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Amyotrophic lateral sclerosis (ALS) is a progressive disease characterised by degeneration of upper and lower motor neurons. The histological feature of skeletal muscles in ALS is the presence of denervated and reinnervated myofibres including small angulated fibres, grouped atrophy and fibre type grouping. Moreover, target/targetoid fibres (TFs) are frequently observed as abnormal structures of myofibres in ALS. A classic study revealed TFs in 50% of cases of biopsy-proven motor neuron diseases.1 The target fibre was first described as a sign of muscle fibre denervation in 1961.1 The name ‘target fibre’ is derived from its appearance on the transverse section that contains three more or less distinct concentric zones,1 and the central zone contains longitudinally oriented wavelike threads, possibly derived from Z-disc and bundles of myofilaments.2 The components of TFs have been identified as LC3, desmin, αB-crystallin, dystrophin, filamin C and Hsp27.2 However, the biological significance of TFs remains unclear. In contrast to the neuropathological changes in motor neurons that are assessable at autopsy, histological evaluation of skeletal muscles can be conducted before the death of the patients, which may contribute to diagnosis at an early-stage disease and evaluation of therapeutic efficacy. The present study aimed to determine the biological significance of the formation of TFs in neurogenic muscular atrophy in ALS. ### Patients and clinical assessments We retrospectively analysed the medical records of 17 consecutive patients with ALS who were admitted to the Department of Neurology, Kumamoto University Hospital, from January 2005 to December 2017, and who underwent muscle biopsy to exclude myopathies because they lacked upper motor neuron (UMN) signs and/or showed elevation of serum creatine kinase (CK) levels. We recorded the clinical characteristics as shown in online supplementary table 1. ### Supplementary data [jnnp-2020-324151supp001.pdf] ### Histological analyses Muscle biopsy samples had been examined by routine histochemical techniques including a series of myofibrillar adenosine triphosphatase …

We report the clinical features of a patient with hereditary transthyretin (ATTR) amyloidosis associated with a novel mutation (Y114S, p.Y134S). A 65-year-old Japanese man was admitted to our hospital after a 3-year history of progressive dyspnea on exertion. Five years previously, he presented dysesthesia in both hands caused by carpal tunnel syndrome. A genetic analysis revealed a base pair substitution of adenine to cytosine in the second codon of exon 4, residue 114, in the TTR gene (c.401A>C). The clinical characteristics were progressive cardiomyopathy with a poor vital prognosis, late onset, sporadic case, bilateral carpal tunnel syndrome, hypothyroidism, and small fiber neuropathy.

Objective We previously reported that decrement of compound muscle action potential (CMAP) by repetitive nerve stimulation (RNS) was greater in the median nerves than in the ulnar nerves of patients with amyotrophic lateral sclerosis (ALS). The aim of this study was to evaluate whether CMAP decrement by RNS is a feasible marker for the differentiation of ALS from other diseases. Materials & methods We performed RNS in the median and ulnar nerves of 51 patients with ALS and 40 patients with other diseases. Results The CMAP decrement was significantly greater in the median nerves of patients with ALS, compared to the disease control patients. In the median nerves of patients with ALS, CMAP decrement was significantly greater in the cervical region-onset group than in the other region-onset group. Conclusions The finding of CMAP decrement in the median nerves can be useful for differentiating ALS patients with cervical region onset from other controls with active neuropathic diseases.

SUMMARYUsing a newly developed rapid test, an outbreak of human metapneumovirus (HMPV) infection in a long-term care facility was detected within only 2 days after the onset of symptoms in a putative index case. The outbreak was almost under control within 8 days mainly by zoning patients, with the exception of two cases of HMPV that were diagnosed 16 and 17 days after the onset of the outbreak. According to an immunological diagnosis as well as the rapid test, it was eventually proven that 18 patients had HMPV infections. We suspected that even asymptomatic residents, who had not been completely separated from the facility population, were a source of infection. That suggested that all asymptomatic residents should be tested and that the separation of the infected patients should be absolute, if an outbreak of HMPV infection is suspected in such a facility.

To better define secondary aberrations that occur in addition to translocation t(11;14)(q13;q32) in mantle cell lymphomas (MCL) and in multiple myelomas (MM), seven t(11;14)-positive MCL cell lines and four t(11;14)-positive MM cell lines were analysed by fluorescence R-banding and spectral karyotyping (SKY). Compared with published data obtained by G-banding, most chromosome aberrations were redefined or further specified. Furthermore, several additional chromosome aberrations were identified. Thus, these cytogenetically well defined t(11;14)-positive MCL and MM cell lines may be useful tools for the identification and characterization of genes that might be involved in the pathogenesis of MCL and MM, respectively. Since MCL and MM were found to have different alterations of chromosome 1, these were investigated in more detail by fluorescence in situ hybridization (FISH) and multicolor banding (MCB) analyses. The most frequently altered and deletion-prone loci in MCL cell lines were regions 1p31 and 1p21. In contrast, breakpoints in MM cell lines most often involved the heterochromatic regions 1p12→p11, and the subcentromeric regions 1q12 and 1q21. These data are in accordance with previously published data of primary lymphomas. Our findings may indicate that different pathways of clonal evolution are involved in these morphologically distinct lymphomas harboring an identical primary chromosome aberration, t(11;14).

Background: Several autoimmune subepidermal blistering diseases with autoantibodies against the epidermal basement membrane zone (BMZ) have been identified. Each shows distinct immunological findings. Objectives: Our patient showed clinical features which were indicative of bullous pemphigoid or linear IgA bullous dermatosis. In his serum, circulating IgG antibodies binding to the dermal side of skin split with 1 M NaCl were detected. To clarify the immunological character of the patient, we performed further studies. Methods: Western immunoblot analysis using normal human skin extracts and indirect immunofluorescence (IF) with affinity-purified IgG antibodies to the detected dermal protein were done. Results: Western immunoblot analysis demonstrated IgG antibodies reacting with a dermal 200-kD protein. Affinity-purified IgG antibodies to the 200-kD protein reacted to the dermal side of the split by indirect IF. Therefore, this dermal 200-kD protein is believed to be the epidermal BMZ antigen. Conclusion: Our patient showed an immunologically unique subepidermal blistering disease.

We describe two new human leukemia cell lines, MOLM-13 and MOLM-14, established from the peripheral blood of a patient at relapse of acute monocytic leukemia, FAB M5a, which had evolved from myelodysplastic syndrome (MDS). Both cell lines express monocyte-specific esterase (MSE) and MLL-AF9 fusion mRNA. Gene fusion is associated with a minute chromosomal insertion, ins(11;9)(q23;p22p23). MOLM-13 and MOLM-14 are the first cell lines with, and represent the third reported case of, MLL gene rearrangement arising via chromosomal insertion. Both cell lines carry trisomy 8 which was also present during the MDS phase, as well as the most frequent trisomies associated with t(9;11), ie, +6, +13, +19 variously present in different subclones. Despite having these features in common, differences in antigen expression were noted between the two cell lines: that of MOLM-13 being CD34+, CD13-, CD14-, CD15+, CD33+; whereas MOLM-14 was CD4+, CD13+, CD14+, CD15+, CD33+. Differentiation to macrophage-like morphology could be induced in both cell lines after stimulation with INF-gamma alone, or in combination with TNF-alpha, which treatment also induced or upregulated, expression of certain myelomonocyte-associated antigens, including CD13, CD14, CD15, CD64, CD65 and CD87. Together, these data confirm that both cell lines are likely to be novel in vitro models for studying monocytic differentiation and leukemogenesis.

We introduced a double-blind controlled clinical study to compare intravenous human epidermal growth factor (hEGF) to cetraxate hydrochloride (CH), an antiulcer drug, for their healing effect on gastric ulcers. We also prospected an oral use of EGF on the basis of our experimental evidence. In the clinical trial, the rate of ulcer healing within 8 weeks was 77.9% (67/86) in patients receiving 6 micrograms EGF intravenously twice a week, being significantly greater than 51.7% (45/87) in those given CH. Taking together all aspects assessed including the healing rate, pain relief, blood examination and adverse reactions, we judged the hEGF to be a useful and safe anticuler drug. In rats, 50 micrograms/kg mouse EGF (mEGF) and 2% hydroxypropyl cellulose (HPC) or 1.0 g/kg sucralfate given by gastric intubation significantly raised the residual mEGF levels in both gastric luminal content (HPC: x 30; sucralfate: x 300 as high as those in EGF alone) and tissue (HPC: x 60; sucralfate: x 100). In addition, the combined treatments significantly promoted healing of rat gastric ulcers whereas each agent alone had no significant effect as compared with control (saline). This indicated the beneficial effect on ulcers of oral administration of EGF with agents allowing it to remain at high levels in the stomach, whereas most reports suggested less effect of oral EGF on healing of gastroduodenal ulcers. Subsequent to the clinical study, evaluation of oral use of EGF may be expected as the next step in the treatment of ulcers. The experimental evidence above would possibly be a guide for such trial.

Advances in interventional radiology have made possible magnetic compression anastomosis between the bile duct and the small intestine as a novel treatment. A 70-year-old man who had undergone subtotal gastrectomy for gastric cancer 2 years previously experienced recurring cholangitis with high fever and jaundice. Diagnostic evaluation subsequently demonstrated complete obstruction of the common bile duct which was attributed to recurrent cholangitis. A parent magnet was placed endoscopically into the afferent loop of the duodenum through the gastrojejunostomy with Billroth II reconstruction. The daughter magnet attached to a guide wire was placed in the obstructed common bile duct through a percutaneous transhepatic cholangiographic drainage tube. Two magnets were immediately attracted towards each other transmurally, and anastomosis was established on day 32 after the procedure. This novel method of magnetic compression anastomosis has the advantages of noninvasiveness and simplicity, as well as being a well-tolerated procedure for indications such as biliary obstruction.

T-cell prolymphocytic leukemia (T-PLL) is a postthymic T-cell neoplasm with a characteristic morphology and heterogeneous immunophenotype. Most cases of T-PLL express membrane T-cell receptors (TCRs) of the alphabeta phenotype. We experienced a 30-year-old man suffering from TCRgammadelta T-cell leukemia with morphology compatible to T-PLL with a postthymic phenotype. He was admitted with skin eruption and pancytopenia. Peripheral blood and bone marrow were occupied with medium-sized lymphocytes, which had moderately condensed chromatin with a single nucleolus and sparse, nongranular basophilic cytoplasm. The immunophenotype was CD1a-, CD2-, CD3+, CD4-, CD5+, CD7+, CD8-, and terminal deoxynucleotidyl transferase negative. Hepatosplenomegaly was absent. He was diagnosed as having T-PLL and was treated with combination chemotherapy. Six months later the leukemic cell became chemoresistant. Although the patient showed transient improvement in response to pentostatin, he died 13 months after the diagnosis. To our knowledge, this is the first case of T-PLL with a TCRgammadelta phenotype.

We describe magnetic resonance imaging findings in a 37-year-old man with a rare entity of isolated polyarteritis nodosa of the epididymis, which correlated well with the histopathologic findings.

Neuroendocrine carcinoma was diagnosed in the left nasal cavity of a free-living Japanese raccoon dog (Nyctereutes procyonoides viverrinus). Microscopically, the tumour consisted of sheets of anaplastic cells separated by narrow zones of fibrovascular stroma. The neoplastic cells had varying numbers of cytoplasmic granules stained by the Grimelius method. Immunohistochemically, the neoplastic cells were variably labelled for cytokeratin AE1/AE3, vimentin, chromogranin A and S-100. Ultrastructurally, some of the neoplastic cells had cytoplasmic membrane-bound dense-core granules of approximate diameter 140-240nm. The tumour had infiltrated the cerebrum and metastasized to the pituitary gland, mandibular and pulmonary lymph nodes, lungs, thyroid gland and adrenal glands.

Primary chondrosarcoma was found in the quadrate lobe of the liver of a 6-year-old, intact, male Golden Retriever. At 6 months after partial hepatectomy, recurrence in the liver occurred. The dog died of its systemic metastases 10 months thereafter. Histologically, the hepatic mass revealed neoplastic chondrocytes with abundant chondroid matrix, and there were few myxoid areas where the cellularity and pleomorphism of the neoplastic cells were more prominent. The neoplastic cells were positive for periodic acid-Schiff and were immunohistochemically positive for vimentin and S-100 protein; the matrix was deeply stained for alcian blue and was metachromatic for toluidine blue stain. This tumor might be derived from pluripotent mesenchymal cells in the connective tissue of the liver. To the best of our knowledge, in all mammalians, including humans, this is the first report of extraskeletal chondrosarcoma primarily arising in the liver.

We describe the case of a 67-year-old man who exhibited unsteadiness in walking, topographical disorientation, and urinary incontinence. Neurological examination revealed somnolence and mild weakness in the lower limbs with slight rigidity in the upper limbs. Cerebrospinal fluid examination showed pleocytosis with "flower cells" and an extremely high level of soluble interleukin-2 receptor. T2-weighted brain imaging revealed symmetrical high-intensity lesions in the bilateral caudate putamen. Positron emission tomography demonstrated intense uptake of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose in the same region. He was diagnosed with central nervous system invasion by adult T-cell leukemia (ATL) and received chemotherapy. Interestingly, chemotherapy ameliorated the lesions and terminally caused the gray matter itself to atrophy in the bilateral caudate nuclei, which may be evidence for the direct infiltration of ATL tumors.

Our experience suggests that there exist what may be termed 3 pedigrees of hereditary prostate cancer. Typical of pedigree 1, three brothers were affected by prostate cancer. A characteristic of this pedigree was the existence of some patients with bladder cancer and some with brain tumor. In pedigree 2, the paternal side of the family had been affected by prostate cancer for 3 generations. It was characteristic of this pedigree that the age at diagnosis was lower with each succeeding generation. In pedigree 3, a father and 2 sons were affected with prostate cancer. In 3 families, there were 9 patients with hereditary prostate cancer. The age at diagnosis ranged from 47 to 84 years, with an average age at diagnosis of 68.7 years, which was 5 years younger than the average age at diagnosis in Japan.

We encountered a 60-year-old man with severe respiratory failure after CABG. The patient received veno-venous extracorporeal membrane oxygenation (ECMO) in which blood was drained from the right atrium through a cannula and was returned via a cannula in the left femoral vein. During ECMO, the flow rate was 2.8-3.0 l/min (about 40 ml/kg/min) and the assist was needed for 5 years. Veno-venous ECMO is a simple and effective therapy for acute respiratory failure unresponsive to conventional treatment.

Antagonist activities of (R)-(-)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropylphenylsulfonyl)-2-(6-methyl- 2-propylpyridin-3-yloxy) acetamide hydrochloride (CAS 188710-94-3, PABSA), a novel endothelin (ET) receptor antagonist, for ETA and ETB receptors were evaluated using rat aortic smooth muscle A7r5 cells and isolated rat thoracic aorta. PABSA concentration-dependently inhibited the ET-1-induced increase in intracellular calcium concentration ([Ca2+]i) mediated via ETA receptors in A7r5 cells with an IC50 of 0.17 nmol/l. PABSA antagonized the ETA receptor-mediated contraction induced by ET-1 in endothelium-denuded rat aorta with a Kb of 0.74 nmol/l. The potency of PABSA in inhibiting ETA receptor-mediated vasocontraction was approximately 40- and 100-fold greater than those of BQ-123, a selective ETA antagonist, and bosentan, a mixed ETA/ETB receptor antagonist, respectively. ETB receptor-mediated endothelium-dependent vasorelaxation induced by ET-3 in the aorta was also antagonized by PABSA, with a Kb of 9.8 nmol/l. In contrast, PABSA affected neither the vasocontraction induced by KCl or norepinephrine nor the vasorelaxation induced by acetylcholine or prostaglandin I2 in the aorta. These results suggest that PABSA is a highly potent and selective ETA receptor antagonist.

Although human lung adenocarcinoma has diverse histological subtypes, the correlation between histological subtypes and occurrence of the p53 gene mutation has been given less attention. We investigated 145 surgically resected lung adenocarcinomas to search for the incidence of p53 mutations and for record data on survival in each histological subtype, according to the new WHO criteria (1999). The frequency of p53 mutation in bronchioloalveolar carcinoma (BAC; 0% in 17 cases) and BAC with invasive growth component (BAC-invasive; 11% in 27 cases), which is conventionally categorized as the mixed subtype in WHO typing, were apparently significantly lower than in other types (non-BAC including acinar, papillary, solid, or mixed histology with these subtypes; 48% in 101 cases; P0.01). Multivariate analysis revealed that the histological subtype including BAC-invasive was a strong, independent, and significant prognostic factor (P0.03), as were tumor size and pathological stage (P0.001 and 0.002, respectively) for overall survival. However, the occurrence of p53 mutation itself was seen to be significant only in case of the univariate analysis. Therefore, histological subtyping may be a better prognostic indicator than is p53 mutation. These findings suggest that the WHO classification with the BAC and BAC-invasive from other histological subtypes may prove useful to predict the outcome for surgically treated patients with lung adenocarcinoma.

Human bone marrow stroma (BST)-dependent myeloma sister cell lines MOLP-6 and MOLP-7 were established from the peripheral blood of a multiple myeloma (MM) patient with IgA kappa type MM (stage IIIB). The growth of the cell lines is constitutively dependent on BST cells; none of the cytokines tested nor the culture supernatant of the BST cells could support the growth. Both cell lines showed typical plasma cell morphology with abundant cytoplasm and one to four nuclei under Wright staining. The immunoprofiles of MOLP-6 and MOLP-7 correspond to that seen typically in primary MM cells: positive for cytoplasmic immunoglobulin (Ig) chains, a heavy and kappa light chains, CD9, CD28, CD40, CD44, CD45, CD56, and PCA-1; the cells were negative for surface Igs and various other B-cell, T-cell and myelomonocyte associated markers. Both cell lines also expressed adhesion molecules including HCAM (CD44), VLA-4 (CD49d/CD29), VLA-6 (CD49f/CD29), ICAM-1 (CD54), NCAM (CD56), LFA-3 (CD58) and L-selectin (CD62L). The doubling time of MOLP-6 and MOLP-7 was 48 and 168 hours, respectively. In addition to this growth characteristic, the maximum cell density of each cell line was obtained at 1.7 x 10(6) cells/ml and 9.7 x 10(5) cells/ml, respectively. The characteristics of each cell line may reflect intraclonal variation of the proliferative capacity. The MOLP-6 together with the MOLP-7 sister will be useful model systems for the investigation of the biology of myeloma.

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.

The novel multiple myeloma (MM) cell line MOLP-5 and its homologous sister cell line B407, a lymphoblastoid cell line (LCL), were established from the peripheral blood of a 71-year-old Japanese patient with Bence-Jones kappa-type multiple myeloma (stage IIIB with hyperammonaemia and hypercalcaemia). The growth of MOLP-5 cells is constitutively dependent on bone marrow stroma (BST) cells; none of the cytokines tested nor the culture supernatant of the bone marrow stroma cells could support the growth of MOLP-5. Wright-Giemsa-stained MOLP-5 cells showed typical plasma cell morphology with abundant cytoplasm and one to three nuclei. The immunoprofile of MOLP-5 corresponds to that seen typically in primary MM cells: positive for cytoplasmic immunoglobulin (Ig) kappa light chain, CD28, CD29, CD38, CD40, CD44, CD49d, CD54, CD56, CD58, CD71, CD138 and PCA-1; the cells were negative for surface Ig and various other B-cell, T-cell and myelomonocyte-associated immunomarkers. Interleukin 6 (IL-6) receptor mRNA was found in the reverse transcriptase polymerase chain reaction (RT-PCR) analysis. IL-6 and IL-10 could induce cellular proliferation in short-term induction experiments. IL-6 or IL-10 production was not detected by specific enzyme-linked immunoabsorbent assay (ELISA). MOLP-5 cells expressed parathyroid hormone-related protein (PTHrP) at the mRNA level. Cytogenetic analysis showed the typical t(11; 14) chromosome abnormality. The novel MOLP-5 cell line together with the B407 B-LCL sister line will be useful model systems in the investigation of the biology of MM.

The angiographic assessment of coronary stenosis has many limitations, especially after coronary intervention. To determine the physiologic significance of such lesions, we measured the mean translesional pressure gradients at rest (P1), those during hyperemia induced by intracoronary administration of papaverine (12 mg in the left and 8 mg in the right coronary artery) (P2), and fractional myocardial flow reserve (FFRmyo) which is derived from the ratio of the mean distal coronary pressure and aortic pressure during hyperemia. Our objective was to determine the relations among P1, P2, and FFRmyo and restenosis as potential predictors of chronic restenosis. The grouped study consisted of 32 patients with ischemic heart disease scheduled to undergo intervention. The distal coronary pressure was measured using a 0.014 inch pressure monitoring wire (Pressure Guide, Radi Medical Systems, Uppsala, Sweden). The guidewire was advanced through the lesional segment. The mean percent diameter stenosis (%DS) was 67.9 +/- 13.3% before intervention and 22.9 +/- 15.3% after intervention. The mean P2 (9.9 +/- 5.3 mmHg) was significantly higher than the mean P1 (4.5 +/- 3.6 mmHg; p0.0001). There was no correlation of P1, P2 or FFRmyo with the %DS after intervention. Follow-up angiography (after 6 months) performed on all patients revealed restenosis (%DSor =50%) in four patients (12.5%). There was no correlation between P1 and the %DS at the follow-up angiography, but the relation between P2, FFRmyo and the %DS at the follow-up angiography was significant (r = 0.599, p0.01; r = 0.703, p0.0001, respectively). As a measurement of P2, FFRmyo is useful for the determination of the endpoint of intervention in consideration of prevention of restenosis. A new endpoint may be established after further evaluation in a greater number of patients.

Alteration of the p53 gene is one of the most frequent events in human tumorigenesis. The inactivation of p53 tumor suppressor function can be caused by chromosome deletion, gene deletion, or mainly by point mutations. p53 mutations occur moderately often in hematopoietic malignancies. A significantly higher frequency of p53 alterations in cell lines vs primary samples has been observed for all types of malignant hematopoietic cell lines. It has been postulated that p53 gene abnormalities arise in cell lines during in vitro establishment of the culture or prolonged culture; but it is also conceivable that those cases that carry p53 mutations may be more suitable for in vitro establishment as permanent cell lines. We analyzed data on the p53 gene status in a panel of matched primary hematopoietic tumor cells and the respective cell lines derived from this original material. In 85% (53/62) of the pairs of matched primary cells and cell lines, the in vivo and in vitro data were identical (both with p53 wild-type or both with the same p53 mutation). In some instances, serial clinical samples (eg at presentation and relapse) and serial sister cell lines were available. These cases showed that a clinical sample at presentation often had a p53 wild-type configuration whereas the derived cell line and a relapse specimen carried an identical p53 point mutation. These findings suggest that a minor clone, at first undetectable by standard analysis, represents a reservoir for the outgrowth of resistant cells in vivo and also a pool of cells with a growth advantage in vitro, providing a significantly higher chance of immortalization in culture. This was further supported by studies employing mutant allele-specific gene amplifications, a technique which is significantly more sensitive (100- to 1000-fold) than the commonly applied SSCP assay with a sensitivity threshold of about 10% mutated cells within a pool of wild-type cells. Taken together, this analysis confirms the usefulness of human hematopoietic cell lines as in vitro model systems for the study of the biology of hematopoietic malignancies. It further underlines the notion that p53 gene alterations confer a survival advantage to, at least some, malignant cells in vitro and presumably also in vivo; however, it is highly unlikely that a p53 mutation alone would suffice for the immortalization of a cell line in vitro or tumor development in vivo. Leukemia (2000) 14, 198-206.

We established three sister cell lines, NALM-30, NALM-31 and NALM-32, with biphenotypic features carrying myeloperoxidase mRNA and protein with complex Philadelphia (Ph) chromosome, t(9;22;10)(q34;q11;q22), from a patient with Ph-positive acute leukemia in relapse. Epstein-Barr virus nuclear antigen was negative. The morphological appearance of the cell lines is that of immature lymphoid cells. Expression of myeloid- and lymphoid-associated surface membrane antigens on these cells was detected allowing for the classification of "biphenotypic" leukemia. Immunophenotypically, the established cell lines reported here fulfill the European Group for the Immunological Characterization of Leukemias (EGIL) criteria for B-lineage derivation, however, surface and cytoplasmic immunoglobulin chains were negative. Whereas TGF-beta R (CD105), MCSFR (CD115), SCFR (CD117), IL-4R/IL-13R (CD124) and IL-6R (CD126) were not expressed, the cell lines were mostly positive for IFN-gamma R (CD119), IL-7R (CD127) and FLT-3R (CD135). The NALM-30, NALM-31 and NALM-32 cell lines together with their serial sister cell lines NALM-27 and NALM-28 which were established from the same patient at diagnosis provide unprecedented opportunities for studying a multitude of biological aspects related to normal and neoplastic immature B-lymphocytes.

The benefits of early extubation and assisted ventilation with mini-tracheostomy and preventive positive pressure ventilation in the early stage after thoracic esophageal cancer operation are examined and compared. Subjects were 23 patients who underwent radical operation for thoracic esophageal cancer in our hospital over a 5 year period. Ten patients (A group) underwent positive pressure ventilation with postoperative intubation for a certain period. Thirteen patients (B group) were extubated the day after operation, then immediately mini-tracheostomized, and then intermittent high-frequency jet ventilation during the daytime and pressure controlled ventilation during the nighttime were conducted. There were no differences in background factors between the two groups. The mean period of tracheal intubation was 8.8 days in the A group and 1.6 days in the B group. The mean period of stay in ICU was 13 days in the A group and 7 days in the B group. Both such periods were significantly shorter in the B group than in the A group. Respiratory control by early extubation and mini-tracheostomy after thoracic esophageal cancer operation is considered to have the following two benefits; 1. The method is performed safely, and makes sputum suction easier and assisted respiration conductible. 2. The method reduces the incidence of pulmonary complications and shortens the period of stay in ICU.

A case of Salmonella subdural empyema developed in chronic subdural hematoma (Infected Subdural Hematoma; ISH) was reported. A 64-year-old man had been in a nearby hospital due to myelodysplastic syndrome with cerebral infarction for two months. His condition there had been almost uneventful. But spike fever occurred and the patient became drowsy two days before his transfer to our medical center. His consciousness level deteriorated progressively and CT scan showed a right chronic subdural hematoma. He had had no history of head trauma in the previous two months. On admission to our center, his consciousness level was semicoma with anisocoria. An emergency operation was performed via a single burr hole initially. From the burr hole, old bloody fluid accompanied by yellowish pus was obtained. Thus so-called ISH was diagnosed and the craniotomy was carried out. Gram stain of the specimen revealed gram negative rods. Although an epileptic state developed after the operation, it was controlled by barbiturate coma therapy for 3 days, followed by phenytoin administration. Fever subsided gradually with antibiotics sensitive to the bacteria and his anisocoria disappeared on the 4th postoperative day. In this case, Salmonella enteritidis was detected from bacterial culture both of the specimen and of the arterial blood. Salmonella enteritidis might have been implanted on the capsule of the chronic subdural hematoma by bacteremia derived from immunological dysfunction due to myelodysplastic syndrome. In conclusion, the possibility of ISH should be considered in chronic subdural hematoma patients with immunological dysfunction.

We established two novel PH-positive acute leukemia cell lines with "biphenotypic" feature, NALM-27 and NALM-28, with t(9;22;10)(q34;q11;q22) from a patient with biphenotypic acute leukemia(BAL). The breakpoint cluster region (bcr) of the BCR gene was found to be rearranged in these cells by Southern blot analysis using a major 3'-side bcr probe. Polymerase chain reaction (PCR) results showed differences in the pattern of expression of the abl-bcr fusion gene in comparison with the diagnosis. In the case of variant Ph translocations, reports have appeared concerning mainly chronic myelogenous leukemia (CML), but there have been few concerning acute leukemia with lymphoid feature. This study thus identifies nonrandomly involved chromosome sites which can then be targeted for detailed molecular analysis to obtain an understanding of abl-bcr fusion in the cells with lymphoid feature. In addition, chromosome band 10q22, involved in this translocation, is the site for several neoplasia. Furthermore, this site is non-randomly involved in the formation of variant Ph translocations in acute lymphoblastic leukemia (ALL). This is the first report on the t(9;22;10)(q34;q11;q22) rearrangement in NALM-27 and NALM-28 cell lines which should prove useful for understanding the translocation of molecular breaks within the bcr of the complex translocation site.

A 64-year-old man was admitted to our hospital because of a 2-year progression of muscular jerks on the bilateral thoracic and abdominal walls. Neurological examination was normal except for myoclonus localized in the bilateral Th5 to L1 segments. Myoclonus in this case was symmetrical and synchronous, and had a tendency to continue rhythmically. It was also segmental and considered to be spinal in origin. The interval between two adjacent myoclonic jerks was short when the amplitude and duration of the first myoclonus were high and long, respectively. We postulated that the activity of anterior horn cells at an impaired segment might be a factor that influences the resting time between jerks. A myoclonic jerk could be induced by a tendon tap given anywhere on this patient's body, with a latency ranging from 40 to 220 msec, irrespective of the sites of tapping. A long latency and polysynaptic reflex may participate in such stimulus sensitivity. The site of the reflex was probably above the motor nucleus of the trigeminal nerve, because jerks could be induced by jaw taps. Our observations support the theory that a spino-bulbo-spinal reflex is manifested at the impaired segment.

Cefozopran (SCE-2787, CZOP), which is already on the market with a variety of approved indications in infectious diseases for adult patients, was administered to premature and newborn patients to evaluate the pharmacokinetics and the clinical efficacy. 1. Pharmacokinetics CZOP was intravenously administered at doses of 10.0 mg/kg, 21.4 mg/kg and 40.0 mg/kg to premature and newborn patients, and the blood concentrations and urinary excretion rate were examined. The blood CZOP concentrations were 31.7 and 65.5 micrograms/ml at 30 minutes after administration of 10.0 mg/kg and 40.0 mg/kg, respectively. The elimination half life was 1.78 hours and 2.31 hours, and the urinary recovery was 110.7% and 53.7% within 6 hours after administration, respectively. In the patient given 21.4 mg/kg, the blood CZOP concentration was 36.4 mg/kg at 1 an hour after administration and the elimination half life was 3.97 hours. The urinary recovery was 29.6% within 5 hours after administration. 2. Clinical results The clinical efficacy was evaluated in 19 patients and judged "good" or better in 13 of them with the efficacy rate or 68.4%. The bacteriological response was evaluated in 10 patients from whom Gram-positive cocci of S. aureus (6 strains), S. pneumoniae (1 strain) and E. faecalis (1 strain) and Gram-negative bacilli of H. influenzae (2 strains) and E. coli (2 strains) were isolated as possible causative organisms. With exception of 1 strain each of S aureus and H influenzae, which were not tested after the treatment with CZOP, all of these strains were found to be eradicated. 3. Adverse drug reactions (ADRs) of signs and symptoms and abnormal alterations of laboratory test values. Safety evaluation was made in 24 patients. ADRs of signs and symptoms were recognized in none of them. As abnormal alterations of laboratory test values, increased eosinophils in 3 patients, elevated GOT in one and elevated GPT in one were recognized. These results indicate that CZOP is a drug useful for treatment of infections in premature and newborn patients.

We describe the first case of T-cell prolymphocytic leukaemia (T-PLL) in which the peripheral blood cells contained a human T-lymphotropic virus (HTLV) related tax sequence. Serum screening tests for anti-HTLV-I/II antibodies were negative. Polymerase chain reaction disclosed the presence of an HTLV-I tax sequence in the peripheral blood. Other sets of oligonucleotide primers for HTLV-I gag, pol, env and the long terminal repeat regions and for the HTLV-II pol region were negative in the DNA of the cells. Although patients with T-PLL have been reported to be seronegative for HTLV-I, our findings point to the possibility that HTLV-I infection might be involved in the aetiology of at least some cases of T-PLL and that there may be alternative mechanisms involved in HTLV-associated leukaemogenesis.

A human acute lymphoblastic leukemia (ALL) cell line, BALM-16, was established from the peripheral blood specimen of a patient with B cell ALL L3 type (ALL-L3) in relapse. As with the original leukemia cells, the established line was negative for both cell surface and cytoplasmic immunoglobulin (Ig) chains. Absence of Ig expression was confirmed by Western blotting. Southern blot analysis demonstrated homozygous deletion of the C kappa gene, germ line configuration of the C lambda and rearrangement of IgJH genes. Cytogenetic analysis of both leukemic bone marrow and BALM-16 cells showed the t(8;22)(q24;q11) abnormality which is specifically associated with ALL-L3 and Burkitt lymphoma. The patient's serum showed hypercalcemia, prompting further investigation of the established cell lines which showed parathyroid hormone-related peptide (PTHrP) mRNA detected by reverse-transcriptase polymerase chain reaction. However, PTHrP production was not detected in the culture supernatant. The established cell line, BALM-16, could provide a useful material for analyzing the lack of Ig expression and of clarifying the pathogenesis of this type of B cell malignancy.

A total of 1840 children and adolescents treated with cyproterone acetate (CPA) to block gonadal function, as a treatment for precocious puberty, short stature and other disorders, were registered to survey for the risk of developing hepatic tumors. Patients responding to follow-up numbered 1552 (85%). The cumulative dose and duration of CPA therapy for boys and girls were 110.4g and 2.6 years, and 122.9 g and 2.8 years, respectively. Among the 1552 patients, five hepatoma cases were found. Four underwent successful surgery and remain alive and well to date. Two of the 5 cases had been given more than 500g, the other 3 more than 1000 g, of CPA. Three had also been given androgens before CPA administration. Although further follow-up is necessary to monitor for the development of adenoma and hepatoma, the risk of developing these tumors among patients to whom limited doses of CPA were administered appears to be negligible.

Azithromycin (AZM), a new oral macrolide antibiotic, in 10% fine granules or 100 mg capsules was given to pediatric patients to treat various infections. The following results were obtained in our studies of AZM for its antibacterial activities against clinical isolates, its pharmacokinetics, its efficacy, and its safety. 1. MICs of AZM, erythromycin (EM) and clarithromycin (CAM) were determined against a total of 57 strains all at 10(6) cfu/ml. Among Gram-positive cocci, MICs of AZM ranged from 0.78 to100 micrograms/ml against Staphylococcus aureus (20 strains), from 0.05 to 0.1 microgram/ml against Streptococcus pyogenes (11 strains), and from 0.0125 to 3.13 micrograms/ml against Streptococcus pneumoniae (10 strains). These MICs were similar to those of the other macrolides. Among Gram-negative bacilli, MICs of AZM were 0.05 micrograms/ml against Moraxella subgenus Branhamella catarrhalis (1 strain), from 0.78 to 3.13 micrograms/ml against Haemophilus influenzae (9 strains), 0.78 micrograms/ml against Haemophilus parainfluenzae (1 strain) and 6.25 micrograms/ml against salmonella sp. (1 strain). These values were similar to or lower than those of the other macrolides. Against Mycoplasma pneumoniae, MICs of AZM wereor = 0.0008 micrograms/ml in three strains. One strain of M. pneumoniae showed tolerance to AZM at MIC 25 micrograms/ml. The other agents exhibited higher MIC than AZM against this organism. 2. Plasma samples were collected from five patients receiving fine granules and four patients receiving capsules for drug level determination. The patients received AZM at 10.0 approximately 16.3 mg/kg body weight once daily for 3 days. Drug concentrations in plasma at two hours after Day 3 dosing were in a range between 0.02 and 0.19 micrograms/ml for fine granules and were in a range between 0.11 and 0.42 micrograms/ml for capsules. 3. Urine samples were collected from four patients receiving fine granules and four patients receiving capsules. Drug levels were determined to be 3 micrograms/ml at post-treatment 48 hours for fine granules and post-treatment 72 hours for capsules. Urinary excretion rates of AZM in three patients on capsules lied in a range between 4.69 and 10.17%. 4. Effectiveness of AZM in fine granules was evaluated in 128 patients having a total of 19 different infections. AZM was rated "excellent" in 51 patients, "good" in 63, "fair" in 8, "poor" in 6, resulting in an efficacy rate of 89.1%. Effectiveness of AZM in capsular form was evaluated in 23 patients with five different infections. AZM was found "excellent" in 13 patients and "good" in 10, resulting in an efficacy rate of 100%. 5. AZM in fine granules eradicated 45 strains of 54 in 8 different bacteria. AZM in capsules eradicated 9 strains of 10 strains in 6 different bacteria. 6. As for adverse reactions, one patient complained of eruption, one vomiting, one loose stool, five diarrhea, when administered with fine granular form of AZM. One patient on AZM capsules experienced urticaria and vomiting. 7. As for abnormal laboratory changes, three patients were found with decreased WBC, seven with increased eosinophil, two with increased GOT and GPT, one with increased GPT. They were all on fine granular form of AZM. As far as abnormalities found in patients administered with AZM in capsular form, two showed decreased WBC, one decreased WBC along with increased eosinophil, and three increased eosinophil.

A 52-year-old man consulted our hospital with a right abdominal mass. Imaging diagnosis revealed a 10.5-cm right renal tumor and bilateral adrenal masses (7 cm on the left side and 2.5 cm on the right). A radical nephrectomy and bilateral adrenalectomy demonstrated renal cell carcinoma with metastases to bilateral adrenal glands. Despite prophylactic treatment with interferon-alpha, a swollen left cervical lymph node and a left renal mass, which seemed to be metastatic lesions, developed respectively 6 and 33 months postoperative. He is alive with disease at 40 months.

The extended V-Y flap, a modified V-Y advancement flap, is very useful in closing relatively large defects on the face. Its extension limb is hinged down as a transposition flap on the end of the V-Y advancement flap to close the most distal portion of the defect. We applied this flap in closing a defect following excision of skin tumors on the face with excellent cosmetic results in 11 patients. However, this flap tended to make a distortion at the base of the flap in the primary closure site. By drawing figures, we concluded that the distortion was due to the characteristic of this technique as a V-Y advancement-rotation flap or V-Y advancement flap with rotation.

The human Evi-1 gene located on chromosome 3q26, encodes a zinc finger protein that functions as a transcription factor. It was frequently overexpressed in leukemias having 3q26 abnormalities such as t(3;3)(q21;q26) and inv(3)(q21 q26), and subjected to structural alteration in t(3;21)(q26;q22). In addition, recent studies indicated that several cases of leukemias without 3q26 abnormalities also expressed Evi-1 gene. In this study we present another case of structural alteration of Evi-1 gene in a case of inv(3)(q21 q26), in which Evi-1 was truncated and a shorter form of Evi-1 protein was expressed upon rearrangement of the gene. We also studied expression of the Evi-1 gene in a variety of leukemias by northern blot analysis. Evi-1 was overexpressed not only in leukemias with 3q26 abnormalities, but, in those without 3q26 abnormalities, especially in blast crisis of CML. Our result also supports an idea that Evi-1 is a relevant oncogene whose overexpression or structural changes might play a crucial role in development of human leukemias.

The sonographic and magnetic resonance imaging findings of three cases of surgically proven malignant lymphoma of the testis were reviewed and their diagnostic implications were evaluated. In all three cases ultrasonography showed striated hypoechoic bands with paralleling hyperechoic lines radiating peripherally from the mediastinum testis. We believe they represented blood vessels. On T1-weighted MR images, the tumor showed homogenous hyperintensity in one case and homogenous isointensity in the other two. On T2-weighted images the tumor showed homogenous hypointensity in two cases and homogenous isointensity in one. After Gd-DTPA administration, the tumor showed homogenous enhancement in two cases and inhomogenous enhancement in one. In two cases there were enhancing striated bands in the tumor. Despite the diffuse infiltration by the tumor, the basic architecture of the testis, epididymis, and spermatic cord was preserved. When MRI and ultrasonography show an infiltrative disease preserving the basic architecture of the testis and ultrasonography presents hypoechoic bands radiating peripherally from the mediastinum testis, a diagnosis of malignant lymphoma should be considered.

Surgical procedure for hypertrophic obstructive cardiomyopathy (HOCM) in a patient chronic hemodialysis has not been reported in Japan. This is a case report of a 61-year-old male who had been suffering from angina pectoris during hemodialysis. Cardiac catheterization showed a systolic pressure gradient of 79 mmHg at the left ventricular outflow tract and left ventriculogram demonstrated severe mitral regurgitation. He underwent mitral valve replacement and left ventricular myectomy with hemodialysis and extracorporeal ultrafiltration method during cardiopulmonary bypass. Postoperative catheterization showed a decrease of pressure gradient to 19 mmHg at the left ventricular outflow tract, and relief of angina was obtained.

Two new B-cell lines, BALM-13 and BALM-14, were established from the bone marrow aspirate of a 13-year-old male patient with acute leukemia. These cell lines are unique in their expression of CD antigens. BALM-13 was characterized as belonging to the Burkitt lymphoma group III cell type (CD10-, CD20+, CD23+, D39+, CD77-), and BALM-14 to the Burkitt lymphoma group I cell type (CD10+, CD20+, CD23-, CD39-, CD77+). The expression of immunoglobulin chains of BALM-13 (lambda delta mu) differed from those of BALM-14 (lambda mu). Furthermore, BALM-13 was positive for Epstein-Barr virus nuclear antigen but BALM-14 was negative. This is a unique pair of cell lines having intraclonal phenotypic heterogeneity.

Acute renal failure (ARF) with loin pain after exercise with development of wedge-shaped contrast enhancement on computed tomography (CT) has been described as a new disease entity. We report 2 patients who developed ARF with severe loin pain after exercise, showing wedge-shaped lesions both on CT and ultrasonography. Renal ultrasonography showed indistinct wedge-shaped lesions when performed at oliguric or recovery phase of ARF, whereas it showed distinct lesions when done between these two phases. Contrast CT performed at the recovery phase disclosed distinct wedge-shaped lesions. Our findings suggested that the best time to detect these lesions by ultrasonography is between at the beginning of diuresis and at the time of serum creatinine levels of 2 mg/dl.

MR imaging was performed with the retrograde administration of ferro-magnetic contrast material and air in 10 patients with rectosigmoid colon cancer. The border of the lesions was well demonstrated in spin echo images, and MR imaging yielded additional diagnostic information to that provided by barium enemas and CT scans in all cases. In conclusion, this type of contrast material seemed promising in the MRI diagnosis of rectal lesions.

A 26-year-old man with high flow priapism after blunt perineal trauma, is described herein. Patient evaluation included intracavernal blood-gasometry, cavernography, color flow Doppler sonography. The blood-gasometry showed pH 7.413, pO2 77.9 mmHg, pCO2 41.0 mmHg, HCO2- 26.1 mmol/L, BE 2.0 mmol/L. By direct cavernosography, pooling of contrast agent was seen at the root of the penis. Color flow Doppler sonography revealed pulsatile, turbulent flow within left corpus cavernosum. Our case was diagnosed as high flow priapism from these findings. Detumescence was not achieved by an alpha-adrenergic agent. Superselective embolization of the deep artery of the penis with autologous blood clot was performed with good results. Our case demonstrates that this procedure is a safe and effective therapy for high flow priapism and that erectile function can return to normal.

A rare case of spontaneous regression of cerebral arterio-venous malformation (AVM) is reported. A 76-year-old male was admitted to Juzen General Hospital due to generalized convulsion on August 24, 1987. On admission, results of physical and neurological examinations were normal. Plain CT scans showed an iso-density lesion with a slightly high density spot in the left frontal lobe, and enhanced CT scans showed multiple, irregularly tubular enhancements in the lesion. Left carotid angiogram (CAG) demonstrated an arteriovenous malformation (AVM) in the left frontal lobe, which was fed by the left ACA and MCA and drained by the ascending cerebral vein and superficial Sylvian vein. There was also an anterior communicating artery aneurysm. At the patient's request, he was treated conservatively and was discharged without neurological deficit. Though he continued to take anticonvulsants thereafter, he felt weakness or numbness of the right extremities once a year. Five years after the first admission, he developed sudden onset of right hemiparesis, aphasia and consciousness disturbance. On admission, his platelet aggregation function was elevated. At this time, enhanced CT scans did not show any enhanced area in the left frontal lobe where AVM had been found previously. T2-weighted magnetic resonance image showed a mixed intensity area without any flow void phenomenon suggesting thrombosis of the nidus. Left CAG demonstrated occlusion of the A1-A2 junction of the anterior cerebral artery and disappearance of the AVM. He was treated conservatively again, and was discharged without neurological deficit.(ABSTRACT TRUNCATED AT 250 WORDS)

A rapid and significant vasodepressor effect was obtained during acute stage before and after surgery on aortic aneurysm with continuous antihypertensive therapy using nicardipine hydrochloride. Twenty patients were treated; 6 patients had an acute dissecting aneurysm of the aorta, 8 were postoperative cases following resection of the thoracic aortic aneurysm, and 6 were postoperative cases of the abdominal aortic aneurysm. Nicardipine hydrochloride is easy to administer, has few side effects, and was found to be effective as antihypertensive therapy before and after surgery. The use of nicardipine hydrochloride has therefore been adopted by this unit as part of the treatment protocol for these patients.

A 75-year-old male, who had undergone left extrapleural plombage for left pulmonary tuberculosis 46 years before, was admitted because of cough and sputum. The Chest X-ray and CT-scan films on admission show fluid collection in plombs. Left postero-lateral thoractomy was performed on January 14, 1994. There were thickness of the parietal pleura and no findings of empyema or fistulas. Extrapleural plombs and partial part of the vegetation were removed safely. There were two damaged plombs and fluid collection in another two plombs. No findings of residual tuberculosis were found on postoperative pathological and bacteriological examinations. He has been well for 8 months postoperatively.

Seven cell lines, MOLM-6, -7, -8, -9, -10, -11 and -12, were established from a single blood sample from a patient with chronic myelogenous leukemia (CML) in blastic phase having the Ph1 chromosome abnormality. Based on immunophenotyping, two of these seven cell lines, MOLM-7 and -11, represented the megakaryoblastoid lineage, and the other five cell lines represented two different maturation stages of the myeloid lineage.

Clinical data of 106 patients (177 renal units) with vesicoureteral reflux diagnosed within first year of life were reviewed to clarify its clinical feature and reflux nephropathy. 1) 82.1% (87/106) of them were boy, 83.1% (147/177) of renal units had high grade reflux (VUR grade III or more). These findings suggested that some of them were Fetal Vesicoureteral Reflux. 2) At presentation, 57.1% (101/177) of renal units showed renal parenchymal scars and 18.9% (20/106) of cases had renal dysfunction (s-Cror = 0.6 mg/dl). Renal dysplasia or hypoplasia was found in rather high incidence of 8.5% (15/177) suggested that normal fetal nephrogenesis is also disturbed in early infants having VUR. 3) The patients having multiple renal scarring bilaterally had significant impaired both tubular and glomerular function, showing reflux nephropathy. 4) During more than 2 years follow-up on 102 renal units, totally 29 of them (28.4%) showed new scar-formation and/or scar-advancement. Among the kidneys more than grade III reflux and undergone antireflux surgery, those with delayed surgery had the incidence of new scar-formation and/or scar-progression as high as 48.6% (18/37). On the other hand, in those with immediate surgery, the incidence was much lower of 14.3% (5/35). In addition, the incidence in case of non-surgery was 38.5% (5/13). Indication or timing of antireflux surgery for infants is still controversial however, the above results suggest that early antireflux surgery which aimed to eliminate reflux and risk of upper urinary tract deterioration from infantile immatured kidney is more beneficial in order to prevent progression of renal scarring and attain normal renal development.(ABSTRACT TRUNCATED AT 250 WORDS)

The genotypes of the CYP2E1 and ALDH2 loci in alcoholic and non-alcoholic (healthy) Japanese were investigated to examine the relationship between the polymorphisms of CYP2E1 (C1/C2) and ALDH2 (ALDH2*1/ALDH2*2), and the susceptibility to alcoholism. There was no significant difference in C2 gene frequency between alcoholics (0.20) and non-alcoholics (0.19), while there was a significant difference in ALDH2 allele frequency, suggesting that the C2 allele of CYP2E1 may have nothing to the risk of developing alcoholism in Japanese, whereas the ALDH2*1 allele may influence drinking behavior and the development of alcoholism.