Translocator protein (TSPO) expression is increased in activated glia, and has been used as a marker of neuroinflammation in PET imaging. However, the extent to which TSPO upregulation reflects a pro‐ or anti‐inflammatory phenotype remains unclear. Our aim was to determine whether TSPO upregulation in astrocytes and microglia/macrophages is limited to a specific inflammatory phenotype. TSPO upregulation was assessed by flow cytometry in cultured astrocytes, microglia, and macrophages stimulated with lipopolysaccharide (LPS), tumor necrosis factor (TNF), or interleukin‐4 (Il‐4). Subsequently, mice were injected intracerebrally with either a TNF‐inducing adenovirus (AdTNF) or IL‐4. Glial expression of TSPO and pro‐/anti‐inflammatory markers was assessed by immunohistochemistry/fluorescence and flow cytometry. Finally, AdTNF or IL‐4 injected mice underwent PET imaging with injection of the TSPO radioligand ¹⁸F‐DPA‐713, followed by ex vivo autoradiography. TSPO expression was significantly increased in pro‐inflammatory microglia/macrophages and astrocytes both in vitro, and in vivo after AdTNF injection (p < .001 vs. control hemisphere), determined both histologically and by FACS. Both PET imaging and autoradiography revealed a significant (p < .001) increase in ¹⁸F‐DPA‐713 binding in the ipsilateral hemisphere of AdTNF‐injected mice. In contrast, no increase in either TSPO expression assessed histologically and by FACS, or ligand binding by PET/autoradiography was observed after IL‐4 injection. Taken together, these results suggest that TSPO imaging specifically reveals the pro‐inflammatory population of activated glial cells in the brain in response to inflammatory stimuli. Since the inflammatory phenotype of glial cells is critical to their role in neurological disease, these findings may enhance the utility and application of TSPO imaging.

Brain metastasis is a common complication of cancer patients and is associated with poor survival. Histological data from patients with brain metastases suggest that microglia are the major immune population activated around the metastatic foci. Microglia and macrophages have the ability to polarise to different phenotypes and to exert both tumorigenic and cytotoxic effects. However, the role of microglia/macrophages during the early stages of metastatic growth in the brain has not yet been determined. The aim of this study was to profile microglial/macrophage activation in a mouse model of breast cancer brain metastasis during the early stages of tumour growth, and to assess the role of the anti-inflammatory microglial population, specifically, during this phase. Following intracerebral injection of 5x103 4T1-GFP mammary carcinoma cells into female BALB/c mice robust microglial/macrophage activation around the 4T1 metastatic foci was evident throughout the time-course studied (28 days) and correlated positively with tumour volume (r2=0.67). Populations of classically (pro-inflammatory) and alternatively (anti-inflammatory) activated microglia/macrophages were identified immunohistochemically by expression of either iNOS/COX2 or MRC1/Arg1, respectively. Temporally, levels of both pro- and anti-inflammatory cells were broadly stable across the time-course. Subsequently, selective depletion of the anti-inflammatory microglia/macrophage population by intracerebral injection of mannosylated clodronate liposomes significantly reduced metastatic tumour burden (p<0.01). Moreover, increased levels of apoptosis were associated with tumours in clodronate liposome treated animals compared to controls (p<0.05). These findings suggest that microglia/macrophages are important effectors of the inflammatory response in the early stages of brain metastasis, and that targeting the anti-inflammatory microglial/macrophage population may offer an effective new therapeutic avenue for patients with brain metastases.

Astrocytes are thought to play a pivotal role in coupling neural activity and cerebral blood flow. However, it has been shown that astrocytes undergo morphologic changes in response to brain metastasis, switching to a reactive phenotype, which has the potential to significantly compromise cerebrovascular function and contribute to the neurological sequelae associated with brain metastasis. Given that STAT3 is a key regulator of astrocyte reactivity, we aimed here to determine the impact of STAT3-mediated astrocyte reactivity on neurovascular function in brain metastasis. Rat models of brain metastasis and ciliary neurotrophic factor were used to induce astrocyte reactivity. Multimodal imaging, electrophysiology, and IHC were performed to determine the relationship between reactive astrocytes and changes in the cerebrovascular response to electrical and physiological stimuli. Subsequently, the STAT3 pathway in astrocytes was inhibited with WP1066 to determine the role of STAT3-mediated astrocyte reactivity, specifically, in brain metastasis. Astrocyte reactivity associated with brain metastases impaired cerebrovascular responses to stimuli at both the cellular and functional level and disrupted astrocyte–endothelial interactions in both animal models and human brain metastasis samples. Inhibition of STAT3-mediated astrocyte reactivity in rats with brain metastases restored cerebrovascular function, as shown by in vivo imaging, and limited cerebrovascular changes associated with tumor growth. Together these findings suggest that inhibiting STAT3-mediated astrocyte reactivity may confer significant improvements in neurological outcome for patients with brain metastases and could potentially be tested in other brain tumors. Significance: These findings demonstrate that selectively targeting STAT3-mediated astrocyte reactivity ameliorates the cerebrovascular dysfunction associated with brain metastasis, providing a potential therapeutic avenue for improved patient outcome.

Background/Objectives: Terbinafine has been the gold standard for the management of superficial fungal infections. The etiological agent generally is Trichophyton rubrum (T. rubrum); however, there has been increased reporting of a new terbinafine-resistant strain of the T. mentagrophytes complex (T. mentagrophytes ITS genotype VIII otherwise known as T. indotineae). Here, we review the epidemiology, clinical features, diagnosis, and treatment of T. rubrum and T. indotineae infections. Methods: We conducted a systematic literature search using PubMed, Embase (Ovid), and Web of Science, resulting in 83 qualified studies with data summarized for clinical features, antifungal susceptibility, and terbinafine resistance mechanisms and mutations. Results: Dermatophytosis is most commonly caused by T. rubrum; however, in certain parts of the world, especially in the Indian subcontinent, T. indotineae infections have been reported more frequently. The majority of T. rubrum isolates remain susceptible to terbinafine (over 60% of isolates show MIC₅₀ and MIC₉₀ < 0.5 µg/mL). In contrast, for T. indotineae, 30% of isolates exhibit MIC₅₀ ≥ 0.5 µg/mL and 80% exhibit MIC₉₀ ≥ 0.5 µg/mL. Frequently detected squalene epoxidase (SQLE) mutations in T. rubrum are Phe397Leu/Ile (41.6%) and Leu393Phe (20.8%); in T. indotineae, these include Phe397Leu (33.0%) and Ala448Thr (24.5%). Other potential terbinafine resistance mechanisms in T. rubrum and T. indotineae are discussed. Conclusions: T. rubrum generally remain susceptible in vitro to terbinafine in contrast to T. indotineae. The essential components of an effective antifungal stewardship emphasize accurate clinical and laboratory diagnosis, susceptibility testing, and appropriate antifungal therapy selection with a multidisciplinary approach.

The goal of this study was to investigate the normal MRI appearance of lymphoid organs in immuno-competent and immuno-deficient mice commonly used in research. Four mice from each of four different mouse strains (nude, NOG, C57BL/6, CB-17 SCID (SCID)) were imaged weekly for one month. Images were acquired with a 3D balanced steady state free precession (bSSFP) sequence. The volume of the lymph nodes and spleens were measured from MR images. In images of nude and SCID mice, lymph nodes sometimes contained a hyperintense region visible on MRI images. Volumes of the nodes were highly variable in nude mice. Nodes in SCID mice were smaller than in nude or C57Bl/6 mice (p<0.0001). Lymph node volumes changed slightly over time in all strains. The spleens of C57Bl/6 and nude mice were similar in size and appearance. Spleens of SCID and NOG mice were significantly smaller (p<0.0001) and abnormal in appearance. The MRI appearance of the normal lymph nodes and spleen varies considerably in the various mouse strains examined in this study. This is important to recognize in order to avoid the misinterpretation of MRI findings as abnormal when these strains are used in MRI imaging studies.

Diabetes Mellitus (DM) is a significant global concern. Many diabetic patients will experience complications due to angiopathy, neuropathy, and immune dysfunction, namely diabetic foot ulcers (DFU) and diabetic foot infections (DFI), which can result in lower limb amputation and potentially death. The prevalence of common superficial fungal infections, such as tinea pedis and onychomycosis, can directly increase a diabetic patient’s risk of developing both DFU and DFI. In this review article, we discuss the etiology of diabetic foot complications as well as considerations for both screening and management. We also discuss the role of the dermatologist within a multidisciplinary care team in prescribing and managing treatments for tinea pedis and onychomycosis infections within this patient population. We believe that reducing the burden of these fungal infections in the context of the diabetic foot will help reduce DFU and DFI complications and their associated morbidity and mortality.