Initiation of the extrinsic pathway of coagulation by human and rabbit alveolar macrophages: a kinetic study

We examined assembly and expression of the factor X activating complex on human and rabbit alveolar macrophages. Kinetic parameters of the factor X activating reaction were determined by functional titrations of factors VII and X with macrophage tissue factor (TF) added. We found rapid activation of factor X to Xa on alveolar macrophage surfaces. Detection of rapid factor Xa formation on macrophages required addition of exogenous factors VII and X. At plasma concentrations of the purified factors, factor Xa was formed on freshly isolated macrophages at approximately 5.4 pmol/min/10(6) cells. After macrophage maturation in culture for 20 hours with LPS (endotoxin) added, the factor X activation rate was increased two- to sixfold. The km' (apparent km) of TF-factor VII enzymatic complexes assembled on alveolar macrophages for factor X were (258 +/- 55 and 475 +/- 264 nmol/L for human and rabbit cells, respectively). The km' did not change during macrophage maturation in culture, but V'max (apparent Vmax) was consistently increased. The K1/2 of human factor VII (concentrations giving half maximal rates of factor X activation) for the interaction with human and rabbit alveolar macrophage TF were 0.191 +/- 0.096 and 1.7 +/- 0.7 etamol/L, respectively. The K1/2 were not significantly changed after maturation, whereas rates of Xa formation at saturation with factor VII were increased. The fast rates of factor X activation observed at physiologic concentrations of plasma-derived factors VII and X indicate that TF on alveolar macrophages is likely to provide sites for binding of factor VII and activation of factor X in vivo during clotting reactions associated with alveolar edema and inflammation.     

Nasal dermoids: the significance of a midline punctum

Nasal dermoids are rare and their diagnosis is often delayed until complications occur. Signs such as a midline nasal punctum may be noted at birth but the significance of this finding frequently passes unrecognised. The cases are reported of two patients which illustrate the typical presentation of these lesions and their subsequent management is discussed.     

COLD PRESSOR TEST DEMONSTRATES RESIDUAL SYMPATHETIC CARDIOVASCULAR ACTIVATION IN FAMILIAL DYSAUTONOMIA

Objectives: Patients with polyneuropathy and antibodies to myelin-associated glycoprotein (MAG) and sulphated glucuronyl paragloboside (SGPG) differ from chronic inflammatory demyelinating polyneuropathy (CIDP) because of a slower, progressive course, symmetrical and predominantly sensory involvement of legs, predominantly distal slowing of motor conductions, and poorer response to therapy. We studied whether a wide set of electrophysiologic parameters may differentiate these two neuropathies. Methods: We reviewed the electrophysiological studies of 10 patients with anti-MAG/SGPG antibodies and 22 with CIDP examining: (1) motor conduction velocity and distal compound muscle action potential amplitude; (2) conduction block (CB) and temporal dispersion; (3) distal motor latency and terminal latency index (TLI); (4) F wave and proximal conduction time; and (5) sensory conduction and occurrence of abnormal median with normal sural sensory potential. Results: Anti-MAG/SGPG neuropathies showed: (1) more severe involvement of peroneal nerves; (2) more frequent disproportionate distal slowing of motor conductions (TLI less than or equal to 0.25) and absent sural potential; and (3) no CB. However 3/22 CIDP patients also had at least two nerves with TLI 0.25 and no CB. Conclusions: Electrophysiologic findings suggest in anti-MAG/SGPG neuropathy a length-dependent process with a likely centripetal evolution. A disproportionate slowing of conduction in distal segments of motor nerves suggests the diagnosis of anti-MAG/SGPG neuropathy, although it is not pathognomonic.     

Treatment of normal individuals with granulocyte-colony-stimulating factor: donor experiences and the effects on peripheral blood CD34+ cell counts and on the collection of peripheral blood stem cells

BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) has been used in patients to increase the level of circulating hematopoietic progenitors. Although G-CSF has been administered to some healthy individuals, the kinetics of mobilization of peripheral blood stem cells (PBSCs), the optimum dose schedule and the incidence and nature of adverse reactions in normal individuals are not completely defined. STUDY DESIGN AND METHODS: Normal individuals (n = 102) who received G- CSF for 5 or 10 days at doses of 2, 5, 7.5, or 10 micrograms per kg per day were studied. The subjects were observed for symptoms and physical changes, and blood samples were obtained for a variety of laboratory tests. After 5 or 10 days of G-CSF treatment, PBSCs were collected by apheresis and analyzed. RESULTS: Overall, 89 percent of the individuals completed the 5-day treatment protocol and 88 percent completed the 10- day protocol without modification of the dose of G-CSF administered. Ninety percent of donors experienced some side effect of G-CSF. The most frequent effects noted were bone pain (83%), headache (39%), body aches (23%), fatigue (14%), and nausea and/or vomiting (12%). The dose of G-CSF administered directly affected the proportion of people with bone pain (p = 0.025) or body aches (p = 0.045) or who were feeling hot or having night sweats (p = 0.02) or taking analgesics (p = 0.01). With the 5-day dose schedule, several changes in serum chemistries occurred, including increases in alkaline phosphatase (p = 0.001), alanine aminotransferase (p = 0.0013), lactate dehydrogenase (p = 0.0001), and sodium (p = 0.0001). Decreases occurred in glucose (p = 0.045), potassium (p = 0.0004), bilirubin (p = 0.001), and blood urea nitrogen (p = 0.0017). In donors who received G-CSF for 5 days, the absolute neutrophil count was increased after one G-CSF dose, and it reached a maximum on Day 6, as did the number of CD34+ cells (64.6 +/? 55.9 × 10(6) cells/L). In those same donors, the platelet count after apheresis on Day 6 was 32 +/? 13 percent lower than pretreatment values (250 +/? 42 × 10(9) cells/L). In donors receiving G-CSF for 10 days, the neutrophil count reached a maximum on Day 8, but the number of CD34+ cells peaked on Day 6 (58.3 +/? 52.1 × 10(5) cells/L) and then declined. The platelet count decreased from pretreatment values by 28 +/? 12 percent prior to apheresis on Day 11. When individuals were treated for 5 days with G-CSF, the quantity of CD34+ cells collected was directly related to the G-CSF dose. When 5 micrograms per kg per day was given, 2.80 +/? 1.81 × 10(8) cells were collected, compared with collection of 4.67 +/? 3.11 × 10(8) cells when 10 micrograms per kg per day was given (p = 0.04). More important, PBSCs collected after 10 days of G-CSF administration (5 micrograms/kg/day) had significantly fewer CD34+ cells (0.82 +/? 0.37 × 10(8) cells, p = 0.01) than did PBSCs collected after 5 days of G-CSF (5 micrograms/kg/day). CONCLUSION: Most normal donors receiving G-CSF experience side effects, but these are mild to moderate in degree. Some alterations in blood chemistries occur, but none were clinically serious. Because of the symptoms associated with G-CSF, these individuals must be monitored closely. The treatment of normal donors with G-CSF for more than 5 days significantly decreased the number of circulating CD34+ cells and the quantity collected by apheresis.     

Donor screening for antibody to hepatitis B core antigen and hepatitis B virus infection in transfusion recipients

BACKGROUND: Testing for antibody to hepatitis B core antigen (anti-HBc) as a surrogate for hepatitis C viremia is no longer needed for blood donor screening. Currently, the important question is how much its use supplements hepatitis B surface antigen (HBsAg) donor screening in preventing transfusion-transmitted hepatitis B virus (HBV) infection. STUDY DESIGN AND METHODS: In a study conducted in the 1970s, 64 blood donors were associated with 15 cases of HBV (1.0%) in 1533 transfusion recipients. Sera from 61 donors at donation and 29 follow-up visits were available for present-day assays for HBsAg, HBV DNA, anti-HBc, and antibody to HBsAg (anti-HBs). RESULTS: HBsAg was found in four previously negative blood donors; HBV DNA was limited to three of these four. Anti-HBc was detected in six HBsAg-negative donors. Two other donors were negative in all assays at donation, but positive for anti- HBc and anti-HBs 2 to 4 months later. The remaining donors were negative for all HBV markers, which left five recipient cases unexplained. No HBV transmission was observed when anti-HBs sample-to- negative control values were > or = 10. CONCLUSION: Some 33 to 50 percent of cases of hepatitis B that could be transmitted by transfusion of blood from HBsAg-negative donors are prevented by anti- HBc screening. Anti-HBc-positive donors unequivocally positive for anti- HBs should be considered noninfectious for HBV and should be allowed to donate. Anti-HBc screening of paid plasmapheresis donors, supplemented by anti-HBs testing, would reduce the amount of HBV to be processed by virus inactivation and increase the content of anti-HBs in plasma pools.     

Donor levels of serum alanine aminotransferase activity and antibody to hepatitis B core antigen associated with recipient hepatitis C and non- B, non-C outcomes

BACKGROUND: Hepatitis virus(es) that are neither hepatitis B (HBV) nor hepatitis C (HCV) (non-B, non-C [NBNC]) may be transmitted by transfusion. The present study assessed donor values for alanine aminotransferase (ALT) and antibody to hepatitis B core antigen (anti- HBc) for their association with HCV and NBNC hepatitis outcomes among allogeneic blood recipients. STUDY DESIGN AND METHODS: Data on blood donors and recipients enrolled in the Transfusion- Transmitted Viruses Study in four United States cities from 1974 through 1980 were supplemented by anti-HBc testing of donors and anti-HCV evaluation of recipients. Two statistical approaches estimated the value of these indirect tests in detecting donors associated with HCV seroconversion and NBNC hepatitis in recipients. RESULTS: For HCV cases, donor ALT alone (at > or = 60 IU/L) had a sensitivity and a specificity of 30 and 96 percent, respectively, and anti-HBc alone (at > or = 60% inhibition) had a sensitivity and specificity of 53 and 86 percent, respectively. The two markers combined had a sensitivity and a specificity of 69 and 83 percent. For NBNC hepatitis cases, each measure had low sensitivity (20%) that was not improved by using both (28%) [corrected]. CONCLUSION: The indirect tests proved to be equal in sensitivity to the first-generation anti-HCV tests. The positive predictive power of these indirect tests in the 1980s was sufficient to affect HCV incidence in studies during that period. Improved anti-HCV assays, however, replaced the need for indirect tests. The sensitivity of indirect tests for NBNC hepatitis contributed little.     

Treatment gaps in the management of cardiovascular risk factors in patients with type 2 diabetes in Canada

OBJECTIVES:

To evaluate vascular protection treatment patterns and attainment of the 2003 Canadian Diabetes Association’s recommended targets in ambulatory patients with type 2 diabetes.

METHODS:

Between 2005 and 2006, 3002 outpatients with type 2 diabetes were enrolled by 229 primary health care settings across Canada. Baseline characteristics, therapeutic regimens and treatment success – defined as the achievement of a blood pressure (BP) of 130/80 mmHg or lower, glycosylated hemoglobin (A1C) of 7% or lower, low-density lipoprotein cholesterol (LDL-C) lower than 2.5 mmol/L and total cholesterol/high-density lipoprotein cholesterol ratio lower than 4.0 – are reported.

RESULTS:

Overall, 46% of individuals had a BP that was above the Canadian Diabetes Association’s recommended target. Of these, 11% were untreated, 28% were receiving monotherapy, 38% were not receiving an angiotensin-converting enzyme inhibitor and 16% were not receiving either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Optimal A1C levels were achieved in 53% of patients. Of those who did not attain A1C targets, 3% were not on glucose-lowering pharmacotherapy and 27% were receiving monotherapy. A total of 74% of patients were treated with statins. Overall, 64% and 62%, respectively, met the target LDL-C and the target total cholesterol/high-density lipoprotein cholesterol ratio. Statins were not prescribed to 43% of patients with LDL-C above target. Antiplatelet therapy was implemented in 81% of patients. In total, 21% achieved the combined targets for BP, A1C and LDL-C.

INTERPRETATION:

A substantial proportion of patients did not achieve guideline-recommended targets and were not receiving evidence-based therapy for vascular protection two years after publication of the Canadian guidelines. More research is warranted, and novel and effective strategies must be tested and implemented to correct this ongoing treatment gap.