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.

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.

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.

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.

Spinal myoclonus in the periscapular muscles after mastectomy assessed by FDG-PET.

We describe a 64-year-old woman who developed spinal myoclonus around the left scapula after long thoracic nerve injury by mastectomy. Involuntary muscle twitching was semi-rhythmic, and ultrasonography identified contraction of the serratus anterior, teres major, and rhomboid muscles. FDG-PET imaging revealed markedly increased glucose uptake only in the serratus anterior. Lidocaine injection into this muscle resulted in complete cessation of the involuntary movement, and then she was successfully treated with botulinum toxin type A. These findings raise the possibility that the myoclonus was primarily caused by ectopic firing of the injured long thoracic nerve, then spreading to adjacent muscles possibly via a central mechanism mediated by group Ia afferents. The new imaging tools, such as FDG-PET and ultrasonography, were useful to determine the therapeutic target muscle.

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.

Neurologic improvement after peripheral blood stem cell transplantation in POEMS syndrome.

BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare multisystem disorder associated with plasma cell dyscrasia. There is increasing evidence that high-dose chemotherapy with autologous peripheral blood stem cell transplantation (Auto-PBSCT) is an efficacious treatment. OBJECTIVE: To elucidate the extent and time course of neurologic improvement after Auto-PBSCT in patients with POEMS syndrome. METHODS: Clinical and electrophysiologic findings in nine patients were reviewed. The median follow-up period was 20 months (range, 8 to 49 months). Serum levels of vascular endothelial growth factor (VEGF) were measured by ELISA. RESULTS: Serum VEGF levels rapidly decreased a month after Auto-PBSCT. Within 3 months, neurologic improvement began, and all the patients showed substantial neurologic recovery during the next 3 months. Particularly, three initially chairbound patients regained ability to walk at 6 months. Nerve conduction studies showed significant increases in conduction velocities and amplitudes within 6 months of treatment. At the end of follow-up periods, neuropathy was still improving, and no patients had recurrence of symptoms. CONCLUSION: Autologous peripheral blood stem cell transplantation results in obvious neurologic improvement within 6 months, presumably by extensive axonal regeneration and remyelination. This therapy could be considered as a first line treatment for patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome with younger onset even if they are tetraplegic.

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.

Aldose reductase inhibition alters nodal Na+ currents and nerve conduction in human diabetics.

BACKGROUND: In diabetic nerves, activation of the polyol pathway via an aldose reductase and the resulting impairment of the Na(+)-K(+) pump would lead to a decreased transaxonal Na+ gradient and thereby reduced nodal Na+ currents. OBJECTIVE: To investigate whether the aldose reductase inhibitor (ARI) epalrestat improves nodal Na+ currents and nerve conduction in human diabetic neuropathy. METHODS: The authors conducted a 6-month, open clinical trial with an ARI, epalrestat, in 30 patients with mild-to-moderate diabetic neuropathy. The latent addition technique and measurements of the strength-duration time constant were used to estimate nodal persistent Na+ currents in median motor axons. Excitability testing and extensive nerve conduction studies including F-wave analyses were performed before and 1 and 6 months after the initiation of treatment with oral epalrestat. RESULTS: Within a month of the start of treatment, there was a significant improvement in nerve conduction, particularly in conduction times across the carpal tunnel and F-wave latencies. The results of latent addition (p < 0.05) and strength-duration time constant (p = 0.06) suggested increased nodal persistent Na+ currents. At 6 months, nerve conduction continued to improve. CONCLUSIONS: Aldose reductase pathway inhibition could rapidly increase nodal Na+ currents and thereby improve the slowing of nerve conduction, presumably because of a restoration of the membranous Na+ gradient.

Primary Sjogren's syndrome presenting with generalized autonomic failure.

A 64 year-old woman developed Raynaud's phenomenon and dry eyes/mouth. Laboratory examination revealed positive Schirmer's test, rheumatoid factor and anti-nuclear antibody, and lymphocytic sialoadenitis on salivary gland biopsy. These features strongly suggested the diagnosis of primary Sjogren's syndrome. Three years later, she gradually developed generalized autonomic failure without apparent sensory neuropathy on nerve conduction study. She had systolic pressure fall of 51 mmHg on head-up tilt test, cardiovascular supersensitivity to diluted norepinephrine infusion, cardiac denervation in [123I]-MIBG scintigraphy, impaired R-R variability, decreased sweating and prolonged colonic transit time. Autoimmune autonomic ganglionopathy was mostly responsible for her autonomic failure.

Analysis of MUC4 mucin expression in lung carcinoma cells and its immunogenicity.

BACKGROUND: MUC4 has been cloned from tracheobronchial mucosa cDNA and reportedly is highly expressed in some human malignancies, including lung carcinoma. However, little is known about molecular and biologic characteristics. The authors analyzed expression levels of MUC4 mRNA and protein in lung carcinoma cells and analyzed the immunogenicity of this mucin. METHODS: Nine cultured lung carcinoma cell lines and 29 tumor samples from patients with lung carcinoma were examined by Northern hybridization for MUC4 mRNA expression and by flow cytometry or an immunohistochemical staining for its protein expression. Sera from the patients were examined for their reactivity with MUC4 by enzyme-linked immunosorbent assay. RESULTS: Forty-four percent of the cell lines and 72% of the tumor samples showed high levels of MUC4 mRNA expression. Although MUC4 protein was not detected in any live carcinoma cell lines by flow cytometry using rabbit antisera reactive with the MUC4 core, pretreatment with paraformaldehyde and sialidase resulted in successful detection of the protein in 50% of the cell lines. An immunohistochemical study revealed that 67% of the tumors exhibited MUC4 protein expression without any digestion. In 29% of the patients, high levels of anti-MUC4 immunoglobulin M or immunoglobulin G were detected. CONCLUSIONS: MUC4 protein expression was elevated in lung carcinoma tissues because of the increase in its mRNA expression and deglycosylation on its core. This mucin is sufficiently immunogenic to elicit humoral and cellular immunity specific for MUC4 in patients with malignant disease. MUC4 is expected to be useful as a target antigen in immunotherapy for patients with carcinoma of the lung.

The elusive benzocyclobutenylidene: a combined computational and experimental attempt.

Ab initio and density functional theory calculations predict that benzocyclobutenylidene (1) has a singlet ground state in contrast to the parent phenylcarbene and many other simply substituted arylcarbenes. Calculations also predict that 1 should lie in a relatively deep potential well, while its triplet state is 14.5 kcal mol(-)(1) higher in energy. However, attempts to observe 1 directly by photolysis of two different nitrogenous precursors were not successful. Irradiation of diazobenzocyclobutene (7) (lambda > 534 nm or lambda > 300 nm) or azibenzocyclobutene (10) (lambda > 328 nm) in Ar matrixes at 10 K leads to the formation of the strained cycloalkyne 7-methylenecyclohepta-3,5-dien-1-yne (3). (13)C-Labeled 3 was also prepared in a similar manner. There is very good agreement between experimental IR spectra and computationally derived harmonic vibrational frequencies for 3 and [(13)C]-3 and excellent agreement between observed and calculated isotopic shifts. Prolonged short-wavelength irradiation converts 3 into benzocyclobutadiene (5). Phenylacetylene (6) and benzocyclobutadiene dimer (11) were identified as products arising from flash vacuum pyrolysis of diazirine 10 at 500 degrees C.

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.

Transmission electron microscopy of fine aromatic hydrocarbon particles.

Fine perylene and pyrene particles were produced by evaporation in helium gas. The particles were sensitive to electron beam radiation. The pyrene particles sublimed under observation. These difficulties were cleared up by reducing electron beam exposure and sandwiching a specimen between two Formvar films. The fine perylene particles were rectangular or hexagonal plates about 50nm thick. The size was about 200-2000nm. The fine pyrene particles were polymorphic with a size of about 300-2000nm. The crystal forms of the perylene and pyrene particles were determined from the electron diffraction patterns to be alpha-perylene and pyrene I, respectively.

Periosteal chondroma of the rib: report of two cases.

We report two cases of periosteal chondroma of the rib, an extremely rare entity. The first case involved a 5-year-old boy who was admitted with pain and swelling around his left fifth rib. Surgery was performed in May 1999, and an 8 x 6 x 5 mm tumor was resected with the fifth rib. The second case involved a 39-year-old man with a 2-month history of cough who was referred to our department after a coin lesion had been detected on a chest roentgenogram. Physical examination on admission did not reveal any pain or tenderness. The rib tumor was resected along with the fourth rib by video-assisted thoracoscopic surgery and minithoracotomy in February 2000. The tumor was well encapsulated and consisted of an elastic hard mass measuring 22 x 15 x 13 mm. Both patients had an uneventful postoperative course and have remained well with no evidence of recurrence. Our review of the literature revealed only six previously documented cases of periosteal chondroma of the rib.

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.

Spontaneous symmetry breaking turing-type pattern formation in a confined Dictyostelium cell mass.

We have discovered a new type of patterning which occurs in a two-dimensionally confined cell mass of the cellular slime mold Dictyostelium discoideum. Besides the longitudinal structure reported earlier, we observed a spontaneous symmetry breaking spot pattern whose wavelength shows similar strain dependency to that of the longitudinal pattern. We propose that these structures are due to a reaction-diffusion Turing instability similar to the one which has been exemplified by CIMA (chlorite-iodide-malonic acid) reaction. The present finding may exhibit the first biochemical Turing structure in a developmental system with a controllable boundary condition.

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.

Encapsulated pericardial fat necrosis treated by video-assisted thoracic surgery: report of a case.

A 55-year-old moderately obese man who was admitted to a local hospital following a traffic accident reported having experienced an episode of sharp and sudden pleuritic pain in the left anterior lower chest 2 days earlier. A computed tomographic scan on admission demonstrated a nonhomogeneous mass in the anterior left side of the chest, abutting the left cardiac margin, and a left-sided pleural effusion. As a mediastinal tumor was suspected, he was referred to our hospital for investigation and treatment. An exploratory thoracotomy was performed by video-assisted thoracic surgery (VATS) about 3 weeks later, which revealed a firm, yellowish mass on the oral side of the pericardial fat pad, adhering to the anterior chest wall. The mass was easily removed. The resected specimen consisted of a lobulated fragment of adipose tissue measuring 5.0 x 3.5 x 2.0 cm, and the final pathologic diagnosis was pericardial fat necrosis. The patient had an uneventful postoperative recovery and has remained free of symptoms for 10 months since his operation. Pericardial fat necrosis remains a rare clinical entity. Surgical excision by VATS achieves symptomatic cure and probably continues to be the treatment of choice because of the need to exclude a neoplasm in the differential diagnosis.

[Squamous cell type lung cancer that produced granulocyte colony-stimulating factor].

A 73-year-old man was hospitalized because of weight loss and fever. Laboratory data showed marked leukocytosis (21,200/mm3), granulocytosis (89.7%), thrombocytosis (47.8 x 10(4)/mm3), increased CRP (15.8 mg/dl), and increased SCC (5.0 ng/ml). Chest X-ray films demonstrated a mass shadow in the right upper lung field. Chest computed tomographic scans revealed a mass shadow 58 mm in diameter with mediastinal pleural invasion in the right S1. Right upper lobectomy and dissection of regional lymph nodes was performed under a diagnosis of lung cancer (squamous cell carcinoma, T3 N0 M0 stage IIB) with concomitant infection. Serum G-CSF was 234 pg/ml pre-operatively and 68.8 pg/ml postoperatively. The cytoplasm of tumor cells stained positively with anti-recombinant human G-CSF monoclonal antibody. No general bacteria or mycobacteria were detected within the specimen. Postoperatively, the patient's white blood cell count, platelet count, and CRP level soon decreased, and the fever disappeared. We diagnosed the disease as G-CSF-producing squamous cell type lung cancer.