MEPROCS framework for Craniofacial Superimposition: Validation study.

Craniofacial Superimposition (CFS) involves the process of overlaying a skull with a number of ante-mortem images of an individual and the analysis of their morphological correspondence. The lack of unified working protocols and the absence of commonly accepted standards, led to contradictory consensus regarding its reliability. One of the more important aims of 'New Methodologies and Protocols of Forensic Identification by Craniofacial Superimposition (MEPROCS)' project was to propose a common framework for CFS, what can be considered the first international standard in the field. The framework aimed to serve as a roadmap for avoiding particular assumptions that could bias the process. At the same time, it provides some empirical support to certain practices, technological means, and morphological criteria expected to facilitate the application of the CFS task and to improve its reliability. In order to confirm the utility and potential benefits of the framework use, there is a need to empirically evaluate it in CFS identification scenarios as close as possible to the reality. Thus, the purpose of this study is to validate the CFS framework developed. For that aim 12 participants were asked to report about a variable number of CFS following all the recommendations of the framework. The results are analysed and discussed according to the framework understanding and fulfilment, the participants' performance, and the correlation between expected decisions and those given by the participants. In view of the quantitative results and qualitative examination criteria we can conclude that those who follow the MEPROCS recommendations improve their performance.

Study on the performance of different craniofacial superimposition approaches (II): Best practices proposal.

Craniofacial superimposition, although existing for one century, is still a controversial technique within the scientific community. Objective and unbiased validation studies over a significant number of cases are required to establish a more solid picture on the reliability. However, there is lack of protocols and standards in the application of the technique leading to contradictory information concerning reliability. Instead of following a uniform methodology, every expert tends to apply his own approach to the problem, based on the available technology and deep knowledge on human craniofacial anatomy, soft tissues, and their relationships. The aim of this study was to assess the reliability of different craniofacial superimposition methodologies and the corresponding technical approaches to this type of identification. With all the data generated, some of the most representative experts in craniofacial identification joined in a discussion intended to identify and agree on the most important issues that have to be considered to properly employ the craniofacial superimposition technique. As a consequence, the consortium has produced the current manuscript, which can be considered the first standard in the field; including good and bad practices, sources of error and uncertainties, technological requirements and desirable features, and finally a common scale for the craniofacial matching evaluation. Such a document is intended to be part of a more complete framework for craniofacial superimposition, to be developed during the FP7-founded project MEPROCS, which will favour and standardize its proper application.

Photo anthropometric variations in Japanese facial features: Establishment of large-sample standard reference data for personal identification using a three-dimensional capture system.

This study clarifies the anthropometric variations of the Japanese face by presenting large-sample population data of photo anthropometric measurements. The measurements can be used as standard reference data for the personal identification of facial images in forensic practices. To this end, three-dimensional (3D) facial images of 1126 Japanese individuals (865 male and 261 female Japanese individuals, aged 19-60 years) were acquired as samples using an already validated 3D capture system, and normative anthropometric analysis was carried out. In this anthropometric analysis, first, anthropological landmarks (22 items, i.e., entocanthion (en), alare (al), cheilion (ch), zygion (zy), gonion (go), sellion (se), gnathion (gn), labrale superius (ls), stomion (sto), labrale inferius (li)) were positioned on each 3D facial image (the direction of which had been adjusted to the Frankfort horizontal plane as the standard position for appropriate anthropometry), and anthropometric absolute measurements (19 items, i.e., bientocanthion breadth (en-en), nose breadth (al-al), mouth breadth (ch-ch), bizygomatic breadth (zy-zy), bigonial breadth (go-go), morphologic face height (se-gn), upper-lip height (ls-sto), lower-lip height (sto-li)) were exported using computer software for the measurement of a 3D digital object. Second, anthropometric indices (21 items, i.e., (se-gn)/(zy-zy), (en-en)/(al-al), (ls-li)/(ch-ch), (ls-sto)/(sto-li)) were calculated from these exported measurements. As a result, basic statistics, such as the mean values, standard deviations, and quartiles, and details of the distributions of these anthropometric results were shown. All of the results except "upper/lower lip ratio (ls-sto)/(sto-li)" were normally distributed. They were acquired as carefully as possible employing a 3D capture system and 3D digital imaging technologies. The sample of images was much larger than any Japanese sample used before for the purpose of personal identification. The measurements will be useful as standard reference data for forensic practices and as material data for future studies in this field.

Study on the performance of different craniofacial superimposition approaches (I).

As part of the scientific tasks coordinated throughout The 'New Methodologies and Protocols of Forensic Identification by Craniofacial Superimposition (MEPROCS)' project, the current study aims to analyse the performance of a diverse set of CFS methodologies and the corresponding technical approaches when dealing with a common dataset of real-world cases. Thus, a multiple-lab study on craniofacial superimposition has been carried out for the first time. In particular, 26 participants from 17 different institutions in 13 countries were asked to deal with 14 identification scenarios, some of them involving the comparison of multiple candidates and unknown skulls. In total, 60 craniofacial superimposition problems divided in two set of females and males. Each participant follow her/his own methodology and employed her/his particular technological means. For each single case they were asked to report the final identification decision (either positive or negative) along with the rationale supporting the decision and at least one image illustrating the overlay/superimposition outcome. This study is expected to provide important insights to better understand the most convenient characteristics of every method included in this study.

Fluvoxamine alleviates ER stress via induction of Sigma-1 receptor.

We recently demonstrated that endoplasmic reticulum (ER) stress induces sigma-1 receptor (Sig-1R) expression through the PERK pathway, which is one of the cell's responses to ER stress. In addition, it has been demonstrated that induction of Sig-1R can repress cell death signaling. Fluvoxamine (Flv) is a selective serotonin reuptake inhibitor (SSRI) with a high affinity for Sig-1R. In the present study, we show that treatment of neuroblastoma cells with Flv induces Sig-1R expression by increasing ATF4 translation directly, through its own activation, without involvement of the PERK pathway. The Flv-mediated induction of Sig-1R prevents neuronal cell death resulting from ER stress. Moreover, Flv-induced ER stress resistance reduces the infarct area in mice after focal cerebral ischemia. Thus, Flv, which is used frequently in clinical practice, can alleviate ER stress. This suggests that Flv could be a feasible therapy for cerebral diseases caused by ER stress.

DNA survival and physical and histological properties of heat-induced alterations in burnt bones.

During forensic casework, it is vital to be able to obtain valuable information from burnt bone fragments to ascertain the identity of the victim. Here, we report the findings of an experimental study on burnt bovine compact bone segments. Compact bones were cut to size and heated in an electric furnace at a temperature range of 100­1,100 °C with 100 °C increments. Heat-induced alterations to the bone color,weight, volume, and density were monitored using gross morphology and micro-focus X-ray computed tomography.We found that the increase in temperature caused the color of the compact bones to change in order of yellow, brown, gray,and white. In contrast to the weight reduction that occurred immediately after burning, we measured no significant reduction in volume even at 600 °C; however, volume reduced drastically once the temperature reached 700 °C. Light microscopic histological observations of burnt bone revealed heat induced alterations such as cracking and separation of the osteons at higher temperatures. In addition to these findings,we sought to examine the survival of DNA in the burnt bones using polymerase chain reaction of mitochondrial DNA. No amplification was found in the specimens burnt at 250 °C or higher, indicating the likely difficulty in testing the DNA of burnt bones from forensic casework. The results of this study will enable an estimation of the burning temperatures of burnt bones found in forensic cases and will provide an important framework with which to interpret data obtained during anthropological testing and DNA typing.

Increased phosphatidylcholine concentration in saliva reduces surface tension and improves airway patency in obstructive sleep apnoea.

Surface tension may have important role for maintaining upper airway patency in patients with obstructive sleep apnoea. It has been demonstrated that elevated surface tension increases the pharyngeal pressures required to reopen the upper airway following collapse. The aim of the study was to evaluate the associations between the concentrations of endogenous surfactants in saliva with indices of upper airway patency in obstructive sleep apnoea. We studied 20 male patients with obstructive sleep apnoea (age: 60·3 ± 10·3 years; BMI: 25·9 ± 4·6 kg m(-2); AHI: 41·5 ± 18·6 events h(-1)). We obtained 100-µL samples of saliva prior to overnight polysomnographic sleep study. The surface tension was determined using the pull-off force technique. The concentration of phosphatidylcholine (PC) was evaluated by liquid chromatography-mass spectrometry (LC-MS/MS). Regression analysis between apnoea, hypopnoea and apnoea/hypopnoea indices and the ratio of hypopnoea time/total disordered breathing time (HT/DBT) with surface tension and PC were performed. P < 0·05 was considered significant. The mean saliva surface tension was 48·8 ± 8·0 mN m(-1) and PC concentration was 15·7 ± 11·1 nM. The surface tension was negatively correlated with the PC concentration (r = -0·48, P = 0·03). There was a significant positive correlation between surface tension with hypopnoea index (r = 0·50, P = 0·03) and HT/DBT (r = 0·6, P = 0·006), but not apnoea or apnoea/hypopnoea index (P > 0·11). Similarly, PC concentration negatively correlated with hypopnoea index (r = -0·45, P = 0·04) and HT/DBT (r = -0·6, P = 0·004), but not with apnoea index or AHI (P > 0·08). An increase in salivary PC concentration may increase upper airway patency in obstructive sleep apnoea through a reduction in surface tension.

Activation of OASIS family, ER stress transducers, is dependent on its stabilization.

Endoplasmic reticulum (ER) stress transducers transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins accumulate in the ER. BBF2 human homolog on chromosome 7 (BBF2H7) and old astrocyte specifically induced substance (OASIS), ER-resident transmembrane proteins, have recently been identified as novel ER stress transducers that have roles in chondrogenesis and osteogenesis, respectively. However, the molecular mechanisms that regulate the activation of BBF2H7 and OASIS under ER stress conditions remain unresolved. Here, we showed that BBF2H7 and OASIS are notably unstable proteins that are easily degraded via the ubiquitin-proteasome pathway under normal conditions. ER stress conditions enhanced the stability of BBF2H7 and OASIS, and promoted transcription of their target genes. HMG-CoA reductase degradation 1 (HRD1), an ER-resident E3 ubiquitin ligase, ubiquitinated BBF2H7 and OASIS under normal conditions, whereas ER stress conditions dissociated the interaction between HRD1 and BBF2H7 or OASIS. The stabilization of OASIS in Hrd1(-/-) cells enhanced the expression of collagen fibers during osteoblast differentiation, whereas a knockdown of OASIS in Hrd1(-/-) cells suppressed the production of collagen fibers. These findings suggest that ER stress stabilizes OASIS family members and this is a novel molecular mechanism for the activation of ER stress transducers.

Effect of endurance training supplemented with green tea extract on substrate metabolism during exercise in humans.

Endurance training and ingestion of green tea extract (GTE), composed mainly of tea catechins (TC), are well known to enhance fat metabolism. However, their synergistic effects remain to be fully elucidated. We tested the hypothesis that endurance training supplemented with GTE would further accelerate whole-body fat utilization during exercise, compared with training alone, in humans. Twelve healthy male subjects [peak oxygen consumption (VO2peak), 50.7 ± 1.3 (SEM) mL/kg/min] were divided into two groups: GTE and placebo (PLA) groups. Subjects in both groups performed a cycle ergometer exercise at 60% of VO2peak for 60 min/day, 3 days/week, and daily ingested 572.8 or 0 mg TC in GTE and PLA groups for 10 weeks, respectively. Before and after training, respiratory gas exchange was measured during 90-min exercise at pre-training ∼55% of VO2peak. After training, the average respiratory exchange ratio during exercise remained unchanged in the PLA group (post-training: 0.834 ± 0.008 vs pre-training: 0.841 ± 0.004), whereas it was lower in the GTE group (post-training: 0.816 ± 0.006 vs pre-training: 0.844 ± 0.005, P<0.05). These results suggest that habitual GTE ingestion, in combination with moderate-intense exercise, was beneficial to increase the proportion of whole-body fat utilization during exercise.

Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial.

BACKGROUND/OBJECTIVES: In spite of the much evidence for the beneficial effects of probiotics, their anti-obesity effects have not been well examined. We evaluated the effects of the probiotic Lactobacillus gasseri SBT2055 (LG2055) on abdominal adiposity, body weight and other body measures in adults with obese tendencies. SUBJECTS/METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled intervention trial. Subjects (n=87) with higher body mass index (BMI) (24.2-30.7 kg/m(2)) and abdominal visceral fat area (81.2-178.5 cm(2)) were randomly assigned to receive either fermented milk (FM) containing LG2055 (active FM; n=43) or FM without LG2055 (control FM; n=44), and were asked to consume 200 g/day of FM for 12 weeks. Abdominal fat area was determined by computed tomography. RESULTS: In the active FM group, abdominal visceral and subcutaneous fat areas significantly (P<0.01) decreased from baseline by an average of 4.6% (mean (confidence interval): -5.8 (-10.0, -1.7) cm(2)) and 3.3% (-7.4 (-11.6, -3.1) cm(2)), respectively. Body weight and other measures also decreased significantly (P<0.001) as follows: body weight, 1.4% (-1.1 (-1.5, -0.7) kg); BMI, 1.5% (-0.4 (-0.5, -0.2) kg/m(2)); waist, 1.8% (-1.7 (-2.1, -1.4) cm); hip, 1.5% (-1.5 (-1.8, -1.1) cm). In the control group, by contrast, none of these parameters decreased significantly. High-molecular weight adiponectin in serum increased significantly (P<0.01) in the active and control groups by 12.7% (0.17 (0.07, 0.26) microg/ml) and 13.6% (0.23 (0.07, 0.38) microg/ml), respectively. CONCLUSION: The probiotic LG2055 showed lowering effects on abdominal adiposity, body weight and other measures, suggesting its beneficial influence on metabolic disorders.

Induction of BiP, an ER-resident protein, prevents the neuronal death induced by transient forebrain ischemia in gerbil.

Endoplasmic reticulum (ER) stress, which is caused by the accumulation of unfolded proteins in the ER lumen, is associated with stroke and neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. We evaluated the effect of a selective inducer of immunoglobulin heavy chain binding protein (BiP) (BiP inducer X; BIX) against both tunicamycin-induced cell death (in SH-SY5Y cells) and the effects of global transient forebrain ischemia (in gerbils). BIX significantly induced BiP expression both in vitro and in vivo. Pretreatment with BIX at 2 or 5 microM reduced the cell death induced by tunicamycin in SH-SY5Y cells. In gerbils subjected to forebrain ischemia, prior treatment with BIX (intracerebroventricular injection at 10 or 40 microg) protected against cell death and decreased TUNEL-positive cells in the hippocampal CA1 subfield. These findings indicate that this selective inducer of BiP could be used to prevent the neuronal damage both in vitro and in vivo.

Involvement of endoplasmic reticulum stress in the neuronal death induced by transient forebrain ischemia in gerbil.

Endoplasmic reticulum (ER) stress, which is caused by an accumulation of unfolded proteins in the ER lumen, is associated with stroke and with neurodegenerative diseases such as Parkinson's and Alzheimer diseases. We assessed the expression patterns of immunoglobulin heavy chain binding protein (BiP)/glucose-regulated protein (GRP) 78 (an ER-resident molecular chaperone whose expression serves as a good marker of ER-stress), activating transcription factor (ATF)-4, and C/EBP homology protein (CHOP) by immunohistochemistry and/or Western blotting after transient forebrain ischemia in gerbils. Double-fluorescent staining involving CHOP immunohistochemistry and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling (TUNEL) method was performed to clarify the involvement of CHOP in cell death. Immunohistochemical and Western blot analyses of the hippocampal Cornet d'Ammon (CA)1 subfield showed that BiP expression was increased at 12 h, peaked at 3 days, then decreased (versus the control group). A transient increase was detected in CA3 at 1 day after ischemia, but BiP expression was unchanged in dentate gyrus and cortex. Signals for ATF-4 and CHOP were increased at 1 day and 3 days in CA1, and at 12 h in CA3. Co-localization of CHOP immunoreactivity and DNA fragmentation was detected by the TUNEL method at 3 days after ischemia in CA1, but not at 12 h in CA3. These findings are consistent with ER stress playing a pivotal role in post-ischemic neuronal death in the gerbil hippocampal CA1 subfield.

A molecular chaperone inducer protects neurons from ER stress.

The endoplasmic reticulum (ER) stress response is a defense system for dealing with the accumulation of unfolded proteins in the ER lumen. Recent reports have shown that ER stress is involved in the pathology of some neurodegenerative diseases and cerebral ischemia. In a screen for compounds that induce the ER-mediated chaperone BiP (immunoglobulin heavy-chain binding protein)/GRP78 (78 kDa glucose-regulated protein), we identified BiP inducer X (BIX). BIX preferentially induced BiP with slight inductions of GRP94 (94 kDa glucose-regulated protein), calreticulin, and C/EBP homologous protein. The induction of BiP mRNA by BIX was mediated by activation of ER stress response elements upstream of the BiP gene, through the ATF6 (activating transcription factor 6) pathway. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress. Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice. In the penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction in the number of apoptotic cells. Considering these results together, it appears that BIX induces BiP to prevent neuronal death by ER stress, suggesting that it may be a potential therapeutic agent for cerebral diseases caused by ER stress.

Branched-chain amino acids supplementation attenuates the accumulation of blood lactate dehydrogenase during distance running.

AIM: We investigated the effect of branched-chain amino acids (BCAA) supplementation on tissue damage during distance running. METHODS: Eight male distance runners (mean +/- standard deviation; age: 20.4+/-1.2 years, body weight: 58.4+/-4.2 kg) participated in a double blinded cross over designed study conducted during training camp. During each intervention period, the subjects were asked to participate in a 25-km run, and the blood BCAA and lactate dehydrogenase (LDH) level, an index of tissue damage, were measured pre- and post-run. Either a drink containing BCAA (0.4% BCAA in a 4% carbohydrate solution) or an iso-calorie placebo drink was provided to the subjects 5 times during the run without any restriction in the volume. RESULTS: The total volume of the drink consumed by the subjects did not differ substantially between the trials: 591+/-188 (2.36 g BCAA) vs 516+/-169 mL in BCAA and placebo trial, respectively. During the run, the blood BCAA concentration was maintained in the BCAA trial. However, the blood BCAA concentration level tended to decrease in the placebo trial (P<0.1). The extent of the blood LDH increase in the BCAA trial was significantly less than that of the placebo trail (48% vs 58%, P<0.05). CONCLUSION: Maintaining the blood BCAA level throughout a long distance run contributes to a reduction in the LDH release and, therefore, the effect of BCAA supplementation is suggested to reduce the degree of muscle damage.

Involvement of endoplasmic reticulum stress after middle cerebral artery occlusion in mice.

The endoplasmic reticulum (ER) plays an important role in ischemic neuronal cell death. ER stress-related markers [immunoglobulin binding protein (BiP)/glucose-regulated protein (GRP) 78, activating transcription factor-4 (ATF-4), and C/EBP-homologous protein (CHOP)] in the striatum and the cortex were investigated after permanent middle cerebral artery occlusion (MCAO) in mice. Using endoplasmic reticulum stress-activated indicator (ERAI) transgenic mice, which show splicing of X-box protein 1 (XBP-1) mRNA as green fluorescence, we monitored the regional changes in fluorescence after MCAO. BiP mRNA (by reverse-transcription polymerase chain reaction [RT-PCR] analysis) was increased in the cortex at 6 h. In immunohistochemical and/or Western blot analysis, the expressions of ER stress-related markers (BiP, ATF-4, and CHOP) were increased in the infarct region, more strongly in the cortex than in the striatum. ERAI fluorescence was observed in the ischemic area starting from 6 and 12 h, respectively, after MCAO, with the peaks at 1 day and the fluorescence co-localized with the 2,3,5-triphenyltetrazolium chloride (TTC)-visible extension of brain infarction. These findings suggest that permanent MCAO induces expression of ER-stress related genes mainly in the periphery of the MCA territory.

Endoplasmic reticulum stress response in dendrites of cultured primary neurons.

The endoplasmic reticulum (ER) is an organelle in which secretory and transmembrane proteins are folded or processed, and is susceptible to various stresses that provoke the accumulation of unfolded proteins in the ER lumen. Recently, ER stress has been reported to be linked to neuronal death in various neurodegenerative diseases. Neurons contain the ER not only in the soma, but also in the dendrites, thus presenting a different case to non-neuronal cells. The ER in the dendrites has potential functions in local protein synthesis and sorting of synthesized proteins to postsynaptic membranes. It raises the possibility that ER stress could occur locally in the dendrites. Here we showed that ER stress sensors, inositol-requiring 1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) exist in the ER of both soma and dendrites in primary mouse neurons, and that under ER stress conditions, GRP78/BiP and phosphorylated eIF2alpha are induced. Furthermore, XBP1 mRNA was localized in the proximal dendrites where IRE1 was rapidly phosphorylated in response to ER stress. These results indicate that the ER in dendrites could respond to ER stress and retain the capacity of protein quality control.

A phase II study of single-agent gefitinib as first-line therapy in patients with stage IV non-small-cell lung cancer.

The aim of this study was to evaluate the efficacy and tolerability of gefitinib ('IRESSA') in Japanese patients with previously untreated stage IV non-small-cell lung cancer (NSCLC). This was a multi-institutional phase II study. Thirty-four patients with previously untreated stage IV NSCLC were enrolled between May 2003 and September 2004. Gefitinib was administered orally 250 mg once a day and was continued until there was either disease progression or severe toxicity. Objective tumour response rate was 26.5% (95% confidence interval, 11.7-41.3%). Adverse events were generally mild (National Cancer Institute-Common Toxicity Criteria grade 1 or 2) and consisted mainly of skin rash, fatigue and liver dysfunction. No pulmonary toxicity was observed. The global health status revealed that there was no change in quality of life during the study. This study found that single-agent gefitinib is active and well tolerated in chemo-naive Japanese patients with advanced NSCLC.

Tonotopic and heterotopic projection systems in physiologically defined auditory cortex.

Combined physiological and connectional studies show significant non-topographic extrinsic projections to frequency-specific domains in the cat auditory cortex. These frequency-mismatched loci in the thalamus, ipsilateral cortex, and commissural system complement the predicted topographic and tonotopic projections. Two tonotopic areas, the primary auditory cortex (AI) and the anterior auditory field (AAF), were electrophysiologically characterized by their frequency organization. Next, either cholera toxin beta subunit or cholera toxin beta subunit gold conjugate was injected into frequency-matched locations in each area to reveal the projection pattern from the thalamus and cortex. Most retrograde labeling was found at tonotopically appropriate locations within a 1 mm-wide strip in the thalamus and a 2-3 mm-wide expanse of cortex (approximately 85%). However, approximately 13-30% of the neurons originated from frequency-mismatched locations far from their predicted positions in thalamic nuclei and cortical areas, respectively. We propose that these heterotopic projections satisfy at least three criteria that may be necessary to support the magnitude and character of plastic changes in physiological studies. First, they are found in the thalamus, ipsilateral and commissural cortex; since this reorganization could arise from any of these routes and may involve each, such projections ought to occur in them. Second, they originate from nuclei and areas with or without tonotopy; it is likely that plasticity is not exclusively shaped by spectral influences and not limited to cochleotopic regions. Finally, the projections are appropriate in magnitude and sign to plausibly support such rearrangements; given the rapidity of some aspects of plastic changes, they should be mediated by substantial existing connections. Alternative roles for these heterotopic projections are also considered.

Longitudinal growth and height velocity of Japanese children with Down's syndrome.

AIM: To determine the natural growth pattern of Japanese children with Down's syndrome. METHODS: Longitudinal height data of 85 patients (43 males, 42 females) from birth to final height were analyzed. Based on these data, semi-longitudinal standard growth curves and height velocity curves for Down's syndrome were drawn. RESULTS: The means +/- SD of final height of males and females with Down's syndrome were 153.2 +/- 5.6 and 141.9 +/- 4.2 cm, respectively. They were -3.0 SD and -2.8 SD for Japanese standards. Mean peak height velocities were 8.9 and 7.5 cm y(-1), and the ages at peak height velocity were 11.6 and 10.2 y for males and females, respectively. CONCLUSION: The mean height of patients with Down's syndrome was around -2 SD for normal children before puberty. Their pubertal growth spurt starts about 1 y earlier and their peak height velocity was about 1.3-1.4 cm shorter than for normal children.