Recombinant growth hormone for idiopathic short stature in children and adolescents.

BACKGROUND: Idiopathic short stature (ISS) refers to children who are very short compared with their peers for unknown or hereditary reasons. Recombinant human growth hormone (GH) has been used to increase growth and final height in children with ISS. OBJECTIVES: To assess the effects of recombinant human GH on short-term growth and final height in children with ISS. SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library, Science Citation Index, BIOSIS and Current Controlled Trials. Article reference lists were assessed for trials and experts and pharmaceutical companies were contacted. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children with ISS with normal GH secretion. GH had to be administered for a minimum of six months and be compared with placebo or no treatment. A growth or height outcome measure had to be assessed. DATA COLLECTION AND ANALYSIS: Two reviewers assessed studies for inclusion criteria and for methodological quality. Data were extracted by one reviewer and checked by a second. The primary outcome was final height and secondary outcomes included short term growth, health related quality of life and adverse effects. To estimate summary treatment effects, data were pooled, when appropriate using a random effects model. MAIN RESULTS: Ten RCTs were included. One trial reported near final height in girls and found that girls treated with GH were 7.5 cm taller than untreated controls (GH group, 155.3 cm +/- 6.4; control, 147.8 cm +/- 2.6; P = 0.003); another trial which reported adult height standard deviation score found that children treated with GH were 3.7 cm taller than children in a placebo-treated group (95% confidence intervals 0.03 to 1.10; P < 0.04). The other trials reported short term outcomes. Results suggest that short-term height gains can range from none to approximately 0.7 SD over one year. One study reported health related quality of life and showed no significant improvement in GH treated children compared with those in the control group, whilst another found no significant evidence that GH treatment impacts psychological adaptation or self-perception in children with ISS. No serious adverse effects of treatment were reported. AUTHORS' CONCLUSIONS: GH therapy can increase short-term growth and improve (near) final height. Increases in height are such that treated individuals remain relatively short when compared with peers of normal stature. Large, multicentre RCTs are required which should focus on final height and address quality of life and cost issues.

Recombinant growth hormone for children and adolescents with Turner syndrome.

BACKGROUND: Turner syndrome (TS) affects about one in 1500 to 2500 live-born females. One of the most prevalent and salient features of the syndrome is extremely short stature. Untreated women are approximately 20 to 21 cm shorter than normal women within their respective populations. Recombinant human growth hormone (hGH) has been used to increase growth and final height in girls who have Turner syndrome. OBJECTIVES: To assess the effects of recombinant growth hormone in children and adolescents with TS. SEARCH STRATEGY: MEDLINE, EMBASE, The Cochrane Library, LILACS, BIOSIS, Science Citation Index and reference lists were used to identify relevant trials. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children with TS before achieving final height. Growth hormone had to be administered for a minimum of six months and compared with a placebo or no treatment control condition. DATA COLLECTION AND ANALYSIS: Two reviewers assessed studies for inclusion criteria and for methodological quality. The primary outcomes were final height and growth. Secondary outcomes included bone age, quality of life, cognitive performance, and adverse effects. MAIN RESULTS: Four RCTs that included 365 participants after one year of treatment were included. Only one trial reported final height in 61 treated women to be 148 cm and 141 cm in 43 untreated women (mean difference (MD) seven cm, 95% CI 6 to 8). Short-term growth velocity was greater in treated than untreated girls after one year (two trials, MD three cm per year, 95% CI 2 to 4) and after two years (one trial, MD two cm per year, 95% CI 1 to 2.3). Skeletal maturity was not accelerated by treatment with recombinant growth hormone (hGH). Adverse effects were minimally reported. AUTHORS' CONCLUSIONS: Recombinant human growth hormone (hGH) doses between 0.3 to 0.375 mg/kg/wk increase short-term growth in girls with Turner syndrome by approximately three (two) cm in the first (second) year of treatment. Treatment in one trial increased final height by approximately six cm over an untreated control group. Despite this increase, the final height of treated women was still outside the normal range. Additional trials of the effects of hGH carried out with control groups until final height is achieved would allow better informed decisions about whether the benefits of hGH treatment outweigh the requirement of treatment over several years at considerable cost.

Recombinant growth hormone in children and adolescents with Turner syndrome.

BACKGROUND: Turner syndrome (TS) affects about one in 1,500 to 2,500 live-born females. One of the most prevalent and salient features of the syndrome is extremely short stature. Untreated women are approximately 20-21 cm shorter than normal women within their respective populations. Recombinant human growth hormone (hGH) has been used to increase growth and final height in women who have Turner syndrome. OBJECTIVES: To assess the effects of recombinant growth hormone on short-term growth and final height in children and adolescents with Turner syndrome. SEARCH STRATEGY: Published and unpublished randomised-controlled trials (RCTs) were sought by searching the Cochrane Central Register of Controlled Trials (Central) (2002, Issue 3), Medline (1981 to July 2002), Embase (1980 to June 2002), PubMed (search 30 July, 2002 for entries in last 180 days), Science Citation Index (search 30 July, 2002), BIOSIS (search 30 July, 2002) and Current Controlled Trials (search 30 July, 2002). Article reference lists were assessed for trials and experts and pharmaceutical companies were contacted. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children with Turner Syndrome before achieving final height. Growth hormone had to be administered for a minimum of six months and compared with a placebo or no treatment control condition. A growth or height outcome measure must have been assessed. In addition, in the context of a growth assessment other outcomes reflecting psychological adjustment were also included. DATA COLLECTION AND ANALYSIS: Two reviewers assessed studies for inclusion criteria and for methodological quality. Data were extracted by one reviewer and checked by a second. The main outcomes were final height (in cm or standard deviation score), growth (in velocity or velocity standard deviation score). Additional outcomes included bone age, quality of life, cognitive performance, and adverse effects. To estimate summary treatment effects, data were pooled using a random effects model (when data were sufficient and appropriate to combine) with calculation of weighted mean differences (WMD) for continuous outcomes. MAIN RESULTS: Four RCTs that included 211 participants after one year of treatment were included. These were described in six publications. Three studies were included in the analyses of growth outcomes (one study did not report any data). Only one trial reported results on final height. This trial reported that average final height in 40 treated women was 146.2 cm and 141.4 cm in 29 untreated women (mean difference (MD) 4.8 cm, 95% CI 2.2 to 7.4). Short-term growth velocity was greater in treated than untreated girls after one year (two trials, weighted mean difference (WMD) 3.3 cm/yr, 95% CI 2.4 to 4.3) after 18 months (one trial, MD 2.6 cm/yr, 95% CI 2.1 to 3.1) and after two years (one trial, MD 1.8 cm/yr, 95% CI 1.3 to 2.3). Results were similar when reported as growth velocity standard deviation scores. Skeletal maturity was not accelerated by treatment with recombinant growth hormone (hGH). Bone age divided by chronological age was approximately one in both treated and untreated groups in one trial after both one and two years of treatment. One trial selectively reported psychological outcomes that suggested that psychological adjustment was better in girls treated with hGH, but selective reporting leaves these results in some doubt. Adverse effects were minimally reported. There is little evidence of serious short-term adverse effects in these trials, but they are underpowered to detect rare adverse effects. REVIEWER'S CONCLUSIONS: Recombinant human growth hormone (hGH) doses between 0.3 - 0.375 mg/kg/wk increase short-term growth in girls with Turner Syndrome (TS) by approximately 3 cm in the first year of treatment and by approximately 2 cm per year after 2 years of treatment. There is little evidence on the effects of hGH on final height. Treatment in one trial increased final height by approximately 5 cm over an untreated control group. Despite this increase, the fated control group. Despite this increase, the final height of treated women was still outside the normal range (more than two standard deviations below the normal population mean). Additional trials of the effects of hGH carried out with control groups until final height is achieved would allow better informed decisions about whether the benefits of hGH treatment outweigh the requirement of treatment over several years at considerable cost.

Vascular tree structure affects lung blood flow heterogeneity simulated in three dimensions.

Pulmonary arterial tree structures related to blood flow heterogeneity were simulated by using a symmetrical, bifurcating model in three-dimensional space. The branch angle (Theta), daughter-parent length ratio (rL), branch rotation angle (phi), and branch fraction of parent flow (gamma) for a single bifurcation were defined and repeated sequentially through 11 generations. With phi fixed at 90 degrees , tree structures were generated with Theta between 60 and 90 degrees , rL between 0.65 and 0.85, and an initial segment length of 5.6 cm and sectioned into 1-cm3 samples for analysis. Blood flow relative dispersions (RD%) between 52 and 42% and fractal dimensions (Ds) between 1.20 and 1.15 in 1-cm3 samples were observed even with equal branch flows. When gamma not equal 0.5, RD% increased, but Ds either decreased with gravity bias of higher branch flows or increased with random assignment of higher flows. Blood flow gradients along gravity and centripetal vectors increased with biased flow assignment of higher flows, and blood flows correlated negatively with distance only when gamma not equal 0.5. Thus a recursive branching vascular tree structure simulated Ds and RD% values for blood flow heterogeneity similar to those observed experimentally in the pulmonary circulation due to differences in the number of terminal arterioles per 1-cm3 sample, but blood flow gradients and a negative correlation of flows with distance required unequal partitioning of blood flows at branch points.

Effects of color and pattern on implicit and explicit picture memory.

The degree to which repetition priming is perceptually specific is informative about the mechanisms of implicit memory as well as of perceptual processing. In 2 sets of experiments with pictures as stimuli, we tested the effects of color and pattern manipulations between study and test on implicit memory (i.e., naming facilitation) and explicit memory (i.e., 2 forms of recognition). These manipulations did not affect priming. However, participants were able to explicitly detect stimulus changes at above-chance levels. Changes in color also produced small decrements in participants' ability to judge that repeated stimuli were old on a recognition test. Experiment 2 showed diminished priming with changes in the stimulus exemplar (i.e., a different picture of the same named object) from study to test, which demonstrated that the picture-naming paradigm is sensitive to changes in physical attributes. The results suggest that physical attributes that are not essential to the formation of a shape representation do not influence repetition priming in a basic identification paradigm. Suggestions for how priming may be mediated are discussed.

The role of parts and spatial relations in object identification.

An investigation of the role of parts and their spatial relations in object identification is reported. At the most general level, two important results were obtained. First, proper spatial relations among components of an object are critical for easy identification. When parts were scrambled on the page, naming times and error rates increased. And, second, the way an object is divided into parts (parsed) affects identification only under the most impoverished viewing conditions. When subjects had as little as 1 s (and sometimes as little as 200 ms) to view an object, the way objects were divided into parts had no effect on naming times or accuracy. There was no hint of an interaction between type of parse and how parts were arranged on the page. This pattern of effects supports theories that suggest that objects typically are recognized without being parsed into parts. The findings are in agreement with theories suggesting that object features (not specifically related to parts) are matched directly with such features stored in long-term memory, with the constraint that the features of a single object are seen from a single viewpoint.

Intact and long-lasting repetition priming in amnesia.

In 2 experiments, we evaluated the ability of amnesic patients to exhibit long-lasting perceptual priming after a single exposure to pictures. Ss named pictures as quickly as possible on a single occasion, and later named the same pictures mixed with new pictures. In Experiment 1, amnesic patients exhibited fully intact priming effects lasting at least 7 days. In Experiment 2, the priming effect for both groups was shown to depend on both highly specific visual information and on less visual, more conceptual information. In contrast, recognition memory was severely impaired in the patients, as assessed by both accuracy and response time. The results provide the first report of a long-lasting priming effect in amnesic patients, based on a single encounter, which occurs as strongly in the patients as in normal Ss. Together with other recent findings, the results suggest that long-lasting priming and recognition memory depend on separate brain systems.

Intact verbal and nonverbal short-term memory following damage to the human hippocampus.

Short-term memory was assessed in two groups of amnesic patients. Six patients had confirmed or suspected damage to the hippocampal formation, and six patients had diencephalic damage as a result of alcoholic Korsakoff's syndrome. Verbal short-term memory was evaluated with seven separate administrations of the standard digit span test in order to obtain a precise measure of short-term memory. Nonverbal short-term memory was evaluated with four tests that assessed apprehension, retention, and the ability to manipulate nonverbal material--all within the span of immediate memory. One of these four tests assessed short-term memory for spatial location. Patients with damage to the hippocampal formation had a digit span equivalent to that of control subjects and also performed normally on the four tests of nonverbal short-term memory. The patients with Korsakoff's syndrome had a marginally low digit span and performed poorly on three of the four nonverbal tasks, a finding consistent with the deficits in attention and visuospatial processing previously described for this patient group. These deficits are likely due to the frontal lobe atrophy typically associated with Korsakoff's syndrome, rather than to diencephalic damage. The results support the view that short-term (immediate) memory, including short-term spatial memory, is independent of the hippocampus.

Equivalent impairment of spatial and nonspatial memory following damage to the human hippocampus.

The hippocampus has sometimes been proposed to function as a cognitive map, a memory system that stores information about allocentric space. Work with experimental animals and memory-impaired patients has raised difficulties with this view by showing that the hippocampus is not performing an exclusively spatial function. However, the possibility has remained that the hippocampus plays a special role in spatial memory or a disproportionately large role in spatial memory compared to other kinds of memory. This study compared spatial and nonspatial memory in amnesic patients with lesions of the hippocampal formation or diencephalon. Subjects studied an array of 16 toy objects and were subsequently tested for object recall, object recognition, and memory for the location of the objects. Control subjects were tested after long retention intervals in order to equate their object memory performance with that of the patients. The main finding was that, when the performance of amnesic patients on the object memory tests was matched to the object memory performance of control subjects, spatial memory performance of the amnesic patients also matched the spatial memory performance of the control subjects. The results were the same for the two groups of patients. These findings suggest that the hippocampus is not especially involved in spatial memory. Spatial memory is simply one instance of a broader category of memory that requires the hippocampus. While cognitive mapping in its most abstract sense may describe hippocampal function, our results support alternative formulation, suggesting that the hippocampus is necessary for the rapid acquisition of relational, configural, or declarative (as opposed to purely spatial) information.

Evidence for two types of spatial representations: hemispheric specialization for categorical and coordinate relations.

Analyses of human object recognition abilities led to the hypothesis that 2 kinds of spatial relation representations are used in human vision. Evidence for the distinction between abstract categorical spatial relation representations and specific coordinate spatial relation representations was provided in 4 experiments. These results indicate that Ss make categorical judgments--on/off, left/right, and above/below--faster when stimuli are initially presented to the left cerebral hemisphere, whereas they make evaluations of distance--in relation to 2 mm, 3 mm, or 1 in. (2.54 cm)--faster when stimuli are initially presented to the right cerebral hemisphere. In addition, there was evidence that categorical representations developed with practice.