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Aims: Cardiac involvement is common in sickle cell disease (SCD). Studies are needed to establish haematological determinants of this involvement and prognostic markers. The aim of the study was to identify haematological factors associated with cardiac involvement in SCD and their impact on prognosis., Methods and Results: This longitudinal observational study was performed on 1780 SCD patients with SS or S-β(0)-thalassemia referred to our centre. Six hundred fifty-six met our inclusion criteria (availability of a blood-workup and echocardiogram obtained <1 year apart, no heart valve surgery and no current pregnancy). Median age was 31 (interquartile range, 25-40) years, and median haemoglobin (Hb) was 87 (80-95)g/L. Left ventricular (LV) dilation, left atrial dilation, cardiac index (CI) >4 L/min/m(2), LV ejection fraction <55%, and tricuspid regurgitant velocity (TRV) ≥2.5 m/s were found in 35, 78, 23, 8.5, and 17% of patients, respectively. Compared with other patients, those in the fourth quartiles (Q4) of LV end-diastolic dimension index (LVEDDind) and left atrial dimension index (LADind) and those with high CI had significantly lower Hb, % foetal Hb (HbF), and red blood cell (RBC) counts; and significantly higher lactate dehydrogenase, bilirubin, and %dense RBCs. Independent haematologic determinants of Q4 LVEDDind and LADind were low RBC count and %HbF; high %dense RBCs were associated with LADind. Low %HbF and RBC count were associated with high CI. High %dense RBCs or no α-thalassemia gene deletion was associated with greater severity of anaemia and cardiac dilation and with higher CI. During the median follow-up of 48 (32-59) months, 50 (7.6%) patients died. Tricuspid regurgitant velocity ≥ 2.5 m/s was a predictor of mortality. The risk of death increased four-fold when left ventricular ejection fraction <55% was present also (P = 0.0001)., Conclusion: Cardiac dilation and CI elevation in patients with SCD are associated with haematologic variables reflecting haemolysis, RBC rigidity, and blood viscosity. Tricuspid regurgitant velocity ≥ 2.5 and LV dysfunction (even mild) predict mortality., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Purpose: Kidneys from haemodynamically unstable donors may suffer from renal ischaemia-reperfusion (RIR) injury. RIR is associated with reactive oxygen species production that induces inflammation and activates the arachidonic acid (AA) pathway which converts AA into prostaglandin E(2). Amifostine was investigated for its renoprotective potential in RIR., Materials and Methods: The effect of amifostine (25 mg/kg  =  910 mg/m(2)) on the COX pathway, enzymatic antioxidant activity, the lipid peroxidation marker MDA, serum creatinine and apoptosis was determined in rats. Kidneys were subjected to 45 min of ischaemia and 1 or 24 h of reperfusion. Control groups (sham: coeliotomy, no ischaemia; r1: 45 min ischaemia/1 h reperfusion; r2: 45 min ischaemia/24 h reperfusion) were administered physiological saline intraperitoneally, and treated groups (E1: 45 min ischaemia/1 h reperfusion; E2: 45 min ischaemia/24 h reperfusion) received amifostine 30 min before reperfusion., Results: Serum creatinine increased in non-treated control rats: r1 vs sham (1.6-fold; P <0.007), r2 vs sham (2-fold; P <0.007). Amifostine decreased serum creatinine levels in treated rats: E1 vs r1 (8%; P <0.0025), E2 vs r2 (44%; P <0.0025). Amifostine reduced acute tubular necrosis (25%) 24 h after reperfusion: E1 vs r1 (P <0.004), E2 vs r2 (P <0.03) and reduced COX-2 and microsomal prostaglandin E synthase expression: E1 vs r1 (P <0.03), E2 vs r2 (P <0.02). Amifostine decreased MDA (P <0.04) and reduced caspase-3 expression but did not alter enzymatic antioxidant activity after RIR., Conclusions: Amifostine decreased the degree and severity of tubular damage after reperfusion, probably by scavenging oxygen free radicals and attenuating the cytotoxic effects of inflammatory infiltrates and apoptosis.

Background: Fetuin-A inhibits inflammation and has a protective effect against myocardial ischemia. Its deficiency has been found to be associated with cardiovascular death in patients with end-stage renal failure disease. We investigated the association between plasma fetuin-A and clinical outcome after ST-elevation acute myocardial infarction (STEMI)., Methods: We measured fetuin-A in 284 consecutive patients with STEMI and correlated these data with the occurrence of death at 6 months (n = 25). We also measured fetuin-A in a control group and chose the 95th percentile as the cutoff to define abnormality., Results: Patient mean (SD) age was 60 (14) years, and creatinine clearance was 83 (31) mL/min; 82% were men. Mean (SD) plasma fetuin-A concentrations at admission [188 (69) mg/L, P = 0.01] and at day 3 [163 (57) mg/L, P <0.0001] were lower in patients than in controls [219 (39) mg/L; 95th percentile 140 mg/L]. Fetuin-A <140 mg/L was observed in 20% of patients at admission vs 40% at day 3 (P <0.001). Fetuin-A concentrations did not correlate with peak cardiac troponin values but did correlate inversely with C-reactive protein (CRP) and NT-pro-brain natriuretic peptide (NT-proBNP). Fetuin-A <140 mg/L at admission (OR = 3.3, P = 0.03) and at day 3 (OR = 6.3, P = 0.002) was an independent correlate of death at 6 months, irrespective of NT-proBNP, CRP, or Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) risk score. Conversely, fetuin-A > or = 140 mg/L was associated with an excellent survival rate [negative predictive value (NPV) = 97% overall], even in high-risk populations with CADILLAC risk score > or = 6 (NPV = 90% in patients)., Conclusions: Fetuin-A is an important predictor of death at 6 months in STEMI patients independent of NT-proBNP, CRP, and CADILLAC risk score.

Circulating prostate cells can be detected in cancer patients by using reverse transcriptase-PCR (RT-PCR) assay for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) mRNA. A quality-control study involving a conventional RT-PCR assay was performed and, surprisingly, detected both transcripts in many negative control cell lines and in normal blood samples. The existence of an illegitimate transcription of the PSA and PSM genes was evidenced by sequence analysis of several PSM and PSA-PCR products. Sequencing indeed demonstrated the presence of a PSA or PSM polymorphism in some but not all the cell lines and patient samples, as well as a heterozygous mutation (G to A; Asp to Asn) in the Jurkat cell line. Moreover, the amount of PSA transcript in MCF-7, a PSA-negative breast line, increased after incubation with cycloheximide. Interestingly, the frequency of positivity was as high as 12% in male samples if only tested once, but dropped to 3% upon multiple testing of the same cDNA. This highlights the stochastic effects in RT-PCR results at high sensitivity, hence the importance of repetitive testing in clinical samples. Decreasing the number of cycles avoided the amplification of illegitimate transcripts but also affected the limit of detection, as evidenced with PSA and PSM cDNA containing plasmids, mixing of LNCap with normal blood samples, and the PSA-PSM-negative K562 cell line. The current data raise the need for a multicentric standardization of the RT-PCR methodology used to amplify PSA and PSM transcripts.

We report the development of a new sensitive nested reverse transcription-polymerase chain reaction (RT-PCR) assay, using primers derived from the prostate-specific membrane antigen (PSM) cDNA sequence, to detect an hematogenous spread of prostate adenocarcinoma cells. In 60 patients with a biopsy-proven prostate cancer, PSM and PSA RT-PCR detected circulating prostate cells in 40 and 20 patients, respectively. In pT4 M+ and pT3 M+ disease patients, nested PSM primers detected cells in 28 of 33 patients (85%), whereas nested PSA primers detected cells in 17 of 33 (51%). In patients with organ-confined cancer spread (pT2a and pT2b patients) before radical prostatectomy, nested PSM RT-PCR detected circulating prostatic epithelial cells in 6 of 17 patients (35%), which suggests that an hematogenous spread of prostate cells may occur early in prostate cancer history. Altogether, these results suggest that the detection of PSM-expressing cells in blood may predict the development of cancer in patients without clinically apparent prostate cancer. Nevertheless, the potential application and the clinical significance of detection of hematogenous prostate cells through the use of nested PSM primers need an extensive longitudinal study.

We compared the diagnostic value of information given by total testosterone (I), free testosterone (II), the free androgen index (III), and testosterone not bound by sex-hormone-binding globulin (SHBG) (IV) as measured by a new differential ammonium sulfate precipitation technique, each step of which is conducted at 37 degrees C. SHBG and albuminemia were also measured. To examine the clinical value of IV, we analyzed single blood samples from 15 hirsute women and 15 age-matched healthy control volunteers. Values for I, II, III, and IV testosterone were all significantly higher in the hirsute group (P less than 0.01), whereas SHBG was decreased (P less than 0.01) and albumin concentrations were similar for the two groups. Overlap between values for normal and for hirsute women was 33.3% for I, 13.3% for II, and 0% for III and IV. The presented data suggest that IV measured by ammonium sulfate precipitation is the preferred discriminator for detecting hyperandrogenism, because this assay is technically simpler and less expensive than the II assay for routine investigation. It closely reflects the pool of bioavailable testosterone; thus, its main use might be as a screening test for androgen excess in women.

Testosterone (T) is a protein-bound substance, the hepatic extraction of which largely exceeds the free plasma fraction. In this study we attempted to determine if the dissociation of T from plasma proteins is the limiting factor for testosterone hepatic uptake in patients with cirrhosis. For this purpose we measured the hepatic uptake of T and the peripheral plasma concentrations of the different fractions of the hormone (total, free, albumin-bound, and sex hormone-binding globulin (SHBG)-bound) in 12 men with alcoholic cirrhosis. The hepatic extraction of T (mean = 42%) greatly exceeded the non-SHBG-bound fraction of T (free T plus albumin-bound T: mean = 13%). Thus, a substantial amount of SHBG-bound T must have entered the liver. A theoretical extraction ratio was calculated based upon the dissociation rate constants of T from albumin and SHBG and upon an estimate of sinusoidal transit time of plasma through the liver. The similarity between the measured and expected values indicates that the limiting step in hepatic uptake of T might be SHBG binding.