Treatment of Hyperammonemia by Transplanting a Symbiotic Pair of Intestinal Microbes

Hyperammonemia is a deleterious and inevitable consequence of liver failure. However, no adequate therapeutic agent is available for hyperammonemia. Although recent studies showed that the pharmabiotic approach could be a therapeutic option for hyperammonemia, its development is clogged with poor identification of etiological microbes and low transplantation efficiency of candidate microbes. In this study, we developed a pharmabiotic treatment for hyperammonemia that employs a symbiotic pair of intestinal microbes that are both able to remove ammonia from the surrounding environment. By a radioactive tracing experiment in mice, we elucidated how the removal of ammonia by probiotics in the intestinal lumen leads to lower blood ammonia levels. After determination of the therapeutic mechanism, ammonia-removing probiotic strains were identified by high-throughput screening of gut microbes. The symbiotic partners of ammonia-removing probiotic strains were identified by screening intestinal microbes of a human gut, and the pairs were administrated to hyperammonemic mice to evaluate therapeutic efficacy. Blood ammonia was in a chemical equilibrium relationship with intestinal ammonia. Lactobacillus reuteri JBD400 removed intestinal ammonia to shift the chemical equilibrium to lower the blood ammonia level. L. reuteri JBD400 was successfully transplanted with a symbiotic partner, Streptococcus rubneri JBD420, improving transplantation efficiency 2.3×103 times more compared to the sole transplantation while lowering blood ammonia levels significantly. This work provides new pharmabiotics for the treatment of hyperammonemia as well as explains its therapeutic mechanism. Also, this approach provides a concept of symbiotic pairs approach in the emerging field of pharmabiotics.

Impact of Granular Activated Carbon on Anaerobic Process and Microbial Community Structure during Mesophilic and Thermophilic Anaerobic Digestion of Chicken Manure

In this work, the impact of granular activated carbon (GAC) on the mesophilic and thermophilic anaerobic digestion of chicken manure and the structure of microbial communities was investigated. These results demonstrated that GAC supplementation effectively enhanced the consumption of produced organic acids in the mesophilic and thermophilic batch tests, accompanied by faster biomethane production in the presence of GAC than from reactors without GAC. However, since the free ammonia level was 3–6 times higher in the thermophilic reactors, this led to the instability of the anaerobic digestion process of the nitrogen-rich substrate at thermophilic temperatures. Bacteroidia and Clostridia were the two main bacterial classes in the mesophilic reactors, whereas the class Clostridia had a competitive advantage over other groups in the thermophilic systems. The archaeal communities in the mesophilic reactors were mainly represented by representatives of the genera Methanosarcina, Methanobacterium, and Methanotrix, whereas the archaeal communities in the thermophilic reactors were mainly represented by members of the genera Methanosarcina, Methanoculleus, and Methanothermobacter. New data obtained in this research will help control and manage biogas reactors in the presence of GAC at different temperatures.

Correlation of Asthma with Ammonia Exposure and Other Risk Factors among Informal Workers of Poultry Farmers

Objective: To determine the prevalence of asthma and its corelation with ammonia exposure among informal workers of poultry farmers.Method: This study design was a cross-sectional analytic to 69 respondents using questionnaires, field observation, physical examination, spirometry measurement, and peak flowmeter test to diagnose work-related asthma and measurement of ammonia level in air environment of farm. All variable were bivariate tested by using Chi-square test or Fischer test. The variables which have p value <0,25 were included into multivariate analysis by using binary logistic regression.Results: The prevalence of asthma in poultry farmers was 21,74%. In bivariate analysis, there was a significant corelation between working periode (p = 0,035 with OR = 7,00) and smoking habit (p = 0,018 with OR = 5,603) with asthma. There was no significant corelation between age, sex, nutritional status, work location, education level and marital status with asthma. The result of measurement of ammonia level in the poultry farm enclosure on average is 2,329 ppm. Multivariate analysis was performed on several risk factors that fulfilled the requirement p <0,25 ie working periode, smoking habit, nutritional status, and work location. From the results of mutivariate found that workers with a history of smoking habits have the strongest corelation p = 0,013 with OR 17,305.Conclusion: The prevalence of asthma in poultry farmers was 21,74%. There was no significant corelation between ammonia exposure in the work environment with asthma. But there was a significant corelation between working periode and smoking habit with asthma.

Risk Factors of Elevated Blood Ammonia Level in Epilepsy Patients Treated With Lamotrigine

Background The aim of this study was to explore the effect of lamotrigine (LTG) on blood ammonia level in patients with epilepsy and identify risk factors affecting blood ammonia level. Methods This study included 91 epilepsy patients who were treated with LTG at Department of Neurology, Zhongshan Hospital, Xiamen University from January 2011 to April 2016, and were followed up for three years. Blood samples were taken during the interictal state and analyzed for blood LTG and ammonia levels. Results Total 46.1% of the samples exceeded the median blood ammonia level, and 2.1% of patients had hyperammonemia. Blood ammonia level was positively correlated with LTG blood concentration. LTG combined with valproic acid (VPA) therapy, seizure within one year, and elevated neutrophils affected blood ammonia level. Conclusion Blood ammonia level was significantly correlated with plasma concentration of LTG. LTG combined with VPA therapy, seizure within one year, and elevated neutrophils may be risk factors for elevated blood ammonia level in epilepsy patients treated with LTG.

Recovery of E. coli From Liver and Spleen of Broiler Birds and the Effects of Induced High Ammonia Level on Haematobiochemical Parameters and Its Amelioration by Different Modifiers

The poultry sector is one of the most vibrant segments of the agriculture industry of Pakistan. In addition to different infections, ammonia (NH3) production from litter material of broiler is the most harmful pollutant and causes serious threats for the environment. To overcome this problem, different methods are proposed assuring poultry bird’s health and production. This study was carried out to evaluate the effect of toxic levels of NH3 on the haematology and serum proteins of broiler birds and its amelioration by using different modifiers. The recovery of Escherichia coli ( E. coli) from liver and spleen of broiler birds was also carried out. A total of 100 birds were divided into 5 separate groups (groups A–D). The groups C, D and E were treated with potassium aluminium sulphate, aluminium silicate and Yucca schidigera plant extract, respectively. Blood and tissue samples were collected after slaughtering the birds at 42 days of age. This study revealed increased RBC, total leucocyte count, Hb and heterophils percentage. Serum proteins were decreased in Yucca-treated and potassium aluminium sulphate–treated groups. This study concluded that NH3 production was reduced by the application of different modifiers, and these modifiers also neutralized the changes in blood parameters induced by NH3.

Clinical Reasoning: Middle-aged Man With Progressive Gait Abnormalities

Progressive spastic paraplegia is the core symptom of hereditary spastic paraplegia (HSP), a group of monogenic disorder characterized pathologically by degeneration of the corticospinal tract and dorsal column and leading to irreversible neurologic deficits. However, acquired causes, such as structural, vascular, inflammatory, infectious, metabolic, toxic, neurodegenerative, and iatrogenic causes can also cause acquired spastic paraplegia. We describe a case of a middle-aged man presenting with progressive spastic paraplegia combined with ataxia and parkinsonism. No mutation of HSP genes was detected. After a comprehensive diagnostic work-up, hyperintensities in the bilateral basal ganglia, mesencephalon, pons, and cerebellum on T1-weighted images were found, which demonstrated hypointensity on susceptibility weighted imaging (SWI). Furthermore, an increased blood ammonia level and diffuse slow wave activity in electroencephalogram were detected. Combined with a 7-year history of hypertension and alcoholic liver cirrhosis and the history of Transjugular Intrahepatic Portosystemic Shunt (TIPS) operation two years prior to the symptom of spastic paraplegia, concurrent acquired hepatocerebral degeneration (AHD) and hepatic myelopathy (HM) was finally diagnosed. The current case provided a detailed diagnostic approach for progressive spastic paraplegias and an exhaustive differential diagnoses of basal ganglia deposits. The take-home message from this case was that acquired causes, especially curable causes should always be excluded first when dealing with patients with progressive spastic paraplegia.

Early Tumor Response and Safety of Atezolizumab Plus Bevacizumab for Patients with Unresectable Hepatocellular Carcinoma in Real-World Practice

The aim of this study was to investigate the early tumor response and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma in real-world practice. Forty patients with Child-Pugh class A liver function and eastern cooperative oncology group performance status 0 or 1 were enrolled. The objective response rate (ORR) at six weeks after the start of treatment, changes in α-fetoprotein (AFP) and des-γ-carboxyprothrombin, incidence of adverse events (AEs), and changes in albumin-bilirubin (ALBI) score and serum ammonia level, were evaluated. Among 40 patients, 24 had histories of prior molecular targeted agents (MTAs). The ORR was 22.5% based on mRECIST. Multivariate analysis showed that an AFP ratio <1.0 at three weeks (odds ratio 39.2, 95% confidence interval CI 2.37–649.0, p = 0.0103) was the only significant factor for predicting early response. There was no significant difference in the frequency of AEs between patients receiving first-line treatments and others. Fatigue, proteinuria, and ascites were more frequent in patients who experienced prior treatment. No decrease in ALBI score or increase in serum ammonia level was observed. Our study demonstrated that AFP may be useful in assessing early response and that this treatment is safe, including in patients with prior MTA treatments.

Case Report of A Rare Idiosyncratic Hepatotoxicity Induced by Valproic Acid

Valproate induced hepatotoxicity is a well-known side effect, which frequently required periodic monitoring of serum drug level. Hepatotoxicity caused by valproate typically occurs at supratherapeutic drug levels. Once in a while, an idiosyncratic reaction is elicited, liver injury might occur despite normal serum valproate level mainly in chronic users. We hereby identify an unusual case of acute idiosyncratic valproate induced hepatotoxicity. We report a case of a 65 years old male with dyslipidemia and history of seizure, on valproic acid therapy, presented with altered mental status and drowsiness. The patient’s home medications include only zenil 10 mg daily and valproate which was started one month ago. At presentation, He was awake, oriented, but lethargic. Laboratory testing reveals hepatocellular injury with elevated transaminase levels, direct hyperbilirubinemia and coagulopathy. The ammonia level was normal and valproate level was within the therapeutic range. Abdomen computed tomography with IV contrast and MRCP results were irrelevant. Idiosyncratic valproate toxicity was diagnosed after exclusion of all other possible etiologies and after a rapid clinical and laboratory improvement once the drug was discontinued. Based on the patient’s clinical context the diagnosis of valproate induced hepatotoxicity was confirmed. This case emphasizes the importance of identifying, diagnosing, and managing valproate toxicity when no alternative clarification for their symptoms. We need further attempts and more researches to improve the detection of adverse hepatic reactions and to obtain reliable information about the discovery of new biomarkers or tools for early prediction of DILI, as well as to obtain accurate information on epidemiology, drug safety, and pathogenesis in order to improve management for better survival.

Recurrent Altered Mental State Associated with Nonhepatic Hyperammonemia Presented in an Elderly Female Patient: Probable Late-Onset Urea Cycle Disorder

Altered mentality associated with hyperammonemia is usually diagnosed in patients with liver disease. Nonhepatic hyperammonemia may be present in critically ill patients or may be caused by high protein diets or certain drugs. Urea cycle disorders (UCDs) rarely present with altered mentality with hyperammonemia in adult patients. An 82-year-old female visited our hospital with complaints of abnormal behavior and confusion. Routine blood tests revealed elevated serum ammonia. Her mentality and serum ammonia level normalized after lactulose enema and she was discharged thereafter. However, she was later re-admitted because of recurrent altered mentality. Amino acid analysis revealed that serum levels of ornithine and glutamine increased significantly, whereas the levels of alanine and glutamic acid increased slightly, and the levels of arginine, lysine, and citrulline were normal, which were probably caused by reduced activity of the mitochondrial ornithine carrier-1. Although our patient was not diagnosed genetically, this case illustrates the under-recognized fact that UCD can occur in a senile age. Clinical suspicion of UCDs in patients with hyperammonemia is critical for early diagnosis and to prevent the significant neurologic sequelae.