Acyloxymethyl acidic drug derivatives: in vitro hydrolytic reactivity

A series of acyloxymethyl drug derivatives of the NH-acidic drugs, phenytoin and theophylline and of the carboxylic acid drugs, thioctic acid and indomethacin, were prepared in order to determine the effect of varying the nature of the drug on the in vitro rate of hydrolysis catalyzed by porcine liver esterase and human plasma. The acyl portion was comprised of either valeric acid (val) or γ-linolenic acid (GLA). With the exception of some GLA prodrugs, the derivatives displayed first-order kinetics in both enzyme systems. The NH-acidic drug derivatives were hydrolyzed faster than the carboxylic drug derivatives by porcine liver esterase and human plasma. It was found that the short chain valeric acid derivatives were hydrolyzed faster than the GLA derivatives. The rates of hydrolysis for the relatively smaller prodrugs of theophylline and thioctic acid were greater than the rates of hydrolysis for the bulkier phenytoin and indomethacin prodrugs indicating steric hindrance was important. The lipophilicity index, log K, of the valeric acid drug derivatives was plotted against the logarithm of the hydrolysis rate constant, k, and it was observed that log k decreased with an increase in log K. A comparison of these results with those of previous studies where the alkyl and acyl moieties were varied of acyloxyalkyl theophylline derivatives has provided a rationale, based on lipophilicity, for the structure of a prodrug to be designed based on an in vitro desired rate of hydrolysis.     

Age Differences In The Magnitude Of Associated Movement

Using a quantitative measure of unintended mirror-movements in the contralateral limb during a unimanual task, the magnitude of associated movement across the ages from six to 16 years was determined. Male children in five age-groups (means 6.5, 8.5, 10.4, 12.4 and 16.5 years) were asked to squeeze their index finger and thumb together to various percentages of their own maximal volitional force. Results indicate that the 6.5-year-old group differ from all other age-groups, exhibiting significantly greater associated movements at all levels of force. The results are discussed in terms of the development of inhibitory control over innate neuromotor synergies.     

The Role of Attention in the Regulation of Associated Movement in Children

The effect of attentional processes in regulating associated movement was studied in 10 male children in each of five age-groups from six to 16 years. They were asked to squeeze their index finger and thumb to 75 per cent of their own maximal volitional force under three conditions: a spontaneous baseline condition, a sensory feedback condition and a post-training condition without sensory feedback. Children of all ages were able to reduce the magnitude of associated movements during the sensory feedback condition. In the post-training condition some of the ability to inhibit was lost, particularly for the six-year-olds. This supports the view that the integration of higher order processes, such as attention, with lower-level neuromotor inhibitory mechanism, plays a role in the reduction of associated movement with increasing age. Implications for therapy with clinical populations are discussed.     

Comparison of Neisseria gonorrhoeae Multiantigen Sequence Typing and porB Sequence Analysis for Identification of Clusters of N. gonorrhoeae Isolates

porB DNA sequence analysis and Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST) methods were compared for their abilities to discriminate strains and to identify epidemiologically congruent pairs of N. gonorrhoeae. Both methods provided high-level discrimination of strains. NG-MAST further differentiated large porB-based clusters. However, considerations of cost suggest that porB DNA sequence analysis is a useful tool for preliminary molecular analysis of the epidemiology of N. gonorrhoeae.     

Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages

Tim-4 is a phosphatidylserine (PS) receptor that is expressed on various macrophage subsets. It mediates phagocytosis of apoptotic cells by peritoneal macrophages. The in vivo functions of Tim-4 in phagocytosis and immune responses, however, are still unclear. In this study, we show that Tim-4 quickly forms punctate caps on contact with apoptotic cells, in contrast to its normal diffused expression on the surface of phagocytes. Despite its expression in marginal zone and tingible body macrophages, Tim-4 deficiency only minimally affects outcomes of several acute immune challenges, including the trapping of apoptotic cells in the marginal zone, the clearance apoptotic cells by tingible body macrophages, and the formation of germinal centers and elicitation of antibody responses against sheep red blood cells (SRBCs). In addition, Tim-4^−/− resident peritoneal macrophages (rPMs) phagocytose necrotic cells and other opsonized targets normally. However, their ability to bind and engulf apoptotic cells is significantly compromised both in vitro and in vivo. Most importantly, Tim-4 deficiency results in increased cellularity in the peritoneum. Resting rPMs produce higher TNF-α in culture. Their response to LPS, on the contrary, is dampened. Our data support an indispensible role of Tim-4 in maintaining the homeostasis of rPMs.     

Bimanual coordination in children: manipulation of object size

An experiment was designed to investigate the temporal and spatial couplings of the transport and grasp components for bimanual movements performed by children. Thirty-one participants aged 4–6 (younger) and 7–10 (older) performed the unimanual task of reaching for, grasping, and lifting a small or large cylinder with the right or left hands or the bimanual task of reaching for, grasping and lifting two small cylinders, two large cylinders, or one small and one large cylinder with the right and left hands. Kinematic measures, relative timing differences between the hands, spatial plots and cluster analysis were used to quantify both temporal and spatial couplings of the limbs. While average kinematic results indicated that children in the 4–6 and 7–10 age range performed bimanual movements similarly to each other, spatio-temporal coupling measures indicated that the younger children performed the bimanual movements in a more sequential (serial) fashion. Kinematic results also indicated that the cost of the increase in task complexity normally seen in adults when grasping two targets bimanually compared to a single target unimanually are not consistently present for children. Instead, the cost associated with increases in task complexity appear to be mediated by whether the bimanual task imposes significantly greater demands on attentional processes. These results indicate that attention demands of the task as well as the intrinsic dynamics of the individual determine the degree of interlimb coupling of children during bimanual reach-to-grasp of different-sized objects.