Genetic variations and haplotype structures of the ABC transporter gene ABCC1 in a Japanese population

Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3'-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5'-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on > or = 10 chromosomes accounted for > or = 91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese.     

The Effects of Adding Reassurance Statements: Cancer Patients' Preferences for Phrases in End-of-Life Discussions

ContextWhen discussing end-of-life issues with cancer patients, the addition of reassurance statements is considered helpful. However, patients' preferences for such statements have not been systematically demonstrated.ObjectivesThe objectives of this study were to clarify if phrases with additional reassurance statements would be more preferable to phrases without them and explore variables associated with patients' preferences.MethodsIn a cross-sectional survey, 412 cancer patients assessed their own preferences for phrases with/without additional statements using a six-point scale (1 = not at all preferable; 6 = very preferable). These included the statements of “hope for the best and prepare for the worst” (“hope/prepare”) when discussing prognosis; symptom palliation when discussing code status; and specific goals, continuity of care, and nonabandonment when discussing hospice referral. We evaluated demographic data and the coping style and conducted multivariate regression analysis.ResultsCompared with the phrase of life expectancy (i.e., median + typical range) alone [mean (SD), 3.5 (1.2); 95% CI, 3.4–3.6], the phrase with the additional “hope/prepare” statement was more preferable [3.8 (1.4); 3.7–3.9]. Compared with the phrase of do-not-resuscitate alone (3.1(1.3); 3.0–3.3), the phrase with the additional statement of symptom palliation was more preferable [3.9 (1.3); 3.7–4.0]. Compared with the phrase of hospice referral alone [3.4 (1.2); 3.3–3.5], phrases with the addition of a specific goal [3.9 (1.0); 3.8–4.0], specific goal and continuity (4.4(1.0); 4.3–4.5), and specific goal, continuity, and nonabandonment [4.8 (1.2); 4.7–4.9] were more preferable. In multivariate analyses, task-oriented coping was significantly correlated with preferences for phrases including additional reassurance statements.ConclusionCancer patients systematically preferred reassurance statements. In end-of-life discussions, especially with patients with task-oriented coping, clinicians may provide additional reassurance statements.     

Cystic hygroma suggested on CT examination

Cystic hygroma (Cystic lymphangioma; hygroma cysticum colli) is a comparatively rare congenital malformation comprised of large lymph-containing cystic spaces that develop in the neck or lower portion of the face. Although it primarily involves the neck, it may extend upward and replace and enlarge the parotid gland, floor of the mouth, cheek, and tongue. It is often noted at birth or in young patients, but it is sometimes first seen in adults^(1–3). This report describes a case of cystic hygroma of a young girl as suggested on the CT examination.     

5-HT1A receptor-mediated inhibition of lateral vestibular nucleus neurons projecting to the abducens nucleus

Electrophysiological studies were performed using cats anesthetized with α-chloralose, to elucidate the 5-hydroxytryptamine (5-HT) receptor subtypes involved in the 5-HT-induced inhibition of the lateral vestibular nucleus (LVN) neurons projecting to or through the abducens nucleus. The effects of 5-HT receptor subtype agonists and antagonist were examined in polysynaptic neurons activated by stimulation of the ipsilateral abducens nucleus (IAN) antidromically, since these neurons are sensitive to 5-HT as shown in our previous study. Iontophoretic application of 5-HT and8-hydroxy-2-(di-n-propylamino)tetrain (8-OH-DPAT), a selective 5-HT_1A agonist, inhibited orthodromic spikes elicited by vestibular nerve stimulation in the majority of polysynaptic neurons activated by stimulation of ipsilateral IAN antidromically. There was a good correlation between the effects of 5-HT and 8-OH-DPAT. Iontophoretically applied 5-HT and 8-OH-DPAT also inhibited glutamate-induced firing in these neurons. Simultaneous application of 1-(2-methoxyphenly)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190), a 5-HT_1A agonist/antagonist, significantly antagonized the 8-OH-DPAT-induced inhibition of glutamate-induced firing, although NAN-190 alone also caused weak suppression of glutamate-induced firing. Microiontophoretically applied 1-(3-chlorophenyl)piperazine (mCPP), a 5-HT_1B agonist inhibited the orthodromic spike elicited by vestibular nerve stimulation and glutamate-induced firing in only a small number of the LVN neurons. 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT₂ agonist, rarely affected these neurons. We postulate that postsynaptically located 5-HT_1A receptors are mainly involved in the 5-HT-induced inhibition of polysynaptic neurons projecting in the region of the IAN.     

Relationship between biopsy and prognosis of breast cancer

Clinical data from 131 patients who underwent primary radical operation for breast cancer at the Second Department of Surgery, Shinshu University Hospital during five-years from January 1976 to the end of December 1980 were analyzed to investigate for the relationship between biopsy and prognosis. The incisional biopsy group had a significant higher recurrence rate as compared with the no biopsy group, cytology group and the cancer negative group after excisional biopsy. Although the puncture aspiration cytology group did not show significant difference in recurrence rate, an any more than 3 weeks of interval between puncture aspiration cytology and radical surgery associated with a significant high recurrence rate. This suggests that the interval also exerts an unfavorable influence upon prognosis. Puncture aspiration cytology was recognized to be apt to result in distant metastasis than any other biopsy methods and also it is tended to have a higher recurrence rate in scirrhous and mucinous carcinoma of the breast.     

Effects of HMG-CoA reductase inhibitors on skeletal muscles of rabbits

This study was undertaken to evaluate the potential of HMG-CoA reductase inhibitors, pravastatin sodium (hereafter abbreviated to pravastatin) and simvastatin, for induction of myopathy and influence on the ubiquinone content of skeletal and cardiac muscles and other tissues in the rabbit. Both drugs were administered orally to New Zealand White rabbits (n=5) at the dose of 50 mg/kg per day for 14 days. Serum cholesterol levels in the pravastatin-and simvastatin-treated groups were reduced significantly by 47% an 58% on day 14 (P<0.05), respectively, as compared with the control group, but the difference between the two treatment groups was not significant. In animals of the simvastatin-treated group, abnormal elevations of creatine kinase (CK) and lactate dehydrogenase (LDH) levels were observed, in association with severe lesions in skeletal muscles, but not cardiac muscle. The ubiquinone content in skeletal muscle in this treatment group was not affected, even in the muscles that had severe lesions, whereas that in liver and cardiac muscle was significantly reduced compared with the control group. The results suggest that there is no direct correlation between myopathy and the decrease of obiquinone content in skeletal muscles. In contrast, the animals in the pravastatin-treated group did not show any changes in CK and LDH levels, ubiquinone content in liver and muscles, or in histopathological features of muscle fibers. The difference between the adverse effects seen with the two drugs could be attributed to physicochemical properties: simvastatin permeates the plasma membrane because of its hydrophobic nature, whereas pravastatin does not, because it is hydrophilic.     

A case of high grade astrocytoma arising in the hand area of precentral gyrus]

A 23-year-old man presented with the right upper monoparesis. The right little finger paresis was apparent at first, and ring finger two weeks later, and middle, index, thumb were simultaneously four weeks later. Then the monoparesis gradually progressed to the proximal upper limb. Magnetic resonance imaging showed a small lesion at the knob of the left precentral gyrus. The lesion was low-intensity on T1-, and high-intensity on T2-weighted images, and clearly detected on high-intensity on FLAIR images, but showed no enhancement by gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). Angiography and thallium scintigraphy showed no remarkable findings. Proton MR spectroscopy demonstrated lower N-acetylaspartate (NAA) and higher choline (Cho) level compared to the contralateral cortico-subcortical area. Diffusion weighted images demonstrated low apparent diffusion coefficient (ADC) value and high intensity on b = 1,000. To clarify the diagnosis of the lesion, we performed open biopsy by using the neuronavigation system to detect the lesion accurately and minimize the biopsy. Histological examination revealed an high grade astrocytoma with high MlIB-1 index over 30%. The progressive symptoms were due to highly infiltrative and proliferative nature of the tumor arising in the focal hand area of the primary motor cortex, according to the homunculus. We discuss herein the neuroimagings of the case that was considered to be in the initial stage of a malignant tumor.