Cancer cachexia demonstrates the energetic impact of gluconeogenesis in human metabolism.

A review-based hypothesis is presented on the energy flow in cancer patients. This hypothesis centres on the hypoxic condition of tumours, the essential metabolic consequences, especially the gluconeogenesis, the adaptation of the body, and the pathogenesis of cancer cachexia. In growing tumours the O(2) concentration is critically low. Mammalian cells need O(2) for the efficient oxidative dissimilation of sugars and fatty acids, which gives 38 and 128 moles of ATP per mole glucose and palmitic acid, respectively. In the absence of sufficient O(2) they have to switch to anaerobic dissimilation, with only 2 moles of ATP and 2 moles of lactic acid from 1 mole of glucose. Since mammalian cells cannot ferment fatty acids, in vivo tumour cells completely depend on glucose fermentation. Therefore, growth of these tumour cells will require about 40 times more glucose than it should require in the presence of sufficient O(2). Since lactic acid lowers the intracellular pH, it decreases the activity of pyruvate dehydrogenase, stimulates fermentation, and thus amplifies its own fermentative production. Compensatory glucose is provided by hepatic gluconeogenesis from lactic acid. However, the liver must invest 3 times more energy to synthesize glucose than can be extracted by tumour cells in an anaerobic way. The liver extracts the required energy from amino acids and especially from fatty acids in an oxidative way. This may account for weight loss, even when food intake seems adequate. In the liver 6 moles of ATP are invested in the gluconeogenesis of one mole of glucose. The energy content of 4 out of these 6 moles of ATP is dissipated as heat. This may account for the elevated body temperature and sweating experience by cancer patients.

[Pneumatosis intestinalis in 9 children with an oncologic disease]. / Pneumatosis intestinalis bij 9 kinderen met een oncologische aandoening.

OBJECTIVE: To acquire knowledge regarding the rare condition pneumatosis intestinalis (PI) in children treated for malignant disease. DESIGN: Retrospective. METHOD: In 1998-1999 PI was diagnosed in 9 of the 140 children with malignant disease in the department of Paediatric Oncology of the UMC St Radboud, Nijmegen, the Netherlands. By examination of the records of these 9 children, data were collected on the symptomatology, diagnostics, treatment and prognosis of PI. RESULTS: The 9 children included 7 boys and 2 girls, varying in age from 2 to 12 years. In 7 patients the underlying disease was acute lymphocytic leukaemia and in 2 it was a stage IV neuroblastoma. The presenting symptoms were nonspecific and included: a distended abdomen, abdominal pain, diarrhoea and constipation. In all children, PI was located in the colon. Supplemental blood and microbiological analysis did not reveal any typical abnormalities. 8 children were treated with lactitol because of constipation. A laparotomy was performed in the first patient, while the other 8 were treated with gastric suctioning, parenteral nutrition and antibiotics. All 9 children recovered within a few weeks. CONCLUSION: With supportive care, PI in children with malignant disease is mostly a self-limiting condition. A pneumoperitoneum in PI is no indication for surgery, except in the presence of an acute abdomen. Chemotherapy can be continued.

Preventive and curative effects of probiotics in atopic patients.

Normally, the transport of allergens through the intestinal epithelia to the blood is limited. It is hypothesised that if these compounds arrive in the blood circulation, they must percolate through the epithelial cell layer. Thus, food allergy (and thus atopic eczema) implies an increased intercellular leakage of the gut wall. Such increased intercellular leakage is thought to be caused by a slightly changed cellular morphology due to a slight cytopathologic effect because of both a limited decay of the cytoskeleton and a slightly reduced turgor. These events may be due to a reduced production of intracellular metabolic energy in the epithelial cells due to an increased concentration of familiar, frequently occurring, potentially toxic bacterial metabolites, i.e., d-lactic acid and/or ethanol. In this hypothesis we suggest that adequate probiotics can (i) prevent the increased characteristic intestinal permeability of children with atopic eczema and food allergy, (ii) can thus prevent the uptake of allergens, and (iii) finally can prevent the expression of the atopic constitution. The use of adequate probiotic lactobacilli, i.e., homolactic and/or facultatively heterolactic l-lactic acid-producing lactobacilli, reduces the intestinal amounts of the bacterial, toxic metabolites, d-lactic acid and ethanol by fermentative production of merely the non-toxic l-lactic acid from glucose. Thus, it is thought that beneficial probiotic micro-organisms promote gut barrier function and both undo and prevent unfavourable intestinal micro-ecological alterations in allergic individuals.

Was isolation of Veillonella from spinal osteomyelitis possible due to poor tissue perfusion?

From a needle biopsy of the body of the 12th thoracic vertebra in a 74-year-old man with spinal osteomyelitis a Veillonella parvula was isolated. The significance of this bacterium as lactic acid indicator has been considered and discussed. Since this strictly anaerobic bacterium mainly uses lactic acid for energy generation, lactic acid must continuously and sufficiently have been produced in or near to the vertebrate body to permit outgrowth of this bacterium. Since neither microbial infections nor tumours could be demonstrated, we finally hypothesised that in this patient poor tissue perfusion has been the primary cause of lactic acid production.

Recombinant human erythropoietin attenuates weight loss in a murine cancer cachexia model.

BACKGROUND: Within hypoxic tumor regions anaerobic dissimilation of glucose is the sole source of energy generation. It yields only 5% of the ATP that is normally gained by means of oxidative glucose catabolism. The increased need for glucose may aggravate cancer cachexia. We investigated the impact of recombinant human erythropoietin (RhEPO) and increased inspiratory oxygen concentrations on weight loss in tumor-bearing mice. METHODS: Fragments of the murine C26-B adenocarcinoma were implanted in 60 BALB/c-mice. The mice were divided into four groups and assigned to: (A) no treatment; (B) RhEPO- administration (25 IU daily from day 1-11, three times per week from day 12); (C) RhEPO and 25% oxygen; and (D) RhEPO and 35% oxygen. Three control groups of four healthy mice each received the same treatment as groups A, B, and D, respectively. Hematocrit and hemoglobin levels, tumor volume, and body weight were monitored. At day 17 the experiment was terminated and the serum lactate concentration was measured. The tumors were excised and weighed and, for each mouse, the percentage weight loss was calculated. The impact of tumor weight and the treatments on lactate concentration and weight loss was evaluated. RESULTS: Significant positive correlations were found between tumor weight and lactate concentration and between tumor weight and percentage weight loss. In the mice with the largest tumors, RhEPO displayed a significant weight loss-reducing effect, and a significant negative correlation was found between hemoglobin concentration and weight loss. An oxygen-rich environment did not appear to influence weight loss. CONCLUSION: Anaerobic glycolysis in a growing C26-B tumor is related to weight loss. RhEPO administration results in a reduction of the percentage weight loss; this effect is probably mediated by an increased hemoglobin concentration.

Cancer cachexia: what is known about its etiology and what should be the current treatment approach?

Cancer cachexia, defined as involuntary weight loss and tissue wasting due to cancer, negatively influences physical condition, quality of life and prognosis. Well known causes, such as ileus or hypercalcemia, do not suffice to explain the entire phenomenon. Metabolic changes induced by the tumor and/or host are supposed to play a deciding role. In the present review current insights into the etiology and treatment are discussed.

The origin of hydrogen sulfide in a newborn with sulfhaemoglobin induced cyanosis.

This report investigated the origin of H(2)S in a newborn boy with sulfhaemoglobin induced cyanosis, who died because of multiple organ failure. Frozen material was collected and studied after death. The results suggest that enzymes had been released from deteriorating organs into the blood and abdominal fluid, and that the reaction of one of these enzymes with sulfur containing amino acids might have resulted in increased H(2)S concentrations. It is hypothesised that this release of enzymes resulted from a haemolysin produced by an invasive haemolytic Escherichia coli that was found in the blood and organs of this patient.

Lactobacilli and acidosis in children with short small bowel.

BACKGROUND: In patients with a short small bowel, D-lactic acidemia and D-lactic aciduria are caused by intestinal lactobacilli. The purpose of this study was to obtain a detailed picture of the metabolic acidosis in young children with short small bowel. METHODS: Feces, blood, and urine of children with short small bowel and acidosis were studied microbiologically and/or biochemically. RESULTS: Previous findings were confirmed that more than 60% of the fecal flora of patients with small short bowel, who are not receiving antibiotics, consists of lactic acid-producing lactobacilli. In blood, D-lactic acid was the most prominent metabolite: the highest serum D-lactate (15.5 mmol/l) was observed in a sample taken immediately after the onset of hyperventilation. The highest D-lactate excretion was in urine collected some hours after the onset of hyperventilation, and amounted to 59 mol/mol creatinine. Acidosis in the patients with short small bowel was related to strongly increased serum D-lactate and anion gap and to strongly decreased serum bicarbonate and pH. CONCLUSION: In children with small short bowel and acidosis, the common intestinal flora of mainly lactobacilli abundantly produces D-lactic acid from easily fermentable carbohydrates. Thus, these bacteria directly cause shifts of bicarbonate, pH, and base excess and indirectly cause shifts of the anion gap, as well as hyperventilation. These kinetic parameters are strongly associated.

In vitro expression of beta-lactam-induced response by clinical gram-negative bacteria with the potential for inducible beta-lactamase production.

The aim of this study was to investigate the in vitro beta-lactam-induced response of clinical Gram-negative bacteria with the potential for inducible beta-lactamase production, in order to be able to discriminate diagnostically between inducible and constitutive beta-lactamase production. A total of 242 clinical Gram-negative isolates of species with inducible chromosomal beta-lactamase were subjected to a disc diffusion test involving agar dilution of the inducers. Cefoxitin (FOX) and imipenem (IPM) were used as inducers and the antibiotics ceftazidime, cefuroxim, cefazolin, amoxycillin and piperacillin as indicators. beta-lactamase induction was observed at concentrations as low as 0.06 mg/l FOX or 0.008 mg/l IPM. In our test, 2 types of antibiotic phenomenon often interfered with inductive effects. Firstly a minor antibiotic effect was seen as an increase in inhibition zones at increasing inducer concentration and, secondly, absence of growth was caused by too high antibiotic activity of the inducer. The induced decrease in zone diameters varied strongly (up to 22 mm). Expressions of resistance were combined in inducibility profiles. Compilation of these profiles allowed an explanation to be proposed for the multi(-beta-lactam)-resistance, i.e. that most isolates combine inducible beta-lactamase synthesis with one or more resistance-potentiating factors. Only a few isolates demonstrated non-inducible resistance, which was probably due to mutation-mediated de-repression of beta-lactamase synthesis. The test presented here may be well-suited to studying inducibility of beta-lactamase production in the diagnostic laboratory.

Role of bacteria in the pathogenesis of short bowel syndrome-associated D-lactic acidemia.

Previously, we have demonstrated that short bowel syndrome (SBS) patients suffer daily from D-lactic acidemia; in these patients rather high amounts of (bacterial) D-lactate emerge in blood and urine with a circadian rhythm. The aim of this study was to establish the microbial basis of D-lactic acidemia in SBS. Therefore, faecal flora of (young and adult) SBS-patients was analysed qualitatively and quantitatively, and compared to that of controls. The isolated bacterial species were screened for massive D- and/or L-lactate production after in vitro growth. After introduction of oral feeding in SBS-infants shortly after the resection, lactobacilli increased from < or = 1% up to 60 +/- 5% of the faecal flora within 2-3 weeks. In the faeces of patients with oral feeding the lactate producers Lactobacillus acidophilus and Lactobacillus fermentum were the major resident bacteria (each with 10(10)-10(12) cfu/g faeces). During active growth in vitro these lactobacilli produced massive amounts of D- and L-lactic acid from glucose. Use of oral antibiotics in two SBS-children did not reduce the total numbers of lactobacilli, but caused shifts within the intestinal populations of at least lactobacilli. It is concluded that the strongly reduced intestinal capacity for carbohydrate absorption and the oral consumption of easily fermentable carbohydrates form the physiological basis for D-lactic acidemia in SBS, and that the fermentative D-lactate production by intestinal bacteria, especially the abundant, resident lactobacilli, forms its microbial basis. In these patients the antimicrobial and therapeutic effects of antibiotics are unpredictable.

D-lactic acidemia and aciduria in pediatric and adult patients with short bowel syndrome.

D-Lactate produced by abundant intestinal lactobacilli during acidotic episodes in short bowel (SB) patients is commonly regarded as a main factor in the pathogenesis of SB syndrome-associated (D-lactic) acidosis. Since we had observed that gram-positive bacteria, mainly lactobacilli, were abundant even in the absence of acidosis, we studied serum concentrations and urinary excretions of D- and L-lactate in young and adult SB patients, especially during nonacidotic periods. Serum L-lactate and urinary L-lactate excretion were similar in adults and children. Serum D-lactate and urinary D-lactate excretion were higher in SB children than in SB adults. Food consumption affects D-lactate production and alters D-lactic acidemia and aciduria. We conclude that D-lactate is frequently present in serum of SB patients even in the absence of acidosis. High serum concentrations and urinary excretions may reflect dietary factors in these patients.