Association of gustatory dysfunction and Alzheimer.

BACKGROUND: Chemosensory dysfunction has been reported to be involved in the pathogenesis of Alzheimer’s disease (AD). Compared with olfaction, gustatory dysfunction in AD has not been evaluated in depth. We reviewed previously published studies regarding gustatory dysfunction in patients with AD compared with healthy controls. METHODS: A systematic review was conducted by searching the MEDLINE, Cochrane Library, Embase, and PubMed databases covering publications from January 2000 to February 2023. The search was performed using the keyword "Alzheimer* AND (gustatory OR taste OR gustation)." Only studies that performed gustatory function testing and compared the results between patients with AD and healthy controls were included. A random-effects meta-analysis was performed. RESULTS: Twelve articles were finally included, and various gustatory tests including taste strips, the taste disk test, taste solutions, and subjective questionnaires were applied. Overall gustatory function based on the taste strip test was significantly decreased in patients with AD compared with controls in two out of three papers. The overall gustatory function of patients with AD was significantly decreased in all studies based on the taste disk and taste solution tests. We also found that the sweet taste test showed low heterogeneity across all the included studies, and there was low publication bias. In studies using subjective questionnaires, gustatory function was not significantly different between patients with AD and healthy controls in the meta-analysis. CONCLUSIONS: Based on these studies, gustatory dysfunction diagnosed by gustatory function testing was closely related to AD. However, the results of subjective questionnaires were not significantly different between patients with AD and healthy controls in the current meta-analysis. As the number of studies and enrolled subjects was limited and unified gustatory function testing was lacking, further studies are needed to confirm this relationship.

High-mobility group box 1 protein induces epithelialmesenchymal transition in upper airway epithelial cells.

BACKGROUND: In the treatment of rhinosinusitis, nasal polyps are a major problem, and the epithelial-to-mesenchymal transition (EMT) process is considered pivotal in their development. Although various studies have addressed the role of high mobility group box 1 (HMGB1) nuclear protein in this setting, its impact on EMT has yet to be evaluated. Our aim was the pathogenic mechanism of HMGB1 in EMT and EMT-induced upper respiratory nasal polyps. METHODS: We investigated the EMT-related effects of HMGB1 in human nasal epithelial (HNE) cells using western blot analysis, transepithelial-electrical resistance (TEER) testing, wound healing assay, and immunofluorescence. HNE cells were incubated in a low-oxygen environment to evaluate the role of HMGB1 in hypoxia-induced EMT. Further support for our in vitro findings was obtained through murine models. Human nasal polyps and nasal lavage fluid samples were collected for western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). RESULTS: HMGB1 increased mesenchymal markers and decreased epithelial markers in HNE cells. Hypoxia-induced HMGB1 in turn induced EMT, apparently through RAGE signaling. We verified HMGB1-induced EMT in the upper respiratory epithelium of mice by instilling intranasal HMGB1. In testing of human nasal polyps, HMGB1 and mesenchymal markers were heightened, whereas epithelial markers were reduced, compared with tissue controls. CONCLUSION: HMGB1 secretion in nasal epithelium may be a major pathogenic factor in upper respiratory EMT, contributing to nasal polyps.

Removal of solitary neurofibroma of the external nose by intranasal approach.

INTRODUCTION: Solitary neurofibroma originating from the external nose is extremely rare, and to our knowledge, only 3 cases have been reported so far in English literatures. It may originate from the ophthalmic (V1) and maxillary (V2) branches of the trigeminal nerve. CASE REPORT: We present a rare case of solitary neurofibroma arising from the external nose, which was successfully removed by intranasal approach with intercartilaginous incision. CONCLUSION: This case emphasizes two important points. First, we should keep in mind that this clinical entity is included in the differential diagnosis of soft tissue masses arising from the external nose. Second, we should choose the best surgical approach for complete removal with the maintenance of cosmetic appearance.

Predictors of general discomfort, limitations in activities of daily living and intention of a second donation in unrelated hematopoietic stem cell donation.

We performed a retrospective study of 1868 consecutive unrelated donors to predict the risk factors related to general discomfort, limitations in activities of daily living (ADLs) and intention of a second donation in hematopoietic stem cell (HSC) donation. General discomfort and limitations in ADLs were assessed by numerical measurement (scores of 0-10) and donor's intention of a second donation by yes or no reply. The post-donation questionnaires were completed within 48 h after HSC collection and at 1 week, 4 weeks, and 4 months thereafter. Predictors of general discomfort included female sex (P<0.0001), bone marrow (BM) collection (P<0.0001) or PBSC collection through a central line (CL; P=0.0349), 2-day collection (P=0.0150) and negative or undetermined intention of a second donation on day 1 (P<0.0001). Predictors of limitations in ADLs included age group of 30-39 years (P=0.0046), female sex (P<0.0001), BM collection (P<0.0001) or PBSC collection through a CL (P<0.0001) and negative or undetermined intention of a second donation on day 1 (P<0.0001). The only predictor of positive intention of a second donation was male sex (P=0.0007). Age, sex and collection method and period should be considered risk factors when unrelated HSC donation is performed.

ROS-dependent HMGB1 secretion upregulates IL-8 in upper airway epithelial cells under hypoxic condition.

High-mobility group box 1 (HMGB1) mediates various functions according to the location. We tried to investigate the role of HMGB1 in upper airway under hypoxic conditions. We cultured primary normal human nasal epithelium (NHNE) cells under hypoxic conditions and evaluated the movement of HMGB1 by western blotting, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) level was evaluated to estimate the translocation mechanism of HMGB1. The role of secreted HMGB1 was evaluated by ELISA assay. Furthermore, we collected human nasal mucosa samples and nasal lavage fluids from patients conditioned under hypoxic and non-hypoxic environment, and compared the expression of HMGB1 in human nasal mucosa samples by immunohistochemistry and the levels of HMGB1 in lavage fluids using ELISA assay. Hypoxia induced translocation of HMGB1 into the extracellular area and it was dependent on ROS produced by dual oxidase 2. Secreted HMGB1 was involved in the upregulation of interleukin (IL)-8. In human samples, HMGB1 was translocated from nucleus to the cytoplasm in hypoxic-conditioned nasal mucosa. HMGB1 was increased in nasal lavage samples of chronic rhinosinusitis patients, whose sinus mucosa was supposed to be hypoxic as compared with controls. We suggest that HMGB1 is secreted in hypoxic condition via ROS-dependent mechanism and secreted HMGB1 participates in IL-8 upregulation mediating inflammatory response.

Differential characteristics of pediatric sinusitis in patients who underwent endoscopic sinus surgery: children vs. adolescents.

OBJECTIVES: We hypothesised that paediatric chronic sinusitis patients might have various clinical characteristics, depending on age, compared symptoms, physical findings and clinical features in younger children and older adolescent patients who underwent endoscopic sinus surgery. DESIGN: A retrospective review of medical records. SETTING: A total of 195 paediatric patients who underwent Endoscopic sinus surgery were enrolled and medical records were reviewed. PARTICIPANTS: The subjects were divided into children (age < 12 years, n = 70, mean age = 9.6 years) and adolescents (age ≥ 12 years, n = 125, mean age = 14.7 years). MAIN OUTCOME MEASURES: Subjective symptoms, physical findings, CT images and clinical features were compared in children and adolescent groups. RESULTS: Cough and nasal obstruction were more common in adolescents, and sleep disturbance was more common in children. Nasal mucosal injection was more common in adolescents, whereas tonsils were larger in children. Septal deviation was a more common finding in adolescents, and total CT score and serum total IgE levels were higher in children. There was no statistical difference in rate of recurrence after endoscopic sinus surgery. CONCLUSION: The clinical features of paediatric chronic sinusitis differed between the younger and older groups. Symptomatic, anatomical and clinical differences between these two groups suggest that further study of paediatric chronic sinusitis should stratify patients by age to better understand the effects of treatment on each age group.

HMGB1 in the pathogenesis of ultraviolet-induced ocular surface inflammation.

High-mobility group box 1 (HMGB1) functions as a transcription-enhancing nuclear protein as well as a crucial cytokine that regulates inflammation. This study demonstrated that secretion of HMGB1 due to ultraviolet (UV) radiation inducing ocular surface inflammation-mediated reactive oxygen species (ROS) production. After treating conjunctival epithelial cells with UV radiation, HMGB1 was translocated from the nucleus to the cytoplasm and then eventually to the extracellular space. HMGB1 played a crucial role in UV-induced conjunctival neutrophil infiltration, which subsided when mice were pretreated with the HMGB1 inhibitors soluble receptor for advanced glycation endproducts (sRAGEs) and HMGB1 A box protein. In case of using ROS quencher, there was decrease in UV-induced HMGB1 secretion in conjunctival epithelial cells and mice. Considering that UV-induced chronic inflammation causes ocular surface change as pterygium, we have confirmed high HMGB1 translocation and ROS expression in human pterygium. Our findings therefore revealed a previously unknown mechanism of UV-induced ocular inflammation related to ROS and HMGB1 suggesting a new medical therapeutic target.

Change of telomerase activity in peripheral whole blood of head and neck squamous cell carcinoma patients before and after surgery: a pilot study.

BACKGROUND The purpose of this study was to evaluate telomerase activity in peripheral whole blood from head and neck squamous cell carcinoma (HNSCC) patients as a biomarker for diagnosis of HNSCC or detection of recurrence during follow-up. MATERIALS AND METHODS Telomerase activity was measured from peripheral whole blood extracts by telomerase repeat amplification protocol (TRAP) in HNSCC patients before and after surgery and in a control group. Sixty-two HNSCC patients and 42 control subjects were included. RESULTS Telomerase activity was found in 41 out of 62 (66.1%) HNSCC patients before surgery and in 8 out of 42 (19.0%) controls (p<0.001). Among 41 HNSCC patients who showed positive telomerase activity before surgery, 32 (78.1%) showed a conversion of telomerase activity to negative after surgery. In follow-up, 6 out of 8 (75%) showed conversion of telomerase activity from negative to positive after recurrence. Telomerase activity was changed to negative in 4 out of 6 (66%) recurred patients with positive telomerase activity after second surgery. CONCLUSION The telomerase activity in peripheral whole blood extracts of HNSCC patients might be a useful biomarker for detecting recurrence after treatment. Further study with larger sample size using a more sensitive detection method of telomerase activity is necessary to verify these results.

Change of telomerase activity in peripheral whole blood of head and neck squamous cell carcinoma patients before and after surgery: a pilot study

BACKGROUND The purpose of this study was to evaluate telomerase activity in peripheral whole blood from head and neck squamous cell carcinoma (HNSCC) patients as a biomarker for diagnosis of HNSCC or detection of recurrence during follow-up. MATERIALS AND METHODS Telomerase activity was measured from peripheral whole blood extracts by telomerase repeat amplification protocol (TRAP) in HNSCC patients before and after surgery and in a control group. Sixty-two HNSCC patients and 42 control subjects were included. RESULTS Telomerase activity was found in 41 out of 62 (66.1%) HNSCC patients before surgery and in 8 out of 42 (19.0%) controls (p<0.001). Among 41 HNSCC patients who showed positive telomerase activity before surgery, 32 (78.1%) showed a conversion of telomerase activity to negative after surgery. In follow-up, 6 out of 8 (75%) showed conversion of telomerase activity from negative to positive after recurrence. Telomerase activity was changed to negative in 4 out of 6 (66%) recurred patients with positive telomerase activity after second surgery. CONCLUSION The telomerase activity in peripheral whole blood extracts of HNSCC patients might be a useful biomarker for detecting recurrence after treatment. Further study with larger sample size using a more sensitive detection method of telomerase activity is necessary to verify these results (AU)

Randomised clinical trial: the efficacy of a 10-day sequential therapy vs. a 14-day standard proton pump inhibitor-based triple therapy for Helicobacter pylori in Korea.

BACKGROUND: The eradication rates of Helicobacter pylori (H. pylori) using a proton pump inhibitor (PPI)-based triple therapy have declined due to antibiotic resistance worldwide. AIM: To compare the eradication rate of the 10-day sequential therapy for H. pylori infection with that of the 14-day standard PPI-based triple therapy. METHODS: This was a prospective, randomised, controlled study. A total of 409 patients with H. pylori infection were randomly assigned to receive either the 10-day sequential therapy regimen, which consisted of pantoprazole (40 mg) plus amoxicillin (1000 mg) twice a day for 5 days, then pantoprazole (40 mg) with clarithromycin (500 mg) and metronidazole (500 mg) twice a day for another five consecutive days or the 14-day PPI-based triple therapy regimen, which consisted of pantoprazole (40 mg) with amoxicillin (1000 mg) and clarithromycin (500 mg) twice a day for 14 days. The pre- and post-treatment H. pylori status were assessed by rapid urease test, urea breath test, or histology. Successful eradication was confirmed at least 4 weeks after finishing the treatment. RESULTS: In the intention-to-treat analysis, the eradication rates of the 10-day sequential therapy and of the 14-day PPI-based triple therapy were 85.9% (176/205) and 75.0% (153/205), respectively (P = 0.006). In the per-protocol analysis, the eradication rates were 92.6% (175/205) and 85% (153/204), respectively (P = 0.019). There was no statistically significant difference between the two investigated groups regarding the occurrence of adverse event rates (18.9% vs. 13.3%, P = 0.143). CONCLUSION: The 10-day sequential therapy achieved significantly higher eradication rates than the 14-day standard PPI-based triple therapy in Korea.

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway.

As we have recently found a novel oncogene, the cancer-upregulated gene 2 (CUG2), which was elevated in a variety of tumor tissues such as the ovary, liver, lung and pancreas, we examined whether reovirus could efficiently induce cytolysis in cancer cells expressing CUG2 and thus be used as a potential cancer therapeutic agent. In this study, we describe experiments in which we use reovirus to treat NIH3T3 cells stably expressing either CUG2 (NIH-CUG2) or vector only (NIH-Vec). NIH-CUG2 cells readily support reoviral proliferation and undergo apoptosis, whereas NIH-Vec cells are highly resistant to reoviral infection and virus-induced apoptosis. This notable result may be explained by the observation that CUG2 expression inhibits PKR activation, leading to reoviral proliferation in nonpermissive NIH3T3 cells. Furthermore, reovirus infection results in almost complete regression of tumorgenic NIH-CUG2 cells in transplanted nude mice. As we found that CUG2 enhances activation of MAPK (ERK, JNK and p38), Src kinase and Ras, we examined whether CUG2 confers reoviral replication independent of the Ras or p38 MAPK signaling pathway. From these experiments we found that either inhibition of p38 MAPK or Ras blocks reoviral proliferation even in the presence of CUG2 but inhibition of ERK, JNK and Src kinase does not, indicating that activation of p38 MAPK and Ras has critical roles in reoviral replication in CUG2-expressing tumor cells. Accordingly, we propose that reovirus can be useful in the treatment of transformed cells expressing CUG2, which is commonly detected in various tumor tissues.

Down-regulation of HIF-1alpha by oncolytic reovirus infection independently of VHL and p53.

Many oncolytic viruses are currently being tested as potential cancer therapeutic agents. To be effective, these viruses must replicate and propagate efficiently through the tumor mass. However, it is possible that the hypoxia that characterizes many tumors may be an obstacle to viral therapy because of its inhibition of viral replication and propagation. We, therefore, decided to test how oncolytic reovirus and its target cells respond to hypoxia. We found that reovirus infection suppresses hypoxia inducible factor (HIF)-1alpha protein levels (but not transcript abundance) in colon cancer HCT116 cells under CoCl(2) or hypoxia. Reovirus infection was able to reduce HIF-1alpha levels in both von Hippel Lindau (VHL)-/- renal carcinoma A498 and p53-/- HCT116 cells, indicating that the decrease of HIF-1alpha mediated by reovirus requires neither VHL nor p53 proteins. However, treatment with the inhibitor MG132 restored HIF-1alpha levels, suggesting that reovirus-induced HIF-1alpha decrease needs proteosomal activity. A498 VHL-/- cells with constitutive expression of HIF-1alpha were relatively resistant to reovirus-induced apoptosis when compared with A498 VHL+/+ cells. However, we found that the use of YC-1 to target HIF-1alpha promoted reovirus-induced apoptosis in A498 VHL-/- cells. Accordingly, we propose that reovirus may be used together with YC-1 as a potential therapeutic agent against chemoresistant or radioresistant tumors that are hypoxic and show increased levels of HIF-1alpha.

Anti-inflammatory activity of p-coumaryl alcohol-gamma-O-methyl ether is mediated through modulation of interferon-gamma production in Th cells.

BACKGROUND AND PURPOSE: p-Coumaryl alcohol-gamma-O-methyl ether (CAME) was isolated from Alpinia galanga and shown to contain a phenylpropanoid structure similar to p-coumaryl diacetate (CDA). CDA is known to have antioxidant and anti-inflammatory activity, but the biochemical activities of CAME are unknown. Inflammation is mediated by inflammatory cytokine production, in particular, by CD4+ T helper cells (Th cells), but it is unclear whether phenylpropanoids affect cytokine production in Th cells. In this study, we decided to investigate the functions of CAME and CDA in CD4+ Th cells. EXPERIMENTAL APPROACH: Mouse CD4+ Th cells were isolated from C57BL6 mice and stimulated with an antibody against T cell receptors in the presence of phenylpropanoids. Cytokine production was measured by elisa and intracellular cytokine staining. Gene knockout mice and tetracycline-inducible transgenic mice were used to examine the molecular mechanisms of phenylpropanoids on modulation of cytokine production. KEY RESULTS: CAME potently reduced intracellular reactive oxygen species in Th cells, as does CDA. However, although CDA was cytotoxic, CAME selectively and potently suppresses interferon-gamma (IFNgamma) production in CD4+ Th cells, without toxicity. This effect was caused by attenuated expression of the transcription factor, T-box protein expressed in T cells (T-bet), and T-bet was essential for CAME to inhibit IFNgamma production in CD4+ Th cells. CONCLUSIONS AND IMPLICATIONS: CAME selectively and substantially suppresses IFNgamma production in CD4+ Th cells by decreasing T-bet expression. As increased IFNgamma production by CD4+ Th cells can mediate inflammatory immune responses, a selective IFNgamma suppressor, such as CAME may be an effective, naturally occurring, compound for modulating inflammatory immune disorders.

Expression of HBX, an oncoprotein of hepatitis B virus, blocks reoviral oncolysis of hepatocellular carcinoma cells.

Although reovirus has been used in tests as a potential cancer therapeutic agent against a variety of cancer cells, its application to hepatocellular carcinoma cells, in which the hepatitis B virus (HBV) X (HBX) protein of HBV plays a primary role, has not yet been explored. Here, we describe experiments in which we use reovirus to treat Chang liver carcinoma cells expressing either a vector only (Chang-vec) or a vector encoding HBX protein (Chang-HBX). Although Chang-vec cells readily support reoviral proliferation and undergo apoptosis, Chang-HBX cells are highly resistant to reoviral infection and virus-induced apoptosis, even though HBX protein induces activation of Ras and inactivation of PKR, which are normally thought to enhance reoviral oncolysis. The resistance of Chang-HBX cells to reovirus may instead be explained by HBX-induced downregulation of death receptor 5 and activation of Stat1. Phosphorylated Stat1 activates interferon (IFN)-stimulated regulatory element (ISRE)- and IFN-gamma-activated sequence (GAS)-mediated transcription, leading to the production of IFN-beta, whereas the reduced expression of Stat1 with its siRNA results in a decrease in IFN-beta production, by which Chang-HBX cells eventually succumb to reovirus infection. This result further indicates that HBX induces the establishment of an antiviral state through Stat1 activation. Thus, it appears that active Ras does not override the antiviral effect mediated by the activation of Stat1. Accordingly, we report that HBX, an oncoprotein of HBV, can prevent reoviral oncolysis of hepatocellular carcinoma. This suggests there may be limits to the practical application of reovirus in the treatment of human cancers already expressing other oncoviral proteins.

alpha-Synuclein gene duplication is present in sporadic Parkinson disease.

OBJECTIVE: alpha-Synuclein gene (SNCA) multiplication was found in familial Parkinson disease (PD). We examined SNCA multiplication in patients with familial and sporadic PD and multiple system atrophy (MSA). METHODS: We screened 1,106 patients with parkinsonism (PD = 906, MSA = 200) for SNCA multiplication by multiplex PCR. Fluorescent in situ hybridization was done to confirm the multiplication. [(123)I]N-omega-Fluoropropyl-2 beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]FP-CIT) SPECT was done in the patients with SNCA multiplication and their family members. RESULTS: Three patients were identified as having SNCA duplication. One patient had a positive family history, and two patients were sporadic. Each patient had asymptomatic carriers in their families. The familial case had early onset parkinsonism with rapidly progressive course, cognitive impairment, and dysautonomia. Sporadic cases were more typical of PD. [(123)I]FP-CIT SPECT was abnormal in the patients and normal in the asymptomatic carriers. CONCLUSION: SNCA multiplication is present in sporadic Parkinson disease (PD) and needs to be screened. Low penetrance, clinical heterogeneity, and normal dopamine transporter imaging in asymptomatic carriers may suggest the presence of other genetic modifiers or environmental triggers that play a role in the pathogenesis of PD due to SNCA duplication.

Alteration of BMP-4 and Runx2 expression patterns in mouse temporomandibular joint after ovariectomy.

OBJECTIVE: Temporomandibular disorder (TMD) includes a number of clinical conditions involving the masticatory musculature or the temporomandibular joint (TMJ) and associated structures. Previous studies have shown the presence of high-affinity estrogen receptors in the TMJ articular cartilage. The aim of this study was to evaluate the developmental changes in mouse TMJ under estrogen deficiency. MATERIALS AND METHODS: Four-month-old ovariectomized mice were killed after certain weeks. We examined the significant alterations of the expression patterns of bone morphogenetic protein (BMP)-4, Runx2, and bone sialoprotein (BSP) after ovariectomy. RESULTS: In the control group, BMP-4, Runx2, and BSP expressions showed no definite difference at any stage. In the ovariectomy group, the intensity of BMP-4 and Runx2 expression increased after ovariectomy. BSP immunoreactivity, however, increased slightly at 2 weeks but then decreased gradually. CONCLUSIONS: Estrogen plays important roles in the metabolism and maintenance of TMJ via regulations of signaling molecules such as BMP-4, Runx2, and BSP. Our results suggest that estrogen deficiency is a candidate cause of TMD. This study revealed further osteogenetic properties of estrogen that may be useful in the clinical treatment and prevention of TMD.

Characterization of salicylic acid-induced genes in Chinese cabbage.

Salicylic acid is a messenger molecule in the activation of defense responses in plants. In this study, we isolated four cDNA clones representing salicylic acid-induced genes in Chinese cabbage (Brassica rapa subsp. pekinensis) by subtractive hybridization. Of the four clones, the BC5-2 clone encodes a putative glucosyltransferase protein. The BC5-3 clone is highly similar to an Arabidopsis gene encoding a putative metal-binding farnesylated protein. The BC6-1 clone is a chitinase gene with similarities to a rapeseed class IV chitinase. Class IV chitinases have deletions in the chitin-binding and catalytic domains and the BC6-1 chitinase has an additional deletion in the catalytic domain. The BCP8-1 clone is most homologous to an Arabidopsis gene that contains a tandem array of two thiJ-like sequences. These four cabbage genes were barely expressed in healthy leaves, but were strongly induced by salicylic acid and benzothiadiazole. Expression of the three genes represented by the BC5-2, BC5-3 and BCP8-1 clones were also induced by Pseudomonas syringae pv. tomato, a nonhost pathogen that elicits a hypersensitive response in Chinese cabbage. None of these four genes, however, was strongly induced by methyl jasmonate or by ethylene.

Solution structure of hanatoxin1, a gating modifier of voltage-dependent K(+) channels: common surface features of gating modifier toxins.

The three-dimensional structure of hanatoxin1 (HaTx1) was determined by using NMR spectroscopy. HaTx1 is a 35 amino acid residue peptide toxin that inhibits the drk1 voltage-gated K(+) channel not by blocking the pore, but by altering the energetics of gating. Both the amino acid sequence of HaTx1 and its unique mechanism of action distinguish this toxin from the previously described K(+) channel inhibitors. Unlike most other K(+) channel-blocking toxins, HaTx1 adopts an "inhibitor cystine knot" motif and is composed of two beta-strands, strand I for residues 19-21 and strand II for residues 28-30, connected by four chain reversals. A comparison of the surface features of HaTx1 with those of other gating modifier toxins of voltage-gated Ca(2+) and Na(+) channels suggests that the combination of a hydrophobic patch and surrounding charged residues is principally responsible for the binding of gating modifier toxins to voltage-gated ion channels.

Mutational abrogation of the PTEN/MMAC1 gene in gastrointestinal polyps in patients with Cowden disease.

BACKGROUND & AIMS: To understand the molecular etiology of Cowden disease-associated gastrointestinal polyps, we analyzed the mutational status of PTEN/MMAC1, a recently identified Cowden disease gene located at 10q23, in gastric hamartomas, colonic adenoma, and juvenile polyps of 3 patients with Cowden disease. METHODS: Messenger RNA expression, gene deletion, and sequence alteration of PTEN/MMAC1 were evaluated by quantitative polymerease chain reaction (PCR), PCR-single-strand conformation polymorphism, and sequencing analysis. RESULTS: Germline missense mutation at codon 289 (AAA to GAA, Lys to Glu) and deletion of the wild-type allele were detected in the polyps of 2 patients with Cowden disease in the same family. Germline allelic deletion and transcriptional silencing of the remaining allele, probably caused by abnormal methylation, were also observed in a gastric hamartoma of 1 patient. CONCLUSIONS: The germline mutation and alteration of the remaining allele observed in this study strongly support that PTEN/MMAC1 functions as a tumor suppressor in Cowden disease. This study is the first to show that the mutational abrogation of PTEN/MMAC1 plays a causal role in the genesis of gastrointestinal polyps in Cowden disease, providing molecular genetic evidence that colonic adenoma, juvenile polyp, and gastric hamartoma could be included in the manifestations of Cowden disease.

Comparison of Cotrel-Dubousset pedicle screws and hooks in the treatment of idiopathic scoliosis.

Eighty-two patients with idiopathic scoliosis were treated by Cotrel-Dubousset instrumentation between 1987 and 1991. Twenty were treated with hooks only, 47 with screws and hooks, and 15 with screws only. The methods were compared and the findings showed that screw fixation can be used in the thoracic spine without neurological complications. The screws provided immediate stability with rigid fixation, together with better correction of frontal, sagittal and rotational deformity. There is less loss of correction, a shorter fusion and less risk of neurological complications because of the placement outside the spinal canal and the rigid fixation in derotation. The technique was simpler and the operating time shorter than with the other methods.