Clonal involvement of granulocytes and monocytes, but not of T and B lymphocytes and natural killer cells in patients with myelodysplasia: analysis by X-linked restriction fragment length polymorphisms and polymerase chain reaction of the phosphoglycerate kinase gene.

To determine the clonal nature of hematopoiesis and to assess lineage involvement in patients with myelodysplastic syndromes (MDS), we used restriction fragment length polymorphisms of the X-linked genes phosphoglycerate kinase (PGK1) and hypoxanthine phosphoribosyltransferase (HPRT) and the X-linked probe M27 beta. Eleven female MDS patients heterozygous for at least one of these probes were studied: 3 with refractory anemia (RA), 2 with RA with ringed sideroblasts (RARS), 2 with chronic myelomonocytic leukemia (CMML), and 4 with RA with excess of blasts in transformation (RAEB-t). All exhibited clonal hematopoiesis as determined by Southern analysis of DNA prepared from peripheral blood (PB) and/or bone marrow (BM) cells. In three of the six patients heterozygous for the PGK1 gene, purified cell suspensions of polymorphonuclear cells (PMN), monocytes, lymphocytes, and/or T cells prepared from PB were tested. In addition, five of these patients were analyzed by a polymerase chain reaction (PCR)-based procedure as described recently. This method was slightly adapted to facilitate the analysis of cell lysates of fluorescence-activated cell sorted (FACS) monocytes, T and B lymphocytes, and natural killer (NK) cells. The outcome of Southern and PCR analysis was concordant, showing that PMN and monocytes were clonally derived, whereas circulating T and B lymphocytes and NK cells exhibited random X-chromosome inactivation compatible with a polyclonal pattern. To address the question of whether T cells are derived from unaffected progenitor cells or that their origin had antedated the onset of MDS, naive and memory T cells were analyzed separately. Both subsets showed a polyclonal pattern. However, in one patient analysis of constitutive DNA suggested a skewed methylation, and the presence of clonal lymphocytes against a background of polyclonal lymphoid cells cannot be ruled out in this patient. PCR analysis of PB and BM cells showed a nonrandom, unilateral pattern of X-inactivation, compatible with a mixture of clonally (myeloid) and polyclonally (lymphoid) derived cells. In conclusion, in some patients, MDS represents a disorder with clonal hematopoiesis restricted to cells of myeloid origin, whereas a random X-inactivation pattern is found in lymphoid cells.     

Brain perfusion territory imaging applying oblique-plane arterial spin labeling with a standard send/receive head coil.

A new method for the selective spin labeling of left- or right-sided supplying arteries of the brain without the need for additional RF coils is demonstrated. A clinical 1.5 T scanner was used. The spatial selectivity of the labeling process is based on the limited coverage of the excitation field of a standard send/receive head coil together with an oblique positioning of the labeling plane. A computer simulation was used to optimize key labeling parameters under the condition of laminar flow. The validity of the computer model results was confirmed by MRI measurements with a flow model. For human studies, a double-inversion continuous arterial spin labeling (CASL) sequence was modified to allow for arbitrary positioning of the labeling plane. The obtained perfusion-weighted images showed a clear delineation of the perfusion territories of the selected arteries in the anterior circulation of the brain and good gray/white matter contrast.     

Cortisol moderates the relationship between testosterone and aggression in delinquent male adolescents.

BACKGROUND: In animals, strong evidence exists for an association between testosterone and aggression. In humans, and particularly in children and adolescents, findings have been less consistent. Previous research has suggested that this may partly be due to moderating effects of other factors, e.g., hormones. This study aims to investigate the moderating effect of cortisol on the relationship between testosterone and subtypes of aggression in delinquent male adolescents. METHODS: Participants were 103 boys (mean age 13.7) referred to a delinquency diversion program. Testosterone and cortisol levels were determined from saliva samples collected during resting conditions and related to self-report scores on overt and covert aggression. RESULTS: Linear regression analyses revealed a significant interaction between cortisol and testosterone in relation to overt aggression, with a significant positive relationship between testosterone and overt aggression in subjects with low cortisol levels but not in subjects with high cortisol levels. Using the same model for covert aggression, no significant effects of testosterone, cortisol, or testosterone x cortisol interaction were found. CONCLUSIONS: These results indicate a moderating effect of cortisol on the relationship between testosterone and overt aggression in delinquent male adolescents. Implications and directions for future research are discussed.     

A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300® (300 mg), Adizem® XL (300 mg)¹, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (c_min), the maximum plasma concentration (c_max), the time to reach that concentration (t_max), the time interval during which the plasma concentration exceeds 50% of c_max (t₅₀), the area under the plasma concentration-time curve (AUC_72–96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC_72–96 (AUC_NDM and AUC_DAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL^-1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.     

Effect of intravenous fat on cholecystokinin secretion and gallbladder motility in man.

During total parenteral nutrition (TPN) gallbladder bile stasis and hypomotility have been well documented. Little is known, however, about the effect of the separate components of TPN on gallbladder motor function. Inasmuch as fat, administered intraduodenally, is a potent stimulus of cholecystokinin (CCK) secretion and gallbladder contraction we have investigated whether intravenous (IV) fat affects gallbladder motility. Six healthy volunteers were studied on two separate occasions, during infusion of Intralipid 10%, 200 mL/h or saline infusion (control) for 3 hours, to evaluate the effect of IV infusion of fat on (1) plasma CCK concentration and gallbladder volume and (2) CCK-induced gallbladder emptying. Intravenous infusion of Intralipid resulted in significant increases in serum triglycerides from 0.9 +/- 0.1 to 5.1 +/- 1.3 mmol/L (at 90 min). During fat infusion no significant changes in plasma CCK and gallbladder volume were noted when compared with basal values or to the control experiment. During IV fat, concomitant infusion of 0.25, 0.5, and 1.0 Ivy dog unit (IDU) per kilogram per hour of CCK-33 resulted in a significant reduction in gallbladder volume from 26 +/- 6 cm3 (basal) to 15 +/- 4 cm3 (p less than .05), 6 +/- 2 cm3 (p less than .05) and 2.5 +/- 1 cm3 (p less than .05), respectively. No significant differences in CCK-induced gallbladder emptying were observed between IV fat and saline infusion (control). It is concluded that, in contrast to intraduodenal fat, IV infusion of fat does not affect (1) basal plasma CCK and gallbladder volume and (2) CCK-induced gallbladder contraction.     

Analysis of observed behaviors displayed by depressed patients during a clinical interview: relationships between behavioral factors and clinical concepts of activation.

In 61 drug-free depressed patients, relationships were studied between observed behaviors and measures of common clinical concepts of activation. The behaviors were observed during a clinical interview and analyzed with ethological methods. Activation was assessed by means of self-ratings (Thayer, AD-ACL) and global judgement (Hamilton, retardation, agitation). Various aspects of patients' speaking and listening behaviors were recorded and analyzed, such as looking, head movements, yes-nodding and no-shaking, leg movements, gesturing, and body and object touching. A factor analysis was applied, enabling grouping of behaviors without using a priori concepts. Five factors reflected different aspects of a conversation: restlessness (leg and hand movements), speech, active listening (head movements and intensive body touching, during listening), speaking effort (looking, gesticulating, head movements, during speaking), and eagerness (yes-nodding and no-shaking). Significant positive relationships were found between the speech factor, the speaking effort factor and the restlessness factor on the one hand, and activation on the other. The eagerness factor was related negatively with activation. The results give insight into the organization of behavior during an interview, and show how this is related to clinical concepts of activation.