A Case of Severe Drug-induced Liver Injury Caused by Over the Counter Herb (Cinnamon): Review of Literature.

A case of severe drug-induced liver injury caused by over the counter (OTC) herb medicine, is reported here. A 40-year-old male took herb drugs "Za ga-doKowa®," "Ohta-Isan®." These two drugs contained the same two herb medicines (cinnamon, fennel). About 4 months later after taking medicine, jaundice appeared. Prothrombin time activation (PT) was 45%, aspartate transaminase (AST) was 1104 IU/l, and total bilirubin (T-bil) 14.7 mg/dL. Serum tests for hepatitis viruses (A, B, C, E) were negative. Lymphocyte stimulating test was positive for Za ga-do Kowa ® and Ohta-I Isan®. Liver 3D constructed by construct-CT revealed findings of the potato-like liver. The liver biopsy specimen revealed multilobular hepatic necrosis accompanied by scar formation, severe zonal degeneration and necrosis of hepatocytes mainly in the central area of the lobule. In the reported 13 cases of cinnamon-induced liver diseases, there has been a severe abnormality of PT and T-bil. Biopsy findings of these cases showed wide ranges of necrosis. Liver injury due to cinnamon shows very severe damages, and the possibility of liver failure due to cinnamon may be imminent. How to cite this article: Higaki H, Onji M, Takeji S, Uehara T, Kawasaki K, Kashimoto Y, Murakami T, Yamaguchi T, Miyaike J, Oomoto M, Abe M. A Case of Severe Drug-induced Liver Injury Caused by Over the Counter Herb (Cinnamon): Review of Literature. Euroasian J Hepatogastroenterol, 2018;8(2):167-171.

Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus.

Parkinson's disease (PD) symptoms do not become apparent until most dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate, suggesting that compensatory mechanisms play a role. Here, we investigated the compensatory involvement of activated microglia in the SN pars reticulata (SNr) and the globus pallidus (GP) in a 6-hydroxydopamine-induced rat hemiparkinsonism model. Activated microglia accumulated more markedly in the SNr than in the SNc in the model. The cells had enlarged somata and expressed phagocytic markers CD68 and NG2 proteoglycan in a limited region of the SNr, where synapsin I- and postsynaptic density 95-immunoreactivities were reduced. The activated microglia engulfed pre- and post-synaptic elements, including NMDA receptors into their phagosomes. Cells in the SNr and GP engulfed red fluorescent DiI that was injected into the subthalamic nucleus (STN) as an anterograde tracer. Rat primary microglia increased their phagocytic activities in response to glutamate, with increased expression of mRNA encoding phagocytosis-related factors. The synthetic glucocorticoid dexamethasone overcame the stimulating effect of glutamate. Subcutaneous single administration of dexamethasone to the PD model rats suppressed microglial activation in the SNr, resulting in aggravated motor dysfunctions, while expression of mRNA encoding glutamatergic, but not GABAergic, synaptic elements increased. These findings suggest that microglia in the SNr and GP become activated and selectively eliminate glutamatergic synapses from the STN in response to increased glutamatergic activity. Thus, microglia may be involved in a negative feedback loop in the indirect pathway of the basal ganglia to compensate for the loss of dopaminergic neurons in PD brains.

The hypnotic bromovalerylurea ameliorates 6-hydroxydopamine-induced dopaminergic neuron loss while suppressing expression of interferon regulatory factors by microglia.

The low molecular weight organic compound bromovalerylurea (BU) has long been used as a hypnotic/sedative. In the present study, we found that BU suppressed mRNA expression of proinflammatory factors and nitric oxide release in lipopolysaccharide (LPS)-treated rat primary microglial cell cultures. BU prevented neuronal degeneration in LPS-treated neuron-microglia cocultures. The anti-inflammatory effects of BU were as strong as those of a synthetic glucocorticoid, dexamethasone. A rat hemi-Parkinsonian model was prepared by injecting 6-hydroxydopamine into the right striatum. BU was orally administered to these rats for 7 days, which ameliorated the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and alleviated motor deficits. BU suppressed the expression of mRNAs for interferon regulatory factors (IRFs) 1, 7 and 8 in the right (lesioned) ventral midbrain as well as those for proinflammatory mediators. BU increased mRNA expression of various neuroprotective factors, including platelet-derived growth factor and hepatocyte growth factor, but it did not increase expression of alternative activation (M2) markers. In microglial culture, BU suppressed the LPS-induced increase in expression of IRFs 1 and 8, and it reduced LPS-induced phosphorylation of JAK1 and STATs 1 and 3. Knockdown of IRFs 1 and 8 suppressed LPS-induced NO release by microglial cells. These results suggest that suppression of microglial IRF expression by BU prevents neuronal cell death in the injured brain region, where microglial activation occurs. Because many Parkinsonian patients suffer from sleep disorders, BU administration before sleep may effectively ameliorate neurological symptoms and alleviate sleep dysfunction.

Outcome evaluation of an intervention to improve the effective and safe use of meropenem.

BACKGROUND: Pharmacists have been involved in promoting the proper and safe use of antimicrobial drugs in our institution since 2010. Setting Kochi Medical School Hospital, Japan. OBJECTIVE: To design and evaluate a plan of administration of meropenem (MEPM) based on its pharmacokinetics and pharmacodynamics, drug sensitivity, bacterial cultures, patient condition and renal function. METHOD: A total of 547 patients admitted between April 2010 and March 2013 with serious infections who were successfully treated with MEPM for three or more days were analysed. Patients were initially divided into two groups according to renal function: group A consisted of patients with mild renal dysfunction [creatinine clearance (CLcr) > 50 mL/min] while group B consisted of patients with moderate to severe renal dysfunction (CLcr ≤ 50 mL/min). These groups were then subdivided into two groups according to the implementation of pharmacist intervention. MAIN OUTCOME MEASURES: Daily dose, frequency of administration, dose interval, duration of therapy, adverse events and cost reduction. RESULTS: In the non-intervention subgroup within group A, the daily dose was 1,000 mg/day, the frequency of administration was 1.8 ± 0.6 times/day, and the duration of therapy was 9.4 ± 5.4 days. In the intervention subgroup within group A, the daily dose was 1,500 mg/day, the administration frequency was 2.5 ± 0.6 times/day, and the duration of therapy was 7.4 ± 3.7 days. Although the dose was higher (P < 0.05) and the duration of therapy was an average of 2 days shorter (P < 0.05) in the intervention subgroup, there was no significant difference in the rate of adverse events between the two subgroups. In group B, there were no significant differences between the two subgroups in the daily dose, administration frequency, or duration of therapy. However, liver dysfunction was significantly more common in the non-intervention subgroup than in the intervention subgroup (P < 0.05). The total reduction in drug cost in the intervention groups was estimated to be US$17,490 over 3 years. CONCLUSION: Pharmacist intervention was associated with a shorter duration of therapy, lower drug costs, and decreased adverse effect. We believe that our intervention is beneficial in terms of effectiveness and safety, and supports proper antimicrobial use.

Association of Merkel cell polyomavirus infection with morphologic differences in Merkel cell carcinoma.

Recently, it has been shown that approximately 80% of Merkel cell carcinomas harbor a novel polyomavirus named Merkel cell polyomavirus, thought to be a carcinogenic agent. However, it is not fully elucidated whether Merkel cell carcinomas differ with regard to the presence or absence of Merkel cell polyomavirus. To address this, we investigated morphologic differences between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas by morphometry. Using polymerase chain reaction and real-time quantitative polymerase chain reaction, Merkel cell polyomavirus was detected in 20 (77%) of 26 Merkel cell carcinoma cases, including 4 Merkel cell carcinomas combined with squamous cell carcinomas. Interestingly, Merkel cell polyomavirus was detected only in ordinary (pure) Merkel cell carcinomas; none of the 4 combined Merkel cell carcinomas + squamous cell carcinomas was positive for Merkel cell polyomavirus (P = .001). Morphometric analyses revealed that Merkel cell polyomavirus-negative Merkel cell carcinomas had more irregular nuclei (P < .001) and more abundant cytoplasm (P = .001) than Merkel cell polyomavirus-positive Merkel cell carcinomas, which had uniform round nuclei and scant cytoplasm. Reliability of the morphometry was confirmed using intraobserver and interobserver reliability tests. These results demonstrated statistically significant differences in tumor cell morphology between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas and reconfirmed the absence of Merkel cell polyomavirus in combined tumors. Furthermore, the results strongly suggest fundamental biological differences between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas, supporting that Merkel cell polyomavirus plays an important role in the pathogenesis of Merkel cell polyomavirus-positive Merkel cell carcinoma.

In vitro Epstein-Barr virus infection model of rabbit lymphocytes from peripheral blood or spleen.

Most humans become lifelong carriers of Epstein-Barr virus (EBV) by adulthood. Primary EBV infection in adolescents causes infectious mononucleosis. EBV infection is associated with various diseases, neoplasms and hematological disorders. Recently, we reported that EBV can infect rabbits by intravenous, intranasal and/or peroral inoculation, which caused primary EBV infection in rabbits with heterogeneous host reactions. Some rabbits showed chronic and lifelong EBV infection with hemophagocytosis. In this study, to reveal detailed mechanisms in rabbit EBV infection, an in vitro investigation was performed. We elucidated that: (1) EBV can infect rabbit peripheral blood mononuclear cells and splenic lymphocytes in vitro, because EBV gene expressions were confirmed. (2) It is highly likely that the B cell is the main target cell of rabbit EBV infection and is immortalized similar to humans. (3) CD8+ T cells increased in the rabbit in vivo model after EBV inoculation, whereas an increase of B cells occurred after their transient decrease. These data suggest that EBV-infected B cells were proliferated, while CD8+ T cells increased to recognize and kill them. This system may explain the paths of rabbit EBV infection and host reaction, simulating human EBV infection. In vitro studies will be helpful to reveal the pathogenesis of rabbit EBV infection and EBV-associated diseases.

Lifelong persistent EBV infection of rabbits with EBER1-positive lymphocyte infiltration and mild sublethal hemophagocytosis.

Most humans become lifelong carriers of Epstein-Barr virus (EBV) by adulthood. Primary EBV infection in adolescents causes in one to two-third of cases infectious mononucleosis. EBV infection is associated with various diseases, neoplasms and hematological disorders. Recently we reported that EBV can infect rabbits frequently by intravenous, intranasal or/and peroral inoculation, which caused primary EBV infection in rabbits with heterogeneous host reactions. Here we presented follow up data that of six primary EBV-infected rabbits out of seven inoculated intravenously with EBV, two out of six EBV-infected rabbits showed lifetime EBV infection. (1) EBV-DNA were detected in blood through life. (2) High antibody titers against EA-D were maintained over 1000 days. (3) A focal mass lesion was transiently observed by ultrasonography in the spleen of one rabbit. (4) Two lifelong EBV-detected rabbits died on day 1522 or 1400, and autopsy revealed proliferation of lymphocytes expressing EBER1 or LMP1 accompanied with mild hemophagocytosis in the spleen or lymph nodes. We hypothesized some EBV-infected rabbits could not eliminate EBV for life and showed somewhat similar features to persistent EBV infection, mild CAEBV and/or mild sublethal hemophagocytosis. These lifelong EBV-infected rabbits might be a new useful animal model for studying lifelong persistent EBV infection, taking place in almost all adults.

Identification of a major yolk protein as an allergen in sea urchin roe.

Anaphylaxis after eating sea urchin roe has been reported. However, its major allergens have not yet been identified. The aim of this study was to identify the major allergens of sea urchin roe. Proteins of sea urchin roe were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and two-dimensional electrophoresis (2-DE). An immunoglobulin (Ig)E-binding protein was detected by immunoblotting using the patient's serum. An allergen isolated from 2DE-gel was identified by peptide mass fingerprinting using matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Immunoblot analysis of sea urchin extracts showed that a 160-kDa protein at pI 6-7 was recognized by the patient's IgE. Peptide mass fingerprint analysis revealed that the protein was the major yolk protein (152 kDa, pI 6.9) of sea urchins. The results show that a major allergen of sea urchin roe is the major yolk protein.