Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition.

Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4 Gy whole-brain radiation dose on postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed on PND 77, 91, and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors, but neuronal integration occurred only after it was discontinued. Also, the treatment ameliorated deficits in spatial learning and memory retention observed in irradiated mice. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with microtubule stabilization, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced loss of hippocampal neurogenesis and cognitive impairment even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.

Hyperbaric oxygen as an adjuvant treatment for patients with COVID-19 severe hypoxaemia: a randomised controlled trial.

BACKGROUND: Hyperbaric oxygen (HBO2) therapy has been proposed to treat hypoxaemia and reduce inflammation in COVID-19. Our objective was to analyse safety and efficacy of HBO2 in treatment of hypoxaemia in patients with COVID-19 and evaluate time to hypoxaemia correction. METHODS: This was a multicentre, open-label randomised controlled trial conducted in Buenos Aires, Argentina, between July and November 2020. Patients with COVID-19 and severe hypoxaemia (SpO2 ≤90% despite oxygen supplementation) were assigned to receive either HBO2 treatment or the standard treatment for respiratory symptoms for 7 days. HBO2 treatment was planned for ≥5 sessions (1 /day) for 90 min at 1.45 atmosphere absolute (ATA). Outcomes were time to normalise oxygen requirement to SpO2 ≥93%, need for mechanical respiratory assistance, development of acute respiratory distress syndrome and mortality within 30 days. A sample size of 80 patients was estimated, with a planned interim analysis after determining outcomes on 50% of patients. RESULTS: The trial was stopped after the interim analysis. 40 patients were randomised, 20 in each group, age was 55.2±9.2 years. At admission, frequent symptoms were dyspnoea, fever and odynophagia; SpO2 was 85.1%±4.3% for the whole group. Patients in the treatment group received an average of 6.2±1.2 HBO2 sessions. Time to correct hypoxaemia was shorter in treatment group versus control group; median 3 days (IQR 1.0-4.5) versus median 9 days (IQR 5.5-12.5), respectively (p<0.010). OR for recovery from hypoxaemia in the HBO2 group at day 3 compared with the control group was 23.2 (95% CI 1.6 to 329.6; p=0.001) Treatment had no statistically significant effect on acute respiratory distress syndrome, mechanical ventilation or death within 30 days after admission. CONCLUSION: Our findings support the safety and efficacy of HBO2 in the treatment of COVID-19 and severe hypoxaemia. TRIAL REGISTRATION NUMBER: NCT04477954.

Benznidazole in Cerebrospinal Fluid: a Case Series of Chagas Disease Meningoencephalitis in HIV-Positive Patients.

Chagas disease reactivation in HIV-positive people is an opportunistic infection with 79 to 100% mortality. It commonly involves the central nervous system (CNS). Early treatment with trypanocidal drugs such as benznidazole (BNZ) is crucial for this severe manifestation of Trypanosoma cruzi infection. However, limited BNZ clinical pharmacology data are available, especially its concentration in the CNS. We report a series of HIV-positive patients undergoing treatment for T. cruzi meningoencephalitis, their clinical response, and cerebrospinal fluid (CSF) and plasma BNZ concentrations. Measurements were carried out using leftover samples originally obtained for routine medical care. A high-performance liquid chromatography/tandem mass spectrometry bioanalytical method designed for BNZ plasma measurements was adapted and validated for CSF samples. Six patients were enrolled in this study from 2015 to 2019. A total of 6 CSF and 19 plasma samples were obtained. Only three of the CSF samples had detectable BNZ levels, all under 1 µg/ml. Fifteen plasma samples had detectable BNZ, and 13 were above 2 µg/ml, which is the putative trypanocidal level. We observed BNZ concentrations in human CSF and plasma. CSF BNZ concentrations were low or not measurable in all patients, suggesting that the usual BNZ doses may be suboptimal in HIV-positive patients with T. cruzi meningoencephalitis. While drug-drug and drug-disease interactions may be in part responsible, the factors leading to low CSF BNZ levels remain to be studied in detail. These findings highlight the potential of therapeutic drug monitoring in BNZ treatment and suggest that the use of higher doses may be useful for Chagas disease CNS reactivations.

Exploring the role of climatic niche changes in the evolution of the southern South American genus Baripus (Coleoptera: Carabidae): optimization of non-hereditary climatic variables and phylogenetic signal measurement.

Baripus is a ground beetle genus endemic to southern South America, currently distributed across grassland and shrub habitats in mountain and lowland regions. The species of this genus are known to have been affected by the Andean orogeny and the climate changes that occurred during this process. In this study, we seek to understand how the orogeny of the Andes may have led to changes in the climatic niches of the species of Baripus over time. We integrated former ecological and historical biogeographic hypotheses, exploring the use of parsimony optimization of phylogenetically structured climate variables and ancestral character state reconstruction methods. We then performed regression analyses of the optimized climatic niche variables within the phylogenetic tree of Baripus. We were able to infer significant climatic niche constraints, and niche changes that provide new insights to the existing knowledge, supporting former ecological and biogeographic hypotheses for this genus. Such trends in climatic niche could be explained by the rain shadow effect caused by the Andean uplift as well as with other climate shifts associated with temperature and precipitation swings that occurred in this region from the Middle Miocene to the Pliocene.

Is hepatitis C direct-acting antiviral therapy a risk factor for the development and recurrence of hepatocellular carcinoma? Narrative literature review and clinical practice recommendations.

The development of direct-acting antivirals (DAAs) has been a turning point in chronic hepatitis C treatment. With an efficacy rate on viral eradication close to 100% and an excellent safety profile, they have replaced interferon-based treatments as first-line therapy for hepatitis C virus (HCV). Following the encouraging results observed during the first years with these treatments, new publications suggested an unexpectedly high incidence of hepatocellular carcinoma (HCC) in patients previously treated with DAAs as well as a higher HCC recurrence rate in them. The possible interaction between DAAs and HCC and its impact on HCC incidence and recurrence still remains controversial. The aim of the present work is to review the current state of the matter by analyzing studies that evaluate the association between chronic hepatitis C treatment with DAAs and the development of HCC either de novo or as a recurrence. Following this, clinical practice recommendations are done.

[Intra-abdominal infections. Update and recommendations]. / Infecciones intraabdominales. Puesta al día y recomendaciones de la Sociedad Argentina de Infectología.

Intra-abdominal infections represent a group of intra and retroperitoneal processes, ranging from localized infections to complicated ones, sepsis and septic shock, associated with a significant mortality rate. They are the third most commonly identified cause of sepsis and the second cause of death in the intensive care unit. Although antimicrobial therapy must be started as soon as possible, especially in critically ill patients, the source control procedure is highly relevant. On account of the importance of this subject, members of the Argentine Society of Infectious Diseases (SADI) and intensive care specialists joined to develop recommendations on diagnosis, treatment, and prevention of intra-abdominal infections. The literature published within the last 10 years was reviewed and analyzed, in addition of expert opinions and local data. This statement provides a basic tool for diagnosis based on clinical and microbiological criteria, orientation on empirical antimicrobial therapy schemes according to source, acquisition place (community or healthcare associated infections), infection severity, treatment duration, importance of source control, and preventive measures aimed to reduce surgical site infection risk. Likewise, it provides a simple algorithm for diagnosis and treatment for use in clinical practice. The work reveals the concern about the management of intra-abdominal infections, establishing local guidelines to optimize diagnosis, treatment and prevention, with the aim of reducing morbidity, mortality, length of stay, costs and antimicrobial resistance.

Unbiased expression mapping identifies a link between the complement and cholinergic systems in the rat central nervous system.

The complement system is activated in a wide spectrum of CNS diseases and is suggested to play a role in degenerative phenomena such as elimination of synaptic terminals. Still, little is known of mechanisms regulating complement activation in the CNS. Loss of synaptic terminals in the spinal cord after an experimental nerve injury is increased in the inbred DA strain compared with the PVG strain and is associated with expression of the upstream complement components C1q and C3, in the absence of membrane attack complex activation and neutrophil infiltration. To further dissect pathways regulating complement expression, we performed genome-wide expression profiling and linkage analysis in a large F2(DA × PVG) intercross, which identified quantitative trait loci regulating expression of C1qa, C1qb, C3, and C9. Unlike C1qa, C1qb, and C9, which all displayed distinct coregulation with different cis-regulated C-type lectins, C3 was regulated in a coexpression network immediately downstream of butyrylcholinesterase. Butyrylcholinesterase hydrolyses acetylcholine, which exerts immunoregulatory effects partly through TNF-α pathways. Accordingly, increased C3, but not C1q, expression was demonstrated in rat and mouse glia following TNF-α stimulation, which was abrogated in a dose-dependent manner by acetylcholine. These findings demonstrate new pathways regulating CNS complement expression using unbiased mapping in an experimental in vivo system. A direct link between cholinergic activity and complement activation is supported by in vitro experiments. The identification of distinct pathways subjected to regulation by naturally occurring genetic variability is of relevance for the understanding of disease mechanisms in neurologic conditions characterized by neuronal injury and complement activation.

Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response.

BACKGROUND: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. METHODS: Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2 (-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. RESULTS: Expression of Cr2 in naïve spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. CONCLUSIONS: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.

Variability in C-type lectin receptors regulates neuropathic pain-like behavior after peripheral nerve injury.

INTRODUCTION: Neuropathic pain is believed to be influenced in part by inflammatory processes. In this study we examined the effect of variability in the C-type lectin gene cluster (Aplec) on the development of neuropathic pain-like behavior after ligation of the L5 spinal nerve in the inbred DA and the congenic Aplec strains, which carries seven C-type lectin genes originating from the PVG strain. RESULTS: While both strains displayed neuropathic pain behavior early after injury, the Aplec strain remained sensitive throughout the whole study period. Analyses of several mRNA transcripts revealed that the expression of Interleukin-1ß, Substance P and Cathepsin S were more up-regulated in the dorsal part of the spinal cord of Aplec rats compared to DA, indicating a stronger inflammatory response. This notion was supported by flow cytometric analysis revealing increased infiltration of activated macrophages into the spinal cord. In addition, macrophages from the Aplec strain stimulated in vitro displayed higher expression of inflammatory cytokines compared to DA cells. Finally, we bred a recombinant congenic strain (R11R6) comprising only four of the seven Aplec genes, which displayed similar clinical and immune phenotypes as the Aplec strain. CONCLUSION: We here for the first time demonstrate that C-type lectins, a family of innate immune receptors with largely unknown functions in the nervous system, are involved in regulation of inflammation and development of neuropathic pain behavior after nerve injury. Further experimental and clinical studies are needed to dissect the underlying mechanisms more in detail as well as any possible relevance for human conditions.

Genetic variability in the rat Aplec C-type lectin gene cluster regulates lymphocyte trafficking and motor neuron survival after traumatic nerve root injury.

BACKGROUND: C-type lectin (CLEC) receptors are important for initiating and shaping immune responses; however, their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. The antigen-presenting lectin-like receptor gene complex (Aplec) contains a few CLEC genes, which differ genetically among inbred rat strains. It was originally thought to be a region that regulates susceptibility to autoimmune arthritis, autoimmune neuroinflammation and infection. METHODS: The inbred rat strains DA and PVG differ substantially in degree of spinal cord motor neuron death following ventral root avulsion (VRA), which is a reproducible model of localized nerve root injury. A large F2 (DAxPVG) intercross was bred and genotyped after which global expressional profiling was performed on spinal cords from F2 rats subjected to VRA. A congenic strain, Aplec, created by transferring a small PVG segment containing only seven genes, all C-type lectins, ontoDA background, was used for further experiments together with the parental strains. RESULTS: Global expressional profiling of F2 (DAxPVG) spinal cords after VRA and genome-wide eQTL mapping identified a strong cis-regulated difference in the expression of Clec4a3 (Dcir3), a C-type lectin gene that is a part of the Aplec cluster. Second, we demonstrate significantly improved motor neuron survival and also increased T-cell infiltration into the spinal cord of congenic rats carrying Aplec from PVG on DA background compared to the parental DA strain. In vitro studies demonstrate that the Aplec genes are expressed on microglia and upregulated upon inflammatory stimuli. However, there were no differences in expression of general microglial activation markers between Aplec and parental DA rats, suggesting that the Aplec genes are involved in the signaling events rather than the primary activation of microglia occurring upon nerve root injury. CONCLUSIONS: In summary, we demonstrate that a genetic variation in Aplec occurring among inbred strains regulates both survival of axotomized motor neurons and the degree of lymphocyte infiltration. These results demonstrate a hitherto unknown role for CLECs for intercellular communication that occurs after damage to the nervous system, which is relevant for neuronal survival.

[Invasive aspergillosis: definitions, diagnosis, and treatment]. / Aspergilosis invasiva: definiciones, diagnóstico y tratamiento.

Invasive aspergillosis (IA) is a serious disease with high mortality. There are several risk factors and in-hospital outbreaks related with construction have been described. An entity related to COVID-19 infection, known as COVID-19 associated pulmonary aspergillosis (CAPA), has recently appeared. Early and appropriate treatment is of paramount importance, especially in immunocompromised and critically ill patients. Diagnosis is based on recognition of predisposing factors, clinical signs, imaging, direct examination, culture, histopathology, and biomarkers such as galactomannan. The drug of choice is voriconazole, but alternative therapies must be taken into account given the increasing presence of resistant isolates.

La aspergilosis invasiva (AI) es una enfermedad grave y con alta mortalidad. Existen factores de riesgo y se describen brotes intrahospitalarios relacionados con construcciones. También se describe una entidad relacionada con la infección por COVID-19, conocida como aspergilosis pulmonar asociada a COVID-19 (APAC). Es de vital importancia implementar un tratamiento adecuado y precoz, especialmente en pacientes inmunocomprometidos y críticamente enfermos. El diagnóstico se basa en reconocer los factores predisponentes, la clínica, la obtención de imágenes, exámenes directos, cultivos, histopatología y biomarcadores como el galactomanano. La droga de elección es el voriconazol, pero se deben conocer las alternativas terapéuticas dada la creciente presencia de aislamientos resistentes.

[A case of monkeypox in intensive care in Argentina]. / Un caso de viruela símica en cuidados intensivos en Argentina.

Monkey pox is a rare zoonotic disease. It was first described in humans in Africa in 1970. On July 23, 2022, in view of the increasing number of cases reported in several countries and territories, the World Health Organization (WHO) concluded that the global outbreak constitutes a public health emergency of international concern. In our country, the first case was reported on May 22, 2022 and up to November 22 of this year, 895 patients were reported. We describe here the first case registered in Argentina requiring intensive care, according to the Epidemiological Bulletin, 46th epidemiological week, National Ministry of Health. The patient was a 44-year-old man with acquired immunodeficiency syndrome and severe Monkeypox, who presented obstructive ventilatory failure due to airway compromise and extensive generalized lesions of the integument, genitalia and fauces. In conclusion, the case presented alerts about potential complications that may require critical care and risk the patient's life.

La viruela símica es una enfermedad zoonótica poco frecuente. Fue descripta en humanos por primera vez en África en 1970. El 23 de julio del 2022, ante la cantidad ascendente de casos notificados en diversos países y territorios, la Organización Mundial de la Salud (OMS) concluyó que el brote mundial constituye una emergencia de salud pública de importancia internacional. En nuestro país el primer caso se notificó el 22 de mayo de 2022 hasta el 22 de noviembre se confirmaron 895 casos. Describimos el primer caso registrado en Argentina, según el boletín epidemiológico de la semana epidemiológica 46, del Ministerio de Salud de la Nación con requerimiento de cuidados intensivos. Se trata de un hombre de 44 años con síndrome de inmunodeficiencia adquirida y viruela símica grave, que presentó insuficiencia ventilatoria obstructiva, por compromiso de vías aéreas y lesiones generalizadas extensas de tegumento, genitales y fauces. En conclusión, el caso presentado alerta sobre las potenciales complicaciones que pueden requerir cuidados críticos y poner en riesgo la vida del paciente.

[Clostridium tertium bacteremia in patient with liver cirrhosis]. / Bacteriemia por Clostridium tertium en un paciente con cirrosis hepática.

Clostridium tertium is a bacterium of the Clostridiaceae family which can be found colonizing the gastrointestinal tract. Unlike other members of its family, it does not produce exotoxins. It was described for the first time in 1917 and in 1963 it was established as a pathogen in humans. Since then, cases have been reported mainly in immunosuppressed hosts, predominantly with primary focus at the abdominal level. The case of a 48-year-old man with a history of cirrhosis and hepatitis C virus infection is described. He presented an obstructed umbilical hernia that required intestinal resection and anastomosis, with positive blood and abdominal fluid cultures for Clostridium tertium. This case is of clinical importance due to the low prevalence of this germ, the possibility of resistance to usual antibiotic regimens and its sub diagnostic given the morphological and growth similarities with Bacillus or Lactobacillus.

Clostridium tertium es una bacteria de la familia Clostridiaceae que se puede encontrar colonizando el tracto gastrointestinal. A diferencia de otros miembros de su familia, no produce exotoxinas. Fue descripto por primera vez en 1917 y en el año 1963 se pudo establecer como patógeno en humanos. Desde entonces, se han reportado casos principalmente en huéspedes inmunosuprimidos, prevalentemente con foco primario abdominal. Se describe el caso de un hombre de 48 años de edad con antecedentes de cirrosis e infección por virus de la hepatitis C, presentó una hernia umbilical atascada que requirió resección y anastomosis intestinal, con cultivos de líquido abdominal y hemocultivos positivos para Clostridium tertium. Este caso es de importancia clínica por la baja prevalencia de este germen, la posibilidad de resistencia a los esquemas antibióticos usuales y de subdiagnóstico del microorganismo dada su similitud morfológica y de crecimiento con Bacillus o Lactobacillus.

Acute colonic pseudo-obstruction syndrome in patients with severe COVID-19 in Buenos Aires, Argentina.

BACKGROUND: Several gastrointestinal complications have been reported in patients with COVID-19, including motility disorders, such as acute colonic pseudo-obstruction (ACPO). This affection is characterized by colonic distention in the absence of mechanical obstruction. ACPO in the context of severe COVID-19 may be related to neurotropism and direct damage of SARS-CoV-2 in enterocytes. METHOD: We conducted a retrospective study of patients who were hospitalized for critical COVID-19 and developed ACPO between March 2020 and September 2021. The diagnostic criteria to define ACPO was the presence of 2 or more of the following: abdominal distension, abdominal pain, and changes in the bowel movements, associated with distension of the colon in computed tomography. Data of sex, age, past medical history, treatment, and outcomes were collected. RESULTS: Five patients were detected. All required admission to the Intensive Care Unit. The ACPO syndrome developed with a mean of 33.8 days from the onset of symptoms. The mean duration of the ACPO syndrome was 24.6 days. The treatment included colonic decompression with placement of rectal and nasogastric tubes, endoscopy decompression in two patients, bowel rest, fluid, and electrolytes replacement. One patient died. The remaining resolved the gastrointestinal symptoms without surgery. CONCLUSIONS: ACPO is an infrequent complication in patients with COVID-19. It occurs especially in patients with critical condition, who require prolonged stays in intensive care and multiple pharmacological treatments. It is important to recognize its presence early and thus establish an appropriate treatment, since the risk of complications is high.

Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy.

Microglial phagocytosis of apoptotic debris prevents buildup damage of neighbor neurons and inflammatory responses. Whereas microglia are very competent phagocytes under physiological conditions, we report their dysfunction in mouse and preclinical monkey models of stroke (macaques and marmosets) by transient occlusion of the medial cerebral artery (tMCAo). By analyzing recently published bulk and single cell RNA sequencing databases, we show that the phagocytosis dysfunction was not explained by transcriptional changes. In contrast, we demonstrate that the impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrient deprivation (OND), which led to reduced process motility, lysosomal exhaustion, and the induction of a protective macroautophagy/autophagy response in microglia. Basal autophagy, in charge of removing and recycling intracellular elements, was critical to maintain microglial physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using pharmacological and transgenic approaches. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro, where it even had a detrimental effect on microglia, suggesting that modulating microglial autophagy to optimal levels may be a hard to achieve goal. Nonetheless, our results show that pharmacological interventions, acting directly on microglia or indirectly on the brain environment, have the potential to recover phagocytosis efficiency in the diseased brain. We propose that phagocytosis is a therapeutic target yet to be explored in stroke and other brain disorders and provide evidence that it can be modulated in vivo using rapamycin.Abbreviations: AIF1/IBA1: allograft inflammatory factor 1; AMBRA1: autophagy/beclin 1 regulator 1; ATG4B: autophagy related 4B, cysteine peptidase; ATP: adenosine triphosphate; BECN1: beclin 1, autophagy related; CASP3: caspase 3; CBF: cerebral blood flow; CCA: common carotid artery; CCR2: chemokine (C-C motif) receptor 2; CIR: cranial irradiation; Csf1r/v-fms: colony stimulating factor 1 receptor; CX3CR1: chemokine (C-X3-C motif) receptor 1; DAPI: 4',6-diamidino-2-phenylindole; DG: dentate gyrus; GO: Gene Ontology; HBSS: Hanks' balanced salt solution; HI: hypoxia-ischemia; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MCA: medial cerebral artery; MTOR: mechanistic target of rapamycin kinase; OND: oxygen and nutrient deprivation; Ph/A coupling: phagocytosis-apoptosis coupling; Ph capacity: phagocytic capacity; Ph index: phagocytic index; SQSTM1: sequestosome 1; RNA-Seq: RNA sequencing; TEM: transmission electron microscopy; tMCAo: transient medial cerebral artery occlusion; ULK1: unc-51 like kinase 1.

Multipotent mesenchymal stromal cells attenuate chronic inflammation and injury-induced sensitivity to mechanical stimuli in experimental spinal cord injury.

PURPOSE: Previous reports established that after a contusion injury to the rat spinal cord, locomotor function was enhanced by the transplantation of cells from bone marrow referred to as either mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). It has also been established that neural stem cells (NSCs) enhance locomotor function after transplantation into the injured rat spinal cord. However, the beneficial effects of NSCs are limited by graft-induced allodynia-like responses. Little is known about the effects of MSCs on sensory function in spinal cord injury. Therefore, the objective of this research was to determine whether transplantation of MSCs into the injured rat spinal cord induces allodynia-like responses. METHODS: Contusion injuries of two different severities were induced in rats to examine the effects of transplantation with MSCs on sensorimotor deficits. The effects of MSCs on chronic inflammation were investigated, since inflammation is reported to have a role in the sensorimotor deficits associated with spinal cord injury. In addition, observations in other models suggest that MSCs possess immunosuppressive effects. RESULTS: We found that in contrast to previous observations with the transplantation of neural stem cells, transplantation of MSCs did not induce allodynia. MSCs attenuated injury-induced sensitivity to mechanical stimuli but had no effect on injury-induced sensitivity to cold stimuli. MSCs also significantly attenuated the chronic inflammatory response as assayed by GFAP immunoreactivity for reactive astrocytes and ED1 immunoreactivity for activated macrophages/microglia. In addition, transplantation of MSCs increased white matter volumes and decreased cyst size in sections of the cord containing the lesion. CONCLUSION: The results suggest that the sensorimotor enhancements produced by MSCs can at least in part be explained by anti-inflammatory/immunosuppressive effects of the cells, similar to such effects of these cells observed in other experimental models.

The Secretome of Microglia Regulate Neural Stem Cell Function.

Brain injury is associated with neuroinflammation, and microglia are key players in this process. Microglia can acquire pro-inflammatory or anti-inflammatory properties, but how this affects neural stem cells (NSCs) remains controversial. Here, NSCs were grown in conditioned media collected from either non-stimulated microglia, or microglia stimulated with pro- or anti-inflammatory agents. NSC survival, proliferation, migration, and differentiation were investigated thereafter. We found that NSCs kept in conditioned medium from the anti-inflammatory microglial subtype had better survival, increased migration, and lower astrocytic differentiation compared to NSCs grown in conditioned medium collected from the pro-inflammatory subtype. Finally, we found that NSCs differentiated in microglial conditioned media generated cells expressing the pro-inflammatory chemokine CCL2, most pronounced when differentiated in medium from the pro-inflammatory microglia subtype. Our results show that microglial subtypes regulate NSCs differently and induce generation of cells with inflammatory properties.

Both MHC and non-MHC genes regulate development of experimental neuropathic pain in rats.

We have previously demonstrated that differences in neuropathic pain-like behaviors after sciatic nerve injury genetically maps to the major histocompatibility complex (MHC) in rats carrying RT1(c) or RT1(av1) haplotypes on the Piebald Virol Glaxo (PVG) background. In order to further explore the genetic contribution to neuropathic pain, we have here examined the MHC-congenic rat strains PVG-RT1(n) and PVG-RT1(av1) and the inbred strains PVG (RT1(c)) and Brown-Norway (BN; RT1(n)). All studied strains developed mechanical hypersensitivity (allodynia-like behavior) of the hind paw after photochemically induced sciatic nerve injury. However, the PVG-RT1(n) and PVG strains displayed significantly more allodynia than PVG-RT1(av1) and BN rats. In addition, the BN strain demonstrated an elevated threshold for the baseline response. The results demonstrate that both MHC and non-MHC genes influence experimental neuropathic pain in rats and also suggest that allelic variation contained in the RT1(av1) haplotype on the PVG background protects against neuropathic pain.

Contrasting genetic effects of major histocompatibility complex on ischemic peripheral nerve and spinal cord injury in female rats.

We have recently shown that the major histocompatibility complex (MHC) exerts a regulatory influence on the development of neuropathic pain-like behaviors after partial sciatic nerve injury in male rats. In the present study, we assessed the role of the MHC in peripheral nerve injury-induced pain as well as central pain following spinal cord injury in female rats using the following inbred strains: Dark Agouti (DA; RT1(av1)), Piebald Virol Glaxo (PVG; RT1(c)) and in the MHC-congenic strain PVG-RT1(av1). In line with our previous observation in male rats, PVG-RT1(c) displayed more severe allodynia compared to the strains carrying the RT1(av1) haplotype (PVG-RT1(av1) and DA-RT1(av1)) following sciatic nerve injury in female rats. However, the MHC did not seem to impact the development of allodynia following spinal cord injury since the two congenic strains PVG-RT1(c) and PVG-RT1(av) did not differ after spinal cord injury. Interestingly, the DA-RT1(av1) strain displayed significantly more severe allodynia than both PVG strains and this difference was not explained by the extent of spinal cord injury. These results suggest that there are differences in the genetic mechanisms for neuropathic pain development following peripheral or central nervous system injury, both in regarding to the role of the MHC complex as well as non-MHC genes.