The relationship between HbA1c and fasting plasma glucose in patients with increased plasma liver enzyme measurements.

BACKGROUND: HbA(1c) is currently being introduced for diagnostic purpose in diabetes. Previous studies have, however, indicated that patients with liver disease have false low HbA(1c) levels. We therefore investigated the correlation between HbA(1c) and plasma glucose in patients with different levels of increased liver enzyme concentrations. METHODS: Data from 10,065 patients with simultaneous measurement of HbA(1c), venous fasting plasma glucose, alanine aminotransferase and γ-glutamyl transferase were extracted from our laboratory database. Correlations were investigated in four patient groups divided according to their liver enzyme concentrations. RESULTS: The correlation between HbA(1c) and plasma glucose was high in all groups, with r = 0.77 for men and r = 0.78 for women (P < 0.001), a correlation confirmed with multiple regression analysis (P < 0.001). However, interaction analysis revealed that linear regression lines were significantly different for men and women, with increase of both liver enzyme measurements and also, for women, with increased alanine aminotransferase. When compared with biological variation for HbA(1c), only men with increased measurements of both liver enzymes had a clinically important decrease in HbA(1c). CONCLUSIONS: Increased liver enzyme concentrations do not bias the correlation between HbA(1c) and fasting plasma glucose. However, men with low plasma glucose and increased concentrations of both liver enzymes do have a slightly decreased HbA(1c) and, if the clinical suspicion is strong enough, one should consider supplement testing.

Adenosine 3'5'-monophosphate phosphodiesterase: multiple molecular forms.

By starch-gel electrophoresis and a specific staining technique, seven different molecular forms of cyclic nucleotide phosphodiesterase have been demonstrated in supernatants from homogenates of rat and rabbit tissues. No tissue contains more than four components, but there are distinct differences in component patterns among the various tissues. Tentative molecular weights of the three most prevalent components of rat tissues have been estimated at 135,000, 150,000, and 167,000 by sucrose density gradient centrifugation.

Evolving subduction zones in the Western United States, as interpreted from igneous rocks.

Variations in the ratio of K(2)O to SiO(2) in andesitic rocks suggest early and middle Cenozoic subduction beneath the western United States along two subparallel imbricate zones dipping about 20 degrees eastward. The western zone emerged at the continental margin, but the eastern zone was entirely beneath the continental plate. Mesozoic subduction apparently occurred along a single steeper zone.

Meteoric water in magmas.

Oxygen isotope analyses of sanidine phenocrysts from rhyolitic sequences in Nevada, Colorado, and the Yellowstone Plateau volcanic field show that delta(18)O decreased in these magmas as a function of time. This decrease in delta(18)O may have been caused by isotopic exchange between the magma and groundwater low in (18)O. For the Yellowstone Plateau rhyolites, 7000 cubic kilometers of magma could decrease in delta(18)O by 2 per mil in 600,000 years by reacting with water equivalent to 3 millimeters of precipitation per year, which is only 0.3 percent of the present annual precipitation in this region. The possibility of reaction between large magmatic bodies and meteoric water at liquidus temperatures has major implications in the possible differentiation history of the magma and in the generation of ore deposits.

Magma Beneath Yellowstone National park.

The Yellowstone plateau volcanic field is less than 2 million years old, lies in a region of intense tectonic and hydrothermal activity, and probably has the potential for further volcanic activity. The youngest of three volcanic cycles in the field climaxed 600,000 years ago with a voluminous ashflow eruption and the collapse of two contiguous cauldron blocks. Doming 150,000 years ago, followed by voluminous rhyolitic extrusions as recently as 70,000 years ago, and high convective heat flow at present indicate that the latest phase of volcanism may represent a new magmatic insurgence. These observations, coupled with (i) localized postglacial arcuate faulting beyond the northeast margin of the Yellowstone caldera, (ii) a major gravity low with steep bounding gradients and an amplitude regionally atypical for the elevation of the plateau, (iii) an aeromagnetic low reflecting extensive hydrothermal alteration and possibly indicating the presence of shallow material above its Curie temperature, (iv) only minor shallow seismicity within the caldera (in contrast to a high level of activity in some areas immediately outside), (v) attenuation and change of character of seismic waves crossing the caldera area, and (vi) a strong azimuthal pattern of teleseismic P-wave delays, strongly suggest that a body composed at least partly of magma underlies the region of the rhyolite plateau, including the Tertiary volcanics immediately to its northeast. The Yellowstone field represents the active end of a system of similar volcanic foci that has migrated progressively northeastward for 15 million years along the trace of the eastern Snake River Plain (8). Regional aeromagnetic patterns suggest that this course was guided by the structure of the Precambrian basement. If, as suggested by several investigators (24), the Yellowstone magma body marks a contemporary deep mantle plume, this plume, in its motion relative to the North American plate, would appear to be "navigating" along a fundamental structure in the relatively shallow and brittle lithosphere overhead. The concept that a northeastwardpropagating major crustal fracture controls the migration path of the major foci of volcanisim is at least equally favored by existing data, as Smith et al. (19) noted.

Randomized clinical trial of root-end resection followed by root-end filling with mineral trioxide aggregate or smoothing of the orthograde gutta-percha root filling--1-year follow-up.

AIM: To compare healing after root-end resection with a root-end filling of mineral trioxide aggregate (MTA) or smoothing of the orthograde gutta-percha (GP) root filling. METHODOLOGY: Forty-four patients (consisting of 52 teeth with periapical infection), average age of 54.6 years (range 30-77) participated in a randomized clinical trial (RCT) comparing the MTA and GP treatment methods. Radiographs produced 1-week and 12 months post-operatively were compared after blinding for treatment method, and healing was assessed as complete, incomplete, uncertain, or unsatisfactory. RESULTS: Six teeth were not available for the 12-month follow-up: three teeth (GP) had been re-operated because of pain and two teeth (one GP, one MTA) had been extracted because of root fracture (these five teeth were classified as failures). One patient (GP) was not available for recall. In the GP group, seven teeth (28%) showed complete healing, six teeth (24%) incomplete healing, six teeth (24%) uncertain healing and two teeth (8%) unsatisfactory healing after 1 year. In the MTA group, 22 teeth (85%) showed complete healing, three teeth (12%) incomplete healing, and none were scored as uncertain or unsatisfactory healing after 1 year. The difference in healing between the GP and the MTA groups was significant (P < 0.001). CONCLUSIONS: The results from this RCT emphasize the importance of placing a root-end filling after root-end resection. Teeth treated with MTA had significantly better healing (96%) than teeth treated by smoothing of the orthograde GP root filling only (52%).

Studies on the mechanism of the inhibitory effects of erucylcarnitine in rat heart mitochondria.

1. The mechanism of the inhibitory effect of erucylcarnitine on palmityl-carnitine oxidation in rat heart mitochondria was studied. 2. Erucylcarnitine inhibited in the same time the oxidation of [U-14-C]-palmitylcarnitine and the total rate of oxygen uptake. Other acylcarnitines competed as well for the oxidation with radioactive palmitylcarnitine, but they were well oxidized themselves, so that the total oxygen uptake did not decrease. 3. The presence of erucylcarnitine did not change the distribution pattern of Krebs cycle intermediates derived from [U-minus 14 C] palmitylcarnitine except that succinate/malate ratio increased. 4. The presence of erucylcarnitine did not lead to the formation of any beta-oxidation cycle intermediates from [U-minus 14 C] palymitylcarnitine. The formation of beta-hydroxy-palmityl derivative when rotenon was included into the incubation medium, decreased in the presence of erucylcarnitine. 5. It is postulated, that the inhibited entrance of palmityl groups into the beta-oxidation cycle is due to the fact that erucylcarnitine and palmitylcarnitine behave as substrate-competitive inhibitors for long chain acyl-CoA dehydrogenase. 6. There was observed a latency of 1-2 min in the effect of erucylcarnitine on the palmitylcarnitine oxidation, which seems to correspond to the time required for the formation of high amounts of intramitochondrial erucyl-CoA. 7. Erucylcarnitine inhibited the total oxygen uptake with long, medium and short chain acylcarnitines, pyruvate and alpha-ketoglutarate as substrates, while the oxidation of succinate was not affected. 8. Sequestration of free CoA in the form of very slowly metabolized erucyl-CoA is proposed as the partial explanation of the observed inhibitory effects of erucylcarnitine on the oxidation of CoA-dependent substrates (alternatively to the inhibition at the level of acyl-CoA dehydrogenases in case of acylcarnitines).

Active transport of butyrobetaine and carnitine into isolated liver cells.

1. The liver cells lose the major part of their carnitine during the commonly used isolation procedure by the collagenase-perfusion method. 2. The cells take up carnitine and the carnitine precursor butyrobetaine when these substances are added to the medium. The carnitine content of isolated liver cells can increase to about 15 mM with no apparent harm to the cells. 3. The data indicate the existence of a common carrier in the plasma membrane which mediates the uphill transport of both carnitine and butyrobetaine. The carrier has a high affinity for butyrobetaine (Km=0.5 mM) and a lower one for carnitine (Km=5.6 mM). 4. The intracellular butyrobetaine is hydroxylated to carnitine with a rate of approximately 0.33 mumol-g wet weight-1-h-1 which is sufficient to cover the turn over of carnitine in the whole rat. Carnitine is effectively esterified in the liver cells to acetylcarnitine and long-chain acylcarnitines. 5. Both carnitine and acetylcarnitine are released from the cells. The release of both compounds is probably physiological since it was found that acetylcarnitine constitutes a similar fraction of the total acid soluble carnitine both in the blood and liver of the intact rat.

Monoethlenic C20 and C22 fatty acids in marine oil and rapeseed oil. Studies on their oxidation and on their relative ability to inhibit palmitate oxidation in heart and liver mitochondria.

1. Carnitine esters of erucic acid (22:1 n-9 cis), cetoleic acid (22:1 n-11 cis), brassidic acid (22:1 n-9 trans), gadoleic acid (20:1 n-9 cis) and oleic acid (18:1 n-9 cis) have been compared as mitochondrial substrates and as inhibitors of palmitoylcarnitine oxidation in heart and liver mitochondria. 2. Both the rate of intramitochondrial-CoA acylation and the rate of beta-oxidation decreases as the chain length increases from C18 to C22. There are no significant differences among the three C22 isomers as oxidizable substrates. 3. All the tested acylcarnitines inhibit palmitoylcarnitine oxidation. The C18 and C20 acylcarnitines inhibit by virtue of being competing substrates; i.e. the respiration is not inhibited. The C22-isomers inhibit also respiration; this shows that the inhibition of palmitolycarnitine oxidation is not compensated for by oxidation of C22-acylcarnitines. Brassidoylcarnitine inhibits the oxidation of palmitoylcarnitine and respiration less than erucoyl-and cetoleoylcarnitine. The different behaviour of the C22-isomers is probably due to the difference in their competitive properties with respect to long-chain acyl-CoA dehydrogenase. 4. All C22 acylcarnitines seem to be relatively better oxidized in the liver than in the heart mitochondria while their inhibitory effect on the usage of the radioactive palmitoylcarnitine is very similar. 5. Palmitoylcarnitine inhibits almost completely the "endogenous" formation of acetyl-CoA presumably from malate via pyruvate in the liver mitochondria while the C22-acylcarnitines cause only a partial inhibiton of this acetyl-CaO formation.

The stimulation of erucate metabolism in isolated rat hepatocytes by rapeseed oil and hydrogenated marine oil-containing diets.

1. The metabolism of palmitate and especially of erucate was studied in hepatocytes isolated from rats fed for 3 weeks a diet containing peanut oil (diet, 1), rapeseed oil (diet 2) and partially hydrogenated marine oil (diet 3). 2. The metabolism of palmitate was not significantly influenced by the diet. The rapeseed oil diet caused 1.4 fold and 1.3 fold increase and marine oil diet 3 fold and 2.2 fold increase in the oxidation and chain-shortening respectively of [14-14C]erucic acid in isolated hepatocytes. 3. Cyanide and antimycin A did not inhibit the chain-shortening of erucate in liver cells of rats fed rapeseed oil and peanut oil. The high capacity of the chain-shortening system in hepatocytes of marine oil-fed rats was partially inhibited. 4. Inhibition of the transfer of fatty acids into the mitochondria by lowering the intracellular carnitine concentration and/or by addition of (+)-decanoyl-carnitine resulted in a very pronounced apparent stimulation of the chain-shortening of erucic acid. It is suggested that the chain-shortening system may be virtually independent of the mitochondria, unless the availability of the extramitochondria NAD+ and/or NADP+ is rate-limiting under conditions of extremely low redox potential of the mitochondria. 5. Feeding marine oil or rapeseed oil to the rats induced a 30% increase in catalase activity, a 25--30% increase in urate oxidase activity and a 50% increase in the total CoA in the liver compared to rats fed peanut oil. 6. It is suggested that the increased metabolism of erucate in hepatocytes of marine oil and rapeseed oil-fed rats may be due to the increase in ther peroxisomal beta-oxidation.

Selection in complex genetic systems III. An effect of allele multiplicity with two loci.

A two-locus model with three alleles at one locus and two at the other is studied. The viability system is such that all double heterozygotes have fitness unity, all single heterozygotes have fitness w smaller than 1 and all double homozygotes have fitness w-2. The following are the major findings: 1. There are more stable equilibria for tight linkage than in the corresponding three-locus model, even though the number of chromosomes is lower. 2. The equilibria stable for tight linkage do not belong to a unique high complementarity class, as is the case for two alleles at each locus. Instead the strength of selection determines the structure of the equilibrium. 3. The increase in number of alleles seems to reduce the possible extent of association between the loci. 4. The measure of this association is not well defined, although we have suggested a statistically standard way of getting over this. 5. A mutation introduced while a population is in linkage disequilibrium may, per medium only of the change in number of alleles, destroy the linkage disequilibrium.

Focal sclerosing glomerulopathy with adverse effects during pregnancy.

Exacerbation of focal sclerosing glomerulopathy (FSGN) during pregnancy was noted in the three patients. All had antecedent asymptomatic proteinuria. Toxemia developed in two of the women during pregnancy and progressed rapidly to renal failure. Severe nephrotic syndrome developed in one patient with pregnancy and remitted after delivery. These cases suggest a deleterious effect of pregnancy on the course of FSGN and indicate the necessity for doing renal biopsy in women of childbearing age with asymptomatic fixed proteinuria or nephrotic syndrome so that those patients with FSGN can be properly counseled about future pregnancies.

Isolation, synthesis, and biological activity of five metabolites of danazol.

Metabolites of danazol (17 alpha-pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol), an orally effective pituitary gonadotropin inhibitory agent devoid of estrogenic and progestational activites, were isolated from urine of a female subject who had taken danzol orally at a dose of 800 mg/day for 7 days, The metabolites isolated were 17-hydroxy-17alpha-pregn-4-en-20-yn-3-one (11), 17-hydroxy-2alpha-(hydroxymethyl)-17alpha-pregn-4-3n-20-yn-3-one (5), 17-hydroxy-2-(hydroxymethyl)-17alpha-pregna-1,4-dien-20-yn-3-one(7), 6beta,17-dihydroxy-2alpha-(hydroxymethyl)-17alphapregn-4-en-20-yn-3-one(8), and 6beta, 17-dihydroxy-2(hydroxymethyl)-17alphapregna-1,4-dien-20yn-3-one(10). None of these metabolites exhibited pituitary inhibiting activity comparable to danazol.

PIP: Urinary metabolites of danazol (17alpha-pregna-2,4-dien-20-yno (2,3-delta)isoxazol-17-01), and inhibitor of pituitary gonadotropins, were isolated from a woman who had been taking the drug orally at a dose of 800 mg/day for 7 days. The isolated metabolites were 17-hydroxy-17alpha-pregn-4-en-20-yn-3-one, 17-hydroxy-2alpha-(hydroxymethyl)-17alpha-pregn-4-en-20-yn-3-one, 47-hydroxy-2-(hydroxymethyl)-17alpha-pregna-1,4-dien-20-yn-3-one, 6beta,17-dihydroxy-2alpha-(hydroxymethyl)-17alpha-pregn-4-en-20-yn-3-one and 6beta,17-dihydroxy-2-(hydroxymethyl)-17alpha-pregna-1,4-dien-20-yn-3-one. The pituitary inhibiting activity of these metabolites was less than that of danazol.

Steroidogenesis inhibitors. 1. Adrenal inhibitory and interceptive activity of trilostane and related compounds.

Several methylated derivatives of trilostane were prepared. Methylation of C-4 or C-4 and C-17 changes this relatively selective adrenal inhibitor to compounds with increased ovarian/placental inhibitory activity with decreased adrenal inhibitory activity.

Androgen receptor affinity of 5'-acyl furanosteroids.

Syntheses of 5'-acyl furanosteroids are described from the corresponding unsubstituted [3,2-b]furanosteroids using acid anhydrides and acid chlorides in the presence or absence of Lewis acids. New methods have been developed to prepare 5'-acetyl derivatives: reduction of a 5'-trichloroacetyl intermediate either by sodium formaldehyde sulfoxylate or with 10% Pd/C. Most of these 5'-acyl derivatives bind to the rat ventral prostate androgen receptor. However the antiandrogenic activity was diminished when compared with 4,5'-methylsulfonyl furanosteroid. Biological studies revealed that 5'-acyl furanosteroids were either androgens or modest antiandrogens. The electrostatic potential maps of the substructures of 3, 4, and 5'-acetyl syn- and anti-furanosteroids showed striking differences which may explain, to some extent, the lack of significant antiandrogenic activity of 5'-acyl furanosteroids.

Antiandrogenic steroidal sulfonylpyrazoles.

The steroidal sulfonylpyrazole 1 bound to the rat ventral prostate androgen receptor in vitro; it inhibited testosterone propionate induced increases in ventral prostate weight in vivo in the castrated, immature male rat with an ED50 of 15 mg/kg po. Compound 1 lacked androgenic activity in vivo in contrast to the parent steroidal pyrazole 5, which was both androgenic and antiandrogenic. The 2'- and 5'-methylsulfonyl isomers 6 and 6a did not bind to the androgen receptor. Introduction of an alkylsulfonyl at the N-1'-position has served, therefore, to isolate the intrinsic antiandrogenic properties of the steroidal heterocycle free of apparent hormone agonist properties. Structure-activity relationship studies revealed that a methylsulfonyl group at N-1' together with a C-17 alpha-substituent were the optimal combination for in vitro androgen receptor binding, in vivo antiandrogenic potency, and a lack of androgenic activity.

The field integrated dose modification (FIDM): three typical clinical applications of a new irradiation technique.

In addition to an earlier developed "compensator integrated modification technique", a method is derived which uses as basic principle the "field integrated dose modification" (FIDM) without need for computer tomographic data. The method enables the radiotherapist to introduce one or more volumes within which doses can be delivered which are different from the one in the main irradiation volume. The steps of practical preparation and clinical application are described in detail. The radiobiological aspects of FIDM, especially those in case of acceleration and hyperfractionation, are elucidated by discussing three typical examples.

The acute vasculitis of Wegener's granulomatosis in renal biopsies.

The kidney biopsy specimens from five patients with Wegener's Granulomatosis were reviewed in an attempt to characterize the early histological lesion when vasculitis was present. The vascular lesions were found mainly in interlobular-sized arteries. The acute vascular lesions were sparse and focal, mainly localized to the intimal area, and with fibrinoid material and platelets constituting the early infiltrate. The electron microscopy and scanning electron microscopy of the involved areas further emphasized the presence of platelets in the early lesion, and accentuated endothelial alterations occurring along with the intimal infiltrate. Morphologic evidence of immune complex presence was not found.

Tonometric measurement of dental pulpal and mandibular marrow blood pressures.

Dental pulpal and mandibular marrow vascular pressures were studied with a tonometric method under conditions of autoperfusion and step flow controlled perfusion. The tonometric pulpal and marrow pressures averaged 17 +/- 5 mm Hg and 20 +/- 6 mm Hg, respectively. The venous end pressure was 16 +/- 8 mm Hg at a perfusion pressure of 156 +/- 28 mm Hg. The tonometric pulpal pressures were lower and were less variable than the comparable canulation pulpal pressures.