Usefulness of thallium-201 muscle scan to investigate perfusion reserve in the lower limbs of patients with systemic lupus erythematusus.

Patients with systemic lupus erythematosus (SLE) may develop premature atherosclerosis, notably peripheral vascular disease presenting with intermittent claudication or gangrene. This study evaluates the usefulness of thallium-201 muscle perfusion scan (Tl-201 muscle scan) for investigating perfusion reserve in the lower limbs of 25 asymptomatic, female SLE patients without peripheral ischemia findings. The patients showed no evidence of peripheral arterial disease in history, physical examination, or Doppler ultrasonography. A control group consisted of 24 healthy, age-matched women. Each subject flexed her right foot maximally both dorsally and plantarly 60 times. In the middle of this exercise, 2 mCi of Tl-201 was injected intravenously. Three minutes after the injection, a posterior image of both calves was obtained using a gamma camera. Rectangular regions of interest were symmetrically drawn over both calves. The total count in the resting calf was subtracted from the total count in the exercising calf, and the percentage of increase, termed the perfusion reserve, was determined. A significant difference was found between the perfusion reserves of the SLE patients and control groups (75.3+/-8.9% and 99.6+/-9.0%, respectively, P <0.05). In conclusion, perfusion reserve in the lower limb muscles of SLE patients may be measured by Tl-201 muscle perfusion scan.

Mutation analysis of a family with hereditary hemorrhagic telangiectasia associated with hepatic arteriovenous malformation.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia. Two related genes, endoglin and activin receptor-like kinase (ALK-1), have been mapped to chromosomes 9q34 and 12q13, respectively. We describe a Taiwanese HHT family with hepatic arteriovenous malformation. Clinical and molecular evaluations were performed in eight members of this family, and HHT symptoms were found in three adults. Short tandem repeat markers were used to perform linkage analysis, and this family was classified as HHT type 2 (ALK-1 gene). The exons of ALK-1 were amplified using the polymerase chain reaction and subjected to direct DNA sequencing. The mutation causing the disease was located at ALK-1 codon 411, causing an arginine to glutamine substitution. Five members of this family carried the mutated ALK-1 gene. This investigation successfully used linkage and sequencing techniques to perform molecular diagnosis of HHT.

Status of trace elements in patients with idiopathic dilated cardiomyopathy in central Taiwan.

BACKGROUND: Sporadic cases of dilated cardiomyopathy (DCM) are often seen in central Taiwan. Though trace elements may play a role in the pathogenesis of idiopathic DCM, there are no reports concerning study of Taiwan's population in relation to trace elements in patients with DCM. METHODS: Serum selenium, zinc, copper and iron concentrations and blood glutathione peroxidase (GPX) activity were measured in 32 patients with DCM (24 males, 8 females; mean age, 44 +/- 14 years) and 31 age-matched normal volunteers (16 males, 15 females; mean age, 38 +/- 12 years). RESULTS: The average serum selenium concentration of 27.6 +/- 8.4 micrograms/l found in the DCM group was significantly lower than the average concentration of 47.2 +/- 14.7 micrograms/l in the normal group. Blood GPX activity was also significantly lower in the DCM group than in the normal group. Serum selenium concentration correlated well with blood GPX activity in the studied subjects. Serum copper and iron concentrations were significantly higher in the DCM group than in the normal group. There was no difference in serum zinc concentration between the two groups. CONCLUSIONS: Deficiency of serum selenium in association with a low blood GPX activity, and high serum copper and iron concentrations, are found in patients with idiopathic DCM in central Taiwan.

Detection of fusion transcripts generated by the inversion 16 chromosome in acute myelogenous leukemia.

Pericentric inversion of chromosome 16 [inv(16)(p13q22)] and the related t(16;16)(p13;q22) are seen in a subset of acute myelogenous leukemia (AML) phenotypically and prognostically differing from other cases. We have recently shown that inv(16) results in fusion of CBFB/PEBP2B, a gene encoded at 16q22 to MYH11, a smooth muscle myosin heavy chain gene encoded at 16p13. Chimeric transcripts consisting of upstream CBFB fused to downstream MYH11 coding sequences result from this fusion. In this study we have examined a series of 37 of these cases using reverse transcriptase-polymerase chain reaction (RT-PCR) to detect expression of a hybrid CBFB/MYH11 transcript. Chimeric cDNAs were detected in all but 1 of 37 leukemias with typical inv(16) or t(16;16). Such chimeric products were not seen in a case with inv(16)(p13q24) (ie, a variant q arm breakpoint) or any of 10 cases of AML without these chromosomal changes. Four different chimeric transcripts were found, representing differing fusion points within MYH11 spliced to position 495 of CBFB. Primer sets are described for efficient amplification of these different cDNA forms. Amplification of cDNA showed that all but 17 codons of the CBFB coding sequence are included in the abnormal transcripts. RT-PCR was shown to be highly sensitive and potentially useful for detection of leukemic cells during morphologic remission.

Isolation of a novel morphinan 3-O-diglucuronide metabolite from dog urine.

Following oral administration of the narcotic antagonist nalmefene [17-(cyclopropylmethyl)-4,5 alpha-epoxy-6-methylenemorphinan-3,14-diol] labeled with 14C to the dog, approximately 50% of the dose was excreted in the urine as a highly polar water-soluble conjugate. Although this major metabolite could be hydrolyzed with beta-glucuronidase to yield nalmefene, the intact conjugate was chromatographically more polar on reversed-phase high-performance liquid chromatography (HPLC) than authentic nalmefene 3-O-glucuronide. Milligram quantities of the metabolite were subsequently isolated and subjected to fast atom bombardment (FAB) mass spectral and nuclear magnetic resonance (NMR) analyses. The conjugate was identified as nalmefene 3-O-beta-diglucuronide with a 1,2-beta linkage between the two glucuronic acids. It is unlikely that this novel form of conjugate is unique to nalmefene and it is probably a metabolite of other morphinans and/or similar drugs in the dog. Nalmefene 3-O-diglucuronide is not a metabolite of nalmefene in man.

Nalmefene: safety and kinetics after single and multiple oral doses of a new opioid antagonist.

The aim of these two studies was to evaluate the safety and pharmacokinetics of oral nalmefene, a new orally effective opioid antagonist. In the first study, single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were administered in double-blind fashion to four groups of healthy men. There were six subjects in each group; four received nalmefene and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, such as lightheadedness, at the higher doses. Model-independent pharmacokinetic analysis of the plasma concentration-time data showed that nalmefene was rapidly absorbed and had an elimination half-life that ranged from seven to 15 hours (mean, 10.7 hr). There was a good linear relationship (r = .97) between administered dose and total area under the curve at each dose level. Only about 4% of the dose was excreted in the urine as unchanged nalmefene, whereas up to 60% was excreted as a beta-glucuronidase/sulfatase hydrolysable conjugate(s) of nalmefene. In the second study, six healthy men were initially administered a single 50-mg dose of drug, and plasma samples were obtained at selected time intervals for 48 hours. A dosing schedule of 20 mg q12h was then started and continued for seven days. Plasma samples were collected immediately before each dose and at selected times for up to 48 hours after the last dose. The drug was well tolerated by all subjects, and no clinically significant adverse effects were observed during the seven-day administration period.(ABSTRACT TRUNCATED AT 250 WORDS)

Nalmefene: intravenous safety and kinetics of a new opioid antagonist.

In a placebo-controlled, double-blind study we evaluated the safety and kinetics of a new narcotic antagonist, nalmefene, after 2, 6, 12, and 24 mg intravenous doses to healthy men. At each dose level four subjects received active drug and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness. The plasma concentration-time data were best fit with a triexponential equation, and the terminal elimination phase had a harmonic mean t1/2 of 8 to 9 hours. Only about 5% of the dose was excreted in the urine as intact nalmefene, with up to 60% excreted as nalmefene glucuronide. Although intersubject differences were noted, mean or dose-normalized mean kinetic parameters such as clearance, steady-state volume of distribution, terminal t1/2, and AUC showed no consistent trends related to increasing doses, indicating that nalmefene has linear pharmacokinetics.