Familial pattern of corticosteroids and their metabolism in adult human subjects--the Scottish Adult Twin Study

Corticosteroids are important in the regulation of normal physiology and are key factors in regulating cardiovascular physiology and disease, the development of which is known to have a genetic component. However, there is little information on the extent to which plasma and urine steroid levels are determined by familial and genetic factors. We have examined basal and ACTH-stimulated plasma steroid levels and 24-h corticosteroid metabolite excretion rates in 146 pairs of adult twins [75 monozygotic (MZ); 71 dizygotic (DZ)]. Intraclass correlation coefficients were measured for all variables; several plasma steroid measurements were strongly related in both (MZ) and (DZ) twins, consistent with a familial pattern. These included basal levels of 11-deoxycortisol and aldosterone. ACTH-stimulated plasma aldosterone levels were also significantly correlated, to a significant degree, in both MZ and DZ twins. The index of 11beta-hydroxysteroid dehydrogenase activity (tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone) and of the more specific index of activity of the type 2 isoform of this enzyme (urine free cortisol/cortisone) also correlated, to a similar degree, in DZ and MZ twins. In contrast, for the basal and ACTH-stimulated plasma concentrations and 24-h urine excretion rates of several corticosteroids, there was evidence of significant heritability (H2), in that correlation in MZ twins was greater than in DZ. For example, basal plasma corticosterone concentrations (B) (H2 = 0.44), basal and stimulated 11-deoxycorticosterone concentrations (DOC) (H2 = 0.44 and 0.41, respectively), stimulated 11-deoxycortisol concentrations (H2 = 0.53), and the index of 11beta-hydroxylase activity DOC/B (H2 = 0.49) were all significantly heritable. For the urinary variables, 24-h tetrahydrodeoxycortisol (H2 = 0.59) and free aldosterone (H2 = 0.56) were significantly heritable. Our data provide the first evidence that plasma and urine levels of important glucocorticoids and mineralocorticoids show a strong familial pattern, and in some instances, there is evidence of a genetic component to this. This suggests that corticosteroids have a plausible role in essential hypertension that has a similar heritable component.     

Lead alters intracellular protein signaling and suppresses pro-inflammatory activation in TLR4 and IFNR-stimulated murine RAW 264.7 cells,in vitro

Lead (Pb) is a persistent environmental pollutant that has a structure and charge similar to many ions, such as calcium, that are essential for normal cellular function. Pb may compete with calcium for protein binding sites and inhibit signaling pathways within the cell affecting many organ systems including the immune system. The aim of the current study was to assess whether the calcium/calmodulin pathway is a principal target of environmentally relevant Pb during pro-inflammatory activation in a RAW 264.7 macrophage cell line. RAW 264.7 cells were cultured with 5 μM Pb(NO₃)₂, LPS, rIFNγ, or LPS+rIFNγ for 12, 24, or 48 hr. Intracellular protein signaling and multiple functional endpoints were investigated to determine Pb-mediated effects on macrophage function. Western blot analysis revealed that Pb initially modulated nuclear localization of NFκB p65 and cytoplasmic phosphorylation of CaMKIV accompanied by increased phosphorylation of STAT1β at 24 hr. Macrophage proliferation was significantly decreased at 12 hr in the presence of Pb, while nitric oxide (NO) was significantly reduced at 12 and 24 hr. Cells cultured with Pb for 12, 24, or 48 hr exhibited altered cytokine levels after specific stimuli activation. Our findings are in agreement with previous reports suggesting that macrophage pro-inflammatory responses are significantly modulated by Pb. Further, Pb-induced phosphorylation of CaMKIV (pCaMKIV), observed in the present study, may be a contributing factor in metal-induced autophagy noted in our previous study with this same cell line.     

Fludarabine: a new agent with major activity against chronic lymphocytic leukemia

Fludarabine was used to treat 68 patients with previously treated chronic lymphocytic leukemia (CLL). Nine (13%) patients achieved a complete remission and 30 (44%) a partial remission. The response rates for Rai stages 0 to 2, 3, and 4 were 64%, 58%, and 50% respectively. Seventeen (43%) of the 40 Rai stage 1 to 3 patients and four (19%) of the Rai stage 4 patients returned to Rai stage 0. Survival was strongly correlated with the final Rai stage achieved. The survival of the 11 partial responders with residual disease consisting only of residual bone-marrow nodules was similar to the complete responders (36+ months) and superior to the other partial response patients (16 months). The response to fludarabine was rapid, with 36 (92%) of the 39 responders having achieved at least a partial response following the first three courses. Complete responses occurred in the blood, liver, spleen, and lymph nodes in 48% to 69% of the patients. Eradication of all disease in the bone marrow occurred in only 13% of the cases. Neutropenia and thrombocytopenia occurred in 56% and 25% of evaluable courses. Major infections occurred in 9% of evaluable courses and fevers of unknown origin or minor infections in 12% of courses respectively. Myelosuppression and infection were more common in patients with initial Rai stages 3 and 4 and in nonresponding patients. Other toxicity was mild. No CNS toxicity was noted.     

A study of HLA (Bg) on red cells and platelets by immunoblotting with monoclonal antibodies

HLA class I antigens (Bg) on red cells (RBCs) are expressed by some normal donors and by many patients with systemic lupus erythematosus (SLE). To identify the membrane components previously detected by hemagglutination with HLA class I-specific monoclonal antibodies (MoAbs), RBC membrane preparations were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotted with the HLA class I MoAbs. Two components were obtained that reacted with the MoAbs: a heavy chain of 45 kDa and a light chain termed beta2-microglobulin (beta2-M) of 11 kDa. The effect of chloroquine and acid elution in stripping HLA antigens is shown to be due to the removal of beta2-M, as only that component was detected in eluates from reactive RBCs. Neither antibody elution method affected the heavy chain expression assessed by immunoblotting. It is concluded that HLA class I antigens on RBCs are integral membrane components of the type normally found and wisely distributed on many nucleated cells. Platelets, which have stronger HLA class I antigen expression, were also studied, and their membrane preparations yielded heavy chain and beta2-M molecules; the effect of chloroquine treatment was harder to assess than that of acid elution, owing to the sensitivity with which both components are detected in immunoblotting. In eluates obtained from acid treatment only beta2-M is detected.     

Continuity of care is associated with well-coordinated care.

CONTEXT: The importance of continuity of care as a means to promote care coordination remains controversial. OBJECTIVE: To determine if there is an association between having an objective measure of continuity of care and parental perception that care is well coordinated. DESIGN: Cross-sectional study. SETTING AND POPULATION: Seven hundred fifty-nine patients presenting to a primary care clinic completed surveys that included 5 items from the Components of Primary Care Index (CPCI) that relate to care coordination. MAIN PREDICTOR VARIABLE: A continuity of care index (COC) that quantifies the degree of dispersion of care among providers. MAIN OUTCOME MEASURES: Likelihood of parents reporting high scores on the care coordination domain as well as each of the 5 individual CPCI items related to care coordination. RESULTS: Greater continuity of care was associated with higher scores on the CPCI care-coordination domain (P <.001). Continuity of care was also specifically associated with increased odds of agreeing with all 5 individual CPCI items, including reporting that their child's provider "always knows about care my child received in other places" (OR 3.97 [2.11-7.49]), "communicates with the other health care providers my child sees" (OR 2.98 [1.63-5.44]), "knows the results of my child's visits to other doctors" (OR 2.02 [1.08-3.80]), and "always follows up on a problem my child has had, either at the next visit or by phone" (OR 6.20 [2.88-13.35]) and wanting one provider to coordinate all of the health care that the child receives (OR 3.28 [1.48-7.27]). CONCLUSIONS: Greater continuity of primary care is associated with better care coordination as perceived by parents. Efforts to improve and maintain continuity may be justified.     

A rare variant of the leptin gene has large effects on blood pressure and carotid intima-medial thickness: a study of 1428 individuals in 248 families

Background: Rare mutations in the leptin (LEP) gene cause severe obesity. Common polymorphisms of LEP have been associated with obesity, but their association with cardiovascular disease has been little studied. We have examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure (BP), subclinical atherosclerosis as measured by carotid intima-medial thickness (CIMT), and body mass index (BMI) in a large family study.

Methods: Five polymorphisms spanning LEP were typed in 1428 individuals from 248 nuclear families. BP, CIMT, BMI, and plasma leptin were measured.

Results: The polymorphisms typed captured all common haplotypes present at LEP. There was strong association between a rare polymorphism in the 3' untranslated region of LEP (C538T) and both pulse pressure (p = 0.0001) and CIMT (p = 0.008). C/T heterozygotes had a 22% lower pulse pressure and a 17% lower CIMT than C/C homozygotes. The polymorphism accounted for 3–5% of the population variation in pulse pressure and CIMT. There was no association between any LEP polymorphism and either BMI or plasma leptin level.

Conclusions: This large family study shows that the rare T allele at the C538T polymorphism of LEP substantially influences pulse pressure and CIMT, but does not appear to exert this effect through actions on plasma leptin level or BMI. This suggests that autocrine or paracrine effects in vascular tissue may be important physiological functions of leptin. This study also provides evidence that rare polymorphisms of particular genes may have substantial effects within the normal range of certain quantitative traits.