A systemic lupus erythematosus patient with thunderclap headache: reversible cerebral vasoconstriction syndrome.

Headaches are common in patients with systemic lupus erythematosus (SLE). It is important to identify the exact cause of headaches in SLE to avoid unnecessary steroid or immunosuppressive therapy like in neuropsychiatric SLE. A 35-year-old woman with SLE suddenly developed severe headache. Magnetic resonance angiography showed multifocal segmental narrowing of cerebral arteries, suggestive of central nervous system vasculitis. However, lack of abnormal enhancement in vessel wall imaging indicated reversible cerebral vasoconstriction syndrome (RCVS) rather than central nervous system vasculitis. The patient was treated with oral nimodipine and she recovered over a period of two months. Following magnetic resonance angiography on day 90 was normal. Herein we report a case of reversible cerebral vasoconstriction syndrome in an SLE patient with literature review.

Genomewide association study of peanut allergy reproduces association with amino acid polymorphisms in HLA-DRB1.

BACKGROUND: Genetic variants for IgE-mediated peanut allergy are yet to be fully characterized and to date only one genomewide association study (GWAS) has been published. OBJECTIVE: To identify genetic variants associated with challenge-proven peanut allergy. METHODS: We carried out a GWAS comparing 73 infants with challenge-proven IgE-mediated peanut allergy against 148 non-allergic infants (all ~ 1 year old). We tested a total of 3.8 million single nucleotide polymorphisms, as well as imputed HLA alleles and amino acids. Replication was assessed by de novo genotyping in a panel of additional 117 cases and 380 controls, and in silico testing in two independent GWAS cohorts. RESULTS: We identified 21 independent associations at P ≤ 5 × 10-5 but were unable to replicate these. The most significant HLA association was the previously reported amino acid variant located at position 71, within the peptide-binding groove of HLA-DRB1 (P = 2 × 10-4 ). Our study therefore reproduced previous findings for the association between peanut allergy and HLA-DRB1 in this Australian population. CONCLUSIONS AND CLINICAL RELEVANCE: Genetic determinants for challenge-proven peanut allergy include alleles at the HLA-DRB1 locus.

A major susceptibility locus for atopic dermatitis maps to chromosome 3q21.

Atopic dermatitis (eczema) is a chronic inflammatory skin disease with onset mainly in early childhood It is commonly the initial clinical manifestation of allergic disease, often preceding the onset of respiratory allergies. Along with asthma and allergic rhinitis, atopic dermatitis is an important manifestation of atopy that is characterized by the formation of allergy antibodies (IgE) to environmental allergens. In the developed countries, the prevalence of atopic dermatitis is approximately 15%, with a steady increase over the past decades. Genetic and environmental factors interact to determine disease susceptibility and expression, and twin studies indicate that the genetic contribution is substantial. To identify susceptibility loci for atopic dermatitis, we ascertained 199 families with at least two affected siblings based on established diagnostic criteria. A genome-wide linkage study revealed highly significant evidence for linkage on chromosome 3q21 (Zall=4.31, P= 8.42 10(-6)). Moreover, this locus provided significant evidence for linkage of allergic sensitization under the assumption of paternal imprinting (hlod=3.71,alpha=44%), further supporting the presence of an atopy gene in this region. Our findings indicate that distinct genetic factors contribute to susceptibility to atopic dermatitis and that the study of this disease opens new avenues to dissect the genetics of atopy.

Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.

Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.

Risk factors for osteoporosis in long-term survivors of intracranial germ cell tumors.

SUMMARY: We measured bone mineral densities in 28 intracranial germ cell tumor long-term survivors. There was the high prevalence of osteoporosis and osteopenia, 25.0% and 42.9%, respectively, and three additional risk factors, male sex, a low lean mass, and adult growth hormone replacement, were identified. INTRODUCTION: Intracranial germ cell tumor long-term survivors (iGCTLS) have many risk factors for osteoporosis, including irradiation from cancer therapy and multiple hormone deficiencies. However, no study of bone mineral density (BMD) has been conducted in iGCTLS because these tumors are rare. The aims of this study were to evaluate the prevalence of osteoporosis and to identify risk factors associated with reduced bone mass in iGCTLS. METHODS: We evaluated BMD and body composition of 28 iGCTLS (10.9 ± 5.2 years after cancer treatment; 13 males) using dual-energy X-ray absorptiometry. To determine risk factors, we analyzed the medical history, including the nature of the tumor, treatment modality, endocrine status, hormone replacement therapy, lifestyle, and biochemical parameters. RESULTS: Twenty-five percent of iGCTLS were diagnosed with osteoporosis and 42.9% with osteopenia. Most males (92.3%) had low BMD. Lean mass (LM) was positively correlated with BMD in all regions of interest, and the starting age of adult growth hormone (GH) replacement was negatively correlated with the BMD Z-score at the femur neck. In logistic regression analysis, male sex and low LM were related to low BMD. CONCLUSIONS: The iGCTLS had a high prevalence of low BMD. We found that male sex, low LM, and delayed start of adult GH replacement were risk factors for osteoporosis. Therefore, the BMD of all iGCTLS should be evaluated, and if it is low, proper management should be started early.

Associations between Hair Mineral Concentrations and Skeletal Muscle Mass in Korean Adults.

OBJECTIVES: Muscle health plays an important role in maintaining function and independence in the elderly, and some nutrients provide protection against the age-related decline of muscle strength and function. Minerals are important nutrients that may contribute to the prevention and treatment of sarcopenia, but they have not been well-studied. This study investigated whether hair mineral concentrations differ between subjects with low muscle mass (LMM) and subjects with normal muscle mass. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: A total of 232 adults ≥ 20 years of age who visited the Health Promotion Center of the University Hospital in Gyeonggi-do, Republic of Korea. MEASUREMENTS: The data from 232 subjects were analyzed and divided into LMM and normal groups based on the appendicular skeletal muscle mass index (ASMI) (LMM was defined as ASMI < 7.0 kg/m2 in men and < 5.7 kg/m2 in women). Skeletal muscle mass was estimated using a multi-frequency bioelectrical impedance analysis (BIA) device with a body composition analyzer. RESULTS: Overall mean age of participants was 50.4±11.6 years (29.7% women). Subjects with LMM showed significantly lower triglyceride levels, greater high-density lipoprotein cholesterol levels, and lower body mass index (BMI), compared with subjects who had normal muscle mass. No significant differences in hair mineral concentrations were observed between subjects with LMM and subjects with normal muscle mass, with the exception of copper. Hair copper concentrations were significantly greater in subjects with LMM than in subjects with normal muscle mass after adjustment for covariates and factors (65.7±14.2 vs 33.1±4.3 µg/g, P = 0.035). CONCLUSION: These results suggest that hair mineral status may play a role in the development of LMM. Therefore, further studies with larger numbers of subjects are required to identify the effects of mineral imbalances, their relationships with sarcopenia, and the differences between subjects with LMM and subjects with normal muscle mass.

Calpain mediates degradation of cytoskeletal proteins during Jurkat T-cell death induced by Entamoeba histolytica.

Entamoeba histolytica is known to induce host cell death via activation of calpain and caspases. In this study, we investigated the specific proteases involved in the degradation of cytoskeletal proteins during Jurkat T-cell death induced by E. histolytica. Amoebic trophozoites induced marked degradation of paxillin, Cas, vimentin, vinculin and talin, as well as α- or ß-spectrin, in Jurkat T cells. The cleavage effects of E. histolytica were strongly retarded by pretreatment with a calpain inhibitor, but not with a pan-caspase inhibitor. In addition, calpain knockdown with siRNA in Jurkat T cells effectively inhibited E. histolytica-induced PARP, paxillin, α-spectrin, ß-spectrin and talin degradation, as compared to scrambled siRNA. These results suggest that calpain plays a crucial role in the cleavage of cytoskeletal proteins during cell death induced by E. histolytica.

Reactive oxygen species-dependent necroptosis in Jurkat T cells induced by pathogenic free-living Naegleria fowleri.

Naegleria fowleri, a free-living amoeba, is the causative pathogen of primary amoebic meningoencephalitis in humans and experimental mice. N. fowleri is capable of destroying tissues and host cells through lytic necrosis. However, the mechanism by which N. fowleri induces host cell death is unknown. Electron microscopy indicated that incubation of Jurkat T cells with N. fowleri trophozoites induced necrotic morphology of the Jurkat T cells. N. fowleri also induced cytoskeletal protein cleavage, extensive poly (ADP-ribose) polymerase hydrolysis and lactate dehydrogenase (LDH) release. Although no activation of caspase-3 was observed in Jurkat T cells co-incubated with amoebae, intracellular reactive oxygen species (ROS) were strongly generated by NADPH oxidase (NOX). Pretreating cells with necroptosis inhibitor necrostatin-1 or NOX inhibitor diphenyleneiodonium chloride (DPI) strongly inhibited amoeba-induced ROS generation and Jurkat cell death, whereas pan-caspase inhibitor z-VAD-fmk did not. N. fowleri-derived secretory products (NfSP) strongly induced intracellular ROS generation and cell death. Necroptotic effects of NfSP were effectively inhibited by pretreating NfSP with proteinase K. Moreover, NfSP-induced LDH release and intracellular ROS accumulation were inhibited by pretreating Jurkat T cells with DPI or necrostatin-1. These results suggest that N. fowleri induces ROS-dependent necroptosis in Jurkat T cells.

Calpain-dependent cleavage of SHP-1 and SHP-2 is involved in the dephosphorylation of Jurkat T cells induced by Entamoeba histolytica.

Host cell death induced by Entamoeba histolytica is an important mechanism for both host defence and microbial immune evasion during human amoebiasis. However, the signalling pathways underlying cell death induced by E. histolytica are not fully understood. This study investigated the involvement of the protein tyrosine phosphatases (PTPs) SHP-1 and SHP-2 in the dephosphorylation associated with E. histolytica-induced host cell death. Incubation with E. histolytica resulted in a marked decrease in protein tyrosine phosphorylation levels and degradation of SHP-1 or SHP-2 in Jurkat cells. Pre-treatment of cells with a calpain inhibitor, calpeptin, impeded the amoeba-induced dephosporylation and cleavage of SHP-1 or SHP-2. Additionally, inhibition of PTPs with phenylarsine oxide (PAO) attenuated Entamoeba-induced dephosphorylation and DNA fragmentation in Jurkat T cells. These results suggest that calpain-dependent cleavage of SHP-1 and SHP-2 may contribute to protein tyrosine dephosphorylation in Jurkat T cell death induced by E. histolytica.

Mitochondrial respiration is required for activation of ERK1/2 and caspase-3 in human eosinophils stimulated with hydrogen peroxide.

BACKGROUND: Eosinophils are important effector cells in the pathogenesis of allergic diseases such as bronchial asthma. Oxidative stress in the form of cellular reactive oxygen species (ROS) has been implicated in the pathogenesis of several allergic diseases. Recently, it has become evident that mitochondrial-derived ROS are important transducers of apoptosis and intracellular signaling. In this study, we investigated the role of mitochondrial ROS in the activation of extracellular signal-regulated kinases (ERK) 1 and 2-mitogen-activated protein kinase (MAPK) and caspase-3 in human eosinophils stimulated with H2O2. METHODS: Human eosinophils were purified using immunomagnetic negative selection and then stimulated with H2O. H2O2-induced eosinophil apoptosis was measured by staining cells with annexin V. Activation of ERK1/2 MAPK and caspases was assessed by Western blotting. Eosinophils were pretreated with rotenone, an inhibitor of the mitochondrial electron transport chain, before H2O2 was added. RESULTS: Treatment with 1 mM H2O2 induced externalization of phosphatidylserine (PS) and activation of caspases in eosinophils. H2O2-triggered PS externalization and cleavage of caspase-3 were markedly inhibited by pretreatment with the mitochondrial ROS scavenger N-acetyl-L-cysteine. In addition, H2O2 strongly induced phosphorylation of ERK1/2, but not ERK5, in eosinophils. Hydrogen peroxide-triggered activation of caspase-3 and ERK1/2 was attenuated by pretreatment with rotenone. CONCLUSIONS: These results suggest that mitochondrial respiration is essential for activation of ERK1/2 and caspase-3 in human eosinophils stimulated with H2O2.

Tissue- and development-specific expression of multiple alternatively spliced transcripts of rat neuronal nitric oxide synthase.

Nitric oxide (NO) functions as an intercellular messenger and mediates numerous biological functions. Among the three isoforms of NO synthase that produce NO, the ubiquitously expressed neuronal NO synthase (nNOS) is responsible for a large part of NO production, yet its regulation is poorly understood. Recent reports of two alternative spliceforms of nNOS in the mouse and in man have raised the possibility of spatial and temporal modulation of expression. This study demonstrates the existence of at least three transcripts of the rat nNOS gene designated nNOSa, nNOSb, and nNOSc, respectively, with distinct 5' untranslated first exons that arise from alternative splicing to a common second exon. Expression of the alternative transcripts occurs with a high degree of tissue and developmental specificity, as demonstrated by RNase protection assays on multiple tissues from both fetal and adult rats. Furthermore, terminal differentiation of rat pheochromocytoma-derived PC12 cells into neurons is associated with induction of nNOSa, suggesting, likewise, development- and tissue-specific transcriptional control of nNOS isoform expression. Physical mapping using a rat yeast artificial chromosome clone shows that the alternatively spliced first exons 1a, 1b, and 1c are separated by at least 15-60 kb from the downstream coding sequence, with exons 1b and 1c being positioned within 200 bp of each other. These findings provide evidence that the biological activity of nNOS is tightly and specifically regulated by a complex pattern of alternative splicing, indicating that the notion of constitutive expression of this isoform needs to be revised.

Identifying fibromyalgia subgroups using cluster analysis: Relationships with clinical variables.

BACKGROUND: Patients with fibromyalgia (FM) exhibit significant clinical heterogeneity, in terms of physical, social and psychological functions, as well as therapeutic responses. Here, we examined FM patients in terms of pain, physical, social and psychological variables to identify clinical subgroups that may be predictive of treatment patterns. METHODS: A total of 313 FM patients were interviewed using a structured questionnaire that included sociodemographic data, current or past FM symptoms and current use of relevant medications. A K-means cluster analysis was conducted using variables reflecting tender points, the Fibromyalgia Impact Questionnaire, Beck Depression Inventory, State-Trait Anxiety Inventor and Social Support Scale. RESULTS: Four distinct clusters were identified in these patients. Group 1 was characterized by high pain levels, severe physical and mental impairment and low social support. Group 2 had moderate pain and physical impairment, mild mental impairment and moderate social support. Group 3 had moderate pain, low physical and moderate mental impairment and low social support. Group 4 had low pain levels, nearly normal physical and mental function and high social support. Group 1 was more often a current or past smoker, more likely to have a variety of symptoms, including swelling, cognitive dysfunction, dizziness, syncope, oesophageal dysmotility, dyspepsia, irritable bladder, vulvodynia and restless leg syndrome. CONCLUSIONS: We identified four subgroups of FM patients based on pain, physical, social and psychological function. These subgroups had different clinical symptoms and medication profiles, suggesting that FM may be better managed using a more comprehensive assessment of an individual patient's symptoms. SIGNIFICANCE: FM patients can be clustered into four distinct subgroups based on clinically measurable variables - pain, physical involvement, psychological function and social support. These subgroups had different clinical symptoms and medication profiles.

Association between catechol-O-methyl transferase gene polymorphisms and fibromyalgia in a Korean population: A case-control study.

BACKGROUND: Although polymorphisms of the catechol-O-methyl transferase (COMT) gene have been implicated in altered pain sensitivity, results concerning the association between COMT gene polymorphisms and fibromyalgia (FM) are equivocal. We assessed the associations between COMT single-nucleotide polymorphisms (SNP) and FM risk and symptom severity. METHODS: In total, 409 FM patients and 423 controls were enrolled. Alleles and genotypes at five positions [rs6269 (A>G), rs4633 (C>T), rs4818 (C>G), rs4680 (C>G) and rs165599 (A>G)] in the COMT gene were genotyped from peripheral blood DNA. RESULTS: Alleles and genotypes of the rs4818 COMT gene polymorphism were significantly associated with increased susceptibility to FM. The rs4818 GG genotype was more strongly associated with FM compared to the CC genotype (OR = 1.680, 95% CI: 1.057, 2.672, p = 0.027). Although allele and genotype frequencies did not differ among groups, the rs4633 CT genotype was not associated with the presence of FM following adjustment for age and sex (OR = 0.745; 95% CI: 0.558, 0.995; p = 0.046). However, no association was observed between clinical measures and individual COMT SNPs. In haplotype analysis, there was a significant association between ACG haplotype and FM susceptibility sex (OR = 2.960, 95% CI: 1.447, 6.056, p = 0.003) and the number of tender points (p = 0.046). CONCLUSIONS: This large-scale study suggests that polymorphisms of the COMT gene may be associated with FM risk and pain sensitivity in Korean FM patients. However, our results differed to those of previous studies, suggesting ethnic variation in COMT gene polymorphisms in FM. WHAT DOES THIS STUDY ADD: By contrast to Caucasian and Latin-American populations, the COMT gene polymorphisms are associated with FM risk and pain sensitivity in Korean FM patients, suggesting ethnic variation in COMT gene polymorphisms.

Localisation of a gene for an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia, and distinctive facies to chromosome 15q26.

BACKGROUND: We have previously described an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia (MED), and distinctive facies in a large, extended Omani family. The MED observed seems to be part of a larger malformation syndrome, since both craniofacial and central nervous system changes were present in the family. We performed a whole genome scan in this family in order to identify the gene locus for this malformation syndrome. METHODS AND RESULTS: Using homozygosity mapping, we show linkage to the telomeric region of the long arm of chromosome 15. The position of both the disease gene and the principal glycoprotein, chondroitin sulphate proteoglycan (aggrecan, AGC1) on chromosome 15q26, suggested that the aggrecan gene is a candidate for the disease in this family. However, three of the four affected children were heterozygous for a polymorphism at position 831 of the coding sequence of AGC1, providing strong evidence against its involvement. CONCLUSION: We have identified a gene locus for a recessive syndrome of macrocephaly, MED, and distinctive facies in a large Omani family. Aggrecan located on chromosome 15q26, within the critical region determined for this syndrome in this family, was excluded as a candidate gene.

The complementary deoxyribonucleic acid sequence of guinea pig endometrial prorelaxin.

The nucleotide sequence of the relaxin gene transcript in the endometrium of the late pregnant guinea pig has been determined. The strategy used was a combination of polymerase chain reaction (PCR) with primers designed from the mRNA sequence of porcine preprorelaxin, rapid amplification of cDNA ends-PCR, and blunt end cloning in M13 mp18. With heterologous primers, a 226-basepair (bp) segment of the guinea pig relaxin gene sequence was obtained and was used to design a guinea pig-specific primer for use with the rapid amplification of cDNA ends-PCR method. The latter allowed completion of the sequence of 336 bp, with a 96-bp overlap. The sequence obtained shows greater homology at both the nucleotide and amino acid levels with porcine and human relaxins H1 and H2 than with rat relaxin, supporting the thesis that the guinea pig is not a rodent. The transcription of the guinea pig endometrial relaxin gene during pregnancy was confirmed by Northern analysis of guinea pig endometrial tissues with a species-specific cDNA probe. The endometrial relaxin gene is transcribed during pregnancy, but not in lactation, consistent with the observed immunostaining for relaxin.

Congenic substitution mapping excludes Sa as a candidate gene locus for a blood pressure quantitative trait locus on rat chromosome 1.

Previously, linkage analysis in several experimental crosses between hypertensive rat strains and their contrasting reference strains have identified a major quantitative trait locus (QTL) for blood pressure on rat chromosome 1 (Chr 1) spanning the Sa gene locus. In this study, we report the further dissection of this Chr 1 blood pressure QTL with congenic substitution mapping. To address whether the Sa gene represents a candidate gene for the Chr 1 blood pressure QTL, congenic strains were developed by introgressing high blood pressure QTL alleles from the stroke-prone spontaneously hypertensive rat (SHRSP) into the normotensive Wistar-Kyoto (WKY-1) reference strain. Congenic animals carrying a chromosomal segment from stroke-prone spontaneously hypertensive rats between genetic markers Mt1pa and D1Rat200 (including the Sa gene locus) show a significant increase in basal systolic and diastolic blood pressure compared with their normotensive Wistar-Kyoto progenitors (P<0.001, respectively), whereas congenic animals carrying a subfragment of this Chr 1 region defined by markers Mt1pa and D1Rat57 (also spanning the Sa gene) do not show elevated basal blood pressure levels (P=0.83 and P=0.9, respectively). Similar results were obtained for NaCl-induced blood pressure values. Thus, the blood pressure QTL on Chr 1 is located centromeric to the Sa gene locus in a region that is syntenic to human chromosome 11p15.4-p15.3. This region excludes the Sa as a blood pressure-elevating candidate gene locus on the basis of congenic substitution mapping approaches.

Synthesis and oral antitumor activity of tetrakis(carboxylato)platinum(IV) complexes.

A novel class of tetrakis(carboxylato)platinum(IV) complexes, [Pt(O(2)CR)(4)(dach)] (dach = trans-(+/-)-1,2-diaminocyclohexane; R = C(n)H(2n+1), n = 1 approximately 5), was synthesized and studied for physicochemical properties and oral antitumor activity. Lipophilicity and aqueous solubility of the title complexes were greatly dependent on the alkyl chain length of the carboxylate ligand, and their partition coefficient and solubility changed by 4 or 5 orders of magnitude from acetate to hexanoate complexes. On the other hand, the range of their cathodic reduction potential (-546 approximately -403 mV) depending on the chain length of the carboxylate ligand was relatively small. Among the title complexes, the tetrakis(propionato)platinum(IV) complex, [Pt(O(2)CC(2)H(5))(4)(dach)], with appropriate lipophilicity (log P = 0.18) and aqueous solubility (14.6 mg/mL) was found to exhibit better oral antitumor activity than JM216 against the human ovarian tumor xenograft SKOV3 in nude mice.

The cardiac renin-angiotensin-aldosterone system and hypertensive cardiac hypertrophy.

Angiotensin-converting enzyme inhibitors have proven to be uniquely effective in inducing regression, or preventing the occurrence, of ventricular hypertrophy associated with systemic hypertension. This has pointed, for many years, to a possible direct involvement of the renin-angiotensin system in the pathogenesis of cardiac hypertrophy. Over the last 10 years further supporting evidence has been forthcoming about direct trophic effects of angiotensin II in several experimental systems. Additionally, we now have rather conclusive evidence for the existence of a local, intracardiac renin-angiotensin system, which is capable of synthesis of all components of the system, and of cleaving, via the classic pathway, angiotensin peptides from the precursor, angiotensinogen. Moreover, a number of studies have demonstrated the capacity of regulatory response and modulation of activity of the local system in response to a variety of pharmacologic perturbations as well as differential expression of specific components under pathologic conditions, including compensatory hypertrophy and remodeling after myocardial infarction, pressure overload hypertrophy, and volume overload hypertrophy. Continued research into the role of the cardiac renin-angiotensin system in the pathogenesis of cardiac hypertrophy and failure will provide us with the tools to devise more specific, targeted strategies for therapeutic intervention or prevention.

Activation of phonological codes during eye fixations in reading.

Two experiments addressed the issue of whether phonological codes are activated early in a fixation during reading using the fast-priming technique (S. C. Sereno & K. Rayner, 1992). Participants read sentences and, at the beginning of the initial fixation in a target location, a priming letter string was displayed, followed by the target word. Phonological priming was assessed by the difference in the gaze duration on the target word between when the prime was a homophone and when it was a control word equated with the homophone on orthographic similarity to the target. Both experiments demonstrated homophonic priming with prime durations of about 35 ms, but only for high-frequency word primes, indicating that lexicality was guiding the speed of the extraction of phonological codes early in a fixation. Evidence was also obtained for orthographic priming, and the data suggest that orthographic and phonological priming effects interact in a mutually facilitating manner.

Bcl-2 expression in neuroblastoma is differentially regulated by differentiation inducers.

Neuroblastoma is characterized by differentiation in vivo and in vitro, and the process is known to be associated with changes in various gene expressions, among which is the bcl-2 gene whose major function may be potentially involved in the resistance to anticancer chemotherapy. We investigated the changing patterns of bcl-2 expression in neuroblastoma cell lines according to differentiation to assess whether the expression patterns can be differentially modulated by different types of differentiation inducers. Differentiation was induced in two neuroblastoma cell lines [SK-N-SH, SK-N-BE(2)] using all-trans-retinoic acid, gamma-interferon and EHS laminin, respectively. The levels of expression of bcl-2 were analysed before and after differentiation using immunoblotting and subsequent densitometry. The expression patterns of bcl-2 differed according to the type of differentiation inducers. Its expression increased when treated with retinoic acid and EHS laminin along with neuronal differentiation, while differentiation with gamma-interferon treatment was associated with decreased bcl-2 expression. Decreased expression of bcl-2 despite neuronal differentiation induced by gamma-interferon was thought to be important in that a certain differentiation pathway without increased drug resistance-related factor expression exists, which in turn has implications for the clinical application of gamma-interferon, combined with chemotherapy.