Decreased hepatic selenium content in alcoholic cirrhosis

Selenium deficiency has been implicated as contributing to hepatic injury in alcoholics. The mechanism by which this occurs is most likely lipoperoxidation secondary to decreased activity of the selenoenzyme glutathione peroxidase. To further assess this relationship, we measured selenium content in autopsy livers in 12 patients with alcoholic cirrhosis compared to 13 patients matched for age and sex dying from other causes, mostly with cardiopulmonary diseases. The mean (±sem) hepatic selenium content in cirrhosis was 0.731±0.077 Μg/g dry weight versus 1.309±0.166 Μg/g in controls (P< 0.005; Student's t test). Clinical and biochemical indices of significant hepatic dysfunction, including encephalopathy, ascites, and elevations of serum bilirubin or prothrombin time, were only present in the cirrhotic group. A significant inverse correlation between hepatic selenium content and the prothrombin time was noted (r=?0.50; Ps<0.02). No significant relationships between hepatic selenium and the abnormalities of bilirubin, albumin, or aspartate aminotransferase were found. We conclude that significantly decreased hepatic selenium stores are present in patients with severe alcoholic cirrhosis compared to controls. The magnitude of that selenium deficit does correlate with some indices of hepatic function, specifically the prothrombin time. These data lend further support to a true selenium deficiency state in alcoholic cirrhosis. It is highly possible that selenium deficiency represents an important link, synergistically joining the nutritional and hepatotoxic backgrounds of alcoholic liver injury and cirrhosis.     

Early radiographic and clinical features associated with bronchiectasis in children

Bronchiectasis among children living in developing regions is associated with respiratory infections during early childhood, but specific risk factors that precede childhood bronchiectasis are not fully characterized. We hypothesized that severe respiratory syncytial viral (RSV) infection in infancy would increase the risk of bronchiectasis among Alaska Native children in rural Alaska. This was a follow-up cohort study of a 1993-1996 case-control study of RSV-hospitalized case patients and their controls. For each 5-8-year-old former case-patient and control subject, we reviewed medical records, interviewed parents, performed physical examinations and spirometry, collected sera, and analyzed all historical chest radiographs. Ten (11%) RSV cases and 10 (9%) controls had radiographic evidence of bronchiectasis. The mean age at radiographic diagnosis of bronchiectasis was 3.3 years (range, 1.2-6.1 years). Children were more likely to develop bronchiectasis if their chest radiographs, when they were < 2 years of age, showed lung parenchymal densities (RR = 3.9, P < 0.013), persistent parenchymal densities > 6 months' duration (RR = 3.0, P = 0.02), or infiltrates on multiple episodes (test for trend, P = 0.003). Radiographic features of hyperinflation and atelectasis among children < 2 years old were not associated with eventual bronchiectasis. A single severe infection with RSV alone did not predispose Alaska Native infants to bronchiectasis. Childhood bronchiectasis was associated with lung and hence airway injury, manifested on radiographs by parenchymal densities or "pneumonia" rather than by hyperinflation or atelectasis.     

Internal tandem duplications of the FLT3 gene are present in leukemia stem cells

Internal tandem duplication mutations of the FLT3 gene (FLT3/ITD mutations) are the most frequent molecular abnormality in acute myeloid leukemia (AML) and are associated with a poor overall survival. While the normal FLT3 receptor is expressed in early hematopoietic progenitor cells, it has not been determined whether FLT3 mutations are present in the leukemic stem cells. In this study, we sorted primary AML samples into stem cell-enriched CD34+/CD38- fractions and then analyzed the sorted and unsorted cells for the FLT3 mutant-wild-type ratio. In each case, the FLT3 mutant-wild-type ratio was not changed by selection of CD34+/CD38- cells, implying that the mutations are present in the leukemic stem cells. We used the stem cell-enriched fraction to engraft nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice and then confirmed that the FLT3/ITD mutation was present in the resultant engrafted marrow. As a final test of the importance of FLT3/ITD signaling in this engraftment model, we used a small molecule FLT3 inhibitor, CEP-701, to inhibit engraftment of FLT3/ITD stem cells. Taken together, these experiments establish that the FLT3/ITD mutations are present in leukemia stem cells, and that FLT3 inhibitors may have activity against these cells.     

Characterization of a nontrypsin cholecystokinin converting enzyme in mammalian brain

An enzyme has been partially purified from canine and porcine cerebral cortical extracts that differs from trypsin in that it manifests some degree of hormone specificity since it converts porcine cholecystokinin to smaller immunoreactive forms, i.e., the COOH-terminal dodecapeptide and octapeptide fragments, but fails to convert big gastrin (34 amino acids) to heptadecapeptide gastrin. This enzyme is distinguishable from trypsin not only in substrate specificity, but also in several physiochemical properties. It is not inhibited in the presence of concentrations of lima bean trypsin inhibitor sufficient to inhibit 1 mg of trypsin per ml of incubation mixture. It is inactivated when incubated with substrate at 45 degrees C for 1 hr, whereas trypsin remains fully active when incubated under the same conditions at 55 degrees C. The enzyme elutes in the void volume on Sephadex G-50 and G-75 gel filtration. On sucrose gradient centrifugation, the proteolytic activity associated with trypsin is recovered above albumin but that of the solubilized brain enzyme is recovered below gamma globulin. The enzyme is not detectable in splenic extracts, which do contain nonspecific proteases capable of completely degrading cholecystokinin. Further investigation is required to determine whether the enzyme in the gut that converts cholecystokinin to the bioactive and immunoactive COOH-terminal fragments resembles or is different from the brain converting enzyme.     

Trends in hospitalization for empyema in Alaska Native children younger than 10 years of age

We analyzed hospitalizations for empyema among Alaska Native (AN) children and the general population of US children <10 years of age during the years 1998 to 2007. We also analyzed invasive pneumococcal disease in AN children. Between 1998 and 2000, the average annual hospitalization rate for empyema was higher for AN children (51.8 per 100,000/yr) than that for US children (24.2 [95% confidence interval: 20.4, 27.9] per 100,000/yr), and had increased in 2004-2007 in both populations (59.6 and 36.0 [95% confidence interval: 30.1, 41.8], respectively). Pneumococcal empyema increased in AN children despite a decrease in invasive pneumococcal disease pneumonia.     

The acute-phase reactant C-reactive protein binds to phosphorylcholine-expressing Neisseria meningitidis and increases uptake by human phagocytes

Neisseria meningitidis is a global cause of meningitis and septicemia. Immunity to N. meningitidis involves both innate and specific mechanisms with killing by serum bactericidal activity and phagocytic cells. C-reactive protein (CRP) is an acute-phase serum protein that has been shown to help protect the host from several bacterial pathogens, which it recognizes by binding to phosphorylcholine (PC) on their surfaces. Pathogenic Neisseria species can exhibit phase-variable PC modification on type 1 and 2 pili. We have shown that CRP can bind to piliated meningococci in a classical calcium-dependent manner. The binding of CRP to the meningococcus was concentration dependent, of low affinity, and specific for PC. CRP appears to act as an opsonin for N. meningitidis, as CRP-opsonized bacteria showed increased uptake by human macrophages and neutrophils. Further investigation into the downstream effects of CRP-bound N. meningitidis may lead us to a better understanding of meningococcal infection and help direct more effective therapeutic interventions.     

Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study

We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (VAD) to receive intensified chemotherapy, that is, melphalan 140 mg/m(2) administered intravenously in 2 doses of 70 mg/m(2) (intermediate-dose melphalan [IDM]) without stem cell rescue (n = 129) or the same regimen followed by myeloablative therapy consisting of cyclophosphamide, total body irradiation, and autologous stem cell reinfusion (n = 132). Interferon-alpha-2a was given as maintenance. Of the eligible patients, 79% received both cycles of IDM and 79% of allocated patients actually received myeloablative treatment. The response rate (complete remission [CR] plus partial remission [PR]) was 88% in the intensified chemotherapy group versus 95% in the myeloablative treatment group. CR was significantly higher after myeloablative therapy (13% versus 29%; P =.002). With a median follow-up of 33 months (range, 8-65 months), the event-free survival (EFS) was not different between the treatments (median 21 months versus 22 months; P =.28). Time to progression (TTP) was significantly longer after myeloablative treatment (25 months versus 31 months; P =.04). The overall survival (OS) was not different (50 months versus 47 months; P =.41). Intensified chemotherapy followed by myeloablative therapy as first-line treatment for multiple myeloma resulted in a higher CR and a longer TTP when compared with intensified chemotherapy alone. However, it did not result in a better EFS and OS.