Human quad liver-on-chip system as a tool toward bridging the gap between animals and humans regarding toxicology and pharmacology of a cannabidiol-rich cannabis extract.

Cannabidiol (CBD) is a major phytocannabinoid from Cannabis sativa. It is currently widely available and widely used in the USA, but despite its rapid progress to market, the pharmacology and toxicology of both CBD and cannabidiol-rich cannabis extracts (CRCE) remain largely unknown. The goals of this study were to investigate the potential of a novel human microphysiological system to emulate CRCE-induced hepatotoxicity and pharmacological properties demonstrated in animal models. For this purpose, C57BL6/J male mice were subjected to dosing with either 0, 61.5, 184.5, or 615 mg/kg of CRCE for 10 days. The liver-on-chip system, incorporating human primary hepatocytes, sinusoidal endothelial cells, as well as Kupffer and stellate cells was subjected to 0, 300, 1,200, or 4,400 ng/mL of CRCE (8 h exposure followed by 16 h washout) for 5 days. Administration of CRCE in mice resulted in nearly 4-fold elevations of plasma ALT at 615 mg/kg (p < 0.01) and a dose-dependent decrease in intrahepatic miR-122. Elevated levels of ALT, paralleled by decreased intrahepatic and increased effluent levels of miR-122, were also observed in the liver-on-chip, although these results were not statistically significant. Exposure to CRCE resulted in a robust and dose-dependent induction of key cytochrome P450 enzymes, namely Cyp1a2, Cyp2b6 (CYP2B10), Cyp2e1, and Cyp2c9 (CYP2C19) in both mouse livers and liver-on-chip. The results of this study demonstrate the congruence between the responses observed in mouse and human liver-on-chip experimental systems and provide evidence of the potential microphysiological systems hold for translating animal data into clinical practice.

Clostridioides difficile Toxin A Remodels Membranes and Mediates DNA Entry Into Cells to Activate Toll-Like Receptor 9 Signaling.

BACKGROUND & AIMS: Clostridioides difficile toxin A (TcdA) activates the innate immune response. TcdA co-purifies with DNA. Toll-like receptor 9 (TLR9) recognizes bacterial DNA to initiate inflammation. We investigated whether DNA bound to TcdA activates an inflammatory response in murine models of C difficile infection via activation of TLR9. METHODS: We performed studies with human colonocytes and monocytes and macrophages from wild-type and TLR9 knockout mice incubated with TcdA or its antagonist (ODN TTAGGG) or transduced with vectors encoding TLR9 or small-interfering RNAs. Cytokine production was measured with enzyme-linked immunosorbent assay. We studied a transduction domain of TcdA (TcdA57-80), which was predicted by machine learning to have cell-penetrating activity and confirmed by synchrotron small-angle X-ray scattering. Intestines of CD1 mice, C57BL6J mice, and mice that express a form of TLR9 that is not activated by CpG DNA were injected with TcdA, TLR9 antagonist, or both. Enterotoxicity was estimated based on loop weight to length ratios. A TLR9 antagonist was tested in mice infected with C difficile. We incubated human colon explants with an antagonist of TLR9 and measured TcdA-induced production of cytokines. RESULTS: The TcdA57-80 protein transduction domain had membrane remodeling activity that allowed TcdA to enter endosomes. TcdA-bound DNA entered human colonocytes. TLR9 was required for production of cytokines by cultured cells and in human colon explants incubated with TcdA. TLR9 was required in TcdA-induced mice intestinal secretions and in the survival of mice infected by C difficile. Even in a protease-rich environment, in which only fragments of TcdA exist, the TcdA57-80 domain organized DNA into a geometrically ordered structure that activated TLR9. CONCLUSIONS: TcdA from C difficile can bind and organize bacterial DNA to activate TLR9. TcdA and TcdA fragments remodel membranes, which allows them to access endosomes and present bacterial DNA to and activate TLR9. Rather than inactivating the ability of DNA to bind TLR9, TcdA appears to chaperone and organize DNA into an inflammatory, spatially periodic structure.

Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration.

The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury-acetaminophen (APAP)-in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400 mg/kg) on day 4 resulted in overt toxicity with 37.5% mortality. No mortality was observed in mice treated with 290 mg/kg of CBD+APAP (MED of 25 mg/kg of CBD) or APAP alone. Following CRCE/APAP co-administration, microscopic examination revealed a sinusoidal obstruction syndrome-like liver injury-the severity of which correlated with the degree of alterations in physiological and clinical biochemistry end points. Mechanistically, glutathione depletion and oxidative stress were observed between the APAP-only and co-administration groups, but co-administration resulted in much greater activation of c-Jun N-terminal kinase (JNK). Strikingly, these effects were not observed in mice gavaged with 290 mg/kg CBD in CRCE followed by APAP administration. These findings highlight the potential for CBD/drug interactions, and reveal an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity.

Pathologic Features of Infectious Gastritis.

This manuscript presents a review of infectious causes of gastritis aimed at the practicing anatomic pathologist. We shall highlight unique histologic findings and clinical attributes that will assist those analyzing endoscopically obtained mucosal biopsies of the stomach or resection specimens.

Prediction of the histopathologic findings of intrahepatic cholangiocarcinoma: qualitative and quantitative assessment of diffusion-weighted imaging.

OBJECTIVE: To correlate qualitative and quantitative diffusion weighted imaging (DWI) characteristics of intrahepatic cholangiocarcinoma (ICC) with histopathologic tumour grade and fibrosis content. METHODS: Fifty-one patients (21M/30F; mean age 61y) with ICC and MRI including DWI were included in this IRB-approved multicentre retrospective study. Qualitative tumour features were assessed. Tumour apparent diffusion coefficient (ADC) mean, minimum, and normalized (nADCliver) values were computed. Tumour grade [well(G1), moderately(G2), or poorly differentiated(G3)] and tumour fibrosis content [minimal(1), moderate(2), or abundant(3)] were categorized pathologically. Imaging findings and ADC values were compared with pathologic measures. Utility of ADC values for predicting tumour grade was assessed using ROC analysis. RESULTS: 51 ICCs (mean size 6.5±1.1 cm) were assessed. 33/51(64%) of ICCs demonstrated diffuse hyperintensity and 15/51(29%) demonstrated target appearance on DWI. Infiltrative morphology (p=0.02) and tumour size (p=0.04) were associated with G3. ADCmean and nADCmean of G3 (1.32±0.47x10-3 mm2/sec and 0.97±0.95) were lower than G1+G2 (1.57±0.39x10-3 mm2/sec and 1.24±0.49; p=0.03 and p=0.04). ADCmean and nADCmean were inversely correlated with tumour grade (p<0.025). No correlation was found between ADC and tumour fibrosis content. AUROC, sensitivity and specificity of nADCmean for G3 versus G1+G2 were 0.71, 89.5% and 55.5%. CONCLUSION: ADC quantification has reasonable accuracy for predicting ICC grade. KEY POINTS: • ADC quantification was useful for predicting ICC tumour grade. • Infiltrative tumour morphology and size were associated with poorly differentiated ICCs. • ADC values depended more on ICC tumour grade than fibrosis content. • Ability to predict ICC tumour grade non-invasively could impact patient management.

Distinct roles of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) in liver regeneration and fibrosis.

Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) are cell surface-located transmembrane ecto-enzymes of the CD39 superfamily which regulate inflammation and tissue repair by catalyzing the phosphohydrolysis of extracellular nucleotides and modulating purinergic signaling. In the liver, NTPDase2 is reportedly expressed on portal fibroblasts, but its functional role in regulating tissue regeneration and fibrosis is incompletely understood. Here, we studied the role of NTPDase2 in several models of liver injury using global knockout mice. Liver regeneration and severity of fibrosis were analyzed at different time points after exposure to carbon tetrachloride (CCl4) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or partial hepatectomy in C57BL/6 wild-type and globally NTPDase2-deficient (Entpd2 null) mice. After chronic CCl4 intoxication, Entpd2 null mice exhibit significantly more severe liver fibrosis, as assessed by collagen content and histology. In contrast, deletion of NTPDase2 does not have a substantial effect on biliary-type fibrosis in the setting of DDC feeding. In injured livers, NTPDase2 expression extends from the portal areas to fibrotic septae in pan-lobular (CCl4-induced) liver fibrosis; the same pattern was observed, albeit to a lesser extent in biliary-type (DDC-induced) fibrosis. Liver regeneration after partial hepatectomy is not substantively impaired in global Entpd2 null mice. NTPDase2 protects from liver fibrosis resulting from hepatocellular injury induced by CCl4. In contrast, Entpd2 deletion does not significantly impact fibrosis secondary to DDC injury or liver regeneration after partial hepatectomy. Our observations highlight mechanisms relating to purinergic signaling in the liver and indicate possible therapeutic avenues and new cellular targets to test in the management of hepatic fibrosis.

Genetic Determinants of Circulating Lipoproteins in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Recent genome-wide association studies have identified 2 genetic polymorphisms in association with nonalcoholic fatty liver disease (NAFLD): patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), both of which appear to influence the production of very low density lipoprotein (VLDL). The impact of these genetic variations on lipoprotein metabolism in the setting of nonalcoholic steatohepatitis and liver fibrosis are not fully characterized. MATERIALS AND METHODS: We measured comprehensive lipoprotein profiles by nuclear magnetic resonance among 170 serially recruited patients in an NAFLD registry, and determined their relationships with PNPLA3 and TM6SF2 genotypes. RESULTS: In this cohort, 72% patients had at least 1 allele of either PNPLA3 I148M or TM6SF2 E167K, and 30% carried 2 alleles. In multivariate models adjusting for histologic features of nonalcoholic steatohepatitis and liver fibrosis, PNPLA3 I148M is associated with a decrease in VLDL particle size. Both PNPLA3 I148M and TM6SF2 E167K genotypes were associated with increases in the size of low density lipoprotein (LDL) and high density lipoprotein particles, phenotypes considered atheroprotective. When adjusted for both genotypes, NAFLD activity score, in particular the degree of hepatic steatosis was strongly associated with increases in the size of VLDL particles, the concentration of LDL, especially small LDL particles, and a decrease in the size of high density lipoprotein particles, all of which are linked with a proatherogenic phenotype. CONCLUSIONS: PNPLA3 and TM6SF2 are common genetic variants among NAFLD patients and impact lipoprotein profiles in slightly different ways. The interactions between genotypes, hepatic steatosis, and lipoprotein metabolism shed lights on the pathophysiology of NAFLD, and provide opportunities for personalized treatment in the era of emerging NAFLD therapeutics.

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses.

We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid esters of hydroxy stearic acids (PAHSAs), with beneficial metabolic and anti-inflammatory effects. We tested whether PAHSAs protect against colitis, which is a chronic inflammatory disease driven predominantly by defects in the innate mucosal barrier and adaptive immune system. There is an unmet clinical need for safe and well tolerated oral therapeutics with direct anti-inflammatory effects. Wild-type mice were pretreated orally with vehicle or 5-PAHSA (10 mg/kg) and 9-PAHSA (5 mg/kg) once daily for 3 days, followed by 10 days of either 0% or 2% dextran sulfate sodium water with continued vehicle or PAHSA treatment. The colon was collected for histopathology, gene expression, and flow cytometry. Intestinal crypt fractions were prepared for ex vivo bactericidal assays. Bone marrow-derived dendritic cells pretreated with vehicle or PAHSA and splenic CD4+ T cells from syngeneic mice were co-cultured to assess antigen presentation and T cell activation in response to LPS. PAHSA treatment prevented weight loss, improved colitis scores (stool consistency, hematochezia, and mouse appearance), and augmented intestinal crypt Paneth cell bactericidal potency via a mechanism that may involve GPR120. In vitro, PAHSAs attenuated dendritic cell activation and subsequent T cell proliferation and Th1 polarization. The anti-inflammatory effects of PAHSAs in vivo resulted in reduced colonic T cell activation and pro-inflammatory cytokine and chemokine expression. These anti-inflammatory effects appear to be partially GPR120-dependent. We conclude that PAHSA treatment regulates innate and adaptive immune responses to prevent mucosal damage and protect against colitis. Thus, PAHSAs may be a novel treatment for colitis and related inflammation-driven diseases.

Lanthanum deposition from oral lanthanum carbonate in the upper gastrointestinal tract.

AIMS: Lanthanum carbonate is used as an alternative to calcium-based phosphate binders to manage hyperphosphataemia in patients with renal failure. The deposition of lanthanum within gastroduodenal mucosa of patients treated with the medication has been described, but given the relative novelty of this entity, the histiocytic deposits in the gastroduodenal mucosa can be confused with a variety of other processes, including infections and other drug-induced forms of injury. METHODS AND RESULTS: We describe five cases of lanthanum phosphate deposition in upper gastrointestinal (GI) tract biopsies. Three cases were confirmed with scanning electron microscopy and energy dispersive X-ray analysis, including one unique patient, status post-renal transplant for polycystic kidney disease, who had last taken lanthanum 7 years prior to biopsy. CONCLUSION: Lanthanum deposition in the upper GI tract is a mimic of other drug-related forms of GI injury, including iron pill-related gastropathy. The key to making this diagnosis is a thorough drug history and awareness of the histological features.

Expanding the differential diagnosis for transaminitis in patients with anorexia nervosa.

Aminotransferase elevations have been described in patients with anorexia nervosa. Hypothesized etiologies have included ischemic hepatitis, refeeding-induced transaminitis, and the process of autophagy. Supervised enteral nutrition is the mainstay of treatment for severe anorexia, but an increase in aminotransferase levels after initiation of enteral feeding presents clinicians with a diagnostic dilemma. We present a 31-year-old woman with anorexia nervosa (body mass index [BMI] of 13.5 kg/m2) who experienced a worsening of aminotransferase elevations even after the initiation of enteral feeding. Despite nutritional supplementation, the patient's weight continued to fall for 6 days. Peak aminotransferase concentrations correlated with the patient's lowest weight and improved only after an increase in BMI was eventually achieved. Secondary causes of severe transaminitis were investigated, and after no cause was found, a liver biopsy was performed. Pathology was consistent with liver injury secondary to severe malnutrition rather than from refeeding syndrome. This case highlights malnutrition as an important cause of aminotransferase elevations and underscores the need for judicious early weight restoration in patients with anorexia and abnormal liver chemistry.

Histology Grade Is Independently Associated With Relapse Risk in Patients With Ulcerative Colitis in Clinical Remission: A Prospective Study.

OBJECTIVES: Objective evidence of inflammation has been associated with the risk of relapse in patients with ulcerative colitis (UC) who are in clinical remission. We compared endoscopic and histologic grades for their ability to predict clinical relapse in this patient population. METHODS: Patients with UC in clinical remission were prospectively enrolled into an observational cohort. Baseline endoscopic scores (Mayo) and histological (Geboes) grades and blood markers were collected. All subjects were followed for 12 months and relapse determined using clinical indices. RESULTS: A total of 179 subjects were enrolled into the study and followed for 12 months. Clinical relapse occurred in 23%; 5% were hospitalized, and 2% underwent colectomy. In univariate analysis, the baseline Mayo endoscopy score and the Geboes histology grade were significantly associated with the later development of clinical relapse (P<0.001 for both), but only the histology grade remained significant in a multivariate model (P=0.006). The relative risk of clinical relapse was 3.5 (95% CI 1.9-6.4, P<0.0001) in subjects whose baseline Geboes grade was ≥3.1. The area under the curve was 0.73 for the Geboes histology grade to identify subjects at risk of future clinical relapse. Of the patients in clinical, endoscopic, and histological remission at baseline (n=82), only 7% had a clinical relapse over the subsequent 12 months. CONCLUSIONS: Histology grade has the strongest association with the risk of clinical relapse in patients with UC who are in clinical remission. Consideration should be given to including this end point in evaluating therapy for UC.

CD39 mediated regulation of Th17-cell effector function is impaired in juvenile autoimmune liver disease.

BACKGROUND & AIMS: T-helper-type 17 (Th17) cells are involved in autoimmune tissue damage. CD39 is an ectonucleotidase that catalyzes extracellular ATP/ADP hydrolysis, culminating in the generation of immunosuppressive adenosine. Functional CD39 expression confers immunosuppressive properties upon immune cells. As the proportion of CD39 lymphocytes is decreased in juvenile autoimmune liver disease (AILD), we have explored whether decreased CD39 expression is present on Th17 cells and whether this phenomenon is associated with heightened effector function and inflammation. METHODS: Thirty-eight patients with juvenile AILD (22 autoimmune hepatitis and 16 autoimmune sclerosing cholangitis), 8 disease controls (DC) and 16 healthy subjects (HS) were studied. Peripheral blood cell phenotype was determined by flow cytometry; ability to suppress by inhibition of cell proliferation/effector cytokine production; ectoenzymatic activity by thin layer chromatography; expression of adenosine receptor, adenosine deaminase (ADA) and phosphodiesterases (PDE) by quantitative real-time PCR or by Western Blot. RESULTS: CD39(+) Th17 (Th17(CD39+)) cells from HS appear activated and contain high frequencies of lymphocytes producing regulatory cytokines. In AILD, however, Th17(CD39+) cells are markedly diminished and fail to generate AMP/adenosine, thereby limiting control of both target cell proliferation and IL-17 production. When compared to HS, Th17 cells from AILD patients also show lower A2A adenosine receptor expression while displaying similar levels of PDE4A, PDE4B and ADA. Only rare Th17(CD39+) cells are observed by liver immunohistochemistry. CONCLUSIONS: Th17(CD39+) cells in juvenile AILD are both quantitatively decreased and qualitatively deficient. Low levels CD39 and A2A expression may contribute to the perpetuation of Th17 cell effector properties and unfettered inflammation in this disease.

Colorectal Cancer Screening in Inflammatory Bowel Disease.

Patients with long-standing ulcerative colitis (UC) or Crohn's colitis are at increased risk of developing colorectal cancer (CRC). Given that most cases of CRC are thought to arise from dysplasia, previous guidelines have recommended endoscopic surveillance with random biopsies obtained from all segments of the colon involved by endoscopic or microscopic inflammation. However, recent evidence has suggested that the majority of dysplastic lesions in patients with inflammatory disease (IBD) are visible, and data have been supportive of chromoendoscopy with targeted biopsies of visible lesions versus traditional random biopsies. This review article will discuss the risk of colon cancer in patients with IBD, as well as current recommendations for CRC screening and surveillance in patients with UC or Crohn's colitis.

MR Enterography of the Ileoanal Pouch: Descriptive Radiologic Analysis With Endoscopic and Pathologic Correlation.

OBJECTIVE: The purpose of this study was to describe the MR enterography (MRE) appearance of inflammation of the ileoanal pouch after ileal pouch-anal anastomosis (IPAA) surgery and to correlate it with pouch endoscopic and histopathologic findings. MATERIALS AND METHODS: All MRE studies performed between October 1, 2007, and September 30, 2013, for patients who had previously undergone IPAA (n = 54) were retrieved. After review of medical records, the patients who underwent MRE, pouch endoscopy, and biopsy within 90 days (14 men, 14 women; mean age, 42.2 years; range, 24-67 years) were selected for inclusion in the study. Two blinded MRI radiologists in consensus retrospectively evaluated MRE studies for multiple MRI features. Two MRI scores were then calculated: an active and a composite inflammation score. A gastroenterologist retrospectively reviewed the pouch endoscopic images, and a pathologist reviewed the slides; both of these investigators were blinded. Both MRI scores were correlated with the pouch endoscopic and histopathologic findings. RESULTS: The composite MRI score had strong positive correlation with the endoscopic score (r = 0.61; p = 0.0005) but weak positive correlation with the histopathologic score (r = 0.31; p = 0.10, not statistically significant). The active inflammation MRI score had moderate positive correlation with the endoscopic score (r = 0.57; p = 0.0017) and weak positive correlation with the histopathologic score (r = 0.20; p = 0.31, not statistically significant). An MRI score ≥ 4 indicated the best results, with sensitivity of 86%, specificity of 79%, positive predictive value of 80%, negative predictive value of 85%, and accuracy of 82% for pouch inflammation. A positive likelihood ratio of 4.00 and negative likelihood ratio of 0.18 were obtained. CONCLUSION: In patients who have undergone IPAA surgery, the MRE findings strongly correlate with the pouch endoscopic findings with high sensitivity and positive predictive value for pouch inflammation. Therefore, MRE is a useful noninvasive test performed without ionizing radiation that can be used to evaluate patients with clinical symptoms and possibly alleviate the need for endoscopy in a select patient population.

MDCT and MRI of the ampulla of Vater. Part I: technique optimization, normal anatomy, and epithelial neoplasms.

The purpose of this two-part article is to review the cross-sectional anatomy of the ampulla and periampullary region, to propose novel and optimized MDCT and MRI techniques that allow accurate evaluation of the ampulla of Vater, and to summarize the cross-sectional imaging features of benign and malignant ampullary conditions. In this first part, we will review the normal anatomy of the ampullary region, provide suggestions on how to optimize evaluation of the ampullary region by MDCT and MRI, and review the imaging features of select epithelial neoplasms of the ampulla. Familiarity with the normal ampullary anatomy and the pathologic conditions involving the ampulla, as well as the use of optimized MDCT and MRI techniques, may improve the diagnostic accuracy of radiologists facing ampullary abnormalities.

MDCT and MRI of the ampulla of Vater. Part II: non-epithelial neoplasms, benign ampullary disorders, and pitfalls.

The purpose of this two-part article is to review the cross-sectional imaging features of benign and malignant ampullary conditions with endoscopic and histopathologic correlation and to present the most common pitfalls in the evaluation of the ampulla. In this part, we will review the mesenchymal and secondary neoplasms of the ampulla, a vast array of benign ampullary conditions, causes of bulging papilla, and pitfalls. Familiarity with ampullary pathologic conditions and pitfalls, as well as the use of optimized MDCT and MRI techniques, may improve the diagnostic accuracy of radiologists facing ampullary abnormalities.

Mammary-type myofibroblastoma of the liver: multi-modality imaging features with histopathologic correlation.

A 46-year-old woman with an incidentally discovered hepatic mass at the time of echocardiography underwent additional imaging for characterization. Ultrasound demonstrated a 5.3 cm solid hyperechoic mass. Computed tomography and magnetic resonance imaging showed intratumoral fat and nodular foci of progressive enhancement. The patient underwent surgical resection, with the mass demonstrating histopathologic and immunohistochemical features diagnostic of a hepatic mammary-type myofibroblastoma. We present herein the clinical, imaging, and pathologic features in this unique case of hepatic mammary-type myofibroblastoma. Mammary-type myofibroblastoma is a benign spindle cell tumor typically composed of groups of myofibroblasts within bands of hyalinized collagenous stroma. Some tumors also have an adipocytic component. The tumor is nearly exclusively seen in the breast and although extramammary soft tissue locations have been described, to our knowledge, this is the first reported case in the liver or any visceral site. Although rare, radiologists and clinicians should, therefore, be aware of the possibility of a mammary-type myofibroblastoma when a solid, non-encapsulated, fat containing tumor in the liver is encountered.

Inter-strain variability in responses to a single administration of the cannabidiol-rich cannabis extract in mice.

Cannabidiol (CBD) has gained widespread popularity; however, its pharmacological and toxicological profiles in the context of human genetic diversity remain largely unexplored. Here, we investigated the variability in metabolism and toxicity of CBD-rich cannabis extract (CRCE) in genetically diverse mouse models: C57BL/6J, B6C3F1/J, and NZO/HlLtJ strains. Mice received a single dose of CRCE containing 57.9% CBD at dosages of 0, 246, 738, and 2460 mg/kg of CBD. At 24 h after treatment, no appreciable histomorphological changes were detected in the liver. Plasma bilirubin levels increased markedly in all strains at the highest CBD dose. Mice in all treatment groups displayed significant but distinct increases in ALT and AST levels. While B6C3F1/J and NZO/HlLtJ mice had negligible plasma CBD levels at 738 mg/kg, C57BL/6J mice exhibited levels exceeding 7000 ng/mL. At 2460 mg/kg, high CBD concentrations were found in B6C3F1/J and C57BL/6J mice, but markedly lower levels were seen in NZO/HlLtJ mice. Gene expression profiling showed significant increases in Cyp2b10 across all strains but varying responses in Cyp1a1 expression, indicating strain-specific CYP dysregulation. Genetically diverse mice exhibited differential pharmacological and toxicological responses to CRCE, suggesting a high potential for inter-individual variability in the pharmacology and toxicology of CBD in humans.

Dacryocystitis secondary to intranasal cocaine abuse: a case report and literature review.

PURPOSE: To report a case of dacryocystitis secondary to intranasal cocaine abuse and to review the literature on the effects of cocaine on sinus, nasal and lacrimal structures. METHODS: Case report and literature review. RESULTS: A 33-year-old male presented with unilateral epiphora and discharge, and clinical examination was consistent with dacryocystitis. He had a 2-year history of intranasal cocaine use. Computed tomography revealed extensive bilateral intranasal and sinus destruction, consistent with cocaine abuse. He was treated with antibiotics followed by dacryocystorhinostomy with silicone intubation. He had 2 recurrences of dacryocystitis and underwent one additional lacrimal surgery. CONCLUSIONS: Cocaine abuse and its accompanying intranasal and sinus destruction should be considered when determining the etiology of nasolacrimal obstruction and dacryocystitis. A medical and social history with specific questions about drug abuse may be useful. Computed tomography is helpful in delineating damage to the sinuses, nose and lacrimal system. Management with antibiotics and dacryocystorhinostomy surgery may result in resolution of symptoms.