Access Management Research and Awareness Program : Phase IV, 1999

Access management involves balancing the dual roles that roadways must play - through travel and access to property and economic activity. When these roles are not in proper balance, the result is a roadway system that functions sub-optimally. Arterial routes that have a too high driveway density and provide overly extensive access to property have high crash rates and begin to suffer in terms of traffic operations. Such routes become congested, delays increase, and mean travel speeds decline. The Iowa access management research and awareness project has had four distinct phases. Phase I involved a detailed review of the extensive national access management literature so lessons learned elsewhere could be applied in Iowa. In Phase II original case study research was conducted in Iowa. Phase III of the project concentrated on outreach and education about access management. Phase IV of the Iowa access management project extended the work conducted during Phases II and III. The main work products for Phase IV were as follows: 1) three additional before and after case studies, illustrating the impacts of various access management treatments on traffic safety, traffic operations, and business vitality; 2) an access management handbook aimed primarily at local governments in Iowa; 3) a modular access management toolkit with brief descriptions of various access management treatments and considerations; and 4) an extensive outreach plan aimed at getting the results of Phases I through IV of the project out to diverse audiences in Iowa and elsewhere.

Intercity Passenger Carrier Improvement Study, Final Report, 1977

The goal of this research was to recommend specific changes relating to service by intercity buses and third level air carriers to propose an appropriate state role in the implementation of changes. Changes contemplated in this research were to be directed to the increased use of intercity buses and third level air carriers in such manner as to exert a benefit to user as well as the general public. Specific objectives of the project included: (1) to analyze the potential for a system of express intercity bus routes in Iowa; (2) to estimate the demand for third level air carrier services in cities having populations under 50,000; (3) to forecast the relationship between economic costs and benefits from an intercity bus system emphasizing express routes between major population centers and supporting a subsystem of local and intraregional public transportation; (4) to estimate the economic feasibility of expanded third level air carrier service with emphasis upon those routes proposed as worth of further evaluation; and (5) to provide guidance for establishing the need for state and local subsidies to institute a system of express intercity buses and to expand third level air carrier services. In addition to passenger movements, enhancing package freight shipments was also to be considered in the evaluation of proposed improvements.

Evaluation of respiratory and dermal occupational exposures to monoethanolamine during cleaning

Professional cleaning is a basic service occupation with a wide variety of tasks carried out in all kind of different sectors and workplaces by a large workforce. One important risk for cleaning workers is the exposure to chemical substances that are present in cleaning products.Monoethanolamine was found to be often present in cleaning products such as general purpose cleaners, bathroom cleaners, floor cleaners and kitchen cleaners. Monoethanolamine can injure the skin, and exposure to monoethanolamine was associated to asthma even when the air concentrations were low. It is a strong irritant and known to be involved in sensitizing mechanisms. It is very likely that the use of cleaning products containing monoethanolamine gives rise to respiratory and dermal exposures. Therefore there is a need to further investigate the exposures to monoethanolamine for both, respiratory and dermal exposure.The determination of monoethanolamine has traditionally been difficult and analytical methods available are little adapted for occupational exposure assessments. For monoethanolamine air concentrations, a sampling and analytical method was already available and could be used. However, a method to analyses samples for skin exposure assessments as well as samples of skin permeation experiments was missing. Therefore one main objective of this master thesis was to search an already developed and described analytical method for the measurement of monoethanolamine in water solutions, and to set it up in the laboratory. Monoethanolamine was analyzed after a derivatisation reaction with o-pthtaldialdehyde. The derivated fluorescing monoethanolamine was then separated with high performance liquid chromatography and detection took place with a fluorescent detector. The method was found to be suitable for qualitative and quantitative analysis of monoethanolamine. An exposure assessment was conducted in the cleaning sector to measure the respiratory and dermal exposures to monoethanolamine during floor cleaning. Stationary air samples (n=36) were collected in 8 companies and samples for dermal exposures (n=12) were collected in two companies. Air concentrations (Mean = 0.18 mg/m3, Standard Deviation = 0.23 mg/m3, geometric Mean = 0.09 mg/m3, Geometric Standard Deviation = 3.50) detected were mostly below 1/10 of the Swiss 8h time weighted average occupational exposure limit. Factors that influenced the measured monoethanolamine air concentrations were room size, ventilation system and the concentration of monoethanolamine in the cleaning product and amount of monoethanolamine used. Measured skin exposures ranged from 0.6 to 128.4 mg/sample. Some cleaning workers that participated in the skin exposure assessment did not use gloves and had direct contact with the solutions containing the cleaning product and monoethanolamine. During the entire sampling campaign, cleaning workers mostly did not use gloves. Cleaning workers are at risk to be regularly exposed to low air concentrations of monoethanolamine. This exposure may be problematic if a worker suffers from allergic reactions (e.g. Asthma). In that case a substitution of the cleaning product may be a good prevention measure as several different cleaning products are available for similar cleaning tasks. Currently there are no occupational exposure limits to compare the skin exposures that were found. To prevent skin exposures, adaptations of the cleaning techniques and the use of gloves should be considered. The simultaneous skin and airborne exposures might accelerate adverse health effects. Overall the risks caused by exposures to monoethanolamine are considered as low to moderate when the cleaning products are used correctly. Whenever possible, skin exposures should be avoided. Further research should consider especially the dermal exposure routes, as very high exposures might occur by skin contact with cleaning products. Dermatitis but also sensitization might be caused by skin exposures. In addition, new biomedical insights are needed to better understand the risks of the dermal exposure. Therefore skin permeability experiments should be considered.

Immunotherapies for uro-genital cancers

Les cancers du col utérin et de la vessie prennent tous deux leur origine dans les sites muqueux et peuvent évoluer lentement de lésions superficielles (lésions squameuses intra-épithéliales de bas à haut grade (HSIL) et carcinomes in situ du col utérin (CIS); ou tumeurs non musculo-invasives de la vessie (NMIBC)) à des cancers invasifs plus avancés. L'éthiologie de ces deux cancers est néanmoins très différente. Le cancer du col utérin est, à l'échelle mondiale, le deuxième cancer le plus mortel chez la femme. Ce cancer résulte de l'infection des cellules basales de l'épithélium stratifié du col utérin par le papillomavirus humain à haut risque (HPV). Les vaccins prophylactiques récemment développés contre le HPV (Gardasil® et Cervarix®) sont des moyens de prévention efficaces lorsqu'ils sont administrés chez les jeunes filles qui ne sont pas encore sexuellement actives; cependant ces vaccins ne permettent pas la régression des lésions déjà existantes. Malgré un développement actif, les vaccins thérapeutiques ciblant les oncogènes viraux E6/E7 n'ont montré qu'une faible efficacité clinique jusqu'à présent. Nous avons récemment démontré qu'une immunisation sous-cutanée (s.c.) était capable de faire régresser les petites tumeurs génitales chez 90% des souris, mais chez seulement 20% des souris présentant de plus grandes tumeurs. Dans cette étude, nous avons développé une nouvelle stratégie où la vaccination est associée à une application locale (intra-vaginale (IVAG)) d'agonistes de TLR. Celle-ci induit une augmentation des cellules T CD8 totales ainsi que T CD8 spécifiques au vaccin, mais pas des cellules T CD4. L'attraction sélective des cellules T CD8 est permise par leur expression des récepteurs de chemokines CCR5 et CXCR3 ainsi que par les ligants E-selectin. La vaccination, suivie de l'application IVAG de CpG, a conduit, chez 75% des souris, à la régression de grandes tumeurs établies. Le cancer de la vessie est le deuxième cancer urologique le plus fréquente. La plupart des tumeurs sont diagnostiquées comme NMIBC et sont restreintes à la muqueuse de la vessie, avec une forte propension à la récurrence et/ou progression après une résection locale. Afin de développer des vaccins contre les antigènes associés à la tumeur (TAA), il est nécessaire de trouver un moyen d'induire une réponse immunitaire CD8 spécifique dans la vessie. Pour ce faire, nous avons comparé différentes voies d'immunisation, en utilisant un vaccin composé d'adjuvants et de l'oncogène de HPV (E7) comme modèle. Les vaccinations s.c. et IVAG ont toutes deux induit un nombre similaire de cellules T CD8 spécifiques du vaccin dans la vessie, alors que l'immunisation intra-nasale fut inefficace. Les voies s.c. et IVAG ont induit des cellules T CD8 spécifiques du vaccin exprimant principalement aL-, a4- et le ligand d'E-selectin, suggérant que ces intégrines/sélectines sont responsables de la relocalisation des cellules T dans la vessie. Une unique immunisation avec E7 a permis une protection tumorale complète lors d'une étude prophylactique, indépendemment de la voie d'immunisation. Dans une étude thérapeutique, seules les vaccinations s.c. et IVAG ont efficacement conduit, chez environ 50% des souris, à la régression de tumeurs de la vessie établies, alors que l'immunisation intra-nasale n'a eu aucun effet. La régression de la tumeur est correlée avec l'infiltration dans la tumeur des cellules T CD8 spécifiques au vaccin et la diminution des cellules T régulatrices (Tregs). Afin d'augmenter l'efficacité de l'immunisation avec le TAA, nous avons testé une vaccination suivie de l'instillation d'agonistes de TLR3 et TLR9, ou d'un vaccin Salmonella Typhi (Ty21a). Cette stratégie a entraîné une augmentation des cellules T CD8 effectrices spécifiques du vaccin dans la vessie, bien qu'à différentes échelles. Ty21a étant l'immunostimulant le plus efficace, il mérite d'être étudié de manière plus approfondie dans le contexte du NMIBC. - Both cervical and bladder cancer originates in mucosal sites and can slowly progress from superficial lesions (low to high-grade squamous intra-epithelial lesions (HSIL) and carcinoma in situ (CIS) in the cervix; or non-muscle invasive tumors in the bladder (NMIBC)), to more advanced invasive cancers. The etiology of these two cancers is however very different. Cervical cancer is the second most common cause of cancer death in women worldwide. This cancer results from the infection of the basal cells of the stratified epithelium of the cervix by high-risk human papillomavirus (HPV). The recent availability of prophylactic vaccines (Gardasil® and Cervarix®) against HPV is an effective strategy to prevent this cancer when administered to young girls before sexual activity; however, these vaccines do not induce regression of established lesions. Despite active development, therapeutic vaccines targeting viral oncogenes E6/E7 had limited clinical efficacy to date. We recently reported that subcutaneous (s.c.) immunization was able to regress small genital tumors in 90% of the mice, but only 20% of mice had regression of larger tumors. Here, we developed a new strategy where vaccination is combined with the local (intravaginal (IVAG)) application of TLR agonists. This new strategy induced an increase of both total and vaccine-specific CD8 T cells in cervix-vagina, but not CD4 T cells. The selective attraction of CD8 T cells is mediated by the expression of CCR5 and CXCR3 chemokine receptors and E-selectin ligands in these cells. Vaccination followed by IVAG application of CpG resulted in tumor regression of large established tumors in 75% of the mice. Bladder cancer is the second most common urological malignancy. Most tumors are diagnosed as NMIBC, and are restricted to the mucosal bladder with a high propensity to recur and/or progress after local resection. Aiming to develop vaccines against tumor associated antigens (TAA) it is necessary to investigate how to target vaccine-specific T-cell immune responses to the bladder. Here we thus compared using an adjuvanted HPV oncogene (E7) vaccine, as a model, different routes of immunization. Both s.c. and IVAG vaccination induced similar number of vaccine-specific CD8 T-cells in the bladder, whereas intranasal (i.n.) immunization was ineffective. S.c. and IVAG routes induced predominantly aL-, a4- and E-selectin ligand-expressing vaccine-specific CD8 T-cells suggesting that these integrin/selectin are responsible for T-cell homing to the bladder. A single E7 immunization conferred full tumor protection in a prophylactic setting, irrespective of the immunization route. In a therapeutic setting, only ivag and s.c. vaccination efficiently regressed established bladder-tumors in ca. 50 % of mice, whereas i.n. immunization had no effect. Tumor regression correlated with vaccine- specific CD8 T cell tumor-infiltration and decrease of regulatory T cells (Tregs). To increase efficacy of TAA immunization, we tested vaccination followed by the local instillation of TLR3 or TLR9 agonist or of a Salmonella Typhi vaccine (Ty21a). This strategy resulted in an increase of vaccine-specific effector CD8 T cells in the bladder, although at different magnitudes. Ty21a being the most efficient, it deserves further investigation in the context of NMIBC. We further tested another strategy to improve therapies of NMIBC. In the murine MB49 bladder tumor model, we replaced the intravesical (ives) BCG therapy by another vaccine strain the Salmonella Ty21a. Ives Ty21a induced bladder tumor regression at least as efficiently as BCG. Ty21a bacteria did not infect nor survive neither in healthy nor in tumor-bearing bladders, suggesting its safety. Moreover, Ty21a induced a transient inflammatory response in healthy bladders, mainly through infiltration of neutrophils and macrophages that rapidly returned to basal levels, confirming its potential safety. The tumor regression was associated to a robust infiltration of immune cells, and secretion of cytokines in urines. Infection of murine tumor cell lines by Ty21a resulted in cell apoptosis. The infection of both murine and human urothelial cell lines induced secretion of in vitro inflammatory cytokines. Ty21a may be an attractive alternative for the ives treatment of NMIBC after transurethral resection and thus deserves more investigation.

Non-viral ocular gene therapy: potential ocular therapeutic avenues.

Non-viral vectors for potential gene replacement and therapy have been developed in order to overcome the drawbacks of viral vectors. The diversity of non-viral vectors allows for a wide range of various products, flexibility of application, ease of use, low-cost of production and enhanced "genomic" safety. Using non-viral strategies, oligonucleotides (ODNs) can be delivered naked (less efficient) or entrapped in cationic lipids, polymers or peptides forming slow release delivery systems, which can be adapted according to the organ targeted and the therapy purposes. Tissue and cell internalization can be further enhanced by changing by physical or chemical means. Moreover, a specific vector can be selected according to disease course and intensity of manifestations fulfilling specific requirements such as the duration of drug release and its level along with cells and tissues specific targeting. From accumulating knowledge and experience, it appears that combination of several non-viral techniques may increase the efficacy and ensure the safety of these evolving and interesting gene therapy strategies.

Combining Internet Monitoring Processes, Packaging and Isotopic Analyses to Determine The Market Structure: Example of Gamma Butyrolactone

The Internet is becoming more and more popular among drug users. The use of websites and forums to obtain illicit drugs and relevant information about the means of consumption is a growing phenomenon mainly for new synthetic drugs. Gamma Butyrolactone (GBL), a chemical precursor of Gamma Hydroxy Butyric acid (GHB), is used as a "club drug" and also in drug facilitated sexual assaults. Its market takes place mainly on the Internet through online websites but the structure of the market remains unknown. This research aims to combine digital, physical and chemical information to help understand the distribution routes and the structure of the GBL market. Based on an Internet monitoring process, thirty-nine websites selling GBL, mainly in the Netherlands, were detected between January 2010 and December 2011. Seventeen websites were categorized into six groups based on digital traces (e.g. IP addresses and contact information). In parallel, twenty-five bulk GBL specimens were purchased from sixteen websites for packaging comparisons and carbon isotopic measurements. Packaging information showed a high correlation with digital data confirming the links previously established whereas chemical information revealed undetected links and provided complementary information. Indeed, while digital and packaging data give relevant information about the retailers, the supply routes and the distribution close to the consumer, the carbon isotopic data provides upstream information about the production level and in particular the synthesis pathways and the chemical precursors. A three-level structured market has been thereby identified with a production level mainly located in China and in Germany, an online distribution level mainly hosted in the Netherlands and the customers who order on the Internet.

Immunopathogenesis of Asthma and Atopic Diseases – The specific Role of a selected Panel of Genes in human T helper Cell Differentiation

T helper cell (Th) functions are crucial for proper immune defence against various intra- and extracellular pathogens. According to the specific immune responses, Th cells can be classified into subtypes, Th1 and Th2 cells being the most frequently characterized classes. Th1 and Th2 cells interact with other immune cells by regulating their functions with specific cytokine production. IFN, IL-2 and TNF- are the cytokines predominantly produced by Th1 cells whereas Th2 cells produce Th2-type cytokines, such as IL-4, IL-5 and IL-13. Upon TCR activation and in the presence of polarizing cytokines, Th cells differentiate into effector subtypes from a common precursor cell. IFN and IL-12 are the predominant Th1 polarizing cytokines whereas IL-4 directs Th2 polarization. The cytokines mediate their effects through specific receptor signalling. The differentiation process is complex, involving various signalling molecules and routes, as well as functions of the specific transcription factors. The functions of the Th1/Th2 cells are tightly regulated; however, knowledge on human Th cell differentiation is, as yet, fairly poor. The susceptibility for many immune-mediated disorders often originates from disturbed Th cell responses. Thus, research is needed for defining the molecular mechanisms involved in the differentiation and balanced functions of the Th cells. Importantly, the new information obtained will be crucial for a better understanding of the pathogenesis of immune-mediated disorders, such as asthma or autoimmune diseases. In the first subproject of this thesis, the role of genetic polymorphisms in the human STAT6, GATA3 and STAT4 genes were investigated for asthma or atopy susceptibility in Finnish asthma families by association analysis. These genes code for key transcription factors regulating Th cell differentiation. The study resulted in the identification of a GATA3 haplotype that associated with asthma and related traits (high serum IgE level). In the second subproject, an optimized method for human primary T cell transfection and enrichment was established. The method can be utilized for functional studies for the selected genes of interest. The method was also utilized in the third subproject, which aimed at the identification of novel genes involved in early human Th cell polarization (0-48h) using genome-wide oligonucleotide arrays. As a result, numerous genes and ESTs with known or unknown functions were identified in the study. Using an shRNA knockdown approach, a panel of novel IL-4/STAT6 regulated genes were identified in the functional studies of the genes. Moreover, one of the genes, NDFIP2, with a previously uncharacterized role in the human Th differentiation, was observed to promote IFN production of the differentiated Th1 cells. Taken together, the results obtained have revealed potential new relevant candidate genes serving as a basis for further studies characterizing the detailed networks involved in the human Th cell differentiation as well as in the genetic susceptibility of Th-mediated immune disorders.

Organofosforiyhdisteille (TBEP ja TEHP) altistuminen työpaikoilla

Työssä mitattiin työilman TBEP- ja TEHP-pitoisuuksia siivousalalla (3 kohdetta) ja muovituoteteollisuudessa (2 kohdetta). Pitoisuutta ilmassa verrattiin työntekijöidenbiomonitorointinäytteistä analysoitujen 2-butoksietikkahapon (2-BAA) ja 2-etyyliheksaanihapon (2-EHA) pitoisuuteen. Tavoitteena oli biomonitoroin-timenetelmän soveltuvuuden selvittäminen altistumisen arvioinnissa sekä tarvittavien lisäsuojaus- ja torjunta-tarpeiden selvittäminen. Biomonitorointia sekoittavien tekijöiden (2-butoksietanoli ja 2-etyyli-1-heksanoli) pitoisuus mitattiin työntekijöidenhengitysilmasta kerätystä VOC-näytteestä. OVS-keräimiin kerätyt TBEP- ja TEHP-näytteet uutettiin ultraäänellä sopivalla liuottimella ja analysoitiin kaasukromatografisesti (GC). VOC-näytteet kerättiin Tenax GR ¿adsorbenttiin, irrotettiin keräimestä termodesorptiolla ja analysoitiin GC:lla. Biomonitorointinäytteiden (virtsa) 2-BAA- ja 2-EHA -pitoisuus analysoitiin myös GC:lla. Lattianvahauksen aikana siivoojien hengitysilmasta mitatuissa TBEP-näytteissä pitoisuudet vaihtelivat välillä 70 - 860 ng/m3 sekä VOC-näytteistä 88 %:sta löytyi2-butoksietanolia, jonka pitoisuus vaihteli välillä 3 - 1800 µg/m3. Virtsan 2-BAA:n pitoisuudet vaihtelivat välillä <0,3 - 26 mmol/mol kreatiniinia ollen korkeimmillaan 43 % toimenpiderajasta. Raskaana olevien toimenpideraja ylitettiin 30 % näytteistä. Muovituotetehtaissa TEHP-pitoisuus työntekijöiden hengitysilmassa oli alle määritysrajan (eli < 1 - < 3 ng/m3). Muovituotetehtaissa kerätyistä VOC-näytteistä 16 %:sta löydettiin 2-etyyli-1-heksanolia, jonka pitoisuus vaihteli välillä 90 - 100 µg/m3. Virtsan 2-EHA-pitoisuudet olivat välillä <0,1 - 0,2 mmol/mol kreatiniinia. Tulosten perusteella siivoojat altistuvat TBEP:lle ja 2-butoksietanolille lattianvahauksen yhteydessä, muttaaltistuminen ei ilman pitoisuuksien ja biomonitoroinnin tulosten mukaan aiheutaterveyshaittaa ainakaan yhden mahdollisen metaboliitin 2-BAA:n kautta. Pois lukien raskaana olevat työntekijät, joille 2-butoksietanolia sisältävän vahanpoistotuotteen käsitteleminen aiheuttaa mahdollista terveyshaittaa. Käytetyillä biomonitorointimenetelmillä ei voitu osoittaa altistumista tapahtuneen mitatuilla TBEP:n ja TEHP:n pitoi-suustasoilla. Metaboliareittien varmistamisen jälkeen on mahdollista tutkia toimivampaa menetelmää altistumisen arviointiin biomonitoroinnin avulla. Työntekijöiden suojautuminen niin muovituotetehtaissa kuin siivoustyössäkin mitattujen yhdisteiden osalta oli pääosin riittävää. Ainoastaan raskaana olevien työntekijöiden, jotka siivoustyössään altistuvat 2-butoksietanolille, suojaukseen tulisi kiinnittää huomiota.

A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss.

Hearing loss can be caused by a variety of insults, including acoustic trauma and exposure to ototoxins, that principally effect the viability of sensory hair cells via the MAP kinase (MAPK) cell death signaling pathway that incorporates c-Jun N-terminal kinase (JNK). We evaluated the otoprotective efficacy of D-JNKI-1, a cell permeable peptide that blocks the MAPK-JNK signal pathway. The experimental studies included organ cultures of neonatal mouse cochlea exposed to an ototoxic drug and cochleae of adult guinea pigs that were exposed to either an ototoxic drug or acoustic trauma. Results obtained from the organ of Corti explants demonstrated that the MAPK-JNK signal pathway is associated with injury and that blocking of this signal pathway prevented apoptosis in areas of aminoglycoside damage. Treatment of the neomycin-exposed organ of Corti explants with D-JNKI-1 completely prevented hair cell death initiated by this ototoxin. Results from in vivo studies showed that direct application of D-JNKI-1 into the scala tympani of the guinea pig cochlea prevented nearly all hair cell death and permanent hearing loss induced by neomycin ototoxicity. Local delivery of D-JNKI-1 also prevented acoustic trauma-induced permanent hearing loss in a dose-dependent manner. These results indicate that the MAPK-JNK signal pathway is involved in both ototoxicity and acoustic trauma-induced hair cell loss and permanent hearing loss. Blocking this signal pathway with D-JNKI-1 is of potential therapeutic value for long-term protection of both the morphological integrity and physiological function of the organ of Corti during times of oxidative stress.

Transitoreitin valintaan vaikuttavat tekijät autotoimialalla: AHP:n soveltaminen

Tämän työn tavoitteena on selvittää transitoreitin valintaan vaikuttavat tekijät sekä Suomen reitin kilpailutekijät verrattuna Baltian maiden, Saksan-Puolan ja Venäjän omiensatamien reitteihin. Lisäksi tavoitteena on testata analyyttista hierarkiaprosessia (AHP) transitoreitin valintaan. Työssä hyödynnetään Suomessa, Venäjällä ja Baltian maissa logistiikkayritysten, ministeriöiden ja viranomaisten kanssa tehtyjä asiantuntijahaastatteluja. Lisäksi suurimmille autotoimialan yrityksille toteutetaan kysely transitoreitin valintaan vaikuttavista tekijöistä. Työssä muodostetaan hierarkia reitin valintaan vaikuttavista tekijöistä. Lisäksi lasketaan analyyttisen hierarkiaprosessin mukaiset painotukset reitin valintaan vaikuttaville tekijöille ja eri reittien kilpailukykyerään autotoimialan vastaajan tapauksessa.

Intragastric and Intranasal Administration of Lactobacillus paracasei NCC2461 Modulates Allergic Airway Inflammation in Mice.

Introduction. Preclinical and clinical evidences for a role of oral probiotics in the management of allergic diseases are emerging. Aim. We aimed at testing the immunomodulatory effects of intranasal versus intragastric administration of Lactobacillus paracasei NCC2461 in a mouse model of allergic airway inflammation and the specificity of different probiotics by comparing L. paracasei NCC2461 to Lactobacillus plantarum NCC1107. Methods. L. paracasei NCC2461 or L. plantarum NCC1107 strains were administered either intragastrically (NCC2461) or intranasally (NCC2461 or NCC1107) to OVA-sensitized mice challenged with OVA aerosols. Inflammatory cell recruitment into BALF, eotaxin and IL-5 production in the lungs were measured. Results. Intranasal L. paracasei NCC2461 efficiently protected sensitized mice upon exposure to OVA aerosols in a dose-dependent manner as compared to control mice. Inflammatory cell number, eotaxin and IL-5 were significantly reduced in BALF. Intranasal supplementation of L. paracasei NCC2461 was more potent than intragastric application in limiting the allergic response and possibly linked to an increase in T regulatory cells in the lungs. Finally, intranasal L. plantarum NCC1107 reduced total and eosinophilic lung inflammation, but increased neutrophilia and macrophages infiltration. Conclusion. A concerted selection of intervention schedule, doses, and administration routes (intranasal versus intragastric) may markedly contribute to modulate airway inflammation in a probiotic strain-specific manner.

Luoteis-Venäjän metsävaratja niiden hyödyntämismahdollisuudet

Tuontipuulla onsuuri merkitys suomalaiselle metsäteollisuudelle. Tämän tutkimuksen tavoitteitaovat Suomen metsäteollisuuden puuntuonnin tärkeimmän alueen, Luoteis-Venäjän metsävarojen kartoittaminen ja niiden hyödyntämismahdollisuuksien arviointi. Työssä käsitellään myös lyhyesti suoria ulkomaisia investointeja Luoteis-Venäjän metsäsektorille. Luoteis-Venäjällä on suuremmat metsävarat kuin muulla Euroopalla yhteensä. Koko maailmassa on vain 5 valtiota, jolla olisi suuremmat metsävarat kuin sillä. Eniten metsiä Luoteis-Venäjällä on Komin tasavallassa ja Arkangelin alueella. Kuusi ja mänty ovat yleisimmät puulajit. Hyvien iikenneyhteyksien varsilta metsät on hakattu ja jätetty uudistamatta, minkä seurauksena koivu ja haapa ovat vallanneet alaa havupuilta. Niinpä alueen metsäteollisuus, etenkin sahateollisuus kärsii puupulasta. Suomen metsäteollisuus on sen sijaan hyötynyt siitä, että koivukuitupuuta on runsaasti saatavilla. Metsävarojen hyödyntämisen suurimmatesteet ovat harva ja huonokuntoinen metsätieverkosto sekä metsien riittämätön hoito. Venäläisestä näkökulmasta alueen metsävarat ovat vajaakäytössä: vuotuiset hakkuut ovat alle puolet kasvusta, suuri osa puusta viedään raakapuuna ulkomaille, ja alueen metsäteollisuuden tuotteiden jalostusarvo jää alhaiseksi. Suoria ulkomaisia investointeja Luoteis-Venäjän metsäsektorille houkuttelevat suuret puuvarat, halpa energia ja tulevaisuudessa etenkin kasvavat markkinat. Investointejahaittaavat huono infrastruktuuri, korruptio ja epävarmuus maan kehityksestä.

Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole

Research on natural products containing hexahydropyrrolo[2,3-b]indole (HPI) has dramatically increased during the past few years. Newly discovered natural products with complex structures and important biological activities have recently been isolated and synthesized. This review summarizes the structures, biological activities, and synthetic routes for natural compounds containing HPI, emphasizing the different strategies for assembling this motif. It covers a broad gamut of molecules, from small alkaloids to complex peptides.

Convergent Approaches for the Synthesis of the Anti-tumoral Peptide, Kahalalide F. Study of Orthogonal Protecting Groups

Kahalalide compounds are peptides that are isolated from a Hawaiian herbivorous marine species of mollusc, Elysia rufescens, and its diet, the green alga Bryopsis sp. Kahalalide F and its synthetic analogues are the most promising compounds of the Kahalalide family because they show anti-tumoral activity. Linear solid-phase syntheses of Kahalalide F have been reported. Here we describe several new improved synthetic routes based on convergent approaches with distinct orthogonal protection schemes for the preparation of Kahaladide analogues. These strategies allow a better control and characterization of the intermediates because more reactions are performed in solution. Five derivatives of Kahalalide F were synthesized using several convergent approaches.

Isolation, structural assignment and total synthesis of Barmumycin

Barmumycin was isolated from an extract of the marine actinomycete Streptomyces sp. BOSC-022A and found to be cytotoxic against various human tumor cell lines. Based on preliminary one- and two-dimensional 1H- and 13C-NMR spectra, the natural compound was initially assigned the structure of macrolactone-type compound 1, which was later prepared by two different routes. However, major spectroscopic differences between isolated barmumycin and 1 led to revision of the proposed structure as E-16. Based on synthesis of this new compound, and subsequent spectroscopic comparison of it to an authentic sample of barmumycin, the structure of the natural compound was indeed confirmed as that of E-16.