Mode of regulation of natural killer cell activity by interferon

Whereas xenogeneic tumors such as baby hamster kidney or HeLa cells grow in nude mice, the same cells persistently infected with a variety of viruses are rejected. Spleen cells from normal nude mice were found to be induced to produce interferon and to exert natural killer (NK) activity on virus persistently infected (PI) tumor cells, and not on uninfected parental cells in vitro. The phenotype of the interferon-producing cells and the NK effector cells was found to be the same namely, Qa 5(+), Ly 5(+), ganglio-N- tetraosylceramide, with 35 percent of the NK cells also expressing Thy 1.2. NK activity against virus PI tumor cell lines could be nonspecifically augmented both in vivo and in vitro by prior contact with virus PI tumor cells. It was unambiguously demonstrated with chemically homogeneous mouse interferon that interferon, and not a contaminant, was responsible for the augmentation of NK activity in vitro. Studies on the mode of interferon action in augmenting NK activity revealed that the target cell for interferon action was serologically distinct from the NK effector cell. Anti-Ly 5 + complement (C)-treated spleen cells were depleted of NK activity and the ability to produce interferon, but, upon incubation with interferon for 1-3 h, regained both NK activity and susceptibility to anti-Ly 5 + C. Treatment with anti-Qa 5 + C eliminated NK activity, which could not be restored by the addition of interferon. We conclude that interferon produced by Ly 5(+) cells in response to virus PI tumor cells acts on Ly 5(-) precursor cells and induces their differentiation into functional Ly 5(+) NK effector cells.     

Hypoxemia after coronary bypass surgery modeled by resistance to oxygen diffusion

OBJECTIVE: To evaluate a model describing postoperative hypoxemia after cardiac surgery by using two variables, i.e., shunt and resistance to oxygen diffusion (Rdff). DESIGN: Estimation of these two variables in normal subjects and postoperative cardiac patients. SETTING: The pulmonary function laboratory for the normal subjects and the intensive care unit for the cardiac patients. PATIENTS/SUBJECTS: Nine postoperative cardiac patients and six healthy subjects. INTERVENTIONS: Inspired oxygen fraction was varied in normal subjects and in cardiac patients 3-6 hrs after surgery. This variation occurred in four to seven steps to achieve arterial oxygen saturations in the range 0.90-1.00. MEASUREMENTS AND MAIN RESULTS: Measurements were taken of arterial oxygen saturation, cardiac output, ventilation, and end-tidal gases at each inspired oxygen fraction. These measurements gave the following estimates for the normal subjects: shunt = 3.9+/-5.4% (mean +/- SD) and Rdiff = -5+/-16 torr/(L/min) [-0.7+/-2.2 kPa/(L/min)]; for the cardiac patients: shunt = 7.7+/-1.8% and Rdiff = 212+/-230 torr/(L/min) [28.2+/-30.6 kPa/(L/min)]. The increase in Rdiff (P = .01) was sufficient to explain the observed hypoxemia in these patients. The value for shunt was not significantly increased in the patients (p = .09). The two-variable model (shunt and Rdff) gave a better prediction of arterial oxygen saturation than a model with shunt as the only variable (p = .02). CONCLUSIONS: In cardiac patients requiring supplementary oxygen, the respiratory abnormality could, in our model, be best described by an increased Rdiff, not by an increased shunt value.     

Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease

Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co‐segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP‐binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2‐linked parkinsonism. © 2010 Movement Disorder Society     

Bone marrow reticulin and collagen content in patients with adult chronic immune thrombocytopenic purpura: a Danish nationwide study

We quantified and differentiated reticulin and collagen content in bone marrow specimens from chronic immune thrombocytopenic (ITP) patients and examined the correlation between some clinical characteristics and the fibrosis grading. Through the Danish National Patient Registry, we identified 378 patients with chronic ITP from 1997 until 2007. Of these, 253 (67%) had undergone at least one bone marrow biopsy, and we retrieved the bone marrow specimens from 187 (74%). We graded the bone marrow content of reticulin and collagen according to the Thiele scale (Grade 0–3). We also retrieved information on patients' clinical characteristics. We examined the prevalence of bone marrow fibrosis grading >0 by patients' age (≤75 years and >75 years), sex, platelet count at baseline (<30 × 10⁹/L, and ≥30 × 10⁹/L), splenomegaly, hepatomegaly, and medications. In total 75 chronic ITP patients (40%) had a bone marrow grading >0. Of these, 72 (39%) had Grade 1 reticulin fibers present. Only three patients (<2%) had collagen fibers present: two had Grade 2 and one had Grade 3. The prevalence of bone marrow grading >0 was lower in patients aged >75 years than ≤75 years (prevalence ratio = 0.64, 95% CI: 0.36–1.15) and lower in men than women (prevalence ratio = 0.70, 95% CI: 0.45–1.09), while a baseline platelet count ≥30 × 10⁹/L was associated with a higher prevalence of grading >0 (prevalence ratio = 1.24, 95% CI: 0.81–1.86). Thus, bone marrow reticulin and collagen content in chronic ITP patients may be associated with some clinical characteristics. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.     

Influence of endotoxin-induced sepsis on the requirements of propofol-fentanyl infusion rate in pigs

Endotoxin-induced sepsis in pigs is a recognized experimental model for the study of human septic shock. Generally, pigs are brought into general anaesthesia before sepsis is induced. It is our experience that drug dosages of propofol and fentanyl need to be reduced during endotoxin-induced sepsis, in order to prevent respiratory and cardiovascular depression, but the scientific evidence for this observation is lacking. Therefore, we measured the consumption of propofol and fentanyl at equal level of anaesthesia in pigs with (n = 5) and without (n = 5) endotoxin-induced sepsis, using the cerebral state index (CSI) as measure of anaesthetic depth. Infusion rates of propofol (P < 0.01) and fentanyl (P < 0.05) were significantly lower in septic pigs. Pigs with endotoxin-induced sepsis had an infusion rate of 2.2 mg/kg/hr (S.D. 0.5) for propofol and 12 microg/kg/hr (S.D. 2) for fentanyl, whereas healthy pigs had infusion rates of 3.5 mg/kg/hr (S.D. 0.6) and 17 microg/kg/hr (S.D. 4), respectively. CSI was equal in both groups throughout the experiment, and had a lowest average value of 47 (S.D. 10) at t = 30 in healthy pigs and reached a highest average value of 67 (S.D. 19) at t = 240 in pigs with endotoxin-induced sepsis. Anaesthetic depth was sufficient, assessed clinically, throughout the experiment in both groups. We concluded that the consumption of propofol and fentanyl was significantly reduced in pigs with endotoxin-induced sepsis. In the present study, we adjusted the level of anaesthesia according to clinical signs, and found good agreement with CSI.