Injury induces increased monocyte expression of tissue factor: factors associated with head injury attenuate the injury-related monocyte expression of tissue factor

BACKGROUND: Activated monocytes are able to express tissue factor (TF), a potent procoagulant. The effect of injury on monocyte TF expression is not known. We have found that patients with head injury (HI) have increased antithrombin activity and decreased platelet function compared with non-head-injured trauma patients. Our objective was to determine whether injury increases TF expression by monocytes and whether this increased TF expression is attenuated in patients with HI. METHODS: We prospectively enrolled 37 trauma patients (meeting the entry criterion of an Injury Severity Score [ISS] > or = 9) and 11 healthy control subjects. We sampled blood on arrival and then at 24, 48, and 72 hours. We performed flow cytometry with antibody markers for monocytes (CD14), platelets (CD42a), and TF. We compared results of patients with HI (Glasgow Coma Scale score < or = 9 and Abbreviated Injury Scale Head/Neck score > or = 3) with patients without HI and with controls. RESULTS: Patients had a mean ISS of 23.9 +/- 2.3 (+/- SEM), mean age of 45 +/- 3 years, and mean length of stay of 17.9 +/- 3.2 days. Seventy-six percent were men, and 97% had blunt trauma. The overall mortality rate was 11%. Trauma patients had greater monocyte TF expression than controls for all time periods (p < 0.05). Trauma patients with HI had elevated monocyte TF expression compared with controls for the initial and 24-hour time periods, but they subsequently had more rapid return of monocyte TF expression to baseline (despite a higher ISS) than trauma patients without HI. Trauma patients both with and without HI had increased platelet-monocyte binding at each time versus controls. CONCLUSION: Trauma induces TF expression on monocytes. Patients with HI have attenuation of this expression by 24 hours after injury. The attenuation of TF expression by monocytes in HI parallels the increase in AT and the decrease in platelet function seen after HI. The correlation of TF expression with platelet-monocyte binding suggests that platelet binding may lead to monocyte activation.     

Selective estrogen receptor modulators inhibit the effects of insulin-like growth factors in hyperparathyroidism

BACKGROUND: Primary hyperparathyroidism (HPT) predominantly affects perimenopausal women, leading to speculations that an estrogen imbalance may be liable. We have previously demonstrated the importance of the insulin-like growth factor (IGF) axis in HPT. Because the antiestrogen tamoxifen has been shown to modulate the IGF axis, we examined the interactions of selective estrogen receptor modulators (SERMs) and IGF in HPT. METHODS; Estrogen receptors were evaluated by Western immunoligand blotting. Sixteen parathyroid glands from 19 patients were included. After adhesion, the cells were treated with IGF (I or II) +/- estrogen +/- SERMs (tamoxifen, ICI 182,780) for 96 hours in serum-free media. Proliferation was assessed by measuring tritiated thymidine incorporation. RESULTS: Both primary and secondary HPT express estrogen receptors alpha and beta. Primary and secondary HPT had comparable responses to SERMs, they were analyzed together. Compared with control (100%), IGFs (I and II) induced a significant increase in DNA synthesis. Estradiol at 10(-8) and 10(-7) mol/L (physiologic range) had no significant effects on IGF (I and II, P >.05). Both tamoxifen and ICI 182,780 inhibited basal DNA synthesis (P <.05) and abolished the effects of both IGF I and II (P <.05). CONCLUSIONS: SERMs are capable of reducing basal and IGF-stimulated DNA synthesis. This reduction in proliferation has implications for cancer biology and therapeutic potential for SERMs in HPT.     

Postoperative cognitive dysfunction in middle-aged patients

BACKGROUND: Postoperative cognitive dysfunction (POCD) after noncardiac surgery is strongly associated with increasing age in elderly patients; middle-aged patients (aged 40-60 yr) may be expected to have a lower incidence, although subjective complaints are frequent. METHODS: The authors compared the changes in neuropsychological test results at 1 week and 3 months in patients aged 40-60 yr, using a battery of neuropsychological tests, with those of age-matched control subjects using Z-score analysis. They assessed risk factors and associations of POCD with measures of subjective cognitive function, depression, and activities of daily living. RESULTS: At 7 days, cognitive dysfunction as defined was present in 19.2% (confidence interval [CI], 15.7-23.1) of the patients and in 4.0% (CI, 1.6-8.0) of control subjects (P < 0.001). After 3 months, the incidence was 6.2% (CI, 4.1-8.9) in patients and 4.1% (CI, 1.7-8.4) in control subjects (not significant). POCD at 7 days was associated with supplementary epidural analgesia and reported avoidance of alcohol consumption. At 3 months, 29% of patients had subjective symptoms of POCD, and this finding was associated with depression. Early POCD was associated with reports of lower activity scores at 3 months. CONCLUSIONS: Postoperative cognitive dysfunction occurs frequently but resolves by 3 months after surgery. It may be associated with decreased activity during this period. Subjective report overestimates the incidence of POCD. Patients may be helped by recognition that the problem is genuine and reassured that it is likely to be transient.     

Impact of breastfeeding on the mobilization of lead from bone

To evaluate the hypothesis that lactation stimulates lead release from bone to blood, the authors analyzed breastfeeding patterns and bone lead concentrations as determinants of blood lead levels among 425 lactating women in Mexico City for 7 months after delivery (1994-1995). The authors measured in vivo patella and tibia lead concentrations at 1 month postpartum using K x-ray fluorescence. Maternal blood samples and questionnaire information were collected at delivery and at 1, 4, and 7 months postpartum. Blood lead was analyzed using graphite furnace atomic absorption spectroscopy. Mean blood lead level at delivery was 8.4 microg/dl (range: 1.8--23.4). Mean cortical and trabecular lead levels were 10.6 microg/g (range: nondetectable to 76.5) and 15.3 microg/g (range: nondetectable to 85.9), respectively, reflecting a population with elevated and diverse past and current lead exposure. The association of bone lead and breastfeeding with blood lead was estimated using generalized estimating equations. Breastfeeding practices and maternal bone lead were important predictors of blood lead level. After adjustment for bone lead and environmental exposure, women who exclusively breastfed their infants had blood lead levels that were increased by 1.4 microg/dl and women who practiced mixed feeding had levels increased by 1.0 microg/dl, in relation to those who had stopped lactation. These results support the hypothesis that lactation is directly related to the amount of lead released from bone.     

Recent studies on lonidamine,the lead compound of the antispermatogenic indazol-carboxylic acids

Lonidamine (LND) or [1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid] is an anticancer and an antispermatogenic drug whose mechanism of action is still incompletely understood. LND is effective against a number of tumors, including head, neck and breast cancers, probably because of the inhibition of mitochondrial electron transport and the enzyme hexokinase and to the induction of apoptosis. Instead, the antispermatogenic activity of LND appeared to be related not only to its energolytic activity but also to other effects activities such as the inhibition of specific chloride channels in the epididymis and the disruption of the inter-Sertoli-germ cell junctions, leading to premature release of germ cells. In addition, we recently reported that, in the rat, LND at the dose of 100 mg/Kg b.w. p.o., a fully active but well tolerated dose, caused specific changes of the testicular and epididymal macroglobulins (alpha(2)-macroglobulin, alpha(1) inhibitor-3 and alpha(1)-macroglobulin). Further studies are needed to elucidate the mechanism of action of LND, the lead compound of an interesting class of antispermatogenic drugs based on the core structure of 1-(2,4-dichlorobenzyl)-indazole-3-carboxylic acid.     

Survival analysis techniques

Statistical methods known as survival analyses are useful for analyzing time-related events, in which time from a benchmark event to an endpoint is the focus of interest. Survival analysis describes not only patient survival statistics (as suggested by the name), but also other dichotomous outcomes such as time of remission, time of breastfeeding, etc. This paper discusses survival analysis techniques, commenting and comparing their utilization, especially in the field of oncology. It also presents and discusses types of epidemiological studies and data sources to which this type of analysis is applied. The authors take into account the difference between hospital-based or clinical series and population-based approaches. Interpretation of results is also discussed.     

Insulin-like growth factor I,but not neurotrophin-3, sustains Akt activation and provides long-term protection of immature oligodendrocytes from glutamate-mediated apoptosis

Glutamate toxicity is a major contributor to death of oligodendroglia in diverse CNS disorders. The goal of these studies was to investigate the mechanisms of glutamate toxicity and trophic factor protection of the immature pro-oligodendroblast (pro-OL). Glutamate induced time- and dose-dependent DNA fragmentation and caspase-3 activation in pro-OLs. IGF-I or NT-3, but not CNTF, prevented apoptosis of pro-OLs by 24 h via a PI3-kinase-dependent pathway; however, only IGF-I protected pro-OLs from glutamate toxicity through 48 h. Long-term protection of pro-OLs by IGF-I was correlated with sustained activation of Akt while NT-3 activation of Akt was transient. The differential ability of IGF-I and NT-3 to maintain Akt activation was due to differences in receptor activation and stability. In the presence of NT-3, TrkC phosphorylation and protein expression decreased significantly while activation of the IGF-IR was maintained in the pro-OLs in the presence of IGF-I.