Next generation imidazothiazole and imidazooxazole derivatives as potential drugs against brain-eating amoebae.

Managing primary amoebic meningoencephalitis, induced by Naegleria fowleri poses a complex medical challenge. There is currently no specific anti-amoebic drug that has proven effectiveness against N. fowleri infection. Ongoing research endeavours are dedicated to uncovering innovative treatment strategies, including the utilization of drugs and immune modulators targeting Naegleria infection. In this study, we explored the potential of imidazo[2,1-b]thiazole and imidazooxazole derivatives that incorporate sulfonate and sulfamate groups as agents with anti-amoebic properties against N. fowleri. We assessed several synthesized compounds (1f, 1m, 1q, 1s, and 1t) for their efficacy in eliminating amoebae, their impact on cytotoxicity, and their influence on the damage caused to human cerebral microvascular endothelial (HBEC-5i) cells when exposed to the N. fowleri (ATCC 30174) strain. The outcomes revealed that, among the five compounds under examination, 1m, 1q, and 1t demonstrated notable anti-parasitic effects against N. fowleri (P ≤ 0.05). Compound 1t exhibited the highest anti-parasitic activity, reducing N. fowleri population by 80%. Additionally, three compounds, 1m, 1q, and 1t, significantly mitigated the damage inflicted on host cells by N. fowleri. However, the results of cytotoxicity analysis indicated that while 1m and 1q had minimal cytotoxic effects on endothelial cells, compound 1t caused moderate cytotoxicity (34%). Consequently, we conclude that imidazo[2,1-b]thiazole and imidazooxazole derivatives containing sulfonate and sulfamate groups exhibit a marked capacity to eliminate amoebae viability while causing limited toxicity to human cells. In aggregate, these findings hold promise that could potentially evolve into novel therapeutic options for treating N. fowleri infection.

A rare case of cerebral phaeohyphomycosis caused by Fonsecaea species in a renal transplant patient.

Cerebral phaeohyphomycosis (CP) is a serious form of phaeohyphomycosis. We report a case of CP caused by Fonsecaea species in a 66-year-old immunocompromised renal transplant recipient female. Craniotomy was performed on an irregularly enhancing right cerebellar hemisphere lesion and abscess and tissue samples collected for microbiological and histological evaluation, showing fungal elements and Fonsecaea species was isolated. Antifungal treatment with voriconazole & liposomal amphotericin B was initiated with a temporary improvement in the patient's condition. Deep vein thrombosis jeopardized patient's prognosis. Despite aggressive surgical and medical intervention, our patient succumbed to the disease. Historically, CP has been linked with fatality rates as high as 65 %, despite surgical intervention and systemic antifungal medication.

In Vivo and In Vitro Characterization of the Recently Emergent PRRSV 1-4-4 L1C Variant (L1C.5) in Comparison with Other PRRSV-2 Lineage 1 Isolates.

The recently emerged PRRSV 1-4-4 L1C variant (L1C.5) was in vivo and in vitro characterized in this study in comparison with three other contemporary 1-4-4 isolates (L1C.1, L1A, and L1H) and one 1-7-4 L1A isolate. Seventy-two 3-week-old PRRSV-naive pigs were divided into six groups with twelve pigs/group. Forty-eight pigs (eight/group) were for inoculation, and 24 pigs (four/group) served as contact pigs. Pigs in pen A of each room were inoculated with the corresponding virus or negative media. At two days post inoculation (DPI), contact pigs were added to pen B adjacent to pen A in each room. Pigs were necropsied at 10 and 28 DPI. Compared to other virus-inoculated groups, the L1C.5-inoculated pigs exhibited more severe anorexia and lethargy, higher mortality, a higher fraction of pigs with fever (>40 °C), higher average temperature at several DPIs, and higher viremia levels at 2 DPI. A higher percentage of the contact pigs in the L1C.5 group became viremic at two days post contact, implying the higher transmissibility of this virus strain. It was also found that some PRRSV isolates caused brain infection in inoculation pigs and/or contact pigs. The complete genome sequences and growth characteristics in ZMAC cells of five PRRSV-2 isolates were further compared. Collectively, this study confirms that the PRRSV 1-4-4 L1C variant (L1C.5) is highly virulent with potential higher transmissibility, but the genetic determinants of virulence remain to be elucidated.

Cerebral Abscess Due to Nocardia beijingensis Associated With HIV: Case Report and Mini Review.

Brain abscesses are severe focal infections of the central nervous system. We report the case of a 37-year-old patient with a recent diagnosis of HIV, who presented with weakness in the left arm that progressed to left hemiplegia, ipsilateral paresthesia, holo cranial headache, fever accompanied by chills, and left tonic-clonic movements. A craniectomy and lesion resection were performed along with antimicrobial treatment. Subsequently, the patient persisted with left hemiplegia, which significantly improved after the procedure and gradually through physical physiotherapy. During the investigation, we complete medical history, physical examination, Image tests, laboratory tests, and cultures. After the finalization of the approach, the final diagnosis was a brain abscess due to Nocardia beijingensis associated with HIV. The patient was managed with anticonvulsants: levetiracetam, antimicrobials: ceftriaxone, trimethoprim/sulfamethoxazole, metronidazole, and vancomycin, Craniotomy plus resection of two brain abscesses, Steroidal anti-inflammatory: dexamethasone and antiretroviral therapy. With this, the patient was discharged successfully from the hospital.

Peculiar Case of Brain Abscess Caused by Propionibacterium acnes in an Immunocompetent Individual Without Prior Neurosurgical Intervention: A Case Report and Literature Review.

Propionibacterium acnes (P. acnes) is a slow-growing, anaerobic, gram-positive bacillus that commonly colonizes the skin and is a rare cause of CNS infections. It was previously viewed as a culture contaminant but is now recognized to infrequently cause indolent cases of CNS infections. It is even more rarely associated with abscesses in patients without a prior history of neurosurgical intervention. Due to being a slow-growing bacteria, P. acnes is frequently discovered to be the causative organism after 16S rRNA sequencing. In this case, the culture was positive. There are only five other reported cases of patients with a P. acnes abscess without prior neurosurgical intervention. Here we present the sixth case of an immunocompetent young male who was found to have a P. acnes brain abscess.

Disseminated Nocardia Brain Abscess Presenting as Primary Lung Cancer With Brain Metastasis.

We present a challenging case of disseminated Nocardia brasiliensis infection manifesting as brain and skin abscesses. Nocardia is an important potential pathogen to consider in patients with a relevant travel history to endemic regions or atypical presentations, such as brain and skin abscesses. About one-third of patients with Nocardia infections are immunocompetent, and their symptoms are nonspecific. This case shows the limitations of imaging studies in diagnosing Nocardia brain abscesses, as the patient's non-magnetic resonance (MR) conditional pacemaker precluded MRI evaluation and led to a diagnostic challenge. Therefore, the patient's initial evaluation was presumed to be primary lung cancer with brain metastasis. High clinical suspicion, imaging studies (especially MRI), and tissue biopsy are needed to diagnose this type of brain abscess in a timely manner to prevent further complications.

Palmitoylethanolamide shows limited efficacy in controlling cerebral cryptococcosis in vivo.

Cryptococcus neoformans (Cn) is an encapsulated neurotropic fungal pathogen and the causative agent of cryptococcal meningoencephalitis (CME) in humans. Recommended treatment for CME is Amphotericin B (AmpB) and 5-fluorocytosine (5-FC). Though effective, AmpB has displayed numerous adverse side effects due to its potency and nephrotoxicity, prompting investigation into alternative treatments. Palmitoylethanolamide (PEA) is an immunomodulatory compound capable of promoting neuroprotection and reducing inflammation. To investigate the efficacy of PEA as a therapeutic alternative for CME, we intracerebrally infected mice with Cn and treated them with PEA or AmpB alone or in combination. Our results demonstrate that PEA alone does not significantly prolong survival nor reduce fungal burden, but when combined with AmpB, PEA exerts an additive effect and promotes both survivability and fungal clearance. However, we compared this combination to traditional AmpB and 5-FC treatment in a survivability study and observed lower efficacy. Overall, our study revealed that PEA alone is not effective as an antifungal agent in the treatment of CME. Importantly, we describe the therapeutic capability of PEA in the context of Cn infection and show that its immunomodulatory properties may confer limited protection when combined with an effective fungicidal agent.

Modelling host- Trypanosoma brucei gambiense interactions in vitro using human induced pluripotent stem cell-derived cortical brain organoids.

Background: Sleeping sickness is caused by the extracellular parasite Trypanosoma brucei and is associated with neuroinflammation and neuropsychiatric disorders, including disruption of sleep/wake patterns, and is now recognised as a circadian disorder. Sleeping sickness is traditionally studied using murine models of infection due to the lack of alternative in vitro systems that fully recapitulate the cellular diversity and functionality of the human brain. The aim of this study is to develop a much-needed in vitro system that reduces and replaces live animals for the study of infections in the central nervous system, using sleeping sickness as a model infection. Methods: We developed a co-culture system using induced pluripotent stem cell (iPSC)-derived cortical human brain organoids and the human pathogen T. b. gambiense to model host-pathogen interactions in vitro. Upon co-culture, we analysed the transcriptional responses of the brain organoids to T. b. gambiense over two time points. Results: We detected broad transcriptional changes in brain organoids exposed to T. b. gambiense, mainly associated with innate immune responses, chemotaxis, and blood vessel differentiation compared to untreated organoids. Conclusions: Our co-culture system provides novel, more ethical avenues to study host-pathogen interactions in the brain as alternative models to experimental infections in mice. Although our data support the use of brain organoids to model host-pathogen interactions during T. brucei infection as an alternative to in vivo models, future work is required to increase the complexity of the organoids ( e.g., addition of microglia and vasculature). We envision that the adoption of organoid systems is beneficial to researchers studying mechanisms of brain infection by protozoan parasites. Furthermore, organoid systems have the potential to be used to study other parasites that affect the brain significantly reducing the number of animals undergoing moderate and/or severe protocols associated with the study of neuroinflammation and brain infections.

Encephalitis and myositis caused by Trachipleistophora hominis diagnosed by metagenomic next-generation sequencing-a case report.

Background: Myositis is the main manifestation of Trachipleistophora hominis (T. hominis) infection and other microsporidians infection in immunocompromised patients. Clinical differential diagnosis of different microsporidians can be challenging, as the standard technique to distinguish various microsporidia species, transmission electron microscopy (TEM), is time-consuming and relies on equipment and experienced staffs who can perform the test and interpret the results. Case presentation: We report a 37-year-old Chinese man with acquired immune deficiency syndrome (AIDS) developed headache and muscle pain in the extremities. Tramadol was used to relieve his pain. Infectious lesions in his brain were detected by cerebral magnetic resonance imaging (MRI). Oval-shaped pathogens was observed by biopsy of right gastrocnemius. Finally, T. hominis was identified by metagenomic next-generation sequencing (mNGS) in the gastrocnemius tissue and cerebrospinal fluid. After a 12-week course of antifungal treatment and antiretroviral therapy, the patient recovered from the encephalitis and myositis caused by T. hominis. Conclusion: This report described the diagnosis and treatment of the first case of encephalitis caused by T. hominis. And mNGS is recommended for the rapid diagnosis of uncommon pathogens.

Population Pharmacokinetic Modeling of Free Plasma and Free Brain Concentrations of Ceftaroline in Healthy and Methicillin-Resistant Staphylococcus aureus-Infected Wistar Rats.

A population pharmacokinetic model was developed to describe alterations in ceftaroline brain disposition caused by meningitis in healthy and methicillin-resistant Staphylococcus aureus (MRSA)-infected rats. Blood and brain microdialysate samples were obtained after a single bolus dose of ceftaroline fosamil (20 mg/kg) administered intravenously. Plasma data were modeled as one compartment, and brain data were added to the model as a second compartment, with bidirectional drug transport between plasma and brain (Qin and Qout). The cardiac output (CO) of the animals showed a significant correlation with the relative recovery (RR) of plasma microdialysis probes, with animals with greater CO presenting lower RR values. The Qin was approximately 60% higher in infected animals, leading to greater brain exposure to ceftaroline. Ceftaroline brain penetration was influenced by MRSA infection, increasing from 17% (Qin/Qout) in healthy animals to 27% in infected animals. Simulations of a 2-h intravenous infusion of 50 mg/kg every 8 h achieved >90% probability of target attainment (PTA) in plasma and brain for the modal MRSA MIC (0.25 mg/L), suggesting that the drug should be considered an option for treating central nervous system infections.

Chronic Toxoplasma gondii infection contributes to perineuronal nets impairment in the primary somatosensory cortex.

Toxoplasma gondii is able to manipulate the host immune system to establish a persistent and efficient infection, contributing to the development of brain abnormalities with behavioral repercussions. In this context, this work aimed to evaluate the effects of T. gondii infection on the systemic inflammatory response and structure of the primary somatosensory cortex (PSC). C57BL/6 and BALB/c mice were infected with T. gondii ME49 strain tissue cysts and accompanied for 30 days. After this period, levels of cytokines IFN-γ, IL-12, TNF-α and TGF-ß were measured. After blood collection, mice were perfused and the brains were submitted to immunohistochemistry for perineuronal net (PNN) evaluation and cyst quantification. The results showed that C57BL/6 mice presented higher levels of TNF-α and IL-12, while the levels of TGF-ß were similar between the two mouse lineages, associated with the elevated number of tissue cysts, with a higher occurrence of cysts in the posterior area of the PSC when compared to BALB/c mice, which presented a more homogeneous cyst distribution. Immunohistochemistry analysis revealed a greater loss of PNN labeling in C57BL/6 animals compared to BALB/c. These data raised a discussion about the ability of T. gondii to stimulate a systemic inflammatory response capable of indirectly interfering in the brain structure and function.

Applications of nanobodies in brain diseases.

Nanobodies are antibody fragments derived from camelids, naturally endowed with properties like low molecular weight, high affinity and low immunogenicity, which contribute to their effective use as research tools, but also as diagnostic and therapeutic agents in a wide range of diseases, including brain diseases. Also, with the success of Caplacizumab, the first approved nanobody drug which was established as a first-in-class medication to treat acquired thrombotic thrombocytopenic purpura, nanobody-based therapy has received increasing attention. In the current review, we first briefly introduce the characterization and manufacturing of nanobodies. Then, we discuss the issue of crossing of the brain-blood-barrier (BBB) by nanobodies, making use of natural methods of BBB penetration, including passive diffusion, active efflux carriers (ATP-binding cassette transporters), carrier-mediated influx via solute carriers and transcytosis (including receptor-mediated transport, and adsorptive mediated transport) as well as various physical and chemical methods or even more complicated methods such as genetic methods via viral vectors to deliver nanobodies to the brain. Next, we give an extensive overview of research, diagnostic and therapeutic applications of nanobodies in brain-related diseases, with emphasis on Alzheimer's disease, Parkinson's disease, and brain tumors. Thanks to the advance of nanobody engineering and modification technologies, nanobodies can be linked to toxins or conjugated with radionuclides, photosensitizers and nanoparticles, according to different requirements. Finally, we provide several perspectives that may facilitate future studies and whereby the versatile nanobodies offer promising perspectives for advancing our knowledge about brain disorders, as well as hopefully yielding diagnostic and therapeutic solutions.

Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation.

Microglia and border-associated macrophages (BAMs) are brain-resident self-renewing cells. Here, we examined the fate of microglia, BAMs, and recruited macrophages upon neuroinflammation and through resolution. Upon infection, Trypanosoma brucei parasites invaded the brain via its border regions, triggering brain barrier disruption and monocyte infiltration. Fate mapping combined with single-cell sequencing revealed microglia accumulation around the ventricles and expansion of epiplexus cells. Depletion experiments using genetic targeting revealed that resident macrophages promoted initial parasite defense and subsequently facilitated monocyte infiltration across brain barriers. These recruited monocyte-derived macrophages outnumbered resident macrophages and exhibited more transcriptional plasticity, adopting antimicrobial gene expression profiles. Recruited macrophages were rapidly removed upon disease resolution, leaving no engrafted monocyte-derived cells in the parenchyma, while resident macrophages progressively reverted toward a homeostatic state. Long-term transcriptional alterations were limited for microglia but more pronounced in BAMs. Thus, brain-resident and recruited macrophages exhibit diverging responses and dynamics during infection and resolution.

Balamuthia mandrillaris brain infection: a rare cause of a ring-enhancing central nervous system lesion. Illustrative case.

BACKGROUND: An 80-year-old man presented with subacute mental status change, dizziness, and left-sided vision loss. Magnetic resonance imaging demonstrated a ring-enhancing right parietooccipital lesion. OBSERVATIONS: Biopsy and laboratory testing demonstrated an amoebic Balamuthia mandrillaris infection. Fewer than 200 cases of this infection have been recognized in the United States, and no standardized treatment regimen currently exists. LESSONS: Rapid antimicrobial therapy with miltefosine, azithromycin, fluconazole, flucytosine, sulfadiazine, and albendazole was initiated. The pathophysiology, diagnosis, and management of this infection and the patient's course were reviewed. The importance of biopsy for pathologic and laboratory diagnosis and rapid treatment initiation with a multidisciplinary team was reinforced.

Ultrasonografía del diámetro de la vaina del nervio óptico en paciente con meningoencefalitis complicada / Ultrasonography of the optic nerve sheath diameter in patient with complicated meningoencephalitis

RESUMEN La ultrasonografía del diámetro de la vaina del nervio óptico es un método no invasivo para monitorizar la presión intracraneal. Se ha utilizado en múltiples patologías neurocríticas, incluyendo la infección complicada del sistema nervioso central. Se presenta el caso de una paciente femenina de 47 años, quien ingresó en la Unidad de Cuidados Intensivos luego de presentar progresión al estado comatoso secundario a cuadro de meningoencefalitis bacteriana. Al ingreso se constata midriasis bilateral arreactiva, ausencia parcial de reflejos del tallo encefálico y bradicardia. Ante la sospecha clínica de hipertensión intracraneal, se indica ultrasonografía del diámetro de la vaina del nervio óptico en plano axial. Se realizaron tres mediciones para cada ojo, mostrando un valor de 6,3, 6,6 y 6,00 mm en ojo derecho, y 6,8, 6,6 y 6,8 mm en el izquierdo (promedio biocular: 6,5 mm). Con esta medición se complementó el diagnóstico sospechado. Esta técnica representa un proceder seguro y no invasivo. Su uso completa los datos recogidos en el examen clínico. El punto de corte universalmente aceptado para el diagnóstico es de 5,0 mm o más para un valor de presión intracraneal > 20 mmHg.

ABSTRACT The optic nerve sheath ultrasonography is a non-invasive method for monitoring intracranial pressure. It has been used in multiple neurocritical pathologies, including the complicated infection of the central nervous system. The case of a 47-year-old female patient is presented; she was admitted to the Intensive Care Unit after presenting progression to comatose state secondary to bacterial meningoencephalitis. On admission, bilateral arreactive mydriasis, partial absence of brainstem reflexes and bradycardia are confirmed. Given the clinical suspicion of intracranial hypertension, ultrasonography of the optic nerve sheath diameter in the axial plane is indicated. Three measurements were made for each eye, showing a value of 6.3, 6.6 and 6.00 in the right eye, and 6.8, 6.6 and 6.8 in the left one (biocular average: 6.5 mm). With this measurement the suspected diagnosis was completed. This technique represents a secure and non-invasive procedure. Its use completes the data collected in the clinical examination. The universally accepted cut-off point for diagnosis is 5.0 mm or more for an intracranial pressure value of > 20 mmHg.

Brain complications from odontogenic infections: A systematic review.

PURPOSE: Odontogenic infections can spread through different routes to more remote anatomical areas, such as the brain. Brain abscesses have an incidence of 0.3-1.3 / 100,000 population and only 2-5% are of dental origin. The main objective is to research brain complications derived from odontogenic infections. Secondary objectives were to identify the most common symptoms in brain abscess, to describe the microbiology involved in these infectious processes, report which parts of the brain complex are most commonly affected and report the sequelae of this patients. METHODS: A systematic review following the PRISMA Guide and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports was carried out in PubMed, Scopus and Web of Science. The search terms were: Brain infection, brain abscess, oral health oral origin, odont* infect*. RESULTS: The database search identified a total of 1000 articles. A total of 18 publications were identified after applying inclusion and exclusion criteria. A total of 38 patients were analyzed. Mean age was 49.64±18.80 years. CONCLUSION: The most common symptoms of patients with brain abscess are neurological affectations first and then fever and headache second, without necessarily presenting as a symptomatological triad. Microbiological diagnosis is key to determining the origin of the infection. Anaerobic pathogens such as Streptococcus (F. Milleri), Fusobacterium Nucleatum and Porfiromonas Gingivalis families are common bacterial agents. The frontal lobe is the most frequently affected, followed by the parietal and temporal lobe. The most frequent brain complications are neurological disorders. However, most patients with brain abscesses recover without sequelae.

Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels.

COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.