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Parenting and providing extensive care to a child with a life-limiting or life-threatening disease while being aware of the future loss of the child are among the most stressful parental experiences. Due to technical and medical improvements, children are living longer and are increasingly cared for at home. To align healthcare professionals' support with the needs of parents, a clear understanding of prominent experiences and main coping strategies of parents caring for a child in need of palliative care is needed. An interpretative qualitative study using thematic analysis was performed. Single or repeated interviews were undertaken with 42 parents of 24 children with malignant or non-malignant diseases receiving palliative care. Prominent reported parental experiences were daily anxiety of child loss, confrontation with loss and related grief, ambiguity towards uncertainty, preservation of a meaningful relationship with their child, tension regarding end-of-life decisions and engagement with professionals. Four closely related coping strategies were identified: suppressing emotions by keeping the loss of their child at bay, seeking support, taking control to arrange optimal childcare and adapting to and accepting the ongoing change(s).Conclusion: Parents need healthcare professionals who understand and carefully handle their worries, losses, parent-child relationship and coping strategies. What is Known: • In paediatric palliative care, parents have a daunting task in fulfilling all caregiving tasks while striving for control of their child's symptoms, a life worth living and a family balance. What is New: • Prominent experiences were: continuous management of anxiety of child loss, feelings of uncertainty, tension with end-of-life decision making and engagement with professionals. Parents experienced unique significance to their child, reinforcing a meaningful parent-child relationship. • Relevant coping strategies were: suppressing emotions, seeking support, taking control to arrange optimal care and adapting to the ongoing changes. • To provide tailored support, professionals need to understand parents' perceptions, relationship with their child and coping strategies.

Objectives: Anticipating case management is considered crucial in pediatric palliative care. In 2012, our children's university hospital initiated a specialized pediatric palliative care team (PPCT) to deliver inbound and outbound case management for children with life-shortening disease. The aim of this report is to gain insight in the first 9 months of this PPCT., Methods: Aspects of care during the first 9 months of the PPCT are presented, and comparison is made between patients with malignant disease (MD) and nonmalignant disease (NMD) in a retrospective study design. Insight in the aspects of care of all patients with a life-shortening disease was retrieved from web-based files and the hour registrations from the PPCT., Results: Forty-three children were supported by the PPCT during the first 9 months: 22 with MD with a median of 50 (1-267) days and 29 minutes (4-615) of case management per patient per day and 21 patients with NMD with a median of 79.5 (5-211) days and 16 minutes of case management per day (6-64). Our data show significantly more interprofessional contacts for patients with MD and more in-hospital contacts for patients with NMD. The median number of admission days per patient was 11 (0-22) for MD (44% for anticancer therapy) and 44 (0-303) for NMD (36% for infectious diseases)., Significance of Results: This overview of aspects of pediatric palliative case management shows shorter but more intensive case management for MD in comparison with NMD. This insight in palliative case management guides the design of a PPCT.

Background: Parents of children with a life-limiting disease have to rely on themselves at home while adequate paediatric palliative care is lacking. In several countries, paediatric palliative care teams are introduced to ensure continuity and quality of care and to support the child and the family. Yet, little is known about how parents experience such multidisciplinary teams., Aim: To obtain insight into the support provided by a new paediatric palliative care team from the parents' perspective., Design: An interpretative qualitative interview study using thematic analysis was performed., Setting/participants: A total of 47 single or repeated interviews were undertaken with 42 parents of 24 children supported by a multidisciplinary paediatric palliative care team located at a university children's hospital. The children suffered from malignant or non-malignant diseases., Results: In advance, parents had limited expectations of the paediatric palliative care team. Some had difficulty accepting the need for palliative care for their child. Once parents experienced what the team achieved for their child and family, they valued the team's involvement. Valuable elements were as follows: (1) process-related aspects such as continuity, coordination of care, and providing one reliable point of contact; (2) practical support; and (3) the team members' sensitive and reliable attitude. As a point of improvement, parents suggested more concrete clarification upfront of the content of the team's support., Conclusion: Parents feel supported by the paediatric palliative care team. The three elements valued by parents probably form the structure that underlies quality of paediatric palliative care. New teams should cover these three valuable elements.

In paediatric palliative care (PPC), parents are confronted with increasing caregiving demands. More children are cared for at home, and the need for PPC of children is lengthened due to technical and medical improvements. Therefore, a clear understanding of the content of parental caregiving in PPC becomes increasingly important. The objective is to gain insight into parental caregiving based on the lived experience of parents with a child with a life-limiting disease. An interpretative qualitative study using thematic analysis was performed. Single or repeated interviews were undertaken with 42 parents of 24 children with a malignant or non-malignant disease, receiving PPC. Based on their ambition to be a 'good parent', parents caring for a child with a life-limiting disease strived for three aims: controlled symptoms and controlled disease, a life worth living for their ill child and family balance. These aims resulted in four tasks that parents performed: providing basic and complex care, organising good quality care and treatment, making sound decisions while managing risks and organising a good family life., Conclusion: Parents need early explanation from professionals about balancing between their aims and the related tasks to get a grip on their situation and to prevent becoming overburdened. What is Known: • In paediatric palliative care, parents are confronted with increasing caregiving demands. • Parenting is often approached from the perspective of stress. What is New: • Parents strive for three aims: controlled symptoms and controlled disease, a life worth living for their child and family balance. • Parents perform four tasks: providing basic and complex care, organising good quality care, making decisions while managing risks and organising a good family life. • Professionals need insight into the parents' aims and tasks from the parental perspective to strengthen parents' resilience.

Background: Case management is a subject of interest within pediatric palliative care. Detailed descriptions of the content of this type of case management are lacking. We aim to describe the contents of care provided, utilization of different disciplines, and times of usage of a pediatric palliative care case management program compared for patients with malignant disease (MD) and non-malignant disease (NMD)., Methods: A three-month prospective study, with questionnaires filled in by members of a pediatric palliative care team (PPCT) for each contact with parents., Results: Four hundred fifty-five contacts took place with parents of 70 patients (27MD, 43NMD). Sixty-two percent of all contacts were with the specialized nurse. The child life specialists, psychologist and social worker were also regularly consulted, the chaplain was not consulted. Ninety-five percent of all contacts took place between 8 am and 6 pm during weekdays, a limited number between 6 pm and 9 pm. Twenty-five percent of all contacts were proactively initiated by the PPCT, 25 % were initiated by parents. In these care characteristics, no differences were seen for MD and NMD patients. Psychosocial topics were addressed most frequently. MD patients consulted the PPCT more often about school and NMD patients about socio-economic issues., Conclusions: All different disciplines of the PPCT were regularly consulted, except for the chaplain. With an easy accessible team with a highly pro-active approach, availability from 8 am to 9 pm seems sufficient to accommodate patient's and parent's needs. More anticipation seems required for socio-economic topics. This insight in pediatric palliative case management can provide guidance in the development of a new PPCT.

Unlabelled: Adequate discharge planning could improve patient health and reduce readmissions. Increased accessibility and adequate use of hospital capacity are asking for an adequate discharge planning by means of efficient prediction of length of stay (LOS). Predictive factors of LOS for paediatric patients are lacking in the current available evidence. We aimed to identify these predictive factors in order to predict an optimal LOS. We conducted a prognostic study of all patients admitted to five different paediatric wards of Emma Children's Hospital, a tertiary university hospital in the Netherlands. We investigated possible predictive factors based on the literature and an expert panel categorised in patient characteristics and medical and non-medical factors. This preliminary list was scored for all patients at the moment of discharge. All significant or relevant factors were used in a linear regression model to predict the LOS. We included 142 patients and explored the relationship between 28 variables, reflecting a mix of patient characteristics, medical and non-medical factors and LOS. In a univariable analysis, 17 variables were significantly related with LOS. Multivariable analysis found seven independent variables: sex, age category, specialism, risk of malnutrition, complications, home care and the involvement of other disciplines. These seven variables explained 48 % of the LOS (R(2) of 0.476)., Conclusion: Predictors of LOS consist patient characteristics, medical factors as well as non-medical factors (i.e. the need for home care and other disciplines). The latter factors can be influenced by changes in hospital policies.

Context: Ber's Comprehensive Integrative Puzzle aims to assess analytical clinical thinking in medical students. We developed a paediatric version, the MATCH test, in which we added two irrelevant options to each question in order to reduce guessing behaviour. We tested its construct validity and studied the development of integrative skills over time., Methods: We administered a test (MATCH 1) to subjects from two universities, both with a 6-year medical training course. Subjects included 30 students from university 1 who had completed a paediatric clerkship in Year 4, 23 students from university 2 who had completed a paediatric clerkship in Year 5, 13 students from both universities who had completed an advanced paediatric clerkship in Year 6, 28 paediatric residents and 17 paediatricians. We repeated this procedure using a second test with different domains in a new, comparable group of subjects (MATCH 2)., Results: Mean MATCH 1 scores for the respective groups were: Year 4 students: 61.2% (standard deviation [SD] 1.3); Year 5 students: 71.3% (SD 1.6); Year 6 students: 76.2% (SD 1.5); paediatric residents: 88.5% (SD 0.7), and paediatricians: 92.2% (SD 1.1) (one-way ANOVA F = 104.00, P < 0.0001). Students of both universities had comparable scores. MATCH 1 and 2 scores were comparable. Cronbach's alpha-values in MATCH 1 and 2 were 0.92 and 0.91, respectively, for all subjects, and 0.82 and 0.87, respectively, for all students., Conclusions: Analytical clinical thinking develops over time, independently of the factual content of the course. This implies that shortened medical training programmes could produce less skilled graduates.

An 8-month-old boy developed pyomyositis of the M. quadriceps femoris following meningitis caused by Streptococcus pneumoniae. The child had no underlying immune defect. Conservative treatment with antibiotics led to complete clinical and radiological resolution of the infection. In Europe, pyomyositis is rarely seen in children. Pyomyositis should be considered in the differential diagnosis in children with fever and complaints of joint pain or myalgia. Ultrasound and MRI are helpful techniques for establishing the diagnosis and for differentiating pyomyositis from other pathological conditions. Treatment consists of adequate antibiotics and in some cases drainage.

A Helicobacter pylori infection is usually acquired during early childhood. Poor socioeconomic circumstances form an important risk factor for this. An untreated infection may lead to peptic ulceration and, particularly in adults, to gastric cancer and mucosa associated lymphoid tissue (MALT) lymphoma. The gold standard for the diagnosis of H. pylori infection is gastroscopy with histology and culture of biopsy specimens. Non-invasive tests are serology, 13C-urea breath test and stool antigen test. The sensitivity and specificity of serology tests are low in children, but for both the 13C-urea breath test and the stool antigen test the sensitivity and specificity are high. A 'test and treat' approach is advised with due consideration for possible symptoms and the risk for peptic ulcers and gastric cancer at a more advanced age. The treatment results must be evaluated. If necessary, young children can be treated at a later age.

Hepatoblastoma (HB) and biliary atresia (BA) are both rare conditions that occurred in the patient described. This is the second such case in the literature. An explanation for this apparent coincidence could possibly be found in the existance of pluripotent liver stem cells. In humans, small epithelial cells (SEC) behave as pluripotent stem cells. These are cells that can develop as biliary epithelial cells or as liver parenchymal cells, and are thought to be the precursor cell of HB. They are present in a much higher concentration in the livers of patients with BA, which may make them prone to develop HB., (Copyright 2004 Wiley-Liss, Inc.)

Objective: To determine the effect of an antiprotozoic treatment on children with persistent abdominal pain and infection with Dientamoeba fragilis., Design: Retrospective., Method: A total of 43 children with D. fragilis infection and persistent gastrointestinal complaints were included in the study. Of these 27 were treated with clioquinol and 16 with a nitroimidazole drug: metronidazole or tinidazole. The parasitological and clinical effects of the treatment were assessed., Results: In 33 of the 43 (77%) children, no parasites were detected during follow-up with a triple faeces test: 22/27 following treatment with clioquinol and 11/16 following treatment with a nitroimidazole drug. In 27 of the 33 (82%) children with a negative follow-up result, gastrointestinal complaints were considerably less or had completely disappeared. In 2 of the 10 (20%) children in which D. fragilis had not disappeared in the follow-up period, the complaints were less or had disappeared., Conclusion: Effective treatment of D. fragilis infection in children with longstanding gastrointestinal complaints often resulted in a reduction or disappearance of the complaints.

Objective: This article documents the characteristics and treatment of an infant patient with a sphenoethmoidal encephalocele. An extracranial, transpalatal approach was used to eliminate the encephalocele.

Purpose: The aim of this study was to compare presentation, complications, diagnosis, and treatment of choledochal cysts in pediatric and adult patients., Methods: Forty-two patients were analyzed after subdivision into 3 groups: group A, less than 2 years (n = 10); group B, 2 to 16 years (n = 11); group C, greater than 16 years (n = 21)., Results: The cysts were classified as extrahepatic (n = 33), intrahepatic (n = 5), and combined (n = 4). Seventy-six percent of patients presented with abdominal pain, (20 of 21 group C), and 57% with jaundice, (10 of 10 group A). Cholangiocarcinoma occurred in 6 patients, 4 of whom had previously undergone internal drainage procedures. Excision of the extrahepatic cyst was performed in 27 of 37 patients. Five patients, of whom, 4 had cholangiocarcinoma, were beyond curative treatment at the time of diagnosis. Six patients had died at the closure of this study, 5 of them had carcinoma., Conclusions: Presenting symptoms are age dependent with jaundice prevailing in children and abdominal pain in adults. In view of the high risk of cholangiocarcinoma, early resection and not internal drainage is the appropriate treatment of extrahepatic cysts. Patients who had undergone internal drainage in the past still should undergo resection of the cyst., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

To date, microvillus inclusion disease (MID) has been diagnosed in six Dutch patients. It is a rare autosomal recessive hereditary intestinal disorder mostly presenting with malabsorption and severe secretory diarrhoea from birth. The diagnosis is confirmed by electron microscopy of intestinal mucosal biopsies, which show characteristic intracytoplasmic vesicles containing clearly recognisable microvilli and irregularly distributed microvilli in the brush border. The two clinical forms of the disease that have been recognised internationally, a 'congenital' and a 'late-onset' form of MID, have also been observed in the Dutch patients. At the last follow-up five patients had died, the sixth was 17 years old and alive. The pathogenesis and genetics of MID are, as yet, unknown. Eventually, all patients die from complications of the disease, notably from the total parenteral nutrition. The only chance of survival is intestinal or combined liver-intestinal transplantation.

The multidrug resistance protein (MRP) family consists of several members and, for some of these transporter proteins, distinct roles in multidrug resistance and normal tissue functions have been well established (MRP1 and MRP2) or are still under investigation (MRP3). MRP3 expression studies in human tissues have been largely restricted to the mRNA level. In this report we extended these studies and further explored MRP3 expression at the protein level. Western blot and immunohistochemistry with two MRP3-specific monoclonal antibodies, M(3)II-9 and M(3)II-21, showed MRP3 protein to be present in adrenal gland, and kidney and in tissues of the intestinal tract: colon, pancreas, gallbladder, and liver. In epithelia, MRP3 was found to be located at the basolateral sides of cell membranes. In normal liver, MRP3 was detected at lower levels than anticipated from the mRNA data and was found present mainly in the bile ducts. In livers from patients with various forms of cholestasis, MRP3 levels were frequently increased in the proliferative cholangiocytes, with sometimes additional staining of the basolateral membranes of the hepatocytes. This was especially evident in patients with type 3 progressive familial intrahepatic cholestasis. The present results support the view that MRP3 plays a role in the cholehepatic and enterohepatic circulation of bile and in protection within the biliary tree and tissues along the bile circulation route against toxic bile constituents. The possible functional roles for MRP3 in the adrenal gland and in the kidney remain as yet unknown. In a panel of 34 tumor samples of various histogenetic origins, distinct amounts of MRP3 were detected in a limited number of cases, including lung, ovarian, and pancreatic cancers. These findings may be of potential clinical relevance when considering the drug treatment regimens for these tumor types.

Fabry's disease, deficiency of the enzyme alpha-galactosidase A, is an X-linked lysosomal storage disorder. Clinical symptoms are caused by continuous deposition of specific glycolipids in endothelial cells, neural cells, skin and cornea. These depositions give rise to skin (angiokeratoma) and eye abnormalities (cornea verticillata), acroparaesthesias and anhidrosis and later in life cause renal insufficiency and cardiovascular complications. Hemizygous males suffer from Fabry's disease, whereas female carriers (heterozygotes) are usually asymptomatic. Recently, an atypical presentation of Fabry's disease was described in males who only presented with cardiac involvement. Therefore, the actual number of Fabry patients in the Netherlands could be higher than the predicted 300. Diagnosis in males can be established by measuring alpha-galactosidase enzyme activity in plasma, leukocytes or fibroblasts. Apart from kidney transplantation only symptomatic therapy is available today. Enzyme supplementation therapy (as shown in Gaucher's disease) and substrate deprivation are possible ways of treatment in the future.

Objective: To evaluate the effects of percutaneous endoscopic gastrostomy (PEG) in children with psychomotor retardation., Design: Prospective., Method: Data on symptoms, pros and cons and complications were collected by means of questionnaires from the parents of children with psychomotor retardation and severe nutritional problems in whom a PEG tube had been introduced between August 1995 and March 1998 in the department of Children's Gastroenterology and Nutrition of the Emma Children's Hospital/Academic Medical Centre in Amsterdam, the Netherlands, comparing the situations before the introduction and 6 and 18 months afterward., Results: The patient group consisted of 17 boys and 23 girls with a mean age of 6 years and 3 months (range 8 months-10 years and 1 month). The frequency of vomiting and of airway infections decreased and the general nutritional condition improved. Restlessness and pain occurred less often in over half the children. The disadvantages most often reported were the logistics concerning the feeding (n = 11) and the reduced contact with the child (n = 10). Thirteen children displayed mild side effects such as skin irritation and proud flesh. Technical problems consisted of leakage (n = 11) and obstruction of the tube (n = 2). In one child, introduction of the tube was followed by a major complication., Conclusion: The PEG tube in this patient group reduced the frequency of complaints about nutrition and constituted a patient-friendly alternative to the nasal tube.

Up to the present, aspecific immunosuppressive medication is still required to prevent rejection of transplanted allogeneic tissues and to treat autoimmune disorders. These drugs are associated with numerous adverse effects. Therefore, alternative forms of immunomodulation are being extensively studied. T-cells play a central role in regulating the immune system. Expanding insight into the cellular mechanisms involved in immune recognition and activation led to the development of new tolerance-inducing strategies. Potential sites for tolerance induction are situated centrally in the thymus as well as in the peripheral T-cell population. Explicitly mentioned tolerance strategies are (a) allogeneic bone marrow transplantation and intrathymic tolerance induction (central tolerance induction), (b) peripheral T-cell clonal deletion, induction of anergy and immune deviation (all three are examples of peripheral tolerance induction).

Liver regeneration after partial hepatectomy was studied in four groups of rats: control rats (n = 12), rats with 1 week of common bile duct obstruction (n = 11), rats with restoration of bile flow after 1 week of obstruction (n = 9) and a sham-operated group (n = 7). Parameters of DNA synthesis--thymidine kinase activity and in vivo bromodeoxyuridine incorporation--were measured at partial hepatectomy (T = 0), and 24 and 48 h after partial hepatectomy. During common bile duct obstruction, DNA synthesis was already stimulated at T = 0, but partial hepatectomy in common bile duct obstruction rats induced a delayed DNA synthesis. After 1 week of restoration of bile flow, normal DNA synthesis had returned at T = 0, but DNA synthesis after partial hepatectomy was still delayed. The sham-operated rats showed a normal regeneration response after partial hepatectomy assessed by bromodeoxyuridine incorporation but delayed as assessed by thymidine kinase activity, partly due to the impaired physical condition of the animals. The present data support the hypothesis that during cholestasis, regeneration promoting, and inhibitory factors accumulate in the liver, their balance determining whether regeneration after partial hepatectomy will occur in a normal, enhanced or delayed way.

Intracerebral microdialysis was applied to monitor the neocortical extracellular levels of the aromatic amino acids phenylalanine, tyrosine, and tryptophan, the neurotransmitters dopamine (DA), noradrenaline (NA), and serotonin (5-HT), and the metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole-3-acetic acid (5-HIAA) in rats with various forms of experimental hepatic encephalopathy (HE). The extracellular aromatic amino acid levels were clearly increased in acute, subacute, and chronic HE. No changes compared with controls in the neocortical DA release could be detected in the three experimental HE rat models investigated. The NA release showed a significant increase only in the subacute HE group. These data suggest that HE may not be associated with any major reduction of neocortical DA or NA release as previously suggested. In acute and subacute HE, decreased extracellular DOPAC but elevated 5-HIAA concentrations were seen. In chronic HE, elevations of both DOPAC and 5-HIAA were observed. Neocortical 5-HT release did not change in subacute and chronic HE, whereas it decreased in acute HE compared with control values. Significant increase in extracellular concentrations of 5-HIAA and of the 5-HIAA/5-HT ratio in the present study are in agreement with previously reported increases in 5-HT turnover in experimental HE. However, a substantially increased 5-HT turnover in experimental HE does not appear to be related to an increase in neuronal neocortical 5-HT release.

The effects of three different techniques of hepatocyte transplantation were investigated: transplantation of free hepatocytes into the spleen and intraperitoneal transplantation of microcarrier-attached hepatocytes or of microencapsulated hepatocytes. The liver-supportive functions of these transplanted hepatocytes were analyzed using either the Gunn rat (hyperbilirubinemia) or rats with acute liver failure. In the Gunn rat intraperitoneal transplantation of microcarrier-attached hepatocytes resulted in a significant reduction of plasma bilirubin for 28 days whereas intraperitoneal transplantation of microencapsulated hepatocytes was ineffective notwithstanding immunosuppression by cyclosporin A. Intrasplenic hepatocyte transplantation was only effective in reducing plasma bilirubin for 14 days. During acute liver failure, liver support was achieved temporarily by hepatocyte transplantation in the spleen, by intraperitoneally transplanted microcarrier-attached hepatocytes, and by microencapsulated hepatocytes to equal extents, the microencapsulated hepatocytes being the least effective after 8 h of liver ischemia.

Both increased gamma-aminobutyric acid (GABA)-ergic and decreased glutamatergic neurotransmission have been suggested relative to the pathophysiology of hepatic encephalopathy. This proposed disturbance in neurotransmitter balance, however, is based mainly on brain tissue analysis. Because the approach of whole tissue analysis is of limited value with regard to in vivo neurotransmission, we have studied the extracellular concentrations in the cerebral cortex of several neuroactive amino acids by application of the in vivo microdialysis technique. During acute hepatic encephalopathy induced in rats by complete liver ischemia, increased extracellular concentrations of the neuroactive amino acids glutamate, taurine, and glycine were observed, whereas extracellular concentrations of aspartate and GABA were unaltered and glutamine decreased. It is therefore suggested that hepatic encephalopathy is associated with glycine potentiated glutamate neurotoxicity rather than with a shortage of the neurotransmitter glutamate. In addition, increased extracellular concentration of taurine might contribute to the disturbed neurotransmitter balance. The observation of decreasing glutamine concentrations, after an initial increase, points to a possible astrocytic dysfunction involved in the pathophysiology of hepatic encephalopathy.

A method is described to selectively measure lactate in vivo using proton zero quantum coherence techniques. The signal from lipids is eliminated. A surface coil and additionally slice selective localization are used. The resulting spectra demonstrate the good performance of the method.

Two benzodiazepine-receptor partial inverse agonists (Ro 15-4513, Ro 15-3505) and one benzodiazepine-receptor antagonist (flumazenil) were administered to rats with hepatic encephalopathy due to acute liver ischemia. Significant improvement (P less than 0.002) of both the clinical grade of hepatic encephalopathy and the electroencephalographic abnormalities was observed after administration of the benzodiazepine-receptor partial inverse agonists: comatose rats with no spontaneous righting reflex regained consciousness immediately after injection of the drug. Only slight improvement in clinical hepatic encephalopathy grade was seen after administration of 25 mg/kg of flumazenil. The present data strongly support a role of increased gamma-aminobutyric acid-ergic tone in the pathogenesis of acute hepatic encephalopathy and provide a rationale for trials of benzodiazepine-receptor partial inverse agonists to restore consciousness in hepatic encephalopathy in humans in the near future.

At present in vivo NMR spectroscopic studies of brain glutamate and glutamine concentrations relative to encephalopathy have mainly been performed in hepatic encephalopathy (HE). In vivo proton NMR studies were performed in rats with hyperammonemia and acute HE due to acute liver ischemia as well as in rats with hyperammonemia due to either repeated urease i.p. injection or i.p. administration of methionine sulfoximine, a well known inhibitor of glutamine synthetase. In man, in vivo proton NMR is described in patients with chronic liver disease: cirrhosis of different etiology and associated with different degrees of HE. In the experimental models proton NMR spectroscopy of the cerebral cortex revealed an increase in glutamine concentration, a decrease in glutamate concentration and a decrease in phosphocholine compounds. In humans no clear distinction between cerebral cortex glutamate and glutamine concentration could be made by in vivo 1H NMR spectroscopy. However, the combined glutamate/glutamine peak increased in a way compatible with an increased cerebral cortex glutamine concentration during chronic HE. In the cirrhotic patients too a decrease in cerebral cortex phosphocholine compounds was observed, the explanation of which is unclear. Both the experimental work and the clinical observations support the hypothesis that impairment of the glutamate/glutamine cycle between astrocytes and neurons plays a role in the pathogenesis of hepatic encephalopathy.

The role of conjugated bilirubin in liver regeneration after partial hepatectomy (PH) was studied in Gunn rats, in transport-mutant (TR-) rats, and in rats with extrahepatic biliary obstruction. Ornithine decarboxylase (ODC) and thymidine kinase (TK) activities in liver homogenates and immunohistochemistry of in vivo bromodeoxyuridine (BrdU) incorporation in hepatic DNA were followed as regeneration parameters at 24 and 48 hr after PH. The results relative to TK activity and BrdU incorporation were consistent with significantly delayed hepatic DNA synthesis in Gunn rats in comparison to control Wistar and TR- rats. This delay in DNA synthesis was not reflected in the hepatic ODC activity. After one week of complete common bile duct obstruction (CBO), an increased TK activity and BrdU incorporation was seen. PH following CBO resulted in a further increase in ODC activity and BrdU incorporation. TK activity did not change, however. These data relative to the regulation of hepatic DNA synthesis after PH in Gunn rats and in rats with extrahepatic biliary obstruction suggest a possible stimulatory role for conjugated bilirubin in hepatic regeneration; however, the normal hepatic DNA synthesis in TR- rats studied before PH and the subnormal DNA synthesis seen 24 hr after PH in TR- rats and in rats with CBO indicate that conjugated bilirubin does not stimulate hepatic DNA synthesis.

Two experimental models of hepatic encephalopathy in the rat have been investigated in order to study the postulated relationship between plasma free fatty acids concentration (C6 - C22:0) and the degree of hepatic encephalopathy. As a model of chronic hepatic encephalopathy, porta caval shunted rats were studied for 15 weeks, whereas rats with acute liver ischemia were used as a model for acute hepatic encephalopathy. In porta caval shunted rats only a minor degree of hepatic encephalopathy developed, whereas plasma ammonia concentration increased significantly (82 +/- 8 to +/- 440 +/- 32 mumol/l). Acute liver ischemia induced severe grades of hepatic encephalopathy associated with high levels of plasma ammonia (+/- 1 200 mumol/l). Since no significant changes in plasma free fatty acids were observed during both chronic and acute hepatic encephalopathy no correlation between plasma free fatty acids and the stage of hepatic encephalopathy was found. Our data do not support an important role of free fatty acids in the pathogenesis of acute or chronic hepatic encephalopathy in the rat.

Using in vivo 1H NMR spectroscopy (1H MRS) and biochemical analysis, the effects of hyperammonemia on cerebral function were studied in three rat models: acute liver ischemia (LIS), administration of urease (UREASE) and administration of methionine sulfoximine (MSO). By means of localization in three dimensions signals were obtained exclusively from the cerebral cortex. Specially developed lineshape correction and fitting methods were used to quantitate the MRS signals. The following concentration changes were observed; a decrease in glutamate and (phospho)choline for all the models; an increase in glutamine in the LIS and UREASE model but a decrease in the MSO model; a marked increase in lactate in the LIS and UREASE group; a tendency to a decrease in N-acetylaspartate in all the models. These changes agree well with the changes in the post-mortem biochemically determined cerebral cortex glutamine and glutamate concentrations. Estimated absolute 1H MRS metabolite concentrations agree well with those obtained by other techniques; cerebral cortex glutamate, however, is underestimated by about 35% by NMR. The present data support the hypothesis that hyperammonemia is associated with a decreased availability of glutamate for neurotransmission.

The effects of hyperammonemia on brain function have been studied in three different experimental models in the rat: acute liver ischemia, urease-treated animals and methionine sulfoximine-treated animals. To quantify the development of encephalopathy, clinical grading and electroencephalographic spectral analysis were used as indicators. In all three experimental models brain ammonia concentrations increased remarkably associated with comparable increases in severity of encephalopathy. Furthermore, in vivo 1H-nuclear magnetic resonance spectroscopy of a localized cerebral cortex region showed a decrease in glutamate concentration in each of the aforementioned experimental models. This decreased cerebral cortex glutamate concentration was confirmed by biochemical analysis of cerebral cortex tissue post mortem. Furthermore, an increase in cerebral cortex glutamine and lactate concentration was observed in urease-treated rats and acute liver ischemia rats. As expected, no increase in cerebral cortex glutamine was observed in methionine sulfoximine-treated rats. These data support the hypothesis that ammonia is of key importance in the pathogenesis of acute hepatic encephalopathy. Decreased availability of cerebral cortex glutamate for neurotransmission might be a contributing factor to the pathogenesis of hyperammonemic encephalopathy. A surprising new finding revealed by 1H-nuclear magnetic resonance spectroscopy was a decrease of cerebral cortex phosphocholine compounds in all three experimental models. The significance of this finding, however, remains speculative.

Short- and long-term effects of intraperitoneally transplanted microcarrier attached liver cells (MAL) have been studied in two experimental models of severe liver insufficiency in the rat: subtotal hepatectomy (HX) and acute liver ischemia. Intraperitoneal transplantation of MAL immediately after subtotal hepatectomy resulted in a significantly lower plasma ammonia level, a higher caffeine clearance, a higher urea production and a significantly smaller loss in body weight in comparison to sham transplanted control rats. Since thymidine kinase activity in the regenerating host liver was only significantly stimulated at t = 48 h it is concluded that the observed metabolic effects are mainly due to the metabolic activity of the transplanted MAL, although a small stimulative effect of MAL-TX on host liver regeneration cannot be excluded. In the course of acute liver ischemia, MAL transplantation results in delayed development of acute hepatic encephalopathy (HE), judged by clinical grading, EEG spectral analysis and Visual Evoked Response (VER) parameters. Furthermore, MAL transplantation is associated with less increased levels of plasma ammonia during acute liver ischemia.

Despite great advances in analysing hemodynamic, morphological and biochemical changes during the process of liver regeneration, the exact (patho)physiological mechanism is still unknown. A short survey of literature is given of the kinetics of liver regeneration and the significance of different hepatotrophic factors. A distinction is made between factors promoting cell hypertrophy and factors stimulating hyperplasia. Loss of cell-cell contact inhibition, metabolic overload or elimination of inhibitory substance are discussed as trigger mechanisms for cell proliferation after partial hepatectomy (PH). Trophic factors like insulin may create optimal conditions for cell growth. The Hepatic Stimulatory Substance (HSS) of LaBrecque is probably the most purified proliferation factor at present, but there are several claims for other hepatotrophic factors too.