Serum amyloid A: an early and accurate marker of neonatal early-onset sepsis.

OBJECTIVES: To evaluate the accuracy of serum amyloid A (SAA), an acute phase protein in the detection of neonatal early-onset sepsis, by means of a fast automated SAA kit. STUDY DESIGN: Full-term infants <72 h of age, who had risk factors and/or were suspected of having sepsis, were eligible for study. The levels of SAA were taken at 0, 24 and 48 h post sepsis evaluation. Thirty matched infants served as a control group for comparing SAA concentrations. RESULTS: Of 104 infants eligible for entry to the study, 23 had sepsis and 81 had not sepsis. The SAA levels of the septic group were significantly higher than those of the nonseptic group at 0, 24 and 48 h (P<0.01 for all time points). In comparison with C-reactive protein (CRP), SAA levels rose earlier and in a sharper manner, had higher levels and returned faster to normal values in infants with early onset sepsis. At 0 h post-sepsis evaluation, serum SAA had an overall better diagnostic accuracy for predicting early onset sepsis than CRP (sensitivity (96 vs 30%), specificity (95 vs 98%), positive predictive value (85 vs 78%), negative predictive value (99 vs 83%), positive likelihood ratio (19 vs 12), and negative likelihood ratio (0.05 vs 0.71). CONCLUSIONS: SSA is advocated as an inflammatory marker of neonatal early-onset sepsis.

Evidence for exercise-induced bone formation in premature infants.

We assessed the effect of a four weeks exercise training intervention on bone turnover markers in premature infants. Twenty-four very low birth weight premature infants were matched for gestational age, birth weight, gender, as well as for corrected age and weight at initiation of the study. Then the subjects were randomly divided into an exercise (n = 12) and a control group (n = 12). Exercise consisted of passive range of motion exercise with gentle compression of both the upper and lower extremities lasting 5 - 10 minutes each day, 5 days per week for 4 weeks. This protocol has been shown to increase bone mineral density in premature infants. Bone formation was assessed by measurements of circulating bone specific alkaline phosphatase (BSAP) and the C-terminal procollagen peptide (PICP). Bone resorption was determined by serum measurements of C- terminal cross-links telopeptide of type-I collagen (ICTP). Training led to a significant (P < 0.05) increase in weight gain (767 +/- 49 versus 586 +/- 24 gr in trained and control premature infants, respectively); and to a significant increase in BSAP (37.2 +/- 14.6 versus 4.1 +/- 8.4 % in trained and control premature infants, respectively). PICP increased also following exercise (34.6 +/- 18.9 versus 5.4 +/- 9.1 % in trained and control subjects, respectively), however, this increase was not statistically significant. Exercise led to a significant decrease in ICTP (-24.7 +/- 3.1 versus -5.5 +/- 5.4 % in trained and control subjects, respectively). A relatively brief exercise intervention was associated with a biochemical evidence of bone formation in very low birth weight premature infants.

Measurements of bone turnover markers in premature infants.

We determined the levels of circulating bone turnover markers in preterm infants during the first weeks of life. Twenty premature infants (mean gestational age 27+/-2.2 weeks, mean birth weight 894+/-231 g) hospitalized in the neonatal intensive care unit (NICU) at the Meir General Hospital, Israel, participated in the study. Measurements of bone turnover markers were performed at birth, and every week thereafter for an average follow-up of 11.2+/-0.7 weeks. Bone osteoblastic activity was assessed by measurements of circulating osteocalcin, bone-specific alkaline phosphatase (BSAP) and the C-terminal procollagen peptide (PICP) levels. Bone resorption was assessed by measurements of serum levels of the carboxy-terminal cross-links telopeptide of type I collagen (ICTP). All three markers of osteoblastic activity increased markedly and significantly during the first three weeks of life, and then continued to increase gradually until week 10 (p<0.01). Circulating ICTP levels increased in the first week of life and then decreased gradually throughout the follow-up (p<0.01). The study participants were divided into premature infants born at extremely low birth weight (ELBW: <1000 g, n=12) and very low birth weight (VLBW: 1000-1250 g, n=8). Osteocalcin (in weeks 2-5 of life), PICP (weeks 3-5), and ICTP levels (weeks 2-3) were significantly higher in VLBW preterms. These results suggest increased bone formation in premature infants in the first three months of life. The increased bone turnover in VLBW compared to ELBW premature infants may be the result of a generally higher morbidity in ELBW preterm infants in early stages of life.

Effect of serum amyloid A, HDL-apolipoprotein, on endothelial cell proliferation. Implication of an enigmatic protein to atherosclerosis.

The possible contribution of apo-HDL serum amyloid A (SAA) to the protective effect of HDL against atherosclerosis was studied by evaluating its effect on bovine aortic endothelial cell (BAEC) proliferation. Our results suggest that human SAA, both purified and recombinant, in concentrations relevant to mild acute phase events, significantly inhibit endothelial cell proliferation in a dose-dependent manner (e.g., 50 micrograms/ml causes approximately 88% inhibition; p < 0.001). This inhibition was attenuated by addition of fibroblast growth factor (FGF), which antagonized the SAA-mediated effect. As levels of TNF may be highly elevated during the acute phase response, its effect on BAEC proliferation was evaluated and found, at concentrations of > 1 pg/ml, to be substantially inhibitory Co-incubation of cells with both SAA and TNF was inhibitory, albeit neither additive nor synergistic. FGF antagonized the effect of both proteins. Amyloidic deposit (AA, i.e. SAA 1-76), derived from pathological proteolysis of SAA, practically retains the inhibitory activity (e.g. 50 micrograms/ml causes approximately 66% inhibition; p < 0.001) but apparently lacks the regulatory site towards FGF. In contrast to the above inhibitory effect, synthetic SAA-related peptide corresponding to the sequence 29-33 of SAA enhances BAEC proliferation (50 micrograms/ml causes approximately 64% increase; p < 0.001). The present data, coupled with our previous observations in which SAA was found to induce endothelial PGI2 formation and to inhibit overproduction of PGI2 by TNF and LPS as well as platelet aggregation, may suggest that SAA contributes to the protective effect of HDL against atherosclerosis. This, by means of its modulatory effect on endothelial cell and platelet activation, primarily in the presence of other regulatory proteins. SAA-derived peptides may, potentially, be used as therapeutic agents in the treatment of atherosclerosis and cardiovascular diseases.

Modulation of prostaglandin I2 production from bovine aortic endothelial cells by serum amyloid A and its N-terminal tetradecapeptide.

The study was aimed to explore the possible involvement of the acute phase HDL apolipoprotein, serum amyloid A (SAA) in the regulation of PGI2 production by endothelial cells. This, in view of the recent detection of SAA mRNA in endothelial cells of human atherosclerotic lesions. Human SAA induces PGI2 formation in bovine aortic endothelial cells culture in a concentration relevant to moderate acute phase events. 50 micrograms/ml of purified human SAA increases PGI2 production from a mean basal level of 2,490 +/- 330 pg/ml by 1.80 +/- 0.1 fold (n = 10; p < 0.01). The PGI2 inducing activity resides apparently in the N-terminal, i.e. amino acid residues 1-14, of the SAA molecule, 50 micrograms/ml of the peptide induces 2.9 +/- 0.5 fold increase of PGI2 production (n = 4; p < 0.03). TNF and LPS each induce PGI2 production in a concentration and time dependent manner. TNF in concentration of 10 ng/ml induces, in the presence of calf serum, an increase of 24.9 +/- 2.3 fold (n = 4; p < 0.001) and LPS in concentration of 1 microgram/ml causes a 18.3 +/- 1.3 fold increase, (n = 4; p < 0.01). In serum-free cultures, only a 2.5 +/- 0.3 fold increase was detected by 10 ng/ml TNF (n = 4), and a 5.9 +/- 0.4 by 1 microgram/ml of LPS. Thus, serum has a strong effect on PGI2 induction. When 50 micrograms/ml SAA is coadministered with 1 ng/ml TNF it reduces the TNF-induction of PGI2 from 7.7 +/- 2.8 to 3.3 +/- 1.2 fold (n = 4; p < 0.01). SAA attenuates, as well, LPS-mediated activity, although in a less pronounced manner. Our finding suggest a potential physiological function for SAA in regulation of basal and cytokine-induced PGI2 production by vascular endothelium. The capacity of SAA to markedly moderate PGI2 induction by TNF and LPS suggest that it may play a role in defending against vessel damage, in cases of atherosclerosis, bacterial infection or septic shock. The induction of PGI2 by SAA through its N-terminal domain, which also exhibits an anti-platelet aggregation activity, suggests a potential therapeutical use for this peptide as an anti-hypertensive and an anti-aggregatory agent.

Inhibitory effect of the calcium antagonist, verapamil, on measles and vaccinia replication in cell culture.

Kidney cell lines MA104 and BGM were infected with vaccinia and measles viruses respectively in the presence of 45Ca. Increased 45Ca level was detected in the virally infected cells as compared with control cells. An enhancement of 28 +/- 6% and 37 +/- 13% was shown in vaccinia and measles respectively following 5 h of infection. The effect of the calcium antagonist verapamil was studied in both vaccinia- and measles-infected cells. In one-step growth experiments, the mean inhibitory effect of 90 microM verapamil on viral yield after 13 h was 97 +/- 1% in the case of vaccinia. In the measles virus after 47 h a mean of 76 +/- 5% inhibition was detected. The suitability of verapamil as a potential antiviral agent is suggested and requires further investigation.

Neural and behavioral correlates of emotion recognition in children and adults.

Event-related potentials (ERPs), accuracy scores, and reaction times were used to examine the recognition of emotional expressions. Adults and 7-year-old children saw upright and inverted chromatic slides of the facial expressions of happiness, fear, surprise, and anger, and were asked to press a button for either "happy" or "angry" faces. A positive-going waveform (P300) was apparent at parietal scalp (Pz) and at left and right temporal scalp. Although the behavioral data were similar for both children and adults (e.g., both had more difficulty recognizing angry expressions than happy ones, and angry expressions were more difficult to recognize upside-down than were happy faces), the ERPs indicated that children responded differently than adults did to happy and angry expressions. Adults showed greater P300 amplitude to happy faces, while children showed greater P300 amplitude to angry faces. In addition, for adults, but not children, there were greater P300 amplitude responses at right vs. left temporal scalp.

Effect of chromium on oxygen free radical metabolism, inhibition of superoxide dismutase and enhancement of 6-hydroxydopamine oxidation.

The effect of chromium on superoxide dismutase activity (SOD) as well as on the rate of hydroxydopamine oxidation was studied in vitro, since chromium is known as an environmental and occupational carcinogen and oxygen free radicals are implicated in carcinogenic processes. Chromium is a strong inhibitor of SOD activity in this system. The degree of inhibition is directly proportional to the chromium concentration (tested chromium range 0.166-0.33 mg/L in reaction mixture), to reaction time (tested range up to 10 minutes), and to substrate concentration. Autoxidation of 6-hydroxydopamine was increased by chromium concentration of 15 mg/L. The combination of excessive oxygen free radical production and inhibition of their elimination by inhibition of SOD activity may contribute to the toxic effects of chromium.

Acute phase protein, serum amyloid A, inhibits IL-1- and TNF-induced fever and hypothalamic PGE2 in mice.

The effect of serum amyloid A (SAA) on fever induced by recombinant interleukin-1 beta (rIL-1 beta) or recombinant tumour necrosis factor alpha (rTNF alpha) was studied in mice. Serum amyloid A is an acute phase protein whose rise in pathological events is induced by the cytokines IL-1, IL-6 and TNF. Administration of human serum amyloid A to mice inhibited fever induced by rIL-1 beta or rTNF alpha in vivo, while the addition of human serum amyloid A to mice hypothalamic slices inhibited IL-1 beta- or TNF alpha-induced prostaglandin E2 (PGE2) production in vitro. Since serum amyloid A did not affect body temperature or hypothalamic PGE2 levels when administered alone, it may represent a specific servo-mechanism for fever regulation in acute events, and it suggests, for the first time, a possible feedback relationship between serum amyloid A and the immunoregulatory cytokines.

Brief psychotherapy of personality disorders.

Thirty-two patients with personality disorder diagnoses were randomly assigned to two treatment conditions that vary on several techniques of brief dynamic psychotherapy. Seventeen patients constituted a waiting list control group. The two brief psychotherapies showed significant improvement on target complaints, SCL-90, and Social Adjustment Scale-SR compared with the control subjects. The two therapy groups were similar in overall outcome but showed interesting differences on several subscale measures. Process measurements of videotaped sessions revealed significant variations in frequencies of therapist interventions across the two treatment conditions, which validated planned differences in the treatment techniques.

Effect of nickel on oxygen free radical metabolism. Inhibition of superoxide dismutase and enhancement of hydroxydopamine autoxidation.

The effect of nickel on superoxide dismutase activity (SOD), as well as on rate of hydroxydopamine oxidation, was studied in vitro since lipid peroxidation has been implicated in cell damage by nickel, whose toxicity and carcinogenicity are well established. Nickel strongly inhibits SOD activity. The degree of inhibition is directly proportion to the nickel concentration (tested range 0.066 to 0.33 microgram/mL in the reaction mixture); to the substrate concentration (tested range 0.4 x 10 4M to 1.1 x 10 4M 6-hydroxydopamine); and to reaction mixture. Autoxidation of 6-hydroxydopamine was increased by nickel concentrations higher than 15 micrograms/mL. The combination of excessive oxygen free radical production and inhibition of their elimination by inhibition of SOD activity may contribute to the nickel toxicity that has been reported in industrial accidents, as well as to the high incidence of cancer occurring in nickel workers. It may also contribute to many complications in uremic patients, in whom increased serum nickel levels were reported to be in a similar range to those inhibiting SOD.

Calcitonin in Ghanaians and Israelis.

Calcitonin (CT) in serum was measured in a group of (black) Ghanaian traumatic fracture patients (GFP) and in two healthy control groups, (black) Ghanaian (GMS) and (white) Israeli (IMS) medical students. CT (mean +/- SD) in GFP, GMS and IMS was, respectively, 17.2 +/- 6.4, 15.5 +/- 2.8 and 7.6 +/- 3.3 pmol/l. The mean difference between the GFP and GMS was not significant, but that between the Ghanaian groups combined and IMS was 8.8 pmol/l, 95% CI 4.1-13.7, P less than 0.001. Observations elsewhere that CT levels in adult blacks in the tropics are higher than those in whites are confirmed.

Serum amyloid A, an acute phase protein, inhibits platelet activation.

The effect of serum amyloid A, an acute phase protein, on platelet function was studied. Serum amyloid A was isolated and purified from sera of patients with recent trauma. Serum amyloid A inhibited thrombin-induced gel-filtered platelet aggregation. However, it did not inhibit aggregation induced by collagen or adenosine diphosphate, nor did it influence the aggregation of platelet-rich plasma activated with thrombin. Further studies of its effect on thrombin-induced activities showed that serum amyloid A, at concentrations of 25 to 100 micrograms/ml (which are found in mild acute events), suppressed the increase of cytosolic [Ca2+], thromboxane generation, and carbon 14-labeled serotonin release in a dose-dependent fashion. Serum amyloid A did not interfere with the clotting or amidolytic activities of thrombin. Therefore, the data suggest a protective role for serum amyloid A in thromboembolic disease by specific interaction with thrombin-induced platelet activation. Amyloid A protein also markedly inhibited thrombin-induced platelet aggregation. Because amyloid A is homologous to the N-terminal portion of serum amyloid A, the observed activity probably resides in that part of the molecule. This finding may be of importance in localization of the active site on serum amyloid A.

Infant proneness-to-distress temperament, maternal personality, and mother-infant attachment: associations and goodness of fit.

66 mother-infant pairs were examined when the infants were 9 and 13 months. The purpose of this report was to examine relations between infant proneness-to-distress temperament, maternal personality characteristics, and mother-infant attachment. There were no main-effect relations between infant proneness-to-distress temperament as assessed at 9 months and infant attachment classification at 13 months. This was true whether security of attachment (A and C vs. B) or proposed temperament (A1-B2 vs. B3-C2) groupings of attachment classifications were examined. Infant proneness-to-distress temperament, however, was associated with maternal behavior and personality. Furthermore, security of attachment could be predicted by an interaction between maternal personality and infant proneness-to-distress. The importance of considering goodness-of-fit relations in predicting attachment security is discussed.

Inhibition of superoxide dismutase activity by silicon.

Elevated silicon levels have been found in the serum of uremic patients, in the brain of patients with senile dementia and in neuroglial tangles of Alzheimer patients. The effect of silicon on superoxide dismutase was studied in vitro, since excessive superoxide production occurs in renal failure, in inflammatory conditions and in the aging process. Silicon in concentrations similar to those found in serum of uremic patients inhibits superoxide dismutase activity. The degree of inhibition is directly proportional to silicon levels. Depression of superoxide dismutase by Si is likely to result in a decrease in oxygen free radical destruction and thus an increase in excessive local availability of oxygen free radicals. The increased silicon levels in brain, kidney, lung and RBC which are especially sensitive to oxygenation damage may contribute to a variety of important clinical complications, by means of excess oxygen free radicals.

Hypocalcaemia and serum levels of inorganic phosphorus, magnesium parathyroid and calcitonin hormones in the last month of pregnancy in Awassi fat-tail ewes.

Serum levels of calcium (Ca), inorganic phosphorus (P), magnesium (Mg), parathyroid (PTH) and calcitonin (CT) hormones of fat-tail Awassi ewes were determined during the last month of pregnancy. The incidence of hypocalcaemia (HCE) was 13.4% of the obstetrical cases examined. Twenty-six (81.3%) of 32 ewes with HCE were 4 yr of age or older. Significant decreases (p less than 0.01) in serum Ca levels from normal values or controls (n = 6; 10.04 +/- 0.22% (w/w)) to pathological values (4.30 +/- 0.35% (w/w)) caused severe clinical manifestations in 75% of affected ewes. This HCE was accompanied by a significant increase in the PTH level (142.6 +/- 9.1 pmol/l in comparison to 99.7 +/- 9.3 pmol/l in controls, p less than 0.05) and significant decrease in serum CT level (98.2 +/- 7.6 pg/ml in comparison to 144.6 +/- 25.7 pg/ml in controls; p less than 0.05). Intravenous administration of Ca borogluconate yielded normal Ca levels which were accompanied by a decrease in serum PTH levels and an increase in CT levels to normal values.

Reduced superoxide dismutase activity in erythrocytes of dialysis patients: a possible factor in the etiology of uremic anemia.

Superoxide dismutase (SOD) plays a major part in the destruction of oxygen-free radicals in the body. SOD activity is impaired by several trace elements including aluminium and silicon which are found in increased levels in plasma and tissues of uremic man. SOD activity was investigated in the erythrocytes of normal controls and of dialysis patients to determine if lack of SOD-protective activity could be a contributory cause to the increased hemolysis of uremia. It was found that SOD levels in red cell hemolysate were significantly lower in dialysis patients (41.4 +/- 9.1 units/100 ml) compared to control (49.3 +/- 7.2 units/100 ml) (U = 7.3; p less than 0.005). When expressed per 100 ml of whole blood SOD levels were 3.25 +/- 0.93 units/100 ml in dialysis patients and 6.46 +/- 0.99 units/100 ml in controls (U = 96; p less than 0.001). It is concluded that inhibition of SOD activity in the erythrocytes of dialysis patients may contribute to their anemia.

Effect of aluminium on superoxide dismutase.

1. The effect of Al3+ on superoxide dismutase in vitro was studied, since in uraemia there is excessive superoxide production and frequently an elevated serum Al3+ level. Thus, the protective role of superoxide dismutase is particularly important. 2. Al3+ in concentrations similar to those found in the serum of uraemic patients inhibits superoxide dismutase activity. The degree of inhibition is directly proportional to the Al3+ level. 3. The combination of excessive oxygen free radical production with an increased Al3+ level may contribute to a variety of complications, including aluminium dementia or initiation and promotion of carcinogenic processes, which are known to be more common in uraemic patients.

Inhibition of growth of Chlamydia trachomatis by the calcium antagonist verapamil.

Treatment of BGM (African Green Monkey kidney) cells with the calcium antagonist Verapamil resulted in a reduced yield of chlamydial infectious particles. The inhibitory effect was concentration-dependent, the maximal effect being achieved at 200 microM-Verapamil, which produced a 99.99% reduction of infectious particle yield. Electron microscopy showed that control Chlamydia trachomatis-infected BGM cells contained typical large inclusions in which most of the particles were elementary bodies, whereas Verapamil-treated infected cells contained small inclusions consisting predominantly of reticulate bodies. The findings indicate a possible therapeutic use of this calcium antagonist as an anti-chlamydial drug.

Effect of uremic toxins--guanidino compounds and creatinine--on proliferation of HL60 and K562 cell lines.

Growth of the promyelocytic cell line HL60 and the erythroleukemia cell line K562 is inhibited by 'uremic toxins': creatinine, guanidino propionic acid and guanidino succinic acid in a concentration range similar to that of uremic sera. Among the tested compounds, creatinine exhibits the strongest and most dose-dependent inhibitory effect on both kinds of cells. These results provide a better understanding of the mechanism involved in the anemia of uremic patients.