Pharmacokinetic study of the oral administration of procaterol hydrochloride hydrate 50 µg in healthy adult Japanese men.

BACKGROUND: The pharmacokinetics of procaterol, a selective beta2-adrenergic agonist with a high intrinsic efficacy in man, could not be determined in humans when the drug was launched because of the low therapeutic dose and the low sensitivity of the analytical methods available at the time. However, a recently established analytical method using LC-MS/MS has been refined to enable the determination of the pharmacokinetic profile of procaterol and its metabolites in humans. METHODS: Procaterol hydrochloride hydrate 50 µg was administered orally to 8 healthy adult Japanese men. Plasma and urine samples collected from the subjects were analyzed by use of LC-MS/MS for procaterol and its metabolites. RESULTS: Following the oral administration of procaterol hydrochloride hydrate 50 µg, the plasma concentration of procaterol reached a Cmax of 136.4 pg/ml at ~1.44 h post-dose. The mean apparent terminal elimination half-life was ~3.83 h. DM-251 and DM-252, glucuronides of the optical isomers of procaterol, were the main metabolites and both were present in plasma at higher levels than procaterol in the plasma. The 24 h urinary excretion rates of unchanged procaterol, DM-251 and DM-252 were 15.7%, 12.4% and 11.2% of the procaterol administered, respectively. CONCLUSION: This study describes the pharmacokinetic profiles of procaterol and its metabolites following the oral administration of procaterol hydrochloride hydrate 50 µg. Procaterol and its glucuronides were found at high levels in the plasma and urine.

The clinical significance of serum procalcitonin levels following direct hemoperfusion with polymyxin B-immobilized fiber column in septic patients with colorectal perforation.

BACKGROUND: The efficacy of direct hemoperfusion with polymyxin B-immobilized fiber columns (PMX) has already been demonstrated in clinical studies for the treatment of septic shock. However, serum procalcitonin levels following PMX remain unknown. METHODS: This prospective, multicenter, nonrandomized clinical study was performed at 12 institutions. Forty-five patients with severe sepsis or septic shock due to colorectal perforation underwent PMX. Patients' outcome as well as circulating levels of endotoxin, procalcitonin and IL-6 were monitored. RESULTS: Before surgery, procalcitonin level, but not endotoxin and IL-6 levels, was elevated according to patients' septic conditions. Procalcitonin was significantly and positively correlated with sequential organ failure assessment score. Circulating levels of procalcitonin peaked 24 h after PMX treatment. Change in serum procalcitonin level was significantly higher in nonsurvivors than survivors. Nine mortalities were observed within 28 days. The best predictor for 28-day mortality was procalcitonin >85.7 ng/ml at 24 h after PMX (area under the receiver operating characteristic curve: 0.808 +/- 0.105). CONCLUSIONS: Procalcitonin may be a good indicator of severity of sepsis secondary to colorectal perforation. Furthermore, procalcitonin level at 24 h after PMX appears to predict outcome after PMX. Therefore, procalcitonin may be a useful diagnostic marker to evaluate patients' condition in candidates for PMX treatment.

[Coagulation and fibrinolysis system in pediatric cardiopulmonary bypass].

Coagulation and fibrinolysis system was evaluated during and after pediatric cardiopulmonary bypass (CPB. Twenty-two atrial septal defect (ASD) patients were surgically repaired under CPB and aortic cross-clamp through right thoracotomy. Drainage was established by gravity, CPB flow was kept 2.4 l/min/m2 and ACT was controlled over 400 seconds. HCT, PLT, fibrinogen, AT-III, D-dimer, thrombin-antithrombin complex (TAT), alpha2 plasmin inhibitor-plasmin complex (PIC), and plasminogen activator inhibitor (PAI-1) were measured at 6 points [after induction of anesthesia, 10 minutes after initiating CPB, end of CPB, on the entrance of intensive care unit (ICU), postoperative day (POD) 1, and at outpatient division]. Both fibrinogen and AT-III showed low values during CPB (121.9 +/- 22.0 mg/dl, 57.6 +/- 10.6%). D-dimer increased at 1 week postoperatively in all patients (5.57 +/- 3.45 microg/ml). There were significantly positive correlations between CPB duration and TAT value at the end of CPB (r = 0.88, p < 0.01), on the entrance of ICU (r = 0.71, p < 0.01). There was also a positive correlation between CPB duration and PIC value on the entrance of ICU (r = 0.53, p < 0.01). Five patients showed high PAI-1 value on the entrance of ICU, which remained high in 2 of them on POD 1. The outcomes from the current study suggest that there is a potential of coagulation-dominant disseminated intravascular coagulation (DIC) during pediatric CPB even in ASD patients who do not need long CPB. Longer CPB and severe hemodilution might become risk factors.

In vitro metabolism of 2,2',3,4',5,5',6-heptachlorobiphenyl (CB187) by liver microsomes from rats, hamsters and guinea pigs.

The metabolism of 2,2',3,4',5,5',6-heptachlorobiphenyl (heptaCB) (CB187) was studied using liver microsomes of rats, hamsters and guinea pigs, and the effect of cytochrome P450 (CYP) inducers, phenobarbital (PB) and 3-methylcholanthrene (MC), was also investigated. In untreated animals, guinea pig liver microsomes formed three metabolites which were deduced to be 4'-hydroxy-2,2',3,5,5',6-hexachlorobiphenyl (M-1), 4'-hydroxy-2,2',3,3',5,5',6-heptaCB (M-2) and 4-OH-CB187 (M-3) from the comparison of GC/MS data with some synthetic authentic samples. The formation rate of M-1, M-2 and M-3 was 18.1, 36.6, 14.7 pmol h-1 mg protein-1, respectively. Liver microsomes of untreated rats and hamsters did not form CB187 metabolites. In guinea pigs, PB-treatment increased M-1 and M-2 significantly to 1.9- and 3.4-fold of untreated animals but did not affect the formation of M-3. In rats, PB-treatment resulted in the appearance of M-2 and M-3 with formation rates of 87.1 and 13.7 pmol h-1 mg protein-1, respectively, but M-1 was not observed. In hamsters, PB-treatment formed only M-2 at a rate of 29.4 pmol h-1 mg protein-1. On the other hand, MC-treatment of guinea pigs decreased the formation of M-1 and M-2 to less than 50% of untreated animals. MC-microsomes of rats and hamsters produced no metabolites. Preincubation of antiserum (300 microl) against guinea pig CYP2B18 with liver microsomes of PB-treated guinea pigs produced 80% inhibition of M-1 and the complete inhibition of M-2 and M-3. These results suggest that PB-inducible CYP forms, especially guinea pig CYP2B18, rat CYP2B1 and hamster CYP2B, are important in CB187 metabolism and that CB187 metabolism in guinea pigs may proceed via the formation of 3,4- or 3',4'-oxide and subsequent NIH-shift or dechlorination.

A specific COX-2 inhibitor attenuates cell infiltration but does not prolong graft survival in murine cardiac transplantation.

COX-2 is a key factor in the progression of inflammation, the effects of a specific COX-2 inhibitor in cardiac transplantation have not yet been elucidated. To test the hypothesis that a COX-2 inhibitor can alter cardiac rejection, we analyzed graft survival using totally allomismatched grafts. Although the COX-2 inhibitor attenuated myocardial cell infiltration, the inhibitor did not prolong survival. We conclude that the COX-2 inhibition may have potential for the suppression of inflammation in cardiac allografts.

Species differences in the tissue distribution of catechol and methylsulphonyl metabolites of 2,4,5,2',5'-penta- and 2,3,4,2',3',6'-hexachlorobiphenyls in rats, mice, hamsters and guinea pigs.

Polychlorinated biphenyls (PCBs) are metabolized to phenolic or methylsulphonyl PCBs (MeSO(2)-CBs) in animal species. The study determined the species differences in the tissue distribution of persistent PCB metabolites in rats, mice, hamsters and guinea pigs 4 days after exposure to 2,4,5,2('),5(')-pentachlorobiphenyl (CB101) or 2,3,4,2('),3('),6(')-hexachlorobiphenyl (CB132). For CB101 metabolism, the hydroxylation in rats, mice and hamsters occurred primarily at the 3(')-position in the 2('),5(')-dichlorinated phenyl ring, whereas the hydroxylation in guinea pigs occurred preferentially at the 3-position. Metabolite profiles in tissues of hamsters were dominated by 3('),4(')-catechol-CB101, whereas metabolite profiles in rats and mice were dominated by 3(')- or 4(')-MeSO(2)-CBs. For CB132 metabolism, rats and mice produced 4(')- and 5(')-MeSO(2)-CBs at similar concentration ratios, whereas guinea pigs produced MeSO(2)-CBs at higher levels and selectively retained 5(')-MeSO(2)-CB in liver. In contrast, hamsters preferentially produced 4('),5(')-catechol-CB132 that was retained in serum. Consequently, hamsters produced catechols, whereas guinea pigs produced meta-substituted MeSO(2)-CBs, preferentially from CB132. These findings indicate that PCBs with 2,3,6-chlorine substitution are preferred substrates for the formation of catechols or MeSO(2)-CBs and the differences in metabolite profiles are related to species-dependent metabolic capacities.

Metabolite of 2,2',4',5-tetrabromobiphenyl, 3-methylsulphonyl-2,2',4',5-tetrabromobiphenyl, a potent inducer of CYP2B1/2 in rat.

1. 3-Methylsulphonyl- and 4-methylsulphonyl-2,2',4',5-tetrabromobiphenyls (3-MeSO(2)- and 4-MeSO(2)-TetraBrBs) were detected in the liver, lung, kidney, adipose tissue and faeces of the 2,2',4',5-tetrabromobiphenyl (TetraBrB)-dosed rat. 2. The administration of 0.05-2.0 micromol kg(-1) doses of 3-MeSO(2)-TetraBrB produced corrresponding increases in the hepatic concentration of the methyl sulphone metabolite, corresponding increases in the content of total cytochrome P450, and corresponding increases in the activities of 7-benzyloxy-, 7-ethoxy- and 7-pentoxyresorufin O-dealkylases. The inducing effects of the 3-MeSO(2)-TetraBrB (0.2 micromol kg(-1)), both on the content of total P450 and on the activities of the three alkoxyresorufin O-dealkylases, were higher than that of the parent TetraBrB (342 micromol kg(-1)). 3. The major phenobarbital (PB)-inducible forms of P450, CYP2B1, CYP2B2, CYP3A2 and CYP2C6, were substantially induced by 3-MeSO(2)-TetraBrB, but CYP1A1 and CYP1A2 were not. On the other hand, the activities of drug-metabolizing enzymes and the four PB-inducible forms of P450 were unchanged by 4-MeSO(2)-TetraBrB treatment. 4. The induction profiles of these enzymes and P450 forms in rat treated with 3-MeSO(2)-TetraBrB were similar to those treated with PB. 5. The inducing ability of 3-MeSO(2)-TetraBrB (0.5 micromol kg(-1)) both on the activities of the three alkoxyresorufin O-dealkylases and on the contents of four PB-inducible forms of P450 was roughly equal to that of PB (431 micromol kg(-1) twice at a 24-h interval) or 3-MeSO(2)-2,2',4',5-tetrachlorobiphenyl (1 micromol kg(-1)). It is noteworthy that the effects of 3-MeSO(2)-TetraBrB on the drug-metabolizing enzymes CYP2B1 and CYP2B2 were several thousand-fold higher than those of parent TetraBrB, while the effect of its isomeric 4-MeSO(2)-TetraBrB were not. 6. The extent of hepatic accumulation of the 3-MeSO(2) metabolite after the administration of TetraBrB (342 micromol kg(-1)) was almost the same as that after the administration of 3-MeSO(2)-TetraBrB (0.1-0.2 micromol kg(-1)). The relationship between the hepatic concentration of the 3-MeSO(2) metabolite and the extent of enzyme induction after the administration of TetraBrB or 3-MeSO(2)-TetraBrB suggests that 3-MeSO(2)-TetraBrB plays an important role in the induction of microsomal drug-metabolizing enzymes by TetraBrB.

Effects of low-density lipoprotein apheresis on coronary and carotid atherosclerosis and diabetic scleredema in patients with severe hypercholesterolemia.

Correlations between serum cholesterol levels and progression of coronary and peripheral atherosclerosis have been found in many recent studies. It has also been demonstrated that aggressive cholesterol-lowering therapy with low-density lipoprotein (LDL) apheresis, a method of LDL elimination by extracorporeal circulation, is effective not only for coronary artery disease, but also for systemic circulatory disturbance in severe hypercholesterolemic patients with familial hypercholesterolemia (FH) in particular. We found that LDL apheresis treatment with medical therapy improved coronary atherosclerotic lesions, based on coronary angiography evaluation and histopathological observation, suppressed progression of early carotid atherosclerotic lesions on annual B-mode ultrasonography, and improved diabetic scleredema in FH patients. This effectiveness of LDL apheresis appears to be due to recovery of vascular endothelial function and improvement of blood rheology. For diseases that are possibly due to circulation disturbance and that are intractable with drugs alone. LDL apheresis may be worth trying, particularly for patients complicated by hyperlipemia.

Ruthenium-catalyzed hydration of 1-alkynes to give aldehydes: insight into anti-Markovnikov regiochemistry.

The mechanism of the selective conversion of 1-alkynes to aldehydes by hydration was investigated by isolating organic and organometallic byproducts, deuterium-labeling experiments, and DFT calculations. The D-labeled acetylenic hydrogen of 1-alkyne was found exclusively in the formyl group of the resulting aldehydes. After the reaction, the presence of metal-coordinated CO was confirmed. All of the experimental results strongly suggest the involvement of a metal-acyl intermediate with the original acetylenic hydrogen also bound to the metal center as a hydride, with the next step being release of aldehyde by reductive elimination. Theoretical analyses suggest that the first step of the catalytic cycle is not oxidative addition of acetylene C [bond] H or tautomerization of eta(2)-alkyne to a vinylidene complex, but rather protonation of the coordinated 1-alkyne at the substituted carbon to form a metal-vinyl intermediate. This cationic intermediate then isomerizes to Ru(IV)-hydride-vinylidene via alpha-hydride migration of the vinyl group to the metal center, followed by attack of the vinylidene alpha-carbon by OH(-) to give the metal-hydride-acyl intermediate.

Roles of native topology and chain-length scaling in protein folding: a simulation study with a Go-like model.

We perform folding simulations on 18 small proteins with using a simple Go-like protein model and analyze the folding rate constants, characteristics of the transition state ensemble, and those of the denatured states in terms of native topology and chain length. Near the folding transition temperature, the folding rate k(F) scales as k(F) approximately exp(-c RCO N(0.6)) where RCO and N are the relative contact order and number of residues, respectively. Here the topology RCO dependence of the rates is close to that found experimentally (k(F) approximately exp(-c RCO)), while the chain length N dependence is in harmony with the predicted scaling property (k(F) approximately exp(-c N(2/3))). Thus, this may provides a unified scaling law in folding rates at the transition temperature, k(F) approximately exp(-c RCO N(2/3)). The degree of residual structure in the denatured state is highly correlated with RCO, namely, proteins with smaller RCO tend to have more ordered structure in the denatured state. This is consistent with the observation that many helical proteins such as myoglobin and protein A, have partial helices, in the denatured states. The characteristics of the transition state ensemble calculated by the current model, which uses native topology but not sequence specific information, are consistent with experimental phi-value data for about half of proteins.

Experimental and theoretical studies on ferromagnetically coupled metal complexes with imino nitroxides.

Copper(II), zinc(II), and nickel(II) complexes with tridentate imino nitroxyl diradicals, [CuCl(bisimpy)(MeOH)](PF(6)) (1), [ZnCl(2)(bisimpy)] (2), and [NiCl(bisimpy)(H(2)O)(2)]Cl x 2H(2)O (3) (bisimpy = 2,6-bis(1'-oxyl-4',4',5',5'-tetramethyl-4',5'-dihydro-1'H-imidazol-2'-yl)pyridine), were prepared, and their magnetic properties were studied. In 1, the Cu(II) ion has a square pyramidal coordination geometry, of which the equatorial coordination sites are occupied by three nitrogen atoms from the bisimpy and a chloride ion. The coordination geometry of the Zn(II) ion in 2 can be described as a trigonal bipyramid, with two chloride ions and a bisimpy. In 3, the Ni(II) ion has a distorted octahedral coordination geometry, of which four coordination sites are coordinated by the bisimpy and chloride ion, and two water molecules occupy the remaining cis positions. Magnetic susceptibility and EPR measurements revealed that in 1 and 3 the Cu(II) and Ni(II) ions with imino nitroxyl diradicals were ferromagnetically coupled, with the coupling constants J (H = -2J(ij) summation operator S(i)S(j)) of +165(1) and 109(2) cm(-1), respectively, and the intraligand ferromagnetic interactions in 1-3 were very weak. DFT molecular orbital calculations were performed on the diradical ligand, 1, and 2 to study the spin density distribution before and after coordination to the metal ions.

Revisiting Markovnikov addition to alkenes via molecular electrostatic potential.

Molecular electrostatic potentials (MESP) surrounding the pi-region of several substituted ethylenes (CH(2)CHR) have been characterized by locating the most negative-valued point (V(min)) in that region. The substituents have been classified as electron donating and withdrawing on the basis of the increase or decrease in the negative character of V(min) in these systems as compared to ethylene. The values of V(min) show a good linear correlation with the Hammett sigma(p) constants, suggesting that the substituent electronic effects in substituted ethylenes and substituted benzenes are basically similar. With electron-donating substituents, the position of MESP minimum is closer to the unsubstituted carbon facilitating the pi-complex formation of it with HCl at this site. Such a regiospecific pi-complex formation is found to favor the formation of Markovnikov-type transition state for the addition of HCl to CH(2)CHR. For the electron-withdrawing substituents, the V(min) location is almost equidistant and farther from the ethylenic carbon atoms. This and the less negative V(min) values account for the less regiospecific CH(2)CHR...HCl pi-complexes as well as the transition states for the HCl addition to CH(2)CHR when R is an electron-withdrawing group. The interaction energy (E(int)) between CH(2)CHR and HCl for the formation of the CH(2)CHR...HCl pi-complex shows a good linear correlation with the corresponding V(min) value.

[Species differences in the in vitro metabolism of 2,4,5,2',3',4'-hexachlorobiphenyl].

In vitro Metabolism of 2,4,5,2',3',4'-hexachlorobiphenyl (CB138) was studied using liver microsomes from rats, hamsters and guinea pigs. Guinea pig liver microsomes formed four metabolites named as M-1, M-2, M-3 and M-4 and these metabolites were all increased to about 4-5 fold of untreated microsomes by pretreatment of phenobarbital. Liver microsomes of rats and hamsters showed much less activity to metabolize CB138 than those of guinea pigs. Only phenobarbital-treated microsomes produced very small amounts of M-3 in rats and M-1, M-2 and M-3 in hamsters, but untreated and MC-treated microsomes did not. When mass spectra of the methylated derivatives of M-1, M-2, M-3 and M-4 were measured in GC/MS, the former two possess the molecular ion of 354 and the latter two had the molecular ion of 388. In addition, the mass fragmentation pattern indicated that M-1, M-2, M-3 and M-4 are 2-OH-4,5,2',3',4'-pentachlorobiphenyl, 5-OH-2,4,2',3',4'-pentachlorobiphenyl, 3-OH-CB138 and 2-OH-3,4,5,2',3',4'-hexachlorobiphenyl, respectively. Of four metabolites, the chemical structures of M-3 and M-4 were supported by the synthesized authentic compounds. From these results, it is suggested that the metabolism of CB138 in guinea pig liver proceeds mainly via 2,3-epoxide as an intermediate and a PB-inducible P450, CYP2B18, is the most important isozyme in CB138 metabolism.

[Assessment of hydroxylated metabolites of polychlorinated biphenyls and polychlorinated dibenzofurans as potential estrogens by yeast two-hybrid system].

The estrogenic activities of several hydroxylated metabolites of PCBs and PCDFs were investigated by yeast two-hybrid assay based on the ligand-dependent interaction of estrogen receptor with coactivator. For the hydroxylated PCBs, the order of estrogenic potency was 4-OH-2',4',6'-triCB > 4-OH-4'-monoCB, 4-OH-biphenyl. These compounds were evaluated as 10(3) to 10(4) less potent than 17 beta-estradiol based on the concentrations of test compounds showing 10% activity of 10(-7) M 17 beta-estradiol. 2-OH-3',4,4'-triCB, 4-OH-2',3,4'-triCB and 3-OH-/4-OH-2,2',5,5'-tetraCB, the metabolites of 2,2',5,5'-tetraCB were inactive as estrogens at the highest concentrations used in this study (10(-5) M). Also 4-OH-3,3',4',5-tetraCB, the metabolite of 3,3',4,4'-tetraCB was inactive as estrogen, indicating that this hydroxylated metabolite did not take part in the estrogenic activity of 3,3',4,4'-tetraCB. OH group at 4-position of biphenyl was necessary for the expression of estrogenicity, but one or two chloro-substitution adjacent to OH group inhibited the activity. For the hydroxylated PCDFs, 8-OH-2-monoCDF, 7-OH-3,4-diCDF, 8-OH-3,4-diCDF, 8-OH-3,4,6-triCDF and 3,8-(OH)2-2-monoCDF exhibited estrogenic activity. The estrogenic activity of 3,8-(OH)2-2-monoCDF was comparable to those of 4-OH-2',4',6'-triCB and 4-nonylphenol (mixture of compounds with branched sidechain). The order of activity was 3,8-(OH)2-monoCDF > 8-OH-3,4-diCDF, 7-OH-3,4-diCDF > 8-OH-2-monoCDF, 8-OH-3,4,6-triCDF. These compounds were evaluated as 2.5 x 10(3) to 3 x 10(4) less potent than 17 beta-estradiol. On the other hand, no estrogenic activity was observed for 2-OH-dibenzofuran, 3-OH-2,8-diCDF, 6-OH-3,4-diCDF and 9-OH-3,4-diCDF at concentrations as high as 10(-4) M. Substitution of OH group at 2(8)- or 3(7)-position of dibenzofuran and no chloro-substitution adjacent to OH group was required for the estrogenic activity.

Correlation between plasma endotoxin, plasma cytokines, and plasminogen activator inhibitor-1 activities in septic patients.

The objective of this study was to evaluate the relation between the clinical and plasma parameters and the changes in plasma endotoxin activity with 2 hours of endotoxin-adsorbing therapy using polymyxin B (PMX). A total of 88 consecutive patients were admitted for PMX treatment of severe sepsis or septic organ failure. Standard supportive care was continued without alteration during PMX treatment. Endotoxin, tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), IL-10, and plasminogen activator inhibitor-1 (PAI-1) activities and clinical parameters were measured before, immediately after, and the day after PMX treatment. The mean APACHE II and III scores were 24.2 +/- 1.0 and 85.8 +/- 3.0, respectively. The 2-week survival rate was 51.1%. In survivors, TNFalpha, IL-6, IL-10, and PAI-1 activities were significantly decreased during the 2-hour PMX treatment, the following day, or both times. There was no significant change in the parameters, except for TNFalpha, after PMX in nonsurvivors. In the subgroup whose plasma endotoxin decreased more than 30%, IL-6, TNFalpha, and PAI-1 significantly decreased after 2 hours of PMX or the following day (or both), but all four parameters in nonsurvivors showed no significant change. Hence PMX adsorbed plasma endotoxins and contributed to reductions in plasma proinflammatory cytokine levels and to improved clinical parameters during the 2-hour treatment. Changes in these parameters correlated with changes in plasma endotoxin activity in survivors whose plasma endotoxin levels were adequately reduced.

Molecular design of a new class of spin-labeled ribonucleosides with N-tert-butylaminoxyl radicals.

We designed a new type of spin-labeled nucleosides with an N-tert-butylaminoxyl radical which is introduced to the nucleobase directly. Purine and pyrimidine ribonucleosides containing the aminoxyl radical such as 1a-d, 2, 3, and 4 were synthesized to investigate the stability and behavior of the N-tert-butylaminoxyl radical on a nucleobase. Lithiation of tri-O-silylated 6-chloropurine ribonucleoside (5) followed by reaction with 2-methyl-2-nitrosopropane (MNP) gave the key compound 6a, which was further converted to 6b-d. Oxidation of the obtained 6a-d and their triols (7a-d) with Ag(2)O led to formation of the corresponding stable spin-labeled nucleosides (8a-d and 1a-d), which were confirmed by EPR spectroscopy. Similarly, the precursors of spin-labeled pyrimidines (13, 20, and 23) were synthesized by site-selective lithiation of tri-O-protected pyrimidine derivatives (9, 18, and 21) followed by the reaction with MNP and deprotection. An EPR study showed that the aminoxyl radicals (2, 3, and 4) were stable and that their hyperfine structures were dependent on the position of the radical. Electron densities of pyrimidine also affected hyperfine structures.

Congenital dyserythropoietic anemia type 1 with fetal onset of severe anemia.

We report a patient with congenital dyserythropoietic anemia type 1 with characteristic anomalies and two novel clinicopathologic presentations: intrauterine onset of severe anemia resulting in cardiac failure and relatively mild dyserythropoietic features on bone marrow aspiration in contrast to severity of anemia. After repeated transfusions and a trial of erythropoietin administration, the patient died from respiratory infection at age 7 months. Autopsy revealed characteristic dyserythropoietic features of the bone marrow by light microscopy and electron microscopy, which confirmed a diagnosis of congenital dyserythropoietic anemia type 1.

Beneficial effect of aggressive low-density lipoprotein apheresis in a familial hypercholesterolemic patient with severe diabetic scleredema.

We present a 59-year-old woman with severe diabetic scleredema (DS) associated with heterozygous familial hypercholesterolemia (FH). She had been treated with drugs to lower blood glucose, with insulin for diabetes mellitus (DM), and with low-density lipoprotein (LDL) apheresis therapy monthly or every 2 weeks in addition to drugs to lower serum lipids for FH. However, her scleredema had not improved. After we had tried weekly LDL apheresis therapy for a period of 3 years to treat her hyperlipidemia, the levels of her serum lipids were reduced to normal ranges, and scleredema in her nape improved. We also demonstrated the histopathological improvement in dermis of her cervical skin. We conclude that weekly LDL apheresis therapy is effective for diabetic scleredema that is resistant to conventional treatments.