HDR syndrome, detected in the neonatal period by newborn hearing screening.

Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder. Because HDR syndrome is caused by haploinsufficiency in GATA3, it exhibits variation in the onset and progression of hearing loss. In previous reports, the automated auditory brainstem response (AABR) was considered insufficient to detect sensorineural hearing loss caused by HDR syndrome. We report a case of HDR syndrome whose congenital hearing loss was detected by newborn hearing screening (NHS) using AABR. In this case, HDR syndrome was suspected due to hearing loss, hypocalcemia, and her family history. Genetic testing confirmed the diagnosis of HDR syndrome at 5 months of age. Because the phenotype of hearing loss due to HDR syndrome is variable and includes progressive hearing loss, these cases may not be detected by the HNS. However, most of the previous reports were published before the NHS became common and given the frequency of hearing loss complications in HDR syndrome. We consider that there is a reasonable number of HDR syndrome cases with abnormalities on the NHS. We believe that the NHS may also be useful for early detection of hearing loss due to HDR syndrome.

Examination of Factors Affecting the Likelihood of Whether Individuals Would Purchase Cartilage Conduction Hearing Aids.

Cartilage conduction hearing aids (CC-HAs) are a novel type of hearing aid relying on cartilage conduction, the so-called third auditory conduction pathway. However, CC-HAs have only recently entered routine clinical use, and therefore data on their usefulness are lacking. The purpose of this study was to examine the possibility of assessing whether individual patients would show good adaptation to CC-HAs. Thirty-three subjects (41 ears in total) underwent a free trial of CC-HAs. Age, disease category, and the pure-tone threshold of air and bone conduction, unaided field sound threshold, aided field sound threshold, and functional gain (FG) at 0.25, 0.5, 1, 2, and 4 kHz were compared between patients who subsequently purchased and did not purchase the CC-HAs. Overall, 65.9% of the subjects purchased CC-HAs after the trial. In comparison to non-purchasers, those who decided to purchase CC-HAs showed better pure tone hearing thresholds at high frequencies for both air conduction (2 and 4 kHz) and bone conduction (1, 2, and 4 kHz), as well as for aided thresholds in the sound field (1, 2, and 4 kHz) when using CC-HAs. Therefore, the high-frequency hearing thresholds of subjects trialing CC-HAs might be helpful for identifying those who are likely to benefit from them.

Possibility of additive effects by the presentation of visual information related to distractor sounds on the contra-sound effects of the N100m responses.

Auditory-evoked responses can be affected by different types of contralateral sounds or by attention modulation. The present study examined the additive effects of presenting visual information about contralateral sounds as distractions during dichotic listening tasks on the contralateral effects of N100m responses in the auditory-evoked cortex in 16 subjects (12 males and 4 females). In magnetoencephalography, a tone-burst of 500 ms duration at a frequency of 1000 Hz was played to the left ear at a level of 70 dB as a stimulus to elicit the N100m response, and a movie clip was used as a distractor stimulus under audio-only, visual-only, and audio-visual conditions. Subjects were instructed to pay attention to the left ear and press the response button each time they heard a tone-burst stimulus in their left ear. The results suggest that the presentation of visual information related to the contralateral sound, which worked as a distractor, significantly suppressed the amplitude of the N100m response compared with only the contralateral sound condition. In contrast, the presentation of visual information related to contralateral sound did not affect the latency of the N100m response. These results suggest that the integration of contralateral sounds and related movies may have resulted in a more perceptually loaded stimulus and reduced the intensity of attention to tone-bursts. Our findings suggest that selective attention and saliency mechanisms may have cross-modal effects on other modes of perception.

Clinical Factors Associated With the Outcomes of Long-Term Middle Ear Ventilation Tube Insertion in Pediatric Patients.

BACKGROUND: Ventilation tube (VT) insertion is the most common treatment for otitis media with effusion (OME). However, OME recurrence and persistent tympanic membrane (TM) perforation after VT removal are encountered in a certain percentage of such children. METHODS: This study was performed to determine the outcomes of children who underwent long-term VT insertion. A total of 326 ears from 192 patients were analyzed. The associations among the patient age, sex, history of OME, history of repeated acute otitis media, placement duration, whether the VT had been removed intentionally or spontaneously, and the outcome (persistent TM perforation or OME recurrence) were analyzed. The outcomes of multiple VT tube insertions were also reviewed. We also analyzed whether or not local or general anesthesia was associated with the early spontaneous extrusion of the VT. RESULT: The OME recurrence and TM perforation rates were 29% (96/326 sides) and 17% (57/326 sides), respectively, for first insertions. In addition, 96 (29%) sides underwent ≥2 insertions. The shorter the duration for which the VT was retained in the middle ear, the more significant the rate of increase in OME recurrence. The OME recurrence was observed more often when VT was spontaneously removed than when intentionally removed. The rate of persistent TM perforation was significantly associated with male sex. Persistent TM perforation was not observed in patients who underwent 4 or 5 insertions. The anesthesia method did not significantly influence the timing of spontaneous extrusion of VT. CONCLUSION: The retention period of VT should be at least 2 years, and VT removal at the age of 7 might be a viable strategy. Multiple VT insertions are recommended for patients with recurrent OME. Ventilation tube under local anesthesia is an effective option for tolerable children.

Thymoma with immunodeficiency/Good syndrome associated with myasthenia gravis.

Good syndrome is a rare condition in which thymoma is associated with hypogammaglobulinemia; it is characterized by repeated respiratory or systemic infections caused by bacteria, viruses, and fungi, as well as with various autoimmune disorders such as pure red cell aplasia. A 65-year-old woman was admitted to our hospital with ptosis and abdominal muscle weakness. Based on the presence of anti-acetylcholine receptor (Ach-R) antibodies, she was diagnosed with myasthenia gravis (MG). At that time, invasive thymoma of Masaoka stage IVa was also detected. Regression of thymoma and clinical remission of MG was achieved by chemotherapy followed by high-dose corticosteroid. However, several months later, the patient started developing repeated bacterial respiratory tract infections, cytomegalovirus infections, and esophageal and systemic candidiasis. Laboratory tests revealed a marked decrease of serum gamma-globulin levels (IgG 586 mg/dl, IgA 32 mg/dl, IgM 29 mg/dl) and severe reduction in the B cells ratio, as well as a decrease in the CD4+CD25+T cell to CD4+CD25-T cell ratio indicative of deregulation of CD4+T cell activation. These results suggested that the patient impaired humoral and cell-mediated immune responses. We continued the treatment with antibiotics and regular immunoglobulin supplementation through intravenous injections. Although autoimmune disorders are often observed in Good syndrome, the association with MG is quite rare. The case report is followed by the review of literature.

The DC2.3 gene in Caenorhabditis elegans encodes a galectin that recognizes the galactoseß1→4fucose disaccharide unit.

Galectins comprise a large family of ß-galactoside-binding proteins in animals and fungi. We previously isolated cDNAs of 10 galectin and galectin-like genes (lec-1 to lec-6 and lec-8 to lec-11) from Caenorhabditis elegans and characterized the carbohydrate-binding properties of their recombinant proteins. In the present study, we isolated cDNA corresponding to an open reading frame of the DC2.3a gene from C. elegans total RNA; this cDNA encodes another potential galectin. A recombinant DC2.3a protein was expressed in Escherichia coli and used for analysis. The protein displayed hemagglutinating activity against rabbit erythrocytes, bound to an asialofetuin-Sepharose column, and was eluted with lactose. Furthermore, frontal affinity chromatography (FAC) analysis confirmed that DC2.3a recognized oligosaccharides with a non-reducing terminal galactose. According to these results, we designated DC2.3 as lec-12. The carbohydrate-binding property of the recombinant DC2.3a/LEC-12a was essentially similar to that of LEC-6. Additionally, DC2.3a/LEC-12a and LEC-6 showed higher affinities for the galactoseß1→4fucose (Galß1→4Fuc) disaccharide than for N-acetyllactosamine. This suggests that the principal recognition unit is the Galß1→4Fuc disaccharide as in the case of the C. elegans galectins. However, the recombinant DC2.3a/LEC-12a showed weak affinity for N-glycan E3, which was previously shown to be a preferential endogenous ligand for LEC-6. The DC2.3a/LEC-12a endogenous ligand structures appear to be somewhat different but contain the same galactose-fucose recognition motif.

Relationship between expression of mutant type glutathione S-transferase theta-1 gene and reactivity of rapamycin in myelodysplastic syndrome.

We previously reported mRNA expression of glutathione S-transferases theta (GSTT)-1, wild type (623 bp) and mutant (500 bp), in patients with myelodysplastic syndrome (MDS). The deletion of 123 bp creates a sequence that is homologous to the mammalian target of rapamycin (mTOR). To analyze the function of mutant GSTT-1 gene, stable transformants for the mutant and wild-type GSTT-1 gene, respectively, were established. In this study, the expression of the wild and mutant type of the GSTT-1 gene of those stable transformants in cell lines and in bone marrow cells from MDS patients by reverse-transcription polymerase chain reaction (RT-PCR) was observed in the presence or absence of rapamycin. Significant growth inhibition by rapamycin was observed among stable transformants for the mutant GSTT-1 gene, but not wild type GSTT-1 gene, and was indicative of typical apoptosis.

Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: Possible clinical application of mTOR inhibitor.

The BCR/ABL tyrosine kinase inhibitor, imatinib mesylate, has shown substantial effects in chronic myelogenous leukemia (CML) and Ph-positive acute lymphoblastic leukemia (Ph(+)ALL). However, most patients relapse after an initial clinical response, indicating that drug resistance is a major problem in patients on imatinib. It is a serious problem that effective treatment choices to T315I, in the ABL kinase domain that shows a strong tolerance in imatinib do not exist clinically. In this study, we propose a new therapeutic approach to Ph(+)ALL with the T315I. Here, we report that the serine/threonine kinase mTOR (the mammalian target of rapamycin) inhibitor, rapamycin, inhibits the growth of not only the Bcr-Abl-positive lymphoid leukemic cell line, SU-Ph2, established from Ph(+)ALL patients, but also the imatinib-resistant cell line, SU/SR, that has acquired T315I. Rapamycin significantly inhibits cell growth in both these cell lines, and easily induces apoptosis at the same dose, thereby acting as an immunosuppressive agent. Our result suggested that the mTOR-signaling pathway has become an important therapeutic target for Ph-positive leukemias in the future, and at the same time, it is also becoming a very effective tool for the treatment of Ph(+)ALL with T315I.

Influence of Epstein-Barr virus infection in adult T-cell leukemia.

The involvement of adult T-cell leukemia (ATL) cells in organs such as the skin and lymph nodes is observed in about 50% of cases of ATL. Epstein-Barr virus (EBV) infection has often been observed in the clinical course of ATL. In this study, we established two B-cell lines from peripheral blood of patients with ATL. EBV DNA, proviral DNA for HTLV-1 and Tax mRNA were detected in both lines. As part of the characterization of these cells, an enhanced expression of intercellular adhesion molecule-1 (ICAM-1) (CD54) or ICAM-3 (ICAM-3) (CD50), lymphocyte function-1 (LFA-1) (CD11a/CD18), and Mac-1 (CD11b/CD18) was observed. To investigate the role of the interaction of these viruses, we transfected EBV and/or HTLV-1 into a healthy donor's lymphocytes, an EBV-infected B cell line, Raji, and a HTLV-1 negative T-cell line, Jurkat. Enhanced expression of adhesion molecules was also observed in double transfectants (EBV and HTLV-1). In the clinical course of ATL, LMP-1, EBNA-2, CD50 and CD54 were detected in lymph nodes and skin specimens by immunohistochemical staining. Furthermore, high levels of interleukin-4 (IL-4) were detected in these cell lines and transfectants. The results indicated that coinfection with HTLV-1 and EBV may induce aggressive organ involvement through the enhanced expression of adhesion molecules via IL-4 signaling. A new mechanism of ATL involvement is discussed.

Clinical efficacy of all-trans retinoic acid for treating adult T cell leukemia.

PURPOSE: We previously reported that all-trans retinoic acid (ATRA) inhibited growth in human T-cell leukemia virus type I (HTLV-I)-positive T-cell lines and in fresh cells from patients with adult T cell leukemia (ATL). Here, we confirmed the clinical effects of ATRA in 20 patients with ATL. MATERIALS AND METHODS: The 20 patients (n = 20) with a median age of 56 (range 35-73) years who were diagnosed with ATL received ATRA orally. RESULTS: The efficacy of treatment was as follows: no complete response (CR), a partial response (PR) in 40% of the patients, no change (NC) in 45% of the patients, and a progressive disease (PD) in 15% of the patients. In seven acute-type ATL patients, a PR was achieved in two (28.5%), NC was observed in two (28.5%), and a PD was observed in three (42.8%). In three lymphoma-type ATL patients, a PR (100%) was achieved. Among four chronic-type ATL patients, a PR was achieved in one (25%) and NC was observed in the remaining three (75%). In six smoldering-type ATL patients, a PR was achieved in two (33.3%) and NC was observed in four (66.6%). The major side effects were headache (n = 5), transient liver dysfunction (n = 2), hyperlipidemia (n = 2), and anorexia (n = 1). CONCLUSION: These results indicated that ATRA might be a useful agent for the safe treatment of ATL.

Partial restoration of immunoglobulin production by cytokines in common variable immunodeficiency.

We describe a 26-year-old female referred to us because of recurrent bacterial pneumonia. Her immunoglobulin profile on admission was; IgG 1920 mg/l, IgA 60 mg/l, IgM 260 mg/l, IgD below 20 mg/l, IgE below 1 kU/l. Antinuclear antibodies, EBV VCA IgM, anti-parvovirus B19 IgM antibodies and hepatitis infection markers were all negative. Bone marrow aspiration revealed normal cellularity without abnormal cells, especially plasma cell proliferation. No rearrangement for IgH and TCR was observed as determined by Southern blot analysis. By the given data, a diagnosis of common variable immunodeficiency (CVID) was made. The genesis of this disease remained unclear. In this study, proliferation and immunoglobulin production with or without several stimulators were examined. Proliferation stimulated by PHA, Con-A, LPS, or IL-2 was decreased compared to that of healthy individuals. Immunoglobulin production after stimulation with several agents was quite low. Interestingly, however, IL-2 or IL-4 could increase IgM production on 6 days culture significantly. These results indicate that IL-2 or IL-4 possibly restore T cell responses to several antigens and induce B cell differentiation.

All-trans retinoic acid attacks reverse transcriptase resulting in inhibition of HIV-1 replication.

We previously reported that all-trans retinoic acid (ATRA) inhibited growth in HTLV-1-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. Interestingly, ATRA significantly inhibited reverse transcriptase (RT) activity similar to azidothimidine (AZT) in HTLV-1-positive T-cell lines. To clarify whether ATRA has an inhibitory effect on the replication of HIV, we examined HIV proviral DNA in a HIV-1-positive cell line (8E5) using real time PCR. ATRA as well as AZT reduced the proviral DNA load of 8E5 in a dose-dependent manner. These results suggest that there is a common element of ATRA signaling in both HTLV-1 and HIV. Furthermore, we examined the effects of ATRA on viral replication in primary lymphocytes of three individuals infected with HIV. ATRA reduced viral replication significantly similar to AZT. These findings suggested that ATRA acts as a RT inhibitor, reducing the HIV-1 proviral DNA load. Finally, we conclude that ATRA may be a potential therapeutic agent for HIV infection.

Possible molecular target therapy with rapamycin in MDS.

The authors previously reported the mRNA expression of Glutathione S-transferases theta (GSTT)-1, wild type (623 bp) and mutant (500 bp) in MDS patients. The deletion of 123 bp creates a sequence that is homologues to mammalian target of rapamycin (mTOR). To analyse the function of mutant GSTT-1 gene, stable transformants for the mutant and wild-type GSTT-1 gene, respectively, were established. In this study, the expression of wild and mutant type GSTT-1 gene of those stable transformants and bone marrow cells from MDS patients by RT-PCR was observed in the presence or absence of rapamycin. In result, exposure of rapamycin led to the disappearance of just the mutant gene band. This phenomenon possibly indicates that rapamycin only attacked the mutant GSTT-1 expressing clone.