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Hyperlipidemia, the hallmark of Metabolic Syndrome that afflicts millions of people worldwide, exacerbates life-threatening infections. We present a new evidence for the mechanism of hyperlipidemic hypersensitivity to microbial inflammation caused by pathogen-derived inducer, LPS. We demonstrate that hyperlipidemic animals succumbed to a non-lethal dose of LPS whereas normolipidemic controls survived. Strikingly, survival of hyperlipidemic animals was restored when the nuclear import of stress-responsive transcription factors (SRTFs), Sterol Regulatory Element-Binding Proteins (SREBPs), and Carbohydrate-Responsive Element-Binding Proteins (ChREBPs) was impeded by targeting the nuclear transport checkpoint with cell-penetrating, biselective nuclear transport modifier (NTM) peptide. Furthermore, the burst of proinflammatory cytokines and chemokines, microvascular endothelial injury in the liver, lungs, heart, and kidneys, and trafficking of inflammatory cells were also suppressed. To dissect the role of nuclear transport signaling pathways we designed and developed importin-selective NTM peptides. Selective targeting of the importin α5, ferrying SRTFs and ChREBPs, protected 70–100% hyperlipidemic animals. Targeting importin β1, that transports SREBPs, was only effective after 3-week treatment that lowered blood triglycerides, cholesterol, glucose, and averted fatty liver. Thus, the mechanism of hyperlipidemic hypersensitivity to lethal microbial inflammation depends on metabolic and proinflammatory transcription factors mobilization, which can be counteracted by targeting the nuclear transport checkpoint.

Endotoxin shock is induced by LPS, one of the most potent virulence factors of the Gram-negative bacteria that cause sepsis. It remains unknown if either proinflammatory stress-responsive transcription factors (SRTFs), ferried to nucleus by importin α5, or lipid-regulating sterol regulatory element binding proteins (SREBPs), transported to the nucleus by importin β1, mediate endotoxin shock. A novel cell-penetrating peptide targeting importin α5 while sparing importin β1 protected 80% of animals from death in response to a high dose of LPS. This peptide suppresses inflammatory mediators, liver glycogen depletion, endothelial injury, neutrophil trafficking, and apoptosis caused by LPS. In d-galactosamine–pretreated mice challenged by 700-times lower dose of LPS, rapid death through massive apoptosis and hemorrhagic necrosis of the liver was also averted by the importin α5–selective peptide. Thus, using a new tool for selective suppression of nuclear transport, we demonstrate that SRTFs, rather than SREBPs, mediate endotoxin shock.

Chiusa et al. show that the RNA-DNA binding protein FUS plays a profibrotic role by binding to the collagen IV gene promoter and commencing its transcription. Reducing nuclear FUS inhibits collagen IV transcription, suggesting that targeting FUS offers a new antifibrotic therapy., Excessive accumulation of collagen leads to fibrosis. Integrin α1β1 (Itgα1β1) prevents kidney fibrosis by reducing collagen production through inhibition of the EGF receptor (EGFR) that phosphorylates cytoplasmic and nuclear proteins. To elucidate how the Itgα1β1/EGFR axis controls collagen synthesis, we analyzed the levels of nuclear tyrosine phosphorylated proteins in WT and Itgα1-null kidney cells. We show that the phosphorylation of the RNA-DNA binding protein fused in sarcoma (FUS) is higher in Itgα1-null cells. FUS contains EGFR-targeted phosphorylation sites and, in Itgα1-null cells, activated EGFR promotes FUS phosphorylation and nuclear translocation. Nuclear FUS binds to the collagen IV promoter, commencing gene transcription that is reduced by inhibiting EGFR, down-regulating FUS, or expressing FUS mutated in the EGFR-targeted phosphorylation sites. Finally, a cell-penetrating peptide that inhibits FUS nuclear translocation reduces FUS nuclear content and collagen IV transcription. Thus, EGFR-mediated FUS phosphorylation regulates FUS nuclear translocation and transcription of a major profibrotic collagen gene. Targeting FUS nuclear translocation offers a new antifibrotic therapy.

Summary Sepsis, also known as septicemia, is one of the 10 leading causes of death worldwide. The rising tide of sepsis due to bacterial, fungal and viral infections cannot be stemmed by current antimicrobial therapies and supportive measures. New paradigms for the mechanism and resolution of sepsis and consequences for sepsis survivors are emerging. Consistent with Benjamin Franklin's dictum ‘an ounce of prevention is worth a pound of cure’, sepsis can be prevented by vaccinations against pneumococci and meningococci. Recently, the NIH NHLBI Panel redefined sepsis as ‘severe endothelial dysfunction syndrome in response to intravascular and extravascular infections causing reversible or irreversible injury to the microcirculation responsible for multiple organ failure’. Microvascular endothelial injury underlies sepsis‐associated hypotension, edema, disseminated intravascular coagulation, acute respiratory distress syndrome and acute kidney injury. Microbial genome products trigger ‘genome wars’ in sepsis that reprogram the human genome and culminate in a ‘genomic storm’ in blood and vascular cells. Sepsis can be averted experimentally by endothelial cytoprotection through targeting nuclear signaling that mediates inflammation and deranged metabolism. Endothelial ‘rheostats’ (e.g. inhibitors of NF‐κB, A20 protein, CRADD/RAIDD protein and microRNAs) regulate endothelial signaling. Physiologic ‘extinguishers’ (e.g. suppressor of cytokine signaling 3) can be replenished through intracellular protein therapy. Lipid mediators (e.g. resolvin D1) hasten sepsis resolution. As sepsis cases rose from 387 330 in 1996 to 1.1 million in 2011, and are estimated to reach 2 million by 2020 in the US, mortality due to sepsis approaches that of heart attacks and exceeds deaths from stroke. More preventive vaccines and therapeutic measures are urgently needed.

Inflammation is the mechanism of diseases caused by microbial, autoimmune, allergic, metabolic and physical insults that produce distinct types of inflammatory responses. This aetiologic view of inflammation informs its classification based on a cause-dependent mechanism as well as a cause-directed therapy and prevention. The genomic era ushered in a new understanding of inflammation by highlighting the cell's nucleus as the centre of the inflammatory response. Exogenous or endogenous inflammatory insults evoke genomic responses in immune and non-immune cells. These genomic responses depend on transcription factors, which switch on and off a myriad of inflammatory genes through their regulatory networks. We discuss the transcriptional paradigm of inflammation based on denying transcription factors' access to the nucleus. We present two approaches that control proinflammatory signalling to the nucleus. The first approach constitutes a novel intracellular protein therapy with bioengineered physiologic suppressors of cytokine signalling. The second approach entails control of proinflammatory transcriptional cascades by targeting nuclear transport with a cell-penetrating peptide that inhibits the expression of 23 out of the 26 mediators of inflammation along with the nine genes required for metabolic responses. We compare these emerging anti-inflammatory countermeasures to current therapies. The transcriptional paradigm of inflammation offers nucleocentric strategies for microbial, autoimmune, metabolic, physical and other types of inflammation afflicting millions of people worldwide.

A child with impaired fasting glucose was found to be heterozygous for a novel variant at c.659G>A in GCK and a variant at c.1663C>T in HNF1A. Structural modeling and clinical correlation suggests that the GCK variant causes monogenic diabetes while the variant in HNF1A is unlikely to be pathogenic.

To assess the feasibility and acute/delayed toxicity of pulsed-dose-rate brachytherapy (PDR BT) in head-and-neck tumors. 45 head and neck cancer patients underwent interstitial or contact PDR BT at a dose of 10.2–70 Gy (median, 70 Gy) and 0.6 or 1.0 Gy/pulse/h. 42 patients were administered BT as part of their curative treatment; 32 of them had sole BT. Three reirradiated patients with recurrent tumor had palliative BT. PDR BT was well tolerated. Intense bleeding was the only complication associated with catheter removal from the tongue and bucca. 44 patients who completed BT experienced acute mucositis. Grade 3 toxicity of skin and oral mucosa occurred in three (6.8%) and six patients (13.6%), respectively. At a median follow-up of 22 months (range, 2–67 months), late serious toxicity (grade 4, for soft tissue and bone) was seen in seven patients (15.9%). Among the parameters analyzed, only dental care performed before BT had a significant impact on mucosal side effects. Acute severe mucositis was observed in 23% of patients without dental care compared to 0% of those with dental care (p = 0.044). Late severe mucositis occurred in 17.7% and 26.9% of the respective patients (p = 0.035), overall in 23%. The larger the volume encompassed by the reference isodose, the more late (p = 0.004) mucosal reactions were observed. PDR BT continued over a few days is a feasible and safe approach in head-and-neck tumors; however, it is accompanied by some toxicity. Dental care should precede isotope application.

Four substituted 4H-benzo[1,2,4]thiadiazines 2 were prepared by condensation of the appropriate anilines and benzonitriles followed by oxidative cyclization. The preparation of three fluorinated derivatives 2b-2d proceeded smoothly, while the synthesis of 2a was problematic, presumably due to the relatively high electron density of the benzene ring. The four-ring derivatives 2c and 2d exhibited liquid crystalline properties (2c: Cr 95 SmA 158 I and 2d: Cr 142 SmA 212 I). 4H-Benzo[1,2,4]thiadiazines 2 were oxidized with AgO to generate the corresponding persistent radicals 1 (g=2.0057). The stability of the radicals followed the order 1b approximately 1d1c1a, and the two fluorinated radicals 1b and 1d were isolated as crude solids. The lower stability of 1c is presumably due to the presence of the reactive benzylic CH position, and 1a lacks the stabilizing effect of the three fluorine atoms. ESR spectra for 1 were simulated using DFT-derived hfcc as the starting point.

Summary Aim To present three cases treated with contact pulsed dose rate (PDR) brachytherapy using individually prepared moulds. Materials/Methods The study group included one case of hard palate cancer treated with brachytherapy, applied as a boost to external beam radical irradiation and two cases of recurrent ethmoid and maxillary sinus cancer in which we administered palliative brachytherapy as the sole treatment for tumours located within previously irradiated areas. Results Good fitting of the moulds to the target was obtained. Satisfactory local control, including complete hard palate cancer remission for six years, and acceptable side effects were achieved. Conclusions Contact PDR brachytherapy using individually constructed moulds allows for the treatment of anatomical structures with difficult access. This method seems to be an effective and relatively safe treatment option for tumours located within previously irradiated areas.

Five persistent radicals 1a-1e were generated by the oxidation of 4H-[1,2,4]thiadiazines 2a-2e and studied with ESR and UV-vis spectroscopy. Three of the radicals, 1a, 1d, and 1e, were generated in high yields (>90%) using either SO(2)Cl(2)/amine in toluene or AgO/K(2)CO(3) in a toluene/MeCN mixture. Halogenated radicals 1d and 1e were sufficiently stable for chromatographic isolation and vacuum sublimation. The solution stability of the fluorinated 1d was measured at t(1/2) approximately 4 months in the absence of oxygen, and 1e at t(1/2) approximately 40 min in the presence of air. The crystal and molecular structures of 1d were determined by X-ray crystallography showing columns of parallel almost evenly spaced planar heterocycles connected by infinite ...N...S... chains. Cyclic voltammetry of 1d and 1e shows reversible reduction waves at about 0 V and irreversible oxidations at about 1.2 V. Spectral and electrochemical properties of 1 were well reproduced by DFT methods.

The rising tide of sepsis, a leading cause of death in the US and globally, is not adequately controlled by current antimicrobial therapies and supportive measures, thereby requiring new adjunctive treatments. Severe microvascular injury and multiple organ failure in sepsis are attributed to a "genomic storm" resulting from changes in microbial and host genomes encoding virulence factors and endogenous inflammatory mediators, respectively. This storm is mediated by stress-responsive transcription factors that are ferried to the nucleus by nuclear transport shuttles importins/karyopherins. We studied the impact of simultaneously targeting two of these shuttles, importin alpha 5 (Imp α5) and importin beta 1 (Imp β1), with a cell-penetrating Nuclear Transport Modifier (NTM) in a mouse model of polymicrobial sepsis. NTM reduced nuclear import of stress-responsive transcription factors nuclear factor kappa B, signal transducer and activator of transcription 1 alpha, and activator protein 1 in liver, which was also protected from sepsis-associated metabolic changes. Strikingly, NTM without antimicrobial therapy improved bacterial clearance in blood, spleen, and lungs, wherein a 700-fold reduction in bacterial burden was achieved while production of proinflammatory cytokines and chemokines in blood plasma was suppressed. Furthermore, NTM significantly improved thrombocytopenia, a prominent sign of microvascular injury in sepsis, inhibited neutrophil infiltration in the liver, decreased L-selectin, and normalized plasma levels of E-selectin and P-selectin, indicating reduced microvascular injury. Importantly, NTM combined with antimicrobial therapy extended the median time to death from 42 to 83 hours and increased survival from 30% to 55% (p = 0.022) as compared to antimicrobial therapy alone. This study documents the fundamental role of nuclear signaling mediated by Imp α5 and Imp β1 in the mechanism of polymicrobial sepsis and highlights the potential for targeting nuclear transport as an adjunctive therapy in sepsis management.

Two families of liquid crystalline compounds have been synthesised, the 4-butyl-4- alkoxyazobenzenes and the 4-pentyl-4-alkoxyazobenzenes; for the second family results are presented for the first time for alkoxy chains longer than butyl. The results for both families have been obtained up to the octadecyl homologues. In both families, on the basis of DSC, polarizing microscopy and thermo-optical analysis, a rich polymorphism has been detected (maximum tetramorphism). The smectic properties start with the hexyl derivative (for the butyl family) and with the heptyl derivative (for the pentyl family). Strong odd-even effects for the temperatures of clearing in both groups of compounds were detected. Our results are compared with those of de Jeu et al. and of Adomenas et al. for the 4-butyl-4- alkoxyazobenzenes, for which only one smectic modification was described.

Background We recently reported that a bifunctional nuclear transport modifier ( NTM ), cSN 50.1 peptide, reduced atherosclerosis, plasma cholesterol, triglycerides, and glucose along with liver fat and inflammatory markers, in a murine model of familial hypercholesterolemia. We determined that cSN 50.1 improved lipid homeostasis by modulating nuclear transport of sterol regulatory element‐binding proteins through interaction with importin β. Previous studies established that cSN 50.1 and related NTM s also modulate nuclear transport of proinflammatory transcription factors mediated by binding of their nuclear localization sequences ( NLS s) to importins/karyopherins α. However, selectivity and specificity of NTM s for importins/karyopherins α were undetermined. Methods and Results We analyzed interaction of the NTM hydrophilic module, N50 peptide, derived from the NLS of NF κB1/p50, with endogenous human importins/karyopherins α to determine the mechanism of NTM modulation of importin α‐mediated nuclear transport. We show that N50 peptide forms stable complexes with multiple importins/karyopherins α. However, only interaction with importin α5 (Imp α5) displayed specific, high‐affinity binding. The 2:1 stoichiometry of the N50‐Imp α5 interaction ( K D 1 =73 nmol/L, K D 2 =140 nmol/L) indicated occupancy of both major and minor NLS binding pockets. Utilizing in silico 3‐dimensional (3‐D) docking models and comparative structural analysis, we identified a structural component of the Imp α5 major NLS binding pocket that may stabilize N50 binding. Imp α5 also displayed rapid stimulus‐induced turnover, which could influence its availability for nuclear transport during the inflammatory response. Conclusions These results provide direct evidence that N50 peptide selectively targets Imp α5, encouraging further refinement of NLS ‐derived peptides as new tools to modulate inflammatory disorders.

Background Elevated cholesterol and triglycerides in blood lead to atherosclerosis and fatty liver, contributing to rising cardiovascular and hepatobiliary morbidity and mortality worldwide. Methods and Results A cell‐penetrating nuclear transport modifier ( NTM ) reduced hyperlipidemia, atherosclerosis, and fatty liver in low‐density lipoprotein receptor‐deficient mice fed a W estern diet. NTM treatment led to lower cholesterol and triglyceride levels in blood compared with control animals (36% and 53%, respectively; P P P P P NTM ‐treated mice, although food intake remained the same as that in control animals. The NTM used in this study, cSN50.1 peptide, is known to modulate nuclear transport of stress‐responsive transcription factors such as nuclear factor kappa B, the master regulator of inflammation. This NTM has now been demonstrated to also modulate nuclear transport of sterol regulatory element‐binding protein ( SREBP ) transcription factors, the master regulators of cholesterol, triglyceride, and fatty acid synthesis. NTM ‐modulated translocation of SREBP s to the nucleus was associated with attenuated transactivation of their cognate genes that contribute to hyperlipidemia. Conclusions Two‐pronged control of inflammation and dyslipidemia by modulating nuclear transport of their critical regulators offers a new approach to comprehensive amelioration of hyperlipidemia, atherosclerosis, fatty liver, and their potential complications.

Acute lung inflammation is a potentially life-threatening complication of infections due to community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), a worldwide emerging pathogen, which causes necrotizing pneumonia and acute respiratory distress syndrome (ARDS). MRSA virulence factors encompass immunotoxins termed superantigens that contribute to lung inflammation. In this study, we demonstrate that staphylococcal enterotoxin B (SEB)-induced lung inflammation is attenuated by a cell-penetrating peptide nuclear import inhibitor of nuclear factor (NF)-kappaB and other stress-responsive transcription factors (SRTFs). This inhibitor suppressed production of a wide spectrum of cytokines and chemokines induced by direct SEB airway exposure. Consequently, trafficking of neutrophils, monocytes/macrophages, and lymphocytes to the bronchoalveolar space was significantly reduced while vascular injury, manifested by increased permeability and protein leakage, was attenuated. Moreover, induction of systemic proinflammatory cytokines and chemokines in response to direct SEB airway exposure was reduced. Thus, intracellular delivery of a nuclear import inhibitory peptide suppresses respiratory and systemic expression of key mediators of lung inflammation evoked by SEB.

Four bicyclic 4H-[1,2,4]thiadiazines 1a-d were prepared in 74-88% yields in two steps from the corresponding amidines 2. Three of them, 1a, 1b, and 1d, were obtained by thermal elimination of propene from the intermediate S-propylsulfilimines 12. The pyrazino derivative 1c was formed upon thermolysis of sulfoxide 14c obtained from 2c. The E(i) mechanism was investigated using DFT methods. The elimination in the sulfilimine appears to be more favorable by about 2 kcal/mol than in the analogous sulfoxide. Crystal and molecular structures of three out of the four thiadiazines were established by single-crystal X-ray analysis. All thiadiazines were found as the 4H tautomers with the heterocyclic ring puckered along the S(1)...N(4) line. The benzo derivative 1a forms a unidimensional N(4)-H...N(2) chain, the pyrazino derivative 1c forms dimeric pairs with two synergistic hydrogen bonds, and the crystal structure of 1d is characterized by strong C(6)F(4)...C(6)H(5) quadrupolar interactions.

Lipopolysaccharide (LPS) is a potent microbial virulence factor that can trigger production of proinflammatory mediators involved in the pathogenesis of localized and systemic inflammation. Importantly, the role of nuclear transport of stress responsive transcription factors in this LPS-generated "genomic storm" remains largely undefined. We developed a new nuclear transport modifier (NTM) peptide, cell-penetrating cSN50.1, which targets nuclear transport shuttles importin α5 and importin β1, to analyze its effect in LPS-induced localized (acute lung injury) and systemic (lethal endotoxic shock) murine inflammation models. We analyzed a human genome database to match 46 genes that encode cytokines, chemokines and their receptors with transcription factors whose nuclear transport is known to be modulated by NTM. We then tested the effect of cSN50.1 peptide on proinflammatory gene expression in murine bone marrow-derived macrophages stimulated with LPS. This NTM suppressed a proinflammatory transcriptome of 37 out of 84 genes analyzed, without altering expression of housekeeping genes or being cytotoxic. Consistent with gene expression analysis in primary macrophages, plasma levels of 23 out of 26 LPS-induced proinflammatory cytokines, chemokines, and growth factors were significantly attenuated in a murine model of LPS-induced systemic inflammation (lethal endotoxic shock) while the anti-inflammatory cytokine, interleukin 10, was enhanced. This anti-inflammatory reprogramming of the endotoxin-induced genomic response was accompanied by complete protection against lethal endotoxic shock with prophylactic NTM treatment, and 75% protection when NTM was first administered after LPS exposure. In a murine model of localized lung inflammation caused by direct airway exposure to LPS, expression of cytokines and chemokines in the bronchoalveolar space was suppressed with a concomitant reduction of neutrophil trafficking. Thus, calming the LPS-triggered "genomic storm" by modulating nuclear transport with cSN50.1 peptide attenuates the systemic inflammatory response associated with lethal shock as well as localized lung inflammation.

New family ofliquid crystalline compounds with the general formula: H2n+1 CHCH3 was synthesised. Polymorphism was detected with the help of the DSC calorimetry and polarizingmicroscopy. Monotropic ordered smectic mesophase for the derivatives from the pentyl up to the dodecylwas found. These phases situations are discussed and they are compared with the structure of other ferroelectric liquid crystalline compounds. Keywords: Liquid crystals, Smectics. Azo compounds. DSC calorimetry, chiral compounds. 1. INTRODUCTION Liquid crystalline compounds with azo group are very interesting and they were the subject of research from the beginning of this century1 . Ferroelectric liquid crystals in 1975 by R.Meyer et all were have been synthesised and they were afterdiscovery ofvery fast ferroelectric liquid crystal displays in 1980 by N.Clark et all broadly investigated. In 1989 Chandaniet all4 described new polar liquid crystalline phases, which have extra antyferroelectric and ferrielectric properties. From

Two families of liquid crystalline compounds: 4-hexyl-4-alkoxyazobenzenes and 4-heptyl-4'-alkoxyawbenzenes have been synthesised for alkyl chain from methoxy up to octadecyloxy. On the base of the DSC calorimetry and polarizing microscopy rich polymorphism was detected. Maximum four mesophases were found: nematic, smectic A, smectic C and smectic I. The interesting even-odd effects for temperature of clearing was observed similar to the other families of 4-alkyl4'-allcyloxyazobenzenes. The phase diagram sequence and temperatures of phase transition are discussed and there are compared their entropy effects to those of the other azobenzene liquid crystalline compounds.

Wstep Brachyterapia pulsacyjna (BT PDR) lączy zalety radiobiologiczne metody LDR oraz techniczne metody HDR. Z tych powodow jest szczegolnie przydatna w przypadkach powtornej radioterapii, obarczonej wysokim ryzykiem powiklan. Obok popularnych technik środjamowych i środtkankowych BT stosuje sie takze BT kontaktową, ktora wymaga sporządzenia indywidualnych utrzymywaczy prowadnic. Material i metody Przedstawiono 3 przypadki chorych poddanych kontaktowej BT PDR z uzyciem indywidualnie wykonanych aplikatorow. W2 przypadkach bylo to powtorne napromienianie po radykalnej radioterapii (RT) raka okolicy oczodolu oraz raka zatoki szczekowej, a w 1 stanowila element pierwotnej radykalnej RT. W powtornym napromienianiu stosowano dawke 50 Gy, a w skojarzonej RT 15 Gy (w obu zastosowaniach 0.6 Gy/puls/1godzine). Rozklad dawki obliczano komputerowo przy uzyciu systemu PLATO na podstawie zdjec TK lub rtg. Akrylowe aplikatory wykonywano na podstawie wycisku pobranego przy uzyciu masyelastomerowej. Wyniki Uzyskano dokladne dopasowanie aplikatorow do jam ciala i/lub lozy po usunietych guzach, co pozwolilo uzyskac zadowalający rozklad dawki i zapobiegalo przemieszczeniom aplikatorow w trakcie leczenia. Chorzy tolerowali leczenie bardzo dobrze. Ostry odczyn popromienny o niewielkim nasileniu obserwowano po uplywie 2–3 tygodni od zakonczenia leczenia. Wnioski Wykonanie indywidualnych aplikatorow umozliwia przeprowadzenie BT w trudno dostepnych obszarach anatomicznych. Dzieki precyzyjnie odwzorowującym podloze nowoczesnym elastomerowym masom stomatologicznym udaje sie wykonac dokladnie dopasowane aplikatory do BT kontaktowej. Uzycie techniki PDR pozwala na precyzyjne napromienienie zaplanowanej objetości przy rownoczesnej ochronie zdrowych tkanek.

Background Insulin-dependent Type 1 diabetes (T1D) is a devastating autoimmune disease that destroys beta cells within the pancreatic islets and afflicts over 10 million people worldwide. These patients face life-long risks for blindness, cardiovascular and renal diseases, and complications of insulin treatment. New therapies that protect islets from autoimmune destruction and allow continuing insulin production are needed. Increasing evidence regarding the pathomechanism of T1D indicates that islets are destroyed by the relentless attack by autoreactive immune cells evolving from an aberrant action of the innate, in addition to adaptive, immune system that produces islet-toxic cytokines, chemokines, and other effectors of islet inflammation. We tested the hypothesis that targeting nuclear import of stress-responsive transcription factors evoked by agonist-stimulated innate and adaptive immunity receptors would protect islets from autoimmune destruction. Principal Findings Here we show that a first-in-class inhibitor of nuclear import, cSN50 peptide, affords in vivo islet protection following a 2-day course of intense treatment in NOD mice, which resulted in a diabetes-free state for one year without apparent toxicity. This nuclear import inhibitor precipitously reduces the accumulation of islet-destructive autoreactive lymphocytes while enhancing activation-induced cell death of T and B lymphocytes derived from autoimmune diabetes-prone, non-obese diabetic (NOD) mice that develop T1D. Moreover, in this widely used model of human T1D we noted attenuation of pro-inflammatory cytokine and chemokine production in immune cells. Conclusions These results indicate that a novel form of immunotherapy that targets nuclear import can arrest inflammation-driven destruction of insulin-producing beta cells at the site of autoimmune attack within pancreatic islets during the progression of T1D.

The temporomandibular joint is the most complicated joint from the anatomic standpoint. Diagnosing it is still a problem to be solved. Modern top quality devices do not provide a complete solution—the barrier here is the high price of a single examination. For this reason, new, cheap methods of diagnosing the temporomandibular joint are being sought. One of these methods is diagnosing on the basis of passive listening for acoustic signals emitted by the joint in motion. This paper presents the application of the FFT and wavelet method for the purpose of examining the acoustic signal analysis of the temporomandibular joint. The advantages and disadvantages of both methods, the Fourier method and wavelet method, are discussed. Finally, the results obtained by the Fourier analysis in time window and by a wavelet method are presented and compared.

Wstep Brachyterapia jest jedną z metod radykalnego leczenia niektorych wczesnych zmian nowotworowych w rejonie glowy i szyi. Dotychczas najcześciej stosowano w tym celu urządzenia emitujące promieniowanie o niskiej lub średniej mocy dawki. Doświadczenie w stosowaniu techniki PDR jest dotychczas niewielkie. Material i metody W okresie od czerwca 1999 do lipca 2000 w Klinice Chirurgii Szczekowo-Twarzowej i w Klinice Onkologii i Radioterapii Akademii Medycznej w Gdansku zastosowano brachyterapie PDR u 9 chorych na raka plaskonablonkowego o nastepującej lokalizacji: warga dolna (5 chorych) oraz policzek (4 chorych). Zastosowano dawke 60–70 Gy, 1 Gy/puis powtarzany co 1 godzine. Stosowano indywidualne plany leczenia opracowane za pomocą komputerowego systemu planowania leczenia (PLATO, Nucletron, Holandia). W 8 przypadkach brachyterapia PDR stanowila wyączną metode leczenia a w 1 przypadku byla elementem skojarzonego napromieniania. Stosowano aparat PDR zawierający zrodlo Ir 192 o aktywności nominalnej 1 Ci. Wyniki Tolerancja leczenia byla bardzo dobra. Odczyny popromienne blony śluzowej jamy ustnej i czerwieni wargowej o średnim nasileniu, pojawialy sie po okolo 3–5 dniach od zakonczenia brachyterapii i ustepowaly po 2–3 tygodniach. We wszystkich przypadkach uzyskano calkowitą remisje zmian nowotworowych. W okresie średnio 6 miesiecy obserwacji (zakres 2–12 miesiecy) nie stwierdzono nawrotu miejscowego. Wnioski W wybranych przypadkach nowotworow jamy ustnej oraz u chorych na raka wargi dolnej brachyterapia PDR stanowi skuteczną metode leczenia radykalnego. Ostateczna ocena wartości metody wymaga zebrania wiekszego materialu klinicznego.