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Biomedical subjects

C Schultz

Publications and source records attributed to C Schultz.

At least 73 records · Page 4Linked to original sources
PubMed2000

Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.

Paullones constitute a new family of benzazepinones with promising antitumoral properties. They were recently described as potent, ATP-competitive, inhibitors of the cell cycle regulating cyclin-dependent kinases (CDKs). We here report that paullones also act as very potent inhibitors of glycogen synthase kinase-3beta (GSK-3beta) (IC50: 4-80 nM) and the neuronal CDK5/p25 (IC50: 20-200 nM). These two enzymes are responsible for most of the hyperphosphorylation of the microtubule-binding protein tau, a feature observed in the brains of patients with Alzheimer's disease and other neurodegenerative 'taupathies'. Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK-3beta. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer's disease. Alsterpaullone also inhibits the CDK5/p25-dependent phosphorylation of DARPP-32 in mouse striatum slices in vitro. This dual specificity of paullones may turn these compounds into very useful tools for the study and possibly treatment of neurodegenerative and proliferative disorders.

Adenosine Triphosphate↗
PubMed2000

Filamentous tau pathology in nerve cells, astrocytes, and oligodendrocytes of aged baboons.

Intracellular filamentous inclusions containing abnormally phosphorylated tau protein are hallmarks of several human neurodegenerative disorders. This study reveals tau-positive cytoskeletal abnormalities in neurons and glial cells of aged baboons. The brains of four baboons (Papio hamadryas, 20-30 yr of age) were examined using the Gallyas silver technique for neurofibrillary changes and phosphorylation-dependent anti-tau antibodies (AT8, AT100, AT270, PHF-1, TG-3). Conspicuous changes were noted in two animals, 26 and 30 yr of age. In both animals, a combination of neuronal and glial cytoskeletal pathology was seen preferentially affecting limbic brain areas, including the hippocampal formation. In the 30-yr-old animal, numerous tau-positive inclusions were seen in the granule cells of the fascia dentata. These cells even exhibited an accumulation of argyrophilic neurofibrillary tangles. The glial changes affected both astrocytes and oligodendrocytes. Tau-positive astrocytes were seen in perivascular, subpial, and subependymal locations. Tau-positive oligodendrocytes preferentially occurred in limbic fiber tracts including the entorhinal perforant path. Ultrastructurally, tau-positive straight filaments (10-14 nm) in both neurons and glial cells were revealed by anti-tau immunoelectron microscopy. This study thus indicates the potential usefulness of aged baboons for experimental investigation of neuronal and glial filamentous tau pathology. This nonhuman primate species may provide valuable information pertinent to the broad spectrum of human tauopathies.

Aging↗
PubMed2000

Sequence of Abeta-protein deposition in the human medial temporal lobe.

The deposition of Abeta protein (Abeta) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Abeta-deposits occurring in the course of AD, as well as for the relationship between the development of Abeta-deposition and that of neurofibrillary pathology. In the first of 4 phases of beta-amyloidosis, diffuse non-neuritic plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-beta and pre-gamma, and fleecy amyloid deposits occur in the internal entorhinal layers pri-alpha, pri-beta, pri-gamma, and in CA1. In the third phase, Abeta-deposits emerge in the molecular layer of the fascia dentata, and band-like Abeta-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Abeta-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only plaques in CA4. Diffuse plaques evolve sporadically in the external entorhinal layer pre-alpha. Parallel to the evolution of beta-amyloidosis as represented by the 4 phases, neuritic plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Abeta and the presence of neurofibrillary tangles in neurons targeting the regions where neuritic plaques evolve. Each of the different types of Abeta-deposits, including neuritic plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of beta-amyloidosis. The 4 phases in the evolution of beta-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.

Adult↗
PubMed2000

Vulnerability of select neuronal types to Alzheimer's disease.

From a morphological perspective, Alzheimer's disease (AD) is primarily a degenerative disorder of the neuronal cytoskeleton involving lipofuscin-laden cortical projection neurons with long, thin, and sparsely myelinated axons. The neocortical primary fields, relatively small in extent but functionally sophisticated, exhibit an early and brief myelination cycle, whereas the much more expansive but relatively simply organized association areas undergo a late and prolonged myelination process. The greater the degree of myelination and the less intense the pigmentation, the more resistant a given projection neuron may be to oxidative stress as well as to the development of AD-related neurofibrillary changes and vice versa. The neurofibrillary pathology commences from those cortical areas that are less completely myelinated and gradually progresses to the most functionally developed cortical fields that display the highest degree of myelination, thereby reflecting a hierarchy in the susceptibility of diverse cortical areas to the evolution of the AD-associated cytoskeletal pathology.

Alzheimer Disease↗
PubMed2000

Maturational changes of lymphocyte surface antigens in human blood: comparison between fetuses, neonates and adults.

The objective of this study was to investigate the maturational changes of lymphocyte surface antigens during ontogeny from fetuses to adults using the proven whole blood lysis technique. Two-color flow cytometric analysis of lymphocyte surface markers was performed on 20 fetal blood samples obtained by cordocentesis, 70 cord blood and 30 adult blood samples. The leukocyte count and all T-cell subsets were highest in neonates compared to fetuses and declined into adulthood. In contrast, the percentage of CD2+ T cells (fetal blood 57% versus adult blood 82%; p </= 0.001), CD3+ T cells (fetal blood 52% versus adult blood 77%; p </= 0.001), CD4+ T cells (fetal blood 39% versus adult blood 50%; p </= 0.05) and CD8+ T cells (fetal blood 15% versus adult blood 24%; p </= 0.001) showed a significant increase from fetuses to adults. The absolute and relative amounts of B cells were highest in fetuses (fetal blood 547 x 10(6)/l, 18%) followed by a steady decline to adulthood (adult blood 243 x 10(6)/l, 13%; p </= 0.001). The discordance between the absolute and relative size of lymphocyte subpopulations emphasizes the consideration of both variables in the assessment of lymphocyte maturation. The presented data may contribute to a better knowledge of the maturation of the immune system.

Adult↗
PubMed2000

Prehospital and emergency department delays after acute stroke: the Genentech Stroke Presentation Survey.

BACKGROUND AND PURPOSE: Patient delays in seeking treatment for stroke and delays within the Emergency Department (ED) are major factors in the lack of use of thrombolytic therapy for stroke. The Genentech Stroke Presentation Survey was a multicentered prospective registry of patients with acute stroke. The study was designed to characterize prehospital delays and delays within the ED. METHODS: Patients with stroke symptoms presenting to 48 EDs participating in a clinical trial of acute stroke therapy were enrolled prospectively. A 1-page data form was completed from patient interviews and medical records. RESULTS: A total of 1207 subjects were entered into the study. Ninety-four percent of the 721 subjects with complete data had a diagnosis of stroke or transient ischemic attack, 13% were black, 50% were female, and 67% were aged >65 years. The median time from symptom onset to ED arrival was 2.6 (interquartile range 1.2 to 6.3) hours. The median time from ED arrival until CT scan completion was 1.1 (0.7 to 1.8) hours, and the total delay time (symptom onset until CT scan completion) had a median of 4.0 (2.3 to 8.3) hours. Patients who arrived by emergency medical services had significantly shorter prehospital delay times and times to CT scan. Age, race, sex, and educational level did not appear to affect prehospital delay times. CONCLUSIONS: Despite its limitations, this large geographically diverse study strongly suggests that the use of emergency medical services is an important modifiable determinant of delay time for the treatment of acute stroke.

Acute Disease↗
PubMed2000

Structure-based design modifications of the paullone molecular scaffold for cyclin-dependent kinase inhibition.

A congeneric series of paullones were characterized using a 3-D QSAR with cyclin-dependent kinase 1 (CDK1) inhibition data. A homology model of CDK1-cyclin B was developed from the crystal structure of CDK2-cyclin A, which subsequently served as the basis for the structure-based design. Paullones were docked into the ATP binding site of the CDK1-cylin B models and were optimized with molecular mechanics. Hydropathic analyses of the paullone-CDK1 complexes were performed after the atom types were assigned based on each ligand's electronic properties calculated from quantum mechanics. Hydropathic descriptors formed a significant multiple regression equation that predicts paullone IC50 data. The results indicate that the combination of hydropathic descriptors with molecular mechanics geometries are sufficient to design overt steric and chemical complementarity of the ligands. However, the electronic properties derived from quantum mechanics helped direct synthetic chemistry efforts to produce ligands that promote better charge transfer and strengthen hydrogen bonding as facilitated by resonance stabilization. Compounds with low affinity for CDK1 were poor charge acceptors and made less than ideal hydrogen bonding arrangements with the receptor. These considerations led to the prediction that structures such as 9-cyanopaullone would be considerably more potent than the parent compound, a finding supported by enzyme inhibition data. Also, 9-nitropaullone emerged as a paullone which also had similar potency in enzyme inhibition as well as a favorable anti-proliferative activity profile in living cells.

Cyclin-Dependent Kinases↗
PubMed1999

A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404.

PURPOSE: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. RESULTS: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem to be due to early deaths in the BUdR arm, not related to toxicity of the treatment. CONCLUSIONS: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be done for at least 3 more years.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity.

The paullones represent a novel class of small molecule cyclin-dependent kinase (CDK) inhibitors. To investigate structure-activity relationships and to develop paullones with antitumor activity, derivatives of the lead structure kenpaullone (9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, 4a) were synthesized. Paullones with different substituents in the 2-, 3-, 4-, 9-, and 11-positions were prepared by a Fischer indole reaction starting from 1H-[1]benzazepine-2,5(3H,4H)-diones 5. Selective substitutions at either the lactam or the indole nitrogen atom were accomplished by treating kenpaullone with alkyl halides in the presence of sodium hydride/THF or potassium hydroxide/acetone, respectively. S-Methylation of the kenpaullone-derived thiolactam 18 yielded the methylthioimidate 19, which gave the hydroxyamidine 20 upon reaction with hydroxylamine. The new paullones were tested both in a CDK1/cyclin B inhibition assay and in the in vitro antitumor cell line-screening program of the National Cancer Institute (NCI). With respect to the CDK1/cyclin B inhibition, electron-withdrawing substituents in the 9-position as well as a 2,3-dimethoxy substitution on the paullone basic scaffold turned out to be favorable. A 9-trifluoromethyl substituent was found to be equivalent to the 9-bromo substituent of kenpaullone. Replacement of the 9-bromo substituent of kenpaullone by a 9-cyano or 9-nitro group produced a substantial increase in enzyme-inhibiting potency. Substitutions in other positions or the replacement of the lactam moiety led to decreased CDK1 inhibition. Noteworthy in vitro antitumor activities (GI(50) values between 1 and 10 microM) were found with the 9-bromo-2,3-dimethoxy-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4t), its 9-trifluoromethyl analogue 4u, the 12-Boc-substituted paullone15, and the methylthioimidate 19, respectively. The 9-nitro-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4j, named alsterpaullone) showed a high CDK1/cyclin B inhibitory activity (IC(50) = 0.035 microM) and exceeded the in vitro antitumor potency of the other paullones by 1 order of magnitude (log GI(50) mean graph midpoint = -6.4 M).

Animals↗
PubMed1999

Inositol 1,3,4-trisphosphate acts in vivo as a specific regulator of cellular signaling by inositol 3,4,5,6-tetrakisphosphate.

Ca2+-activated Cl- channels are inhibited by inositol 3,4,5, 6-tetrakisphosphate (Ins(3,4,5,6)P4) (Xie, W., Kaetzel, M. A., Bruzik, K. S., Dedman, J. R., Shears, S. B., and Nelson, D. J. (1996) J. Biol. Chem. 271, 14092-14097), a novel second messenger that is formed after stimulus-dependent activation of phospholipase C (PLC). In this study, we show that inositol 1,3,4-trisphosphate (Ins(1,3,4)P3) is the specific signal that ties increased cellular levels of Ins(3,4,5,6)P4 to changes in PLC activity. We first demonstrated that Ins(1,3,4)P3 inhibited Ins(3,4,5,6)P4 1-kinase activity that was either (i) in lysates of AR4-2J pancreatoma cells or (ii) purified 22,500-fold (yield = 13%) from bovine aorta. Next, we incubated [3H]inositol-labeled AR4-2J cells with cell permeant and non-radiolabeled 2,5,6-tri-O-butyryl-myo-inositol 1,3, 4-trisphosphate-hexakis(acetoxymethyl) ester. This treatment increased cellular levels of Ins(1,3,4)P3 2.7-fold, while [3H]Ins(3, 4,5,6)P4 levels increased 2-fold; there were no changes to levels of other 3H-labeled inositol phosphates. This experiment provides the first direct evidence that levels of Ins(3,4,5,6)P4 are regulated by Ins(1,3,4)P3 in vivo, independently of Ins(1,3,4)P3 being metabolized to Ins(3,4,5,6)P4. In addition, we found that the Ins(1, 3,4)P3 metabolites, namely Ins(1,3)P2 and Ins(3,4)P2, were >100-fold weaker inhibitors of the 1-kinase compared with Ins(1,3,4)P3 itself (IC50 = 0.17 microM). This result shows that dephosphorylation of Ins(1,3,4)P3 in vivo is an efficient mechanism to "switch-off" the cellular regulation of Ins(3,4,5,6)P4 levels that comes from Ins(1,3, 4)P3-mediated inhibition of the 1-kinase. We also found that Ins(1,3, 6)P3 and Ins(1,4,6)P3 were poor inhibitors of the 1-kinase (IC50 = 17 and >30 microM, respectively). The non-physiological trisphosphates, D/L-Ins(1,2,4)P3, inhibited 1-kinase relatively potently (IC50 = 0.7 microM), thereby suggesting a new strategy for the rational design of therapeutically useful kinase inhibitors. Overall, our data provide new information to support the idea that Ins(1,3,4)P3 acts in an important signaling cascade.

Animals↗
PubMed1999

Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission.

We describe two additional instances of atelosteogenesis, type III, in a woman and her son. Clinical and radiographic information concerning these individuals allows further definition of this rare skeletal dysplasia. This is the first documentation of survival to adulthood of an individual with this disorder, of prenatal diagnostic assessment of an affected individual, and of vertical transmission suggestive of autosomal dominant inheritance. The clinical and radiologic phenotype of atelosteogenesis, type III overlaps with that of another skeletal dysplasia, autosomal dominant Larsen syndrome; these most likely represent allelic conditions.

Adult↗
PubMed1999

Sex-dependent cytoskeletal changes of the human hypothalamus develop independently of Alzheimer's disease.

This study examines a sex-dependent variant of neurofibrillary pathology recently identified in the hypothalamus of elderly human males. Here we focus upon the relationship between the sex-dependent hypothalamic changes and Alzheimer's disease (AD)-related neurofibrillary pathology. To this end, autopsy brains of 31 males (mean age 84.1 years) and 26 age-matched females (mean age 86.7 years) were examined. Both the male and the female subjects exhibited either particularly mild (stage I) or fully developed (stage V) AD-related neurofibrillary brain pathology. Serial 100-micron hypothalamic sections were cut in the frontal plane and stained for hyperphosphorylated tau protein using the monoclonal antibody AT8. Argyrophilic neurofibrillary pathology was demonstrated using a modified Gallyas silver-iodide technique. A conspicuous pathology, characterized by neurofibrillary tangles, a network of dystrophic neurites, and terminal-like vessel-associated processes, was identified in the infundibular nucleus which is located in the mediobasal tuber cinereum. This pathology was noted in 20 males (64.5%), but did not occur in the female group. No statistically significant correlation was noted between the degree of sex-dependent pathology and the presence of AD-related cortical pathology. In particular, the expression of the sex-dependent changes did not differ between males with AD stage I and males with AD stage V. In summary, the existence of a sex-dependent variant of neurofibrillary pathology was confirmed. In addition, our findings strongly suggest that the sex-dependent changes develop independently of the neurofibrillary changes associated with senile dementia of the Alzheimer type. Instead, the sex-dependent hypothalamic pathology probably corresponds to a distinct neurodegenerative entity preferentially affecting elderly males.

Aged↗
PubMed1999

Intussusception in preterm infants: case report and literature review.

UNLABELLED: Intussusception is an extremely rare disorder in preterm infants. An infant of 29 weeks gestational age with this condition is reported and a retrospective analysis of 17 previously reported cases presented. In the reviewed preterm infants, risk factors for intussusception seemed to be multifactorial. Clinical features included severe abdominal distension (17/17), gastric aspirates (13/17), commonly bilious, bloody stools (10/17) and rarely a palpable abdominal mass (5/17). Diagnostic features were signs of small bowel obstruction on the abdominal radiographs. Signs and symptoms were similar to those seen in necrotizing enterocolitis, therefore difficulties in establishing a correct diagnosis led to an average delay of 7 days between the onset of symptoms and abdominal surgery, increasing the risk of developing a compromised bowel. CONCLUSION: The differential diagnosis of an intussusception should be considered in preterm infants with acute abdominal distension and tenderness.

Diagnosis, Differential↗
PubMed1999

Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival.

Increased apoptosis in the bone marrow (BM) may contribute to the cytopenias that occur in myelodysplastic syndromes (MDS). The Fas receptor, Fas ligand (FasL) pathway is a major mechanism of apoptosis. Since hematopoietic progenitors can express the Fas receptor, they may be susceptible to apoptosis induced by FasL-expressing cells. We examined FasL expression in the BM of patients with MDS (n = 50), de novo acute myeloid leukemia (AML; n = 10), AML following prior MDS (n = 6), and normal controls (n = 6). Compared to controls, FasL expression was increased in MDS, and was highest in AML. In MDS, FasL expression was seen in myeloid blasts, erythroblasts, maturing myeloid cells, megakaryocytes and dysplastic cells, whereas in AML, intense expression was seen in the blasts. FasL expression correlated with the FAB subtype groups of MDS, and also correlated directly with the percentage of abnormal metaphases on cytogenetic analysis. The FasL expressed in MDS BM inhibited the growth of clonogenic hematopoietic progenitors. This inhibition could be blocked by a soluble recombinant FasFc protein. In MDS, FasL expression in the initial diagnostic BM was higher in patients who were more anemic, correlated directly with red cell transfusion requirements over the subsequent course of the disease, and was predictive of survival. These studies indicate that FasL expression in MDS is of prognostic significance, and suggest that pharmacological blockade of the Fas-FasL pathway may be of clinical benefit.

Acute Disease↗
PubMed1999

Glycaemic control and familial factors determine hyperlipidaemia in early childhood diabetes. Oxford Regional Prospective Study of Childhood Diabetes.

AIMS: To determine whether abnormal lipid levels in children with Type 1 diabetes mellitus are the result of poor metabolic control or may in part be determined by genetic factors. METHODS: Non-fasting lipid levels were measured in 141 children with Type 1 diabetes (age range 7.7-19 years) 3 years after diagnosis, and in 192 of their parents. Glycosylated haemoglobin and the urinary albumin-creatinine ratio (three urine samples) were estimated in each child annually. RESULTS: The children had a mean total cholesterol of 4.46 +/- 1.25 mmol/l (+/- SD) and a median triacylglycerol of 1.18 mmol/l (range 0.32-4.7). A total of 15.3% of the population had a total cholesterol > 5.2 mmol/l and 17.9% had a triacylglycerol > 1.7 mmol/l; in 5.6% both total cholesterol and triacylglycerol were greater than these cut-off points. Total cholesterol, triacylglycerol and very low density lipoprotein-cholesterol were significantly correlated to glycaemic control. However, total cholesterol was also significantly related to parental total cholesterol either as analysed separately or as mean parental total cholesterol (r = 0.37, P = 0.0001). In stepwise multiple regression analysis both mean parental total cholesterol (P = 0.001) and HbA1c (P = 0.015) were significant determinants of the child's total cholesterol. The children studied were being followed prospectively for the development of microalbuminuria and there was a weak association across tertiles of total cholesterol, linking higher levels to the development of microalbuminuria (P < 0.05). CONCLUSIONS: We conclude that both glycaemic control and familial factors may be important determinants of lipid levels in young people with diabetes. Both may contribute to the subsequent risk of cardiovascular disease and possibly the development of incipient diabetic nephropathy.

Adolescent↗
PubMed1999

Bone growth from 11 to 17 years: relationship to growth, gender and changes with pubertal status including timing of menarche.

The tempo and change in bone growth during puberty in relation to physical growth is described in a cohort of 56 boys and 52 girls. Distal forearm bone width, mineral content and volumetric density, anthropometry and pubertal status were measured at ages 11, 13, 15 and 17 y, and bone age at 17 y. Bone width and mineral content increased independently with age for each pubertal stage. Volumetric density fell during early puberty and then increased rapidly. Maximal increase of all bone variables occurred earlier in girls than in boys and earliest for bone width, then mineral content, then density. In girls most change occurred in the 12 mo before and after menarche. The degree of tracking was similar to that for height. Bone growth followed physical growth but at a slower tempo. By age 17 y boys had attained 86% of the reference adult bone mineral content and volumetric density; girls had attained 93% of the reference adult bone mineral content and 94% of volumetric density. Those skeletally mature at 17 y had greater mineral content and volumetric density. To maximize peak bone mass, modifiable environmental factors should be optimized before the onset of puberty and be maintained throughout this period of rapid growth and beyond attainment of sexual maturity.

Adolescent↗
PubMed1999

Familial and environmental influences on bone growth from 11-17 years.

The influences on bone growth of familial factors, nutrition and physical activity are described in a cohort of 108 children (56M, 52F). Distal forearm bone width, mineral content and volumetric density, anthropometry, pubertal status, nutritional intake and physical activity were measured at ages 11, 13, 15 and 17 y. Parental forearm bone status was also determined. Both mothers' and fathers' bone variables were significant predictors of the respective children's bone variables, but heritability estimates were greater between mothers and their children than between fathers and their children. By age 17 y boys had attained 101%, 85% and 89% of their fathers' height, bone mineral content and volumetric density, respectively; girls had attained 103%, 95% and 98% of their mothers' height, bone mineral content and volumetric density, respectively. There were no consistent associations among nutrient variables and bone status or rate of change in bone status. However, there was a significantly greater increase in bone mineral content and density from 11-17 y in those girls with consistently high calcium intake. There were no significant correlations between physical activity and bone values or rate of change of bone values. Age, gender, pubertal status, height, weight and parental bone values accounted for 80%, 71% and 49% of the variance of bone mineral content, bone width and volumetric density, respectively and 52%, 55% and 58% respectively of the variance of change in these variables. After age, gender, sexual maturity and body size, heritability accounts for the greatest variance in bone values through adolescence.

Adolescent↗