Local Administration Research Articles

Effectiveness of autologous leukocyte-platelet-rich fibrin on the rate of maxillary canine retraction, rotation, pain, and soft tissue healing: A split-mouth randomized controlled trial.

To assess the effectiveness of leukocyte-platelet-rich fibrin (L-PRF) compared with conventional treatment on canine retraction, rotation, pain, and soft tissue healing. Sixteen adult patients aged 18-25 years (10 females, and 6 males; mean age 22.25 ± 2.26 years) with Class I bimaxillary protrusion and Class II div 1 malocclusion participated in this single-center, split-mouth randomized controlled trial at the Orthodontics Department of a single hospital in SCB Dental College and Hospital, Cuttack, India. Randomization was performed using a computer-assisted function with a 1:1 allocation ratio. The intervention included the placement of L-PRF on the experimental side and follow-up for 90 days. The primary outcome measures were canine retraction, rotation, pain, and soft tissue healing. The range of tooth movement was evaluated at 15-day intervals: 0th day (T0), 15th day (T1), 30th day (T2), 45th day (T3), 60th day (T4), 75th day (T5), and 90th day (T6). Canine rotation was assessed at T0 and T6, and pain and soft tissue healing were evaluated on the 3rd, 7th, and 15th days of the treatment. Cumulatively, the L-PRF group demonstrated a significantly greater tooth movement as compared to conventional treatment group (P < 0.001). Overall, canine retraction was 1.5 times greater on the L-PRF side than on the control side. Canine rotation showed no significant relationship, whereas pain and soft tissue healing were significantly better on the L-PRF side than on the control side. Local administration of L-PRF amplifies canine retraction while improving pain and soft tissue repair.

Bioconjugated Antibody-Trojan Immune Converter Enhance Cancer Immunotherapy with Minimized Toxicity by Programmed Two-Step Immunomodulation of Myeloid Cells.

Current immune checkpoint blockade therapy (ICBT) predominantly targets T cells to harness the antitumor effects of adaptive immune system. However, the effectiveness of ICBT is reduced by immunosuppressive innate myeloid cells in tumor microenvironments (TMEs). Toll-like receptor 7/8 agonists (TLR7/8a) are often used to address this problem because they can reprogram myeloid-derived suppressor cells (MDSCs) and tumor-associated M2 macrophages, and boost dendritic cell (DC)-based T-cell generation; however, the systemic toxicity of TLR7/8a limits its clinical translation. Here, to address this limitation and utilize the effectiveness of TLR7/8a, this work suggests a programmed two-step activation strategy via Antibody-Trojan Immune Converter Conjugates (ATICC) that specifically targets myeloid cells by anti-SIRPα followed by reactivation of transiently inactivated Trojan TLR7/8a after antibody-mediated endocytosis. ATICC blocks the CD47-SIRPα ("don't eat me" signal), enhances phagocytosis, reprograms M2 macrophages and MDSCs,and increases cross-presentation by DCs, resulting in antigen-specific CD8+ T-cell generation in tumor-draining lymph nodes and TME while minimizing systemic toxicity. The local or systemic administration of ATICC improves ICBT responsiveness through reprogramming of the immunosuppressive TME, increased infiltration of antigen-specific CD8+ T cells,and antibody-dependent cellular phagocytosis. These results highlight the programmed and target immunomodulation via ATICC could enhance cancer immunotherapy with minimized systemic toxicities.

Enhancement the Legal Regulation of the Activities of Local Administration amidst the Spread of Diseases Posing a Danger to the Population

This article examines the current theme of improving the public authority activities in the context of the spread of diseases that pose a particular danger to people. This research is aimed at studying the legal and organizational measures taken by public authorities, municipalities in the context of the spread diseases that pose a threat to all countries world -wide. The article analyzes the authorities of public bodies and the rights of citizens in connection with the provision of operational measures targeted at prevention, restraint, averting of dangerous diseases. The crucial role and responsibility of public authorities to ensure the sphere of citizens’ health protection and provide medical assistance to the population is specified. The assessment of the medical care availability in urgent situations is effected. The issues of creating conditions for the provision of high quality, qualified, prompt medical care to people are considered. The study has identified shortcomings in the activities of public authorities in timely response to violations of citizens' rights in the field of health care. It also pays attention to taking measures to reduce death rates, providing high-quality medications, conditions of sanitary and epidemiological well-being of the population, since these important factors affect the degree of stability of social and industrial activities, the country economy, direct communication in household and economic activities.

#1118 Direct delivery of novel gene therapy to podocytes enables pathway to clinical translation for the treatment of glomerular diseases

Abstract Background and Aims Adeno associated vector (AAV) gene therapy has the potential to treat a wide range of kidney diseases via the targeted delivery of genes to kidney cells to repair cellular and renal function. Despite the potential to impact many kidney conditions, kidney AAV gene therapy has proven challenging due to technical and physiological hurdles limiting the ability of AAV to be effectively delivered to podocytes. We have developed a novel AAV gene therapy, PS-001, and local method of administration, to effectively and safely deliver the podocin gene NPHS2 to podocytes. Biallelic NPHS2 mutations are the most common cause of monogenic childhood nephrotic syndrome. Curative efficacy and resolution of disease phenotype was demonstrated in transgenic murine models following PS-001 gene therapy treatment. The potential for translation of this approach to NPHS2 nephropathy patients in the clinic was also demonstrated in pre-clinical studies in Gottingen Minipigs. Method Transgenic murine models representative of NPHS2-driven nephropathy were treated with an AAV gene therapy encoding NPHS2, including a knock in mouse model (Nphs2R140Q/−) which introduces a R140Q mutation in the podocin gene. Mice were assessed for improvement in disease phenotype via analysis of proteinuria, serum albumin, renal histopathology and survival. Mice were treated with an analogue of PS-001, as the PS-001 capsid is not permissive in rodents. Gottingen minipigs were treated with PS-001 and followed for 4 weeks. Clinically relevant doses and a procedure for local administration specifically to the kidney were established. In-life safety assessments from blood and urine were monitored and at study end pig tissues were assessed for podocin biodistribution using multiple assays (qPCR, RT-qPCR, ELISA, RNAScope and IF) and for toxicological effects via histopathological analysis. Results Using our AAV gene therapy platform, which includes a capsid that is highly effective at transducing human podocytes and promoter that drives gene expression specifically in the podocyte, the gene therapy product PS-001 encoding NPHS2 was generated. Using a murine analogue of PS-001, in vivo proof of concept studies in a translationally relevant murine disease model (Nphs2R140Q/−) showed NPHS2 delivery and podocin expression in glomeruli and efficacy in terms of renal function rescue. This was demonstrated by resolution of severe proteinuria (mean ACR ug/mg 6049 ± 2803 vs 192 ± 51 in PS-001 treated animals, n = 11), improved serum albumin (g/L 27.50 ± 3.33 g/L vs 30.75 ± 2.46 in PS-001 treated animals, P = .021) and reduction in glomerulosclerosis (mean sclerosed glomeruli 81% ± 19 vs 18.75% ± 12 in PS-001 treated animals, P &amp;lt; .0001). The methods to translate the approach to the clinical setting using a local administration were established in pigs. Administration of PS-001 resulted in transgene mRNA expression across 89% ± 11% of kidney glomeruli as assessed by RNAScope (n = 3 pigs), and transgene derived podocin could be specifically detected in podocytes as assessed by IF analysis. Using qPCR, RT-PCR and ELISA it was shown that using local administration, podocin gene expression was restricted exclusively to the kidney glomerulus, with gene expression undetectable in off-target organs including the liver. Additional toxicological assessments of renal and other organ function from urine and blood, and post-study histopathological assessments revealed no pre-clinical treatment-related safety concerns. Conclusion We present data showing development of an AAV gene therapy and method of administration for the delivery of transgenes specifically to podocytes. We have shown transgenes can be efficiently targeted to podocytes to replace defective genes or to use the podocyte as a protein factory to modulate glomerular biology. This technology therefore provides an important novel modality for potentially treating a broad range of glomerular disease. PS-001 is being developed as a novel approach to treat steroid resistant nephrotic syndrome caused by mutated NPHS2, and may become the first podocyte targeted gene therapy to enter clinical development.

Shikonin-loaded PLGA nanoparticles: A promising strategy for psoriasis treatment

Psoriasis is an inflammation-based skin illness marked by aggravated proliferation of epidermal cells. Shikonin is a natural naphthoquinone obtained from Arnebiae radix. It exerts anti-inflammatory and immunosuppressive effects. However, the poor water solubility and low bioavailability of shikonin limit its application. In this study, shikosin-loaded PLGA nanoparticle hydrogel was prepared and used to deliver the drug to the epidermis of psoriasis mice through local administration. The results demonstrated that shikosin-loaded PLGA nanoparticles inhibited HaCaT cell multiplication, increased drug uptake, and induced apoptosis of HaCaT cells. Results from Western blotting assays indicated that shikosin down-regulated the protein expressions of p65 and p-p65. Furthermore, shikonin mitigated psoriasis and decreased the concentrations of inflammation-inducing cytokines, i.e., IL17A, IL-17F, IL-22, IL-1β, and TNF-α. Taken together, these results suggest that shikonin-PLGA nanoparticles loaded in hydrogel system possess promising therapeutic potential for psoriasis.

Women’s Role in Local Development: Enhancing Gender Equality in Wan Yai District, Mukdahan Province, Thailand

Purpose: This research was conducted using a qualitative method. The objectives were: 1) to study women’s roles in local development; 2) to analyze the supporting and hindrance factors that affect the roles of women in the local area; and 3) to suggest pathways for the roles of women in local development to reduce gender inequality in Thai society. Method: The collective data came from in-depth interviews with provincial and district developers. Women's empowerment working groups conducted focus groups in four districts: Wan-Yai, Cha-Note, Bang-Sai Noi, and Pong-Kam Dong-Moo. Furthermore, the researcher focused on the women villagers to analyze the factors that influence women's empowerment in the local area and make recommendations to the local administration's women's development strategic plan. Results: Women's role in the Wan Yai district is significant. Women also participate in many aspects of the local community. Regarding politics, some women are interested in applying for local elections, and others work as public health volunteers. In economic terms, many women are essential to generating income and development in the area. Most women in the district are members of the Women's Empowerment Fund, a low-interest source promoting job creation and building careers. Research Implication: Regarding culture, women's groups participated in local traditions, such as the Twelve Annual Festivals of Isan People and the Christmas Celebration. Strong women's organizations and women's participation at all levels supported women's empowerment. However, the obstructing factors to women's development were competition from locals with similar careers and the emigration of the working-age population and younger generations. Originality/Value: In summary, the recommendations for the relevant organizations are the network and women's empowerment organizations, NGOs, and educational institutions to integrate abstractly, investigate, and evaluate continually towards the provincial strategic plan.

УПРАВЛЕНИЕ АРХИТЕКТУРНО-СТРОИТЕЛЬНЫМИ ПРОЦЕССАМИ В ВОРОНЕЖСКОЙ ГУБЕРНИИ В КОНЦЕ XVIII – 60-х гг. XIX в.

The influence of all-Russian legislation and local administration on the formation and activities of the architectural and construction service in the Voronezh province during the period under study is analyzed. Based on archival data, changes in its structure and personnel composition, the activities of provincial and city architects in implementing installations coming from the capital were studied. Using the example of a province, the process of gradual decentralization of construction management on a state scale was studied, which led to the creation of an extensive structure of architectural and construction services built into local authorities. It is shown that in a number of cases the Voronezh experience had priority over the all-Russian one. The history of the creation of the first regular plan of Voronezh in 1774, which became an example of the interaction of provincial administrations with the “Commission on the stone structure of St. Petersburg and Moscow,” is studied. It has been proven that the position of provincial architect in Voronezh has existed since 1773, which is a unique phenomenon for the province. It has been established that Voronezh became one of the first provincial cities where the position of city architect was introduced. In 1805 it was occupied by T.S. Kondratiev. Previously unpublished materials from the collections of the Russian State Historical Archive and the State Archive of the Voronezh Region were analyzed and introduced into scientific circulation.

Analysis of a European general wildlife health surveillance program: Chances, challenges and recommendations.

In a One Health perspective general wildlife health surveillance (GWHS) gains importance worldwide, as pathogen transmission among wildlife, domestic animals and humans raises health, conservation and economic concerns. However, GWHS programs operate in the face of legal, geographical, financial, or administrative challenges. The present study uses a multi-tiered approach to understand the current characteristics, strengths and gaps of a European GWHS that operates in a fragmented legislative and multi-stakeholder environment. The aim is to support the implementation or improvement of other GWHS systems by managers, surveillance experts, and administrations. To assess the current state of wildlife health investigations and trends within the GWHS, we retrospectively analyzed 20 years of wildlife diagnostic data to explore alterations in annual case numbers, diagnosed diseases, and submitter types, conducted an online survey and phone interviews with official field partners (hunting administrators, game wardens and hunters) to assess their case submission criteria as well as their needs for post-mortem investigations, and performed in-house time estimations of post-mortem investigations to conduct a time-per-task analysis. Firstly, we found that infectious disease dynamics, the level of public awareness for specific diseases, research activities and increasing population sizes of in depth-monitored protected species, together with biogeographical and political boundaries all impacted case numbers and can present unexpected challenges to a GWHS. Secondly, we found that even a seemingly comprehensive GWHS can feature pronounced information gaps, with underrepresentation of common or easily recognizable diseases, blind spots in non-hunted species and only a fraction of discovered carcasses being submitted. Thirdly, we found that substantial amounts of wildlife health data may be available at local hunting administrations or disease specialist centers, but outside the reach of the GWHS and its processes. In conclusion, we recommend that fragmented and federalist GWHS programs like the one addressed require a central, consistent and accessible collection of wildlife health data. Also, considering the growing role of citizen observers in environmental research, we recommend using online reporting systems to harness decentrally available information and fill wildlife health information gaps.

Improving The Quality Of Catchment Area Model Public Services Based On Governance 4.0

This research is to examine Public Service Improvement using the Cathcment Area model based on governance 4.0. The implementation of e-government has experienced challenges since the growth of the industrial era 4.0. The development of technology is so rapid and unstoppable. Digitalisation is starting to enter the cracks of our daily lives. The Catchment Area perspective in this study is an important factor to see the efficiency and effectiveness of services to the community in local government administration based on governance 4.0. The research locus is Sidoarjo Regency. This research uses a qualitative approach. Research focus (1). Identifying factors that affect service quality. Research Results: factors that can affect the catchment area include the function of the region on the condition of the regional economy and also the national economy which is unique in nature, tax sources that can be explored potentially and in real terms to be able to achieve balance between various regions, the efficiency and effectiveness of services to the community in an area that is seen based on the optimal area for the service itself, participation that can be achieved effectively and mutual supervision between citizens and local bureaucracy.

Targeting Inflammation and Oxidative Stress to Improve Outcomes in a TNBS Murine Crohn's Colitis Model.

Inflammation and oxidative stress are implicated in the pathogenesis of Crohn's disease. Cerium oxide nanoparticle (CNP) conjugated to microRNA 146a (miR146a) (CNP-miR146a) is a novel compound with anti-inflammatory and antioxidative properties. We hypothesized that local administration of CNP-miR146a would improve colitis in a 2,4,6-Trinitrobenzenesulfonic acid (TNBS) mouse model for Crohn's disease by decreasing colonic inflammation. Balb/c mice were instilled with TNBS enemas to induce colitis. Two days later, the mice received cellulose gel enema, cellulose gel with CNP-miR146a enema, or no treatment. Control mice received initial enemas of 50% ethanol and PBS enemas on day two. The mice were monitored daily for weight loss and clinical disease activity. The mice were euthanized on days two or five to evaluate their miR146a expression, inflammation on histology, and colonic IL-6 and TNF gene expressions and protein concentrations. CNP-miR146a enema successfully increased colonic miR146a expression at 12 h following delivery. At the end of five days from TNBS instillation, the mice treated with CNP-miR146a demonstrated reduced weight loss, improved inflammation scores on histology, and reduced gene expressions and protein concentrations of IL-6 and TNF. The local delivery of CNP-miR146a in a TNBS mouse model of acute Crohn's colitis dramatically decreased inflammatory signaling, resulting in improved clinical disease.

Simplify and Deter: Nudging waste collection fee debtors

A field quasi-experiment was conducted in cooperation with the local public administration on the waste collection agenda, testing two versions of a standard notice were tested against a control notice targeted at debtors. Both simplified versions, which included a deterrence message, were more effective than the control notice in promoting compliance. However, the version that emphasized the negative consequences of nonpayment, specifically the risk of high interest rates, was more effective in increasing tax compliance than the version that included a descriptive social norm to soften the communication toward fee debtors. The study suggests that adding a social norm to a simplified notice with deterrence does not further increase tax compliance. In addition, the notice had a greater positive effect on fee debtors who had missed only one payment than on those who had missed multiple payments of waste collection fee.

The persistence of anti-Protestant policies from the Fascist period in post-World War II Italy: ideologies, practices and legislation

ABSTRACT The aim of this article is to examine the continuities between Fascist Italy and the early republican period in terms of anti-Protestant policy. To this end, it analyses three main issues: the ideology behind Catholic anti-Protestantism and the role played by Catholic hierarchies and Holy See itself; Italian legislation and norms in religious matters, with reference to minority denominations; and the concrete attitudes of State organs at central and peripheral levels. Drawing on extensive archival documentation (from Italian, Vatican and international archives), this article shows the profound continuities, but also the differences, in anti-Protestant legislation and practice between Fascist period and the early Republican era, marked by a strong Catholic and Christian-Democrat hegemony. Thanks to this extensive documentation, this article highlights the role played by various State actors (government, central ministerial apparatuses, local administrations, judiciary) in determining the contrasting side-lining of anti-Protestant policies, which took place in the mid-fifties.

Human MuStem cells are competent to fuse with nonhuman primate myofibers in a clinically relevant transplantation context: A proof-of-concept study.

We previously reported that human muscle-derived stem cells (hMuStem cells) contribute to tissue repair after local administration into injured skeletal muscle or infarcted heart in immunodeficient rodent models. However, extrapolation of these findings to a clinical context is problematic owing to the considerable differences often seen between in vivo findings in humans versus rodents. Therefore, we investigated whether the muscle regenerative behavior of hMuStem cells is maintained in a clinically relevant transplantation context. Human MuStem cells were intramuscularly administered by high-density microinjection matrices into nonhuman primates receiving tacrolimus-based immunosuppression thereby reproducing the protocol that has so far produced the best results in clinical trials of cell therapy in myopathies. Four and 9 weeks after administration, histological analysis of cell injection sites revealed large numbers of hMuStem cell-derived nuclei in all cases. Most graft-derived nuclei were distributed in small myofiber groups in which no signs of a specific immune response were observed. Importantly, hMuStem cells contributed to simian tissue repair by fusing mainly with host myofibers, demonstrating their capacity for myofiber regeneration in this model. Together, these findings obtained in a valid preclinical model provide new insights supporting the potential of hMuStem cells in future cell therapies for muscle diseases.

The efficacy of lumbar epidural steroid injections in “failed back surgery syndrome” and lumbar radiculopathy

Aims: Lumbago is one of the common conditions in our present community. Definite periods of human’s life people encountered in the form of usually regressing attacks that %10-%15 of this important condition requires surgical therapy. Cause of wrong diagnosis and treatment Spinal surgery may not always give favourable result. Patients undergone one or more back surgery exist back and/or leg pain which does not improve, is called failed back surgery syndrome. Epidural steroid administration is one of the most invasive method which is used in back pain. Effects and application results are controversial. In this study we aimed to compare the effects of steroid and local anesthetic solutions which administered by epidural way on pain controlling between the patients that have chronic back pain because of lomber radiculopathy, undergone surgery and not surgery. Methods: It was evaluated retrospectively pain controlling effect of administered steroid and local anesthetics by interlaminal epidural way to ASA 1-2-3, between 18-80 aged 40 patient which undergone piror one or plural back surgery and have no surgery between May 2009-December 2009 apply with back pain complaint to İstanbul Education and Research Hospital Algology Department. Patient’s visuel analog scala (VAS) and severity of back pains, before procedure, second week after procedure, fourth week after procedure, sixth week after procedure in either two groups out of ten points was estimated. Results: Totally of 7 ml solution which contains 1 ml triamsinolon asetonid 40 mg/ml (Sinakort-A ampul, İ.E. Ulugay), 3 ml levobupivacaine 5mg/ml ( Chirocaine ampul, Abbott) and 3 ml serum phsiyologic ( % 0,9 NaCl ) administered by epidural way into either two group patients. There were no significant difference between two groups by mean of age, weight, height, BMI and back pain durations. Evaluating the groups into themselves, opioid requirements and VAS scores before injection was markedly higher than 2,4 and 6. week scores in either two groups (p&lt;0.05). There was no statistically significant difference when we compare into groups of 2,4 and 6. week opioid requirements and VAS scores in either two groups. All patient manifested their pleasure and there was no complication occured. Conclusion: Consequently; it was thought that epidural administration of steroid (triamsinolon) ,local anesthetics (levobupivacaine) and serum physiologic solution was effective especially on early back pain treatment, also safe method and beneficial to patient satisfaction in the patients who has failed back surgery and chronic back pain.

Inflammatory macrophage reprogramming strategy of fucoidan microneedles-mediated ROS-responsive polymers for rheumatoid arthritis

During the pathogenesis of rheumatoid arthritis, inflammatory cells usually infiltrate synovial tissues, notably, M1-type macrophages, whose redox imbalance leads to the degradation of joint structures and deterioration of function. Natural active products play a vital role in immune modulation and antioxidants. In this study, we constructed a ROS-responsive nanoparticle called FTL@SIN, which consists of fucoidan (Fuc) and luteolin (Lut) connected by a ROS-responsive bond, Thioketal (TK), and encapsulated with an anti-rheumatic drug, Sinomenine (SIN), for synergistic anti-inflammatory effects. The FTL@SIN is then dispersed in high molecular weight Fuc-fabricated dissolvable microneedles (FTL@SIN MNs) for local administration. Therapy of FTL@SIN MNs afforded a significant decrease in macrophage inflammation while decreasing key pro-inflammatory cytokines and repolarizing M1 type to M2 type, thereby ameliorating synovial inflammation, and promoting cartilage repair. Additionally, our investigations have revealed that Fucoidan (Fuc) demonstrates synergistic effects, exhibiting superior mechanical strength and enhanced physical stability when compared to microneedles formulated solely with hyaluronic acid. This study combines nanomedicine with traditional Chinese medicine, a novel drug delivery strategy that presents a promising avenue for therapeutic intervention in rheumatoid arthritis.

METTL3 Modulates Ctsk+ Lineage Supporting Cranial Osteogenesis via Hedgehog

N6-methyladenosine (m6A) modification, a eukaryotic messenger RNA modification catalyzed by methyltransferase-like 3 (METTL3), plays a pivotal role in stem cell fate determination. Calvarial bone development and maintenance are orchestrated by the cranial sutures. Cathepsin K (CTSK)–positive calvarial stem cells (CSCs) contribute to mice calvarial ossification. However, the role of m6A modification in regulating Ctsk+ lineage cells during calvarial development remains elusive. Here, we showed that METTL3 was colocalized with cranial nonosteoclastic Ctsk+ lineage cells, which were also associated with GLI1 expression. During neonatal development, depletion of Mettl3 in the Ctsk+ lineage cells delayed suture formation and decreased mineralization. During adulthood maintenance, loss of Mettl3 in the Ctsk+ lineage cells impaired calvarial bone formation, which was featured by the increased bone porosity, enhanced bone marrow cavity, and decreased number of osteocytes with the less-developed cellular outline. The analysis of methylated RNA immunoprecipitation sequencing and RNA sequencing data indicated that loss of METTL3 reduced Hedgehog (Hh) signaling pathway. Restoration of Hh signaling pathway by crossing Sufufl/+ alleles or by local administration of SAG21 partially rescued the abnormity. Our data indicate that METTL3 modulates Ctsk+ lineage cells supporting calvarial bone formation by regulating the Hh signaling pathway, providing new insights for clinical treatment of skull vault osseous diseases.

Benthic Macroinvertebrates as Indicators of Organic Pollution in Upstream Batena River, Hossana, Central Ethiopia

Benthic macro invertebrates are insects and other organism without a back bone that can be seen without magnification and that live in the bottom of all water bodies. They are bio monitor species in determining the water quality in fresh water and other aquatic ecosystems as they are indicator of environmental change of aquatic ecosystem and fresh water ecosystem. The aim of this study was to assess Organic pollution by using benthic macro invertebrate as indicator in upstream parts of Batena River and implication to the water quality of the river. Benthic Macro invertebrates were collected using Scrubber net and sieve with mesh size of 1mm. A total of 57 individual within 4 families belong to 4 orders and one class was identified during the study period. Most dominant group was Hemiptera 29(50.8%), Diptera14 for Chironomidae (Red) (24.56%) and for Diptera family chironomidae (Pale) (19.3%). Sphendiea, Psephyendiea and class of Turbilaria accounts the same percentage (1.75%) and their total abundance was also similar. The pollution level of the river was assessed using Hillsenhoff Family Biotic Index (HFBI) and the value was 7.96. Over all study showed that the river is polluted and have poor water quality as result of diverse Organic pollutant agents. Therefore, the local people and administration of the river should work hard to prevent further deterioration of the river quality by raising public awareness, prevention of waste disposal and treat the waste water before discharging it directly to the river.

Tourists' assessment of economic value, benefits and negative impacts of pedestrian walkways: Case-studies of the Paiva River (Arouca) and the Mondego River (Guarda) in Portugal

Hiking tourism becomes a popular wellness travel trend across the world. In recent years, we have witnessed the construction of walkways or boardwalks aiming to leverage the attractiveness of nature-based tourism destinations. This paper aims to assess the quality and economic value of two walkways/boardwalks in Portugal (MRW-Mondego River and PRW-Paiva River). A questionnaire applied to visitors at the entrances/exits of those linear walkways obtained 301 (MRW) and 188 (PRW) responses. In both case-studies, visitors provided high scores for the walkways' attributes and their overall satisfaction, which is positively correlated with their willingness to pay for a ticket to access the walkway (MRW- €4.56 and PRW- €6.31 respectively). This study also conducted a K-means cluster analysis for the Mondego RW sub-sample, that identified four different clusters: Cluster 1- (N = 8) Older and heavy spenders, a small segment of male visitors that spend a high amount of money during more than a 2-day stay in the region; Cluster 2- (N = 35) Heavy donators women, composed mainly by women who are willing to donate an higher amount for the conservation of the walkway; Cluster 3- (N = 62)- Average visitor whose members have a profile with characteristics similar to the average scores of the sample; and Cluster 4- (N = 189) Low spenders younger women, that plan their journey avoiding all the consumption moments and spending the lowest amount as possible (about €24). Based on the proposed theoretical framework and on the claims shared by visitors on the survey, this paper provides some recommendations for public decision-makers. Management implications•The local administration should reinvest the direct revenues from the walkways in new support infrastructures (e.g. accessibility, litter collection or the fire prevention/evacuation plan). They must also design an environmental education program for visitors to mitigate conflicts with local population.•The tourism operators must advertise and diversify the experiences, targeting the preferences of the four major visitors’ segments identified in the cluster analysis aiming to extend their stay in the region. The quality and variety of the restaurants should be improved and a new line of certified merchandising products is a potential source of shop owners’ revenues.

A phase I/II clinical trial of ex-vivo expanded human bone marrow derived allogeneic mesenchymal stromal cells in adult patients with perianal fistulizing Crohn’s Disease

BackgroundPerianal fistulas (PF) affect one-third patients with Crohn’s disease (CD) with limited therapeutic options. There is dearth of literature on safety and efficacy of bone marrow-derived mesenchymal stromal cells (BMSCs) in this population.MethodsAn open-label, phase I/II, single-arm study was conducted involving local administration of human allogeneic bone marrow-derived mesenchymal stromal cells in perianal fistula of patients with Crohn’s disease refractory to standard therapies. Clinical severity and biomarkers were assessed at baseline and periodically until week 104 , and MRI at week 24 and 104. Primary and secondary objectives were to assess safety and efficacy respectively. Fistula remission was complete closure of fistula openings with < 2 cm perianal collection on MRI, and fistula response was decrease in drainage by ≥ 50%. Change in perianal disease activity index, quality-of-life and Van Assche index on MRI over time was assessed using mixed-effect linear regression model.ResultsTen patients (male:8, mean age:27.4 ± 12.0years) were recruited. Self-resolving procedure-related adverse events occurred in three patients, with no follow-up adverse events. In intention to treat analysis at week 24, two patients (20%) achieved fistula remission and seven (70%) had fistula response. At week 52, two (20%) patients were in remission and seven (70%) maintained response. At 104 weeks, two (20%) patients maintained response and one (10%) was in remission. Statistically significant decrease in perianal disease activity index (P = 0.008), Van Assche Index (P = 0.008) and improvement in quality-of-life (P = 0.001) were observed over time.ConclusionsAllogeneic BMSCs are safe and effective for the treatment of perianal fistulizing CD with significant improvement in clinical severity and radiological healing.Trial registrationThe study was prospectively registered on Clinical trials registry – India (CTRI), CTRI/2020/01/022743 on 14 January 2020, http://ctri.nic.in.

Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis

BackgroundMultiple sclerosis (MS) is a progressive neurodegenerative disease of the central nervous system characterized by inflammation-driven synaptic abnormalities. Interleukin-9 (IL-9) is emerging as a pleiotropic cytokine involved in MS pathophysiology.MethodsThrough biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS.ResultsWe demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects.ConclusionsThe data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system.