Hepatitis B genotypes in Aboriginal and Torres Strait Islander Australians: correlation with clinical course and implications for management.

BACKGROUND: The prevalence of chronic hepatitis B (CHB) in Aboriginal and Torres Strait Islander Australians in Far North Queensland (FNQ) is greater than twice that of the general Australian population. CHB is common in Torres Strait Islanders diagnosed with hepatocellular carcinoma (HCC) - and in Aboriginals with HCC living in the Northern Territory - however, Aboriginals diagnosed with HCC in FNQ very rarely have CHB. The explanation for this apparent disparity is uncertain. AIMS: To determine the HBV genotypes in the FNQ Aboriginal and Torres Strait Islander population and their correlation with clinical phenotype. METHODS: We determined the HBV genotype of Aboriginal and Torres Strait Islander Australians living with CHB in FNQ and correlated this with demographic and clinical findings. RESULTS: 134/197 (68%) enrolled individuals had a sufficient viral load for genotyping. All 40 people with HBV/D genotype had Aboriginal heritage, whereas 85/93 (91%) with HBV/C had Torres Strait Islander heritage (P < 0.0001). Individuals with HBV/D were younger than those with HBV/C (median (interquartile range) age: 43 (39-48) vs 53 (42-66) years, P = 0.0002). However, they were less likely to be HBeAg positive (1/40 (3%) vs 23/93 (25%), P = 0.001). All three HCCs developed in Torres Strait Islanders; two-thirds were infected with HBV/C14; genotyping was not possible in the other individual. All 10 diagnoses of cirrhosis occurred in Torres Strait Islanders, 6/10 were infected with HBV/C14, genotyping was not possible in the other four individuals. CONCLUSIONS: HBV genotypes in Aboriginal and Torres Strait Islander Australians in FNQ differ markedly, which could explain the significant differences in the clinical phenotype in the two populations and might be used to inform cost-effective CHB care in the region.

Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

The high burden of comorbidities in Aboriginal and Torres Strait Islander Australians living with chronic hepatitis B in Far North Queensland, Australia, and the implications for patient management.

BACKGROUND: Aboriginal and Torres Strait Islander Australians living with chronic hepatitis B virus (HBV) infection have a significant burden of hepatocellular carcinoma (HCC). The prevalence of comorbidities that increase the risk of HCC in this population is incompletely defined. METHODS: This cross-sectional study was performed in remote tropical Queensland, Australia in January 2021. All individuals living with chronic HBV in the region were identified; the prevalence of relevant comorbidities was determined by reviewing medical records. RESULTS: All 236 individuals in the cohort identified as Aboriginal and Torres Strait Islander Australians; their median (interquartile range (IQR)) age was 48 (40-62) years; 120/236 (50.9%) were female. Of the 194/236 (82.2%) engaged in HBV care, 61 (31.4%) met criteria for HBV therapy and 38 (62.2%) were receiving it. However, 142/236 (60.2%) were obese, 73/236 (30.9%) were current smokers and 57/236 (24.2%) were drinking alcohol hazardously; 70/236 (29.7%) had ≥2 of these additional risk factors for HCC, only 43/236 (18.2%) had none. Among the 19 patients with confirmed cirrhosis, 9 (47%) were obese, 8 (42%) were currently-or had a history of-drinking alcohol hazardously and 5 (26.3%) were current smokers. Patients also had a median (IQR) of 3 (2-4) cardiovascular risk factors (cigarette smoking, hypertension, impaired glucose tolerance, dyslipidaemia, renal impairment/proteinuria). Only 9/236 (3.8%) did not have one of these 5 comorbidities. CONCLUSIONS: Aboriginal and Torres Strait Islander Australians living with chronic HBV in this region of remote Australia have a high engagement with HBV care and the majority of individuals eligible for antiviral therapy are receiving it. However, a significant comorbidity burden increases their risk of cirrhosis, HCC, and premature death. It is essential to integrate chronic HBV care with management of these comorbidities-rather than focusing on HBV alone-to achieve optimal health outcomes.

Prevention of Diabetes-Associated Cognitive Dysfunction Through Oral Administration of Lipopolysaccharide Derived From Pantoea agglomerans.

Diabetes-related cognitive dysfunction (DRCD) is a serious complication induced by diabetes. However, there are currently no specific remedies for DRCD. Here, we show that streptozotocin-induced DRCD can be prevented without causing side effects through oral administration of lipopolysaccharide (LPS) derived from Pantoea agglomerans. Oral administration of LPS (OAL) prevented the cerebral cortex atrophy and tau phosphorylation induced by DRCD. Moreover, we observed that neuroprotective transformation of microglia (brain tissue-resident macrophages) is important for preventing DRCD through OAL. These findings are contrary to the general recognition of LPS as an inflammatory agent when injected systemically. Furthermore, our results strongly suggest that OAL promotes membrane-bound colony stimulating factor 1 (CSF1) expression on peripheral leukocytes, which activates the CSF1 receptor on microglia, leading to their transformation to the neuroprotective phenotype. Taken together, the present study indicates that controlling innate immune modulation through the simple and safe strategy of OAL can be an innovative prophylaxis for intractable neurological diseases such as DRCD. In a sense, for modern people living in an LPS-depleted environment, OAL is like a time machine that returns microglia to the good old LPS-abundant era.

Validation and Reliability of the Japanese Version of the Modified Parkinson Activity Scale (M-PAS).

OBJECTIVE: The Modified Parkinson Activity Scale (M-PAS) is used to identify the most important activity limitations in patients with Parkinson's disease. We developed a Japanese version of the M-PAS and evaluated its reliability and validity. METHODS: Twenty-five patients with Parkinson's disease (median age 71 years old, range 58-83) were enrolled, and two raters used the Japanese version of M-PAS to assess the subjects. The inter-rater reliability was evaluated using Cohen's weighted kappa coefficient for the total score and three domain scores; systematic error was investigated using Bland-Altman analysis. Concurrent validity of the Japanese M-PAS was measured using Spearman's rank correlation coefficients. RESULTS: Cohen's kappa coefficients for the total score and the three domain scores were in the range 0.81-0.98, and 95% confidence intervals included zero for each item, suggesting excellent agreement and no systematic errors. The scores of the Japanese version of M-PAS were significantly correlated with the scores of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part II (Spearman's rho=-0.56, P <0.01) and Part III (Spearman's rho=-0.32, P <0.01). The percentage of patients with the highest and the lowest scores in the Japanese version of M-PAS suggested no ceiling or floor effects. CONCLUSION: The Japanese version of M-PAS showed excellent inter-rater reliability and good concurrent validity without ceiling or floor effects.

A unique hybrid characteristic having both pro- and anti-inflammatory phenotype transformed by repetitive low-dose lipopolysaccharide in C8-B4 microglia.

Although lipopolysaccharide (LPS) is regarded as an inducer of inflammation, previous studies have suggested that repetitive low-dose LPS has neuroprotective effects via immunomodulation of microglia, resident macrophages of brain. However, microglia transformed by the stimulus of repetitive low-dose LPS (REPELL-microglia) are not well characterized, whereas microglia transformed by repetitive high-dose LPS are well studied as an endotoxin tolerance model in which the induction of pro-inflammatory molecules is suppressed. In this study, to characterize REPELL-microglia, the gene expression and phagocytic activity of REPELL-microglia were analyzed with the murine C8-B4 microglia cell line. The REPELL-microglia were characterized by a high expression of pro-inflammatory molecules (Nos2, Ccl1, IL-12B, and CD86), anti-inflammatory molecules (IL-10, Arg1, Il13ra2, and Mrc1), and neuroprotective molecules (Ntf5, Ccl7, and Gipr). In addition, the phagocytic activity of REPELL-microglia was promoted as high as that of microglia transformed by single low-dose LPS. These results suggest the potential of REPELL-microglia for inflammatory regulation, neuroprotection, and phagocytic clearance. Moreover, this study revealed that gene expression of REPELL-microglia was distinct from that of microglia transformed by repetitive high-dose LPS treatment, suggesting the diversity of microglia transformation by different doses of LPS.

Subchronic (90-day) toxicity assessment of Somacy-FP100, a lipopolysaccharide-containing fermented wheat flour extract from Pantoea agglomerans.

Pantoea agglomerans is a Gram-negative bacterium that is ubiquitous in the environment, colonizing animals, humans, and numerous plants, including cotton and wheat. A lipopolysaccharide-containing fermented wheat flour extract from P. agglomerans (Somacy-FP100) is proposed for use as a food ingredient for individuals seeking foods for healthy aging. Previously published genotoxicity studies with Somacy-FP100 reported its lack of genotoxicity in vitro, but a subchronic toxicity study has not yet been performed. Therefore, to demonstrate the safety of Somacy-FP100 for use as a food ingredient, a 90-day oral (gavage) toxicity study in rats was conducted. Male and female Han Wistar rats were administered vehicle (control) or Somacy-FP100 at 500, 1500, or 4500 mg/kg body weight/day at a dose volume of 10 mL/kg body weight, for at least 90 days. No test article-related adverse clinical signs or effects on body weight, food consumption, or clinical pathology were observed, and there were no macroscopic or microscopic findings related to the test article. Therefore, 4500 mg/kg body weight/day (the highest dose tested and highest feasible dose) was established as the no-observed-adverse-effect level. This absence of subchronic toxicity, in addition to the previously reported lack of genotoxicity, demonstrates the safety of Somacy-FP100 for use as a food ingredient.

Effects of 3 months continuous intake of supplement containing Pantoea agglomerans LPS to maintain normal bloodstream in adults: Parallel double-blind randomized controlled study.

In this study, the effects on the maintenance of normal bloodstream by lipopolysaccharide (LPS) were investigated in the parallel-group randomized double-blind study using supplement containing Pantoea agglomerans LPS (201.5 µg/tablet as LPS). Screening was previously performed in the implementation of the study. Adult males and females with normal value to borderline (healthy subjects) in the hematologic parameters, for which reference values were given, were chosen in this study. The period of ingestion of the supplement was 3 months. As the result, a significant decrease in the rate of change (the ratio when the baseline was 1) of HbA1c, which is a glycative stress marker, was found in the group which ingested LPS supplement after 3 months. Also, a significant increase in the number of fingertip capillary vessels was found compared with the control group. From these results, the effects of the maintenance of bloodstream by ingestion of LPS were shown.

Effects of the Subaleurone Layer of Rice on Macrophage Activation and Protection of Pollen Allergy in a Murine Model.

BACKGROUND/AIM: Oral intake of lipopolysaccharide (LPS) has been demonstrated to be effective in the prevention of various diseases. We have found that the subaleurone layer of rice contains a large amount of LPS. The aim of this study was to evaluate the role of this layer in innate immunity. MATERIALS AND METHODS: Using the Saika-style rice polishing process, a sbaleurone layer and the rice retaining a subaleurone layer and polished white rice were prepared from brown rice. Using hot-water extracts from rice, LPS content was measured by the Limulus reaction and the effect of activation of macrophages was evaluated on the basis of their phagocytic activity and nitric monoxide (NO) and tumor necrosis factor (TNF) production levels. Toll-like receptor (TLR)-2-, TLR-4- and TLR-9-transfected human embryonic kidney (HEK) cells were used to identify the activation pathway. An allergy mouse model was used to evaluate the prevention of pollen allergy. RESULTS: When compared to polished white rice, rice retaining a subaleurone layer had a 6-fold increase in LPS and an increased macrophage activation when phagocytic activity and NO and TNF production were used as indices. TRL4 was the major pathway for such activation. Anti-allergy test by oral intake of subaleurone showed a significant preventive effect for pollen allergy. CONCLUSION: Compared to polished white rice, rice retaining a subaleurone layer contained a high level of LPS with higher macrophage activation. Furthermore, oral administration of the rice demonstrated a preventive effect for pollen allergy, thus indicating its utility as a functional food that has a regulatory effect on innate immunity.

Oral Administration of Lipopolysaccharide of Acetic Acid Bacteria Protects Pollen Allergy in a Murine Model.

BACKGROUND/AIM: Lipopolysaccharide (LPS), a major component of the cell wall of Gram-negative bacteria, is known to possess strong immune-regulatory activity. We have found and reported the existence of biologically-active LPS in acetic acid bacteria. The LPS shows Limulus-positive activity and activation of macrophages to produce nitric oxide and tumor necrosis factor. In this study, we investigated the anti-allergic effect of an orally-administrated acetic acid bacteria extract containing LPS; the cedar pollinosis model was used. MATERIALS AND METHODS: Acetic acid bacteria were isolated from various fruits by Nodai kaihen medium. Then, the anti-allergic effect of acetic acid bacteria extracts was investigated. BALB/c mice were immunized with a mixture of cedar pollen and alum into their peritoneal cavity; they also received additional immunizations of pollen to nasal cavity. After immunizing the mice with pollen into their nasal cavity to trigger an allergic reaction, the frequency of nose scratching was counted for 5 min. RESULTS: The bacteria were cultured and prepared and the water-extract contained about 1-10 mg/ml of Limulus positive substances. The extract of acetic acid bacteria induced higher levels of interleukin (IL)-10 and FOXP3 mRNA expression in macrophages (RAW246.7 cell), as assessed by DNA microarray analysis. Oral administration of the acetic acid bacteria extract demonstrated significantly less scratching numbers than control water group with pollen immunization. CONCLUSION: These results showed that LPS in acetic acid bacteria has the potential to protect from an allergic reaction, especially from cedar pollinosis.

Pantoea agglomerans lipopolysaccharide maintains bone density in premenopausal women: a randomized, double-blind, placebo-controlled trial.

Lipopolysaccharide fromPantoea agglomerans (LPSp) facilitates Ca and P turnover in chicken calvaria and femurs. This study investigated osteoporosis prevention by the oral administration of LPSp in mice and in double-blind clinical tests. Using ovariectomized (OVX) osteoporosis mice model, we investigated the effects of LPSp on the bone density and Ca concentration after ingesting LPSp-containing water for 4 weeks. Oral administration of LPSp tended to suppress the decline in the bone density and the cortical bone thickness in the OVX mice. Moreover, the Ca concentrations were maintained in the OVX-LPSp mice. The effects of LPSp on bone turnover were tested in randomized and double-blind clinical test subjects, who were healthy women aged 40-79 years. The subjects ingested either soy milk without LPSp (control group) or with LPSp (LPSp group) for 3 months. The results showed that the LPSp group on premenopause maintained their bone density compared with the control group pre- and postmenopause. Moreover, these effects were maintained for 2 months postobservation. LPSp maintains bone volume and density in vivo. Thus, a combination of soy milk and LPSp may be useful for osteoporosis prevention.

[A case of subglottic stenosis with bridging granuloma after intubation with double-lumen endotracheal tube].

We present a case of subglottic stenosis with rare bridging granuloma after intubation with double-lumen endotracheal tube. An 81-year-old woman was diagnosed with the lung tumor and scheduled for the thoracoscopic surgery. We induced anesthesia with propofol, remifentanil and rocuronium. A 35 Fr double-lumen intratracheal tube was inserted to the trachea with some resistance, when the tube passed through the glottis. A few days later, she suffered from respiratory discomfort. An otolaryngologist examined her larynx and subglottis. Laryngoscopic examination revealed bridging granuloma leading to tracheal stenosis. Tracheostomy and resection of granuloma were performed, and her symptom improved. If we feel resistance in intubating a double-lumen endotracheal tube in a patient with a history of intubation with a tracheal tube, we should operate gently adjusting the size of the tracheal tube.

Chronic hepatitis B--care delivery and patient knowledge in the Torres Strait region of Australia.

BACKGROUND: Chronic hepatitis B (CHB) disproportionately affects Indigenous Australians. This article reports the findings of two studies in the Torres Strait and Northern Peninsula area (T&NPA) of Queensland in Australia. The aim of the first study was to assess CHB care delivery, the second assessed CHB patient knowledge about the condition. METHODS: A pathology database search (1997-2009) identified a cohort of potential CHB patients in T&NPA. A file audit assessed care delivery for a random sample of 83 CHB patients. A survey assessed knowledge of 42 CHB patients. RESULTS: A total of 365 hepatitis B positive patients were identified. There are gaps in patient review, monitoring, follow up and specialist referral. Patients had limited knowledge about CHB and measures to reduce its health impact. DISCUSSION: Chronic hepatitis B affects a substantial number of Indigenous adults in the T&NPA. There is limited adherence to clinical guidelines. Improved uptake of clinical guidelines adapted for remote areas, incorporation of CHB into systematic chronic disease care, and culturally appropriate patient education resources and programs are needed.

[Involvement of zinc in taste disturbance occurring during treatment for malignant tumor in the chest and the effects of polaprezinc oral disintegrating tablets (a retrospective study)].

We analyzed the correlation between serum zinc levels and taste disturbance, and between patient backgrounds and serum zinc levels or taste disturbance, and evaluated the effects of polaprezinc oral disintegrating tablets on taste disturbance in 29 patients with lung cancer and one patient with malignant pleural mesothelioma who were receiving chemotherapy. Taste disturbance developed in 11 (36.7%) out of 30 patients. Serum zinc levels significantly correlated with taste disturbance (p=0.0227). Serum zinc levels were significantly lower (p=0.0235) and taste disturbance tended to be more frequent (p=0.0625) in males. Polaprezinc improved taste disturbance in 5 of 8 patients.