High-resolution copy number variation analysis of schizophrenia in Japan.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Detection of IgE autoantibodies to BP180 and BP230 and their relationship to clinical features in bullous pemphigoid.

BACKGROUND: IgE autoantibodies are considered to be involved in the pathogenesis of bullous pemphigoid (BP), particularly inflammatory and erythematous phenotypes. OBJECTIVES: To develop reliable enzyme-linked immunosorbent assays (ELISAs) for the detection of IgE autoantibodies to both BP180 and BP230 in BP sera, and to compare the ELISA results with clinical features. METHODS: We used commercially available IgG ELISAs to develop IgE ELISAs for both BP180 and BP230. To determine the influence of excess amounts of IgG autoantibodies, all normal and BP sera were tested before and after IgG adsorption. The results of the IgE ELISAs were statistically compared with various ELISAs and various clinical parameters, including our own severity scores and BP phenotypes. RESULTS: IgG adsorption generally showed no changes in sensitivity and specificity for IgE ELISAs, although slight cross-reactivity of anti-IgE secondary antibody to IgG and interference of excess amounts of IgG autoantibodies to IgE reactivity were suggested. IgE autoantibodies to BP180 were found in 21 of 36 BP sera and IgE autoantibodies to BP230 were found in 18 of 36 BP sera. The results of IgG and IgE ELISAs for both BP180 and BP230 were well correlated. IgG and IgE anti-BP180 antibodies correlated with disease activity but IgG and IgE anti-BP230 autoantibodies did not. IgE anti-BP230 autoantibodies correlated with nodular phenotype but not erythematous phenotype. CONCLUSIONS: The results of this study indicated that IgE autoantibodies to both BP180 and BP230 are frequently detected in BP sera. IgE anti-BP180 autoantibodies seemed to be pathogenic, while an association between IgE autoantibodies and inflammatory BP phenotype was not indicated.

Case report of multiple pustules of the bilateral lower limbs caused by a granulocyte colony-stimulating factor-producing solid pseudopapillary tumour of the pancreas.

Here we report a rare case of neutrophilic dermatoses related to a granulocyte colony-stimulating factor (G-CSF)-producing solid pseudopapillary tumour (SPT). The patient was a 39-year-old woman presenting with scattered pustules and crusts of the palms, heels and thighs and plaques of the bilateral lower legs. The skin biopsy revealed dense neutrophil infiltration in the epidermis to the dermis. A pancreatic head tumour was detected using computed tomography. A pathological examination of the resected specimen suggested an SPT. As the skin eruption promptly disappeared after SPT resection, we hypothesized that SPT secretes growth factors including epidermal growth factor (EGF) and G-CSF. The SPT cells stained positive for both EGF and G-CSF tumour cells. The serum levels of interleukin (IL)-6 and IL-10 and tumour necrosis factor-α were within normal limits before and after the SPT resection. In contrast, the serum IL-8, EGF and G-CSF levels decreased after the SPT resection. This is a rare case of neutrophilic dermatoses related to a G-CSF-producing SPT. The present case suggests that physicians should be aware that a G-CSF-producing tumour is a differential diagnosis to consider in patients with unusual aseptic pustulosis.

Clinical and immunological findings in 104 cases of paraneoplastic pemphigus.

BACKGROUND: Although there are many reports of sporadic patients with paraneoplastic pemphigus (PNP), only a few systematic studies on large cohorts of patients with PNP have been reported. OBJECTIVES: To analyse the clinical and immunological findings in a large cohort of patients with PNP. METHODS: This retrospective study consisted of 104 patients with PNP. Clinical and histopathological manifestations, associated neoplasms, complicating diseases, prognosis and results of immunofluorescence, immunoblotting and enzyme-linked immunosorbent assays (ELISAs) were analysed. RESULTS: The clinical and histopathological findings in this study were generally similar to those in previous reports. The most common associated neoplasms included malignant lymphomas, malignant solid tumours and Castleman disease, in that order, while 12 patients had no detectable tumours. Novel ELISAs for desmocollins (Dscs) showed that 19 (18·6%), 42 (41·2%) and 62 (60·8%) of 102 patients with PNP showed antibodies to Dsc1, Dsc2 and Dsc3, respectively. Thirty-two (60%) of 53 patients had antibodies to alpha-2-macroglobulin-like protein 1 (A2ML1). We found statistically significant correlations between positive desmoglein 3 reactivity and genital lesions, and between positive desmoglein 3 reactivity and bronchiolitis obliterans. CONCLUSIONS: We consider that antibodies to Dscs and A2ML1 are useful for the diagnosis of PNP.

Anti-desmocollin autoantibodies in nonclassical pemphigus.

BACKGROUND: Despite the established pathogenic role of anti-desmoglein (Dsg) antibodies in classical pemphigus, the significance of autoantibodies to another desmosomal cadherin, desmocollin (Dsc) is at present unknown. No consistent immunoassay for immunoglobulin (Ig) G autoantibodies to Dscs has been developed. OBJECTIVES: The aim of this study was to develop reliable assays to detect anti-Dsc autoantibodies. METHODS: We expressed soluble recombinant proteins (RPs) of human Dsc1-3 in mammalian cells and examined sera of various types of pemphigus, including 79 paraneoplastic pemphigus (PNP) sera, by novel enzyme-linked immunosorbent assays (ELISAs) using the RPs. We also performed ELISAs of Dsc baculoproteins and used the complementary DNA (cDNA) transfection method, and compared the results with those of mammalian ELISAs. RESULTS: Through mammalian ELISAs, IgG autoantibodies to Dsc1, Dsc2 and Dsc3 were detected in 16.5%, 36.7% and 59.5% of PNP sera, respectively, and considerable numbers of pemphigus herpetiformis (PH) and pemphigus vegetans (PVeg) sera reacted strongly with Dsc1 and Dsc3. Mammalian ELISAs were highly specific and more sensitive than baculoprotein ELISAs or the cDNA transfection method. Several Dsc-positive sera, particularly PH sera, showed no reactivity with Dsgs. The reactivity of PNP serum and PVeg serum with Dscs was not abolished by pre-absorption with Dsg RPs. CONCLUSIONS: The results of these novel ELISAs indicated that IgG anti-Dsc autoantibodies were frequently detected and potentially pathogenic in nonclassical pemphigus.

Nano-pulverization of poorly water soluble compounds with low melting points by a rotation/revolution pulverizer.

We report a method for pulverizing poorly water soluble compounds with low melting points to nanoparticles without producing an amorphous phase using a rotation/revolution pulverizer. Fenofibrate, flurbiprofen, and probucol were used as crystalline model compounds. They were suspended in a methylcellulose aqueous solution and pulverized with zirconia balls by the rotation/revolution pulverizer. Beeswax, an amorphous compound, was also examined to investigate whether nano-pulverization of a compound with a low melting point was possible. Beeswax was suspended in ethyl alcohol cooled with liquid nitrogen and pulverized with zirconia balls by the rotation/revolution pulverizer. By optimizing the pulverization parameters, nanoparticles (D50 < 0.15 microm) of the crystalline compounds were obtained with narrow particle size distributions at a rotation/revolution speed of 1000 rpm and a rotation/revolution ratio of 1.0 when the vessel was 0 degrees C. Amorphous fenofibrate and flurbiprofen were not detected by differential scanning calorimetry or powder X-ray diffraction, whereas small amounts of amorphous probucol were detected. Beeswax was pulverized to nanoparticles (D50 = 0.14 microm) with ethyl alcohol cooled with liquid nitrogen. Fine nanoparticles of these poorly water soluble compounds with low melting points were obtained by controlling the rotation/revolution speed and reducing the vessel temperature.

Bdp, a new member of a family of DNA-binding proteins, associates with the retinoblastoma gene product.

We have cloned a gene, BDP, encoding a protein with homology to the retinoblastoma-binding proteins Rbp1 and Rbp2. It also has homology to DNA-binding proteins such as Bright, a B-cell-specific trans-activator, and the Drosophila melanogaster dead ringer gene product. Like MyoD, Bdp binds to the COOH-terminal region of pRb through its conserved region and to hypophosphorylated pRb. It also binds to the MAR of the immunoglobulin heavy-chain locus. Thus Bdp may contribute to the transcriptional regulation of genes involved in differentiation and tissue-specific expression.

New E2A/PBX1 fusion transcript in a patient with t(1;19)(q23;p13) acute lymphoblastic leukemia.

About 25% of the children with pre-B cell acute lymphoblastic leukemia (ALL) have a chromosomal translocation of t(1;19)(q23;p13). This translocation juxtaposes the E2A gene on chromosome 19 to the PBX1 gene on chromosome 1, leading to production of a fusion transcript. The fusion sites of the E2A and PBX1 coding sequence have been identical among all cases of t(1;19) ALL studied so far. Here we described a new fusion site of the E2A and PBX1 genes, which was detected in the leukemic blasts of a child with t(1;19) pre-B ALL using the reverse transcriptase polymerase chain reaction and direct sequencing. The fusion site was located just upstream of the DNA binding domain of the E2A gene, and was close to a homeodomain of the PBX1 gene.

Etoposide-related acute promyelocytic leukemia.

The development of therapy-related acute myeloid leukemia (t-AML) has become a growing concern over the past decade, because of the increase in the percentage of long-term survivors of primary malignancy. We reviewed 17 cases with etoposide-related acute promyelocytic leukemia (APL) reported in the literature. The close association between treatment with etoposide for Langerhans cell histiocytosis (LCH) and the development of etoposide-related APL was demonstrated among Japanese and Italians. Our data on the breakpoints (b/ps) of the PML and RARalpha genes are presented. It is suggested that chromatin structure might be more important than specific consensus sequence in the distribution of b/ps in etoposide-related APL.

Acute type A aortic dissection repair with mild-to-moderate hypothermic circulatory arrest and selective cerebral perfusion.

AIM: The purpose of this study was to evaluate surgical results of aortic repair with antegrade selective cerebral perfusion (ASCP) and mild-to-moderate hypothermia (MH) from 28 to 31°C comparing with previous series with hypothermia from 20°C to 27 °C. METHODS: Between 2000 and 2011, 109 consecutive patients underwent surgical repair for acute type A aortic dissection with circulatory arrest and ASCP and MH in our institution. Mean patient age was 67±11 years old. Total arch replacement was performed in 85 patients (78%). Thirty (27%) patients had shock status preoperatively. The patients were divided into two different subsets, which is group A (circulatory arrest at less than 27.9 °C, N.=70), and group B (at more than 28 °C, N.=39). RESULTS: The mean extra-corporeal circulation time was 185±47 minutes in group A and 155±38 minutes in group B (P<0.001). The hospital mortality was 11.4% in group A and 10.3% in group B (P>0.05). Permanent neurological deficit occurred in 10 patients (14.3%) in group A, and in 5 (12.8%) in group B (P>0.05). Two (2.8%) paraplegia occurred in group A, and none in group B (P>0.05). The incidence of renal failure requiring hemodialysis was 17.1% in group A and 7.7% in group B, (P>0.05). Respiratory failure after surgery occurred in 27.1% of patients in group A, and 5.1% in group B (P=0.005). CONCLUSION: Circulatory arrest at more than 28 °C offered sufficient cerebral and distal organ protection for acute type A aortic dissection.

Replacement of the morphologically tricuspid valve in children with discordant atrioventricular connections.

BACKGROUND AND AIM OF THE STUDY: Our clinical experience was reviewed to determine the efficacy of replacement of the atrioventricular (AV) valve for the systemic circulation in children with discordant AV connections undergoing functional biventricular repair. METHODS: Nine children underwent replacement of the morphologically tricuspid valve at the age of 10 months to 15 years. Ventriculoarterial connections were discordant in five children, and double outlet right ventricle with pulmonary stenosis or atresia in four. In all children the prosthesis chosen was a mechanical valve; valve sizes ranged from 19 mm to 31 mm. RESULTS: One patient died of ventricular failure immediately after surgery. Two patients underwent reoperation for re-replacement at eight and 68 months after the initial replacement because of non-structural dysfunction. Complete AV block occurred after intracardiac maneuvers in the non-survivor. Transient AV dissociation was noted in another patient. General conditions improved greatly after surgery in all survivors. In the morphologically right ventricle placed for the systemic circulation the end-diastolic volume fell from 327 +/- 182% (range: 109-621%) to 169 +/- 97% (range: 85-352%) of the anticipated normal value (p = 0.03), while pressure fell from 13 +/- 4 (range: 7-19) mmHg to 8 +/- 3 (range: 2-12) mmHg (p = 0.005). The ejection fraction was only marginally reduced (47 +/- 13% (range: 26-62%) preoperatively versus 34 +/- 11% (range: 20-54%) postoperatively; p = 0.13). CONCLUSIONS: In children with discordant atrioventricular connections and severe regurgitation across the morphologically tricuspid valve, the valve can be efficiently replaced for the systemic circulation.

Ruptured left ventricular pseudoaneurysm penetrating into the left pleural cavity.

We experienced a rare case of ruptured left ventricular pseudoaneurysm penetrating into the left pleural cavity. A 77-year-old woman was first diagnosed with unstable angina due to sudden chest pain onset and abnormal electrocardiographic findings. In 2 days, massive left pleural effusion was recognized by chest X-ray, though subsequent computed tomographic scans did not show any aortic pathology. We observed her with left thoracentesis alone. Two days later, cardiac arrest suddenly occurred and emergency surgery was undertaken after resuscitation by percutaneous cardiopulmonary support. In surgery, a moderate amount of intrapericardial hematoma caused by rupture of a left ventricular pseudoaneurysm penetrating into the left pleural cavity was found and successfully repaired. This rare rupture of a left ventricular pseudoaneurysm penetrating into the left pleural cavity generated massive hemo-hydrothorax.

[Aortic valve-sparing root reconstruction in Marfan syndrome].

The outcome of aortic valve-sparing root reconstruction in Marfan syndrome was reviewed. Thirteen patients with Marfan syndrome underwent aortic valve-sparing root reconstruction for annuloaortic ectasia or aortic root dissection between 1994 and 1999. The grade of preoperative aortic regurgitation was I in 4, II in 2, III in 5, IV in 2 patients. The procedures of aortic valve-sparing were reimplantation in 7 and remodeling in 5 patients. There was no hospital and late death. Recurrence of aortic regurgitation greater than moderate grade developed in 1 patient immediately after the surgery and in the other 4 patients in the late stage. One patient of them required aortic valve replacement for it. Aortic valve-sparing root reconstruction is applicable in Marfan patients, although the indication should be cautious. Close observation is needed for recurrence of aortic regurgitation.

[T4 carcinoma of the oral cavity responsive to bilateral 5-FU intra-arterial infusion and simultaneous irradiation].

5-FU intra-arterial infusion and simultaneous irradiation can cure head and neck cancer without leaving any functional disturbance. Catheters were inserted into the bilateral superficial temporal arteries in a case of T4 carcinoma of the oral cavity, and this treatment was performed. The patient was a 54-year-old male with squamous cell carcinoma involving the right tonsil, right and left sides of the soft palate, the uvula, right gingiva, right lingual margin, and right buccal mucous membrane. The right soft palate was partially defective. The total dose of intra-arterial 5-FU was 4,000 mg on the right side and 2,600 mg on the left side, and the total dose of irradiation was 40 Gy. After this treatment, residual cancer was found on the right margin of the uvula only. Due to the defect in the soft palate, the effect of intra-arterial infusion was considered to be insufficient for this region, and it was excised together with the surrounding tissue. Rhinolalia aperta remains, but there is no dysphagia, and the course has been good with no evidence of recurrence so far. When it is found that a catheter cannot be readily inserted, it can usually be inserted properly by using a guide wire. For fixing the catheter, a satisfactory result is obtained by cutting the protruding end to 15-20 cm, attaching a connector, and suturing it to the skin of the temporal region.

[The relationship between blood sugar control and vascular complications in elderly diabetic patients--investigative study in 17 hospitals of Kochi Prefecture. Kochi Working Group on Diabetes Mellitus].

The aim of this study was to clarify whether the control state of fasting blood sugar can influence the occurrence of diabetic microangiopathy and macroangiopathy even in elderly patients with diabetes mellitus. In Kochi Prefecture 18 internal physicians participated in evaluating clinical courses of 898 patients, consisting of 466 males and 432 females, for an average of 69 months. Elderly cases aged 65 years or more old (group 1) consisted of patients who were aged 71.8 +/- 5.2 years old (M +/- SD). The average age of 481 adult cases under 65 years of age (group II) was 54.4 +/- 8.4 years old. Between the good and poor control groups, there was no difference in terms of blood pressure, body mass index (BMI) and serum lipids. Arteriosclerotic diseases such as myocardial infarction, cerebral infarction and arteriosclerosis obliterans appeared about as frequently in both the good and the poor control groups, while microangiopathies such as retinopathy, nephropathy and neuropathy were significantly more frequent in the poor control group compared to the good control group. The same tendency concerning these complications was seen in group II. Concerning treatment, diet treatment without drug treatment was significantly more frequent in the good control group compared to the poor control group, while hypoglycemic agents and subcutaneous insulin injection were used more often in the poor control group, the more severe state of diabetes mellitus in the latter group. Concerning the main reasons for good control, successful diet treatment was cited most often, followed by regular intake of medications. On the other hand disturbed diet treatment was the most frequent reason for poor control, indicating the strategic importance of diet treatment. Arteriosclerotic diseases were found more often in group I than group II, while the frequency of microangiopathies was similar. Concerning sexes, male patients tended to suffer more often from arteriosclerotic diseases than female patients, but the frequency of microangiopathy was similar. From the above findings it was concluded that poor control of fasting blood sugar level was related to microangiopathies in both non-elderly adult and elderly patients.

[Partial splenic embolization for the treatment of liver cirrhosis with hypersplenism: assessment of clinical response and liver function].

We have evaluated the efficacy of partial splenic embolization (SE) in the treatment in 10 cirrhotic patients with marked hypersplenism. The mean infarction rate of the spleen was 84%. The change of spleen size, peripheral blood cell counts and liver function tests after SE were investigated during 3 years, and also 10 cirrhotic patients without SE were followed as control. The residual spleens after SE did not enlarged except 1 case with 65% infarction rate of the spleen. In these cases, the SE led not only to a sustained increase in both platelet and white blood cell counts but also to a significant improvement of hepatic function tests (hepaplastin test, total cholesterol and albumin) during observation period. On the other hand, these parameters tended to decrease in control patients without SE. This study suggests that SE performed with a high infarction rate of spleen is an useful therapy for hypersplenism in cirrhosis.

[Detection of minimal residual disease using reverse transcriptase polymerase chain reaction technique].

Polymerase chain reaction (PCR) is a highly sensitive technique to detect minimal residual disease (MRD) of hematological malignancy by amplifying tumor specific nucleotide sequences. When breakpoint is located over large lesions of genomic DNA, like t(9;22) leukemia, PCR amplifying cDNA of chimeric mRNA, called reverse transcriptase PCR (RT-PCR), can be utilized. We applied this method for the detection of MRD in patients with t(1; 19) acute lymphoblastic leukemia. RT-PCR detection of MRD in patients with leukemia might be useful for estimating of the depth of remission, for disclosing preclinical relapse, and for evaluating the efficacy of in vitro purging in autologous bone marrow transplantation.