Dysregulation of ribosome-associated quality control elicits cognitive disorders via overaccumulation of TTC3.

Ribosome-associated quality control (RQC) pathway is responsible for degradation of nascent polypeptides in aberrantly stalled ribosomes, and its defects may lead to neurological diseases. However, the underlying molecular mechanism of how RQC dysfunction elicits neurological disorders remains poorly understood. Here we revealed that neurons with knockout (KO) of ubiquitin ligase LTN1, a key gene in the RQC pathway, show developmental defects in neurons via upregulation of TTC3 and UFMylation signaling proteins. The abnormally enhanced TTC3 protein in Ltn1 KO neurons reduced further accumulation of translationally arrested products by preventing translation initiation of selective genes. However, the overaccumulated TTC3 protein in turn caused dendritic abnormalities and reduced surface-localized GABAA receptors during neuronal development. Ltn1 KO mice showed behavioral deficits associated with cognitive disorders, a subset of which were restored by TTC3 knockdown in medial prefrontal cortex. Together, the overactivated cellular compensatory mechanism against defective RQC through TTC3 overaccumulation induced synaptic and cognitive deficits. More broadly, these findings represent a novel cellular mechanism underlying neuronal dysfunctions triggered by exaggerated cellular stress response to accumulated abnormal translation products in neurons.

Azelnidipine protects HL-1 cardiomyocytes from hypoxia/reoxygenation injury by enhancement of NO production independently of effects on gene expression.

It remains to be elucidated whether Ca2+ antagonists induce pharmacological preconditioning to protect the heart against ischemia/reperfusion injury. The aim of this study was to determine whether and how pretreatment with a Ca2+ antagonist, azelnidipine, could protect cardiomyocytes against hypoxia/reoxygenation (H/R) injury in vitro. Using HL-1 cardiomyocytes, we studied effects of azelnidipine on NO synthase (NOS) expression, NO production, cell death and apoptosis during H/R. Action potential durations (APDs) were determined by the whole-cell patch-clamp technique. Azelnidipine enhanced endothelial NOS phosphorylation and NO production in HL-1 cells under normoxia, which was abolished by a heat shock protein 90 inhibitor, geldanamycin, and an antioxidant, N-acetylcysteine. Pretreatment with azelnidipine reduced cell death and shortened APDs during H/R. These effects of azelnidipine were diminished by a NOS inhibitor, L-NAME, but were influenced by neither a T-type Ca2+ channel inhibitor, NiCl2, nor a N-type Ca2+ channel inhibitor, ω-conotoxin. The azelnidipine-induced reduction in cell death was not significantly enhanced by either additional azelnidipine treatment during H/R or increasing extracellular Ca2+ concentrations. RNA sequence (RNA-seq) data indicated that azelnidipine-induced attenuation of cell death, which depended on enhanced NO production, did not involve any significant modifications of gene expression responsible for the NO/cGMP/PKG pathway. We conclude that pretreatment with azelnidipine protects HL-1 cardiomyocytes against H/R injury via NO-dependent APD shortening and L-type Ca2+ channel blockade independently of effects on gene expression.

Analysis of the spatial distribution of the landslides triggered by the 1923 Great Kanto Earthquake, Japan.

The Great Kanto Earthquake that occurred in the southern part of Kanto district, Japan, on September 1, 1923, was reported to have triggered numerous landslides (over 89,080 slope failures over an area of 86.32 km2). This study investigated the relationship between the landslide occurrence caused by this earthquake and geomorphology, geology, soil, seismic ground motion, and coseismic deformation. We found that a higher landslide density was mainly related to a larger absolute curvature and a higher slope angle, as well as to several geological units (Neogene plutonic rock, accretionary prism, and metamorphic rocks). Moreover, we performed decision tree analyses, which showed that slope angle, geology, and coseismic deformation were correlated to landslide density in that order. However, no clear correlation was found between landslide density and seismic ground motion. These results suggest that landslide density was greater in areas of large slope angle or fragile geology in the area with strong shaking enough to trigger landslides.

Hsp70 promotes maturation of uromodulin mutants that cause familial juvenile hyperuricemic nephropathy and suppresses cellular damage.

BACKGROUND: Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations in UMOD. Here we studied effects of genetic expression and pharmacological induction of Hsp70 on the UMOD mutants C112Y and C217G. METHODS: We expressed wild type (WT), C112Y and C217G in HEK293 cells and studied their maturation and cellular damage using western blot and flow cytometry. RESULTS: Expression of C112Y or C217G increased pro-apoptotic proteins, decreased anti-apoptotic proteins, and induced cellular apoptosis as examined by annexin V staining and flow cytometry. Overexpression of Hsp70 or administration of an Hsp70 inducer geranylgeranylacetone (GGA) promoted maturation of the mutant proteins, increased their secreted forms, normalized the levels of pro- and anti-apoptotic proteins and suppressed apoptosis. CONCLUSION: These findings indicated that Hsp70 enhanced maturation of C112Y and C217G and reduced cellular apoptosis, suggesting that Hsp70 induction might be of a therapeutic value for treatment of FJHN.

The Effects of Volatile Anesthetics on Lung Ischemia-Reperfusion Injury: Basic to Clinical Studies.

Case reports from as early as the 1970s have shown that intravenous injection of even a small dose of volatile anesthetics result in fatal lung injury. Direct contact between volatile anesthetics and pulmonary vasculature triggers chemical damage in the vessel walls. A wide variety of factors are involved in lung ischemia-reperfusion injury (LIRI), such as pulmonary endothelial cells, alveolar epithelial cells, alveolar macrophages, neutrophils, mast cells, platelets, proinflammatory cytokines, and surfactant. With a constellation of factors involved, the assessment of the protective effect of volatile anesthetics in LIRI is difficult. Multiple animal studies have reported that with regards to LIRI, sevoflurane demonstrates an anti-inflammatory effect in immunocompetent cells and an anti-apoptotic effect on lung tissue. Scattered studies have dismissed a protective effect of desflurane against LIRI. While a single-center randomized controlled trial (RCT) found that volatile anesthetics including desflurane demonstrated a lung-protective effect in thoracic surgery, a multicenter RCT did not demonstrate a lung-protective effect of desflurane. LIRI is common in lung transplantation. One study, although limited due to its small sample size, found that the use of volatile anesthetics in organ procurement surgery involving "death by neurologic criteria" donors did not improve lung graft survival. Future studies on the protective effect of volatile anesthetics against LIRI must examine not only the mechanism of the protective effect but also differences in the effects of different types of volatile anesthetics, their optimal dosage, and the appropriateness of their use in the event of marked alveolar capillary barrier damage.

Isolation of oxygenase genes for indigo-forming activity from an artificially polluted soil metagenome by functional screening using Pseudomonas putida strains as hosts.

Metagenomes contain the DNA from many microorganisms, both culturable and non-culturable, and are a potential resource of novel genes. In this study, a 5.2-Gb metagenomic DNA library was constructed from a soil sample (artificially polluted with four aromatic compounds, i.e., biphenyl, phenanthrene, carbazole, and 3-chlorobenzoate) in Escherichia coli by using a broad-host-range cosmid vector. The resultant library was introduced into naphthalene-degrading Pseudomonas putida-derived strains having deficiencies in their naphthalene dioxygenase components, and indigo-forming clones on the indole-containing agar plates were screened. Cosmids isolated from 29 positive clones were classified by their various properties (original screening hosts, hosts showing indigo-forming activity, and digestion patterns with restriction enzymes), and six representative cosmids were chosen. Sequencing and in vitro transposon mutagenesis of the six cosmids resulted in the identification of genes encoding putative class B and D flavoprotein monooxygenases, a multicomponent hydroxylase, and a reductase that were responsible for the indigo-forming activity in the host cells. Among them, the genes encoding the multicomponent hydroxylase were demonstrated to be involved in phenol degradation. Furthermore, two genes encoding ring-cleavage dioxygenases were also found adjacent to the genes responsible for the indigo formation, and their functions were experimentally confirmed.

Electrophysiological properties of prion-positive cardiac progenitors derived from murine embryonic stem cells.

BACKGROUND: The prion protein (PrP) has been reported to serve as a surface maker for isolation of cardiomyogenic progenitors from murine embryonic stem (ES) cells. Although PrP-positive cells exhibited automaticity, their electrophysiological characteristics remain unresolved. The aim of the present study was therefore to investigate the electrophysiological properties of PrP-positive cells in comparison with those of HCN4p-or Nkx2.5-positive cells. METHODS AND RESULTS: Differentiation of AB1, HCN5p-EGFP and hcgp7 ES cells into cardiac progenitors was induced by embryoid body (EB) formation. EBs were dissociated and cells expressing PrP, HCN4-EGFP and/or Nkx2.5-GFP were collected via flow cytometry. Sorted cells were subjected to reverse transcriptase-polymerase chain reaction, immunostaining and patch-clamp experiments. PrP-positive cells expressed mRNA of undifferentiation markers, first and second heart field markers, and cardiac-specific genes and ion channels, indicating their commitment to cardiomyogenic progenitors. PrP-positive cells with automaticity showed positive and negative chronotropic responses to isoproterenol and carbamylcholine, respectively. Hyperpolarization-activated cation current (I(f)) was barely detectable, whereas Na(+) and L-type Ca(2+) channel currents were frequently observed. Their spontaneous activity was slowed by inhibition of sarcoplasmic reticulum Ca(2+) uptake and release but not by blocking I(f). The maximum diastolic potential of their spontaneous firings was more depolarized than that of Nkx2.5-GFP-positive cells. CONCLUSIONS: PrP-positive cells contained cardiac progenitors that separated from the lineage of sinoatrial node cells. PrP can be used as a marker to enrich nascent cardiac progenitors.

A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders.

Recent genetic approaches have demonstrated that genetic factors contribute to the pathologic origins of neuropsychiatric disorders. Nevertheless, the exact pathophysiological mechanism for most cases remains unclear. Recent studies have demonstrated alterations in pathways of protein homeostasis (proteostasis) and identified several proteins that are misfolded and/or aggregated in the brains of patients with neuropsychiatric disorders, thus providing early evidence that disrupted proteostasis may be a contributing factor to their pathophysiology. Unlike neurodegenerative disorders in which massive neuronal and synaptic losses are observed, proteostasis impairments in neuropsychiatric disorders do not lead to robust neuronal death, but rather likely act via loss- and gain-of-function effects to disrupt neuronal and synaptic functions. Furthermore, abnormal activation of or overwhelmed endoplasmic reticulum and mitochondrial quality control pathways may exacerbate the pathophysiological changes initiated by impaired proteostasis, as these organelles are critical for proper neuronal functions and involved in the maintenance of proteostasis. This perspective article reviews recent findings implicating proteostasis impairments in the pathophysiology of neuropsychiatric disorders and explores how neuronal and synaptic functions may be impacted by disruptions in protein homeostasis. A greater understanding of the contributions by proteostasis impairment in neuropsychiatric disorders will help guide future studies to identify additional candidate proteins and new targets for therapeutic development.

A Case of Iliopsoas Hematoma Caused by Prophylactic Anticoagulation against COVID-19.

BACKGROUND: COVID-19 is associated with an increased risk of venous thromboembolism (VTE), and prophylactic anticoagulation is recommended for the prevention of VTE in COVID-19 patients. We encountered a patient with COVID-19 who developed iliopsoas hematoma (IPH) that was likely caused by prophylactic anticoagulation against VTE; we report the case here because IPH is an important risk in rehabilitation treatment. CASE: The patient was a 73-year-old man with severe COVID-19 who received anticoagulation therapy from the time of admission (day 0). On day 22, decreased hemoglobin levels, muscle weakness in the left lower extremity, and pain on passive movement of the left hip joint were noted. On day 29, computed tomography (CT) was performed and revealed a mass lesion suspicious of a hematoma in the left iliopsoas muscle. On day 36, magnetic resonance imaging (MRI) was carried out to re-evaluate the mass lesion and revealed a multicystic lesion that could also have been an abscess. CT-guided puncture drainage was performed, but no pus-like material was collected; this finding led to a diagnosis of IPH. Subsequent exercise loads were gradually increased while the status of the hematoma was assessed. DISCUSSION: The prevalence of IPH in COVID-19 patients has been reported to be 7.6 cases per 1000 admissions, and the use of anticoagulation is likely to increase the risk of IPH. Because rehabilitative interventions can lead to the discovery or aggravation of IPH, the possibility of IPH should be kept in mind when providing rehabilitation treatment for COVID-19 patients.

Tracing conformational transition of abnormal prion proteins during interspecies transmission by using novel antibodies.

Conformational differences in abnormal prion proteins (PrP(Sc)) have been postulated to produce different prion phenotypes. During the interspecies transmission of prions, the conformation of PrP(Sc) may change with passage; however, little is known about the mechanism of PrP(Sc) transition. In this study, novel PrP(Sc)-specific monoclonal antibodies (mAbs) were developed that could detect the PrP(Sc) of mouse but not that of sheep. By using these mAbs, we attempted to examine PrP(Sc) accumulated in mice inoculated with sheep scrapie serially up to five passages. The presence of PrP(Sc) in the mice was confirmed at all passages; however, mAb-bound PrP(Sc) conformer was detected only from the third passage onward. The generated mAb enabled tracing of a particular conformer during adaptation in sheep-to-mice transmission of prion, suggesting that the conformational transition of PrP(Sc) was caused by propagation of this conformer. Such mAbs capable of discriminating conformational differences may allow us to address questions concerning PrP(Sc) conformation and strain diversity.

The lin genes for γ-hexachlorocyclohexane degradation in Sphingomonas sp. MM-1 proved to be dispersed across multiple plasmids.

A γ-hexachlorocyclohexane (HCH)-degrading bacterium, Sphingomonas sp. MM-1, was isolated from soil contaminated with HCH isomers. Cultivation of MM-1 in the presence of γ-HCH led to the detection of five γ-HCH metabolites, γ-pentachlorocyclohexene, 2,5-dichloro-2,5-cyclohexadiene-1,4-diol, 2,5-dichlorohydroquinone, 1,2,4-trichlorobenzene, and 2,5-dichlorophenol, strongly suggesting that MM-1 has the lin genes for γ-HCH degradation originally identified in the well-studied γ-HCH-degrading strain Sphingobium japonicum UT26. Southern blot, PCR amplification, and sequencing analyses indicated that MM-1 has seven lin genes for the conversion of γ-HCH to ß-ketoadipate (six structural genes, linA to linF, and one regulatory gene, linR). MM-1 carried four plasmids, of 200, 50, 40, and 30 kb. Southern blot analysis revealed that all seven lin genes were dispersed across three of the four plasmids, and that IS6100, often found close to the lin genes, was present on all four plasmids.

Complete genome sequence of the representative γ-hexachlorocyclohexane-degrading bacterium Sphingobium japonicum UT26.

Sphingobium japonicum strain UT26 utilizes γ-hexachlorocyclohexane (γ-HCH), a man-made chlorinated pesticide that causes serious environmental problems due to its toxicity and long persistence, as a sole source of carbon and energy. Here, we report the complete genome sequence of UT26, which consists of two chromosomes and three plasmids. The 15 lin genes involved in γ-HCH degradation are dispersed on the two chromosomes and one of the three plasmids.

Commitment of 1-methyl-4-phenylpyrinidinium ion-induced neuronal cell death by proteasome-mediated degradation of p35 cyclin-dependent kinase 5 activator.

The dysfunction of proteasomes and mitochondria has been implicated in the pathogenesis of Parkinson disease. However, the mechanism by which this dysfunction causes neuronal cell death is unknown. We studied the role of cyclin-dependent kinase 5 (Cdk5)-p35 in the neuronal cell death induced by 1-methyl-4-phenylpyrinidinium ion (MPP+), which has been used as an in vitro model of Parkinson disease. When cultured neurons were treated with 100 microM MPP+, p35 was degraded by proteasomes at 3 h, much earlier than the neurons underwent cell death at 12-24 h. The degradation of p35 was accompanied by the down-regulation of Cdk5 activity. We looked for the primary target of MPP+ that triggered the proteasome-mediated degradation of p35. MPP+ treatment for 3 h induced the fragmentation of the mitochondria, reduced complex I activity of the respiratory chain without affecting ATP levels, and impaired the mitochondrial import system. The dysfunction of the mitochondrial import system is suggested to up-regulate proteasome activity, leading to the ubiquitin-independent degradation of p35. The overexpression of p35 attenuated MPP+-induced neuronal cell death. In contrast, depletion of p35 with short hairpin RNA not only induced cell death but also sensitized to MPP+ treatment. These results indicate that a brief MPP+ treatment triggers the delayed neuronal cell death by the down-regulation of Cdk5 activity via mitochondrial dysfunction-induced up-regulation of proteasome activity. We propose a role for Cdk5-p35 as a survival factor in countering MPP+-induced neuronal cell death.

Regulation and role of cyclin-dependent kinase activity in neuronal survival and death.

Cyclin-dependent kinase (Cdk)5 is a proline-directed Ser/Thr protein kinase that functions mainly in neurons and is activated by binding to a regulatory subunit, p35 or p39. Kinase activity is mainly determined by the amount of p35 available, which is controlled by a balance between synthesis and degradation. Kinase activity is also regulated by Cdk5 phosphorylation, but the activity of phosphorylated Cdk5 is in contrast to that of cycling Cdks. Cdk5 is a versatile protein kinase that regulates multiple neuronal activities including neuronal migration and synaptic signaling. Further, Cdk5 plays a role in both survival and death of neurons. Long-term inactivation of Cdk5 triggers cell death, and the survival activity of Cdk5 is apparent when neurons suffer from stress. In contrast, hyper-activation of Cdk5 by p25 promotes cell death, probably by reactivating cell-cycle machinery in the nucleus. The pro-death activity is suppressed by membrane association of Cdk5 via myristoylation of p35. Appropriate activity, localization, and regulation of Cdk5 may be critical for long-term survival of neurons, which is more than 80 years in the case of humans.

Pretreatment with cilnidipine attenuates hypoxia/reoxygenation injury in HL-1 cardiomyocytes through enhanced NO production and action potential shortening.

Myocardial ischemia/reperfusion injury worsens in the absence of nitric oxide synthase (NOS). Cilnidipine, a Ca2+ channel blocker, has been reported to activate endothelial NOS (eNOS) and increases nitric oxide (NO) in vascular endothelial cells. We examined whether pretreatment with cilnidipine could attenuate cardiac cell deaths including apoptosis caused by hypoxia/reoxygenation (H/R) injury. HL-1 mouse atrial myocytes as well as H9c2 rat ventricular cells were exposed to H/R, and cell viability was evaluated by an autoanalyzer and flow cytometry; eNOS expression, NO production, and electrophysiological properties were also evaluated by western blotting, colorimetry, and patch clamping, respectively, in the absence and presence of cilnidipine. Cilnidipine enhanced phosphorylation of eNOS and NO production in a concentration-dependent manner, which was abolished by siRNAs against eNOS or an Hsp90 inhibitor, geldanamycin. Pretreatment with cilnidipine attenuated cell deaths including apoptosis during H/R; this effect was reproduced by an NO donor and a xanthine oxidase inhibitor. The NOS inhibitor L-NAME abolished the protective action of cilnidipine. Pretreatment with cilnidipine also attenuated H9c2 cell death during H/R. Additional cilnidipine treatment during H/R did not significantly enhance its protective action. There was no significant difference in the protective effect of cilnidipine under normal and high Ca2+ conditions. Action potential duration (APD) of HL-1 cells was shortened by cilnidipine, with this shortening augmented after H/R. L-NAME attenuated the APD shortening caused by cilnidipine. These findings indicate that cilnidipine enhances NO production, shortens APD in part by L-type Ca2+ channel block, and thereby prevents HL-1 cell deaths during H/R.

Translation from the Ribosome to the Clinic: Implication in Neurological Disorders and New Perspectives from Recent Advances.

De novo protein synthesis by the ribosome and its multitude of co-factors must occur in a tightly regulated manner to ensure that the correct proteins are produced accurately at the right time and, in some cases, also in the proper location. With novel techniques such as ribosome profiling and cryogenic electron microscopy, our understanding of this basic biological process is better than ever and continues to grow. Concurrently, increasing attention is focused on how translational regulation in the brain may be disrupted during the progression of various neurological disorders. In fact, translational dysregulation is now recognized as the de facto pathogenic cause for some disorders. Novel mechanisms including ribosome stalling, ribosome-associated quality control, and liquid-liquid phase separation are closely linked to translational regulation, and may thus be involved in the pathogenic process. The relationships between translational dysregulation and neurological disorders, as well as the ways through which we may be able to reverse those detrimental effects, will be examined in this review.

Peripartum myocardial infarction associated with coronary spasm and acquired protein S deficiency: A case report.

RATIONALE: Coronary angiography (CAG) findings of acute myocardial infarction (AMI) in pregnant women are characterized by a high incidence of normal coronary arteries. This is the first report of AMI with normal coronary arteries during pregnancy, showing coronary spasm and pregnancy-related acquired protein S (PS) deficiency. PATIENT CONCERNS: A 30-year-old Japanese woman was admitted to an emergency department. One hour before admission, she developed sudden onset of precordial discomfort, back pain, and dyspnea. She was a primigravida at 39 weeks' gestation and had no abnormality in the pregnancy thus far. She had no history of heart disease, diabetes, hypertension, dyslipidemia, deep vein thrombosis (DVT), smoking, or oral contraceptive use and no family history of ischemic heart disease, hemostasis disorder, or DVT. She did not take any medication. DIAGNOSIS: Electrocardiography showed ST-segment elevations in leads II, III, aVF, and V2-V6. Heart-type fatty acid-binding protein was positive. Echocardiography showed hypokinesis of the anterior interventricular septum and inferior wall. Continuous intravenous infusion of isosorbide dinitrate was initiated. Coronary computed tomography angiography revealed diffuse narrowing of the apical segment of the left anterior descending coronary artery. Three hours after admission, troponin T became positive, and the following enzymes reached their peak levels: creatine kinase (CK), 1,886 U/L; CK-muscle/brain, 130 U/L. She was diagnosed with transmural AMI due to severe coronary spasm and administered benidipine hydrochloride. Five hours after admission, premature membrane rupture occurred. INTERVENTIONS: Emergency cesarean section was performed. There were no anesthetic or obstetrical complications during the operation. On postpartum day 1, the free PS antigen level was low (29%). On postpartum day 18, she was discharged with no reduction in physical performance. OUTCOMES: Four months after the infarction, CAG showed normal coronary arteries. Acetylcholine provocation test showed diffuse vasospasm in the coronary artery. She was advised that her next pregnancy should be carefully planned. Two years after delivery, free PS antigen level was within normal range, at 86%. She had not experienced recurrence of angina during the 2-year period. Her child was also developing normally. LESSONS: In addition to coronary spasm, pregnancy-related acquired PS deficiency may be involved in AMI etiology.

GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior.

Dysfunctional mTOR signaling is associated with the pathogenesis of neurodevelopmental and neuropsychiatric disorders. However, it is unclear what molecular mechanisms and pathogenic mediators are involved and whether mTOR-regulated autophagy continues to be crucial beyond neurodevelopment. Here, we selectively deleted Atg7 in forebrain GABAergic interneurons in adolescent mice and unexpectedly found that these mice showed a set of behavioral deficits similar to Atg7 deletion in forebrain excitatory neurons. By unbiased quantitative proteomic analysis, we identified γ-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2) to differentially form high-molecular weight species in autophagy-deficient brains. Further functional analyses revealed a novel pathogenic mechanism involving the p62-dependent sequestration of GABARAP family proteins, leading to the reduction of surface GABAA receptor levels. Our work demonstrates a novel physiological role for autophagy in regulating GABA signaling beyond postnatal neurodevelopment, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neuropsychiatric disorders with mTOR hyperactivation.

Lactoferrin induces cell surface retention of prion protein and inhibits prion accumulation.

Prion diseases are fatal neurodegenerative disorders, and the conformational conversion of normal cellular prion protein (PrP(C)) into its pathogenic, amyloidogenic isoform (PrP(Sc)) is the essential event in the pathogenesis of these diseases. Lactoferrin (LF) is a cationic iron-binding glycoprotein belonging to the transferrin (TF) family, which accumulates in the amyloid deposits in the brain in neurodegenerative disorders, such as Alzheimer's disease and Pick's disease. In the present study, we have examined the effects of LF on PrP(Sc) formation by using cell culture models. Bovine LF inhibited PrP(Sc) accumulation in scrapie-infected cells in a time- and dose-dependent manner, whereas TF was not inhibitory. Bioassays of LF-treated cells demonstrated prolonged incubation periods compared with non-treated cells indicating a reduction of prion infectivity. LF mediated the cell surface retention of PrP(C) by diminishing its internalization and was capable of interacting with PrP(C) in addition to PrP(Sc). Furthermore, LF partially inhibited the formation of protease-resistant PrP as determined by the protein misfolding cyclic amplification assay. Our results suggest that LF has multifunctional antiprion activities.

[A study of surgical procedures for inverted papilloma in the nasal cavity and paranasal sinuses].

Inverted papilloma, although benign, recurs frequently and may become malignant, making definitive initial resection extremely important. We evaluated surgical procedures for recurrence and sites, with special reference to management of the orbital plate of the ethmoid and lacrimal bones, in 24 patients (32 cases) with inverted papilloma of the nasal cavity and paranasal sinuses undergoing surgical resection from 2000. Nine of the 32 showed recurrence, all around the ethmoid orbital plate. Up to 2002, recurrence was noted in 7 of 17 cases (41%), so we changed surgical selection criteria. Since 2003, we have conducted partial and combined excision of the orbital plate of the ethmoid and lacrimal bones (extended operation of the extranasal ethmoid and frontal sinuses) in cases in which tumors adhered to the orbital plate, noting recurrences in only 2 of 15 cases (13%). A number of reports advocate endoscopic sinus surgery to minimize invasiveness for inverted papilloma, but partial and combined excision of the orbital plate is indispensable, in progressive inverted papilloma cases to reduce recurrent.