The Cause of Acute Respiratory Failure Predicts the Outcome of Noninvasive Ventilation in Immunocompromised Children.

BACKGROUND: Noninvasive ventilation (NIV) may be superior to conventional therapy in immunocompromised children with respiratory failure. METHODS: Mortality, success rate, prognostic factors and side effects of NIV for acute respiratory failure (ARF) were investigated retrospectively in 41 in children with primary immunodeficiency, after stem cell transplantation or chemotherapy for oncologic disease. RESULTS: In 11/41 (27%) children invasive ventilation was avoided and patients were discharged from ICU. In children with NIV failure ICU-mortality was 19/30 (63%). 8/11 (72%) children with NIV success had recurrence of ARF after 27 days. Only 4/11 (36%) children with first episode NIV success and 8/30 (27%) with NIV failure survived to hospital discharge. Lower FiO2, SpO2/FiO2 and blood culture positive bacterial sepsis were predictive for NIV success, while fungal sepsis or culture negative ARF were predictive for NIV failure. We observed catecholamine treatment in 14/41 (34%), pneumothorax in 2/41 (5%), mediastinal emphysema in 3/41 (7%), a life threatening nasopharyngeal hemorrhage and need for resuscitation during intubation in 5/41 (12%) NIV-episodes. CONCLUSIONS: The prognosis of ARF in immunocompromised children remains guarded independent of initial success or failure of NIV due to a high rate of recurrent ARF. Reversible causes like bacterial sepsis had a higher NIV response rate. Relevant side effects of NIV were observed.

A new paradigm to understand and treat diabetic neuropathy.

The clinical symptoms of diabetic neuropathy (DN) manifest in a time dependent manner as a positive symptoms (i. e. pain, hypersensitivity, tingling, cramps, cold feet etc.) during its early stages and by a loss of function (i. e. loss of sensory perception, delayed wound healing etc.) predominating in the later stages. Elevated blood glucose alone cannot explain the development and progression of DN and the lowering of blood glucose is insufficient in preventing and/or reversing neuropathy in patients with type 2 diabetes. Recently it has been shown that the endogenous reactive metabolite methylglyoxal (MG) can contribute to the gain of function via post-translational modification in DN of neuronal ion channels involved in chemosensing and action potential generation in nociceptive nerve endings. Dicarbonyls, such as MG, that are elevated in diabetic patients, modify DNA as well as extra- and intracellular proteins, leading to the formation of advanced glycation endproducts (AGEs). Increased formation of AGEs leads to increased cellular stress, dysfunction and ultimately cell death. The interaction of AGE-modified proteins through cell surface receptors, such as RAGE, can lead to increased cellular activation and sustained inflammatory responses, which are the molecular hallmarks of the later, degenerative, stages of DN. The direct and indirect effects of dicarbonyls on nerves or neuronal microvascular network provides a unifying mechanism for the development and progression of DN. Targeting the accumulation of MG and/or prevention of RAGE interactions may therefore provide new, more effective, therapeutic approaches for the treatment of DN.

Effects of short sustained lung inflations on cerebral blood flow and cerebral tissue oxygenation in the juvenile rabbit.

BACKGROUND: Sustained lung inflations improve oxygenation but may impair hemodynamics. This study aimed to determine effects of short sustained inflations on cerebral blood flow and cerebral tissue oxygenation in experimental lung injury. METHODS: Experiments were performed in 6 juvenile ventilated New Zealand white rabbits. The effects of a series of sustained inflations at 20, 25 and 30 cmH2O pressure for 15 seconds duration each on hemodynamics, cerebral blood flow and cerebral tissue oxygenation were determined by laser Doppler flowmetry and cerebral tissue oxygen tension measurement in naive animals, after surfactant depletion and subsequent fluid filling of the lung. RESULTS: During the series of sustained inflations the mean arterial blood pressure decreased by 73%, 52% and 32% and the mean cerebral blood flow decreased by 73%, 39% and 30% in naive animals, after surfactant depletion and with fluid filling of the lung respectively. Arterial oxygen saturation was maintained or increased, while mean cerebral tissue oxygenation decreased by 48% (naive), 8% (surfactant depletion) or increased by 81% (surfactant depletion and fluid filling). Three minutes after the sustained inflations blood gases were similar to the blood gases prior to the sustained inflations. CONCLUSION: A series of short sustained lung inflations of 15 seconds duration can impair cerebral blood flow but increase arterial oxygen saturation in this juvenile animal model. The combination of these effects resulted in either a decrease or increase in regional cerebral tissue oxygenation.

Understanding diabetic polyneuropathy and longevity: what can we learn from the nematode Caenorhabditis elegans?

Pathogenesis of late diabetic complications is influenced by a complex interplay of multiple exogenous and intrinsic factors. The well characterised nematode Caenorhabditis elegans is an ideal model to study causes of diabetic polyneuropathy because of its easily accessible nervous system. A repertoire of methods allows the assessment of both morphological and functional glucotoxic damages as well as reduction of lifespan, thereby helping to examine the influence of different pathways and mechanisms on neurodegeneration. Its insulin signalling system allows to directly visualize effects of insulin on high glucose induced neuronal damage, leading to a better understanding of diabetic polyneuropathy.

Predictors of early nasal CPAP failure and effects of various intubation criteria on the rate of mechanical ventilation in preterm infants of <29 weeks gestational age.

INTRODUCTION: Delivery room management using early nasal continuous positive airway pressure (nCPAP) may delay surfactant therapy. OBJECTIVE: To identify factors associated with early nCPAP failure and effects of various intubation criteria on rate and time of intubation. DESIGN: Retrospective analysis of the first 48 h in infants of 23-28 weeks gestational age (GA) treated with sustained inflations followed by early nCPAP. RESULTS: Of 225 infants (GA 26.2±1.6 weeks) 140 (62%) could be stabilised with nCPAP in the delivery room, of whom 68 (49%; GA 26.9±1.5 weeks) succeeded on nCPAP with favourable outcome and 72 infants (51%; GA 26.3±1.4 weeks) failed nCPAP within 48 h at a median (IQR) age of 5.6 (3.3-19.3) h. History or initial blood gases were poor predictors of subsequent nCPAP failure. Intubation at fraction of inspired oxygen (FiO(2))≥0.35 versus 0.4 versus 0.45 instead of ≥0.6 would have resulted in unnecessary intubations of 16% versus 9% versus 6% of infants with nCPAP success but decreased the age at intubation of infants with nCPAP failure to 3.1 (2.2-5.2) versus 3.8 (2.5-8.7) versus 4.4 (2.7-10.9) h. CONCLUSIONS: Medical history or initial blood gas values are poor predictors of subsequent nCPAP failure. A threshold FiO(2) of ≥0.35-0.45 compared to ≥0.6 for intubation would shorten the time to surfactant delivery without a relevant increase in intubation rate. An individualised approach with a trial of early nCPAP and prompt intubation and surfactant treatment at low thresholds may be the best approach in very low birthweight infants.

Venesection therapy of insulin resistance-associated hepatic iron overload.

BACKGROUND/AIMS: The association of hepatic iron overload with metabolic disorders has been coined as the insulin resistance-associated hepatic iron overload syndrome (IR-HIO). METHODS: Fifty-six IR-HIO patients were phlebotomized either weekly (n = 14) or bimonthly (n = 42) and compared with C282Y homozygotes and with ten IR-HIO patients treated by a low calorie diet alone. RESULTS: In venesected patients, the median amount of mobilized iron was 0.6 g in 2.8 months in females and 1.8 g in 5 months in males. Mobilized iron did not differ depending on the frequency of venesections or HFE genotype. When compared with C282Y homozygotes, IR-HIO patients had a similar amount of mobilized iron, but three-fold serum ferritin levels. The presenting symptoms (chronic fatigue and/or polyarthralgias) improved in 6/7 patients. Phlebotomies were well tolerated. In patients treated by a low calorie diet, serum ferritin levels remained stable. CONCLUSIONS: In IR-HIO patients, body iron stores are significantly increased, overestimated by serum ferritin, not modified by a low calorie diet, and safely removed by phlebotomies. Based on these data and on studies indicating that iron excess is associated with increased risk for hepatic fibrosis, cancer and cardiovascular disorders, venesection therapy can be recommended in IR-HIO patients.

Histologic features of the liver in insulin resistance-associated iron overload. A study of 139 patients.

The aim of the present study was to describe histologic features of the liver in insulin resistance-associated hepatic iron overload (IR-HIO), defined as the association of metabolic disorders and hepatic iron overload. We included 139 patients in the study on the basis of one or more metabolic disorders and liver iron overload unrelated to usual causes. Liver biopsy specimens were reviewed, and histologic data were compared with those of a previously published, well-defined population with genetic hemochromatosis. Iron overload was characterized by a mixed pattern with iron deposits in hepatocytes and sinusoidal cells. Steatosis was present in 59.7% of patients with inflammation in 32.4% of cases. Periportal fibrosis was found in 67.4% of patients. These patients were older, had higher sinusoidal iron scores, and had a higher prevalence of steatosis and inflammation than patients without fibrosis. Iron overload in IR-HIO was histologically different from that in genetic hemochromatosis.

Interferon and ursodeoxycholic acid combined therapy in chronic viral C hepatitis: controlled randomized trial in 203 patients.

AIMS: This prospective randomized trial was carried out in order to determine whether the long-term administration of ursodeoxycholic acid after discontinuation of interferon had any beneficial effect on the clinical course of hepatitis C virus infection. METHODS: Enrolled in the study were 203 patients with chronic active hepatitis C. They were all given: interferon alpha-2a (3 MU subcutaneously thrice a week) and ursodeoxycholic acid (10 mg/kg/day) for 9 months. At month 9, biochemical responders only were randomized into ursodeoxycholic acid treatment or placebo for 12 additional months (double blind study). RESULTS: At the end of interferon therapy, 71 patients (37%) were virological responders and 107 (56%) patients were biochemical responders and were randomized: 54 into the ursodeoxycholic acid group and 53 into the placebo group. Sustained response was evaluated 12 months after withdrawal of interferon. Sustained biochemical and virological responses were, respectively, 30% and 22% in the ursodeoxycholic acid group and 46% and 32% in the placebo group, which did not significantly differ. Histological evolution of fibrosis and necrotic inflammatory activity were similar in the two groups. CONCLUSION: Continuation of ursodeoxycholic acid therapy after withdrawal of interferon in patients with end-of-treatment response did not result in any significant improvement either in the maintenance of response to interferon or in liver histology.

[Primary T-cell lymphoma of the common bile duct]. / Lymphome T primitif de la voie biliaire principale.

Involvement of the gastrointestinal tract is frequently reported among the extranodal sites of non-Hodgkin's lymphoma, but primary lymphoma of the common bile duct is extremely rare. We report the case of a 29-year-old man who presented with obstructive jaundice, leading to the diagnosis of high-grade primary non Hodgkin's T-cell lymphoma, originating from the extrahepatic biliary tract, and confirmed by endosonography and magnetic resonance cholangiography. This patient was treated by sequential chemotherapy without resection and remained in complete remission after one year.

Respective value of alkaline phosphatase, gamma-glutamyl transpeptidase and 5' nucleotidase serum activity in the diagnosis of cholestasis: a prospective study of 80 patients.

We studied the value of alkaline phosphatase (AP), gamma-glutamyl transpeptidase (GGT), and 5'-nucleotidase (5'-NU) activities in the diagnosis of intrahepatic (IHC) versus extra-hepatic cholestasis (EHC). Eighty patients were included prospectively. All presented with cholestasis as defined by a concomitant increase in at least two of three cholestatic enzymes (AP, GGT, 5'-NU), a low cytolytic ratio (alanine aminotransferase/AP [xN/xN] < or = 5), and no evidence for associated liver tumor. We compared 43 patients with IHC due to chronic liver disease to 37 patients with EHC due to main bile duct obstruction. Fasting blood samples for activity determination (AP, GGT, 5'-NU) were taken before performing liver biopsy in cases of IHC and before endoscopic or surgical management in cases of EHC. Enzyme activities were compared using univariate and multivariate analysis. AP (276 IU/L [35-3,140] vs. 123 IU/L [37-699]: p < 0.0001), GGT (595 IU/L [98-5,200] vs. 211 IU/L [38-925]; p < 0.0001), and 5'-NU (32 IU/L [10-142] vs. 16 IU/L [4-107]: p < 0.0003) were significantly higher in EHC when compared to IHC. Only in GGT and 5'-NU activities were independent variables significantly linked to the mechanism of cholestasis. In IHC, the ratio GGT/5'-NU (xN/xN) was significantly lower than in EHC (2.8 [0.7-7.2] vs. 3.7 [1.8-10.5]: p < 0.006). A threshold of GGT/5'-NU < 1.9 had a sensitivity of 40% and a specificity of 100% for the diagnosis of IHC. Although such hepatobiliary enzymes cannot be regarded as diagnostic, they can provide useful information to orientate the clinician in the diagnosis of cholestasis.

Insulin resistance-associated hepatic iron overload.

BACKGROUND & AIMS: Hepatic iron overload has been reported in various metabolic conditions, including the insulin-resistance syndrome (IRS) and nonalcoholic steatohepatitis (NASH). The aim of this study was to show that such hepatic iron overload is part of a unique and unrecognized entity. METHODS: A total of 161 non-C282Y-homozygous patients with unexplained hepatic iron overload were included. We determined the age; sex; presence of IRS (1 or more of the following: body mass index of >25, diabetes, or hyperlipidemia); serum iron tests and liver iron concentration (LIC; reference value, <36 micromol/g); liver function test results; C282Y and H63D HFE mutations; and liver histological status. RESULTS: Patients were predominantly male and middle-aged. Most (94%) had IRS. Transferrin saturation was increased in 35% (median, 42%; range, 13%-94%). LIC ranged from 38 to 332 micromol/g (median, 90 micromol/g), and LIC/age ratio ranged from 0.5 to 4.8 (median, 1.8). Allelic frequencies of both HFE mutations were significantly increased compared with values in normal controls (C282Y, 20% vs. 9%; H63D, 30% vs. 17%), only because of a higher prevalence of compound heterozygotes. Patients with no HFE mutations had similar degrees of iron overload as those with other genotypes, except for compound heterozygotes, who had slightly more iron burden. Steatosis was present in 25% of patients and NASH in 27%. Portal fibrosis (grades 0-3) was present in 62% of patients (grade 2 or 3 in 12%) in association with steatosis, inflammation, and increased age. Sex ratio, IRS, transferrin saturation, and LIC did not vary with liver damage. Serum ferritin concentration, liver function test results, and fibrosis grade were more elevated in patients with steatosis and NASH than in others, but LIC and allelic frequencies of HFE mutations were similar. CONCLUSIONS: This study shows that patients with unexplained hepatic iron overload are characterized by a mild to moderate iron burden and the nearly constant association of an IRS irrespective of liver damage.

[Importance of liver puncture biopsy and endoscopic retrograde cholangiography in patients with chronic anicteric unexplained cholestasis. A retrospective study in 79 patients]. / Intérêt de la ponction-biopsie hépatique et de la cholangiographie rétrograde endoscopique chez les malades ayant une cholestase chronique anictérique inexpliquée. Etude rétrospective chez 79 malades.

AIM: To determine the diagnostic value of systematic liver needle biopsy and endoscopic retrograde cholangiography in patients with unexplained chronic anicteric cholestasis. METHODS: Seventy nine patients presented with anicteric cholestasis for over 6 months as defined by: a concomitant increase in at least 2 of 3 cholestatic enzymes (GGT, alkaline phosphatase, 5'nucleotidase); a low cytolytic ratio (ALT/AP (xN/xN) < or = 5); and negative test results (normal ultrasound scan; no antimitochondrial antibodies, viral, drug-induced, or toxic hepatitis, or known ulcerative cholitis). Based on liver biopsy and endoscopic retrograde cholangiography, 5 groups were determined; group A: normal liver biopsy and endoscopic retrograde cholangiography; group B: primary sclerosing cholangitis with histological biliary lesions; group C: primary sclerosing cholangitis with normal histology; group D: histologic biliary lesions alone; group E: other (aspecific histologic lesions, isolated anomalies of intrahepatic bile ducts on endoscopic retrograde cholangiography). RESULTS: Diagnosis of cholestasis was fortuitous in 43% of cases. Group A: 5 patients had normal liver biopsy and endoscopic retrograde cholangiography; group B (10 patients): 5 with destructive cholangitis, 5 with degenerative cholangitis, associated with portal fibrosis in 90%; group C: none of the patients had primary sclerosing cholangitis with normal histology; group D: 39 patients {idiopathic ductopenia (1), Caroli's disease (1), benign recurrent cholestasis (1), regenerative nodular hyperplasia (4), destructive cholangitis without ductopenia (7), degenerative cholangitis (15), ductular proliferation (10)}; group E: 24 patients with aspecific histologic lesions, and one patient with isolated anomalies of the intrahepatic bile ducts on endoscopic retrograde cholangiography. CONCLUSIONS: In the present population: a) 13% presented with intense cholangitis and primary sclerosing cholangitis on endoscopic retrograde cholangiography; b) 49% presented with various histologic biliary lesions without primary sclerosing cholangitis. We conclude that in chronic anicteric cholestasis of unexplained origin, first choice work-up should include liver biopsy, and endoscopic retrograde cholangiography should only be performed when intense histologic cholangitis is observed.

Fecal incontinence with normal anal canal pressures: where is the pitfall?

OBJECTIVE: One third of subjects who suffer from fecal incontinence are found to have values within the normal range when anal manometry is performed. For these patients, one hypothesis is that impaired rectal adaptation to distension may occur. The aim of our study was to analyze anorectal responses to rectal isobaric distension in this population. METHODS: This was a prospective study conducted in 51 consecutive incontinent patients (45 female, six male) divided into two groups according to their functional anal state: absence (19 patients aged 55 +/- 6 yr) or presence of manometric anal weakness (32 patients aged 59 +/- 2 yr). The subjects were submitted to two randomized modes of rectal isobaric distension (tonic, phasic) with an electronic barostat. Anal pressures, perception, and volumes of the rectum were recorded at six different preselected pressures. RESULTS: As compared with those having anal weakness, patients with no anal weakness retained higher mean pressures at both upper (36.9 +/- 2.2 vs 22.9 +/- 1.4 mm Hg; p = 0.01) and lower parts (41.0 +/- 2.0 vs 23.3 +/- 1.4 mm Hg; p = 0.002) of the anal canal, similar perception scores, but much lower rectal volumes (68.5 +/- 5.5 vs 121.8 +/- 7.0 ml; p = 0.008) in response to rectal isobaric distension. CONCLUSION: A decrease in rectal adaptation could be involved in fecal leakage in patients with no anal manometric weakness.

A pilot study of iron depletion as adjuvant therapy in chronic hepatitis C patients not responding to interferon.

The aim of this study was to assess the efficacy of iron depletion obtained by phlebotomy to enhance interferon response in 11 patients who had failed to respond to a standard 3-month interferon treatment. Despite a significant effect on serum aminotransferase levels, there was no effect on viremia, and iron depletion was unable to trigger interferon response.

Magnetic resonance iron-free nodules in genetic hemochromatosis.

OBJECTIVE: In hemochromatosis, areas of normal hepatic magnetic resonance (MR) signal intensity indicate the presence of iron-free-nodules, which are strongly suspected of being neoplastic. The goal of the study was to define the prevalence and the nature of these iron-free MR nodules at the time of diagnosis in 116 patients included in a prospective study assessing the accuracy of MR imaging (MRI) in the quantification of liver iron overload. METHODS: Seventy-nine of the 116 patients had homozygous hemochromatosis on a phenotypic basis. Fifteen-millimeter-thick contiguous slices were performed using T1- and T2-weighted gradient echo sequences with a 0.5 Tesla magnet. RESULTS: Six of 79 homozygous hemochromatotic patients had one or more MR iron-free nodules. Five of the six patients proved to have malignant tumors. Four of six iron-free nodules were hepatocellular carcinoma (5% in the hemochromatosis group and 17.5% in hemochromatotic patients with severe fibrosis). CONCLUSIONS: The present data confirm the high prevalence of liver cancer at the time of diagnosis, mainly in cirrhotic patients greater than 45 years of age, and indicate that, when performing MRI for liver iron quantification, a complete hepatic MRI examination is preferable to a simple signal measurement in patients at risk for hepatocellular carcinoma.

In patients with cirrhosis, serum albumin determination should be carried out by immunonephelometry rather than by protein electrophoresis.

OBJECTIVE: Serum albumin is a key parameter for prognosis in cirrhosis. We compared levels of serum albumin determined by both protein electrophoresis and immunonephelometry, with special reference to the Child-Pugh classification. DESIGN AND METHODS: One hundred and thirty-one patients, including 39 with cirrhosis, were included prospectively during 2 months. The aetiology of cirrhosis was mainly alcoholism (67%) and hepatitis C virus (HCV) (18%). Serum albumin was determined simultaneously by electrophoresis (Hydrasys SEBIA following protein determination by the biuret reaction) and by immunonephelometry (BECKMAN Nephelometer). Values were compared by non-parametric tests. RESULTS: For the whole population, electrophoretic and immunonephelometric values correlated (p = 0.85; P < 0.0001), but electrophoresis significantly overestimated serum albumin by a median 1.6 g/l (P < 0.0001) with a large spread in values (range, -3.9 to 12.7). Median overestimation in cirrhosis was 2.6 g/l (P < 0.0001; range, -2.0 to 10.2) and 1.0 g/l (P < 0.0001; range, -3.9 to 12.7) in patients without cirrhosis (difference, P < 0.02). For 6/39 (15.4%) patients with cirrhosis, this overestimation led to an underestimation in the Child-Pugh classification. CONCLUSION: In our experience, electrophoresis can lead to serum albumin values which are significantly different compared to those obtained by immunonephelometry. This discrepancy may lead to an incorrect Child-Pugh classification. Therefore, in the follow-up of cirrhotic patients, serum albumin should be determined by immunonephelometry.