Phagocytosis and production of reactive oxygen species by peripheral blood phagocytes in patients with different stages of alcohol-induced liver disease: effect of acute exposure to low ethanol concentrations

BACKGROUND: In rodents, the development of alcoholic liver disease (ALD) after chronic alcohol feeding was shown to depend on the activity of enzymes that are necessary for production of reactive oxygen species (ROS) in phagocytes. The aim of this study was to determine the formation of ROS by resting and challenged phagocytes of patients with different stages of ALD in the presence of ethanol concentrations commonly found in the blood of alcohol abusers. PATIENTS AND METHODS: The release of ROS and the phagocytosis of bacteria by neutrophils and monocytes obtained from 60 patients, who were categorized in three groups due to the severity of ALD, were compared to that of 28 healthy controls. ROS release by these phagocytes was measured after challenging with endotoxin and the addition of ethanol (22 and 44 mM). RESULTS: Resting neutrophils but not monocytes from patients with severe stages of ALD produced significantly more ROS than those of healthy controls. Basal values of ROS production from neutrophils correlated closely to markers of the severity of ALD. ROS formation was depressed dose-dependently by ethanol in the healthy controls but not in alcohol abusers. CONCLUSIONS: Changes in the ROS metabolism of phagocytes found in this study might contribute to both the development of ALD and the impaired immune response occurring in patients with severe ALD.     

Herpes zoster as an immune restoration disease in AIDS patients during therapy including protease inhibitors

A prospective study to evaluate the incidence of herpes zoster (HZ) as an immune restoration disease in patients with AIDS during highly active antiretroviral therapy (HAART) was conducted in a series of 115 patients diagnosed with AIDS initiated on HAART between 1 January 2000 and 31 July 2001. Of these, a single dermatomal HZ episode occurred in 14 (12%) patients within one and 15 months of HAART (median eight months). The HZ patients were similar to the non-HZ patients in age, sex, and HIV transmission risk factor, but had a more advanced disease. Compared with the baseline values, the viral loads significantly (P<0.01) decreased, while the mean CD4+ T-cell counts increased by almost four-fold (P<0.01) in both groups at the time of the HZ episode (or equivalent in non-HZ), but remained below 400/mL in the HZ patients. HZ during HAART is an immunopathological consequence of the improvement of the host immuneresponse, correlating with the beginning of immune restoration.     

Acute reversible hypoxemia in systemic lupus erythematosus

OBJECTIVE: To determine the frequency of unexplained reversible hypoxemia in patients with systemic lupus erythematosus and to assess the relation between hypoxemia and elevated plasma levels of complement split products. DESIGN: Cohort study. SETTING: Inpatient and outpatient facilities of the New York University Medical Center/Bellevue Hospital and the Hospital for Joint Diseases. PATIENTS: Case patients were 22 patients hospitalized with disease exacerbation and no evidence of parenchymal lung disease on chest roentgenogram. Four patients with stable disease were followed in the outpatient clinic, and five healthy normal volunteers served as controls. MEASUREMENTS: Plasma levels of complement split products (C3a, factor Bb fragment), alveolar-arterial (A-a) Po2 gradients, and pulmonary function were measured. MAIN RESULTS: Nine episodes of hypoxemia or hypocapnia (mean A-a gradient, 30.4 +/- 4.8 mm Hg) or both (despite normal chest roentgenogram results) were noted in six hospitalized patients (group 1). Gas exchange improved within 72 hours of steroid therapy (mean A-a gradient, 11.6 +/- 4.3 mm Hg; P less than 0.01). These patients had an elevated initial mean C3a level (938.4 +/- 246.8 ng/mL) that decreased within 72 hours (407.8 +/- 80.9 ng/mL; P less than 0.01), concomitant with improved oxygenation. Ventilation-perfusion scans, obtained for four of six group 1 patients, excluded pulmonary emboli. Four hospitalized patients (group 2) had a normal A-a gradient (mean, 7.5 +/- 2.7 mm Hg). The mean C3a level of this group (358.3 +/- 39.2 ng/mL) was lower than that of group 1 (P less than 0.05). Four patients with stable disease (group 3) had a mean A-a gradient and a mean C3a level of 3.3 +/- 2.7 mm Hg and 237.8 +/- 105.7 ng/mL, respectively, similar to values found in five normal volunteers, in whom the mean A-a gradient was 3.7 +/- 1.7 mm Hg and the mean C3a level was 124.8 +/- 9.2 ng/mL. CONCLUSION: A syndrome of reversible hypoxemia, unassociated with parenchymal lung disease, is unexpectedly common in acutely ill, hospitalized patients with systemic lupus erythematosus. The pathogenesis of this syndrome is unclear, although the data are compatible with the hypothesis that hypoxemia may be related to pulmonary leukoaggregation.     

Carotid artery disease: Stenting versus endarterectomy

Atherosclerotic carotid artery stenosis is a major cause of disabling stroke or death. Although carotid endarterectomy (CEA) is currently considered to be the standard of care for patients with a severe symptomatic stenosis and selected patients with an asymptomatic carotid stenosis, carotid angioplasty and stenting (CAS) is increasingly being used as an alternative treatment modality. This article briefly summarizes the current trial data on CEA and CAS. More importantly, potential risk factors for CEA and CAS are reviewed and the complementary role of these techniques in the management of the individual patient is discussed.     

Neutrophil activation and production of reactive oxygen species in pre-eclampsia

OBJECTIVE: To investigate neutrophil NADPH oxidase activation and subsequent production of reactive oxygen species (ROS) in pre-eclampsia. DESIGN: Baseline values and the activated response of neutrophils upon stimulation of the NADPH oxidase with the agonists was measured. Neutrophils from 17 third-trimester pre-eclamptic and 17 age- and gestation-matched normal pregnant women were examined. METHODS: Neutrophil ROS production was measured by both lucigenin- and luminol-derived chemiluminescence. The abundance of the various phox proteins was examined using Western blotting techniques. Lucigenin-derived ROS generation was significantly increased in neutrophils isolated from women with pre-eclampsia compared with normotensive controls in the case of both agonists [n-formyl-met-leu-phe (fMLP): pre-eclamptic 2.071 +/- 0.336 relative light units seconds (RLU.s) and normotensive 1.141 +/- 0.249 RLU.s, P = 0.035; phorbol-12-myristate-13-acetate (PMA): pre-eclamptic 34.954 +/- 2.634 RLU.s and normotensive 17.208 +/- 3.325 RLU.s, P = 0.0001]. Luminol-derived ROS generation was also significantly increased in the neutrophils isolated from the women with pre-eclampsia compared with the normotensive controls in the case of both agonists (fMLP: pre-eclamptic 1.955 +/- 0.316 RLU.s and normotensive 1.058 +/- 0.191 RLU.s, P = 0.023; PMA: pre-eclamptic 4.108 +/- 0.351 RLU.s and normotensive 3.073 +/- 0.332 RLU.s, P = 0.042). There were no differences between the relative abundance of the phox proteins in the two groups. CONCLUSIONS: Neutrophils isolated from women with pre-eclampsia during the third trimester showed increased sensitivity to agonist stimulation and produced significantly more ROS than age-matched normotensive controls. This was not due to an increased abundance of any of the phox proteins. Increased ROS production in pre-eclampsia may highlight a role for neutrophils in the oxidative stress and associated endothelial dysfunction that are characteristic of the condition.     

Novel Atlantic bottlenose dolphin parainfluenza virus TtPIV-1 clusters with bovine PIV-3 genotype B strains

Parainfluenza virus 3 (PIV-3) is a common viral infection not only in humans, but also in many other species. Serological evidence suggests that nearly 100 % of children in the United States have been infected with PIV-3 by 5 years of age. Similarly, in cattle, PIV-3 is commonly associated with bovine respiratory disease complex. A novel dolphin PIV-3 (TtPIV-1) was described by Nollens et al. in 2008 from a dolphin that was diagnosed with an unknown respiratory illness. At that time, TtPIV-1 was found to be most similar to, but distinct from, bovine PIV-3 (BPIV-3). In the present study, similar viral growth kinetics and pro-inflammatory cytokine (IL-1β, IL-6, and CXCL8) production were seen between BPIV-3 and TtPIV-1 in BEAS-2B, MDBK, and Vero cell lines. Initial nomenclature of TtPIV-1 was based on partial sequence of the fusion and RNA polymerase genes. Based on the similarities we saw with the in vitro work, it was important to examine the TtPIV-1 genome in more detail. Full genome sequencing and subsequent phylogenetic analysis revealed that all six viral genes of TtPIV-1 clustered within the recently described BPIV-3 genotype B strains, and it is proposed that TtPIV-1 be re-classified with BPIV-3 genotype B strains.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.