Perceived treatment group affects behavioral and neural responses to visceral pain in a deceptive placebo study

Background To assess effects of perceived treatment (i.e. drug vs placebo) on behavioral and neural responses to rectal pain stimuli delivered in a deceptive placebo condition. Methods This fMRI study analyzed the behavioral and neural responses during expectation‐mediated placebo analgesia in a rectal pain model. In N = 36 healthy subjects, the blood oxygen level‐dependent (BOLD) response during cued anticipation and painful stimulation was measured after participants were informed that they had a 50% chance of receiving either a potent analgesic drug or an inert substance (i.e., double‐blind administration). In reality, all received placebo. We compared responses in subjects who retrospectively indicated that they received the drug and those who believed to have received placebo. Key Results 55.6% (N = 20) of subjects believed that they had received a placebo, whereas 36.1% (N = 13) believed that they had received a potent analgesic drug. Subjects who were uncertain (8.3%, N = 3) were excluded. Rectal pain‐induced discomfort was significantly lower in the perceived drug treatment group (P < 0.05), along with significantly reduced activation of the insular, the posterior and anterior cingulate cortices during pain anticipation, and of the anterior cingulate cortex during pain (all P < 0.05 in regions‐of‐interest analyses). Conclusions & Inferences Perceived treatment constitutes an important aspect in placebo analgesia. A more refined understanding of individual treatment expectations and perceived treatment allocation has multiple implications for the design and interpretation of clinical trials and experimental studies on placebo and nocebo effects.     

Ambulatory blood pressure monitoring and target organ damage: effects of age and sex

OBJECTIVE: The objective of the present study was to investigate the effect of age and sex in the ambulatory blood pressure measurements, and target organ damage. METHODS: A total of 1596 patients (50.6% male and 49.4% female), aged 10-87 years, referred to our Hypertension Center for borderline hypertension, underwent 24-h ambulatory blood pressure monitoring, left ventricular echocardiography and measurement of intima-media thickness of carotid arteries. RESULTS: Adolescent girls had higher mean 24-h and clinic systolic and diastolic blood pressure values than adolescent boys. Men aged 20-60 years had higher mean 24-h and clinic systolic and diastolic blood pressure values than women of the same age. Men older than 60 years had higher mean 24-h systolic and diastolic blood pressure values than women of the same age, but women older than 60 years had higher clinic systolic and diastolic blood pressure values. White-coat effect increased with age in both sexes, but the magnitude of the white-coat effect was higher in women than in men at older ages. Men had higher left ventricular mass corrected for body surface area or height than women in all ages and significantly higher differences in ages between 30 and 80 years. In addition, men had greater carotid intima-media thickness than women in all ages and significantly higher differences in ages between 30 and 80 years. CONCLUSIONS: Men have greater ambulatory blood pressure values and target organ damage than women of the same age.     

Impact of gender on 24-h ambulatory blood pressure and target organ damage

Differences between male and female subjects in mean 24 h blood pressure (BP) values and target organ damage such as left ventricular mass (LVMASS) and intima-media thickness (IMT) of carotid arteries were explained. The study population consisted of 1,445 subjects. All subjects underwent 24 h ambulatory BP monitoring, left ventricular echocardiography and measurement of IMT of carotid arteries. Men and women did not differ in age, body mass index (BMI) and clinic BP values. Mean 24 h systolic and diastolic BP were significantly higher in men compared to women. LVMASS corrected for body surface area or height(2.7), IMT of common (MCCA) and internal (MICA) carotid arteries were found to be significantly higher in men compared to women. Analysis of covariance showed that men had significantly higher LVMASS, MCCA and MICA than women, after adjustment for BMI, age, smoking status, mean 24 h systolic and diastolic BPs, fasting serum glucose, total cholesterol and triglycerides. These findings indicate that male sex could be an important predictor of higher mean 24 h BP and target organ damage for subjects of similar BMI and clinic BP values.     

Target organ damage in "white coat hypertension" and "masked hypertension"

BACKGROUND: In this study we investigated (i) the prevalence of white coat hypertension (WCH) and masked hypertension (MH) in patients who had never been treated earlier with antihypertensive medication, and (ii) the association of these conditions with target organ damage. METHODS: A total of 1,535 consecutive patients underwent office blood pressure (BP) measurements, 24-h ambulatory BP monitoring (ABPM), echocardiography, and ultrasonography of the carotid arteries. Subjects who showed normotension or hypertension on the basis of both office and ambulatory BP (ABP) measurement were characterized as having confirmed normotension or confirmed hypertension, respectively. WCH was defined as office hypertension with ambulatory normotension, and MH as office normotension with ambulatory hypertension. RESULTS: WCH was found in 17.9% and MH in 14.5% of the subjects. The prevalence of WCH was significantly higher in subjects with obesity, while the prevalence of MH was significantly higher in normal-weight subjects. The confirmed hypertensive subjects as well as the masked hypertensive subjects had significantly higher left ventricular mass (LVM) (corrected for body surface area) and carotid intima media thickness (cIMT) than the confirmed normotensive subjects did (108.9 +/- 30.6, 107.1 +/- 29.1 vs. 101.4 +/- 29.9 g/m(2) and 0.68 +/- 0.16, 0.68 +/- 0.21 vs. 0.63 +/- 0.15 mm, respectively, P < 0.005). White coat hypertensive subjects did not have a significantly higher LVM index than confirmed normotensive subjects (101.5 +/- 25.9 vs. 101.4 +/- 29.9 g/m(2)); they tended to have higher cIMT than the confirmed normotensive subjects, but the difference was not statistically significant (0.67 +/- 0.15 vs. 0.63 +/- 0.15 mm). CONCLUSIONS: WCH and MH are common conditions in patients who visit hypertension outpatient clinics. Confirmed hypertension and MH are accompanied by increased LVM index and cIMT, even after adjusting for other risk factors.     

The cellular basis for different fetal hemoglobin levels among sickle cell individuals with two, three, and four alpha-globin genes

Fetal hemoglobin (HbF) levels vary widely among individuals with sickle cell anemia (SS). Previous studies have suggested that HbF levels in SS individuals with alpha-thalassemia (two or three functional alpha- globin genes) are lower than HbF levels in SS individuals with four normal alpha-globin genes. Using immunocytochemical techniques, we studied F cell production as measured by % F reticulocytes, the amount of HbF per F cell, and the preferential survival of F cells versus non- F cells in 51 subjects with four alpha genes, 32 subjects with three alpha genes, and 18 subjects with two alpha genes. Comparison between alpha-globin gene groups was performed for the total sample as well as for a subset of 82 individuals who had replicate samples and a further subset of 39 age-matched individuals. %HbF levels were 6.8, 4.9, and 4.5 percent for the total four-, three-, and two-alpha-globin-gene groups, respectively. The percentage of F reticulocytes, percentage HbF per F cell, and the enrichment ratio (% F cell/% F reticulocytes) did not change significantly with alpha-globin gene number. Moreover, no correlation existed between alpha-globin gene number and the absolute number of F cells in any group studied. However, there was a strong inverse correlation (r = -0.407, P = .0001) between non-F cell levels (1.7 +/- 2, 2.2 +/- 5, 3.0 +/- 1.0 X 10(12)/L) and decreasing alpha- globin gene number. These data suggest that falling HbF levels among SS individuals with lessened numbers of alpha-globin genes reflect prolonged survival of non-F cells and are not due to intrinsic differences in F cell production or in the amount of HbF per F cell. The improved survival of non-F cells in SS alpha-thalassemia is presumed to be due to the lower MCHC observed in such individuals.     

Factor VIII/von Willebrand factor in subendothelium mediates platelet adhesion

The present studies were undertaken to determine whether factor VIII/von Willebrand factor (vWF) present in the vessel wall (in addition to that in plasma) may mediate the attachment of platelets to subendothelium. Subendothelium from everted rabbit aorta was exposed to human citrated blood flowing through an annular perfusion chamber at 40 mL/min (wall shear rate of 2,600 s-1 for five minutes). The vessel segments were incubated at 37 degrees C for one hour with various dilutions of either goat-anti-rabbit factor VIII/vWF serum or an IgG fraction prepared from the serum. Control segments were incubated with serum or IgG from a nonimmunized goat. Values of platelet contact (C), platelet adhesion (C + S), and thrombus formation (T) on the subendothelium were evaluated by a morphometric technique. Compared with vessels incubated with fractions prepared from a normal goat, a significant decrease in platelet adhesion (C + S), ranging from 45% to 65%, was observed on vessels incubated with various dilutions (1:5 to 1:50) of either serum or IgG fractions of goat-anti-rabbit factor VIII/vWF. A similar decrease in platelet adhesion was observed with vessels incubated with an F(ab')2 fragment against rabbit factor VIII/vWF prepared in the goat. When goat-anti-rabbit factor VIII/vWF IgG was added to rabbit blood (1:75 dilution), platelet adhesion was reduced to the same extent (65%) on normal rabbit vessels and on vessels pre-incubated with goat-anti-rabbit factor VIII/vWF. Immunofluorescence studies revealed the presence of rabbit factor VIII/vWF in the subendothelium of rabbit aorta and the continued binding of the goat-anti-factor VIII/vWF antibodies on subendothelium during the perfusion studies. No uptake of human factor VIII/vWF on the rabbit subendothelium was observed by this immunologic technique; human factor VIII/vWF was found to be entirely associated with the attached human platelets. Thus, factor VIII/vWF in the vessel wall may mediate platelet attachment to subendothelium in a manner similar to that of plasma factor VIII/vWF.     

Arterial stiffness assessed by pulse wave analysis in essential hypertension: relation to 24-h blood pressure profile

BACKGROUND: Arterial stiffness is a risk factor for cardiovascular morbidity and mortality and appears to be increased in arterial hypertension. The purpose of the present study was to relate systemic arterial stiffness assessed by pulse wave analysis to variables of 24-h ambulatory blood pressure monitoring (ABPM) in patients with essential hypertension. METHODS: Seventy-two subjects with untreated mild to moderate arterial hypertension underwent evaluation with 24-h ambulatory blood pressure monitoring. In the same subjects, applanation tonometry and pulse wave analysis was performed for evaluation of systemic arterial stiffness expressed as augmentation index and estimated aortic pulse wave velocity. RESULTS: Clinic systolic blood pressure, mean heart rate during 24-h blood pressure monitoring and height were independent predictors of augmentation index and estimated aortic pulse wave velocity. The 41 patients with blunted reduction in nighttime blood pressure (nondippers) showed higher mean systolic blood pressure (p=0.02), lower systolic and diastolic blood pressure variability (p<0.001), higher pulse pressure during 24-h monitoring (p=0.05) and higher estimated aortic pulse wave velocity (p=0.03), indicating stiffer arteries in this group. CONCLUSIONS: These results suggest that blood pressure change from day- to nighttime is an important determinant of arterial stiffness assessed by pulse wave analysis; this association could contribute to the higher cardiovascular risk in nondippers.     

Indication of an involvement of interleukin-1 beta converting enzyme- like protease in intramedullary apoptotic cell death in the bone marrow of patients with myelodysplastic syndromes

Our previous studies using in situ end labeling (ISEL) of fragmented DNA revealed extensive apoptotic cell death in the bone marrows (BM) of patients with myelodysplastic syndromes (MDS) involving both stromal and hematopoietic cells. In the present report we show greater synthesis of interleukin-1 beta (IL-1 beta) in 4 hour cultures of density separated BM aspirate mononuclear (BMAM) cells from MDS patients as compared to the cultures of normal BM from healthy donors or lymphoma patients (1.7 +/- 0.37 pg/10(5) cells, n = 29 v 0.42 +/- 0.24 pg/10(5) cells, n = 11, respectively, P = .049). Further, these amounts of IL-1 beta in MDS showed a significant correlation with the extent of apoptosis detected by ISEL in corresponding plastic embedded BM biopsies (r = .480, n = 30, P = .007). In contrast normal BMs did not show any correlation between the two (r = .091, n = 12, P = .779). No significant correlation was found between the amounts of IL-1 beta and % S-phase cells (labeling index; LI%) in MDS determined in BM biopsies using immunohistochemistry following in vivo infusions of iodo- and/or bromodeoxyuridine. Neither anti-IL-1 beta antibody nor IL-1 receptor antagonist blocked the apoptotic death of BMAM cells in 4 hour cultures (n = 5) determined by ISEL (apoptotic index; AI%), although the latter led to a dose-dependent accumulation of active IL-1 beta in the culture supernatants. On the other hand, a specific tetrapetide- aldehyde inhibitor of ICE significantly retarded the apoptotic death of BMAM cells at 1 mumol/L in 5/6 MDS cases studied (AI% = 2.99 +/- 0.30 in controls v 1.58 +/- 0.40 with ICE-inhibitor, P = .05) and also reduced the levels of active IL-1 beta synthesized (5.59 +/- 2.63 v 2.24 +/- 0.93 pg/10(6) cells, respectively). In normal cells, neither IL-1 blockers nor the ICE inhibitor showed any effect on the marginal increase in apoptosis observed in 4 hour cultures. Our data thus suggest a possible involvement of an ICE-like protease in the intramedullary apoptotic cell death in the BMs of MDS patients.