Migraine improvement during short lasting ketogenesis: a proof-of-concept study.

BACKGROUND AND PURPOSE: Ketogenesis is a physiological phenomenon due to starvation or a ketogenic diet (KD), a drastic restricted carbohydrate dietary regimen that induces lipid metabolism and ketone body synthesis. Two patients whose migraines disappeared only during, and not outside, cycles of very-low-calorie KD performed to reduce their weight were recently observed. To confirm our observation, in a dietitian clinical setting two parallel groups of migraineurs, one receiving a 1-month very-low-calorie KD prescription followed by a 5-month standard low-calorie diet (SD) and the other a 6-month SD, were followed. METHODS: Ninety-six overweight female migraineurs were enrolled in a diet clinic and blindly received a KD (n = 45) or an SD (n = 51) prescription. Mean monthly attack frequency, number of days with headaches and tablet intake were assessed before and 1, 2, 3 and 6 months after diet initiation. RESULTS: In the KD group, the baseline attack frequency (2.9 attacks per month), number of days with headaches (5.11 days per month) and tablet intake (4.91 doses per month) were significantly reduced after the first month of diet (respectively 0.71, 0.91, 0.51; overall, KD versus baseline, P < 0.0001). During the transition period (first versus second month), the KD group showed a transient worsening of each clinical headache variable (respectively 2.60, 3.60, 3.07), despite being improved compared with baseline, with continuous improvement up to month 6 (respectively 2.16, 2.78, 3.71). In the SD group, significant decreases in the number of days with headaches and tablet intake were observed only from month 3 (P < 0.0001), and in attack frequency at month 6 (P < 0.0001). CONCLUSIONS: The underlying mechanisms of KD efficacy could be related to its ability to enhance mitochondrial energy metabolism and counteract neural inflammation.

Sources of interference in field studies of diesel exhaust emissions.

This article describes interferences encountered in a variety of occupational settings during industrial hygiene surveys of diesel particulate material (DPM) using the NIOSH 5040 Method. The method yields time-weighted-average measurements of elemental carbon (EC), organic carbon (OC), and total carbon (TC = EC + OC). NIOSH recommends EC as proxy for DPM, but other agencies (e.g., MSHA) regulate exposure as TC. Surveys were conducted in an engine factory and a wood treatment plant where diesel equipment was used, and in a foundry where its use was being considered. Full shift samples were collected using open-faced cassettes and cyclones fitted with 37-mm quartz fiber filters analyzed by the NIOSH 5040 Method. Non-DPM-related interferences were noted for both the OC and EC. In the engine factory and wood treatment facility, OC measurements were very high (range of 10.0-1600 microg/m(3)), while EC levels were mostly below the LOD. These findings almost certainly reflect interferences by cutting oil mists and airborne creosote respectively. In the foundry, EC levels were high and comprised mainly of larger (>4 microm) particles (open face samples: arithmetic mean = 136 microg/m(3), geometric mean = 74.0 microg/m(3); cyclone samples: arithmetic mean = 30.2 microg/m(3), geometric mean = 14.7 microg/m(3)). These findings suggest that OC interferences should be suspected if the EC:TC ratio is <0.35 and, if DPM surveys are performed with open-faced samplers, at least a small number of size-selective samplers should be employed to assure that results do not reflect EC interference by larger (i.e., >1-4 microm) particles. They also support the ACGIH decision to modify its proposed DPM TLV to specifically consider elemental carbon, rather than total carbon.

Comparison of NIOSH 5040 method versus Aethalometer to monitor diesel particulate in school buses and at work sites.

This study, undertaken initially to understand apparent differences between two recent reports of diesel particulate matter (DPM) inside school buses, involved side-by-side comparisons of two different methods for measuring ambient and occupational exposures to DPM. The NIOSH 5040 method yields time-weighted-average measurements of elemental carbon (EC) and organic carbon (OC), whereas the Aethalometer yields near-real time measures of carbonaceous particles (black carbon or BC) by optical absorption. The two methods were compared on three school buses and in three different work sites. Three side-by-side sampling configurations were used (open-faced filter with and without two different cyclones) in triplicate along with two or three Aethalometers. BC readings were correlated with results from open-faced cassettes, but there were statistically significant differences between the results of side-by-side Aethalometers. In addition, Aethalometer airflow rates were inaccurate, the instruments were sensitive to vibration, optical calibration could not be performed, and historically derived conversion factors to relate EC and BC were not appropriate. The Aethalometer could prove useful for monitoring of industrial work sites, but only after a method for external calibration and improvements in pump design and vibration isolation are developed.

Observations on the suitability of the aethalometer for vehicular and workplace monitoring.

A field study was undertaken to evaluate the suitability of the aethalometer, an instrument capable of performing near-real-time measurement of low-level (10-1,000 ng/m3) airborne combustion products, for vehicular and workplace monitoring. Several technical limitations were identified: (1) there was no ready means for external calibration of optical measurements; (2) airflow rates were unstable; (3) effective range of concentrations was limited; and (4) the aethalometer demonstrated sensitivity to movement and vibration. Unless addressed, these limitations will restrict future uses of the aethalometer for vehicular and workplace monitoring.

Exposure of miners to diesel exhaust particulates in underground nonmetal mines.

A study was initiated to examine worker exposures in seven underground nonmetal mines and to examine the precision of the National Institute for Occupational Safety and Health (NIOSH) 5040 sampling and analytical method for diesel exhaust that has recently been adopted for compliance monitoring by the Mine Safety and Health Administration (MSHA). Approximately 1000 air samples using cyclones were taken on workers and in areas throughout the mines. Results indicated that worker exposures were consistently above the MSHA final limit of 160 micrograms/m3 (time-weighted average; TWA) for total carbon as determined by the NIOSH 5040 method and greater than the proposed American Conference of Governmental Industrial Hygienists TLV limit of 20 micrograms/m3 (TWA) for elemental carbon. A number of difficulties were documented when sampling for diesel exhaust using organic carbon: high and variable blank values from filters, a high variability (+/- 20%) from duplicate punches from the same sampling filter, a consistent positive interference (+26%) when open-faced monitors were sampled side-by-side with cyclones, poor correlation (r 2 = 0.38) to elemental carbon levels, and an interference from limestone that could not be adequately corrected by acid-washing of filters. The sampling and analytical precision (relative standard deviation) was approximately 11% for elemental carbon, 17% for organic carbon, and 11% for total carbon. An hypothesis is presented and supported with data that gaseous organic carbon constituents of diesel exhaust adsorb onto not only the submicron elemental carbon particles found in diesel exhaust, but also mining ore dusts. Such mining dusts are mostly nonrespirable and should not be considered equivalent to submicron diesel particulates in their potential for adverse pulmonary effects. It is recommended that size-selective sampling be employed, rather than open-faced monitoring, when using the NIOSH 5040 method.

Inhibition of esterolysis of enalapril by paraoxon increases the urinary clearance in isolated perfused rat kidney.

The effect of competing elimination pathways on the metabolic and excretory clearance estimates was examined with tracer concentrations of [(3)H]enalapril, which was both metabolized and excreted by the rat kidney. Perturbation was achieved with use of the carboxylesterase inhibitor paraoxon, which inhibited [(3)H]enalapril metabolism to [(3)H]enalaprilat in rat renal S9 fraction. At 0.1, 0.5, 1, and 10 microM paraoxon, esterolysis of enalapril was inhibited by 76 +/- 7, 93 +/- 5, 96 +/- 5, and 93 +/- 6%, respectively. The lowest concentration (0.1 microM) of paraoxon was chosen for single-pass isolated perfused kidney (IPK) studies because viability was least compromised, and the sodium and glucose reabsorptive functions of the IPK remained constant. After an equilibration period (15-20 min at constant pressure, 90-100 mm Hg), perfusion of the rat kidney with [(3)H]enalapril was carried out under constant flow (8 ml/min) for 30 min in the absence and presence of paraoxon (0.1 microM). The metabolic (from 1.83 +/- 0.52 to 1.48 +/- 0.47 ml/min/g) and total renal (from 1.87 +/- 0.46 to 1. 57 +/- 0.41 ml/min/g) clearances of [(3)H]enalapril in the IPKs were decreased significantly (p <.05) in the presence of paraoxon when compared with controls. Concomitantly, the urinary clearance (from 0. 04 +/- 0.07 to 0.09 +/- 0.09 ml/min/g) and the fractional excretion (from 0.23 +/- 0.18 to 0.52 +/- 0.25) of [(3)H]enalapril doubled (p <.05). The study illustrates that a reduction in cellular metabolism of the kidney brings forth a rise in the estimate of clearance of its complimentary pathway, estimate of the excretory (urinary) clearance.

Intracellular and not intraluminal esterolysis of enalapril in kidney. Studies with the single pass perfused nonfiltering rat kidney.

Two possible sites of renal metabolism exist: intracellular, by enzymes within the peritubular cells, and intraluminal, by ecto-enzymes embedded on the brush border membrane. The esterolysis of enalapril to its dicarboxylate metabolite, enalaprilat, was studied in the isolated perfused, nonfiltering rat kidney preparation (NFK) and compared with that observed for the isolated perfused rat kidney (IPK) to ascertain the site of metabolic conversion. For the NFK, filtration was obliterated with the high oncotic pressure (8% bovine serum albumin in plasma) and ligation of the ureter, thus preventing enalapril from reaching intraluminal sites by filtration. The steady-state renal plasma clearance of enalapril in the NFK was 2.0 ml/min/g, a value similar to that (2.1 ml/min/g) observed previously for the IPK. The rate of appearance of enalaprilat, the metabolite, in venous plasma for the NFK (30 +/- 3% of the input rate of enalapril) was also comparable with that for the IPK (27 +/- 4%). Further, identification of the site of enalapril metabolism (cellular or luminal) was aided by simulations based on physiological models and parameters obtained previously on the renal handling of enalapril and enalaprilat. These parameters were optimized to match closely the experimental observations. The predicted total and metabolic renal clearances for the IPK or for the NFK were similar for both the "cellular model" and "luminal model": in both instances, values for the NFK were 59-65% of those for the IPK. By contrast, predictions for the venous output rate of enalaprilat (as a percent of the input rate of enalapril) were different: the "cellular model" predicted no change in value between the NFK and the IPK, whereas metabolite appearance was greatly magnified for the NFK (289% that of the IPK) with luminal metabolism. The lack of difference in venous outflow of enalaprilat for the NFK and IPK was more congruent with the notion of intracellular and not intraluminal esterolysis of enalapril.

Organ clearance concepts: new perspectives on old principles.

The removal capacity of an eliminating organ by metabolism and/or excretion is often expressed as its clearance. Metabolic and excretory clearances are considered to be mutually independent, and the sum of these constitute the whole organ clearance. The influence of metabolism on estimates of the excretory clearance and vice versa was examined for the liver and kidney with physiologically based models. Mass transfer first-order rate equations describing transport and removal were derived. Upon inversion of the matrices originating from the coefficients of these equations, the area under the curve (AUC) and clearance (dose/AUC) were obtained with the liver or kidney as the eliminating organ. A more complex solution was found to exist for the kidney since glomerular filtration, secretion; reabsorption, and intrarenal metabolism were present. To ascertain the effect of excretion on estimates of the metabolic clearance as well as the effect of metabolism on estimates of the excretory clearance, intrinsic clearances for excretion or metabolism were set to zero. Clearance values were found to be altered when alternate pathways were present. Whereas excretory clearance estimates were consistently reduced in the presence of metabolism, metabolic clearance estimates were affected differentially by excretion and varied according to the site of metabolism. Excretion reduced metabolic clearance estimates when metabolism occurred intracellularly. If metabolism occurred intraluminally (e.g., on the renal brush border or luminal membrane), the metabolic clearance estimate could become higher since the substrate was made available to the enzymes following its excretion. As expected, these changes depended on the relative magnitudes of the intrinsic clearances for metabolism and excretion. The above theory was applied to the elimination of enalapril which is both metabolized and excreted by the perfused rat liver and kidney preparations. Data obtained in these studies were consistent with a set of published physiologic parameters denoting transfer and intrinsic clearances. Perturbations on clearance estimates were studied by setting the metabolic/excretory intrinsic clearance to zero, then to some finite value. In liver, the avid hepatocellular metabolism of enalapril reduced biliary clearance by 73%. For the kidney, the fractional excretion (FE or unbound excretory clearance/glomerular filtration rate) was decreased modestly (from 0.64 to 0.44) with intracellular esterolysis, whereas if metabolism had occurred intraluminally, FE would have been significantly decreased (from 1.8 to 0.45). Simulation results show clearly that clearance estimates are affected by the presence of alternate removal pathways, and question the well-established principle the metabolic and excretory clearance estimates are independent of each other.