No association of presenilin-1 intronic polymorphism and Alzheimer's disease in Australia.

We screened 703 Australian subjects for an intronic polymorphism in the presenilin-1 (PS-1) gene. PS-1 intronic allele 1 homozygosity was not associated with individuals with early- or late-onset sporadic Alzheimer's disease (EOAD or LOAD). Carriers for the PS-1 intronic allele 1 were also not associated with significantly increased risk for AD regardless of gender. Our results for the Australian population are consistent with those of recent reports for other populations and do not support the conclusion that the PS-1 intronic polymorphism is associated with AD.

Fibronectin and other DIC-related variables in patients with moderately severe infections receiving cryoprecipitate.

Plasma fibronectin (Fn), a glucoprotein of suggested importance in host defence during infections also seems to be involved in blood coagulation and to be consumed during clot formation. Low Fn concentrations have been found in patients with DIC, but also in patients with infections without signs of overt DIC. In a randomized trial of Fn supplementation 28 patients with moderately severe infections, hospitalized in the Department for Infectious Diseases, were scheduled to receive either cryoprecipitate from 30 donors (n = 14) or 250-300 ml of stored plasma (n = 14). To elucidate the relationship between Fn plasma levels, Fn-rich cryoprecipitate infusion, and possible low-grade DIC in these patients, we measured platelet count, prothrombin complex (NT), fibrinogen, F V, F VIIIR:Ag, F VIII:C, F XII, plasminogen (Plg), antiplasmin (AP), antithrombin III (AT), kallikrein-inhibiting activity (KI) and spontaneous proteolytic activity (SPA). Compared to healthy controls, high initial values (p less than .001) were found for fibrinogen, F VIIIR:Ag, F VIII:C and SPA. Most values for platelets, F V, Plg, AP and KI were within the reference range. Low levels (p less than .001) were found for Fn, NT, F XII, AT and for the ratio F VIII:C/F CIIIR:Ag. A significant correlation was found between F XII, Plg and AT. Fn correlated poorly to the other variables. Cryoprecipitate infusion normalized the Fn concentration, but had no influence on other measured variables. Thus, although no patient had clinically overt DIC, and all survived, we observed a distinct pattern indicating activation of the coagulation system. Fn levels were low, but were not specifically related to this activation.

Fibronectin and other DIC-related variables in septic ICU patients receiving cryoprecipitate.

In a controlled study of fibronectin supplementation in sepsis, 11 ICU patients in septic shock were scheduled to receive either cryoprecipitate from 20-40 donors (n = 6) or 250-300 ml of stored plasma (n = 5) (two infusions over 24 h). We wanted to: compare some "conventional" DIC variables in the ICU (platelet count, prothrombin complex = NT, FDP) to additional variables: Fibronectin (Fn), fibrinogen (Fg), F V, FVIII R:Ag, F VIII:C activity, F XII, plasminogen (Plg), antiplasmin (AP), antithrombin (AT), kallikrein inhibiting activity (KI) and spontaneous proteolytic activity (SPA): study the effects of cryoprecipitate or plasma infusion on three variables. Samples were taken before the first infusion, and 24 and 48 h after. At onset, high levels (p less than .001 when compared to blood donors) of Fg, VIIIR:Ag and VIII:C were seen. KI levels were within the normal range. F V was low (p less than .05). Fn, NT, XII, Plg, AP and AT were markedly low (p less than .001). SPA showed great variation. When compared to 28 patients with severe infections, but not in septic shock, the ICU group had higher VIIIR:Ag (p less than .05) and VIII:C (p less than .01), and lower XII, Plg, AP and AT (p less than .001). FDP was elevated in all ICU patients. Five patients were thrombocytopenic, and in these a pattern with low levels of Plg and AT was observed. Fn did not correlate well to the other variables measured. These results indicate a marked activation of coagulation and fibrinolysis in these severely ill patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Letter: Oestrous cycles in swes grazing different cultivars of subterranean clover.

PIP: A brief account of an experiment concerning conception rates for Merino ewes grazing on high-estrogen and on low-estrogen cultivars is given. The ewes were mated to Merino rams for 8 weeks annually during March and April. Cycle lengths were measured over 5 mating periods on 87 Merino ewes and 62 crossbred ewes on high-estrogen cultivars and on 46 Merino ewes and 36 crossbred ewes on low-estrogen cultivars. There was a lack of significant interaction over time and of significant differences for mean cycle lengths between Merinos and crossbreds and between ewes grazing the 5 cultivars. The results support the conclusions of Underwood that the infertility of ewes grazing high-estrogen clover is unrelated to a disturbance of the estrous cycle. The results of Loghtfoot who found no significant difference in incidence of estrous and ovarian activity in 16 crossbred ewes and 16 control ewes grazing Dwalganup pastures are supported.^ieng

Restimulation of PPD-stimulated lymphocytes: decreased responsiveness of prestimulated cells to a second challenge with PPD and PHA.

Lymphocytes stimulated with purified protein derivative (PPD) were inhibited in their response to a second stimulation with PPD or phytohaemagglutinin (PHA). The degree of inhibition was related to the PPD concentration during prestimulation, the dose-response curve for inhibition resembling very much that of stimulation. The decreased reactivity was neither due to a toxic effect of PPD nor to altered proliferation kinetics of the prestimulated cells. Lymphocytes preincubated for 6 h or 16 days with PPD were equally refractory, and the non-reactivity persisted even if the cells were incubated without stimulant for 1 week or more. The prestimulated cells were able to suppress the PHA stimulation of fresh lymphocytes. These results indicate that the decreased reactivity of the prestimulated lymphocytes is due to the action of suppressor lymphocytes, generated during the primary stimulation.

Brief report. In vitro effects of Rubella virus, strain RA 27/3, on human lymphocytes. III. Inhibition of mitogen stimulation transferred by supernatants from virus-infected cultures.

When lymphocytes from humans with serological immunity against rubella were incubated with live rubella virus, supernatants were obtained which when added to non-infected lymphocytes gave a significant inhibition of phytohaemagglutinin (PHA)-induced proliferation. In contrast, supernatants from virus-infected lymphocytes from donors lacking immunity against rubella gave no inhibition of the PHA response.

In vitro effects of rubella virus, strain RA 27/3, on human lymphocytes. I. Viral inhibition of mitogen stimulation in relation to Rubella Haemagglutination inhibition antibodies.

The inhibiting effect of rubella virus on lymphocyte stimulation in vitro was studied, using purified virus of the attenuated strain RA 27/3. Addition of the virus to human lymphocytes from twenty healthy blood donors before stimulation with leuco-agglutinin (LA), a component of phytohaemagglutinin, caused a considerable inhibition of the LA response in some experiments, whereas in other experiments the inhibition was slight or non-existent. If further analysed, the results showed a correlation between the degree of inhibition and the immunity of the lymphocyte donor against rubella, as measured by haemagglutination inhibition (HI). Thus the LA-response was significantly more depressed in a group of lymphocyte donors with HI-titres ranging from 20 to 160 than in another group with HI-titre less than 5. Possible explanations of the virus-induced inhibition of the LA response and possible connection between this phenomenon and the immune response against rubella are discussed.

In vitro effects of Rubella virus, strain RA 27/3, on human lymphocytes. II. Specific antigen stimulation in relation to Rubella haemagglutination inhibition antibodies.

Investigation has been made of the specific in vitro stimulation of human lymphocytes by live or inactivated rubella virus of the strain RA 27/3. The thymidine incorporation of lymphocytes from blood donors with different serological immunity against rubella was measured following incubation with the viral antigens. UV-inactivated rubella virus caused a moderate degree of stimulation of lymphocytes from seropositive individuals. On the other hand, live rubella virus stimulated lymphocytes from donors with low titres of anti-rubella HI-antibodies but not lymphocytes from donors with high antibody titres. Possible explanations for this discrepancy are discussed.

Mitogen stimulation and distribution of T- and B-lymphocytes during natural rubella infection.

The phytohaemagglutinin (PHA) response of lymphocytes from seven patients with natural rubella infection was investigated during the acute, early and late convalescence stages of disease. When the lymphocytes were cultured in autologous serum, a moderate depression of the response, following stimulation with PHA in both optimal and suboptimal concentrations was obtained two weeks after the onset of exanthema (early convalescence). Two months later (late convalescence), the lymphocyte stimulation response had returned to almost normal values. On the other hand, lymphocytes incubated in pooled homologous serum reacted normally to PHA in optimal concentrations at all three stages. Determination of T- and B-lymphocytes did not reveal any change in the relative proportion of T-lymphocytes during the course of the disease. However, in late convalescence, a significant decrease in the relative number of B-lymphocytes was recorded.

Inhibition of aminoglycoside activity in heparin.

Measurements of aminoglycosides by an agar disk diffusion assay are inhibited by heparin in a dose-dependent way. When assayed by a homogeneous immunoassay, this was only evident for tobramycin. This indicates that specimens for aminoglycoside measurement should not be obtained in heparinized tubes. When heparin is used clinically as an anticoagulant, the amount in blood does not reach levels that affect the aminoglycoside activity.

Testing for the presence of immune or cured individuals in censored survival data.

In a sample of censored survival times, the presence of an immune proportion of individuals who are not subject to death, failure, or relapse, etc., may be indicated by a relatively high number of individuals with large censored survival times. We summarise some recent theoretical work which justifies analogues of the usual model fitting and testing techniques for such data. In particular, we discuss a 'boundary' test for the presence of immunes in the population and goodness of fit tests for parametric descriptions of the data. The methods are illustrated on some data on the relapse times of leukemia patients.

Haemophilus parainfluenzae infection of the central nervous system. A report on two infants.

Two cases of infection of the central nervous system (CNS) with Haemophilus parainfluenzae--a 12-month-old girl with meningitis and a 17-month-old girl with brain abscess--are reported. Both infants had long-standing upper respiratory infection before CNS disease. Both recovered after treatment.

A study of amikacin given once versus twice daily in serious infections.

Forty-five mostly elderly patients with serious infections were treated in a prospective, comparative and randomized pharmacokinetic study with amikacin 11.0 or 15.0 mg/kg administered in a single daily dose as an intravenous, short-term infusion or with amikacin 7.5 mg/kg administered twice daily in the same way. The results indicate that administration of amikacin 15 mg/kg in a single daily dose should be a practical and safe principle of administration. However elderly patients often have reduced creatinine clearance and should preferably be given a lower dose of 11 mg/kg bw. The risk of nephrotoxicity did not increase, but conclusions on ototoxicity and clinical efficacy cannot be drawn from this limited study. This should be considered as an initial part of a future multicentre trial.

Postantibiotic effect of aminoglycosides on gram-negative bacteria evaluated by a new method.

The in-vitro postantibiotic effect (PAE) of amikacin, gentamicin, netilmicin and tobramycin was investigated by a bioluminescent assay of bacterial ATP. Two strains each of Escherichia coli and Pseudomonas aeruginosa were exposed for 1 h to different concentrations of the aminoglycosides. The aminoglycoside was removed by a 10(-3) dilution, and regrowth of bacteria was followed at hourly intervals by monitoring bacterial ATP. This method simplified the PAE studies and made such studies possible at high aminoglycoside concentrations. The length of the PAE was dose-dependent for all the aminoglycosides studied. The PAEs ranged between three and seven hours for all four strains at the aminoglycoside concentrations normally reached in serum during standard dosing. The long PAE of aminoglycosides, especially after exposure to high drug concentrations, constitutes an argument in favour of administering aminoglycosides in higher-than-usual doses with longer intervals between doses. This proposal is also supported by recent pharmacokinetic, bacteriological and toxicity data.

Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcome.

Fatal multiple organ failure after severe infection may be related to an early activation of protease cascade systems. This study aimed to relate changes in coagulation, fibrinolysis, and kallikrein to shock and outcome. Of 53 patients with severe infection, 30 did not develop shock, 12 survived septic shock, and 11 died from organ failure after septic shock. No patient had overt disseminated intravascular coagulation. We measured 17 components of the coagulation/fibrinolysis/kallikrein pathways on admission and on the next 2 days. High values for fibrinogen, factor VIII:C, von Willebrand factor antigen, and D-dimer were seen in all patients; factor XII, prekallikrein, factor VII, antithrombin, protein C, and fibronectin were low. The patients thus appeared to be hypercoagulable. These disturbances were more pronounced in septic shock survivors, who also had low plasminogen and antiplasmin, indicating ongoing fibrinolysis. Nonsurvivors of sepsis were distinguished mainly by high plasminogen activator inhibitor values; this suggests an impaired functional fibrinolysis in fatal sepsis, with possible therapeutic implications. Cryoprecipitate infusion increased the fibronectin concentration, but did not influence the other factors studied.