Madrid Newborn Sickle Cell Disease Cohort: clinical outcomes, stroke prevention and survival.

In May 2003, Madrid established the universal newborn screening (NBS) for sickle cell disease (SCD). However, there are no studies resembling the evolution of a SCD neonate cohort followed according to national guidelines in Spain. The aim of this study is to describe the morbimortality and the stroke prevention programme in patients diagnosed by SCD NBS in Madrid. This is a multicentre, observational, prospective cohort study between 2003 and 2018; 187 patients diagnosed with SCD were included (151 HbSS, 6 HbSß0, 27 HbSC, 3 HbSß +), and median follow-up was 5.2 years (0.03-14.9). There were 5 deaths: 2 related to SCD in patients with severe genotype (HbSS/HbSß0). Overall survival reached 95% and SCD-related survival 96.8%. The most frequent events were fever without focus, vaso-occlusive crises and acute chest syndromes. Eight strokes occurred in 5 patients which led to a 90.7% stroke-free survival in severe genotype patients (first stroke rate, 0.54 per 100 patient-years). Transcranial Doppler (TCD) was performed in 95% of eligible patients; 75% of children with pathological TCD remained stroke-free. Regarding HbSS/HbSß0 patients, 50.1% received hydroxyurea and 9.5% haematopoietic stem cell transplantation. This study reflects the evolution of Madrid SCD cohort and provides morbimortality data similar to other developed countries.

Epidemic intelligence data of Crimean-Congo haemorrhagic fever, European Region, 2012 to 2022: a new opportunity for risk mapping of neglected diseases.

BackgroundThe Epidemic Intelligence from Open Sources (EIOS) system, jointly developed by the World Health Organisation (WHO), the Joint Research Centre (JRC) of the European Commission and various partners, is a web-based platform that facilitate the monitoring of information on public health threats in near real-time from thousands of online sources.AimsTo assess the capacity of the EIOS system to strengthen data collection for neglected diseases of public health importance, and to evaluate the use of EIOS data for improving the understanding of the geographic extents of diseases and their level of risk.MethodsA Bayesian additive regression trees (BART) model was implemented to map the risk of Crimean-Congo haemorrhagic fever (CCHF) occurrence in 52 countries and territories within the European Region between January 2012 and March 2022 using data on CCHF occurrence retrieved from the EIOS system.ResultsThe model found a positive association between all temperature-related variables and the probability of CCHF occurrence, with an increased risk in warmer and drier areas. The highest risk of CCHF was found in the Mediterranean basin and in areas bordering the Black Sea. There was a general decreasing risk trend from south to north across the entire European Region.ConclusionThe study highlights that the information gathered by public health intelligence can be used to build a disease risk map. Internet-based sources could aid in the assessment of new or changing risks and planning effective actions in target areas.

Spanish version of the readiness for interprofessional learning scale (RIPLS) in an undergraduate health sciences student context.

The Readiness for Interprofessional Learning Scale (RIPLS) has been widely used to measure students' and professionals' attitudes toward interprofessional learning. However, inconsistencies have been reported concerning its validity and reliability. This study aimed to translate, adapt, and validate the RIPLS questionnaire to be applied to Spanish-speaking health sciences students in Chile. Content and construct validity evidence of the newly created Spanish version of the RIPLS scale were analyzed. An exploratory (EFA) and confirmatory (CFA) analysis were conducted, determining goodness-of-fit indexes. Reliability was evaluated through Cronbach's Alpha Coefficient. We assessed sensitivity to change of the RIPLS scale by comparing pre- and post-interprofessional education workshop scores. The EFA showed that there were three factors. In the CFA, most of the standardized factor loadings were higher than 0.3. Regarding internal consistency, Cronbach's Alpha was 0.86. The differences between the total RIPLS scores before and after the workshops were statistically significant. The Spanish version of RIPLS showed evidence of validity and reliability for use amongst health sciences students. The construct was adequately measured and was shown that it could be used to assess the impact of interprofessional education workshops.

Topical 15% Paromomycin-Aquaphilic for Bolivian Leishmania braziliensis Cutaneous Leishmaniasis: A Randomized, Placebo-controlled Trial.

BACKGROUND: Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% paromomycin topical formulations have been in clinical experimentation. Recently, 15% paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. METHODS: We performed a randomized trial of 15% paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia. RESULTS: Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5-88%) for paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3-30%) for Aquaphilic vehicle (P < .0001 vs paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48-85.5%) for intralesional pentamidine. Both paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5-10% of patients. CONCLUSIONS: Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% paromomycin-Aquaphilic from one form of Old World CL to CL more generally. CLINICAL TRIALS REGISTRATION: NCT03096457.

7 Log Virus Removal in a Simple Functionalized Sand Filter.

Viral contamination of drinking water due to fecal contamination is difficult to detect and treat effectively, leading to frequent outbreaks worldwide. The purpose of this paper is to report on the molecular mechanism for unprecedented high virus removal from a practical sand filter. Sand filters functionalized using a water extract of Moringa oleifera (MO) seeds, functionalized sand (f-sand) filters, achieved a ∼7 log10 virus removal. These tests were conducted with MS2 bacteriophage, a recognized surrogate for pathogenic norovirus and rotavirus. We studied the molecular mechanism of this high removal since it can have important implications for sand filtration, the most common water treatment technology worldwide. Our data reveal that the virus removal activity of f-sand is due to the presence of a chitin-binding protein, M. oleifera chitin-binding protein (MoCBP) on f-sand. Standard column experiments were supported by proteomic analysis and molecular docking simulations. Our simulations show that MoCBP binds preferentially to MS2 capsid proteins demonstrating that specific molecular interactions are responsible for enhanced virus removal. In addition, we simplified the process of making f-sand and evinced how it could be regenerated using saline water. At present, no definitive solution exists for the challenge of treating fecally contaminated drinking and irrigation water for viruses without using technologies that demand high energy or chemical consumption. We propose functionalized sand (f-sand) filters as a highly effective, energy-efficient, and practical technology for virus removal applicable to both developing and developed countries.

Metal bashing: iron deficiency and manganese overexposure impact on peripheral nerves.

Iron (Fe) deficiency (FeD) and manganese (Mn) overexposure (MnOE) may result in several neurological alterations in the nervous system. Iron deficiency produces unique neurological deficits due to its elemental role in central nervous system (CNS) development and myelination, which might persist after normalization of Fe in the diet. Conversely, MnOE is associated with diverse neurocognitive deficits. Despite these well-known neurotoxic effects on the CNS, the influence of FeD and MnOE on the peripheral nervous system (PNS) remains poorly understood. The aim of the present investigation was to examine the effects of developmental FeD and MnOE or their combination on the sciatic nerve of young and adult rats. The parameters measured included divalent metal transporter 1 (DMT1), transferrin receptor (TfR), myelin basic protein (MBP) and peripheral myelin protein 22 (PMP22) expression, as well as Fe levels in the nerve. Our results showed that FeD produced a significant reduction in MBP and PMP22 content at P29, which persisted at P60 after Fe-sufficient diet replenishment regardless of Mn exposure levels. At P60 MnOE significantly increased sciatic nerve Fe content and DMT1 expression. However, the combination of FeD and MnOE produced no marked motor skill impairment. Evidence indicates that FeD appears to hinder developmental peripheral myelination, while MnOE may directly alter Fe homeostasis. Further studies are required to elucidate the interplay between these pathological conditions.

EGFP transgene: a useful tool to track transplanted bone marrow mononuclear cell contribution to peripheral remyelination.

Bone marrow mononuclear cells (BMMC) constitute a heterogeneous population with potential to promote tissue regeneration. For this reason, this cell fraction has recently become a therapeutic alternative to mesenchymal stem cells, as culture is not required and phenotypic transformations can be hence avoided. In this work, and in order to attain long-lasting cell labeling and study longer survival times, we used BMMC isolated from adult transgenic rats expressing GFP to reproduce our wild type model and evaluate their remyelination ability in a reversible model of Wallerian degeneration. RT-PCR and flow cytometry analysis confirmed that cells isolated from the transgenic strain exhibited similar expression levels of markers specific to multipotent progenitors (CD34, CD90 and CD105) and Schwann cells (MPZ, MBP, S100ß and p75NTR) compared to wild type BMMC. BMMC expressing GFP retained their migration capacity, arriving exclusively at the injured nerve. Most importantly, and as detected through long-lasting cell tracking, some of these BMMC settled in the demyelinated area, mingled with endogenous cells, underwent phenotypic changes and colocalized with Schwann cell markers MBP and S100ß. Also worth highlighting, transgenic BMMC replicated wild type BMMC effects in terms of MBP organization and levels. On the basis of these findings, BMMC isolated from transgenic animals constitute a useful tool to evaluate their role in peripheral nervous system demyelination-remyelination and the underlying mechanisms.

FMR1 gene mutations in patients with fragile X syndrome and obligate carriers: 30 years of experience in Chile.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and co-morbid autism. It is caused by an amplification of the CGG repeat (>200), which is known as the full mutation, within the 5'UTR of the FMR1 gene. Expansions between 55-200 CGG repeats are termed premutation and are associated with a greater risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated premature ovarian insufficiency. Intermediate alleles, also called the grey zone, include approximately 45-54 repeats and are considered borderline. Individuals with less than 45 repeats have a normal FMR1 gene. We report the occurrence of CGG expansions of the FMR1 gene in Chile among patients with ID and families with a known history of FXS. Here, we present a retrospective review conducted on 2321 cases (2202 probands and 119 relatives) referred for FXS diagnosis and cascade screening at the Institute of Nutrition and Food Technology (INTA), University of Chile. Samples were analysed using traditional cytogenetic methods and/or PCR. Southern blot was used to confirm the diagnosis. Overall frequency of FMR1 expansions observed among probands was 194 (8·8%), the average age of diagnosis was 8·8 ± 5·4 years. Of 119 family members studied, 72 (60%) were diagnosed with a CGG expansion. Our results indicated that the prevalence of CGG expansions of the FMR1 gene among probands is relatively higher than other populations. The average age of diagnosis is also higher than reference values. PCR and Southern blot represent a reliable molecular technique in the diagnosis of FXS.

An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients.

The possibility of HIV-1 eradication has been limited by the existence of latently infected cellular reservoirs. Studies to examine control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells found in vivo. Major conceptual leaps have been facilitated by the use of latently infected T cell lines and primary cells. However, notable differences exist among cell model systems. Furthermore, screening efforts in specific cell models have identified drug candidates for "anti-latency" therapy, which often fail to reactivate HIV uniformly across different models. Therefore, the activity of a given drug candidate, demonstrated in a particular cellular model, cannot reliably predict its activity in other cell model systems or in infected patient cells, tested ex vivo. This situation represents a critical knowledge gap that adversely affects our ability to identify promising treatment compounds and hinders the advancement of drug testing into relevant animal models and clinical trials. To begin to understand the biological characteristics that are inherent to each HIV-1 latency model, we compared the response properties of five primary T cell models, four J-Lat cell models and those obtained with a viral outgrowth assay using patient-derived infected cells. A panel of thirteen stimuli that are known to reactivate HIV by defined mechanisms of action was selected and tested in parallel in all models. Our results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients. Most cell models demonstrated that sensitivity to HIV reactivation was skewed toward or against specific drug classes. Protein kinase C agonists and PHA reactivated latent HIV uniformly across models, although drugs in most other classes did not.

Enhanced T cell function in a mouse model of human glycosylation.

Clinical evidence for a more active immune response in humans compared with our closest hominid relative, the chimpanzee, includes the progression of HIV infection to AIDS, hepatitis B- and C-related inflammation, autoimmunity, and unwanted harmful immune responses to viral gene transfer vectors. Humans have a unique mutation of the enzyme CMP-N-acetylneuraminic acid hydroxylase (CMAH), causing loss of expression of the sialic acid Neu5Gc. This mutation, occurring 2 million years ago, likely altered the expression and function of ITIM-bearing inhibitory receptors (Siglecs) that bind sialic acids. Previous work showed that human T cells proliferate faster than chimpanzee T cells upon equivalent stimulation. In this article, we report that Cmah(-/-) mouse T cells proliferate faster and have greater expression of activation markers than wild-type mouse T cells. Metabolically reintroducing Neu5Gc diminishes the proliferation and activation of both human and murine Cmah(-/-) T cells. Importantly, Cmah(-/-) mice mount greater T cell responses to an adenovirus encoding an adeno-associated virus capsid transgene. Upon lymphocytic choriomeningitis virus infection, Cmah(-/-) mice make more lymphocytic choriomeningitis virus-specific T cells than WT mice, and these T cells are more polyfunctional. Therefore, a uniquely human glycosylation mutation, modeled in mice, leads to a more proliferative and active T cell population. These findings in a human-like mouse model have implications for understanding the hyperimmune responses that characterize some human diseases.

Loss of Siglec-14 reduces the risk of chronic obstructive pulmonary disease exacerbation.

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. COPD exacerbation, or episodic worsening of symptoms, often results in hospitalization and increased mortality rates. Airway infections by new bacterial strains, such as nontypeable Haemophilus influenzae (NTHi), are a major cause of COPD exacerbation. NTHi express lipooligosaccharides that contain sialic acids, and may interact with Siglec-14, a sialic acid recognition protein on myeloid cells that serves as an activating signal transduction receptor. A null allele polymorphism in SIGLEC14 may attenuate the inflammatory responses to NTHi by eliminating Siglec-14 expression. We asked if the loss of Siglec-14 attenuates the inflammatory response by myeloid cells against NTHi, and if the SIGLEC14-null polymorphism has any effect on COPD exacerbation. We found that NTHi interacts with Siglec-14 to enhance proinflammatory cytokine production in a tissue culture model. Inhibitors of the Syk tyrosine kinase suppress this response. Loss of Siglec-14, due to SIGLEC14-null allele homozygosity, is associated with a reduced risk of COPD exacerbation in a Japanese patient population. Taken together, Siglec-14 and its downstream signaling pathway facilitate the "infection-inflammation-exacerbation" axis of COPD disease progression, and may represent promising targets for therapeutic intervention.

All the PNS is a Stage: Transplanted Bone Marrow Cells Play an Immunomodulatory Role in Peripheral Nerve Regeneration.

SUMMARY STATEMENT: Bone marrow cell transplant has proven to be an effective therapeutic approach to treat peripheral nervous system injuries as it not only promoted regeneration and remyelination of the injured nerve but also had a potent effect on neuropathic pain.

Relative over-reactivity of human versus chimpanzee lymphocytes: implications for the human diseases associated with immune activation.

Although humans and chimpanzees share >99% identity in alignable protein sequences, they differ surprisingly in the incidence and severity of some common diseases. In general, humans infected with various viruses, such as HIV and hepatitis C virus, appear to develop stronger reactions and long-term complications. Humans also appear to suffer more from other diseases associated with over-reactivity of the adaptive immune system, such as asthma, psoriasis, and rheumatoid arthritis. In this study, we show that human T cells are more reactive than chimpanzee T cells to a wide variety of stimuli, including anti-TCR Abs of multiple isotypes, l-phytohemagglutin, Staphylococcus aureus superantigen, a superagonist anti-CD28 Ab, and in MLRs. We also extend this observation to B cells, again showing a human propensity to react more strongly to stimuli. Finally, we show a relative increase in activation markers and cytokine production in human lymphocytes in response to uridine-rich (viral-like) ssRNA. Thus, humans manifest a generalized lymphocyte over-reactivity relative to chimpanzees, a finding that is correlated with decreased levels of inhibitory sialic acid-recognizing Ig-superfamily lectins (Siglecs; particularly Siglec-5) on human T and B cells. Furthermore, Siglec-5 levels are upregulated by activation in chimpanzee but not human lymphocytes, and human T cell reactivity can be downmodulated by forced expression of Siglec-5. Thus, a key difference in the immune reactivity of chimp and human lymphocytes appears to be related to the differential expression of Siglec-5. Taken together, these data may help explain human propensities for diseases associated with excessive activation of the adaptive immune system.

Treatment of Bolivian Leishmania braziliensis Cutaneous and Mucosal Leishmaniasis.

Although infection with Leishmania braziliensis is perhaps the key reason to treat New World cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML), the total literature contains relatively few reported cases. With the aim of supplementing the meager clinical information available, we searched the records of Jorochito (Dermatology) Hospital, Bolivia, for the years 1999-2020 and identified treatment records for 1,696 naive CL patients and 355 naive ML patients. Because follow-up was poor for this real-world treatment experience in the developing world, only 255 CL patients (15%) and 114 ML patients (32%) attended follow-up at Hospital. We therefore engaged in an Active Search for "lost" patients, located a further 542 CL patients (32%) and 142 ML patients (44%), thus eventually accomplished follow up on 697 CL patients (41%) and 256 ML patients (72%). Granular adverse event data derived from hospital records is listed for the 902 CL and 86 ML patients administered Glucantime intramuscularly, the 401 CL and 202 ML patients administered Glucantime intravenously, and the 163 CL and 89 ML patients administered miltefosine orally. Efficacy was obtained from hospital records for patients seen at hospital and from patient recall communicated by telephone for the patients found in the Active Search. The overall CL cure rate was 508 of 697 CL patients (73%) with follow-up: intramuscular Glucantime-196/293 (67%); intravenous Glucantime-90/126 (71%); intralesional Glucantime-34/54 (63%); oral miltefosine-52/69 (75%). The overall ML cure rate was 161 of 256 ML patients (63%) with follow-up: intramuscular Glucantime-26/48 (54%); intravenous Glucantime-66/104 (63%); intravenous amphotericin B deoxycholate-19/35 (54%); oral miltefosine-50/71 (70%). We offer this extensive adverse event and efficacy experience as useful guides for clinicians presented with a L. braziliensis infection. The cure rates also illustrate the quandary of New World CL and ML chemotherapy: sufficiently high to be useful but nevertheless needing augmentation with new agents.

Sclerosing pneumocytoma with carcinoid tumorlets and neuroendocrine cell hyperplasia.

Sclerosing pneumocytoma is an uncommon pulmonary tumor which generally behaves benignly and occurs predominately in women. Rarely, it is associated with neuroendocrine proliferations such as hyperplasia, tumorlets and carcinoid tumors, which may be observed in relation to the tumor or in the distant lung parenchyma; the mechanism underlying this neuroendocrine differentiation is not clear. We present a case of a 33 year-old male with sclerosing pnemocytoma with coexistent neuroendocrine hyperplasia and combined carcinoid tumorlets. Taking into account the pluripotentiality of the round cells present in the sclerosing pneumocytoma, with positive staining for stem cells markers, it is possible that the different components of this neoplasia share a common origin, in accordance with previously reported findings.

HIV-1 latency is established preferentially in minimally activated and non-dividing cells during productive infection of primary CD4 T cells.

Latently infected CD4 T cells form a stable reservoir of HIV that leads to life-long viral persistence; the mechanisms involved in establishment of this latency are not well understood. Three scenarios have been proposed: 1) an activated, proliferating cell becomes infected and reverts back to a resting state; 2) an activated cell becomes infected during its return to resting; or 3) infection is established directly in a resting cell. The aim of this study was, therefore, to investigate the relationship between T cell activation and proliferation and the establishment of HIV latency. Isolated primary CD4 cells were infected at different time points before or after TCR-induced stimulation. Cell proliferation within acutely infected cultures was tracked using CFSE viable dye over 14 days; and cell subsets that underwent varying degrees of proliferation were isolated at end of culture by flow cytometric sorting. Recovered cell subpopulations were analyzed for the amount of integrated HIV DNA, and the ability to produce virus, upon a second round of cell stimulation. We show that cell cultures exposed to virus, prior to stimulus addition, contained the highest levels of integrated and replication-competent provirus after returning to quiescence; whereas, cells infected during the height of cell proliferation retained the least. Cells that did not divide or exhibited limited division, following virus exposure and stimulation contained greater amounts of integrated and inducible HIV than did cells that had divided many times. Based on these results, co-culture experiments were conducted to demonstrate that latent infection could be established directly in non-dividing cells via cell-to-cell transmission from autologous productively infected cells. Together, the findings from our studies implicate the likely importance of direct infection of sub-optimally activated T cells in establishment of latently infected reservoirs in vivo, especially in CD4 lymphocytes that surround productive viral foci within immune tissue microenvironments.

Effects of Occupational Therapy Program Based on Active Meditation on Hair Cortisol Levels in Undergraduate Healthcare Students.

Methods: Undergraduate students from the University of Chile's health careers were divided at random into control (n = 7) and treated groups (n = 15). The treated group participated in an active meditation program once a week for three months. This treatment included different techniques such as Chakra Sounds, Nataraj, Mandala, Kundalini, Devavani, Gourishankar, and Nadabrahma. Hair samples were taken before and after the treatment period to measure cortisol. Results: The control group increased cortisol level 168.9 ± 76.8 pg/mg compared with initial levels. The treated group shows a decrease of initial cortisol values in 28.5 ± 12.8 pg/mg after meditation protocol application. Conclusions: Blending active meditation in students' daily routine through occupational therapy intervention might prevent undergraduate students' stress in healthcare careers.

Sensitivity of an international notification system for wildlife diseases: A case study using the OIE-WAHIS data on tularemia.

The World Organization for Animal Health (OIE) has recently developed a Wildlife Health Framework to respond to the need of members to manage the risk from emerging diseases at the animal-human-ecosystem interface. One of its objectives is to improve surveillance systems, early detection and notification of wildlife diseases. Members share information on disease occurrence by reporting through the OIE World Animal Health Information System (OIE-WAHIS-formerly known as 'WAHIS'). To evaluate the capacity of a surveillance system to detect disease events, it is important to quantify the gap between all known events and those officially notified to the OIE. This study used capture-recapture analysis to estimate the sensitivity of the OIE-WAHIS system for a OIE-listed wildlife disease by comparing information from publicly available sources to identify undetected events. This article presents a case study of the occurrence of tularemia in lagomorphs among selected North American and European countries during the period 2014-2019. First, an analysis using three data sources (OIE-WAHIS, ProMED, WHO-EIOS [Epidemic Intelligence from Open Sources]) was conducted. Subsequent analysis then explored the model integrating information from a fourth source (scientific literature collected in PubMed). Two models were built to evaluate both the sensitivity of the OIE-WAHIS using media reports (ProMED and WHO-EIOS), which is likely to represent current closer to real-time events, and published scientific data, which is more useful for retrospective analysis. Using the three-source approach, the predicted number of tularemia events was 93 (95% CI: 75-114), with an OIE-WAHIS sensitivity of 90%. In the four-source approach, the number of predicted events increased to 120 (95% CI: 99-143), dropping the sensitivity of the OIE-WAHIS to 70%. The results indicate a good sensitivity of the OIE-WAHIS system using the three-source approach, but lower sensitivity when including information from the scientific literature. Further analysis should be undertaken to identify diseases and regions for which international reporting presents a low sensitivity. This will enable evaluation and prioritization of underreported OIE-listed wildlife diseases and identify areas of focus as part of the Wildlife Health Framework. This study also highlights the need for stronger collaborations between academia and National Veterinary Services to enhance surveillance systems for notifiable diseases.

Evolution of Rabies in South America and Inter-Species Dynamics (2009-2018).

Rabies is listed as one of the World Health Organisation's (WHO) Neglected Tropical Diseases Worldwide, with a significant impact in South America. This paper explores the dynamics of rabies cases in humans, pets (dogs and cats), livestock and wildlife (bats in particular) in South America during the period 2009-2018. The data used in this study were derived from the two main databases for rabies in South America: the OIE-WAHIS from the World Organisation for Animal Health (OIE) and PANAFTOSA's Regional Information System for the Epidemiological Surveillance of Rabies (SIRVERA). Being a neglected disease with possible underreporting in some areas, the reported rabies cases may not always represent the real disease burden. The analysis focuses on the evolution of the number of cases in time and their spatial distribution, as well as on the main source of infections in humans, determined by laboratory assays of the antigenic variant or through epidemiological investigations. Additionally, Generalised Linear Mixed Models (GLMM) were used to evaluate the risk factors associated with the occurrence of human cases. Our results show that the highest impact of the disease in terms of number of cases was reported on livestock, while the overall number of cases (in animals and humans) progressively decreased along the study period. The spatial distribution of rabies in livestock showed two main clusters in the north-western (mainly Colombia) and in the south-eastern part of the affected area (Brazil), and a third smaller cluster in Peru. A cluster in dogs was observed in Bolivia. Out of the 192 human cases reported during the study period, 70% of them were transmitted by bats. The number of human cases reported during the study period were significantly associated with the number of rabies cases reported in livestock, pets and wildlife. Despite the overall decreasing case report rate, the disease still represents a major animal and public health concern in South America, and new strategies for compiling systematic information, networking and education are needed, as well as the education and training of veterinary staff.

Sciatic nerve regeneration after traumatic injury using magnetic targeted adipose-derived mesenchymal stem cells.

Traumatic peripheral nerve injuries constitute a huge concern to public health. Nerve damage leads to a decrease or even loss of mobility of the innervated area. Adult stem cell therapies have shown some encouraging results and have been identified as promising treatment candidates for nerve regeneration. A major obstacle to that approach is securing a sufficient number of cells at the injured site to produce measurable therapeutic effects. The present work tackles this issue and demonstrates enhanced nerve regeneration ability promoted by magnetic targeted cell therapy in an in vivo Wallerian degeneration model. To this end, adipose-derived mesenchymal stem cells (AdMSC) were loaded with citric acid coated superparamagnetic iron oxide nanoparticles (SPIONs), systemically transplanted and magnetically recruited to the injured sciatic nerve. AdMSC arrival to the injured nerve was significantly increased using magnetic targeting and their beneficial effects surpassed the regenerative properties of the stand-alone cell therapy. AdMSC-SPIONs group showed a partially conserved nerve structure with many intact myelinated axons. Also, a very remarkable restoration in myelin basic protein organization, indicative of remyelination, was observed. This resulted in an improvement in nerve conduction, demonstrating functional recovery. In summary, our results demonstrate that magnetically assisted delivery of AdMSC, using a non-invasive and non-traumatic method, is a highly promising strategy to promote cell recruitment and sciatic nerve regeneration after traumatic injury. Last but not least, our results validate magnetic targeting in vivo exceeding previous reports in less complex models through cell magnetic targeting in vitro and ex vivo. STATEMENT OF SIGNIFICANCE: Traumatic peripheral nerve injuries constitute a huge public health concern. They can lead to a decrease or even loss of mobility of innervated areas. Due to their complex pathophysiology, current pharmacological and surgical approaches are only partially effective. Cell-based therapies have emerged as a useful tool to achieve full tissue regeneration. However, a major bottleneck is securing enough cells at injured sites. Therefore, our proposal combining biological (adipose derived mesenchymal stem cells) and nanotechnological strategies (magnetic targeting) is of great relevance, reporting the first in vivo experiments involving "magnetic stem cell" targeting for peripheral nerve regeneration. Using a non-invasive and non-traumatic method, cell recruitment in the injured nerve was improved, fostering nerve remyelination and functional recovery.