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Abstract As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug’s host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

Chromoblastomycosis is a primary implantation mycosis caused by melanized fungi. It affects mainly populations from remote and rural areas, and may cause significant morbidity and mortality. A 69-year-old kidney transplant recipient woman presented with a dark nodule on the first left toe and a satellite lesion. Dermoscopic exam showed multiple clustered black dots, blackened homogenous area and chrysalides, which led to the diagnostic hypothesis of melanoma. Histopathological examination was compatible with chromoblastomycosis.

Abstract Lymphocytic thrombophilic arteritis is a recently described entity, histopathologically characterized by lymphocytic vasculitis that affects the arterioles of the dermo-hypodermic junction, associated with deposition of fibrin and a luminal fibrin ring. A 49-year-old female patient presented with achromic maculae and a well-defined ulcer on the medial aspect of the left lower limb. The biopsy showed intense inflammatory infiltrate in the papillary dermis with a predominance of lymphocytes, and medium-caliber vessels surrounded by mononuclear infiltrates in the deep reticular dermis. Masson’s trichrome staining showed intense destruction of the muscle layer of the vascular wall and a fibrin ring. Good clinical response was attained with azathioprine. The authors believe that the ulceration might be another clinical presentation or represent an atypical progression of this condition.

Abstract Living organisms are vulnerable to thermal stress, which causes a diversity of physiological outcomes. Previous work has shown that the snail vectors (Biomphalaria glabrata) of an important human pathogen, Schistosoma mansoni, revert from resistant to susceptible after short exposure to a heat stress as low as 31°C; however, due to lack of replicability among labs and genetic lines of snails, it has been hypothesized that this effect is genotype dependent. We examined the effects of heat shock on the resistance of two species of snail vectors including B. glabrata and Biomphalaria sudanica. We used three different inbred laboratory snail lines in addition to the F1 generation of field‐collected snails from Lake Victoria, Kenya, an area with high levels of schistosomiasis transmission. Our results showed marginal effects of heat shock on prevalence of infection in B. glabrata, and that this response was genotype specific. We found no evidence of a heat shock effect on prevalence of infection in B. sudanica or on intensity of infection (number of infectious stages shed) in either snail species. Such environmentally influenced defense responses stress the importance of considering this unique interaction between snail and parasite genotypes in determining infection dynamics under climate changes.

In many solid tumors including triple‐negative breast cancer (TNBC), upregulation of the interleukin‐4 receptor (IL‐4R) has been shown to promote cancer cell proliferation, apoptotic resistance, metastatic potential, and a Th2 response in the tumor microenvironment (TME). Since immunosuppressive cells in the TME and spleen including myeloid‐derived suppressor cells (MDSCs) and tumor‐associated macrophages (TAMs) also express the IL‐4R, we hypothesized that selective depletion of IL‐4R‐bearing cells in TNBC would result in the direct killing of tumor cells and the depletion of immunosuppressive cells and lead to an enhanced antitumor response. To selectively target IL‐4R+ cells, we employed DABIL‐4, a fusion protein toxin consisting of the catalytic and translocation domains of diphtheria toxin fused to murine IL‐4. As anticipated, DABIL‐4 has potent cytotoxic activity against TNBC cells both in vitro and in vivo. We demonstrate in the murine 4T1 TNBC model that DABIL‐4 significantly reduces tumor growth, splenomegaly, and lung metastases. Importantly, we also show that the administration of DABIL‐4 results in the selective depletion of MDSCs, TAMs, and regulatory T cells in treated mice, with a concomitant increase in IFN‐γ+ CD8 effector T cells in the TME. Since the 4T1 antitumor activity of DABIL‐4 was largely diminished in IL‐4R knockout mice, we postulate that DABIL‐4 functions primarily as an immunotherapeutic by the depletion of MDSCs, TAMs, and regulatory T cells. NanoString analysis of control and treated tumors confirmed and extended these observations by showing a marked decline of mRNA transcripts that are associated with tumorigenesis and metastasis. In conclusion, we demonstrate that DABIL‐4 targeting of both tumor and immunosuppressive host cells likely represents a novel and effective treatment strategy for 4T1 TNBC and warrants further study.

Abstract Background Global ischemia is the resulting effect of a cardiopulmonary arrest (CPA). Presently there is no effective treatment to address neurological deficits in patients who survived a CPA. Granulocyte-colony stimulating factor is a growth factor (G-CSF) with a plethora of beneficial effects, including neuroprotection. Clinical application of human G-CSF (hG-CSF) is limited due to its plasma half-life of 4 h. Therefore, novel approaches need to be investigated that would (1) enable prolonged manifestation of hG-CSF and (2) demonstrate G-CSF efficacy from studying the underlying protective mechanisms of hG-CSF. In our previous work, we used the self-complementary adeno-associated virus (stereotype2: scAAV2) as a vector to transfect the hG-CSF gene into the global ischemic brain of a mouse. As an extension of that work, we now seek to elucidate the protective mechanisms of hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia. Method A single drop of either AAV-CMV-hG-CSF or AAV-CMV-GFP was dropped into the conjunctival sac of the Swiss Webster mouse’s left eye, 30–60 min after bilateral common artery occlusion (BCAO). The efficacy of the expressed hG-CSF gene product was analyzed by monitoring the expression levels of endoplasmic reticulum stress (ER), mitochondrial dynamics and autophagic proteins over 4- and 7-days post-BCAO in vulnerable brain regions including the striatum, overlying cortex (frontal brain regions) and the hippocampus (middle brain regions). Statistical analysis was performed using mostly One-Way Analysis of variance (ANOVA), except for behavioral analysis, which used Repeated Measures Two-Way ANOVA, post hoc analysis was performed using the Tukey test. Results Several biomarkers that facilitated cellular death, including CHOP and GRP78 (ER stress) DRP1 (mitochondrial dynamics) and Beclin 1, p62 and LC3-ll (autophagy) were significantly downregulated by hG-CSF gene transfer. hG-CSF gene therapy also significantly upregulated antiapoptotic Bcl2 while downregulating pro-apoptotic Bax. The beneficial effects of hG-CSF gene therapy resulted in an overall improvement in functional behavior. Conclusion Taken together, this study has substantiated the approach of sustaining the protein expression of hG-CSF by eye drop administration of the hG-CSF gene. In addition, the study has validated the efficacy of using hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia.

Chromoblastomycosis is a primary implantation mycosis caused by melanized fungi. It affects mainly populations from remote and rural areas, and may cause significant morbidity and mortality. A 69-year-old kidney transplant recipient woman presented with a dark nodule on the first left toe and a satellite lesion. Dermoscopic exam showed multiple clustered black dots, blackened homogenous area and chrysalides, which led to the diagnostic hypothesis of melanoma. Histopathological examination was compatible with chromoblastomycosis. [ABSTRACT FROM AUTHOR]

The use of hyaluronic acid (HA) fillers for facial rejuvenation has grown widely and is now one of the most performed noninvasive cosmetic procedures. Viral infections can occur, albeit rarely. This report describes a 65-year-old female patient with significant fat tissue loss in the malar region who developed herpes zoster after receiving HA filler for facial volumization. We performed volumization with a total of 2mL of HA in one session. Two days after the procedure, the patient began feeling mild pain in the malar region bilaterally and in the right side of the nasolabial fold. Upon physical examination, vesicles and erythema were observed. Due to the possibility of herpes zoster virus (HZV) infection, the patient was treated with valacyclovir. Ultrasonography with arterial and venous Doppler study revealed normal blood flow in the angular artery path and adequate positioning of the filler. After seven days of valacyclovir, the patient had complete resolution of the lesions. Herpes virus reactivation can be caused by direct axon damage by the needle, by tissue manipulation, and by inflammatory reaction. Herpes simplex virus (HSV) is the virus most commonly involved and its incidence does not exceed 1.45 percent of the complication cases, and HZV is even rarer. Reactivation of HZV might mimic tissue ischemia. Ultrasonography is a noninvasive, fast, and useful tool to evaluate vascular impairment and the positioning of the filler. [ABSTRACT FROM AUTHOR]

Background. Expansion of vascularized composite allograft (VCA) transplantation depends on the public’s willingness to donate VCA organs, including face, extremities, and genitourinary organs. This study evaluated the effectiveness of video messaging on VCA donation willingness in US military veterans, a key stakeholder in VCA transplantation. Methods. Participants (n = 556) were randomized to 1 of 3 VCA video messaging interventions (informational, testimonial, or blended), a general (non-VCA) organ donation video message, or a control (nondonation) video message. Questionnaires were completed at pre- and postintervention and at 3-wk follow-up. Results. Veterans exposed to any VCA video messaging were more likely to express VCA donation willingness (69%, n = 203/296) than those exposed to general donation messaging (53%, n = 47 of 89; P = 0.006) or No Donation Messaging (37%, n = 36 of 97; P