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Background & Aims: Cystic fibrosis-related liver disease (CFLD) is a chronic cholangiopathy that increases morbidity and mortality in patients with CF. Current treatments are unsatisfactory, and incomplete understanding of CFLD pathogenesis hampers therapeutic development. We have previously shown that mouse CF cholangiocytes respond to lipopolysaccharide with excessive inflammation. Thus, we investigated the role of the gut-liver axis in the pathogenesis of CFLD., Methods: Wild-type (WT), whole-body Cftr knockout (CFTR-KO) and gut-corrected (CFTR-KO-GC) mice were studied. Liver changes were assessed by immunohistochemistry and single-cell transcriptomics (single-cell RNA sequencing), inflammatory mediators were analysed by proteome array, faecal microbiota by 16S ribosomal RNA sequencing and gut permeability by FITC-dextran assay., Results: The livers of CFTR-KO mice showed ductular proliferation and periportal inflammation, whereas livers of CFTR-KO-GC mice had no evident pathology. Single-cell RNA sequencing analysis of periportal cells showed increased presence of neutrophils, macrophages and T cells, and activation of pro-inflammatory and pathogen-mediated immune pathways in CFTR-KO livers, consistent with a response to gut-derived stimuli. CFTR-KO mice exhibited gut dysbiosis with enrichment of Enterobacteriaceae and Enterococcus spp., which was associated with increased intestinal permeability and mucosal inflammation, whereas gut dysbiosis and inflammation were absent in CFTR-KO-GC mice. Treatment with nonabsorbable antibiotics ameliorated intestinal permeability and liver inflammation in CFTR-KO mice. Faecal microbiota transfer from CFTR-KO to germ-free WT mice did not result in dysbiosis nor liver pathology, indicating that defective intestinal CFTR is required to maintain dysbiosis., Conclusion: Defective CFTR in the gut sustains a pathogenic microbiota, creates an inflammatory milieu, and alters intestinal permeability. These changes are necessary for the development of cholangiopathy. Restoring CFTR in the intestine or modulating the microbiota could be a promising strategy to prevent or attenuate liver disease., Impact and Implications: Severe cystic fibrosis-related liver disease (CFLD) affects 10% of patients with cystic fibrosis (CF) and contributes to increased morbidity and mortality. Treatment options remain limited due to a lack of understanding of disease pathophysiology. The cystic fibrosis transmembrane conductance regulator (CFTR) mediates Cl - and HCO 3 - secretion in the biliary epithelium and its defective function is thought to cause cholestasis and excessive inflammatory responses in CF. However, our study in Cftr-knockout mice demonstrates that microbial dysbiosis, combined with increased intestinal permeability caused by defective CFTR in the intestinal mucosa, acts as a necessary co-factor for the development of CFLD-like liver pathology in mice. These findings uncover a major role for the gut microbiota in CFLD pathogenesis and call for further investigation and clinical validation to develop targeted therapeutic strategies acting on the gut-liver axis in CF., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections., Competing Interests: Competing interests statement:A.I. co-founded and consults for RIGImmune, Xanadu Bio and PanV, consults for Paratus Sciences, InvisiShield Technologies, and is a member of the Board of Directors of Roche Holding Ltd.

The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The "on-demand" induction of this machinery required γδ T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of γδ T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for γδ T cells in nutrient sensing., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

This study presents new information on tentaculariid trypanorhynchs from the Indo-Pacific region around Bali, Indonesia. Two new tentaculariid species, Nybelinia balinensis n. sp. and N. mobulicola n. sp., are described from the stomach of their myliobatid host Mobula japanica (Müller & Henle). Nybelinia balinensis n. sp. is a large-sized tentaculariid (scolex length, 6766-10,991). It can be distinguished from its congeners by a falcate metabasal armature, a unique basal armature of four rows of triangular shaped hooks, craspedote proglottids, and testes arranged in multiple layers in two separate lateral fields. N. mobulicola n. sp. can be characterized by short tentacles of 25 rows of hooks and 60 testes not reaching posterior to the ovary. A combination of a shorter basal armature of uncinate hooks without anterior extension of the base and fewer metabasal uncinate hooks with anterior extension of the base distinguishes it from N. lingualis (Cuvier, 1817). It differs from N. balinensis n. sp. in the possession of uncinate rather triangular shaped basal hooks. The Nybelinia Poche, 1926 fauna of M. japanica is highly specific, in line with a unique trypanorhynch fauna earlier described for the devil rays. This reflects their unique position as oceanic plankton feeders within the marine food web.

The optimal management of recurrent painful episodes in individuals living with sickle cell disease (SCD) remains unclear. Currently, the primary treatment for these episodes remains supportive, using fluids and intravenous opioid and anti-inflammatory medications. Few reports have described the use of adjunct subanesthetic doses of ketamine to opioids for treatment of refractory pain in SCD. This article reports a retrospective case series of five patients admitted to the intensive care unit (ICU) with prolonged vaso-occlusive episodes (VOEs). Patients were treated with a continuous-infusion of low-dose ketamine (up to 5 µg/kg/min) after insufficient pain control with opioid analgesic therapy. Outcomes studied included impact on opioid analgesic use, a description of ketamine dosing strategy, and an analysis of adverse events due to opioid or ketamine analgesia. Descriptive statistics are provided. During ketamine infusion, patients experienced a lower reported pain score (mean numeric rating scale [NRS] score 7.2 vs. 6.4), reduced opioid-induced adverse effects, and decreased opioid dosing requirements (median reduction of 90 mg morphine equivalents per patient). The average duration of severe pain during admission prior to ketamine therapy was 8 days. Only one of five patients reported an adverse effect (vivid dreams) secondary to ketamine infusion. The Richmond Agitation Sedation Scale (RASS) was assessed throughout therapy, with only one patient experiencing light drowsiness. Low-dose ketamine infusion may be considered as an adjunct analgesic agent in patients with vaso-occlusive episodes who report continued severe pain despite high-dose opioid therapy, particularly those experiencing opioid-induced adverse effects.

Type 1 diabetes (T1D) is a multifactorial autoimmune disease whose etiology involves complex interactions between the immune system and the intestinal microbiota. Recent studies by Rouxel et al. (2017) suggest that innate-like mucosal-associated invariant T cells (MAIT cells) may link gut integrity, the microbiota, and T1D., (Copyright © 2017. Published by Elsevier Inc.)

Semaphorins play an essential role in axonal guidance, and emerging evidence points to diverse functions of several Semaphorin family members in the immune system. Semaphorin 7A (Sema7A) promotes axonal growth in the central nervous system. Here, we show that Sema7A also plays a critical role in negative regulation of T cell activation and function. T cells deficient in Sema7A exhibit enhanced homeostatic and antigen-induced proliferative response. Moreover, autoreactive Sema7A-deficient T cells mediate aggressive autoimmune disease. The deficiency in Sema7A leads to defective TCR downmodulation and T cell hyperresponsiveness. These results demonstrate an important role of Sema7A in limiting autoimmune responses and add to growing evidence of shared signaling pathways used by the immune and nervous systems.

IL-4 was found to be the essential differentiation factor for Th2 cells and simultaneously to be a potent inhibitor of Th1 development that is induced by IFN-gamma and IL-12. Furthermore, it was demonstrated that TGF-beta can also inhibit Thl development. In this work, we demonstrate that polyclonal activation of Mel-14highCD4+ T cells by immobilized anti-alphabetaTCR mAb together with a mixture of IL-4 and TGF-beta can lead to the development of both Th1 and Th2 cells, depending on the concentration of these cytokines. Additional experiments revealed that Th1 induction by a combination of IL-4 and TGF-beta depends on the presence of endogenous IFN-gamma, and that this alternative Th1 development is further enhanced by IL-12, but is not dependent on this cytokine. Moreover, naive OVA323-339-specific Th cells that were stimulated by APCs and OVA323-339 peptide differentiated toward Th1 cells after priming in the presence of IL-4 in combination with TGF-beta. Hence, this finding confirmed the results obtained by polyclonal activation of naive CD4+ Th cells and implicates that this alternative Th1 development may also occur in vivo under the influence of TGF-beta and IL-4 independently of the Th1-promoting effect of IL-12.

Cytokines were found to play a key role in Th cell differentiation. Among them IL-12 was shown to be a potent differentiation factor for Th1 cells, whereas IL-4 is the only known cytokine that promotes the development of Th2 cells. Upon addition of comparable amounts of IL-4 and IL-12 to a primary culture of naive CD4+ T cells activated by immobilized anti-CD3 mAb, it was found that the Th1-inducing capacity of IL-12 is dominated by the Th2-promoting effect of IL-4. However, high amounts of IL-12 (10,000 U/ml) in combination with low amounts of IL-4 (100 U/ml) led to the development of a Th cell population that, upon rechallenge, showed a substantial secondary IFN-gamma (Th1 cytokine) production concomitantly with the production of high amounts of IL-4 (Th2 cytokine). This can be due to the coexistence of Th1 and Th2 cells or to the development of Th0 cells producing a mixed pattern of cytokines. Immunofluorescence double staining of intracellular IL-4 and IFN-gamma in combination with flow cytometry (FACS) revealed that most of the emerging Th cells produced either IL-4 or IFN-gamma. Only a few double producers could be detected. This finding indicates that individual naive CD4+ T cells can differentiate under the same conditions towards Th1 or Th2 cells and implicates that the development of Th1 and Th2 cells is not necessarily mutually exclusive.

This retrospective study evaluates paclitaxel (Taxol) monotherapy in the treatment of advanced ovarian cancer, previously treated with cisplatin. Forty-six patients with FIGO stage IC to IV were given Taxol in doses of 175 mg/m2 and 135 mg/m2 as a 3-h continuous infusion. All patients were given premedication (prednisone, clemastin, cimetidine) to prevent hypersensitivity reactions. One allergic reaction was observed. Thirty-nine patients showed progress of their disease during treatment and seven showed a response (overall response rate 15.2%; 95% c.i. 4.8-25.6%). There were five total (10.9%) and two partial responses. Among 20 patients who had progressed during or within 6 months of prior cisplatin-based therapy two were responders and two showed partial response (10%). Among 26 patients who had responded to cisplatin but suffered recurrence more than 6 months after cisplatin treatment, there were five total responders (19.2%). We conclude that Taxol treatment does not alter the fact that advanced ovarian carcinoma still carries a grave prognosis. Taxol monotherapy treatment of patients not responding to first line platinum treatment or having relapse within six months of completed therapy, seems to have a limited effect. For those patients responding to the first line platinum treatment that lasts for at least six months the effect of Taxol treatment is more encouraging.

Activation of naive dense CD4+ T cells by plate-bound anti-CD3 antibodies favors the development of Th1 cells which, upon re-stimulation, produce significant amounts of IFN-gamma but no IL-4. However, co-activation of such naive T cells in the presence of IgE [anti-dinitrophenyl (DNP)]-loaded bone marrow-derived mast cells (BMMC) on plates coated with anti-CD3 antibodies and DNP-BSA led to the development of IL-4-producing Th2 cells. The same result could be observed if irradiated (800 rad) BMMC were applied as co-stimulators. Moreover, BMMC could be replaced by the supernatant of IgE-activated BMMC suggesting that a soluble mediator, presumably IL-4, was responsible for this effect. This assumption was substantiated using neutralizing anti-IL-4 antibodies which abolished the BMMC-mediated Th2 development in all cases. Addition of IL-12, a cytokine that was shown to antagonize the Th2-promoting effect of IL-4 in vivo, could not inhibit the development of IL-4-producing T cells, but gave rise to a T cell population which produced relatively high amounts of IL-4 and IFN-gamma. Since BMMC represent the in vitro equivalent of mucosal mast cells these data suggest that IgE-activated mucosal mast cells can bias an emerging T cell dependent immune response towards a Th2 dominated reaction by the initial production of IL-4.

Ergonomics is an increasing health concern for all work environments in the 1990s. Ergonomic stresses do exist in the dental office for all personnel, and proposed regulatory activity will include dentistry. Hopefully, the pace of regulation will be met by scientific investigation that quantifies these stresses and defines their proper management and prevention. If so, ergonomics will become well-understood and will not develop as a new frontier of misapplied regulation.

It was observed in vitro and in vivo that both interferon (IFN)-gamma and interleukin (IL)-12 can promote the development of T helper type 1 (TH1) cells. Since IL-12 was shown to be a costimulator for the production of IFN-gamma by T or natural killer (NK) cells, IL-12 might play only an indirect role in TH1 differentiation by providing IFN-gamma which represents the essential differentiation factor. Using anti-CD3 monoclonal antibody (mAb) for activation of naive CD4+ T cells in the absence of accessory cells we could demonstrate that costimulation by IFN-gamma alone results only in marginal TH1 development. Similarly, IL-12 in the absence of IFN-gamma is only a poor costimulator for inducing differentiation towards the TH1 phenotype. Our data indicate that both cytokines are required to allow optimal TH1 development and that IL-12 has a dual role, it promotes differentiation by direct costimulation of the T cells and also enhances the production of IFN-gamma which serves as a second costimulator by an autocrine mechanism. Another cytokine that was reported to favor TH1 differentiation in certain experimental systems is transforming growth factor (TGF)-beta. With naive CD4+ T cells employed in this study TGF-beta strongly inhibited the production of IFN-gamma triggered by IL-12 as well as the IL-12-induced TH1 development. When TGF-beta was combined with anti-IFN-gamma mAb for neutralization of endogenous IFN-gamma the TH1-inducing capacity of IL-12 was completely suppressed.

A patient with Sturge-Weber disease was treated for a facial infection. Particular attention is given to oral histopathologic changes, and the special care needed for patients with this disease is outlined.