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1.  Obesity, the deadly quartet and the contribution of the neglected daily organ rest - a new dimension of un-health and its prevention 
The “deadly quartet”: excessive weight, hypertension, impaired glucose homeostasis, and atherogenic dyslipidemia constitute a greater threat to health than the added effects of smoking and alcohol abuse. It is strongly associated with unrestricted consumption of processed, refined foods. Recent observations from experience in South East Asia shows that the interval between lifestyle changes and associated change in disease pattern is shorter than earlier believed. Recent experience from obesity studies in Africa demonstrates not only dramatic changes in health but also large social consequences from being overweight. Obesity is not only a result of overeating - dozens of other factors are known to contribute. Our palaeolithic forefathers and those living a similar lifestyle today are reported to rarely have diseases and to live a long life. One such group is the Hunzas, living in Northern Pakistan, are reported to live on a daily 1,800-calorie 99% plant-based diet, consisting in 73% of mostly unrefined/unprocessed carbohydrates, 17% fat and 10% protein. They, and most likely also our forefathers, do/did most likely only eat twice a day, at noon and early evening. Calorie-restriction (CR) and also fasting was early recommended and has been so during thousands of years - early Greek medicine and giants such as Hippocrates, Galenus and later also Paracelsus prescribed restrictions in eating and fasting. So did Middle Age physicians and other nutrition experts such as Louis Cornado. Today it is again practiced around the World. Overeating and heavy postprandial metabolism is a great burden to the body causing elevated levels in blood of endotoxin, increased inflammatory and oxidative stress, release of tumor necrosis factor-α, and other pro-inflammatory cytokines, increases in numbers of and activating of leukocytes, a reaction that is potentiated by the presence of large-chain fatty acids and sugars. Various metabolic, uremic, microbiota-derived and environmental poisons accumulate in large amounts in the adipose tissues. High levels of poisons in the adipose tissues decreases the turnover of fats in order to protect other organs. The content in adipose of POPs - altogether 17 dioxins/furans and 18 polychlorinated biphenyl congeners, has been reported to be 2-3 times higher in obese compared to lean persons. Daily fasting consisting in 16 to 18 hours of avoidance of calorie intake offers an interesting alternative. An attractive policy is to abstain from eating between 18:00 in the evening and 10:00 or 12:00 AM, a plan, which I personally have practiced during many years.
PMCID: PMC4526765  PMID: 26312244
Postprandial; hyperglycaemia; detoxification; organ rest; sleep deprivation
2.  Nutrition of the Critically Ill—A 21st-Century Perspective 
Nutrients  2013;5(1):162-207.
Health care-induced diseases constitute a fast-increasing problem. Just one type of these health care-associated infections (HCAI) constitutes the fourth leading cause of death in Western countries. About 25 million individuals worldwide are estimated each year to undergo major surgery, of which approximately 3 million will never return home from the hospital. Furthermore, the quality of life is reported to be significantly impaired for the rest of the lives of those who, during their hospital stay, suffered life-threatening infections/sepsis. Severe infections are strongly associated with a high degree of systemic inflammation in the body, and intimately associated with significantly reduced and malfunctioning GI microbiota, a condition called dysbiosis. Deranged composition and function of the gastrointestinal microbiota, occurring from the mouth to the anus, has been found to cause impaired ability to maintain intact mucosal membrane functions and prevent leakage of toxins—bacterial endotoxins, as well as whole bacteria or debris of bacteria, the DNA of which are commonly found in most cells of the body, often in adipocytes of obese individuals or in arteriosclerotic plaques. Foods rich in proteotoxins such as gluten, casein and zein, and proteins, have been observed to have endotoxin-like effects that can contribute to dysbiosis. About 75% of the food in the Western diet is of limited or no benefit to the microbiota in the lower gut. Most of it, comprised specifically of refined carbohydrates, is already absorbed in the upper part of the GI tract, and what eventually reaches the large intestine is of limited value, as it contains only small amounts of the minerals, vitamins and other nutrients necessary for maintenance of the microbiota. The consequence is that the microbiota of modern humans is greatly reduced, both in terms of numbers and diversity when compared to the diets of our paleolithic forebears and the individuals living a rural lifestyle today. It is the artificial treatment provided in modern medical care—unfortunately often the only alternative provided—which constitute the main contributors to a poor outcome. These treatments include artificial ventilation, artificial nutrition, hygienic measures, use of skin-penetrating devices, tubes and catheters, frequent use of pharmaceuticals; they are all known to severely impair the microbiomes in various locations of the body, which, to a large extent, are ultimately responsible for a poor outcome. Attempts to reconstitute a normal microbiome by supply of probiotics have often failed as they are almost always undertaken as a complement to—and not as an alternative to—existing treatment schemes, especially those based on antibiotics, but also other pharmaceuticals.
PMCID: PMC3571643  PMID: 23344250
health care; surgery; stress; trauma; transplantation; liver cirrhosis; liver steatosis; obesity; osteoarthritis; pancreatitis; critical care; nutrition; enteral nutrition; parenteral nutrition; microbiota; microbiome; microbial translocation; probiotic bacteria; lactobacillus; lactobacillus plantarum; lactobacillus paracasei; microbial translocation; inflammation; infection; Toll-like; neutrophils; pharmaceuticals; biological; eco-biologicals; nutraceuticals; curcumin; resveratrol; antibiotics; chemotherapeutics; barriers; leakage; gut; airways; oral cavity; skin; vagina; placenta; amnion; blood-brain barrier; growth; replication; apoptosis; mucosa; endothelium; plaques; cytokines; IL1; NF-kB; TNF; growth factors; insulinogenic; IGF-1; prebiotics; plant fibers; greens; fruits; vegetables; minerals; fat diet; refined carbohydrate diet; advanced glycation end products (AGEs); advanced lipoxidation end products (ALEs); endotoxin; LPS; proteotoxins; casein; gluten; zein; western lifestyle; paleolithic lifestyle; food habits of the chimpanzee
3.  Nutrition of the critically ill - emphasis on liver and pancreas 
About 25 million individuals undergo high risk surgery each year. Of these about 3 million will never return home from hospital, and the quality of life for many of those who return is often significantly impaired. Furthermore, many of those who manage to leave hospital have undergone severe life-threatening complications, mostly infections/sepsis. The development is strongly associated with the level of systemic inflammation in the body, which again is entirely a result of malfunctioning GI microbiota, a condition called dysbiosis, with deranged composition and function of the gastrointestinal microbiota from the mouth to the anus and impaired ability to maintain intact mucosal membrane functions and prevent leakage of toxins-bacterial endotoxins and whole or debris of bacteria, but also foods containing proteotoxins gluten, casein and zein and heat-induced molecules such as advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs). Markedly lower total anaerobic bacterial counts, particularly of the beneficial Bifidobacterium and Lactobacillus and higher counts of total facultative anaerobes such as Staphylococcus and Pseudomonas are often observed when analyzing the colonic microbiota. In addition Gram-negative facultative anaerobes are commonly identified microbial organisms in mesenteric lymph nodes and at serosal “scrapings” at laparotomy in patients suffering what is called “Systemic inflammation response system” (SIRS). Clearly the outcome is influenced by preexisting conditions in those undergoing surgery, but not to the extent as one could expect. Several studies have for example been unable to find significant influence of pre-existing obesity. The outcome seems much more to be related to the life-style of the individual and her/his “maintenance” of the microbiota e.g., size and diversity of microbiota, normal microbiota, eubiosis, being highly preventive.
About 75% of the food Westerners consume does not benefit microbiota in the lower gut. Most of it, refined carbohydrates, is already absorbed in the upper part of the GI tract, and of what reaches the large intestine is of limited value containing less minerals, less vitamins and other nutrients important for maintenance of the microbiota. The consequence is that the microbiota of modern man has a much reduced size and diversity in comparison to what our Palelithic forefathers had, and individuals living a rural life have today. It is the artificial treatment provided by modern care, unfortunately often the only alternative, which belongs to the main contributor to poor outcome, among them; artificial ventilation, artificial nutrition, hygienic measures, use of skin penetrating devices, tubes and catheters, frequent use of pharmaceuticals, all known to significantly impair the total microbiome of the body and dramatically contribute to poor outcome. Attempts to reconstitute a normal microbiome have often failed as they have always been undertaken as a complement to and not an alternative to existing treatment schemes, especially treatments with antibiotics. Modern nutrition formulas are clearly too artificial as they are based on mixture of a variety of chemicals, which alone or together induce inflammation. Alternative formulas, based on regular food ingredients, especially rich in raw fresh greens, vegetables and fruits and with them healthy bacteria are suggested to be developed and tried.
PMCID: PMC3924628  PMID: 24570901
Health care; surgery; stress; trauma; transplantation; liver cirrhosis; liver steatosis; obesity; osteoarthritis; pancreatitis; critical care; nutrition; enteral nutrition; parenteral nutrition; microbiota; microbiome; microbial translocation; probiotic bacteria; lactobacillus; lactobacillus plantarum; lactobacillus paracasei; microbial translocation; inflammation; infection; toll-like; neutrophils; pharmaceuticals; biological; eco-biologicals; nutraceuticals; antioxidants; curcumin; antibiotics; chemotherapeutics; barriers; leakage; gut; airways; oral cavity; skin; vagina; placenta; amnion; blood-brain barrier; growth; replication; apoptosis; mucosa; endothelium; plaques; cCtokines; IL1; NF-kB; TNF; growth factors; insulinogenic; IGF-1; prebiotics; plant fibers; greens; fruits; vegetables; minerals; fat diet; refined carbohydrate diet; advanced glycation end products (AGEs); advanced lipoxidation end products (ALEs); endotoxin; LPS; proteotoxins; casein; gluten; zein; whey; western lifestyle; paleolithic lifestyle; schimpanzee; avocado; amaranth; buckwheat; quinoa; olive oils; red palm oil; soy; fatty acids; long-chained; medium chained; short-chained; poly-unsaturated; saturated fatty acids; monsaturated
4.  Randomized pilot trial of a synbiotic dietary supplement in chronic HIV-1 infection 
Infection with HIV-1 results in marked immunologic insults and structural damage to the intestinal mucosa, including compromised barrier function. While the development of highly active antiretroviral therapy (HAART) has been a major advancement in the treatment of HIV-1 infection, the need for novel complementary interventions to help restore intestinal structural and functional integrity remains unmet. Known properties of pre-, pro-, and synbiotics suggest that they may be useful tools in achieving this goal.
This was a 4-week parallel, placebo-controlled, randomized pilot trial in HIV-infected women on antiretroviral therapy. A synbiotic formulation (Synbiotic 2000®) containing 4 strains of probiotic bacteria (1010 each) plus 4 nondigestible, fermentable dietary fibers (2.5 g each) was provided each day, versus a fiber-only placebo formulation. The primary outcome was bacterial translocation. Secondary outcomes included the levels of supplemented bacteria in stool, the activation phenotype of peripheral T-cells and monocytes, and plasma levels of C-reactive protein and soluble CD14.
Microbial translocation, as measured by plasma bacterial 16S ribosomal DNA concentration, was not altered by synbiotic treatment. In contrast, the synbiotic formulation resulted in significantly elevated levels of supplemented probiotic bacterial strains in stool, including L. plantarum and P. pentosaceus, with the colonization of these two species being positively correlated with each other. T-cell activation phenotype of peripheral blood lymphocytes showed modest changes in response to synbiotic exposure, with HLA-DR expression slightly elevated on a minor population of CD4+ T-cells which lack expression of HLA-DR or PD-1. In addition, CD38 expression on CD8+ T-cells was slightly lower in the fiber-only group. Plasma levels of soluble CD14 and C-reactive protein were unaffected by synbiotic treatment in this study.
Synbiotic treatment for 4 weeks can successfully augment the levels of probiotic species in the gut during chronic HIV-1 infection. Associated changes in microbial translocation appear to be absent, and markers of systemic immune activation appear largely unchanged. These findings may help inform future studies aimed at testing pre- and probiotic approaches to improve gut function and mucosal immunity in chronic HIV-1 infection.
Trial registration
Clinical NCT00688311
PMCID: PMC3414771  PMID: 22747752
Human immunodeficiency virus-1 (HIV-1); synbiotics; probiotics; prebiotics; microbial translocation; immune activation; highly active antiretroviral therapy (HAART); combined antiretroviral therapy (CART); complementary therapy.
5.  Integrative medicine and human health - the role of pre-, pro- and synbiotics 
Western lifestyle is associated with a sustained low grade increase in inflammation -increased levels of endotoxin in the body and increased activation of Toll-like receptors and neutrophils, which leads to impaired immunity and reduced resistance to disease, changes which might explain the epidemic of chronic diseases spreading around the globe. The immune system cannot function properly without access to bacteria and raw plants, rich not only in bacteria but also in plant fibre, antioxidants, healthy fats and numerous other nutrients. Modern food technology with plant breeding, separation, condensation of food ingredients, heating, freezing, drying, irradiation, microwaving, are effective tool to counteract optimal immune function, and suspected to be a leading cause of so called Western diseases. Supply of pre-, pro-, and synbiotics have sometimes proved to be effective tools to counteract, especially acute diseases, but have often failed, especially in chronic diseases. Thousands of factors contribute to unhealth and numerous alterations in life style and food habits are often needed, in order to prevent and cure “treatment-resistant” chronic diseases. Such alterations include avoiding processed foods rich in pro-inflammatory molecules, but also a focus on consuming substantial amounts of foods with documented anti-inflammatory effects, often raw and fresh green vegetables and tubers such as turmeric/curcumin.
PMCID: PMC3552567  PMID: 23369440
6.  Pro- and Synbiotics to Prevent Sepsis in Major Surgery and Severe Emergencies  
Nutrients  2012;4(2):91-111.
Septic morbidity associated with advanced surgical and medical treatments is unacceptably high, and so is the incidence of complications occurring in connection with acute emergencies such as severe trauma and severe acute pancreatitis. Only considering the US, it will annually affect approximately (app) 300 million (mill) of a population of almost one million inhabitants and cause the death of more than 200,000 patients, making sepsis the tenth most common cause of death in the US. Two major factors affect this, the lifestyle-associated increased weakness of the immune defense systems, but more than this the artificial environment associated with modern treatments such as mechanical ventilation, use of tubes, drains, intravascular lines, artificial nutrition and extensive use of synthetic chemical drugs, methods all known to reduce or eliminate the human microbiota and impair immune functions and increase systemic inflammation. Attempts to recondition the gut by the supply of microorganisms have sometimes shown remarkably good results, but too often failed. Many factors contribute to the lack of success: unsuitable choice of probiotic species, too low dose, but most importantly, this bio-ecological treatment has never been given the opportunity to be tried as an alternative treatment. Instead it has most often been applied as complementary to all the other treatments mentioned above, including antibiotic treatment. The supplemented lactic acid bacteria have most often been killed already before they have reached their targeted organs.
PMCID: PMC3296993  PMID: 22413064
probiotics; microbiota; nutrition; sepsis; pancreatitis; encephalopathy
7.  Effect of Probiotic Bacteria on Microbial Host Defense, Growth, and Immune Function in Human Immunodeficiency Virus Type-1 Infection  
Nutrients  2011;3(12):1042-1070.
The hypothesis that probiotic administration protects the gut surface and could delay progression of Human Immunodeficiency Virus type1 (HIV-1) infection to the Acquired Immunodeficiency Syndrome (AIDS) was proposed in 1995. Over the last five years, new studies have clarified the significance of HIV-1 infection of the gut associated lymphoid tissue (GALT) for subsequent alterations in the microflora and breakdown of the gut mucosal barrier leading to pathogenesis and development of AIDS. Current studies show that loss of gut CD4+ Th17 cells, which differentiate in response to normal microflora, occurs early in HIV-1 disease. Microbial translocation and suppression of the T regulatory (Treg) cell response is associated with chronic immune activation and inflammation. Combinations of probiotic bacteria which upregulate Treg activation have shown promise in suppressing pro inflammatory immune response in models of autoimmunity including inflammatory bowel disease and provide a rationale for use of probiotics in HIV-1/AIDS. Disturbance of the microbiota early in HIV-1 infection leads to greater dominance of potential pathogens, reducing levels of bifidobacteria and lactobacillus species and increasing mucosal inflammation. The interaction of chronic or recurrent infections, and immune activation contributes to nutritional deficiencies that have lasting consequences especially in the HIV-1 infected child. While effective anti-retroviral therapy (ART) has enhanced survival, wasting is still an independent predictor of survival and a major presenting symptom. Congenital exposure to HIV-1 is a risk factor for growth delay in both infected and non-infected infants. Nutritional intervention after 6 months of age appears to be largely ineffective. A meta analysis of randomized, controlled clinical trials of infant formulae supplemented with Bifidobacterium lactis showed that weight gain was significantly greater in infants who received B. lactis compared to formula alone. Pilot studies have shown that probiotic bacteria given as a supplement have improved growth and protected against loss of CD4+ T cells. The recognition that normal bacterial flora prime neonatal immune response and that abnormal flora have a profound impact on metabolism has generated insight into potential mechanisms of gut dysfunction in many settings including HIV-1 infection. As discussed here, current and emerging studies support the concept that probiotic bacteria can provide specific benefit in HIV-1 infection. Probiotic bacteria have proven active against bacterial vaginosis in HIV-1 positive women and have enhanced growth in infants with congenital HIV-1 infection. Probiotic bacteria may stabilize CD4+ T cell numbers in HIV-1 infected children and are likely to have protective effects against inflammation and chronic immune activation of the gastrointestinal immune system.
PMCID: PMC3260491  PMID: 22292110
microbial translocation; inflammation; probiotic bacteria; lactobacillus; HIV-1; AIDS; children; women; anti retroviral therapy; growth; failure-to-thrive; gut associated lymphoid tissue (GALT); mucosal barrier; microflora; CD4+ Th17 cells; CD4+ CD25+ FoxP3+ T regulatory cells; immune development; micronutrient; nutrition; body mass index (BMI); body cellular mass; BCM; anti-retroviral therapy (ART)
8.  Nutrigenomics Therapy of Hepatisis C Virus Induced-hepatosteatosis 
BMC Gastroenterology  2010;10:49.
Nutrigenomics is a relatively new branch of nutrition science, which aim is to study the impact of the foods we eat on the function of our genes. Hepatosteatosis is strongly associated with hepatitis C virus infection, which is known to increase the risk of the disease progression and reduce the likelihood of responding to anti- virus treatment. It is well documented that hepatitis C virus can directly alter host cell lipid metabolism through nuclear transcription factors. To date, only a limited number of studies have been on the effect of human foods on the nuclear transcription factors of hepatitis C virus -induced hepatosteatosis.
Three nutrients, selected among 46 different nutrients: β-carotene, vitamin D2, and linoleic acid were found in a cell culture system to inhibit hepatitis C virus RNA replication. In addition, polyunsaturated fatty acids (PUFAs) especially arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) have been demonstrated to inhibit hepatitis C virus RNA replication. These PUFAs, in particular the highly unsaturated n-3 fatty acids change the gene expression of PPARa and SREBP, suppress the expression of mRNAs encoding key metabolic enzymes and hereby suppress hepatic lipogenesis and triglyceride synthesis, as well as secretion and accumulation in tissues. A recent prospective clinical trial of 1,084 chronic hepatitis C patients compared to 2,326 healthy subjects suggests that chronic hepatitis C patients may benefit from strict dietary instructions.
Increasing evidence suggest that some crucial nuclear transcription factors related to hepatitis C virus -associated hepatosteatosis and hepatitis C virus RNA itself can be controlled by specific anti- hepatitis C virus nutrition. It seems important that these findings are taken into account and specific nutritional supplements developed to be used in combination with interferon as adjunctive therapy with the aim to improve both the early as well as the sustained virological response.
PMCID: PMC2896340  PMID: 20487553
9.  The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD) 
Nonalcoholic fatty liver disease is increasingly regarded as a hepatic manifestation of metabolic syndrome, and the severity of nonalcoholic fatty liver disease seems to increase in parallel with other features of metabolic syndrome. Excess lipid accumulation in the liver cells is not only a mediator of Metabolic Syndrome and indicator of a lipid overload but also accompanied by a range of histological alterations varying from 'simple' steatosis to nonalcoholic steatohepatitis, with time progressing to manifest cirrhosis. Hepatocellular carcinoma may also occur in nonalcoholic steatohepatitis -related cirrhosis with a mortality rate similar to or worse than for cirrhosis associated with hepatitis C. This review summarizes the knowledge about the causal relationship between hepatic fat accumulation, insulin resistance, liver damage and the etiological role of hepatic fat accumulation in pathogenesis of extra- and intra-hepatic manifestations. Special emphasis is given suggestions of new targets treatment and prevention of nonalcoholic fatty liver disease.
PMCID: PMC2873482  PMID: 20426802
10.  Comparative study of the intestinal mucus barrier in normal and inflamed colon 
Gut  2006;56(3):343-350.
To study the role of mucus in the spatial separation of intestinal bacteria from mucosa.
Patients and methods
Mucus barrier characteristics were evaluated using histological material obtained by biopsy from purged colon, colon prepared with enema and material from untreated appendices fixed with non‐aqueous Carnoy solution. Bacteria were evaluated using fluorescence in situ hybridization, with bacterial 16S RNA probes and related to the periodic acid Schiff alcian blue stain. Biopsies from controls (n = 20), patients with self‐limiting colitis (SLC; n = 20), ulcerative colitis (n = 20) and 60 randomly selected appendices were investigated.
The mucosal surface beneath the mucus layer was free of bacteria in ⩾80% of the normal appendices and biopsies from controls. The thickness of the mucus layer and its spread decreased with increasing severity of the inflammation; the epithelial surface showed bacterial adherence, epithelial tissue defects and deep mucosal infiltration with bacteria and leucocytes. Bacteria and leucocytes were found within mucus in all biopsy specimens from patients with ulcerative colitis, SLC, and acute appendicitis. The concentration of bacteria within mucus was inversely correlated to the numbers of leucocytes.
The large bowel mucus layer effectively prevents contact between the highly concentrated luminal bacteria and the epithelial cells in all parts of the normal colon. Colonic inflammation is always accompanied by breaks in the mucus barrier. Although the inflammatory response gradually reduces the number of bacteria in mucus and faeces, the inflammation itself is not capable of preventing bacterial migration, adherence to and invasion of the mucosa.
PMCID: PMC1856798  PMID: 16908512
11.  Aggressive Management of Surgical Emergencies 
Increasing evidence suggests that two factors significantly influence outcome in a surgical emergency – premorbid health and the degree of inflammation during the first 24 h following trauma. Repeat observations suggest that the depth of post-trauma immunoparalysis reflects the height of early inflammatory response. Administration to surgical emergencies, as was routine in the past, of larger amounts of fluid and electrolytes, fat, sugar and nutrients seems counterproductive as it increases immune dysfunction, impairs resistance to disease and, in fact, increases morbidity. Instead, strong efforts should be made to limit the obvious superinflammation, which occurs during the first 24 h after trauma and, thereby, reduce the subsequent immuno-paralysis. paralysis. Several approaches show efficacy in limiting early superinflammation such as strict control of blood glucose, avoida nce of stored blood when possible, supply of antioxidants, live lactic acid bacteria and plant fibres. This review focuses mainly on use of live lactic acid bacteria and plant fibres, often called synbiotics. Encouraging experience is reported from clinical trials in liver transplantation, severe pancreatitis and extensive trauma. Immediate control of inflammation by enteral nutrition and supply of antioxidants, lactic acid bacteria and fibres is facilitated by feeding tubes, introduced as early as possible on arrival at the hospital.
PMCID: PMC1963814  PMID: 17132308
Surgical emergency; Superinflammation; Synbiotics; Lactic acid bacteria; Plant fibres
12.  NF-κB- and AP-1-Mediated Induction of Human Beta Defensin-2 in Intestinal Epithelial Cells by Escherichia coli Nissle 1917: a Novel Effect of a Probiotic Bacterium  
Infection and Immunity  2004;72(10):5750-5758.
Little is known about the defensive mechanisms induced in epithelial cells by pathogenic versus probiotic bacteria. The aim of our study was to compare probiotic bacterial strains such as Escherichia coli Nissle 1917 with nonprobiotic, pathogenic and nonpathogenic bacteria with respect to innate defense mechanisms in the intestinal mucosal cell. Here we report that E. coli strain Nissle 1917 and a variety of other probiotic bacteria, including lactobacilli—in contrast to more than 40 different E. coli strains tested—strongly induce the expression of the antimicrobial peptide human beta-defensin-2 (hBD-2) in Caco-2 intestinal epithelial cells in a time- and dose-dependent manner. Induction of hBD-2 through E. coli Nissle 1917 was further confirmed by activation of the hBD-2 promoter and detection of the hBD-2 peptide in the culture supernatants of E. coli Nissle 1917-treated Caco-2 cells. Luciferase gene reporter analyses and site-directed mutagenesis experiments demonstrated that functional binding sites for NF-κB and AP-1 in the hBD-2 promoter are required for induction of hBD-2 through E. coli Nissle 1917. Treatment with the NF-κB inhibitor Helenalin, as well as with SP600125, a selective inhibitor of c-Jun N-terminal kinase, blocked hBD-2 induction by E. coli Nissle 1917 in Caco-2 cells. SB 202190, a specific p38 mitogen-activated protein kinase inhibitor, and PD 98059, a selective inhibitor of extracellular signal-regulated kinase 1/2, were ineffective. This report demonstrates that probiotic bacteria may stimulate the intestinal innate defense through the upregulation of inducible antimicrobial peptides such as hBD-2. The induction of hBD-2 may contribute to an enhanced mucosal barrier to the luminal bacteria.
PMCID: PMC517557  PMID: 15385474
13.  Reticuloendothelial System Function Following Acute Liver Failure Induced by 90% Hepatectomy in the Rat 
HPB Surgery  1993;6(3):151-162.
Sepsis and bacterial infections are frequent complications of acute liver failure and following major liver resection. The mechanisms underlying this phenomenon are unclear. In this study, RES function and blood clearance of radiolabelled E. coli was immediately impaired following 90% hepatectomy, although the reduction in liver volume resulted in an increase in splenic (temporary) and pulmonary (persisting) uptake. A significant correlation between liver function and host RES function was observed. The uptake capacity of the RES in the liver remnant and spleen did not correlate with subserosal blood flow. The uptake in the brain gradually increased with time, paralleling an increased leakage across the blood-brain barrier. Thus, a significantly impaired RES function resulted from experimental 90% hepatectomy-induced acute liver failure, which might explain the high incidence of septic events in the clinical situation.
PMCID: PMC2443046  PMID: 8489965
14.  The Effect of Biliary Decompression on Bacterial Translocation in Jaundiced Rats 
HPB Surgery  1993;7(2):99-110.
Patients with obstructive jaundice are prone to septic complications after biliary tract operations. Restoring bile flow to the intestine may help to decrease the complication rate. The present study is aimed at evaluating the effect of biliary decompression on bacterial translocation in jaundiced rats.
Sixty-six male Sprague-Dawley rats were randomly allocated to six groups subjected to common bile duct ligation (CBDL) and transection (groups 2–6) or sham operation (group 1). In groups and 2 the incidence of enteric bacterial translocation was determined 2 weeks after sham operation or CBDL. In groups 3–6, biliary decompression was achieved by performing a choledochoduodenostomy after 2 weeks of biliary decompression. Bacterial translocation was then studied 1,2,3 and 5 weeks following biliary decompression.
The rate of bacterial translocation to mesenteric lymph nodes in obstructive jaundice was significantly higher as compared with controls, and decreased with time to nil three weeks following biliary decompression. The incidence of bacterial translocation was closely correlated (r = 0.844; p = 0.034) with serum alkaline phosphatase activity and seemed to fit with the morphological changes noted in the small intestine. The decrease in bacterial translocation, however, lags behind the recovery of liver function as measured by routine liver function tests and antipyrine clearance.
Obstructive jaundice thus promotes bacterial translocation in the rat. Biliary decompression gradually decreases the rate of bacterial translocation.
PMCID: PMC2423694  PMID: 8268113
15.  Collateral Formation After Repeated Transient Dearterialization of the Rat Liver 
HPB Surgery  1992;6(2):105-113.
Hepatic artery ligation is used for the palliation of patients with malignant liver tumours. Collaterals are developed rapidly and could to some extent explain why the growth is affected for only a short period. With intermittent dearterialization, collaterals seem to be avoided and possibly a more extended effect should be expected. The most efficient period of dearterialization to avoid collaterals was studied in this experiment. Five groups of rats were treated with daily repeated transient dearterializations for 0 (n = 3), 60 (n = 6), 120 (n = 6), 180 (n = 6) and 240 minutes (n = 6) respectively for 5 days and compared to another group (n = 3) that was permanently dearterialized. After treatment, celiac angiograms were obtained. All hepatic arteries were reliably occluded and patent after 5 days of daily blockades in all but two rats. There were no collaterals demonstrable on the angiograms in the first four groups after 5 days of intermittent obstruction of the arterial blood flow to the liver. After 240 minutes of dearterialization as well as after collaterals developed and were clearly demonstrated on the angiograms after six days. Liver enzymes were normal even after 4 hours of dearterialization. Repeated occlusions of the hepatic artery was reliably achieved with the implantable minioccluder. Repeated, transient dearterializations for 1, 2 or 3 hours could be performed without development of collaterals and without damage to the liver.
PMCID: PMC2443026  PMID: 1284031
16.  Pharmacokinetics of Mitomycin C Following Hepatic Arterial Chemoembolization With Gelfoam 
HPB Surgery  1992;5(3):161-169.
Twelve mongrel dogs were randomly allocated into two groups using matched paired-design. Catheters were inserted into the hepatic artery, hepatic vein and the femoral vein, respectively. In the first group, gelfoam supplemented with mitomycin C (MMC) was injected into the hepatic artery, whereas the second group received a hepatic arterial injection of MMC solution alone. Simultaneous blood sampling from the hepatic and femoral veins at regular intervals was performed. MMC concentrations in plasma was determined using high performance liquid chromatography (HPLC) and the pharmacokinetics of MMC were determined. MMC concentrations in hepatic and femoral veins did not differ and no significant difference in pharmacokinetics was found when comparing MMC administration into the hepatic artery with or without gelfoam supplementation. Thus, our results revealed that gelfoam could not delay the clearance of MMC from the liver.
PMCID: PMC2442952  PMID: 1510890
17.  Implantable Drainage After Major Abdominal Surgery in Compromised Patients 
HPB Surgery  1990;2(4):261-264.
The risk of superinfection following routine abdominal drainage after major surgery is debated. Especially in patients with malignant diseases and a compromised host defense, this might be a factor increasing morbidity and mortality. During a 3-year period (1986–1988) 41 patients operated on for malignant abdominal conditions received a peritoneal catheter connected to a subcutaneous portal inserted in order to participate in a trial on postoperative intraperitoneal chemotherapy using 5- Fluorouracil. No abdominal drains were inserted. In 15 patients, the subcutaneous portal was used for evacuation of postoperative fluid accumulation within the abdomen. The mean age was 53 (range 41–70) years. Inserted catheters were used for drainage up to 14 days postoperatively. The daily amount of fluid drained varied from 20 to 2 000 ml with a mean of 610 ml/patient and day. One patient required removal of the catheter due to infection around the subcutaneous chamber. Otherwise, the catheter system was not associated with any other complications or complaints. One patient developed a postoperative left subphrenic abscess drained percutaneously by the guidance of ultrasonography, a complication that could not be attributed to the catheter system but merely to the major operation per se. An implantable device for peritoneal access thus also seem useful for drainage of postoperative fluid collection, as evaluated in this preliminary report.
PMCID: PMC2423593  PMID: 2278924
18.  Percutaneous Management of Pyogenic Hepatic Abscesses 
HPB Surgery  1990;2(3):185-188.
Twelve patients (9 men, 3 women) with a mean age of 65 (54–78) years, with pyogenic hepatic abscesses were managed by percutaneous drainage between 1979 and 1987. Biliary origin was most common (4 patients), followed by hepatic abscesses as a late postoperative complication (seen in 3 patients) and hepatic abscesses occurring in association with acute appendicitis (2 patients). The origin was unknown in 3 patients. Diagnosis was reached by computed tomography or ultrasonography with a diagnostic delay of in mean 11 days. Seventeen abscesses were found among the 12 patients. The median abscess size (maximal diameter) was 7 (1–12) cm. Nine patients were treated with percutaneous drainage with an indwelling catheter within the abscess cavity for up to 3 weeks, while 3 patients were managed with percutaneous puncture and aspiration alone. The most commonly isolated organism from the drained hepatic abscess was E.coli. The course following percutaneous treatment was uneventful, without mortality and recurrence of the hepatic abscess during follow-up. One patient required surgical drainage of an additional hepatic abscess.
Percutaneous drainage of hepatic abscesses, independent of origin, thus seems as a safe and reliable method, which should be considered as the treatment of choice if facilities and knowledge of percutaneous management are provided.
PMCID: PMC2423570  PMID: 2278915
19.  Bile Peritonitis in Acute Cholecystitis 
HPB Surgery  1990;2(1):7-13.
A review of all patients treated for acute cholecystitis (n=5848) during an 18-year period (1969–1986) at two hospitals (one practising early surgery in patients with acute cholecystitis and the other not) disclosed that 104 (1.8%) had bile within the abdominal cavity at surgery; 71 with a visible perforation of the gallbladder and 33 without. The bile was infected in 82% of performed cultures (most commonly with Escherichia coli). Mortality was 7.7% (8/104 patients), being 20% (4/20)in the hospital practising delayed surgery and 5% (4/84) in the hospital practising early surgery (p<0.10). Infectious complications were responsible for the deaths by leading to multiple organ failure with pulmonary or renal insufficiency or gastro-intestinal bleeding. The timing of surgery was the only factor that had prognostic significance, i.e. the longer the hospital delay before surgery the higher the mortality, although elderly patients or patients with perforation tended to have a worse prognosis. In conclusion, the results of this study indicated that early surgery is important in patients with acute cholecystitis as a means of lowering mortality in bile peritonitis in this condition.
PMCID: PMC2423559  PMID: 2282332
20.  Subtotal Pancreatectomy for Cancer: Closure of the Pancreatic Remnant With Staplers 
HPB Surgery  1990;2(1):29-39.
This paper presents a 2-year series of 26 consecutive pancreatectomies for periampullary cancer where the pancreatic tail was closed with a stapler in order to avoid complications related to a pancreatico-digestive anastomosis. The follow-up period was 14 months or more. Seven patients developed operative complications. Pancreatic fistulas developed in 3 patients. The fistulas closed spontaneously in 2 of the patients after 2-4 months, lntraabdominal abscesses developed in 4 patients and required surgical drainage. In 1 of these patients, the abscess eroded a large vessel with a fatal outcome resulting in an operative mortality rate of 3.8%. A transient postoperative gastric stasis was observed in seven patients. Postoperative hospital median stay was 27 days (range 10–83 days). Eighteeen patients have died after 4–30 months in recurrent disease and seven patients are alive after a follow-up period of 15–29 months. Pancreatic endocrine function seemed well preserved; diabetes mellitus has developed in only one patient. In conclusion, it appears that subtotal pancreatectomy with closure of the pancreatic remnant with staples gives a low morbidity and mortality. Although the conclusion should be tempered by the small number of patients, the results justify continued evaluation of this technique with long-term follow-up.
PMCID: PMC2423556  PMID: 2282328
21.  Reresection of Colorectal Liver Secondaries: A Preliminary Report 
HPB Surgery  1990;2(1):69-72.
During a 4.5–year period, 5 patients underwent reresection of colorectal liver metastases. Two patients died of recurrent disease, 9–11 months after reresection. Three patients are alive, one without and two with recurrent disease, 15, 15 and 68 months after reresection. Although our results suggest that liver reresection may be meaningful in selected patients with colorectal liver metastases, further studies are necessary in order to define candidates for this procedure.
PMCID: PMC2423551  PMID: 2282331
22.  Hemoperitoneum After Spontaneous Rupture of Liver Tumor: Results of Surgical Treatment 
HPB Surgery  1988;1(1):81-83.
Five cases of massive hemoperitoneum caused by spontaneous rupture of liver tumors, collected during a 27-year period, are reported. Four patients had a primary liver malignancy and one patient a liver cyst with hemangioma. Initial symptoms were obscure and hemoperitoneum was suspected pre-operatively in only one patient. At operation, a mean of 3100 ml of blood was found in the abdomen. Hemostatis was achieved by liver resection in four patients and by suture ligation in one. Two patients died during or shortly after operation. The three patients surviving the operation had primary liver cancer and lived for 6 months to 6.5 years. It is concluded that liver resection, whenever possible, is the treatment of choice and that pre-operative delay and mortality may be diminished by increased awareness of this condition.
PMCID: PMC2423501  PMID: 2856434
23.  Ischaemic and Metabolic Treatment of Hepatic Tumours 
HPB Surgery  1988;1(1):3-14.
For treatment of malignancies, physical and metabolic differences between tumour cells and host cells have guided the development of new approaches. In this review, two new approaches to be used in the treatment of liver malignancies are outlined: ischaemic therapy and interferences with the glucose metabolism. Ischaemic therapy of liver malignancies has been used in different forms during the last 20 years: from ligation of the hepatic artery, embolization of the arterial tree, transient occlusion of the hepatic artery to the present day use of temporary, intermittent, transient hepatic arterial occlusion. The beneficial effect of ischaemic therapy on malignancies is supposed to depend on oxygen and nutritional deficiency, formation of oxygen-derived free radicals and loss of function in cellular enzymes. The tumour cells seem thereby to be more sensitive than the host cells. Also, ischaemia might potentiate the effect of cytotoxic drugs. Intereferencies with glucose metabolism might be directed either towards the exaggerated tumour glycolysis, for example by glucose analogues like 2-deoxy-glucose, or towards the exaggerated host gluconeogenesis, for example by hydrazine sulphate. These treatments result in reduction of the glucose availability in the intracellular glucose metabolism in the tumour cells and have experimentally been demonstrated to be correlated to reduced tumour growth. It is concluded that both these approaches, ischaemic therapy and manipulations with the glucose metabolism, seem promising for the future. What is needed now is research to clarify the mechanims behind the effects, to establish their full consequences, and to identify the clinical use of these treatments and their possible combinations.
PMCID: PMC2423500  PMID: 3153774
24.  Editorial 
HPB Surgery  1988;1(1):1-2.
PMCID: PMC2423499  PMID: 3153771

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