A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome.

A novel causative variant (c.608G>A, p.Arg203Gln) in PACS1.

A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK.

A novel causative variant (c. 464T>C, p.Leu155Pro) in the heterogeneous nuclear ribonucleoprotein K (HNRNPK) gene.

Intercellular adhesion molecule-1 on synovial cells attenuated interleukin-6-induced inhibition of osteoclastogenesis induced by receptor activator for nuclear factor κB ligand.

In a co-culture of osteoclast precursor cells and synovial cells, interleukin-6 (IL-6) induces osteoclast formation. In contrast, in a monoculture of osteoclast precursor cells, IL-6 directly suppresses receptor activator for nuclear factor κB ligand (RANKL)-induced differentiation of osteoclast precursor cells into osteoclasts. In the present study, we explored why the effect of IL-6 differed between the monoculture and the co-culture systems. In the monoculture, mouse osteoclast precursor cell line, RAW 264·7 (RAW) cells were cultured with soluble RANKL (sRANKL) for 24 h or 3 days. sRANKL increased both expression of osteoclastogenesis marker, tartrate-resistant acid phosphatase isoform 5b (TRAP5b) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1), whereas the co-addition of IL-6 decreased them both in a dose-dependent manner. In the co-culture, RAW cells and human synovial cell line, SW982 cells were cultured with IL-6+soluble IL-6 receptor (sIL-6R) for 3 days. TRAP5b and NFATc1 expression reduced by IL-6 was increased by the addition of SW982 cells in a manner dependent upon the number of added cells. IL-6+sIL-6R treatment significantly induced RANKL production in SW982 cells, and anti-RANKL antibody inhibited IL-6+sIL-6R-induced osteoclastogenesis. SW982 cells expressed high levels of ICAM-1 originally, and ICAM-1 expression was increased significantly by IL-6+sIL-6R. Anti-ICAM-1 antibody suppressed IL-6-induced osteoclastogenesis. Finally, in the monoculture system, addition of sICAM-1 dose-dependently restored the expression of TRAP5b reduced by IL-6. Similar results were obtained when the formation of TRAP-positive multi-nuclear cells were examined using mouse bone marrow cells. In conclusion, IL-6 gave different results in the co-culture and monoculture systems because in the co-culture, ICAM-1 from the synovial cells restored osteoclastogenesis suppressed by IL-6.

Four-year study of lamivudine and adefovir combination therapy in lamivudine-resistant hepatitis B patients: influence of hepatitis B virus genotype and resistance mutation pattern.

To investigate the efficacy of long-term lamivudine (3TC) and adefovir dipivoxil (ADV) combination therapy in 3TC-resistant chronic hepatitis B virus (HBV) infected patients, we analysed 28 3TC-resistant patients treated with the combination therapy during 47 months (range, 9-75). At 12, 24, 36, and 48 months, the rates of virological response with undetectable HBV DNA (≤ 2.6 log copies/mL) were 56, 80, 86, and 92%, respectively. Among 17 hepatitis B e antigen (HBeAg)-positive patients, HBeAg disappeared in 24% at 12 months, 25% at 24 months, 62% at 36 months, and 88% at 48 months. When HBV genotypes were compared, patients with genotype B achieved virological response significantly more rapidly than those with genotype C (P=0.0496). One patient developed virological breakthrough after 54 months, and sequence analysis of HBV obtained from the patient was performed. An rtA200V mutation was present in the majority of HBV clones, in addition to the 3TC-resistant mutations of rtL180M+M204V. The rtN236T ADV-resistant mutation was observed in only 25% clones. In vitro analysis showed that the rtA200V mutation recovered the impaired replication capacity of the clone with the rtL180M+M204V mutations and induced resistance to ADV. Moreover, rtT184S and rtS202C, which are known entecavir-resistant mutations, emerged in some rtL180M+M204V clones without rtA200V or rtN236T. In conclusion, 3TC+ADV combination therapy was effective for most 3TC-resistant patients, especially with genotype B HBV, but the risk of emergence of multiple drug-resistant strains with long-term therapy should be considered. The mutation rtA200V with rtL180M+M204V may be sufficient for failure of 3TC+ADV therapy.

Development of Neonatal Airway Management Simulator for Evaluation of Tracheal Intubation.

The long-term goal of this study is a training system that can simulate medical cases and advise physicians based on quantitative evaluation of neonatal resuscitation. In this paper, we designed and manufactured a neonatal airway management simulator for quantitative evaluation of tracheal intubation. This robotic simulator is equipped with 25 sensors of 6 types, which detect motions that lead to complications, inside the manikin replicated a neonate. A performance experiment of the developed sensor and an evaluation experiment with physicians were conducted. We observed that an erroneous operation in the laryngoscopy can be detected by the sensors in our simulator.

Antigen-specific antibody production of human B cells in NOG mice reconstituted with the human immune system.

Passive antibody administration shows strong potential as a new therapeutic method. In clinical applications, human-derived antibodies with antigen specificity are more useful without putting individuals at risk. Production of human-derived antibodies against given antigens can be obtained from animal models if the human immune system is established in the animals. In fact, past reports revealed that human T and B cells develop from hematopoietic progenitor cells in immunodeficient mice. However, there have been few reports on sufficient induction of antigen-specific antibodies, particularly IgG, in immunodeficient mice reconstituted with human immune cells. In this chapter, we discuss a major shortcoming of induction of antigen-specific IgG antibodies in human immune cells developed in the murine environment based on our data. We demonstrated that human T cell development is restricted by the murine MHC and consequently T cells may not achieve cognate interaction with human B cells. Human B cells developed in the mouse are mainly CD5+B1 cells that preferentially produce IgM. At the same time, human LN transplantation on the spleen enabled NOG mice to produce antigen-specific IgG antibody. These results suggest that if efficient cognate interaction mediated by a certain antigen on MHC class II between human T and B-2 cells occurs, human B cells can produce IgG antibody against a given antigen in the murine environment.

Radical hysterectomy for invasive cervical cancer during pregnancy: a retrospective analysis of a single institution experience.

PURPOSE: To evaluate long-term prognosis and patient safety for a radical hysterectomy in pregnant women with invasive cervical cancer. PATIENTS AND METHODS: We retrospectively analyzed 12 cases of radical hysterectomy (RH) performed for invasive cervical cancer during pregnancy. Four patients underwent RH with the fetus in situ and another eight patients underwent RH followed by cesarean section. RESULTS: The median treatment period was 17 weeks of gestation (range: 9 to 39), the mean blood loss was 550.1 +/- 162.5 g (range: 275 to 850). Pelvic lymph node metastases were observed in three patients and parametrial invasion was observed in one patient. Although one patient experienced a recurrence at the vaginal stump, all patients were alive at a median follow-up interval of 105 months (range: 61 to 234). CONCLUSION: RH during pregnancy can be safely performed even with the fetus in situ and a subsequent cesarean section.

A PLK4 mutation causing azoospermia in a man with Sertoli cell-only syndrome.

About 15% of couples wishing to have children are infertile; approximately half these cases involve a male factor. Polo-like kinase 4 (PLK-4) is a member of the polo protein family and a key regulator of centriole duplication. Male mice with a point mutation in the Plk4 gene show azoospermia associated with germ cell loss. Mutational analysis of 81 patients with azoospermia and Sertoli cell-only syndrome (SCOS) identified one man with a heterozygous 13-bp deletion in the Ser/Thr kinase domain of PLK4. Division of centrioles occurred in wild-type PLK4-transfected cells, but was hampered in PLK-4-mutant transfectants, which also showed abnormal nuclei. Thus, this PLK4 mutation might be a cause of human SCOS and nonobstructive azoospermia.

Anti-Gal-C antibodies in GBS subsequent to mycoplasma infection: evidence of molecular mimicry.

The authors previously reported the presence of antibody against galactocerebroside (Gal-C) in sera from patients with Guillain-Barré syndrome subsequent to Mycoplasma pneumoniae infection. Anti-Gal-C antibody activities in these sera were inhibited specifically by the M. pneumoniae reagent. A rabbit anti-Gal-C antibody recognized several glycolipids in M. pneumoniae. These data show that a Gal-C-like structure is present in M. pneumoniae, indicative of molecular mimicry between a major myelin glycolipid, Gal-C, and M. pneumoniae.

Guillain-Barré syndrome associated with IgG monospecific to ganglioside GD1b.

The authors examined serum antiglycolipid antibodies in 445 patients with Guillain-Barré syndrome (GBS). Among them, nine had anti-GD1b IgG antibodies with no reactivity to other glycolipids tested. All those patients had sensory disturbance, and none had the primary axonal form. Anti-GD1b IgG antibodies may bind to primary sensory neurons and paranodal myelin, where GD1b is localized, and be involved in the pathogenesis of sensory disturbance and demyelination. However, more study is needed to substantiate the roles of anti-GD1b IgG antibodies.

Variability in immunohistochemistries of IgM M-proteins binding to sulfated glucuronyl paragloboside.

Serum IgMs from 4 of 12 patients with polyneuropathy and IgM M-proteins that bind to sulfated glucuronyl paragloboside (SGPG) strongly immunostained the human peripheral nerve myelin (group A), whereas those from the other eight patients strongly immunostained the cytoplasm of the Schwann cells surrounding the myelin sheath with only weak staining of the myelin (group B). Strong immunostaining of peripheral myelin by IgMs from group A patients may be due to the strong cross-reactivities against P0 and peripheral myelin protein-22 (PMP-22), which are localized in compact myelin. Only three patients (all in group B) showed some response to the immunotherapies. Weak reactivities to P0 and and PMP-22 might indicate the possibility of improvement after the immunotherapies.

In vitro cytokine production of peripheral blood mononuclear cells in response to HCV core antigen stimulation during interferon-beta treatment and its relevance to sCD8 and sCD30.

We investigated the responses of peripheral blood mononuclear cells (PBMCs) to hepatitis C virus core protein in ten patients with chronic hepatitis C during interferon (IFN)-beta treatment to determine if the modulation of the immune reaction to hepatitis C virus by IFN treatment is associated with the viral clearance. Interleukin-2, interleukin-4, interleukin-10, and interferon-gamma in the supernatant of the patients' PBMC co-cultured with the HCV core antigen-presenting autologous PBMCs were measured by ELISA. Serum levels of soluble CD (sCD) 8 and sCD30 in these patients were also measured by ELISA. The production of interleukin-2 and interferon-gamma by PBMCs of sustained responders (SRs) increased after IFN-treatment, although it did not reach a significant level. Interleukin-10 was detected only in non-responders (NRs) at 0 and 4 weeks after the start of IFN treatment. Serum sCD8 level increased significantly in SR with IFN treatment. A close correlation between the serum sCD8 levels and interferon-gamma levels in the supernatant at week 8 was observed in SR. These results suggest that IFN treatment potentiates the cellular immune reaction against HCV core protein more efficiently in SR than in NR.

Staging of palpable T1-2 invasive breast cancer with helical CT.

BACKGROUND: The purpose of this study was to evaluate the accuracy of contrast-enhanced high resolution helical computed tomography (CT) for assessing locoregional staging of palpable T1-2 invasive breast cancer. METHODS: Helical CT studies of 156 lesions from 156 patients with invasive breast cancer before breast-conserving surgery were examined. A lesion was defined as positive if focal enhancement was detected by CT within 100 seconds after contrast material administration. After resection, tumors were histopathologically mapped and comparison made with the extent of contrast enhancement. RESULTS: Helical CT enabled detection of all 156 index tumors. CT enabled detection of 28 of 43 multifocal lesions (65%) and five of five multicentric lesions (100%). In 24 of 33 lesions (73%), CT revealed additional cancers not seen on mammography. The extent of tumor significantly correlated with CT measurements (r=0.76, p<0.0001). CONCLUSION: Helical CT of the breast is an accurate preoperative imaging modality for assessing the locoregional staging of T1-2 invasive breast cancer.

Primary retroperitoneal mucinous cystadenocarcinoma: report of a case.

A case of primary retroperitoneal mucinous cystadenocarcinoma is presented. Ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) examinations demonstrated a large cystic tumor with solid excrescences. Angiographic examination demonstrated an avascular area with small areas of faint blush. It must be borne in mind that mucinous cystadenocarcinoma originating from the retroperitoneum can occur, although it is very rare.

[Clinical experience with ampicillin-cloxacillin (Viccillin S 'Meiji') by intravenous drip infusion in gynecological infections (author's transl)].

Ampicillin-cloxacillin (Viccillin S 'Meiji') by intravenous drip infusion was used in gynecological infections, with the following satisfactory results. 1) The drug was markedly effective in 2 out of 6 cases, effective in 4, being the efficacy rate 100%. 2) No abnormal laboratory findings and side effects were observed in our study.

[Localizing methods of primary hyperparathyroidism and those results].

The results of several pre-operative localizing methods and pathological findings were compared in 11 patients with primary hyperparathyroidism. 1. The accuracy rate was highest with selective blood sampling from the thyroid vein and MRI, which was 75% with both methods. The 3rd was dual photon scintigraphy, the accuracy rate being 62.5%. The 4th was ultrasonography, 57.1%, and the rate was lowest with CT, 25%. 2. MRI-a new localizing method-has a weak point that it cannot differentiate lymph nodes from parathyroid adenoma/hyperplasia. 3. Not to overlook small lesion of primary hyperplasia, several localizing methods should be performed before initial neck exploration.

[Clinical evaluation of Fuji computed radiography (FCR) by physicians including non-radiologists].

In Niigata university hospital, most of conventional radiography were changed to FCR from July 1988. To evaluate its clinical utility, questionnaires relating to FCR image were distributed to all physicians including non-radiologists in the hospital after three months. The ratio of the physicians evaluated FCR image to be better than conventional image was 75% in chest radiography, 64% in abdominal radiography. FCR tomography of bone, joint, cranium and chest was also evaluated to be better than conventional by most of the physicians. Reduced size of the film and difficulty in detecting interstitial shadows of the lung were mentioned to be the fault of FCR.