Pathogenicity of memory Th2 cells is linked to stage of allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) consists of three developmental stages that are based on the presence/absence of antigen-specific IgE and symptoms. The pathogenic Th2 (Tpath2) cells constitute a population of Th2 cells with additional potentially pathogenic characteristics. We examined the relationship between Tpath2 cells and the stages of allergic rhinitis by focusing on ST2, which is an IL-33 receptor. METHODS: Patients with Japanese cedar pollen-induced AR (JCP-AR) and healthy volunteers were divided into "nonsensitized," "asymptomatic sensitized (AS)," and "JCP-AR" groups. We analyzed the ST2 expression and the Th2 function of cultured CD4+ T cells. Next, we observed the progress of patients in the AS stage around the time of seasonal pollen dispersal, with the characteristics of Th2 cells. RESULTS: The ST2 expression of T cells was only upregulated in the AR group. The production of IL-4 and IL-13 was found in CD4+ T cells obtained from AS by stimulation with JCP, but reactivity to IL-33 was not observed. Although IL-33 did not induce the elevation of IL-4 production in the JCP-AR group, IL-33 substantially increased the production of IL-5 and IL-13 in comparison with antigen stimulation alone. In newly afflicted patients, the increased expression of ST2 and elevated reactivity to IL-33 was observed, even before the pollen dispersal season. CONCLUSIONS: Our study demonstrated that the pathogenicity of memory Th2 cells is linked to sensitization and the stage of allergic rhinitis. Therefore, Tpath2 cells may provide useful insights into the mechanism of the onset and progression of allergic rhinitis.

JTK-853, a novel non-nucleoside hepatitis C virus polymerase inhibitor, demonstrates a high genetic barrier to resistance in vitro.

JTK-853 is a novel, non-nucleoside, palm site-binding hepatitis C virus (HCV) polymerase inhibitor that has demonstrated antiviral activity in HCV-infected patients during 3 days of treatment. To estimate the genetic barrier of JTK-853 to resistance in vitro, colony formation assays were conducted using HCV replicon cells (genotypes 1a and 1b). The colony formation assays revealed that the numbers of resistant colonies for JTK-853 were much lower than those for other direct-acting antivirals, including palm site- or thumb pocket-binding non-nucleoside HCV polymerase inhibitors (NNIs), an NS5A inhibitor (NS5Ai), and a protease inhibitor (PI). Furthermore, the numbers of resistant colonies for JTK-853 in combination with the NS5Ai or PI were lower than those for other combinations of NS5Ai + NNI, and NS5Ai + PI. Our findings demonstrate that JTK-853 has a high genetic barrier to resistance, and suggest that its combination therapies will be potent in suppressing the emergence of drug resistance in HCV-infected patients.

Paraumbilical peritoneal incision using the little finger in shunt operations for hydrocephalus: technical note.

INTRODUCTION: The shunt operation remains the standard procedure for the treatment of hydrocephalus. We describe a simple minilaparotomy method that involves perforation of the peritoneum with the surgeon's little finger. TECHNIQUE: After placing a small paraumbilical incision at the skin and fascia, the little finger is introduced through the incision to perforate the pre-peritoneal fat and peritoneum. The finger should be inserted at a 30-45° angle to the horizontal plane to avoid injuring the underlying viscera and major blood vessels and to put sufficient shear force on the peritoneum. A catheter is inserted into the abdominal cavity after visual confirmation of proper perforation. CONCLUSION: As the paraumbilical wound is not noticeable postoperatively due to the presence of the natural umbilical skin fold, this method yields a cosmetically appealing result.

Differences in immunological alterations and underlying viral infections in two well-defined severe drug eruptions.

BACKGROUND: Similar drugs (e.g. anticonvulsants) have been implicated in the development of two distinct forms of severe cutaneous drug reactions, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS). AIM: To investigate immunological alterations and underlying viral infections that could contribute to the variability in the clinical presentations of these diseases. METHODS: We retrospectively analysed clinical variables, serum immunoglobulin levels, numbers of circulating white blood cells, lymphocytes and their subsets, serum levels of several cytokines, and underlying viral infections in both drug reactions, using samples obtained at onset from 9 patients with SJS/TEN and 19 patients with DIHS/DRESS. RESULTS: There were significant differences between the two drug eruptions in the duration of drug intake before onset, the levels of IgG, IgA and IgM, the numbers of circulating white blood cell, lymphocyte, CD3+ T cell and CD8+ T cells, the serum levels of interferon-γ, and the titres of anti-herpes simplex virus IgG at onset. CONCLUSIONS: The difference in the pattern of immune responses shaped in part by previous and underlying viral infections at the time of drug exposure could cause a marked deviation in the pathological phenotype of severe drug eruptions. Elucidating these host factors may provide a basis for therapeutic approaches in patients with severe drug reactions.

Element-selective single atom imaging.

Electron energy-loss spectroscopy (EELS) is widely used to identify elemental compositions of materials studied by microscopy. We demonstrate that the sensitivity and spatial resolution of EELS can be extended to the single-atom limit. A chemical map for gadolinium (Gd) clearly reveals the distribution of Gd atoms inside a single chain of metallofullerene molecules (Gd@C82) generated within a single-wall carbon nanotube. This characterization technique thus provides the "eyes" to see and identify individual atoms in nanostructures. It is likely to find broad application in nanoscale science and technology research.

Systemic lupus erythematosus presenting with Kikuchi-Fujimoto's disease as a long-term sequela of drug-induced hypersensitivity syndrome. A possible role of Epstein-Barr virus reactivation.

Drug-induced hypersensitivity syndrome (DIHS) is a severe form of drug eruptions associated with viral reactivations. Autoimmune diseases have been reported to develop several months or years after the resolution of DIHS. We describe a 36-year-old man with cervical lymphadenopathy and an erythematous eruption affecting the face and neck, which evolved into clinically evident systemic lupus erythematosus. He had had an episode of DIHS 4 years previously, in which human herpesvirus-6 and Epstein-Barr virus (EBV) were reactivated. Expression of EBV-encoded RNA was detected in the lymph node. On the basis of findings in this patient, we suggest that EBV is pathogenically important in the sequence of events leading to the onset of systemic lupus erythematosus and that patients with a history of DIHS may be at a risk of eventually developing autoimmune diseases.

Risk factors for severe impetiginized atopic dermatitis in Japan and assessment of its microbiological features.

Patients with atopic dermatitis (AD) are susceptible to cutaneous bacterial infection. When such patients develop infection, some have extensive impetiginized dermatitis with high fever. To clarify the risk factors for severe impetiginized AD and its microbiological features, we reviewed clinical and microbiological data of 14 patients with impetiginized AD who were admitted to our hospital between the years 1999 and 2006. All patients had poorly controlled AD with eczematous lesions on the extensive body surface. The mean age was 28.2 years (range 18-35). Cultures of the lesional skin yielded both Streptococcus pyogenes and Staphylococcus aureus in 12 patients. S. pyogenes alone was isolated in two cases. These observations suggest that poorly controlled AD in adults is a risk factor for severe impetiginized AD and that S. pyogenes might play an important role in the development of severe clinical symptoms.

Retention of carbon dioxide in tissue following carbonic anhydrase inhibition in dogs.

To evaluate the retention of carbon dioxide in tissue during the reduction of carbonic anhydrase activity following the administration of 5, 10, 20, or 30 mg/kg of acetazolamide in dogs, we measured carbon dioxide pressure (PCO2) in arterial blood, mixed venous blood, alveoli, and tissue. Respiration was maintained at a constant level. In the control (noninjected) group, PCO2 in tissue did not change for 3 hours under controlled respiration. Following the injection of 5 to 30 mg/kg of acetazolamide, PCO2 increased in arterial blood, mixed venous blood, and tissue in a dose-related manner, and decreased in the alveoli. The (a-et)PCO2 widened to 21.9 +/- 1.0 mmHg from 0.6 +/- 1.0 mmHg, and the (t-v)PCO2 to 16.1 +/- 2.0 mmHg from 5.1 +/- 0.6 mmHg, in response to acetazolamide. It is suggested that carbon dioxide is retained in tissue when carbonic anhydrase activity is inhibited by acetazolamide.

Prevention by ulinastatin of decreased carbonic anhydrase activity induced by PMN elastase in vitro.

Disturbed carbon dioxide (CO2) elimination in adult respiratory distress syndrome (ARDS) has been considered to result from the dead space created by microthrombosis and vasoconstriction. However, another disturbance factor in CO2 elimination has been reported; the chemical dead space resulting from the inhibition of carbonic anhydrase (CA). This experiment was conducted to quantify the inhibition of CA activity by polymorphonucleocyte (PMN) elastase, which increases in ARDS. Different flasks containing solutions of CA, buffer, elastase, ulinastatin (an elastase antagonist), CA with PMN elastase, and CA with both PMN elastase and ulinastatin were prepared. Each flask was injected with sodium bicarbonate labeled with radioactive carbon (14C) and was shaken for 20 minutes; CA activity in each flask was measured by calculating the decrease in the coefficient (K) of 14C. It was observed that CA activity was inhibited dose-dependently by PMN elastase and that the inhibited activity was recovered by ulinastatin, which can inhibit PMN elastase. These findings indicate that CA activity in vitro could be inhibited by PMN elastase, which increases in ARDS, and suggests that disturbance of CO2 elimination could be reduced by using ulinastatin. It was concluded that ulinastatin could prevent the CA activity induced by PMN elastase in vitro.

Suppressive effect of human blood coagulation factor XIII on the vascular permeability induced by anti-guinea pig endothelial cell antiserum in guinea pigs.

We investigated the effect of blood coagulation factor XIII (FXIII) on enhanced permeability induced by anti-endothelial cell antiserum, that was produced by the immunization of guinea pig endothelial cells with adjuvant into rabbits repeatedly. We have found that this antiserum reacts to human and guinea pig endothelial cells but not guinea pig fibroblast cells. The permeability was enhanced by intradermal injection of 400-fold dilution of this antiserum into dorsal skin of guinea pigs. The mixture of equal volume of antiserum and FXIII was intradermally injected into dorsal skin of guinea pig after Evans blue injection, and 15 minutes later the quantity of Evans blue at the each injection site was determined. We recognized the suppressive effect of FXIII on the dye leakage. We also studied the suppressive effect on swelling induced by the antiserum. After the subcutaneous injection of the mixture of antiserum and FXIII into the back of guinea pigs, we measured the thickness of skins at the injection site after day 1, 2 and 3. As a result, FXIII significantly suppressed the swelling. We found that FXIII suppresses the acute and subacute permeability enhancement. These results suggest that FXIII plays an important role on an inflammatory site and that it may exert as an anti-inflammatory protein.

The effect of human thrombomodulin on the inactivation of thrombin by human antithrombin III.

The effect of human thrombomodulin (TM) on the inactivation of thrombin by human antithrombin III (ATIII) was evaluated in comparison with that produced from rabbits. Human TM did not accelerate the thrombin inhibition by ATIII but rabbit TM enhanced the activity of ATIII. Also inclusion of human TM at increasing concentration suppressed the thrombin inhibitory activity of ATIII. The intensity of ATIII activity in the presence of heparin (0.01U/ml) was also diminished by the human TM. However, this ATIII- heparin cofactor activity recovered with the addition of a 10-fold amount of heparin (0.1U/ml). In SDS-polyacrylamide gel electrophoresis and immunoblotting analysis, we found a complex formation of ATIII with both human and rabbit TM (and further confirmed their presence with isoelectrofocusing electrophoresis- data not shown). These results indicate that human TM is substantially different from rabbit TM. Our results suggest that human TM show the crucial role on protein C activation system via thrombin.

Hydrocephalus due to villous hypertrophy of the choroid plexus in the lateral ventricles. Case report.

A case is reported of hydrocephalus due to overproduction of cerebrospinal fluid (CSF) caused by villous hypertrophy of the choroid plexus in the lateral ventricles. A 7-year-old girl with mental retardation developed gait disturbance; hydrocephalus and a Dandy-Walker cyst were detected on computerized tomography. She was initially treated with a ventriculoperitoneal shunt; however, shunting failed to control the hydrocephalus. The excessive outflow of CSF suggested choroid plexus abnormality, and magnetic resonance (MR) imaging revealed enlargement of the choroid plexus in both lateral ventricles. The patient was therefore diagnosed as having hydrocephalus induced by overproduction of CSF, which was controlled by resection of the choroid plexus. Histological examination showed the structure typical of normal choroid plexus. This is a rare case of villous hypertrophy of the choroid plexus in which MR imaging assisted in the diagnosis.

Regulation of cyclic AMP-dependent Cl- channel in heart.

(1) alpha 1-Adrenoceptor stimulation inhibited the beta-adrenergic activation of Cl- current in guinea-pig ventricular cells. This alpha 1- and beta-adrenergic interaction appeared to be upstream in the cascade of adenylate cyclase activation. (2) Single Cl(-)-channel currents were recorded in cell-attached and excised outside-out patch membranes. Experiments were performed to investigate the dependence of channel behavior on the agonist concentrations.

Intracellular Mg2+ depletion depresses the delayed rectifier K+ current in guinea pig ventricular myocytes.

The effects of various [Mg2+]i, particularly low [Mg2+]i, on the delayed rectifier K+ current (IK) were studied in guinea pig ventricular myocytes with the patch clamp technique. The magnitude of IK was evaluated from the amplitude of its tail current elicited on repolarization following the depolarizing steps. The pipette-perfusion technique was also used. The initial variations of IK magnitude were dependent on [Mg2+]i in the internal solutions with which the whole-cell recording was begun. With 0.03 to 1 mM [Mg2+]i, IK was relatively stable after patch rupture, showing a minimal decay with time; with 3 mM [Mg2+]i, IK rapidly declined; with [Mg2+]i, less than 0.01 mM IK transiently increased after patch break, but declined progressively thereafter as the magnitude of IK decreased to about 30% of the initial magnitude in 10 min. The decline of IK at low [Mg2+]i showed the following features. The decline was accompanied little by changes in the voltage-activation relation or by changes in the kinetics of current deactivation. The decline was not related to changes in [Ca2+]i and was also observed in ATP gamma S-loaded, isoprenaline-stimulated cells, in which IK channels were presumed to be persistently phosphorylated. An application of okadaic acid did not prevent the decline of IK during Mg2+ depletion. It is suggested that a presence of [Mg2+]i higher than 0.01 mM is required to maintain IK in guinea pig ventricular cells. The depression of IK at low [Mg2+]i appears to involve a phosphorylation-dephosphorylation-independent mechanism.

Massive pericardial effusion in a patient with Hashimoto's thyroiditis: histological examination of underlying cardiomyopathy.

An unusual case of a hypothyroid patient with huge pericardial effusion due to Hashimoto's thyroiditis is reported. Cardiac tamponade occurred during admission. Eight hundred milliliters of pericardial effusion was withdrawn by pericardiocentesis. Even after successful replacement of thyroid hormone, she had recurrent effusion two years later. Refractory pericardial effusion is a rare complication in treated hypothyroid patients. Underlying cardiomyopathy was presented with hemodynamic and histological examinations.

Fever of unknown origin: a review of 80 patients from the Shin'etsu area of Japan from 1986-1992.

In this survey involving 10 hospitals, we analyzed data on 80 Japanese patients from the Shin'etsu area (Nagano-ken and Niigata-ken) who were observed for fever of unknown origin (FUO). Our objectives were to identify the underlying causes and the relevant diagnostic methods. Fourteen of the patients died of the underlying illness. The cause of the FUO was infection in 43 patients, allergic or autoimmune disease in 13, neoplasm in 7, miscellaneous causes in 3, and undetermined in 14. FUO was self-limited in 13 patients and persistent in one patient. Methods successfully used to establish the final diagnosis in 66 patients were: evaluation of the clinical course or response to treatment in 16, serologic tests in 12, bacteriologic studies in 10, biopsy in 9, cytologic examination in 6, conventional radiology in 6, necropsy in 3, endoscopy in 2, and biochemical testing in 2.

Preferential acetazolamide-induced vasodilation based on vessel size and organ: confirmation of peripheral vasodilation with use of colored microspheres.

When carbonic anhydrase activity decreases, the regional blood flow (rBF) in organs increases as hypercapnia develops. However, the effects of acetazolamide (AZ)-induced vasodilation have not been estimated with respect to vessel size and organs. The aim of this study was to determine the diameter of the capillaries in various organs that respond to inhibition of carbonic anhydrase activity by AZ. White rabbits were anesthetized with urethane and ketamine and infused with AZ. While the systolic blood pressure (SBP), pH, hemoglobin concentration, and base excess did not change, the partial pressure of arterial oxygen (PaO2) increased significantly and the partial pressure of arterial carbon dioxide (PaCO2) decreased significantly with AZ. The rBF was calculated by using 3 different sizes (15, 25, and 50 microm) of colored microspheres (CM). The rBF measured with 15 microm CM in the brain, kidneys, and liver increased in response to AZ, and the rBF in these organs was different with the different sizes of CM. However, the rBF calculated by using the different sizes of CM in the stomach and abdominal muscle did not change after the administration of AZ. The AZ-induced vasodilation occurred in all sizes of vessels in the liver, in the small and medium-sized vessels in kidneys, and in the larger capillaries in the brain.

Extra-axial ependymoma--case report.

A 13-year-old boy presented with a very unusual ependymoma extending extra-axially. Computed tomography demonstrated a tumor with a cyst and calcification adjacent to the dura and extending over the right occipital and parietal lobes. The cyst wall and solid tumor were enhanced postcontrast. Magnetic resonance imaging revealed that the solid tumor was isointense on T1-weighted images and a mixed iso- and high-intensity on T2-weighted images. The solid tumor and tissue surrounding the cyst were enhanced markedly by gadolinium-diethylenetriaminepentaacetic acid. Sagittal and coronal images demonstrated a multilocular tumor shadow. Cerebral angiography demonstrated a tumor fed by a posterior branch of the right middle meningeal artery but no feeders from the internal carotid and vertebral arteries. The tumor was removed en bloc. The histological diagnosis was clear cell-type ependymoma.

[Transcranial magnetic stimulation of the facial nerve].

It was the object of the present study to determine whether transcranial facial nerve stimulation using a magnetic coil can be clinically applicable, and to find the site where the facial nerve is best stimulated. A magnetic coil was placed over the parieto-occipital skull of the subjects for stimulation, and the facial nerve was electrically stimulated in its intracranial and peripheral courses. Then an electromyogram was recorded from the nasalis muscle of the face on the stimulated side. In 9 healthy volunteers, 18 facial nerves received magnetic and electric stimuli in the peripheral region, and the actual site of stimulation was estimated from the conduction velocity of the nerve. The conduction velocity was 56.6 +/- 4.8 m/s, and the latency between CMAPs for electric at the magnetic stimuli to the posterior tragus was 1.23 +/- 0.21 ms. Therefore, the position stimulated by magnetic coil was estimated to be 70.0 +/- 11.4 mm central to the posterior tragus, i.e., near the root exit zone. In two patients undergoing surgery in the cerebellopontine angle, transcranial magnetic stimulation and electrical stimulation of the intracranial facial nerve were compared intraoperatively. The CMAP produced by transcranial magnetic stimulation coincided closely with that produced by direct electrical stimulation of the root exit zone. Thus, the facial nerve was stimulated at the root exit zone, and this method could be expected to be useful for evaluation of disorders of the intracranial facial nerve.

[Persistent primitive hypoglossal artery associated with intracranial aneurysm (author's transl)].

A case of the persistent left primitive hypoglossal artery associated with an intracranial aneurysm was reported. The thirty-year-old man was admitted to hospital in the diagnosis of subarachnoid hemorrhage at seven days after the onset. Bilateral carotid angiograms revealed a saccular aneurysm at the right internal carotid-posterior communicating artery junction and a persistent left hypoglossal artery arising from the left internal carotid artery at the level of the C-1 vertebra. Retrograde vertebral angiograms revealed right hypoplastic vertebral artery (2mm in diameter) and markedly hypoplastic left vertebral artery, vanishing at the level of the C-3 vertebra. The axial view of the left carotid angiogram demonstrated the hypoglossal artery entered into the cranial cavity through the hypoglossal canal. Linear tomogram in the modified reversed Stenvers projection demonstrated the enlarged left hypoglossal canal measuring 9 X 10 mm. The normal right canal measured 5 X 6 mm. The right frontotemporal craniotomy was performed and the aneurysm was successfully clipped at its neck under an operative microscope. The patient discharged without any neurological deficit. The persistent hypoglossal artery is one of the persistent carotidbasilar anastomoses. Ninety-six cases of the hypoglossal arteries have been reported in literature. Twenty cases of them were associated with intracranial aneurysms. The authors reviewed these twenty cases and discussed the genesis of the intracranial congenital aneurysm in relation to the persistent artery.