Michael A. Singer

Of mice and men and elephants: Metabolic rate sets glomerular filtration rate

Allometric scaling deals with the functional consequences of changes in size or scale among geometrically dissimilar animals (ie, animals differing in proportions). For adult mammals ranging in size and proportion from mouse to elephant, the data describe an interdependent set of functions consisting of metabolism (measured as metabolic rate), glomerular filtration rate (GFR), effective renal plasma flow, excretion of nitrogenous waste products, cardiac output, and pulmonary function-related variables. Within this set of functions, evidence indicates that metabolic rate is the primary process. One important design feature is given by the ratio of GFR to metabolic rate. Because this ratio is independent of size, it can be generalized to all mammals in this series. The numeric value of this ratio gives the optimal GFR for each unit of metabolic rate. A simple hypothesis is proposed: metabolic rate, the primary process, sets GFR. This relationship is unidirectional. A decrease in GFR, for example, caused by nephron loss, should not lead to a change in metabolic rate. This hypothesis was tested in four natural experiments: human growth and development, thyroid dysfunction, chronic renal failure, and hibernation. The results are consistent with this hypothesis.

Physical functioning and mental health in patients with chronic medical conditions

There is evidence to suggest that a decline in physical functioning with advancing age is independent of mental health, which appears to remain relatively stable. There is additional evidence to suggest that those with a chronic disease also experience a decline in physical function while the mental health remains relatively stable. Using a cross-sectional design, data from the US population norms for the Medical Outcomes Study SF-36 are examined and compared to SF-36 data collected for four patient groups. Patient groups include kidney dialysis patients, multiple sclerosis patients, kidney transplant patients and patients with severe osteoarthritis of the hip prior to total hip replacement. Overall scores and scores within 10-year age groupings are examined in order to compare the physical functioning and mental health scores of the general population with those of the four patient groups. Results support the hypothesis that physical functioning declines with advancing age and with the development of chronic disease, but mental health remains remarkably stable regardless of chronic disease and/or advancing age. This observation suggests a process of psychological adjustment or adaptation to the physical difficulties encountered with advanced age or disability, and implies that this adjustment process may in fact be quite strong.

The permeability and the effect of acyl-chain length for phospholipid bilayers containing cholesterol: theory and experiment

The model of Cruzeiro-Hansson et al. (Biochim. Biophys. Acta (1989) 979, 166-1176) for lipid-cholesterol bilayers at low cholesterol concentrations is used to predict the thermodynamic properties and the passive ion permeability of lipid bilayers as a function of acyl-chain length and cholesterol concentration. Numerical simulations based on the Monte Carlo method are used to determine the equilibrium state of the system near the main gel-fluid phase transition. The permeability is calculated using an ansatz which relates the passive permeability to the amount of interfaces formed in the bilayer when cholesterol is present. The model predicts at low cholesterol contents an increase in the membrane permeability in the transition region both for increasing cholesterol concentration and for decreasing chain length at a given value of the reduced temperature. This is in contrast to the case of lipid bilayers containing high cholesterol concentrations where the cholesterol strongly suppresses the permeability. Experimental results for the Na+ permeability of C15PC and DPPC (C16PC) bilayers containing cholesterol are presented which confirm the theoretical predictions at low cholesterol concentrations.

Measurement of health-related quality of life in multiple sclerosis patients.

BACKGROUND Patient outcomes in multiple sclerosis (MS) have generally been measured by their neurological impairment using specific scales such as the Kurtzke Expanded Disability Status Scale (EDSS). However, this scale does not measure the multiple dimensions of health-related quality of life (HRQOL) such as functional status and general well-being, which are also important outcomes along with disease-specific measurements. METHODS HRQOL was measured in a group of 97 MS patients using the RAND 36-item Health Survey 1.0. The EDSS score was assigned by the clinic neurologist. Additional data were collected from the clinical record for each patient. RESULTS MS patients scored poorly in a number of HRQOL domains such as physical and role functioning and energy or vitality. Disability as quantified by the EDSS correlated only with the physical functioning domain. Regression models were developed to measure the relationship between patient characteristics (independent variables) and HRQOL domains (dependent variables). DISCUSSION A number of patient characteristics were associated with higher or lower scores on the HRQOL domains. Of particular interest is the finding that a family history of MS was associated with poorer physical and social functioning as well as more pain and less vitality. The occurrence of seizures had a negative impact on role functioning, social functioning and general health perceptions. HRQOL gives caregivers a broader measure of disease burden than the EDSS alone, and should be useful in planning and monitoring interventions.

Permeability of phosphatidylcholine and phosphatidylethanolamine bilayers

Abstract Sodium and glucose effluxes were measured in liposomes formed from a series of saturated phosphatidylcholines (PC) and phosphatidylethanolamines (PE). Vesicles composed of a saturated PC display a local permeability maximum in the region of the lipid transition temperature. The height of this maximum is predominantly a function of the thickness of the hydrocarbon chain region. Liposomes formed from a saturated PE do not display such a permeability maximum and in these vesicles the permeability process appears to be controlled by the head group region. It is postulated that the control exerted by the ethanolamine group is due to the reorganization of water structure it induces at the bilayer surface.

Do mammals, birds, reptiles and fish have similar nitrogen conserving systems?

Comparative physiological studies are a powerful tool for revealing common animal adaptations. Amino acid catabolism produces ammonia which is detoxified through the synthesis of urea (mammals, some fish), uric acid (birds), or urea and uric acid (reptiles). In mammalian herbivores and omnivores, urea nitrogen is salvaged by a series of steps involving urea transfer into the intestine, microbial mediated urea hydrolysis with synthesis of amino acids utilizing the liberated ammonia and transfer of the amino acids back to the host. A similar series of steps occur in omnivorous/granivorous and herbivorous birds, although in this case urine, containing uric acid, is refluxed directly into the intestine where microbes degrade the uric acid and utilize the liberated ammonia for amino acid synthesis. These amino acids are transferred back to the host. In reptiles and ureotelic fish not all of these steps have been experimentally confirmed. Reptiles like birds, reflux urine into the intestine where it is exposed to the microflora. However, the capacity of these microbes to breakdown the uric acid and urea and utilize ammonia for amino acid synthesis has not been documented. Ureotelic fish transfer urea into the intestine where urease (presumably of bacterial origin) hydrolyzes the urea. However, the amino acid synthesizing capacity of the intestinal microflora has not been studied. The series of steps, as outlined, would define the prevailing nitrogen conservation system for herbivores and omnivores at least. However, it would appear that some animals, in particular the fruit-eating bat and perhaps the fruit-eating bird, may have evolved alternative, as yet uncharacterized, adaptations to a very limited nitrogen intake.

Interaction of dibucaine and propranolol with phospholipid bilayer membranes—Effect of alterations in fatty acyl composition

Abstract Sodium 22 efflux was measured, at various temperatures both in the presence and absence of dibucaine or propranolol, in multilamellar liposomes composed of different phosphatidylcholines and dicetylphosphate. Such vesicles display a marked increase in sodium permeability in the temperature region of the phase transition of the component phospholipid. Both local anesthetics lower the temperature of onset of this permeability increase, the extent of the reduction being dependent upon the anesthetic concentration. The liposomes used in these experiments possess a negative charge due to the presence of dicetylphosphate. When exposed to dibucaine, these vesicles develop a significant positive surface potential at the same temperature at which this anesthetic increases 22Na efflux. In a parallel series of experiments, a spin-labeled fatty acid ester was incorporated into similar liposomes and the mobility of the label used as a measure of lipid hydrocarbon chain motion. The phase transition of a phospholipid is associated with a marked increase in fatty acyl chain motion. Both anesthetics lower the temperature at which the lipid chains display significant motional freedom. These observations indicate that dibucaine and propranolol interact with liposomes so as to bring about the phase transition (i.e. melt the hydrocarbon chains) of the membrane lipids at a temperature below that at which this event normally occurs.

Mouse to elephant: Biological scaling and Kt/v

The construct Kt/V is used by the nephrology community in prescribing dialysis dose. The concerns that have been raised as to what value of V to use in the calculation of Kt/V touch on the more central question of whether filtration rate should be normalized by a parameter other than V. Within the animal kingdom, a number of physiological variables scale to body size according to an equation of the form Y = YoMb, where Yo is a constant, M is body mass, and b is a scaling exponent. Glomerular filtration rate (GFR) in mammals weighing from 30 g to 503 kg scales to body weight with an exponent of 0.77. Hence, GFR per unit body weight (or Kt/V) decreases significantly with increasing body size. Metabolic rate also scales to body size in a wide range of mammals according to the same general equation and with a scaling exponent of 0.75. Because GFR and metabolic rate scale to body mass with virtually the same exponent, a ratio of the two yields a constant independent of body size. We propose that the ratio (filtration rate/metabolic rate) replace Kt/V. Such a ratio would underscore the linkage between filtration rate (and dialysis therapy) and the metabolic demands of the body.

Use of Computerized Tomography to Evaluate Bleeding after Renal Biopsy

Perirenal bleeding following biopsy was assessed in 25 consecutive cases using computerized axial tomography (CT) scanning. Perirenal hematomas were found in 15 patients (60%). In 8 patients the hematomas were moderate or large in size. There was no correlation between the clinical findings, fall in hemoglobin, presence of macroscopic hematuria and the finding of perirenal hematoma by CT scanning.

Interaction of butylated hydroxytoluene (BHT) with phospholipid bilayer membranes: Effect on 22Na permeability and membrane fluidity

Abstract Butylated hydroxytoluene (BHT) is a small lipophilic molecule that is widely used as a food preservative. The interaction of this chemical with phospholipid bilayer membranes was monitored by measuring changes in 22Na transport and hydrocarbon chain motion. Vesicles composed of saturated phospholipids display a marked increase in 22Na permeability in the temperature region of the phase transition temperature of the component phospholipid. BHT greatly reduces this permeability increase. When a series of structural analogues was examined, there was found to be a poor correlation between lipid solubility and the capacity to decrease 22Na transport. However, the presence of a hydroxyl group appeared to be an important structural requirement for the permeability change. In a parallel set of experiments, a spin labelled fatty acid ester was incorporated into similar vesicles and the mobility of the label used as a measure of lipid hydrocarbon chain motion. The phase transition temperature of a phospholipid is associated with a marked increase in fatty acyl chain motion. BHT lowers the temperature at which the lipid chains display significant motional freedom (i.e. melt). Since this change in membrane fluidity cannot account for the capacity of BHT to reduce 22Na permeability some additional perturbation must be occurring. It is proposed that this additional perturbation involves an alteration at the interface.