How often and when Fisher syndrome is overlapped by Guillain-Barré syndrome or Bickerstaff brainstem encephalitis?

BACKGROUND AND PURPOSE: Fisher syndrome (FS) may overlap with Guillain-Barré syndrome (GBS), in particular the pharyngeal-cervical-brachial variant form (PCB-GBS), or Bickerstaff brainstem encephalitis (BBE). Our aim was to elucidate the frequency of this overlap and the patterns of clinical progression in patients with FS. METHODS: Sixty consecutive patients with FS were studied. FS/PCB-GBS was diagnosed when the patients developed pharyngeal, cervical and/or brachial weakness. Patients with flaccid tetraparesis were diagnosed as having FS/conventional GBS. FS/BBE was defined as the development of consciousness disturbances. RESULTS: All 60 patients initially developed the FS clinical triad alone (pure FS). Of these, 30 (50%) patients had pure FS throughout their course, whereas the remaining 50% of patients showed an overlap: PCB-GBS in 14 (23%) patients, conventional GBS in nine (15%) patients and BBE in seven (12%) patients. The median (range) durations from FS onset to progression to FS/PCB-GBS, FS/GBS or FS/BBE were 5 (1-7), 3 (1-4) and 3 (1-5) days, respectively. Patients with overlap syndromes more frequently received immune-modulating treatment, and the outcomes were generally favourable. The frequencies of positivity for anti-GQ1b, GT1a, GD1a, GD1b, GalNAc-GD1a and GM1 antibodies were not significantly different amongst the four groups. CONCLUSIONS: Of the patients with pure FS, 50% later developed an overlap with PCB-GBS, conventional GBS or BBE. The overlap occurred within 7 days of FS onset; thus, physicians should pay attention to the possible development of this overlap during the first week after FS onset.

Physicochemical property changes of amino acid residues that accompany missense mutations in SCN1A affect epilepsy phenotype severity.

BACKGROUND: Several different missense mutations in the voltage-gated sodium channel subunit gene SCN1A have been identified in epileptic patients with benign phenotype and patients with severe phenotype. However, the reason why similar missense mutations in SCN1A result in different phenotypes has not yet been fully clarified. OBJECTIVE: To clarify the phenotype-genotype relationship in SCN1A, a meta-analysis was performed to quantitatively determine the effect of amino acid substitutions in SCN1A on epilepsy severity phenotype using physicochemical property indices of the amino acid, and to discuss in the context of the molecular evolution of the proteins. METHODS: PubMed was searched for articles and information was extracted on localisation and types of SCN1A missense mutations in patients with benign and severe epileptic syndromes; detailed information was also extracted. RESULTS: Meta-analysis quantitatively revealed that the physicochemical properties of several amino acids significantly affected epilepsy phenotype severity. It showed that missense mutations that decreased protein hydrophobicity were significantly associated with severe epilepsy phenotypes. It also showed that the phenotype severity of SCN1A missense mutations in the transmembrane domains of SCN1A (128/155; 82.6%) could be predicted with high sensitivity and positive predictive values using the physicochemical property changes, indicating the possibility of phenotype prediction for entirely new missense mutations using analytical methods. CONCLUSIONS: The results show that changes in the physicochemical properties of amino acids affected both the phenotype and clinical symptoms of patients with SCN1A missense mutations. This meta-analysis study provides new insights into SCN1A gene functions and a new strategy for genetic diagnosis, genetic counselling and epilepsy treatment.

Chediak-Higashi Syndrome With Epstein-Barr Virus Triggered Hemophagocytic Lymphohistiocytosis: A Case Report.

Chediak-Higashi syndrome (CHS) is a rare, autosomal-recessive disorder characterized by oculocutaneous albinism, recurrent bacterial infections, progressive neurologic abnormalities, coagulation defects and a high risk of developing hemophagocytic lymphohistiocytosis characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult with poor prognosis. Here, we report a two-and-a-half-year-old male child who was diagnosed with Chediak-Higashi Syndrome based on silvery hair, pathognomonic hair microscopy and giant azurophilic granules in granulocytes. The patient was in advanced stage of HLH induced by an Epstein-Barr virus (EBV) infection and given etoposide, cyclosporine and dexamethasone according to hemophagocytic lymphohistiocytosis (HLH)-2004 protocol but did not survive.

Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a rare multi-system disorder associated with plasma-cell dyscrasia. Several case series and reports have suggested that high-dose chemotherapy with autologous peripheral blood stem-cell transplantation is efficacious treatment, but this transplantation is not indicated for elderly patients and patients with renal failure. OBJECTIVE: To investigate the effects of thalidomide treatment for POEMS syndrome. METHODS: Nine patients, who were not indicated for high-dose chemotherapy, were treated with thalidomide. Neurological disability scores, nerve conduction studies and serum levels of vascular endothelial growth factor (VEGF) were prospectively examined. VEGF levels were measured by an enzyme-linked immunosorbent assay. RESULTS: During follow-up periods of 8-23 months (mean, 15 months), all patients showed substantial clinical improvement (n = 6) or stabilisation of symptoms (n = 3). Serum VEGF levels decreased in all patients and were normalised in five patients. Nerve conduction velocities in the median nerve increased in seven patients. There were no serious adverse effects, including thalidomide neuropathy. CONCLUSION: Thalidomide treatment should be further studied as a treatment for POEMS syndrome, particularly for patients who are not indicated for transplantation therapy.

Organization and expression of the chicken N-myc gene.

We cloned the chicken N-myc gene and analyzed its structure and expression. We found that it consisted of three exons with coding regions in exons 2 and 3. Comparison to mammalian N-myc genomic sequence indicated that nucleotide sequences of the 5'-flanking region, noncoding exon 1, and introns were not conserved, but coding and 3' noncoding sequences showed significant homology to mammalian N-myc. Alignment of deduced amino acid sequences of chicken and mammalian N-myc proteins revealed nine conserved domains interrupted by different lengths of nonhomologous sequences. Two of the domains were specific to N-myc proteins, and the other seven were common to c-myc proteins. Northern blot (immunoblot) and in situ hybridization analyses of 3.5-day-old chicken embryos revealed that high-level expression of the N-myc gene was confirmed to certain tissues, e.g., the central nervous system, neural crest derivatives, and mesenchyme of limb buds. In the beak and limb primordia, N-myc expression in the mesenchyme was higher toward the distal end, suggesting possible involvement in positional assignment of the tissue within the rudimentary structures.

HES-1 repression of differentiation and proliferation in PC12 cells: role for the helix 3-helix 4 domain in transcription repression.

HES-1 is a Hairy-related basic helix-loop-helix protein with three evolutionarily conserved regions known to define its function as a transcription repressor. The basic region, helix-loop-helix domain, and WRPW motif have been characterized for their molecular function in DNA binding, dimer formation, and corepressor recruitment, respectively. In contrast, the function conferred by a fourth conserved region, the helix 3-helix 4 (H-3/4) domain, is not known. To better understand H-3/4 domain function, we expressed HES-1 variants under tetracycline-inducible control in PC12 cells. As expected, the induced expression of moderate levels of wild-type HES-1 in PC12 cells strongly inhibited nerve growth factor-induced differentiation. This repression was dependent on the H-3/4 domain. Unexpectedly, expression of HES-1 also arrested cell growth, an effect that could be reversed upon down regulation of HES-1. Concomitant with growth arrest, there was a strong reduction in bromodeoxyuridine incorporation and PCNA protein levels, although not in cyclin D1 expression. Expression of a HES-1 protein carrying the H-3/4 domain, but not the WRPW domain, still partially inhibited both proliferation and differentiation. Transcription assays in PC12 cells directly demonstrated that the H-3/4 domain can mediate DNA-binding-dependent transcription repression, even in the absence of corepressor recruitment by the WRPW motif. HES-1 expression strongly repressed transcription of the p21(cip1) promoter, a cyclin-cyclin-dependent kinase inhibitor up regulated during NGF-induced differentiation, and the H-3/4 domain is necessary for this repression. Thus, the H-3/4 domain of HES-1 contributes to transcription repression independently of WRPW function, inhibits neurite formation, and facilitates two distinct and previously uncharacterized roles for HES-1: the inhibition of cell proliferation and the direct transcriptional repression of the NGF-induced gene, p21.

The microfluidic lighthouse: an omnidirectional gradient generator.

Studies of chemotactic cell migration rely heavily on various assay systems designed to evaluate the ability of cells to move in response to attractant molecules. In particular, the development of microfluidics-based devices in recent years has made it possible to spatially distribute attractant molecules in graded profiles that are sufficiently stable and precise to test theoretical predictions regarding the accuracy and efficiency of chemotaxis and the underlying mechanism of stimulus perception. However, because the gradient is fixed in a direction orthogonal to the laminar flow and thus the chamber geometry, conventional devices are limited for the study of cell re-orientation to gradients that move or change directions. Here, we describe the development of a simple radially symmetric microfluidics device that can deliver laminar flow in 360°. A stimulant introduced either from the central inlet or by photo uncaging is focused into the laminar flow in a direction determined by the relative rate of regulated flow from multiple side channels. Schemes for flow regulation and an extended duplexed device were designed to generate and move gradients in desired orientations and speed, and then tested to steer cell migration of Dictyostelium and neutrophil-like HL60 cells. The device provided a high degree of freedom in the positioning and orientation of attractant gradients, and thus may serve as a versatile platform for studying cell migration, re-orientation, and steering.

A zebrafish Id homologue and its pattern of expression during embryogenesis.

We describe the cloning, sequencing and pattern of transcript distribution during embryogenesis of a zebrafish Id homologue that we have called Id6. Transcription of the gene is spatially regulated, and its pattern of transcription shows considerable overlaps with those of other zebrafish genes with homology to Drosophila neurogenic genes, such as Notch and Delta. Since all these genes are coexpressed in particular cells, they may function together in a single genetic circuit in zebrafish as they do in Drosophila. A zebrafish homologue of Drosophila AS-C proteins can activate transcription of a CAT reporter gene by binding to an E-box in mouse 3T3 cells, either alone or in conjunction with ZfE12. The activation of transcription is inhibited in the presence of Id6. This indicates that the zebrafish gene described here is a genuine member of the Id family, and suggests that it may serve a function similar to that of the Drosophila gene emc and mammalian Ids during development.

Autologous dendritic cells or cells expressing both B7-1 and MUC1 can rescue tumor-specific cytotoxic T lymphocytes from MUC1-mediated apoptotic cell death.

We attempted to induce MUC1-specific cytotoxic T lymphocytes (CTLs) by mixed-lymphocyte tumor cell culture (MLTC) using two allogeneic MUC1-positive cancer cell lines, T-47D and MCF7. The induced CTLs exhibited MUC1-specific cytotoxicity 16 days after the initial stimulation. However, these CTLs underwent apoptotic death within 16 days. To examine whether the B7-1 molecule is required for the expansion of the responder cells, a B7-1(+)/MUC1(-) cell line was transfected with MUC1 cDNA, and the resulting transfectant was employed as a stimulator in an autologous MLTC. The CTLs exhibited MUC1 specificity but also continued to propagate. In parallel, autologous dendritic cells (DCs) were added to an MLTC containing peripheral blood lymphocytes (PBLs) and the allogeneic MUC1-positive stimulators. The CTLs demonstrated MUC1 specificity and their number increased. This suggests that the B7-1 molecule is required for rescuing CTLs from MUC1-mediated apoptotic death, but not for the induction of MUC1-specific responsiveness. This strategy to obtain the CTLs efficiently may be useful for adoptive immunotherapy against cancer.

Vascular endothelial growth factor as a predictive marker for POEMS syndrome treatment response: retrospective cohort study.

OBJECTIVE: POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome is a rare multisystem disease characterised by plasma cell dyscrasia and overproduction of vascular endothelial growth factor (VEGF). VEGF is assumed to be useful in monitoring disease activity, because VEGF levels usually decrease after treatment. However, there is no study to investigate whether the extent of decrease in VEGF correlates with clinical outcome. We tested the predictive efficacy of serum VEGF levels in POEMS syndrome. METHOD: This was an institutional review board approved retrospective observational cohort study of 20 patients with POEMS monitored regularly for more than 12 months (median follow-up, 87 months) after treatment onset using our prospectively accumulated database of POEMS from 1999 to 2015. Patients were treated by autologous peripheral blood stem cell transplantation or thalidomide administration. Serum VEGF was measured by ELISA. Outcome measures included clinical and laboratory findings and relapse-free survival. RESULTS: Serum VEGF levels decreased rapidly after treatment, and stabilised by 6 months post treatment. Patients with normalised serum VEGF levels (<1040 pg/mL) at 6 months showed prolonged relapse-free survival (HR=12.81, 95% CI 2.691 to 90.96; p=0.0001) and greater later clinical improvement. The rate of serum VEGF reduction over the first 6 months post treatment correlated with increased grip strength, serum albumin levels, and compound muscle action potential amplitudes at 12 months. CONCLUSIONS: Serum VEGF level at 6 months post treatment is a predicative biomarker for disease activity and prognosis in POEMS syndrome. Serum VEGF could be used as a surrogate endpoint for relapse-free survival or clinical or laboratory improvement of POEMS syndrome for clinical trials.

Physical development of surgically treated patients with primary spontaneous pneumothorax.

STUDY OBJECTIVES: There have been many studies on the physical characteristics at the time of contraction of a primary spontaneous pneumothorax (PSP), but it has not been shown when and how such physical characteristics develop. These issues were investigated. PATIENTS AND DESIGN: Physical development of 27 male patients with PSP were examined. Their physical records were collected with the patients' permission, and standard curves, estimated from the Japanese nationwide records in the year corresponding to the ages of the patients, were plotted as control values. RESULTS: The height of patients was already greater at 6 years of age. It showed a marked increase from 11 to 14 years. The body weight was more than the standard until 9 years, but it became less after age 11, and this difference increased after age 15. Rohrer's index was significantly lower than the standard at all ages, and the difference was particularly large from 11 to 15 years. In the standard group, there was a balance between the annual height and weight gain. In the patient group, annual weight gain was similar to that in the standard group whereas height began to increase 2 years earlier, and as a result, ectomorphy, which was also observed before this age, became marked at this age. CONCLUSIONS: The rapid increase in the vertical dimension of the thorax compared with the horizontal dimension during the period of rapid physical development is considered to affect intrathoracic pressure at the apex of lung, which would have some influence on enhancing cyst formation.

Late diagnosis of nonconjoined monoamniotic twins using computed tomographic imaging: a case report.

Monoamniotic twin gestations, although rare, are associated with a high perinatal mortality rate. Early antenatal diagnosis is important to ensure optimal perinatal care. However, the diagnosis can be difficult to confirm, especially in late gestation when a dividing membrane may be difficult to visualize. Intra-amniotic injection of Renografin followed by a single-slice computed tomographic scan at the level of the umbilicus is described. This imaging method assisted in the confirmation of monoamniotic twinning.

Fetal lung maturation: the combined use of corticosteroids and thyrotropin-releasing hormone.

The purpose of this randomized study was to evaluate whether the combined use of corticosteroids and thyrotropin-releasing hormone would enhance fetal lung maturation to a greater degree than would corticosteroids alone. The study was restricted to patients under 34 weeks' gestation with a lecithin/sphingomyelin (L/S) ratio less than 2.0. The patients were randomized into a study group receiving intravenous thyrotropin-releasing hormone along with intramuscular corticosteroids over 48 hours and a control group receiving only corticosteroids. Patients undelivered 1 week after the onset of therapy underwent a repeat amniocentesis to document changes in the L/S ratio. In those patients delivering within 1 week of therapy, the neonatal clinical course was established by two investigators blinded to the antenatal therapy. Compared with the control group, the group receiving antenatal corticosteroids plus thyrotropin-releasing hormone showed a greater post-therapy increase in L/S ratio, fewer respirator days, and a lower incidence of bronchopulmonary dysplasia. The results of this study suggest that the combined use of corticosteroids and thyrotropin-releasing hormone results in enhanced fetal pulmonic maturation superior to that achieved with corticosteroids alone.

Pre-induction cervical ripening: a randomized comparison of two methods.

OBJECTIVES: To compare two methods of pre-induction cervical ripening in a randomized clinical trial. METHODS: A single intracervical prostaglandin E2 (PGE2) gel application was compared with a single insertion of hygroscopic dilators in 441 women at term with unfavorable cervical scores. Induction success was defined as entry into active labor within 6 hours of oxytocin infusion. RESULTS: There was no statistical difference in pre- or post-ripening cervical scores. In the group receiving hygroscopic dilators, only 28% entered the active phase of labor within 6 hours of oxytocin infusion compared with 45% (P < .001) in the PGE2 group. Thus, in this study, a change in cervical score did not directly predict induction success. There was a higher rate of postpartum endometritis (24 versus 14%; P = .007) and suspected neonatal infection (10 versus 5%; P = .03) in the dilator group. CONCLUSIONS: Pre-induction ripening by hygroscopic dilators and intracervical PGE2 was equivalent as measured by changes in the cervical score. The change in cervical score, however, was not predictive of successful induction, and PGE2 was more frequently associated with induction success. Hygroscopic dilators were associated with a higher incidence of postpartum maternal and neonatal infection because of a longer duration of labor. Hospital charges for intracervical PGE2 gel totaled $522 compared with $91 for the insertion of three dilators.

Sequential outpatient application of intravaginal prostaglandin E2 gel in the management of postdates pregnancies.

A randomized blinded investigation was undertaken to determine the efficacy and safety of sequentially applied intravaginal prostaglandin E2 (PGE2) gel for accelerating cervical ripening in an outpatient setting in low-risk prolonged pregnancies. Fifty women with uncomplicated pregnancies at or beyond 41 weeks' gestation and Bishop scores below 9 received twice-weekly outpatient administration of gel containing 2.0 mg of PGE2 or placebo. Thirty nulliparas and 20 multiparas were enrolled. The PGE2 gel failed to improve cervical ripening over placebo, as judged by Bishop scores. There was no difference between the groups in gestational age on admission to the labor and delivery suite, number of gel applications, requirement for oxytocin, incidence of cesarean delivery, or neonatal outcome. Only two patients (4%) experienced regular uterine contractions after gel insertion; these subsided spontaneously in both. None of the subjects experienced labor, tetanic contractions, evidence of fetal distress, or any other side effects related to gel insertion. We conclude that PGE2 gel in this dosage may be used safely in an outpatient setting, but more frequent application or earlier initiation may be required to produce a clinical effect.

Patient-administered outpatient intravaginal prostaglandin E2 suppositories in post-date pregnancies: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: To shorten post-date pregnancies in a safe, effective manner by outpatient acceleration of cervical ripening. METHODS: Eighty patients with uncomplicated pregnancies at or beyond 41 weeks' gestation and a cervical Bishop score less than 9 were randomized to daily self-administered, 2-mg intravaginal prostaglandin E2 (PGE2) or placebo suppositories. Each followed a standard post-date antepartum surveillance protocol. Patients were admitted for spontaneous labor or for induction if the Bishop score reached 9, antepartum testing was nonreassuring, exclusion criteria were fulfilled, or if the gestational age reached 44 weeks. RESULTS: Fewer suppositories were used in the PGE2 group (four versus seven; P = .006), resulting in earlier gestational age on admission (295 versus 297 days; P = .021) and lower antepartum testing charges ($476.97 versus $647.29; P = .001). Labor and delivery time was significantly decreased in nulliparas (10.7 +/- 5.1 versus 15.3 +/- 7.6 hours; P = .035). CONCLUSIONS: Daily low-dose, patient-administered PGE2 vaginal suppositories can decrease the gestational length and cost of uncomplicated post-date pregnancies by reducing the time to achieve a favorable cervix, the need for antepartum testing, and, potentially, post-date-related complications.

Comparison by carcinoembryonic antigen doubling time of hepatic injection and infusion for unresectable hepatic metastasis from colorectal cancer.

This study explored the efficacy of hepatic arterial therapy, comparing both injection and infusion of 5-fluorouracil (5-FU) in prolonging the survival of 92 patients with recurrent unresectable hepatic metastasis from colorectal cancer. With respect to pretreatment carcinoembryonic antigen doubling time (CEA-DT), 56 patients were treated with intra-arterial injection, and 36 with intra-arterial infusion. In 21 patients with a CEA-DT of less than 40 days, the cumulative survival of patients treated with arterial injection was significantly longer than that of patients treated with arterial infusion. In 45 patients with a CEA-DT of 40-80 days, the survival curves of patients did not differ from each other. Of the remaining 26 patients with a CEA-DT of more than 80 days, those treated using arterial infusion had an excellent prognosis, in contrast to those treated using arterial injection, with statistical significance. CEA-DT may be useful when choosing a chemotherapy regimen, and may help to accurately establish the prognosis of patients with unresectable hepatic metastasis from colorectal cancer.

Involvement of granzyme B and perforin in suppressing nodal metastasis of cancer cells in breast and lung cancers.

AIMS: Granzyme B and perforin, which are contained in cytotoxic granules produced by tumour-infiltrating immune cells, have been reported to be involved in suppression of cancer progression. In this study, the relationship between expression of these molecules and clinical factors in cancer patients was studied. METHODS: Tumour tissue obtained from 23 breast cancer patients and 13 lung cancer patients were examined for expression of granzyme B, perforin and B7-1, using an immunohistochemical technique. The percentage of cells positive for expression of these molecules and the clinical status of each case were compared. RESULTS: Both granzyme B and perforin were distributed in the cytoplasm of cancer cells in many cases rather than in tumour-infiltrating lymphocytes. This was observed even in cases of early-stage tumours. In both breast and lung cancer patients, the percentage of cells positive for granzyme B and perforin expression was inversely correlated with the status of regional node metastasis. A competitive RT-PCR analysis confirmed that the expression of mRNA from these molecules extracted from the tumours was consistent with the immunohistochemical results. CONCLUSION: Granzyme B and perforin may play a role in the suppression of nodal metastasis of cancer cells in breast and lung cancers.

Diploid/triploid mosaic placenta with fetus. Towards A better understanding of 'partial moles'.

We describe a case of partial molar change in a placenta that was associated with a normal female fetus who died in utero. The analysis of molar and normal placental tissue, as well as the karyotypic study of amnionic fluid indicate a complex origin of this conceptus. We review the possible mechanisms leading to this pregnancy and the general topic of partial hydatidiform mole. The formation of moles is complex and it is not easily divisible into so-called partial and complete hydatidiform moles. Rather, individual genetic study is needed to make an accurate diagnosis because macroscopic or microscopic examination alone fails to assess the complexity of these entities.

[3H]mepyramine binding sites, histamine H1-receptors, in bovine retinal blood vessels.

The presence of histamine H1-receptors in the bovine retinal blood vessels was studied with a [3H]mepyramine binding assay. The membranes of purified vessels obtained from bovine retinas showed specific [3H]mepyramine binding sites with a dissociation constant (KD) of 2.78 +/- 0.32 nM. This was similar to values obtained from the retinal neuronal fractions. The binding capacity (Bmax) was 53.8 +/- 1.7 fmol/mg protein, which was about a half that of the retinal neuronal fractions (108.9 +/- 3.1 fmol/mg protein). Some H1-antagonists proved to be potent competitors for [3H]mepyramine binding sites in bovine retinal blood vessels. These results indicate that histamine H1-receptors exist in the retinal blood vessels which may be involved in the physiological and the pathological responses of blood circulation in retinas.