Delayed clearance of pneumocystis carinii infection, increased inflammation, and altered nitric oxide metabolism in lungs of surfactant protein-D knockout mice

Surfactant protein-D (SP-D), a member of the "collectin" family, has been shown to play a role in innate immunity through modulation of inflammation and clearance of organisms. The role of SP-D in host defense against Pneumocystis carinii pneumonia was assessed using SP-D knockout (KO) mice. When inoculated with P. carinii, both wild-type (wt) and SP-D KO mice required CD4 cell depletion to develop infection. In CD4 cell-depleted models, 2 weeks after infection with P. carinii, SP-D KO mice developed increased intensity of infection, compared with wt mice, despite higher lung-inflammation scores and increased amounts of alveolar inflammatory cells. The increased inflammation seen in SP-D KO mice was accompanied by increases in lung weight, expression of inducible nitric oxide (NO) synthase, total NO levels, and 3-nitrotyrosine levels in lung tissue. These results indicate that SP-D plays a role in host defense against P. carinii in vivo by modulating clearance of organisms, lung inflammation, and metabolism of NO.     

Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers

OBJECTIVE: To evaluate the safety and pharmacokinetic interaction between GW433908, ritonavir (RTV), and efavirenz (EFV). METHODS: In period 1, subjects received either a once daily (QD) regimen of GW433908 1395 mg + RTV 200 mg (Study 1) or a twice daily (bid) regimen of GW433908 700 mg + RTV 100 mg (Study 2) for 14 days. In period 2, subjects received EFV 600 mg QD with either the same GW433908 + RTV regimen as in period 1 (arm 1) or with a GW433908 + RTV regimen that included an additional 100 mg of RTV (arm 2) for 14 days. Amprenavir (APV) pharmacokinetic sampling and safety assessments were performed on the last day of each period. RESULTS: Plasma APV exposure was not significantly altered when EFV was coadministered with GW433908 700 mg twice daily (BID) + RTV 100 mg BID. Plasma APV exposure was decreased when EFV was coadministered with GW433908 1395 mg QD + RTV 200 mg QD. However, administration of EFV with GW433908 1395 mg QD + RTV 300 mg QD (i.e., adding an extra 100 mg of RTV) was able to negate this interaction. Adverse events were consistent with prior data for each of the separate agents. CONCLUSION: When EFV is coadministered with the GW433908 700 mg + RTV 100 mg BID regimen, no dosage adjustment is recommended. However, when EFV is coadministered with the GW433908 1400 mg + RTV 200 mg QD regimen, an increase to RTV 300 mg QD is needed to maintain plasma APV exposure.     

Molecular heterogeneity in acute leukemia lineage switch

Six cases of acute leukemia that underwent lineage switch from acute lymphocytic leukemia to acute myelogenous leukemia are reported. The mean age of the patients was 24 years, time to conversion was 36 months, and survival after conversion was only 3 months. Of the three cases which showed abnormal metaphases at both diagnosis and conversion, two (cases 2, 5) showed related cytogenetic abnormalities, and the third showed (case 3) independent chromosomal changes. Molecular analysis for immunoglobulin heavy chain and T-cell receptor beta chain genes showed that five of the six cases had rearrangement of at least one of these lymphoid associated genes at conversion to acute myelogenous leukemia. The single case (case 3) in which there were no lymphoid gene rearrangements at conversion was also the only case in which independent karyotypic abnormalities at diagnosis and conversion were demonstrated. Our findings suggest that lineage switch can represent either relapse of the original clone with heterogeneity at the molecular level or the emergence of a second new leukemic clone without molecular heterogeneity.     

Guide-lines for near patient testing: haematology

Summary These guide-lines provide a framework for the local arrangement of near patient testing (NPT) services for haematology tests. The guidance may be applied to medical and surgical units within hospitals (e.g. ITU, renal dialysis units, casualty) as well as general practitioners' surgeries, for blood counts and coagulation testing. The professional head of the central laboratory must take responsibility for all aspects of the NPT service, although there should be full discussion with the clinical departments involved and joint ownership of the results. NPT operators must be trained and accredited by the central laboratory. Equipment selected should normally have received a satisfactory evaluation report from the Medical Devices Agency (MDA), and should generate results that are comparable with those of the central laboratory. If a full MDA operation evaluation has not been performed, the purchaser should perform a local assessment according to the protocol in this document. The suitability of the equipment, imprecision, and comparability must be studied. The NPT equipment must be properly maintained and calibrated, and a record of patient identity, date and time of testing, reagent lot numbers, and operator must be kept. The central laboratory must participate in a suitable external quality assessment programme (EQA), and provide systems for EQA and internal quality control (IQC) of the NPT site.     

Patient compliance with Hawley retainers fitted with the SMART® sensor: A prospective clinical pilot study

Objective:To evaluate the compliance of patients while wearing maxillary Hawley retainers embedded with SMART microsensors.Methods:The sample population consisted of 22 patients who were divided into an experimental (group A) and a control group (group B). Group A was informed that they would be monitored through the use of SMART microsensors, while group B was not informed that they would be monitored. After the delivery of the retainers (T0), the patients were evaluated at T1 and T2, represented by 6- and 12-week follow-up visits, respectively. At T1, group B was informed of our ability to monitor their compliance. Both groups continued wearing their retainers during T1 to T2.Results:During T0–T1, Group A wore their retainers for an average of 16.3 hours (SD 4.39), while group B wore their appliances for an average of 10.6 hours (SD 5.36, t  =  2.426, P  =  .027). Although group B increased their retainer wear by 0.5 hours/day from T1 to T2, this increase was not statistically significant.Conclusions:Despite significant differences being noted between the two groups at T1, group B did not show significant mean changes in their wear time before and after becoming aware of the use of the SMART microsensor.     

Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4

Heparin-induced thrombocytopenia (HIT) is an important complication of heparin therapy. Although there is general agreement that platelet activation in vitro by the HIT IgG is mediated by the platelet Fc receptor, the interaction among the antibody, heparin, and platelet membrane components is uncertain and debated. In this report, we describe studies designed to address these interactions. We found, as others have noted, that a variety of other sulfated polysaccharides could substitute for heparin in the reaction. Using polysaccharides selected for both size and charge, we found that reactivity depended on two independent factors: a certain minimum degree of sulfation per saccharide unit and a certain minimum size. Hence, highly sulfated but small (< 1,000 daltons) polysaccharides were not reactive nor were large but poorly sulfated polysaccharides. The ability of HIT IgG to recognize heparin by itself was tested by Ouchterlony gel diffusion, ammonium sulfate and polyethylene glycol precipitation, and equilibrium dialysis. No technique demonstrated reactivity. However, when platelet releasate was added to heparin and HIT IgG, a 50-fold increase in binding of radio-labeled heparin to HIT IgG was observed. The releasate was then depleted of proteins capable of binding to heparin by immunoaffinity chromatography. Only platelet factor 4-immunodepleted releasate lost its reactivity with HIT IgG and heparin. Finally, to determine whether the reaction occurred on the surface of platelets or in the fluid phase, washed platelets were incubated with HIT IgG or heparin and after a wash step, heparin or HIT IgG was added, respectively. Reactivity was only noted when platelets were preincubated with heparin. Consistent with these observations was the demonstration of the presence of PF4 on platelets using flow cytometry. These studies indicate that heparin and other large, highly sulfated polysaccharides bind to PF4 to form a reactive antigen on the platelet surface. HIT IgG then binds to this complex with activation of platelets through the platelet Fc receptors.