Biomedical subjects

P M Hall

Publications and source records attributed to P M Hall.

At least 37 records · Page 2Linked to original sources

PubMed1995

Iothalamate clearance and its use in large-scale clinical trials.

Several recently completed or ongoing large-scale clinical trials, including the Modification of Diet in Renal Disease Study, the Diabetes Control and Complications Trial, and the African-American Study of Kidney Disease and Hypertension, have all chosen the renal clearance of sodium 125I-iothalmate to monitor renal disease progression. The need for accurate and precise renal testing at multiple clinical sites, with centralized renal sample processing, clearly exceeds the limited scope of most other glomerular filtration rate methods. Analysis of 3580 studies combined from the Modification of Diet in Renal Disease Study and Diabetes Control and Complications Trial demonstrates that trained clinical personnel can successfully perform the 125I-iothalamate clearance glomerular filtration rate method in large-scale studies. Overall, intratest and interest glomerular filtration rate coefficients of variation of approximately 10 and 6% are acceptable for such studies. Strict standardization of glomerular filtration rate protocol with respect to water loading, equilibration time after injection, and pre-study fasting is of crucial importance. Other confounding phenomena, including regression to the mean of progression slopes, must be considered before renal results of an intervention can be assessed. The 125I-iothalamate clearance glomerular filtration rate method offers good accuracy and precision, reasonable clinical convenience, straightforward and efficient central laboratory analysis, and reasonable cost and safety for large-scale clinical trials.

Clinical Trials as Topic↗

PubMed1995

Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues.

The human CYP3A subfamily is of interest due to its multiplicity, activity toward known carcinogens, and extrahepatic expression. In situ hybridisation analysis of formalin fixed, routinely processed biopsy specimens was used to localise CYP3A mRNA in human gastrointestinal tissues from several individuals. CYP3A mRNA is abundant in human liver and in mucosal epithelial cells of all segments of the human small intestine. RNA blot analyses showed that the mRNA species observed in most livers and in human small intestine represent CYP3A3/3A4 transcripts. This was confirmed at the protein level by immunoblot comparison of small intestine microsomes to in vitro expressed CYP3A4 and CYP3A5 proteins. In liver and small intestine, CYP3A mRNA is not uniformly distributed, with grain density highest in cells within the respective non-proliferative compartments. CYP3A mRNA was also observed in human oesophagus and colon. RNA blot analysis of multiple colons showed heterogeneity in the CYP3A mRNAs present. Two CYP3A mRNAs (CYP3A3/3A4 and CYP3A5) were detected in colon samples from several individuals. In addition to those localisation studies, the capacity of expressed CYP3A4 and CYP3A5 to activate the dietary heterocyclic amine MeIQ in the presence of alpha-naphthoflavone was shown. These results show that there is considerable heterogeneity in the expression of the CYP3A subfamily in human gastrointestinal tissues.

Adult↗

PubMed1994

Enteric hyperoxaluria associated with external biliary drainage.

Several chronic disorders of small bowel function have been associated with enteric hyperoxaluria. We report on a patient in whom enteric hyperoxaluria and recurrent calcium oxalate calculi developed during treatment with temporary external biliary drainage for sclerosing cholangitis. The hyperoxaluria subsequently resolved with reestablishment of intraluminal biliary flow at successful liver transplantation. We propose a mechanism for this previously unrecognized cause of hyperoxaluria.

Adult↗

PubMed1994

A model for fatal halothane hepatitis in the guinea pig.

BACKGROUND: In the guinea pig, depleting hepatic glutathione before inhaling subanesthetic 0.1% halothane increases covalent binding of halothane biotransformation intermediates to hepatic protein and potentiates resultant liver injury. Because inhalation of a higher concentration of halothane is known to produce greater levels of covalent binding than with subanesthetic halothane, this study was undertaken with 0.25-1.0% halothane concentrations to further examine glutathione depletion as an etiology for halothane hepatitis. METHODS: Male Hartley guinea pigs were injected intraperitoneally with either vehicle control solution (Veh) or 1.6 g/kg buthionine sulfoximine (BSO), to decrease hepatic glutathione by > 80%, 24 h before a 4-h exposure to 0.25%, 0.5%, or (v/v) halothane with 40% O2. Some BSO-pretreated animals also received 2.0 g/kg glutathione monoethyl ester (GEE), intraperitoneally, 2 h before inhaling halothane to replenish hepatic glutathione. RESULTS: Glutathione-depleted animals developed significantly worse hepatic injury with each halothane concentration. One-third to one-half of BSO+halothane-treated animals developed fatal submassive to massive hepatic necrosis. Covalent binding of halothane intermediates to hepatic protein increased by 45% in BSO + 1.0% halothane-treated guinea pigs. Administration of GEE to BSO-pretreated animals before 1.0% halothane decreased binding to protein and blunted development of liver necrosis. Following Veh + 1.0% halothane, hepatic glutathione was found to be decreased by 60%. CONCLUSIONS: Glutathione would appear to help protect hepatocytes to some degree from covalent binding by reactive halothane biotransformation intermediates. These studies present the first animal model to produce fatal halothane-induced hepatic necrosis.

Animals↗

PubMed1994

Transient diabetes insipidus and acute fatty liver of pregnancy.

OBJECTIVE: To review the association of transient diabetes insipidus and acute fatty liver of pregnancy. DESIGN: A retrospective study. SETTING: Six women presenting with polyuria and polydipsia in the third trimester or in the immediate postpartum period, referred over a two and a half year period; five out of six were primigravida. All had raised liver transaminases and biopsy-proven acute fatty liver of pregnancy. Four out of six also had pre-eclampsia. SUBJECTS: Tertiary referral centre. MAIN OUTCOME MEASURES: There were no maternal deaths and only one fetal death. Desamino-cys-1-D-arg-8-vasopressin administration produced a reduction in urine output in all five women to whom it was administered. In all cases symptoms had resolved by the end of the fourth postpartum week. Three of the women have had subsequent pregnancies uncomplicated by either transient diabetes insipidus or acute fatty liver of pregnancy. CONCLUSIONS: The association of transient diabetes insipidus and acute fatty liver of pregnancy appears more common than previously recognised. Both may be part of the spectrum of pre-eclampsia.

Acute Disease↗

PubMed1993

Can citrate therapy prevent nephrolithiasis?

This prospective study was done to help determine whether or not oral citrate therapy can elevate urinary citrate levels and reduce the incidence of recurrent calcium stones in patients with hypocitraturia (urinary citrate less than 320 mg/24 hr). The treatment group (Group I) consisted of 10 patients treated with oral citrate and hydration. The control group (Group II) was treated with hydration alone. In Group I, the new stone formation rate (stones per patient year) fell from 1.17 +/- 0.26 to 0.45 +/- 0.32 (p = 0.07) and the twenty-four-hour urinary citrate excretion rose from 69 +/- 14 mg to 473 +/- 96 mg (p = 0.002). In Group II, the new stone formation rate fell from 0.9 +/- 0.25 to 0.27 +/- 0.13 (p = 0.03). The twenty-four-hour urinary citrate excretion increased, though not significantly, from 166 +/- 21 mg to 326 +/- 77 mg (p = 0.06). We conclude that oral citrate therapy can significantly increase urinary citrate levels in patients with recurrent stones associated with hypocitraturia but that oral citrate therapy and hydration were no better than hydration alone in reducing the incidence of recurrent stones.

Calcium Oxalate↗

PubMed1993

Renal effects of multiple infusion of pyridoxalated-hemoglobin-polyoxyethylene conjugate (PHP) solution in dogs.

Pyridoxalated-hemoglobin-polyoxyethylene conjugate (PHP), which is made from out-dated human red blood cells by two major chemical modifications, namely pyridoxalation and conjugation with polyoxyethylene (POE), is currently under development as a physiological oxygen carrier. This study assessed the effects of PHP-88 solution, which contains 8% (wt/vol) each of hemoglobin (Hb) and maltose, on renal function when it was infused 3 times every other day into the intact circulation of 8 dogs (5 dogs for the PHP group and 3 for the control group; 20 ml/kg for the first infusion, and 10 ml/kg each for the second and third infusions, at the rate of 2.5 ml/h/kg). Serial determinations of glomerular filtration rate (GFR) and renal plasma flow (RPF) were carried out pre- and postinfusion for up to 3 months along with measurements of blood and urine analyses, urine output rate, fractional excretion of sodium (FES), and free water clearance (CH2O). The results showed that plasma colloid osmotic pressure (COP) elevated an average of 3.3 mm Hg (p = 0.0085), and GFR and RPF tended to increase by 13% (NS) and 38% (NS), respectively, immediately after the third infusion with PHP solution. Urine output rate increased during and after the infusion, and FES and CH2O also increased for 24 h after the infusion in both groups. Blood urea nitrogen, serum creatinine, and serum Na+ concentrations were not affected greatly by the infusions, but hematocrit was decreased by 8% in the PHP group, indicating approximately a 42% expansion of plasma volume. These changes were observed to return to their preinfusion levels by 1 week postinfusion. Renal histology of the PHP group obtained at 2 weeks postinfusion revealed vacuole formation in the proximal tubules which was not associated with any pathologic changes indicative of cell death or regeneration. In 4 out of 5 dogs at 3 months postinfusion (necropsy), the vacuoles were not present. Though urinary N-acetyl-beta-glucosaminidase (NAG) activity had significantly increased after infusion, it returned to the preinfusion level by 1 month postinfusion. No detrimental effect of vacuoles on the assessed renal tubular functions was confirmed in the present study. The results demonstrated that multiple infusions of PHP solutions were well tolerated in normal dogs, and the observed effects were conceived predominantly attributable to the physiological response of the kidneys to an oncotic load into the circulation, which produced plasma volume expansion.

Animals↗

PubMed1993

Glomerular filtration rate measurements in clinical trials. Modification of Diet in Renal Disease Study Group and the Diabetes Control and Complications Trial Research Group.

To assess the utility and precision of GFR measurements in multicenter trials, the test performance and variability of GFR were analyzed in 2,250 patients enrolled in 44 clinical centers participating in either the Modification of Diet in Renal Disease (MDRD) Study or the Diabetes Control and Complications Trial (DCCT). GRF was measured as the renal clearance of [125I]iothalamate after an sc injection without epinephrine. The studies used similar protocols for obtaining blood and urine, training clinical center staff, and processing specimens in central laboratories. The performance of GFR measurements, assessed from adherence to protocol and quality control analyses, was excellent. The variability among the four clearance periods (intratest coefficient of variation [CV]) was acceptable; the median intratest CV for GFR was 9.4% in the MDRD Study and 11.7% in the DCCT. The pattern of decline in serum counts was better approximated by an exponential rather than a linear relationship. The cause of the intratest variability in GFR measurements was explored by univariate and multivariate analysis. The intratest CV was highest at the extremes of GFR. Among patients with a high GFR (> 90 mL/min per 1.73 m2), most of whom were participants in the DCCT, the higher intratest GFR was due, in part, to a systematic decline in GFR during the test. Among patients with a very low GFR (< 13 mL/min per 1.73 m2), technical difficulties in urine collections contributed substantially to the higher intratest CV. Other patient characteristics, including age, gender, weight, serum glucose, renal diagnosis, and use of diuretics, were not strongly correlated with the intratest CV. The precision of GFR measurements was assessed from the variability from measurement to measurement (interest CV). Among MDRD Study subjects, in whom two measurements of GFR were performed over a 3-month interval, the median interest CV was relatively low (6.3%) and was only weakly related to the intratest CV. Thus, GFR measurements are reasonably precise, even if the intratest CV is high. Given the relatively high intratest CV that is characteristic of GFR measurements, the estimate of GFR in an individual is more precise if multiple clearance periods, rather than a single period, are included. Similarly, the estimate of mean GFR for a population is also more precise if multiple clearance periods are included. In conclusion, by the use of standardized methods, an acceptable precision of GFR results can be obtained in multicenter trials. The same methods can be applied in clinical practice.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1992

Metabolism of food-derived heterocyclic amines in human and rabbit tissues by P4503A proteins in the presence of flavonoids.

The ability of human and rabbit gastrointestinal-tract microsomes to metabolize the heterocyclic amine 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) to a mutagen was determined with the Ames test. When human jejunal and ileal microsomes were used as the metabolic activation source, MeIQ produced 1675 and 388 revertants/mg of microsomal protein, respectively, and this increased to 29,230 and 17,963 revertants/mg of microsomal protein, respectively, in the presence of 100 microM alpha-naphthoflavone. MeIQ in the presence of control rabbit duodenal, jejunal, and ileal microsomes produced 2304 +/- 1018, 988 +/- 386, and 444 +/- 134 (mean +/- SD, four samples) revertants/mg of microsomal protein, respectively. In the presence of alpha-naphthoflavone (100 microM), these activities increased greater than 7-fold. P4503A proteins were detectable on Western blots of microsomes prepared from both human and rabbit small intestine. Further, rifampicin-induced rabbit hepatic-microsomal activation of MeIQ was completely inhibited at low concentrations of alpha-naphthoflavone, but at higher concentrations (i.e., 100 microM) this returned to control levels. Flavone also caused a marked stimulation of MeIQ activation in human and rabbit gastrointestinal-tract microsomes. The aforementioned data suggest that flavonoids markedly increase the ability of P4503A isozymes to activate heterocyclic amines to mutagens in the Ames test.

Animals↗

PubMed1992

Glutathione depletion enhances subanesthetic halothane hepatotoxicity in guinea pigs.

Reduced glutathione has a potential role in protecting the liver against the reactive acyl acid chloride intermediate generated during the oxidative biotransformation of halothane. Glutathione is also important in maintaining the integrity of an injured cell. Thus, the effect of decreased hepatic glutathione concentrations on covalent binding of halothane metabolic intermediates to hepatic protein and lipid and the resultant hepatic injury were investigated in male, outbred Hartley guinea pigs. The animals were injected with either 1.6 g.kg-1 dl-buthionine-S,R-sulfoximine to deplete hepatic glutathione or vehicle-control solution 24 h before exposure to 0.1% (subanesthetic) halothane for 4 h (fractional inspired oxygen tension = 0.40). Buthionine sulfoximine pretreatment depleted liver glutathione concentrations by 85% at the time of halothane exposure, without affecting the degree of halothane biotransformation or causing hepatic injury. Glutathione depletion caused a significant increase in the level of organic fluorine covalently bound to hepatic protein but not lipid after halothane exposure. Glutathione-depleted animals also exhibited a significant enhancement of hepatotoxicity after halothane exposure; plasma isocitrate dehydrogenase activity was 25-fold greater than the increase observed 48 h after exposure in animals treated with vehicle plus halothane, and the incidence and severity of hepatic injury were significantly greater, as observed by light microscopic examination of tissue 96 h after exposure. These findings are in agreement with a previously proposed mechanism of halothane-associated hepatotoxicity in guinea pigs and indicate that hepatic glutathione status may play an important role in the susceptibility of patients to halothane-induced liver injury.

Animals↗

PubMed1992

Rapid resolution of duck hepatitis B virus infections occurs after massive hepatocellular involvement.

A study was carried out to determine some of the factors that might distinguish transient from chronic hepadnavirus infection. First, to better characterize chronic infection, Pekin ducks, congenitally infected with the duck hepatitis B virus (DHBV), were used to assess age-dependent variations in viremia, percentage of DHBV-infected hepatocytes, and average levels of DNA replication intermediates in the cytoplasm and of covalently closed circular DNA in the nuclei of infected hepatocytes. Levels of viremia and viral DNA were found to peak at about the time of hatching but persisted at relatively constant levels in chronically infected birds up to 2 years of age. The percentage of infected hepatocytes was also constant, with DHBV replication in virtually 100% of hepatocytes in all birds. Next, we found that adolescent ducks inoculated intravenously with a large dose of DHBV also developed massive infection of hepatocytes with an early but low-level viremia, followed by rapid development of a neutralizing antibody response. No obvious quantitative or qualitative differences between transiently and chronically infected liver tissue were detected in the intracellular markers of viral replication examined. However, in the adolescent duck experiment, DHBV infection was rapidly cleared from the liver even when up to 80% of hepatocytes were initially infected. In all of these ducks, clearance of infection was accompanied by only a mild hepatitis, with no evidence that massive cell death contributed to the clearance. This finding suggested that mechanisms in addition to immune-mediated destruction of hepatocytes might make major contributions to clearance of infections, including physiological turnover of hepatocytes in the presence of a neutralizing antibody response and/or spontaneous loss of the capacity of hepatocytes to support virus replication.

Age Factors↗

PubMed1991

Assessing the progression of renal disease in clinical studies: effects of duration of follow-up and regression to the mean. Modification of Diet in Renal Disease (MDRD) Study Group.

Many clinical studies of the effects of low-protein and low-phosphorus diets on the course of chronic renal disease have used the rate of decline in renal function to assess the rate of progression. In this report, data from the feasibility phase of the Modification of Diet in Renal Disease Study were used to analyze methods used in other studies. The focus is particularly on the effects of duration of follow-up and of regression to the mean. The findings are summarized as follows. (1) During the mean follow-up period of 14.1 months, rates of decline in glomerular filtration rate, creatinine clearance, and the reciprocal of the serum creatinine concentration were highly variable among individuals, and mean rates of decline were slow. (2) Precision of estimates of individual rates of decline in renal function were relatively low and improved with increasing duration of follow-up. (3) Correlations between rates of decline in creatinine clearance and the reciprocal of the serum creatinine concentration with glomerular filtration rate in individuals were significant but weak and became stronger with increasing duration of follow-up. (4) After entry into the study, mean rate of decline in the reciprocal of the serum creatinine concentration became less negative. The change predicted simply from regression to the mean was 68.4% of the observed change.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Isoniazid potentiation of a guinea pig model of halothane-associated hepatotoxicity.

Isoniazid (INH) is a selective inducer of cytochrome P-450 isozymes that are involved in the biotransformation of organohalogen anesthetics. It has been used to produce a rat model of halothane-associated hepatotoxicity that was linked to enhanced oxidative biotransformation of the anesthetic. Guinea pigs were pretreated with INH in order to potentiate halothane-induced hepatic necrosis and to study the oxidative pathway as a hepatotoxic mechanism in this species. The animals received either 12.5, 25.0 or 50.0 mg kg-1 INH i.p. for 7 days. Following halothane exposure, there were dose-dependent increases in plasma levels of the oxidative halothane metabolite, trifluoroacetic acid. These increases were associated with increases in 48 h plasma alanine aminotransferase (ALT) levels. When combined with halothane exposure, the two higher doses of INH killed the animals before planned termination. These deaths were not attributable to hepatic failure. Dividing the 25 mg kg-1 INH dose into twice daily injections of 12.5 mg kg-1 reduced deaths. INH pretreatment control animals exhibited occasional non-dose-dependent increases in ALT as well as the occurrence of fatty vacuolization of hepatocytes at the highest dose. Even though INH pretreatment enhanced oxidative halothane biotransformation and subsequent hepatotoxicity, sensitivity of guinea pigs to the deleterious actions of INH would contraindicate its use as a cytochrome P-450 induction agent.

Alanine Transaminase↗

PubMed1990

Influence of enzyme induction and exposure profile on liver injury due to chlorinated hydrocarbon inhalation.

Rats were exposed for four weeks either to air or to vapours of chloroform, carbon tetrachloride or 1,1-dichloroethylene given either as a constant concentration (continuous profile) or as repeated exposures for 6 hr per day, 5 days per week (fluctuating profile). Vapour concentrations were used such that the total exposure (concentration x time) was the same for the two profiles. Within each group, some animals received the enzyme-inducing agents, phenobarbitone or 1,3-butanediol, in their drinking water. Separate experiments were conducted to determine the influence of enzyme inducers and vapour concentration on chlorocarbon uptake and metabolism. In the case of chloroform, hepatic injury was more severe in animals exposed to constant vapour concentration, while dichloroethylene was more toxic when given as a fluctuating profile, especially in butanediol-treated rats. Carbon tetrachloride hepatotoxicity was similar in the two exposure profiles but was exacerbated by butanediol treatment. Butanediol-treated animals in the fluctuating profile group showed evidence of developing cirrhosis. These results could not be fully explained on the basis of the effect of enzyme inducers and exposure profile on amount of agent metabolized. Both the amount of toxic metabolites and the temporal pattern of their formation appear to be important determinants of liver injury.

Administration, Inhalation↗

PubMed1990

Hypertension in women.

Hypertension is a common disorder which affects over 40 million individuals in the United States alone. Systemic (idiopathic) hypertension is particularly prevalent in elderly women who seem to tolerate this affliction better than their male counterparts. Women with hypertension should be cautioned about the effects of estrogen-containing oral contraceptives which may cause a further elevation in systemic blood pressure. However, postmenopausal estrogen supplementation does not produce adverse effects on blood pressure and, in fact, may offer cardiovascular protection. Renovascular hypertension, particularly as a result of fibromuscular hyperplasia, is more prevalent in women than men. For women, as for men, tobacco abuse and advanced age are associated with an increased prevalence of atherosclerotic renal artery stenosis.

Contraceptives, Oral, Hormonal↗

PubMed1989

Can progression of renal disease be prevented?

Renal disease from a variety of causes often progresses to end-stage renal failure. The progression may be caused by factors accompanying, but not initiating, renal injury. These factors include glomerular hyperfiltration, glomerular hypertension, systemic hypertension, and hyperlipidemia. Studies, primarily in animals, indicate that causative factors may be altered by control of systemic hypertension, dietary protein restriction, administration of angiotensin-converting enzyme inhibitors or calcium channel blockers, and plasma lipid control. Whether such interventions will significantly alter progressive renal disease in humans is, as yet, uncertain.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1989

Immunohistochemical localization of NADPH-cytochrome P450 reductase in human tissues.

In an attempt to elucidate the mechanism(s) behind the susceptibility of tissues to the toxic effects of chemicals, NADPH-cytochrome P450 reductase IgG has been used to map the distribution and localization of the cytochrome P450 system in hepatic and extrahepatic human tissues. Employing the Western blot procedure this antibody recognized a single band in human liver microsomes which corresponded in mol. wt to the purified reductase. Immunoreactive NADPH-cytochrome P450 reductase staining was detected in all zones of the liver acinus, with maximal staining in hepatocytes adjacent to the terminal hepatic venules (zone 3). Considerable variation in the intensity of reductase staining was observed in different segments of the gastrointestinal tract. Staining was most intense in the enterocytes of the small intestine, with maximal staining at the tips of the villi. Colonic epithelial cells were variably positive while the rectum was negative. Pancreatic ductal cells were positive whereas exocrine cells were negative. In the lung, reductase was detected in bronchiolar and bronchial epithelial cells, Clara cells and alveolar lining cells. In the kidney, the proximal and distal convoluted tubules, the loops of Henle, the collecting ducts in the medulla and the transitional epithelium all stained positively for reductase. The results demonstrate specific cellular localization of NADPH-cytochrome P450 reductase, and hence the cytochrome P450 system, in human tissues. The differential distribution of the reductase within human tissues may lead to a better understanding of the mechanism underlining site-specific carcinogenesis.

Adrenal Glands↗

PubMed1989

Creatinine filtration, secretion and excretion during progressive renal disease. Modification of Diet in Renal Disease (MDRD) Study Group.

The Modification of Diet in Renal Disease (MDRD) Study is a multicenter, randomized, controlled trial to determine acceptance, safety, and efficacy of low protein and phosphorus diets in patients with progressive renal disease. During the feasibility phase, 96 patients aged 18 to 75 years, with previously declining reciprocal serum creatinine concentration (1/PCr) and current glomerular filtration rate (GFR) from 7.5 to 80 ml/min/1.73 m2, were randomly assigned four study diets. After randomization, 91 patients were followed for a mean duration of 14.1 months. GFR, 1/PCr and creatinine clearance (CCr) were measured every three months. In an earlier report, we demonstrated relatively weak correlations of rates of change in GFR and 1/PCr during the feasibility phase; the proportion of variability in 1/PCr slopes that was explained by variability in GFR slopes (r2) was only 0.49 to 0.55. In this study, we examined the relationship of GFR and 1/PCr to other determinants of the serum creatinine concentration, including filtration (GFCr), secretion (TSCr), and total renal excretion (UCrV) of creatinine. Our results show that these parameters varied widely among individuals and changed over time. These findings may explain, in part, the relatively weak correlations. These results strengthen our previous suggestion that the rate of change in 1/PCr may not be an accurate index of the rate of change in GFR and raise questions about the validity of conclusions from other studies in which the efficacy of dietary modification in retarding the progression of renal disease was based principally on measurements of 1/PCr.

Adolescent↗