Comparative study of efficacy of prepartum injection of multivitamins and selenium- vitamin E (ά-tocopherol)-combination on post-partum clinical findings, serum steroids, calf and placental weights, and milk antioxidant biomarkers changes in female dromed

Background: All concentrates given to camels were enriched in selenium (Se) in selenite form. The impacts of Se supplementation on lactating female health, milk, and Se/antioxidant statuses received no research interest. Aim: The current study aimed to compare the efficacy of long-term prepartum injection of Se-vitamin E combination and multivitamins on maternal post-calving clinical findings, serum steroid hormones, milk antioxidants, milk somatic cell count (SCC) status, calf body weight, placental weight (PW), and vaginal wash isolates. Methods: From three equal groups of postpartum she-camels (n = 45), one group received no treatment and served as control group (Cont.; n = 15). For 3 months prepartum, one group had received a combination of vitamin E (ά-tocopherol) and Se (VitE-Se-; n = 15), and the third one received multivitamins (Multi-; n = 15). All dams were subjected to clinical and laboratory assays including milk total antioxidant capacity (TAC), Se, vitamin E, and milk SCC on Days 14, 21, and 28 post-calving. Steroid hormones and calf and PW were estimated at birth (Day 0). Results: The study reported higher efficacy of Se-vitamin E combination comparing with that of multivitamins as a long-term prepartum injection in recently calved she-camels that was reflected through significant changes in steroids hormones (Drop), i.e., progesterone (P4) and estradiol (E2), the milk antioxidant biomarkers (Elevation), i.e., TAC, Se, vitamin E, and milk SCCs (Reduction). Both two therapeutic regimens had a more powerful effect that the control one. Conclusion: The applied therapeutic supplements had no significant effect on clinical and hematological changes as well as calves’ body weights and PWs. Body weights were significantly higher in male camel calves than those of female calves either in Cont., VitE-Se-, or Multi-

Does Weight Loss Through Means of Bariatric Surgery Reduce the Risk of Type 2 Diabetes in Obese Qatari Patients: A retrospective analysis

Background and objectives: The use of bariatric surgeries such as Gastric Bypass and Sleeve Gastrectomy in managing obesity and associated diseases such as type 2 diabetes mellitus (T2DM) has been induced in clinical practice. Weight reduction through means of bariatric surgery has metabolic benefits and may improve the management of T2DM. The aim of this study was to investigate if weight loss through bariatric surgery can reduce the risk of T2DM in patients without the onset of T2DM. Study design: A retrospective analysis was conducted on post-bariatric patients at the department of bariatric and metabolic surgery at Hamad General Hospital. Methods: Tow hundred and two eligible pre-diabetic Qatari patients who have undergone bariatric surgery in 2016 and satisfied the inclusion and exclusion criteria of the study were analyzed. Data on Glucose, Insulin and C-peptides levels at baseline and follow-up were extracted in order to compare the change of these variables at baseline, 6 and 10 months follow up before and after 10 months from the date of surgery. Results: Seventy one males with mean age of 32.73 ± 10.37 and one hundred and thirty one females with mean age of 33.90 ± 9.88 were included in the analysis. Change in weight was strongly and positively associated with change in insulin level (0.701, 95% CI: 0.027, 1.347, p= 0.042) also, as weight changes fasting glucose changes (1.993, 95% CI: 0.359, 3.627, p= 0.017). Follow-up period greater than 6 months was not found to be significantly associated with weight loss (2.049, 95% CI: -2.249, 6.349, p= 0.313). Conclusion: Our study confirms results from international studies that weight loss through bariatric surgery can reduce the risk of developing Type 2 Diabetes in Qatari obese patients. The results of the study also suggest that post-surgery periods can be detrimental to the fate of fasting glucose and insulin levels and therefore compliance maybe of great importance to ensure success and sustainability of weight loss and diabetes prevention. Larger samples size and longer follow-up period is required to confirm these findings.Qatar University and Hamad Medical Corporatio

Nuclear translocation of FGFR1 and FGF2 in pancreatic stellate cells facilitates pancreatic cancer cell invasion

Pancreatic cancer is characterised by desmoplasia, driven by activated pancreatic stellate cells (PSCs). Over-expression of FGFs and their receptors is a feature of pancreatic cancer and correlates with poor prognosis, but whether their expression impacts on PSCs is unclear. At the invasive front of human pancreatic cancer, FGF2 and FGFR1 localise to the nucleus in activated PSCs but not cancer cells. In vitro, inhibiting FGFR1 and FGF2 in PSCs, using RNAi or chemical inhibition, resulted in significantly reduced cell proliferation, which was not seen in cancer cells. In physiomimetic organotypic co-cultures, FGFR inhibition prevented PSC as well as cancer cell invasion. FGFR inhibition resulted in cytoplasmic localisation of FGFR1 and FGF2, in contrast to vehicle-treated conditions where PSCs with nuclear FGFR1 and FGF2 led cancer cells to invade the underlying extra-cellular matrix. Strikingly, abrogation of nuclear FGFR1 and FGF2 in PSCs abolished cancer cell invasion. These findings suggest a novel therapeutic approach, where preventing nuclear FGF/FGFR mediated proliferation and invasion in PSCs leads to disruption of the tumour microenvironment, preventing pancreatic cancer cell invasion

Review: Healthcare Informatics , Nurses And Assistant, And Healthcare Management Responsibilities In Facilitating Obstacles Facing Patients Centred Care

Healthcare systems, organizations, and providers, including healthcare informatics, nurses, assistants, and healthcare administration, face the challenge of arranging patient care within limited resources. In order to effectively implement patient-centred care (PCC), it is necessary to remove any obstacles or hindrances that may arise. Thus far, there has been a dearth of thorough examinations on potential factors influencing patient-centered care (PCC) in diverse health and social care organizations (HSCOs). The findings underscored the patient\u27s uniqueness, cultural beliefs, comprehensive care, the significance of robust healthcare provider-patient connections, and a patient-focused setting. The nursing, administrative, and informatics staff regarded PCC as having a good impact on the quality of nursing care and the job satisfaction of nurses. The findings provide detailed insights into the viewpoints of nurse managers regarding patient-centeredness and identify specific areas that require improvement

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Zeitlich-räumliche Modellierung von Leberschädigung und Regeneration unter Berücksichtigung des Lebermetabolismus

Die Leber spielt eine zentrale Rolle bei der Aufrechterhaltung des metabolischen Gleichgewichts. Akutes Leberversagen ist daher lebensbedrohlich. Relativ wenig ist bekannt, wie metabolische Funktionen während und nach Leberschädigung aufrechterhalten werden. Die Ziele dieser Arbeit waren daher 1) metabolische Veränderungen der Leber der Maus während Leberschädigung- und Regeneration zu untersuchen, 2) die Ammoniak-Entgiftung zu modellieren, 3) die Veränderungen der metabolischen Zonierung des Leberläppchens während Leberschädigung und Regeneration zu berücksichtigen, 4) mögliche Kompensationsmechanismen während der Schädigungs- und Regenerationsphase zu identifizieren. Für diese Untersuchungen wurden Mäuse eingesetzt, denen Tetrachlorkohlenstoff (CCl4) zur Verursachung eines akuten Leberschadens injiziert wurde. Für den Ammoniakstoffwechsel relevante Parameter wurden Zeit- und Dosisabhängig nach Injektion von CCl4 erfasst: Ammoniak, Harnstoff, Glutamin, Glutamat, Glucose, Laktat, Pyruvat, Alanin, und alpha-Ketoglutarat. Diese Analysen wurden durchgeführt in Blut aus a) der Portalvene, welche den Lebereingang repräsentiert, b) der Lebervene als Leberausfluss und c) der rechten Herzkammer, um auch gemischt venöses Blut zu erfassen.Um die komplexen Vorgänge des Ammoniakstoffwechsels quantitativ erfassen zu können, wurde ein metabolisches Modell eingesetzt. Vorhersagen dieses metabolischen Modells (welches alle zur Zeit wesentlichen Prozesse des Ammoniakstoffwechsels einschließt) wurden mit den experimentellen Daten verglichen. Nach mehreren Zyklen von Experimenten und Modellierung wurde hierbei gezeigt, dass die bisher bekannten Mechanismen nicht ausreichen, den Ammoniakstoffwechsel während Leberschädigung quantitativ zu beschreiben. Vielmehr wurde der folgende Mechanismus identifiziert, welcher für das Verständnis der gesamten Situation wesentlich ist: nach Leberschädigung setzen geschädigte Hepatozyten neben zahlreichen weiteren Proteinen Glutamatdehydrogenase (GDH) in dem systemischen Blutkreislauf frei. Sobald die Ammoniakkonzentrationen im Blut ansteigen, findet eine GDH-Reaktion in umgekehrter Richtung statt. Bei dieser Reaktion wird der toxische Ammoniak dadurch entgiftet, dass er mit Ammoniak zum relativ untoxischen Glutamat verbunden wird. Ein neuer Aspekt ist hierbei, dass Ammoniakentgiftung in Folge der GDH-Freisetzung nicht nur in der Leber, sondern auch systemisch im Blut stattfindet. Allerdings kann diese entgiftende Reaktion im Blut nur so lange stattfinden, bis das dort vorhandene alpha-Ketoglutarat durch die GDH-Reaktion verbraucht wurde. Diese Beobachtung ist möglicherweise von klinischer Relevanz. Denn sobald die alpha-Ketoglutarat Konzentration in der Leber als Folge der GDH-Reaktion absinkt, könnte es therapeutisch substituiert werden. Dieser Mechanismus der reversen GDH-Reaktion wurde bei Experimenten mit Plasma von Mäuse und mit kultivierten Hepatozyten der Maus beobachtet. Nach Verabreichung von CCl4 an Mäusen wurde eine transiente Zunahme von GDH im Plasma beobachtet. Dies ging einher mit einer sehr starken Abnahme des alpha-Ketoglutarat. Falls Plasma in diesem Zustand Mäusen entnommen wurde, konnte Ammoniak-Entgiftung zu Glutatmat nur dann beobachtet werden, nachdem alpha-Ketoglutarat zugesetzt worden war. Weiterhin konnten im Plasma sowohl die Ammoniakentgiftung, als auch die Bildung von Glutamat durch den GDH-Inhibitor 2,6 Pyridine dicarboxylsäure (PDAC) gehemmt werden. In kultivierten Hepatozyten steigerte PDAC die Toxizität des Ammoniaks. Bemerkenswert ist, dass kultivierte Hepatozyten nur bei hohen Ammoniakkonzentrationen im Kulturmedium Ammoniak zu Glutamat entgifteten. Bei niedrigen Konzentrationen gaben Hepatozyten sogar noch Ammoniak in das Kulturmedium ab. Auch diese Beobachtung passt zur Hypothese des GDH switch , wobei GDH bei niedrigen Ammoniakkonzentrationen Ammoniak produziert, hingegen bei hohen Konzentrationen konsumiert. Leberschädigung mit CCl4 verursachte eine transiente Störung der metabolischen Zonierung des Läppchens. Zum Beispiel wurde eine verzögerte Erholung des perizentralen Markers Glutaminsynthetase beobachtet. Im Gegensatz hierzu dehnte das normalerweise auf die periportale Region begrenzte Enzym Carbamoylphosphat-Synthetase sein Territorium auf das gesamte Leberläppchen aus. Dies wurde zwischen Tag 4 und 6 nach Intoxikation mit CCl4 beobachtet. Nachdem sämtliche neue Mechanismen im Modell berücksichtigt wurden, ergab sich eine gute Übereinstimmung zwischen der Modellsimulation und den experimentellen Daten. Zusammenfassend kann festgestellt werden, dass die Leber nach akuter Schädigung einen systemischen Schutz gegen Hyperammonämie durch Freisetzung von GDH vermittelt. Eine mögliche klinische Relevanz dieser Beobachtung besteht darin, dass alpha-Ketoglutarat im Plasma therapeutisch substituiert werden könnte, sobald es durch die GDH Reaktion verbraucht worden ist.The liver is responsible for maintaining the metabolic homeostasis throughout the body. Therefore, acute liver failure is life threatening. Only little is known about how the complex metabolic function of the liver is restored after liver injury. The goals of this thesis were to 1) study the metabolic alterations during liver damage and regeneration, 2) model ammonia detoxification during liver damage and regeneration, 3) study the alterations of metabolic zonation and to 4) identify possible compensatory mechanisms for ammonia detoxification during liver damage and regeneration. For this purpose I used a mouse system where the hepatotoxic agent CCl4 was injected to induce acute liver damage. Metabolic parameters relevant for ammonia and carbohydrate metabolism were quantified in a time and in a dose-dependent manner after CCl4 intoxication including ammonia, urea, glutamine, glutamate, glucose, lactate, pyruvate, alanine, arginine and alpha-ketoglutarate. The measurement was done in blood collected from the portal vein representing the liver inflow , the hepatic vein representing the liver outflow and from the heart representing the mixed venous blood .For deeper understanding of ammonia metabolism during liver damage and regeneration, a model of ammonia detoxification was established. Model predictions and experimental data were compared. After iterative cycles of modeling and experiments the following so far unknown mechanism was identified. Upon acute liver damage hepatocytes release glutamate dehydrogenase (GDH) (together with further liver enzymes) into the systemic circulation. As soon as blood ammonia concentrations increase, the GDH reaction takes place in a reversed manner. This means that GDH uses ammonia and alpha-ketoglutarate (A-KG) as substrates to form glutamate. By this reaction the toxic ammonia is detoxified to form the non-toxic glutamate. Interestingly, this reaction is not limited to the liver itself but upon release of GDH from damaged hepatocytes protection against ammonia is provided systemically in blood. However, this protection lasts only as long as A-KG is present in the blood. It can not continue when A-KG has been consumed by the GDH reaction. This observation is of clinical relevance since it might be possible to therapeutically substitute &#945;-KG after induction of acute liver damage. This mechanism was discovered in experiments with plasma of mice and in vitro with cultivated hepatocytes. After administration of CCl4 a transient increase of plasma GDH was observed which was accompanied by a decrease in A-KG. When plasma was taken from such mice detoxification of ammonia to glutamate was only observed when A-KG was added. Ammonia detoxification as well as glutamate production were both blocked by addition of the GDH inhibitor 2,6-pyridinedicarboxylic acid (PDAC). In cultivated hepatocytes PDAC increased ammonia cytotoxicity. Interestingly, hepatocytes decreased the ammonia concentrations in the culture medium at high ammonia concentrations. In contrast, hepatocytes released ammonia if its concentrations in the culture medium were relatively low. This fits to the mechanism that GDH switches from ammonia production to ammonia detoxification if the concentrations of ammonia increase.Studying the metabolic zonation after CCl4 intoxication showed a transient disturbance of metabolic zonation during liver regeneration. This included the delayed recovery of the pericentral marker glutamine synthetase. In contrast, the territory of the periportal marker carbamoyl phosphate synthetase1 is extended to cover the whole liver parenchyma on days four and six after CCl4 intoxication. When these findings were included into the model, the predictions of both ammonia and glutamine were in a good accordance with the experimentally obtained data.In conclusion, the acutely damaged liver provides systemic protection against hyperammonemia by the release of GDH into the blood. As soon as plasma A-KG is consumed by the GDH reaction it should be therapeutically substituted