Continuous partially hydrolyzed guar gum intake reduces cold-like symptoms: a randomized, placebo-controlled, double-blinded trial in healthy adults.

OBJECTIVE: Partially hydrolyzed guar gum (PHGG), a water-soluble dietary fiber produced by the controlled partial enzymatic hydrolysis of guar gum beans, has various physiological roles. PHGG is expected to influence the immune function and prevent infections. The objective of this study was to examine the effect of continuous ingestion of PHGG for 12 weeks on the development of cold-like symptoms. PATIENTS AND METHODS: A placebo-controlled, double blind, randomized, parallel-group comparative study was conducted. 96 healthy Japanese adults received 5.2 g PHGG or placebo daily for 12 weeks. Cold-like symptoms were assessed based on patient diary, and the levels of short-chain fatty acids (SCFAs) in stool and blood immune markers at baseline and at weeks 6 and 12. RESULTS: The cumulative number of "no symptoms" days for all symptoms was significantly larger in the PHGG than in the placebo group. The result of the analysis by severity of cold-like symptoms also showed significant differences, with the PHGG group having a lower severity of cold-like symptoms. Propionic acid at weeks 6 and 12 and n-butyric acid and total SCFAs at week 12 were significantly higher in the PHGG than in the placebo group. The Interferon-γ level was significantly lower at week 6 in the PHGG than in the placebo group. CONCLUSIONS: PHGG intake may affect immune function and suppress cold-like symptoms through the production of SCFAs in healthy adults.

Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses.

The epidermal growth factor receptor variant III (EGFRvIII) is exclusively expressed on the cell surface in ~50% of glioblastoma multiforme (GBM). This variant strongly and persistently activates the phosphatidylinositol 3-kinase-Akt signaling pathway in a ligand-independent manner resulting in enhanced tumorigenicity, cellular motility and resistance to chemoradiotherapy. Our group generated a recombinant single-chain variable fragment (scFv) antibody specific to the EGFRvIII, referred to as 3C10-scFv. In the current study, we constructed a lentiviral vector transducing the chimeric antigen receptor (CAR) that consisted of 3C10-scFv, CD3ζ, CD28 and 4-1BB (3C10-CAR). The 3C10-CAR-transduced peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells specifically lysed the glioma cells that express EGFRvIII. Moreover, we demonstrated that CAR CD3(+) T cells migrated to the intracranial xenograft of GBM in the mice treated with 3C10-CAR PBMCs. An important and novel finding of our study was that a thalidomide derivative lenalidomide induced 3C10-CAR PBMC proliferation and enhanced the persistent antitumor effect of the cells in vivo. Lenalidomide also exhibited enhanced immunological synapses between the effector cells and the target cells as determined by CD11a and F-actin polymerization. Collectively, lentiviral-mediated transduction of CAR effectors targeting the EGFRvIII showed specific efficacy, and lenalidomide even intensified CAR cell therapy by enhanced formation of immunological synapses.

Longitudinal analysis of the peripapillary retinal nerve fiber layer thinning in patients with retinitis pigmentosa.

PURPOSE: To investigate longitudinal changes in peripapillary retinal nerve fiber layer (RNFL) thickness in patients with retinitis pigmentosa (RP). METHODS: We re-examined 103 RP patients whose RNFL thickness was previously examined and reported. RNFL thickness was measured using Stratus optical coherence tomography and was compared with the previous measurements. The results were also compared with that of previously reported normal subjects. Association between the decrease rate and visual acuity, and visual field was also investigated. RESULTS: The mean follow-up period was 56.9 months. After excluding the patients in whom RNFL images were of poor quality, 88 patients were eventually analyzed. The average RNFL thickness decreased from 105.8 to 98.2 µm during the period, with the average rate of decrease being 1.6 µm/year. The decrease in RNFL was more evident in superior and inferior sectors. Cross-sectional linear regression analysis also revealed an age-dependent decrease in RNFL, with the slower rate of decrease being 0.94 µm/year. The decrease in RNFL thickness was significantly faster than that reported in normal subjects. The decrease rate was not associated with visual functions. CONCLUSION: Age-dependent RNFL thinning occurs at a faster rate in RP patients as compared with that in normal subjects. The result supports the notion that pathologic changes involve inner retina as well as outer retina in eyes with RP. Considering the discrepancy in the rate of RNFL thinning estimated from trend analysis and longitudinal measurement, care should be taken when interpreting the result of cross-sectional analysis.

Technical considerations of endoscopic septostomy using a biportal approach in a case of hydrocephalus associated with tuberous sclerosis.

INTRODUCTION: We report herein the technical considerations for endoscopic septostomy in a case of hydrocephalus associated with tuberous sclerosis. CASE REPORT: A 17-year-old boy presented with visual and gait disturbances. Computed tomography revealed an intraventricular mass obstructing the foramen of Monro bilaterally and marked hydrocephalus. First, we planned a ventriculo-peritoneal shunt with endoscopic septostomy using a biportal approach to resolve the hydrocephalus. Guidance by a rigid endoscope inserted into the anterior horn of the left lateral ventricle allowed us to easily and safely perform septostomy using the fiberscope inserted into the anterior horn of the right lateral ventricle. CONCLUSION: A biportal approach such as the dual endoscopic technique is useful in the treatment of complicated intraventricular lesions with loss of midline structures.

Photoreceptor integrity and visual acuity in cystoid macular oedema associated with retinitis pigmentosa.

AIMS: To assess the correlation between macular morphology and visual acuity in retinitis pigmentosa (RP) patients with cystoid macular oedema (CME). DESIGN: Retrospective cross-sectional study. PATIENTS AND METHODS: Forty-one eyes of 25 RP patients with CME. Patients underwent cross-sectional scans with optical coherence tomography (Stratus OCT). Age, total retinal thickness, photoreceptor thickness, and the transverse and vertical lengths of the cystoid space were measured. Correlation between visual acuity and each of the measurements were examined. Additionally, the status of the inner segment/outer segment junction (IS/OS) was classified as being absent, discontinuous, or distinct. Measurements were then compared among the three groups. RESULTS: Total retinal thickness or photoreceptor thickness was not correlated with visual acuity. There was a correlation between the transverse length of the cystoid space and visual acuity, although the correlation coefficient was weak (r=0.30). The logMAR visual acuity in the IS/OS absent group (0.67+/-0.43) was worse than that seen in the IS/OS discontinuous (0.22+/-0.19) or IS/OS distinct groups (0.07+/-0.16) (P<0.001). CONCLUSIONS: When monitoring CME associated with RP, the status of IS/OS is the essential parameter that needs to be examined.

Retinal nerve fiber layer thickness in patients with retinitis pigmentosa.

PURPOSE: To study retinal nerve fiber layer (RNFL) thickness in patients with retinitis pigmentosa (RP). DESIGN: Cross-sectional observational study. METHODS: One hundred and thirty-seven eyes of 137 patients with RP were examined. The effect of age, gender, laterality, inheritance trait, spherical equivalent refractive error, visual acuity, and the extent of visual field defect on RNFL thickness measured with optical coherence tomography were analyzed by a multiple linear regression model. RESULTS: The average RNFL thickness was 104.1+/-21.7 microm. The multiple R(2) for the model was 0.349. Among the variables studied, ageing and being male were significant risk factors for thinner RNFL thickness. RNFL thickness was not correlated with inheritance trait, laterality, refractive error, visual acuity, or the extent of visual field defect. CONCLUSION: RNFL thickness in RP patients was not correlated with visual function but ageing as in the normal subjects. Currently proposed therapies, including photoreceptor rescue/transplantation and visual prosthesis, are based on the premise that the inner retinal structures are relatively retained despite the profound loss of photoreceptors. The present result supports this notion.

Optical coherence tomographic pattern and focal electroretinogram in patients with retinitis pigmentosa.

PURPOSE: The foveal function of patients with retinitis pigmentosa (RP) has been estimated by visual acuity (VA) or visual field (VF) tests. In the present study, the potential of optical coherence tomography (OCT) and focal electroretinogram (fERG) for monitoring macular function in RP patients was investigated. DESIGN: Cross-sectional observational study. METHODS: A total of 56 eyes of 56 patients with RP underwent ophthalmic examination including VA, VF, fERG, and OCT. Patients were morphologically divided into three groups by the appearance of photoreceptor inner/outer segment junction (IS/OS) that were depicted with OCT; type 1: no IS/OS visible, type 2: IS/OS was visible but the length was < or =2 mm, and type 3: IS/OS >2 mm was confirmed. Functional results for VA and fERG were compared and analysed based on the three groups. RESULTS: The average VA of type 1 patients was significantly lower than that of types 2 or 3 patients (P<0.001). There were no significant VA differences detected between types 2 and 3 patients. While most of the type 1 patients (21/22) showed non-recordable fERG, 3 out of 18 type 2 patients and none of type 3 patients showed non-recordable fERG. Significant differences of the fERG amplitudes were observed among the three groups (a-wave, b-wave, and OP, P<0.001 in all three components). However, the implicit time showed no difference between type 2 and 3. CONCLUSIONS: Analysing the IS/OS with OCT and the amplitudes of fERG may be helpful for monitoring RP patients in addition to VA and VF.

Tentorial incision in a lateral-medial direction with minimal retraction of the temporal lobe in the subtemporal transtentorial approach to the middle tentorial incisural space.

OBJECTIVE: The subtemporal transtentorial approach provides excellent exposure of the middle incisural space. A modification of the subtemporal transtentorial approach with use of a partial mastoidectomy is presented to avoid damage to the temporal lobe as a result of retraction as well as damage to venous structures. METHODS: Four patients, one with a superior cerebellar artery aneurysm, one with a metastatic tumor in the midbrain, one with a tentorial meningioma, and one with a tentorial schwannoma were treated with the present approach. After subtemporal craniotomy, all of the cortical bone overlying the mastoid was removed. The mastoid air cells were drilled down, and the upper part of Trautman's triangle was exposed above the level of the lateral semicircular canal. The presigmoid dura and the temporal dura were opened and connected by incising the superior petrosal sinus. The cerebellar tentorium was incised in a lateral-medial direction along the angle of the tentorium. RESULTS: In each case, the tentorium was incised with minimal retraction of the temporal lobe without any damage to the temporal lobe, or venous structures. The present approach yielded excellent visualization of the lesion and adjacent neurovascular structures. In 3 of 4 cases, the lesions were successfully treated. In the patient with a tentorial schwannoma extending from the middle to posterior incisural space, the extreme lateral supracerebellar-infratentorial approach was combined with the present approach. CONCLUSIONS: Although additional partial mastoidectomy is time-consuming, it reduces the risk of damage to the temporal lobe as a result of retraction as well as damage to venous structures.

Neuroendoscopic removal of intraventricular hemorrhage combined with hydrocephalus.

OBJECTIVE: The neuroendoscope is playing an increasing role in the diagnosis and treatment of several types of lesions, in particular in the ventricular system. Hydrocephalus associated with intraventricular hemorrhage (IVH) is a good indication for neuroendoscopic surgery. We describe herein our experiences with 17 cases of IVH combined with hydrocephalus treated using a neuroendoscope. PATIENTS AND METHODS: The subjects comprised 17 patients with IVH combined with hydrocephalus treated in our department, including cases of thalamic hemorrhage (n=10), caudate hemorrhage (n=5), moya-moya disease (n=1), and dural arteriovenous fistula (n=1). We used a flexible fiberscope that was inserted into the anterior horn of the lateral ventricle. Hematoma was easily evacuated through the working channel of the neuroendoscope by manual maneuvers. Hematomas in the third ventricle, aqueduct and fourth ventricle could also be evacuated. With the addition of septostomy, hematomas in the contralateral lateral ventricle could also be evacuated. RESULTS: All patients underwent successful procedures with good outcomes. No permanent morbidity and mortality was associated with any neuroendoscopic procedures. Shunt insertion was required in 3 cases due to malabsorption of cerebrospinal fluid (CSF) in the chronic stage. CONCLUSIONS: Neuroendoscopic procedures with a flexible fiberscope for the removal of IVH allow resolution of the disturbed CSF circulation. This procedure improves the safety and accuracy of treatment for IVH combined with hydrocephalus.

The impact of cavernous sinus drainage pattern on the results of venous sampling in patients with suspected cushing syndrome.

BACKGROUND AND PURPOSE: Selective venous sampling from the posterior portion of the cavernous sinus (CS) is recommended for the diagnosis of Cushing disease, because samples from the posterior portion yield higher adrenocorticotropic hormone (ACTH) levels than those from the anterior and middle portions. We prospectively assessed this intracavernous gradient of ACTH level to determine which site in the CS yields adequate sampling. MATERIALS AND METHODS: In 5 patients with Cushing syndrome, cavernous sinography was performed to assess drainage pattern of the CS. Sampling was performed from the anterior, middle, and posterior parts of the CS, inferior petrosal sinus (IPS), and the peripheral vein. The ratio of the concentration in CS and IPS to that in peripheral blood plasma (C/P ratio) was calculated. RESULTS: Cavernous sinography showed that the main drainage route was the IPS in 6 sides and that the pterygoid plexus (PP) was developed to the same extent as the IPS in 3 sides. In 1 patient, the CS drained mainly to the PP. In 1 patient with an ectopic lesion, no increase in ACTH level was detected. In 3 of 4 patients with Cushing disease, the highest C/P ratio was obtained from the posterior portion. In 1 patient whose main drainage route was the PP, the highest C/P ratio was obtained from the anterior portion. In this case, sampling data from the posterior portion and the IPS yielded false-negative results. CONCLUSION: Understanding the drainage patterns of the CS is essential for interpretation of sampling data from the CS and avoiding false-negative results.

Thrombin-induced cell proliferation and platelet-derived growth factor-AB release from A172 human glioblastoma cells.

BACKGROUND: In a previous study, we found that thrombin induced proliferation of TM-1 and T98G human glioma cells and that the mitogenic effect was abolished by hirudin. OBJECTIVES: We investigated thrombin's effects on the proliferation of A172 human glioblastoma cells and the induction of growth factors. Furthermore, we examined whether or not the expression of heparin cofactor II (HCII) in A172 cells using adenovirus vector could suppress thrombin's effects. METHODS: The effect of thrombin on cell proliferation was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. The amount of growth factors in the conditioned medium was measured by enzyme-linked immunosorbent assay. The level of platelet-derived growth factor (PDGF)-B mRNA was assessed by reverse transcriptase-polymerase chain reaction analysis. RESULTS: Thrombin-induced proliferation of A172 cells primarily depended on the enhanced secretion of PDGF-AB by thrombin. The action of thrombin depended on its proteolytic activity. However, thrombin-induced PDGF-AB secretion was not abolished by anti-protease-activated receptor (PAR) antibody. The PAR-1 agonist peptide had no effect on cell growth and PDGF-AB levels. Thrombin did not increase PDGF-B gene expression. Expression of HCII effectively suppressed thrombin-induced PDGF-AB release. CONCLUSIONS: These results indicate that thrombin may play an important role in the proliferation of A172 cells by inducing PDGF-AB secretion and that thrombin's action is mediated by its proteolytic activity. Inhibition of thrombin's proteolytic activity may be a new therapeutic method for gliomas.

Successive changes in tissue migration capacity of developing larvae of an intestinal nematode, Strongyloides venezuelensis.

Infective larvae of an intestinal nematode, Strongyloides venezuelensis, enter rodent hosts percutaneously, and migrate through connective tissues and lungs. Then they arrive at the small intestine, where they reach maturity. It is not known how S. venezuelensis larvae develop during tissue migration. Here we demonstrate that tissue invasion ability of S. venezuelensis larvae changes drastically during tissue migration, and that the changes are associated with stage-specific protein expression. Infective larvae, connective tissue larvae, lung larvae, and mucosal larvae were used to infect mice by various infection methods, including percutaneous, subcutaneous, oral, and intraduodenal inoculation. Among different migration stages, only infective larvae penetrated mouse skin. Larvae, once inside the host, quickly lost skin penetration ability, which was associated with the disappearance of an infective larva-specific metalloprotease. Migrating larvae had connective tissue migration ability until in the lungs, where larvae became able to settle down in the intestinal mucosa. Lung larvae and mucosal larvae were capable of producing and secreting adhesion molecules.

Efficacy of a navigation system in neuro-endoscopic surgery.

OBJECTIVE: Neuro-endoscopy is playing a greater role in the diagnosis and treatment of several types of lesions, especially in the ventricular system. However, surgical planning and intraoperative orientation during endoscopic surgery are sometimes difficult. The efficacy of a neurosurgical navigation system using three-dimensional computer graphics of magnetic resonance (MR) images in neuro-endoscopic surgery was evaluated in this study. METHODS: We have developed a navigational endoscopic system designed to monitor the tip and direction of the endoscope, with the mirror marker of the navigation connected to a rigid endoscope. Eight patients, 3 cases of aqueductal stenting for isolated fourth ventricle, 3 cases of cystostomy for ependymal cyst, 1 case of septostomy for isolated lateral ventricle, and 1 case of ventricular tap in narrow ventricles, underwent endoscopic surgery using the present system. RESULTS: All patients underwent successful procedures with good outcomes. The present system was very useful in the cases of an accurate ventricular tap in narrow ventricles, identification of anatomic structures, and determining the appropriate route to the target point. CONCLUSIONS: This navigational endoscopic system improved the safety and accuracy of neuro-endoscopic surgery.

Impact of neuronavigation and image-guided extensive resection for adult patients with supratentorial malignant astrocytomas: a single-institution retrospective study.

Neuronavigation has become an effective therapeutic modality and is used routinely for intra-axial tumor removal. This retrospective study was conducted to evaluate the clinical impact of neuronavigation and image-guided extensive resection for adult patients with supratentorial malignant astrocytomas. Between 1990 and 2002, 76 adult patients with pathologically confirmed malignant astrocytomas underwent craniotomy and removal of the tumors at the Toyama Medical and Pharmaceutical University Hospital. Of these 76 patients, 42 were treated using neuronavigation with conventional microneurosurgery and the other 34 were treated with conventional microneurosurgery alone. Postoperative early MRI with contrast enhancement was done, and gross total resection was defined as the complete absence of residual tumor. Survival time was analyzed with the Kaplan-Meier method. Prognostic factors were obtained from the Cox proportional hazards model. In univariate analysis, age (< 65), grade 3, preoperative KPS (>/= 80), use of neuronavigation, and gross total resection were significantly associated with longer survival. However, when the data were submitted to multivariate analysis, grade 3, preoperative KPS (>/= 80), and gross total resection were independent prognostic factors. The median survival periods of patients receiving gross total resection (vs. partial resection) and neuronavigation (vs. no neuronavigation) were 16 (vs. 9) months and 16 (vs. 10) months, respectively. The percentage of a gross total resection was significantly higher in the neuronavigation group compared to that in the no-navigation group (64.3 % vs. 38.2 %, p < 0.05). Neurological deterioration occurred in 4 of 42 (9.5 %) and in 6 of 34 (17.6 %) patients after surgery with neuronavigation and surgery without neuronavigation, respectively, although this difference was not statistically significant. Our results showed that neuronavigation increases the radicality in the resection of malignant astrocytomas and is objectively useful for improving survival time.

Human intestinal epithelial cell-derived interleukin (IL)-18, along with IL-2, IL-7 and IL-15, is a potent synergistic factor for the proliferation of intraepithelial lymphocytes.

Intestinal epithelial cell (IEC)-derived cytokines, such as stem cell factor (SCF), interleukin (IL)-7 and IL-15 are known to be required for the development of intestinal intraepithelial lymphocytes (IELs). A newly described cytokine, IL-18, has also been shown to be produced by intestinal epithelial cells. To demonstrate the functional effects of IL-18 on human IELs, we assessed IL-18/IL-18 receptor expression in IEC/IEL and proliferation following stimulation of intestinal IELs by IL-18. IL-18 transcripts were detected both in freshly isolated human colonic epithelial cells and in various colonic epithelial cell lines. IL-18 protein was also detected by ELISA and flow cytometric analysis using antihuman IL-18-specific monoclonal antibody (MoAb). Furthermore, IELs constitutively expressed the IL-18 receptor in addition to the IL-2 and IL-7 receptors. More importantly, IL-18 augmented significant proliferative responses of IEL in combination with IL-2, IL-7 and IL-15 both in the presence and in absence of anti-CD3 MoAb. These results suggest that IL-18 might play a crucial role in the proliferation and maintenance of intestinal IELs.

Trehalose: a review of properties, history of use and human tolerance, and results of multiple safety studies.

This paper contains a review of the history, natural occurrence, human consumption, metabolism, manufacture, and the results of eight standardized animal safety studies using trehalose. Trehalose (alpha,alpha-trehalose) is a naturally occurring sugar containing two D-glucose units in an alpha,alpha-1,1 linkage. Trehalose functions in many organisms as an energy source or a protectant against the effects of freezing or dehydration. It also possesses physical and/or chemical properties that are different than other sugars, which may make trehalose an attractive ingredient in food, health and beauty and pharmaceutical products. Data are presented supporting safe human consumption of trehalose in doses up to 50 g, and the physiologic ability of humans to digest it. No consistent treatment-related, dose-dependent adverse effects were observed in any of the eight safety studies performed at doses up to 10% of the diets. On the basis of these toxicity studies, human studies in which doses of trehalose were administered to various populations, and consumption of trehalose in commercial products in Japan, it is concluded that trehalose is safe for use as an ingredient in consumer products when used in accordance with current Good Manufacturing Practices.

Analysis of the antiviral activities of natural IFN-alpha preparations and their subtype compositions.

Here we report on the antiviral effects of two commercially available natural interferon-alpha (IFN-alpha) preparations, their subtype compositions, and the effects of combinations of pairs of the subtypes on virally infected cells. Our results show that the antiviral effects of these preparations depend on the target cell and on the infecting virus. The component subtypes vary with the preparations, and combinations of pairs of IFN-alpha subtypes may have synergistic or competitive effects. Our results suggest that optimal preparations of synergistically acting subtypes may provide more therapeutic benefit to patients.

Cerebrospinal fluid membrane-bound tissue factor and myelin basic protein in the course of vasospasm after subarachnoid hemorrhage.

No marker that predicts accurately the time of occurrence of cerebral vasospasm due to subarachnoid hemorrhage (SAH) has been reported. In the present study, membrane-bound tissue factor (mTF) and myelin basic protein (MBP) concentrations in cerebrospinal fluid (CSF) were evaluated as a predictor of the time of occurrence of cerebral vasospasm. The mTF and MBP concentrations were measured in the CSF from 28 patients with SAH due to ruptured aneurysm. Serial assays were performed from day 4 to day 14 after SAH. CSF mTF and MBP concentrations from days 5 to 9 correlated with the volume of cerebral infarction due to vasospasm and outcome three months after SAH. From the serial assays, CSF mTF measurements predicted the time of occurrence and severity and irreversibility of symptoms due to vasospasm. In conclusion, CSF mTF is predictive of the occurrence and the recovery of cerebral vasospasm, while CSF MBP is only an indicator of severity of brain damage due to vasospasm.

Malignant transformation of cerebello-pontine angle epidermoid.

A 55-year-old woman presented with fever and a stiff neck due to an intracranial poorly differentiated carcinoma at the right cerebellopontine angle. The patient suffered from typical trigeminal pain and had undergone a removal of the right cerebellopontine angle epidermoid 13 years before at another hospital. On admission, MRI imaging showed a lesion at the right cerebellopontine angle with marked contrast enhancement. Partial removal of the tumor was achieved. A histological examination of the tumor showed a poorly differentiated carcinoma accompanied by typical desquamated tissue of the epidermoid. The patient died 3 months after the operation because of aggressive meningeal carcinomatosis.