The evolution of bicontinuous polymeric nanospheres in aqueous solution.

Complex polymeric nanospheres in aqueous solution are desirable for their promising potential in encapsulation and templating applications. Understanding how they evolve in solution enables better control of the final structures. By unifying insights from cryoTEM and small angle X-ray scattering (SAXS), we present a mechanism for the development of bicontinuous polymeric nanospheres (BPNs) in aqueous solution from a semi-crystalline comb-like block copolymer that possesses temperature-responsive functionality. During the initial stages of water addition to THF solutions of the copolymer the aggregates are predominantly vesicles; but above a water content of 53% irregular aggregates of phase separated material appear, often microns in diameter and of indeterminate shape. We also observe a cononsolvency regime for the copolymer in THF-water mixtures from 22 to 36%. The structured large aggregates gradually decrease in size throughout dialysis, and the BPNs only appear upon cooling the fully aqueous dispersions from 35 °C to 5 °C. Thus, the final BPNs are ultimately the result of a reversible temperature-induced morphological transition.

Information processing deficits associated with developmental coordination disorder: a meta-analysis of research findings.

A meta-analysis was conducted to identify information processing factors that characterise children with Developmental Coordination Disorder (DCD). A total of 50 studies yielded 374 effect sizes based on 983 DCD and 987 control children. A mild generalised performance deficit was indicated, since motor-impaired children were inferior on almost all measures of information processing. There were, however, several areas where their deficiencies were more pronounced. The greatest deficiency was in visual-spatial processing. This was evident regardless of whether or not the tasks involved a motor component. Most other deficiencies were in the small-to-moderate range and included kinaesthetic and cross-modal processing. The findings support the notion that perceptual problems, particularly in the visual modality, are associated with difficulties in motor coordination.

Covert orienting of visuospatial attention in children with developmental coordination disorder.

It is still unclear whether impairments in visuospatial processing in children with developmental coordination disorder (DCD) are a consequence of their motor deficits or are independent of them. In two experiments, 20 children with DCD and 20 matched controls were tested on the covert orienting of a visuospatial attention task (COVAT). Experiment 1 used a COVAT with peripheral cues and an 80% probability that targets would appear at the cued location. While the results suggested a deficit in the disengage operation of orienting covert attention for the DCD group, they were difficult to reconcile with models of covert orienting and the results of past research. Experiment 2 tested subjects on two new versions of the COVAT: the first used peripheral cues and no probability information (exogenous mode), and the second used central cues and an 80% probability that targets would appear at the cued location (endogenous mode). The DCD group displayed attentional orienting deficits only for the endogenous mode. These results suggest that impairments in the endogenous control of visuospatial attention are independent of motor deficits in DCD.

A developmental toxicity study of tretinoin emollient cream (Renova) applied topically to New Zealand white rabbits.

BACKGROUND: Embryofetal developmental toxicity associated with oral administration of vitamin A analogs has led to concern about risks from topical application. OBJECTIVE: This study was conducted to evaluate the potential developmental toxicity of tretinoin emollient cream when applied to the skin of pregnant New Zealand white rabbits during organogenesis (gestational days 7 through 19). METHODS: Twenty rabbits each were randomly assigned to a control group (group I) or to receive vehicle (group II) or tretinoin emollient cream topically at dosages of 10 (0.05 mg/kg*, group III) or 100 (0.5 mg/kg*, group IV) times that used clinically in humans. Does and fetuses were examined for tretinoin-induced toxic effects, and maternal plasma tretinoin and metabolite levels were measured. RESULTS: The rate of abortion was increased significantly in does in group IV (p < or = 0.01) compared with the control group. Dosage-dependent increases in incidence and severity of skin reactions occurred in groups administered the vehicle and the two dosages of tretinoin. Does in groups III and IV had clinical and necropsy observations that were considered direct or indirect effects of tretinoin administration, persistent weight loss, and reduced feed consumption. Maternal endogenous plasma tretinoin levels were below the lower limit of quantitation of 5 ng/ml and were not significantly altered with treatment. Group IV had significantly reduced mean fetal body weight (p < or = 0.01) and a greater frequency of resorptions compared with group I. Although external, visceral, or skeletal alterations occurred at significantly greater levels in group III, they were unrelated to tretinoin administration because the fetal incidences were not dosage dependent, and the litter incidence did not significantly differ from the control group values. CONCLUSION: Maternally toxic dosages of tretinoin were associated with an increased incidence of abortions and resorptions and reduced fetal body weight, two end points of developmental toxicity. Consistent with the absence of detectable tretinoin plasma levels, however, no changes in fetal morphology were attributable to tretinoin administration. *The milligrams per kilogram dosage refers to the amount of active ingredient (tretinoin). The 0.05 mg/kg and 0.5 mg/kg groups were treated with 0.005% and 0.05% wt/wt tretinoin emollient cream formulation. The 0.05% tretinoin emollient cream is the Renova clinical formulation. The 10 and 100 times clinical multiples refer to Renova clinical multiples and are based on a 50 kg adult patient's applying 500 mg of 0.05% tretinoin emollient cream formulation daily to yield a clinical dosage of 0.005 mg/kg.

Anticipatory reaching by infants and adults: the effect of object features and apertures in opaque and transparent screens.

Perception of the manner in which objects may be grasped was examined in a series of experiments with adults and 10-month-old infants; visuomotor adjustment in hand orientation before making contact with objects served as the index throughout. In the first experiment, infants modified their hand orientation to match more closely the long axis of an object. They did so even though the target object could have been grasped by either end with hands oriented orthogonally to the long axis of the object. In two subsequent experiments involving reaching through narrow apertures to grasp the target, anticipatory adjustments in hand posture were evident for adults but not for infants. However, anticipatory adjustments by infants, sometimes appropriate and sometimes inappropriate, were made when the object was of such a size that it could neither be grasped nor retrieved through the aperture. In the final experiment, infants directed their hands first toward a handle, the only graspable part of an object, and oriented their hands so as to be nearly parallel with it prior to contact. This was the only orientation in which a grasp was possible. It was concluded that infants at 10 months respond more appropriately to object properties than to surface apertures that place limitations on how an object may be grasped.

The spatial coding strategies of one-year-old infants in a locomotor search task.

The ability of 1-year-old infants to remember the location of a nonvisible target was investigated in 3 experiments. Infants searched for a toy hidden in one of many possible locations within a circular bounded space. The presence, number, and spatial arrangement of local cues or "landmarks" within this space were varied. The results of Experiment 1 showed that search performance was highly successful when a landmark was coincident with the location of the toy ("direct"), but less successful when a landmark was adjacent to the target location ("indirect"). The results of Experiment 2 suggested that search with an indirect landmark may be more fragile than search with no landmarks at all. In Experiments 3a and 3b, 2 different configurations of indirect landmarks were employed; search performance was equally poor with both of these and was inferior to search with no landmarks. It is concluded that infants of this age are able to associate a nonvisible target with a direct landmark and are able to code the distance and direction of a target with respect to themselves or with respect to the larger framework. However, there was no evidence that they can code the distance and direction of a target relative to another object. The difficulty of coding with indirect landmarks is interpreted in terms of cognitive complexity and conflict between spatial strategies.

Effective action by infants to contact objects by reaching and leaning.

The ability of infants aged 8-12 months to coordinate their arm and trunk movements to contact an object located in different positions was investigated in 2 experiments. In the first, 8- and 10-month-old infants reached for near objects but both reached and leaned for more distant ones indicating that they perceived that forward leaning extends the range of contact beyond that of reaching alone. In addition, arm and trunk movements were initiated simultaneously; visual information concerning object distance was sufficient to activate an integrated reaching-and-leaning response. Object distances were increased and a mechanical aid was provided on half the trials in the second experiment with 10- and 12-month-old infants. For both age groups the degree of leaning was reduced for objects that were out of reach without the aid. Only older infants were able to use the aid to extend partially their range of contact. Overall the results support the conclusions that, by at least 8 months, infants perceive that leaning extends their effective reaching space; by 10 months they perceive the limits within which reaching together with leaning is likely to be effective; and by 12 months they begin to perceive how this space may be extended by a mechanical aid.

Cross-modal transfer of sequential visual and haptic shape information by clumsy children.

The ability of clumsy children aged 9 to 13 years to transfer sequential shape information between the haptic and visual modalities was examined in a matching-to-sample task. In both modalities, spatiotemporal integration of information relevant for shape was involved and transfer was examined between them by using intramodal transfer scores as covariates. The responses of clumsy children were not different from those of nonclumsy children of similar age, sex, and intelligence in the cross-modal condition involving matching of a haptic standard to a visual shape. However, when matching a visual standard to a haptic shape they were consistently both faster and less accurate. It was concluded that a specific visual-to-haptic translation process possibly involving poor visual memory for shape distinguishes clumsy children from their nonclumsy peers.

Integration of sequential information for shape perception by infants: a developmental study.

Perception of form by spatiotemporal integration was investigated in 3 experiments. In the first, infants aged 8, 10, and 12 months were tested using a novelty-preference procedure to determine the earliest age at which recognition of rectilinear and curvilinear form occurred. Infants were shown a light-point tracing of the outline of a figure, followed by simultaneous presentation of 2 test objects, one of the same shape as the tracing and one of a different shape. The tracing was double the size of the test objects. Only infants in the oldest group responded selectively by looking longer at the object of different shape. In the second experiment with 12-month-old infants only, it was shown that recognition of rectilinear, but not curvilinear, form occurred despite a difference in the orientation and size of tracing and object. Computer-generated tracings were used in the final experiment to compare form recognition for 2D and 3D stimuli. Selective responding occurred only for the latter. These findings show that by 12 months infants perceive the correspondence between the figural properties of a tracing and its extended form, but that this perception is dependent on the provision of depth cues.

Spatial updating and training effects in the first year of human infancy.

The ability of infants to locate an invisible target after reorientation in their direction of facing was examined in a series of experiments. In a featureless environment, localization of the target site improved between 4 and 8 months. At 8 months it was shown to be dependent on the training procedure. Infants received either instrumental training in which they were trained to anticipate the occurrence of an event at the site, or association training in which one event immediately followed another regardless of their responses. After instrumental training, localization was dependent on visual cues whereas after association training it occurred whether or not visual cues were provided. Contrary to earlier findings, it was concluded that an updating strategy based on proprioceptive information is operative from the second half of the first year.

Do infants use their own images to locate objects reflected in a mirror?

The ability of infants to locate a toy from a mirror reflection was investigated in 3 experiments. In the first, it was found that a minority of 22-month-old infants turned to locate the toy that was the source of the reflection, and that localization of the toy occurred regardless of whether the infants' own image was visible in the mirror. The results of 2 further experiments indicated that younger infants aged 14 and 18 months rarely use mirror information to locate a toy. When they do so, they also turn whether or not images of themselves are visible. It is concluded that tasks involving the localization of objects or events from mirror images are not direct indices of self-recognition. Rather, they indicate the skill of infants in using the mirror as a perceptual tool.

Toxicologic evaluation of ofloxacin.

Results of studies conducted to characterize local, systemic, reproductive, and mutagenic effects indicate that ofloxacin is well tolerated within reasonable multiples of the intended clinical dose. Quinolone-associated arthropathic effects characterized by blister, erosion, and increased synovial fluid occurred in rats and dogs and appeared to be both age- and dose-related. Maternal toxicity and embryotoxicity were noted, but there was no teratogenicity in rats or rabbits. There was no impairment of fertility, and no adverse effects on late fetal development, labor, delivery, lactation, neonatal viability, or growth of offspring occurred. Target-organ studies revealed no evidence of ocular toxicity in rats, nephrotoxicity in rabbits, or antigenicity or ototoxicity in guinea pigs. Overall, the toxicologic evaluation of ofloxacin has shown this compound to be a drug with a low toxicologic potential.

Guidelines and requirements for the evaluation of contraceptive steroids.

Since their introduction in the early 1960s, the oral contraceptive (OCs) steroids have been subjected to preclinical and clinical investigations unprecedented in medical history. As a result of such extensive studies, it is now possible to make a comprehensive review of preclinical and clinical data on oral contraceptives. The OCs were introduced at a time when the Food and Drug Administration (FDA) was undergoing drastic changes as a result of the thalidomide tragedy, the introduction of the Kefauver-Harris Amendment, and the desire for greater control over the pharmaceutical industry. The initial requirements for the safety evaluation of OCs were identical to those of other drugs. There were no explicit requirements for OCs although it was generally felt that the requirements should be more stringent because the OCs were being used in otherwise healthy women for long periods of time and with minimal medical supervision. In the 1960s when it became apparent from ongoing studies that there was an increased incidence of mammary tumors in dogs treated with some progestins, the FDA made the decision to terminate clinical studies and established the requirement for 7- and 10-yr studies in dogs and monkeys, respectively. The primary purpose of this paper is to present an historical perspective of the evolution of the preclinical requirements for the evaluation of the safety of OCs prior to their use in the various phases (I, II, III) of clinical trials. Some proposed changes in the requirements are discussed. This information will form the basis for other presentations dealing with the safety assessment of OCs in rats, dogs, and monkeys.

PIP: Sufficient preclinical and clinical data are now available to formulate guidelines on the use of oral contraceptives (OCs). The 1961 introduction of OCs coincided with the implemented of detailed study testing requirements of new drugs, including 3 phases of clinical trials each preceded by animal toxicity studies. Phase I human safety studies involved 10-20 subjects and focus on drug tolerance and clinical pharmacology. Phase II trials seek to demonstrate optimal dosage, efficacy, and relative safety in 50-100 subjects. Phase III trails are conducted under field conditions and involve up to 1000 human subjects. Before Phase III trials are initiated, 2-year studies in rats, dogs, and monkeys must be completed and 7- and 10-year studies in dogs and monkeys initiated. Over the past 3 decades, it has become apparent that there are significant differences in the responsiveness of target organs to OCs between humans and rats, dogs, and monkeys--the recommended animal models. The impossibility of accurately and completely predicting all the effects of OCs on humans on the basis of animal research has led to proposals to update the official requirements for the preclinical and clinical assessment of new fertility regulating drugs. A 1987 meeting on Methods for Improving the Safety Requirements for Contraceptive Steroids has developed guidelines aimed at increasing the reliability of OC safety data. The US Food and Drug Administration has accepted many of these proposals and added others, including acute toxicity studies in 3-4 species and multidose studies of toxicity in a rodent and monkey. Final approval requires 1-year toxicity studies in rodent and nonrodent species and a 3-year dog study.

Spatial localization in infancy: position constancy in a square and circular room with and without a landmark.

The ability of 8-month-old infants to localize an event from a new direction of facing was tested in a square and a circular room with and without a landmark. Subjects were trained to anticipate the site from 2 directions of facing and then tested in a new direction of facing. The number of trials to a criterion of learning, the number of subjects looking first at the event site after reorientation, and the time spent in doing so were recorded. Taken together, the results show that at 8 months ability to identify the site of an event after reorientation is based on the spatial relationship between the event and environmental features. The latter include features associated with room shape as well as a landmark at the site of the event.

Unstable ocular dominance and reading ability.

An ocular anomaly, unstable ocular dominance, has been shown to be associated with poor reading performance in clinically selected subjects. A study is reported in which this anomaly was examined in a nonclinical sample. Two groups of children of similar reading performance and IQ but differing in chronological age were selected. The older children had a mean discrepancy between their reading and chronological age of 19 months. Unstable ocular dominance was more frequent in these poor readers. The hypothesis that this instability would lead to more errors and longer decision times for distinguishing left-right mirror-image figures was not supported. If unstable ocular dominance is to be established as anything other than a correlate of specific reading retardation, it is necessary to establish the processes through which it is operative. These have yet to be determined.

Teratology study of intravaginally administered nonoxynol-9-containing contraceptive cream in rats.

Pregnant Long-Evans Hooded rats were intravaginally administered nonoxynol-9, a non-ionic surfactant used as a spermicidal agent in Delfen Contraceptive Cream (Ortho Pharmaceutical Corporation, Raritan, N.J.) at dosages of 4 or 40 mg/kg/day (2 and 20 times the clinical usage) on days 6 through 15 of gestation. Untreated, vehicle and sham control groups were also incorporated into the study protocol. No meaningful differences were observed between the treated and control groups in maternal toxicity, gross and microscopic appearance of vagina, maternal reproductive parameters, fetal toxicity, and the incidence of visceral and skeletal malformations.

Bromperidol, a new butyrophenone neuroleptic: a review.

This review compares and contrasts the preclinical pharmacology of bromperidol with another butyrophenone neuroleptic, haloperidol, and the phenothiazine neuroleptic chlorpromazine. Its pharmacokinetics, biotransformation, and safety in several laboratory animal species are also summarized. These preclinical data support its use as an antipsychotic agent and show that it is well absorbed following oral administration with an apparent elimination half-life of approximately 24 h, supporting a once-daily dose regimen. Animal toxicity (including acute- and multiple-dose toxicology and reproductive and mutagenicity studies) show that bromperidol is well tolerated.

Light and electron microscopic study of the livers of pregnant mice infected with Listeria monocytogenes.

Listeria monocytogenes cells were observed in the hepatic cell cytoplasm or in the phagosome at 24 and 48 hours but not at 72 hours after inoculation in pregnant mice. The presence of bacteria initially in a membrane-bound vesicle indicates that the bacteria enter the hepatic cells by endocytosis, resulting in eventual destruction of hepatic cells. Characteristic lesions of the liver at 24 and 48 hours after inoculation consist of multiple focal areas of necrosis. The initial neutrophilic reaction seems to give way to a mononuclear reaction (listeriomas) at 72 hours after inoculation. Dilation of rough endoplasmic reticulum and release of many of the bound ribosomes with a relative increase in the number of free ribosomes was observed. Hepatic lesions were not observed in control (nonpregnant) mice.

Intracerebral migration of Cuterebra larva in a kitten.

Verminous encephalitis in a 4-week-old kitten was manifested by depression, hysteria, and terminal convulsions. Necropsy revealed a second instar of Cutebra sp in the right cerebral hemisphere. The main lesions in the brain were those of acute focal hemorrhagic encephalomalacia.