nerve cells after a delay of 10-15 years. Similar investigations in brains from senile demented subjects demonstrate that the change in glycolytic turnover is much more a quantitative than a qualitative phenomenon. In comparison with age-matched controls a decrease in glycolytic turnover of more than 60% is observed. Morphometric investigations of the nerve cell sizes in the brain cortex of senile demented subjects showed a decrease of 45-55% when compared with age-matched controls. When normal aging is compared with senile dementia it seems that old age dementia is a threshold phenomenon which starts if the glycolytic turnover drops below 50% of its value in young healthy adults. Physiological aging, however, stays within the range of the reserve capacity of normal brain performance. In conclusion, it seems that the exhaustion of the functional reserve capacity may shift an aging brain into a dementia syndrome.

Pathogenesis of decreased glucose turnover and oxidative phosphorylation in ischemic and trauma-induced dementia of the Alzheimer type.

The pathogenetic mechanisms causing a dementing brain disease after temporary ischemia, heat shock, or brain trauma are surveyed. These lesions increase beta amyloid precursor protein (beta APP) synthesis. This process is potentiated by an ischemic glutamate release that opens cellular Ca2+ channels, inhibiting glucose turnover and ATP production, which is, under these conditions, accompanied by the generation of beta amyloid (beta A), even in young persons. Beta amyloid starts a vicious circle by inactivating the glycolytic key enzyme, phosphofructokinase, which, with age, exhausts the functional reserve capacity of the brain. This demonstrates that beta A is an epiphenomenon of a dementing brain disease, triggered by the disturbance of glucose turnover and oxidative phosphorylation. Clinical studies have shown that a dementing brain disease can be clearly objectified and monitored by 18F-2-deoxyglucose PET studies. This paper looks briefly at pharmacologic approaches to this disease using models of temporary ischemia, the testing of 14C-deoxyglucose turnover, or examination with 31P magnetic resonance spectroscopy techniques. In conclusion, the key process of all dementing brain diseases of the Alzheimer type is a decreased glucose turnover and subsequently decreased oxidative phosphorylation, linked directly to a secondary amyloid formation and nerve cell atrophy.

What is primary and what secondary for amyloid deposition in Alzheimer's disease.

The fact that physiologically beta-amyloid precursor proteins are synthesized by all cells of the body without any amyloid deposition in other organs raises a question about an isolated deposition of amyloid in the brain. One of the most important mechanisms in the pathogenesis of senile dementia of the Alzheimer type is the marked decrease of the cerebral glucose metabolism, a cholinergic deficit, by a disturbed acetyl-CoA synthesis and a critically lowered oxidative phosphorylation. Remembering that aging is the most important predisposing factor in the development of Alzheimer's disease, it is argued that a decrease of the oxidative energy metabolism in senile dementia and the resulting ATP deficit may change protein degradation, synaptic transmission and ion homeostasis. Therefore, a more than 50% decline of oxidative energy turnover could be a trigger for an accumulation of beta-amyloid in the brain, because the degradation of beta-amyloid precursor protein could be directly or indirectly disturbed by an ATP deficit. Amyloidosis and a cholinergic deficit in SDAT would then be a secondary phenomenon of the decreased glucose metabolism in the brain.

Age-related white matter atrophy in the human brain.

Aging of the brain involves not only appreciable shrinkage of the cortex and other gray matter structures but above all loss of white matter. This could be due to a decline in the number of myelinated fibers or to a loss of water. To assess the role played by each of these factors we studied brains from 33 neurologically intact subjects at autopsy representing three different age groups: 15-50, 51-70, and 71-93 years. The precentral gyrus, gyrus rectus, and corpus callosum were selected for investigation, with staining for alkaline phosphatase on native cryostat sections to visualize the capillary network, and staining for myelin on semithin sections for nerve fiber visualization. Atrophy was objectified by measuring the number of capillaries, the intercapillary distance, and capillary length, since the capillary network remains constant throughout normal life. A mean difference of 16-20% was found, representing white matter atrophy, between the oldest and youngest age-groups. The cortex of the corresponding gyri, on the other hand, showed a difference of less than 6%. Morphometric investigation of sections stained for myelin showed that the brains with a mean age of 78.7 +/- 6.6 years had 10-15% fewer myelinated fibers. This was only partly offset by an increase in the volume of extracellular space. Our findings show that the age-related decline in brain volume is much more a question of white matter atrophy than of brain cortex atrophy. White matter atrophy could be an indirect indicator of nerve cell loss, since the volume of a nerve cell is much smaller than its myelinated fiber.

Morphological adaptive response of the synaptic junctional zones in the human dentate gyrus during aging and Alzheimer's disease.

A computer-assisted morphometric study has been carried out on ethanol phosphotungstic acid (E-PTA) stained synaptic junctions in the human dentate gyrus supragranular layer from adult, old and Alzheimer's disease (AD)-affected patients. The number of synapses per unit volume of tissue (Nv = numerical density), the average area of the single junction (S) and the total area of the synaptic contact zones in a unit volume of tissue (Sv = surface density) were the 3 parameters taken into account. The synapse to neurone ratio was also calculated for each patient. During physiological aging, Nv and Sv significantly decreased and S increased, respectively. In the AD hippocampi, Nv and Sv underwent a further decrease which was in the range of more than 40% with reference to the adult values. S was the same as the old control group. In comparison with the adult values, the number of synapse/neurone decreased by 15.6 and 48% in old and AD patients, respectively. Nv, S and Sv, while reporting on discrete ultrastructural features of the synaptic junctional zones, are closely related to each other and, taken together per group of patients, may represent a reliable index of the morphological adaptive changes taking place at the synapses. Thus, the significant increase of S both in old and AD hippocampi may be regarded as a CNS plastic response to aging and disease, although the marked decrease of Nv and Sv supports that in AD synaptic ultrastructural alterations proceed beyond a critical threshold for functional recovery.

Morphological plasticity of synaptic mitochondria during aging.

A morphometric investigation has been carried out on the synaptic mitochondria of cerebellar glomeruli in young, adult and old rats by means of a computer-assisted image analysis technique. Mitochondrial volume density (Vv), numerical density (Nv), average volume (V) and average length (Skeleton = Sk) were investigated in tissue samples fixed, embedded and sectioned according to conventional electron microscopic methods. Vv was unchanged in the three groups of age taken into account. Nv was significantly increased in adult vs. young animals, whereas it was decreased in the old group as compared to both the other two groups investigated. V and Sk showed the same age-dependent changes: they significantly decreased in the adult vs. the young and the old groups of rats while increased significantly in the old rats vs. both the adult and young animals. A percentage distribution of Sk demonstrated that in the old group 20.6% of the population of synaptic mitochondria accounts for elongated organelles (> 5 microns) as compared to 8.6% and 5.3% in young and adult animals, respectively. The present findings match the changes previously reported by us on the ultrastructure of synaptic contact zones both in rats and human beings, and support the idea of an age-dependent dynamic adaptation in the morphology of synaptic mitochondria to cope with the metabolic needs of the pattern of synaptic connectivity they subserve.

Aquagenic pruritus. Water-induced activation of acetylcholinesterase.

Four patients with aquagenic pruritus (AP), one patient with polycythemia rubra vera, one patient with cold urticaria, and three normal control volunteers were studied to better understand the pathophysiology of water-induced itching. Punch biopsy specimens were taken before and after water contact; the specimens were immediately frozen, sectioned, and stained histochemically for acetylcholinesterase (AChE) activity. This was localized in the nerve fibers surrounding eccrine sweat glands and was quantified by microspectrophotometry. In AP and polycythemia rubra vera after water exposure a significantly increased AChE activity suggesting acetylcholine release was observed, whereas in the patient with cold urticaria and the controls, a significant decrease was noted. Two related patients with AP had an inherited abnormality of serum cholinesterase, which, however, had no obvious correlation with their particular disease. The proof of AChE activation might support the clinical diagnosis and indicate a hypothetical involvement of eccrine sweat glands in the pathogenesis of AP.

Effects of brovincamine on the stereological parameters of corticocerebral capillaries.

A number of clinical studies in patients with cerebrovascular insufficiency or symptoms resulting from multiple cerebral infarctions have shown that brovincamine significantly reduces the number of ischaemic regions and the left/right asymmetry of blood flow to the hemispheres, and brings about general improvement of the microcirculation. An optical-electronic image analysis technique was used to investigate whether brovincamine (7.5 mg/kg/day orally for 4 weeks) had any effect on stereological parameters of the corticocerebral capillaries of 1-year-old and 3-year-old OFA rats (n = 20). The older group of rats was included since in man changes in capillary geometry are known to be one of the manifestations of aging. The results show that brovincamine significantly increases the efficiency of capillary clearance, which is accompanied by an increase in capillary length and capillary volume per unit volume of tissue, resulting in a shortening of the mean intercapillary diffusion paths, a rise in capillary density and an increase in capillary diffusion area. No significant difference was observable between young and old rats. The changes in both groups of animals took the same form. From the above findings it was concluded that brovincamine improves the corticocerebral microcirculation by virtue of its effect on capillary geometry.

Morphometric determination of the methodological criteria for the diagnosis of intestinal neuronal dysplasia (IND B).

Intestinal neuronal dysplasia of the submucous plexus (IND B) is an indicator of a developmental abnormality of vegetative gut innervation. It is the mildest form of an inborn error of intestinal innervation. The diagnosis of IND B does not result in a functional conclusion or clinical recommendation but is often accompanied by oligoneuronal hypoganglionosis of the myenteric plexus or an aganglionosis of the rectum. The aim of this study was to demonstrate by morphometric means a way in which the diagnosis of IND B could be made much more reliable. In 20 control subjects, 40 IND B cases and 10 hypoganglionoses with IND B, it was shown that a specific nerve cell staining (e.g. Lactic dehydrogenase, Succinic dehydrogenase, Diaphorase reaction or an immunohistochemical nerve cell staining) was necessary for diagnosis. Cross sections of giant ganglions and cross sections with large nerve cell numbers (> 7 nerve cell profiles) were the most reliable diagnostic criteria. The morphometric examinations were performed with an optic electronic image analysis system. Biopsy serial sections of the rectum-mucosa that contained submucosa demonstrated that 30-40% of the sections contained no submucous ganglion. Sixty to 70% of the sections showed ganglia of the submucous plexus. In 100 biopsy sections in subjects with IND B, 20 +/- 5% contained giant ganglions cross sections. In the patients with hypoganglionosis of the submucous plexus, 55 +/- 4% sections had no ganglion and 18 +/- 3% had giant ganglion cross sections. The data demonstrate that for a reliable diagnosis of IND B, at least 30 sections are necessary, stained with a dehydrogenase reaction that contain a minimum of 4 giant ganglion cross sections. These data demonstrate that IND B is not a qualitative diagnosis as Hirschsprung's disease but rather a quantitative diagnosis.

Computer-assisted morphometry of synaptic plasticity during aging and dementia.

A computer assisted morphometric study has been carried out on synaptic membranes in the dentate gyrus supragranular layer and cerebellar glomerulus from adult, old and demented patients. Numerical (Nv) and surface (Sv) densities as well as average area (S) of the synaptic contact zones were calculated directly on electron microscopic negatives by means of an ASBA (Wild Leitz, AG) image analyzer properly programmed. The results showed a decrease of Nv in both the CNS areas investigated during aging and, to a higher extent, in senile dementia. S was found to be significantly increased in old and demented CNS as compared with adult values. In the old hippocampus Sv was decreased by 40% whereas no significant difference was present between old and adult cerebellum; in senile dementia this parameter underwent a significant decrease in both areas investigated. We interpret the present findings in terms of morphological remodelling capability of the synaptic junctional zones during aging and disease.

Enlargement of synaptic size as a compensative reaction in aging and dementia.

A quantitative investigation has been carried out on synaptic contact zones of dentate gyrus supragranular layer and cerebellar glomeruli in autoptic samples from adult, old and demented patients. During physiological aging and senile dementia, the synaptic average area was significantly increased as compared to adult values in both the CNS areas investigated. Conversely, the number of contacts and their total surface contact area per unit volume of tissue were decreased. Current literature reports that, in animal models, enlarged synapses undergo perforations and splitting to modify synaptic connectivity. As against these assumptions, the increased synaptic size observed in our study appears to represent a compensative reaction of old and demented CNS to counteract the reduction in number and in total contact area of the synaptic junctions.

Quantitative cytochemical mapping of mitochondrial enzymes in rat cerebella.

Mitochondrial metabolic competence, defined as the organelle's capacity to provide adequate amounts of ATP in due time, appears to constitute an important determinant in several biological processes and pathological conditions. Thus, the assessment of the metabolic efficiency of the mitochondrial population in a given tissue area or cellular compartment may provide clues to identifying alterations of the cellular bioenergetic machinery, which may constitute a predisposing condition leading to impaired organ and system functions. In the cerebellar cortex of adult rats, the activities of the enzymes cytochrome oxidase (COX) and succinic dehydrogenase (SDH) were, respectively, evidenced by means of the diaminobenzidine and copper ferrocyanide preferential cytochemical techniques. At the electron microscope, the activities of these two key molecules of the respiratory chain were clearly visualised as dark precipitates at the inner mitochondrial membrane sites where COX and SDH are located. By means of the disector method, unbiased mitochondrial samplings were carried out to measure: the number of mitochondria/microm(3) of tissue (numeric density: Nv); the mitochondrial volume fraction/microm(3) of tissue (volume density: Vv) and the average mitochondrial volume (V) both on COX- and SDH-positive organelles in the cerebellar glomeruli and Purkinje cells, respectively. The ratio R (total area of the precipitates due either to COX or SDH activity within the single mitochondrion/area of the same organelle) was also evaluated to get information on the enzyme activity related to mitochondrial size.The documented accumulation of mutant mitochondrial DNA particularly in postmitotic cells results in a marked heteroplasmy (mixtures of normal and mutated genomes) at mitochondrial and cellular levels, thus the cellular potential for energy production is demanded to a mosaic of organelles with different functional capabilities. Assessment of the mitochondrial mosaic outline by means of quantitative cytochemistry of key enzymes of the respiratory chain, such as COX and SDH, may allow for the morphofunctional metabolic mapping of mitochondrial efficiency in discrete cellular or tissue compartments.