Deceleration area and capacity during labour-like umbilical cord occlusions identify evolving hypotension: a controlled study in fetal sheep.

OBJECTIVE: Cardiotocography is widely used to assess fetal well-being during labour. The positive predictive value of current clinical algorithms to identify hypoxia-ischaemia is poor. In experimental studies, fetal hypotension is the strongest predictor of hypoxic-ischaemic injury. Cohort studies suggest that deceleration area and deceleration capacity of the fetal heart rate trace correlate with fetal acidaemia, but it is not known whether they are indices of fetal arterial hypotension. DESIGN: Prospective, controlled study. SETTING: Laboratory. SAMPLE: Near-term fetal sheep. METHODS: One minute of complete umbilical cord occlusions (UCOs) every 5 minutes (1:5 min, n = 6) or every 2.5 minutes (1:2.5 min, n = 12) for 4 hours or until fetal mean arterial blood pressure fell <20 mmHg. MAIN OUTCOME MEASURES: Deceleration area and capacity during the UCO series were related to evolving hypotension. RESULTS: The 1:5 min group developed only mild metabolic acidaemia, without hypotension. By contrast, 10/12 fetuses in the 1:2.5-min group progressively developed severe metabolic acidaemia and hypotension, reaching 16.8 ± 0.9 mmHg after 71.2 ± 6.7 UCOs. Deceleration area and capacity remained unchanged throughout the UCO series in the 1:5-min group, but progressively increased in the 1:2.5-min group. The severity of hypotension was closely correlated with both deceleration area (P < 0.001, R2  = 0.66, n = 18) and capacity (P < 0.001, R2  = 0.67, n = 18). Deceleration area and capacity predicted development of hypotension at a median of 103 and 123 minutes before the final occlusion, respectively. CONCLUSIONS: Both deceleration area and capacity were strongly associated with developing fetal hypotension, supporting their potential to improve identification of fetuses at risk of hypotension leading to hypoxic-ischaemic injury during labour. TWEETABLE ABSTRACT: Deceleration area and capacity of fetal heart rate identify developing hypotension during labour-like hypoxia.

Krukenberg tumor in a 18-year-old-female: a rare case.

BACKGROUND: Krukenberg tumors mostly occur after 40 years. Metastatic ovarian tumors in young age are very rare. CASE: A 18-year-old female presented with colon cancer which was accompanied by Krukenberg tumor. The present case was a very rare case of metastatic ovarian tumor in very young age. The present patient presented with abdominal pain. On examination, colon tumor was detected and bilateral ovary were almost normal with only slight swelling. During the operation for colon tumor, biopsy of bilateral ovary was performed for histopathological evaluation. Although there were no specific findings in bilateral ovary, microscopic examination revealed poorly differentiated adenocarcinoma, diffusely invading the ovarian parenchyma. Diagnosis of colon cancer was made postoperatively and ovarian Krukenberg tumor was confirmed. CONCLUSION: In case of suspecting colon cancer even in very young patient with normal ovary, biopsy of ovary should be considered for the diagnosis of Krukenberg tumor.

Primary mediastinal choriocarcinoma with brain metastasis in a female patient.

Nongestational choriocarcinoma is very rare and carries a poor prognosis in female patients. In this report, the authors present a case of nongestational choriocarcinoma with brain metastasis in a female. A 58-year-old female with intermittent back pain was referred to a private hospital. On examination, a mediastinal tumor and a pancreatic tumor were detected. Endoscopic ultrasound-guided fine needle aspiration biopsy of the tumor was performed for histological evaluation. Pathological diagnosis was difficult because only a small amount of tissue was collected. Head MRI showed multiple metastatic tumors in the brain. The patient was diagnosed with primary mediastinal choriocarcinoma with brain metastasis. She was treated with one course of an etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine regimen, but her general condition gradually deteriorated, and she died on day 41. Nongestational choriocarcinoma is drug resistant, whereas gestational choriocarcinoma has better chemotherapeutic sensitivity.

Serum carcinoembryonic antigen as a tumour marker in patients with endometrial cancer.

BACKGROUND: No potential tumour markers have been validated for prognosis in endometrial cancer. However, carcinoembryonic antigen (cea) is one of the most widely used tumour markers in various types of cancer. Although cea expression in endometrial cancer has been investigated, its prognostic value remains controversial, and no studies have investigated serum cea levels in large case series. In the present study, we investigated diagnostic and prognostic applications of serum cea for endometrial cancer. METHODS: This prospective study was approved by our Institutional Review Board. Between January 2006 and December 2012, serum cea was measured prospectively in 215 patients with endometrial cancer and was subsequently measured during treatment and at scheduled follow-up examinations in patients with elevated baseline serum cea. RESULTS: During the study period, 215 patients (142 stage i, 19 stage ii, 32 stage iii, 22 stage iv) were treated for endometrial cancer. By the time of last follow-up, 52 had relapsed (24.2%), and the median follow-up duration was 45 months (range: 1-95 months). Elevated serum cea was identified in 25 patients (11.6%) and was associated with histologic type (p = 0.04), histologic grade (p = 0.03), and myometrial invasion depth (p = 0.01). Elevated serum cea was not related to clinical stage, lymph node metastasis, distant metastasis, age, menopausal status, or body mass index. Relapse of disease was related to elevated serum cea (p = 0.006). CONCLUSIONS: Serum cea is a potential prognostic indicator for endometrial cancer.

Early operative treatment of anti-N-methyl D-aspartate (anti-NMDA) receptor encephalitis in a patient with ovarian teratoma.

BACKGROUND: Anti-N-methyl D-aspartate (anti-NMDA) receptor encephalitis is often accompanied by ovarian teratoma. Early tumor resection is reported to be effective as a treatment. CASE: A 21-year-old woman presented with anti-NMDA receptor encephalitis which was accompanied by ovarian teratoma. The present case was a very rare case of an early stage of anti-NMDA receptor encephalitis receiving operative treatment before confirming the presence of anti-NMDA receptor antibody. The diagnosis was established postoperatively by identifying anti-NMDA receptor antibody. CONCLUSION: In case of suspecting anti-NMDA receptor encephalitis in a patient with ovarian teratoma, early operative treatment should be considered even before confirming the presence of anti-NMDA receptor antibody.

A novel gene, Translin, encodes a recombination hotspot binding protein associated with chromosomal translocations.

We have identified a novel gene, Translin, encoding a protein which specifically binds to consensus sequences at breakpoint junctions of chromosomal translocations in many cases of lymphoid malignancies. The encoded protein, Translin, is a previously undescribed type with no significant similarity to known proteins. In the native form, Translin polypeptides form a multimeric structure which is responsible for its DNA binding activity. Nuclear localization of Translin is limited to lymphoid cell lines, raising the intriguing possibility that nuclear transport of Translin is regulated in a physiologically significant way such that active nuclear transport is associated with the lymphoid specific process known as Ig/TCR gene rearrangement.

Thrombopoietin receptor agonists in refractory immune thrombocytopenia: differential responses to eltrombopag and romiplostim: a case report and possible explanations.

WHAT IS KNOWN AND OBJECTIVE: Although new thrombopoietin (TPO) receptor agonist drugs, such as romiplostim and eltrombopag, are highly effective and well tolerated for patients with immune thrombocytopenia (ITP) refractory to first-line treatments such as prednisolone, the cross-resistance of these two TPO receptor agonists is still unknown. CASE SUMMARY: An 84-year-old Japanese female patient with steroid-refractory ITP received eltrombopag with a gradually increasing dose schedule from 12.5 to 25 mg/day, 37.5 mg/day and finally 50 mg/day. As no increase in platelet count was observed even at the maximum dose of 50 mg/day, and eltrombopag-related grade 3 elevation of aspartate aminotransferase was observed, another TPO receptor agonist, romiplostim, was administered at 1 µg/kg/week subcutaneously. A rapid increase in platelet count was observed 1 week after the first injection. The dose of romiplostim was escalated to 4 µg/kg according to the platelet count and a complete response was achieved 7 weeks after the first injection without any adverse events. WHAT IS NEW AND CONCLUSION: The successful treatment of ITP refractory to eltrombopag with romiplostim strongly suggests that the absence of cross-resistance between these two approved TPO receptor agonists and possible differences in mechanism of action. Further study of the mechanisms of action of TPO receptor agonists is called for along with further exploration of the potential of romiplostim in refractory ITP.

A new differentiation antigen (FT-1) shared with fetal thymocytes and leukemic cells in the mouse.

A mouse monoclonal antibody (IgM) was obtained by cell hybridization between X63-Ag8.653 myeloma cells and spleen cells from a BALB mouse that was immunized with GRSL leukemia cells of the GR strain. This antibody identified a unique fetal antigen, which is expressed exclusively on embryonic thymocytes of all strains tested. Therefore, the antigen defined was named fetal thymus antigen-1, FT-1. The proportion of FT-1+ fetal thymocytes detected by immunofluorescence assay sharply decreases as gestation time increases, and finally they disappear from the thymus. On the other hand, Thy-1+ cells increase in inverse proportion. The immunofluorescence studies and absorption tests showed that FT-1 antigen is not detectable on brain, liver, kidney, or lymphoid tissue cells of adult mice. However, it is expressed on some leukemia cells of various mouse strains, which demonstrated that this is the first example of an oncofetal antigen of a mouse leukemia. The molecular weight of FT-1 antigen on leukemia cells was estimated to be 130,000 by means of biosynthetic labeling with [3H]galactose and [35S]methionine. The two-dimensional gel electrophoresis pattern of FT-1 antigen shows a family of glycoproteins with extensive charge heterogeneity. It was also shown that the FT-1 antigen molecule carries the receptor for DBA lectin.

Medullary but not cortical thymic epithelial cells present soluble antigens to helper T cells.

Thymic epithelial cell lines (TECs) were established from newborn C57BL/6 mice. They were classified into two types (medullary and cortical TECs) by using the monoclonal antibody (Th-3) that recognizes the meshwork structure of thymic cortical epithelial cells. Antigen-presenting activity of each TEC was determined by using ovalbumin-specific, I-Ab-restricted helper T cell lines. It was demonstrated that the medullary but not the cortical TECs functioned as antigen-presenting cells. This is the first evidence for the functional difference between the cortical and the medullary TEC.

Direct evidence that natural killer cells in nonimmune spleen cell populations prevent tumor growth in vivo.

Relatively large numbers of nonimmune spleen cells do not protect against the local growth of two lymphomas. However, this heterogeneous population of splenic lymphocytes contains a subset of cells that efficiently protects against in vivo tumor growth. This cell population (cell-surface phenotype Thyl.2(-)Ig(-)Ly5.1(+)) represents less than 5 percent of the spleen cell population and is responsible for in vitro NK-mediated lysis. Although these studies clearly and directly demonstrate that Ly5(+) NK cells selected from a heterogeneous lymphoid population from nonimmune mice can protect syngeneic mice against local in vivo growth of two different types of tumor cells (in contrast to other lymphocyte sets within the spleen), they do not directly bear upon the role of NK cells in immunosurveillance. They do indicate that highly enriched Ig(-)Thyl(-)Ly5(+) cells, which account for virtually all in vitro NK activity, can retard tumor growth in vivo. It is difficult to ascribe all anti-tumor surveillance activity to NK cells, because they probably do not recirculate freely throughout the various organ systems of the body. Perhaps NK ceils may play a role in prevention of neoplastic growth within discrete anatomic compartments where there is rapid differentiation of stem cells to mature progeny (e.g., bone marrow, spleen, and portions of the gastrointestinal tract)and may normally act to regulate the growth and differentiation of non-neoplastic stem cells. Long-term observation of chimeric mice repopulated with bone marrow from congenic or mutant donors expressing very low or very high NK activity may help to answer these questions.

Antiglycolipid autoantibody detected in the sera from systemic lupus erythematosus patients.

A high incidence of autoantibody against the neutral glycolipid "asialo GM1" was observed in sera from patients with systemic lupus erythematosus (SLE) with neurological disorders, using an immunoflocculation test. The sera from 14 out of 17 cases of SLE with neurological disorders showed antibody activity against asialo GM1 but not against the following glycolipids: asialo GM2 GM1, and galactocerebroside. In another 87 cases of SLE without any history of seizures, as well as 61 cases of other autoimmune diseases (rheumatoid arthritis, progressive systemic sclerosis, mixed connective tissue disease, etc.) and 20 cases of various neurological diseases (epilepsy, multiple sclerosis, etc.), no antibody could be detected. In general, the antibody titer was high several months, even years, before and/or after the seizure, though the titer was low at the time that patients showed definite neurological symptoms. Immunochemical characterization with Sephadex G-200 chromatogrphy and protein A-Sepharose CL-4B affinity column indicated that the antiasialo GM1 was probably an autoantibody belonging to the immunoglobulin G class. The above results suggest that this newly found autoantibody plays a role in the pathogenesis of neurological disorders accompanying SLE.

Molecular involvement of the pvt-1 locus in a gamma/delta T-cell leukemia bearing a variant t(8;14)(q24;q11) translocation.

A highly malignant human T-cell receptor (TCR) gamma/delta+ T-cell leukemia was shown to have a productive rearrangement of the TCR delta locus on one chromosome 14 and a novel t(8;14)(q24;q11) rearrangement involving the J delta 1 gene segment on the other chromosome 14. Chromosome walking coupled with pulsed-field gel electrophoretic (PFGE) analysis determined that the TCR J delta 1 gene fragment of the involved chromosome was relocated approximately 280 kb downstream of the c-myc proto-oncogene locus found on chromosome band 8q24. This rearrangement was reminiscent of the Burkitt's lymphoma variants that translocate to a region identified as the pvt-1 locus. Sequence comparison of the breakpoint junctions of interchromosomal rearrangements in T-cell leukemias involving the TCR delta-chain locus revealed novel signal-like sequence motifs, GCAGA(A/T)C and CCCA(C/G)GAC. These sequences were found on chromosome 8 at the 5' flanking site of the breakpoint junction of chromosome 8 in the TCR gamma/delta leukemic cells reported here and also on chromosome 1 in T-cell acute lymphocytic leukemia patients carrying the t(1;14)(p32;q11) rearrangement. These results suggest that (i) during early stages of gamma delta T-cell ontogeny, the region 280 kb 3' of the c-myc proto-oncogene on chromosome 8 is fragile and accessible to the lymphoid recombination machinery and (ii) rearrangements to both 8q24 and 1p32 may be governed by novel sequence motifs and be subject to common enzymatic mechanisms.

Analysis of donor-type chimerism in lineage-specific cell populations after allogeneic myeloablative and non-myeloablative stem cell transplantation.

We analyzed donor-type chimerism in CD3+, CD14.15+ and CD56+ cells from 36 patients who had undergone conventional-intensity allogeneic stem cell transplantation (CST) and 34 patients who had undergone non-myeloablative allogeneic stem cell transplantation (NST) for hematological malignancies. On day 28 after transplantation, all fractions in NST patients and CD3+ cells in CST patients who received a non-total body irradiation (TBI) regimen showed more frequent mixed chimerism (<90% donor cells) than those in patients who had received TBI. NST patients with acute graft-versus-host disease (grade II-IV) frequently showed more than 50% donor-type chimerism in CD3+ cells on day 14 (P=0.029). NST patients with <50% donor-type chimerism on day 14 and with <90% donor-type chimerism on day 28 in CD56+ cells had significantly poor 1-year overall survival (0 vs 91%, P<0.001 and 20 vs 74%, P=0.002, respectively). Both NST and CST patients with <90% donor-type chimerism in CD14.15+ cells on day 28 had significantly poor 1-year overall survival (14 vs 70%, P=0.005 and 0 vs 66%, P=0.002, respectively). Our data show that the extent of donor-type chimerism in lineage-specific cells appears to have an impact on outcome after allogeneic stem cell transplantation.

Value of chemotherapy before allogeneic hematopoietic stem cell transplantation from an HLA-identical sibling donor for myelodysplastic syndrome.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative treatment for myelodysplastic syndrome (MDS). The object of this study was to evaluate the impact of chemotherapy before allo-SCT. We analyzed the data of 283 patients who underwent allo-SCT from an HLA-identical sibling donor for MDS that were reported to the Japan Society for Hematopoietic Cell Transplantation. The cumulative incidence of grade II-IV acute GVHD was 33%. Overall survival (OS) at 5 and 10 years was 48.8 and 42.5%, respectively. Multivariate analyses identified karyotype, FAB classification, and the history of chemotherapy before allo-SCT as significant predictors for OS. OS at 5 years was 57% for patients who underwent allo-SCT as a primary treatment for refractory anemia with excess blasts in transformation (RAEB-t) or secondary acute myeloid leukemia (AML) and 54% for those who underwent allo-SCT in remission after induction chemotherapy (P=0.81). The proportion of patients with a poor karyotype was equivalent between the two groups (P=0.44). Although only a randomized controlled trial will be able to establish a definite conclusion, these results do not support the administration of induction chemotherapy for patients with RAEB-t or secondary AML before allo-SCT.

Detection of boundaries of subthalamic nucleus by multiple-cell spike density analysis in deep brain stimulation for Parkinson's disease.

When microelectrode recording of single cell activity is employed for targeting the subthalamic nucleus (STN), multiple sampling of single cells is needed to determine whether the electrode has passed through the ventral boundaries of the STN. In contrast, stepwise recording of multiple cell activities by a semimicroelectrode reveals robust changes in such activities at the dorsal and ventral boundaries. We attempted to quantify changes in multiple cell activities by computing multiple-cell spike density (MSD). We analyzed MSD in 60 sides of 30 patients with Parkinson's disease. Neural noise level was defined as the lowest cut-off level at which neural noise is separated from larger amplitude spikes. MSD was analyzed at cut-off levels ranging from 1.2 to 2.0-fold the neural noise level in the white matter in each trajectory. Both the dorsal and ventral boundaries were clearly identified by an increase and a decrease (p < 0.0001) in MSD, respectively, in all the 60 sides. The cut-off level of 1.2-fold showed the clearest change in MSD between the STN and the pars reticulata of substantia nigra. MSD analysis by semimicroelectrode recording represents the most practical means of identifying the boundaries of STN.

Increased sensitivity of murine leukemia virus-infected tumor cells to lymphocyte-mediated cytotoxicity.

The cytotoxic sensitivity of murine leukemia virus (MuLV)-infected and noninfected fibrosarcoma cells in syngeneic inbred WKA/Hok rats was compared by in vitro cell-mediated 51Cr release cytotoxicity assay. A highly significant increase in cytotoxic sensitivity of target cells was observe in MuLV-infected tumor cells as compared with noninfected cells when spleen cells from syngeneic tumor-bearing hosts (TBH) were used as a source of effector lymphocytes. The cytotoxicity of spleen cells against MuLV-infected tumor cells was specifically directed to the tumor-associated antigen (TAA), but not to the virus-associated antigen. However, there was no quantitative difference in the amount of TAA on the cell membranes between virus-infected and noninfected tumor cells as measured by a quantitative absorption test of anti-TAA serum. The cytotoxic activity of spleen cells from TBH against MuLV-infected tumor cells was abrogated by the treatment of anti-T-serum plus complement and significantly decreased after trypsin treatment. Spleen cells from normal rats given injections of immune sera from TBH acquired the cytotoxic activity against MuLV-infected tumor cells.

Characterization and classification of rat leukemias and lymphomas by membrane markers.

An immunological characterization of leukemias and lymphomas was made in the rat by using a panel of membrane markers in combination with morphological analysis. In the present study, five antigen markers and three surface markers were used for the characterization of 20 rat leukemias and lymphomas, and it was indicated that they could be divided into at least six groups. Of the lymphomas studied, six thymic lymphomas (Group 1) had the Thy-1.1 antigen, T-cell antigen, and receptors for guinea pig red blood cells; five extrathymic lymphomas (Group 2) lacked T- and B-cell antigens, receptors for guinea pig red blood cells, and surface immunoglobulin, but three of them had complement receptors. An absorption test revealed that Group 2 lymphomas possess a very low amount of the Thy-1.1 antigen compared to Group 1 lymphomas. None of the leukemias studied had detectable T- and B-cell antigen. Four leukemias had undifferentiated blast cell morphology and bore the Thy-1.1 antigen; three leukemias (Group 3) reacted with anti-lymphocyte serum, but one leukemia (Group 4) did not. Two leukemias (Group 5) had only the complement receptor and morphologically showed granulocytic appearance. Three leukemias (Group 6) had none of the membrane markers used and morphologically resembled erythroblasts. Based on these results, an attempt was made to classify these leukemias and lymphomas into T-cell lineage, B-cell lineage, stem cell, myeloid, and erythroid groups, respectively. Furthermore, the stage of differentiation in the lymphocyte maturational pathway of the leukemias and lymphomas belonging to Groups 1 to 4 is discussed.

Heterologous antiserum to chemically induced rat non-T, non-B leukemia and its application to characterization of rat leukemias.

Antisera to the 1-butyl-1-nitrosourea-induced "non-T, non-B" rat leukemia line DBLA-6 were raised in rabbits. Following absorption with syngeneic hepatoma cells, the antisera were very similar in specificity to antisera raised to rat Thy-1 antigen. Anti-DBLA-6 serum was cytotoxic in the presence of complement against 70 to 90% of thymocytes and 40 to 50% of neonatal spleen cells. In contrast, no significant cytotoxicity was observed against cells from bone marrow, lymph node, spleen, and peritoneum. An absorption test revealed that an antigen recognized by anti-DBLA-6 serum was present in brain tissue but absent in liver and kidney tissues. Nineteen rat leukemias and lymphomas were divided into six groups based on antigenic and morphological characteristics and the presence of receptor for guinea pig red blood cells. These tumors were investigated for the presence of the antigen recognized by anti-DBLA-6 serum. Of the leukemias and lymphomas studied, anti-DBLA-6 serum reacted with all thymic (Group 1) and extrathymic (Group 2) lymphomas and unclassified leukemias (Groups 3 and 4), while all myelogenous leukemias (Group 5) and erythroleukemias (Group 6) were negative. The position of leukemias and lymphomas reactive with anti-DBLA-6 serum in the lymphocyte maturational pathway is discussed.