Divergent clinical and neuropathological phenotype in a Gerstmann-Sträussler-Scheinker P102L family.

OBJECTIVES: Gerstmann-Sträussler-Scheinker syndrome belongs to the genetic prion diseases being associated with mutations in the prion protein gene (PRNP). The most common is the point mutation at codon 102, leading to the substitution of proline to leucine (P102L). Previous reports have indicated a phenotypic heterogeneity among individuals with this mutation. Here, we describe the clinical and pathological phenotype in members of the first Finnish kindred with the P102L mutation in the PNRP gene. MATERIALS AND METHODS: Genetic and clinical information was available in five members of a family, while a systematic histologic and immunohistochemical assessment of the post-mortem brain was carried out in three. RESULTS: Clinical presentation, disease duration and the clinical phenotype (ataxia vs dementia) varied between patients. There was a significant correlation between clinical symptoms and the neuroanatomical distribution of prion protein-immunoreactive aggregates, i.e. subtentorial predominance in ataxia vs cortical predominance in dementia. A significant concomitant Alzheimer is disease-related pathology was observed in the brain of one patient with dementia as onset symptom. CONCLUSIONS: This is the first Scandinavian family carrying the P102L mutation in the PRNP gene. Gerstmann-Sträussler-Scheinker syndrome should be considered in the differential diagnosis when handling with patients with ataxia and/or dementia of unclear aetiology.

Interpositional Arthroplasty of the First Metatarsophalangeal Joint with Bioresorbable Pldla Implant in the Treatment of Hallux Rigidus and Arthritic Hallux Valgus: A 9-Year Case Series Follow-Up.

BACKGROUND AND AIMS: The interpositional arthroplasty was developed to retain foot function and to relieve pain due to the arthritis of the first metatarsophalangeal joint. The bioabsorbable poly-L-D-lactic acid RegJoint® interpositional implant provides temporary support to the joint, and the implant is subsequently replaced by the patient's own tissue. In this study, we retrospectively examined the results of the poly-L-D-lactic acid interpositional arthroplasty in a 9-year follow-up study among patients with hallux valgus with end-stage arthrosis or hallux rigidus. MATERIAL AND METHODS: Eighteen patients and 21 joints underwent interpositional arthroplasty using the poly-L-D-lactic acid implant between February 1997 and October 2002 at Tampere University Hospital. Of these, 15 (83.3%) (21 joints) patients were compliant with clinical examination and radiographic examination in long-term (average 9.4 years) follow-up. The mean age of the patients was 48.3 (from 28 to 67) years at the time of the operation. Six patients underwent the operation due to arthritic hallux valgus and nine patients due to hallux rigidus. RESULTS: The mean Ankle Society Hallux Metatarsophalangeal-Interphalangeal Scale and visual analogue scale (VAS) for pain scores improved after the operation in all patients. The decrease of pain (visual analogue scale) after the operation was statistically significant (77.5 vs 10.0; p < 0.001). Postoperative complications were observed in 3 (14.3%) joints of two hallux rigidus patients. For these patients, surgery had only temporarily relieved the pain, and they underwent reoperation with arthrodesis. CONCLUSION: In conclusion, interpositional arthroplasty using a poly-L-D-lactic acid implant yielded good results. This study indicates that the poly-L-D-lactic acid interpositional implant may be a good alternative for arthrodesis for treatment of end-stage degeneration of the first metatarsophalangeal joint.

Exogenous sex hormone use and risk of meningioma: a population-based case-control study in Finland.

BACKGROUND: Previous studies on association of exogenous female sex hormones and risk for meningioma have yielded conflicting results. The aim of this study was to evaluate the potential relation between prior use of menopausal hormone therapy or oral contraception and risk of meningioma. METHODS: This population-based case-control study was conducted during years 2000-2002 in Finland. All women aged 20-69 years with meningioma diagnosis were identified from five university hospitals, and frequency-matched controls were randomly chosen from population register. A total of 264 cases and 505 controls were interviewed on their use of menopausal hormone therapy, oral and other contraception, fertility treatment, treatment for gynecological problems, age at menarche, and number of children. We also analyzed separately tumors expressing progesterone or estrogen receptors. Of the successfully stained tumor specimens, 86.3% were positive for progesterone receptor and 50% for estrogen receptor. RESULTS: Postmenopausal hormonal treatment, use of contraceptives, or fertility treatment did not influence the risk of meningioma. In further analysis by hormone receptor status, there was some indication for an increased risk of progesterone receptor-positive meningiomas associated with oral contraceptive use (OR 1.39, 95% confidence interval 0.92-2.10) and other hormonal contraception (OR 1.50, 95% CI 0.95-2.36). CONCLUSIONS: Overall, we found little indication that reproductive factors or use of exogenous sex hormones affect meningioma risk.

Expression of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins in human ependymoma relates to tumor location, WHO grade, and patient age.

Three human leucine-rich repeats and immunoglobulin-like domains (LRIG1-3) genes and proteins have recently been characterized. LRIG1 has been shown to be a suppressor of tumor growth by counteracting the signaling of epidermal growth factor receptor (EGFR) family members, including EGFR (ERBB1). Expression of LRIG proteins seems to be of importance in the pathogenesis of astrocytic tumors. In this study, the expression of LRIG1-3 was evaluated in 51 human ependymomas by immunohistochemistry. LRIG proteins were detected in all ependymomas analyzed, however, with a pronounced heterogeneity in expression and subcellular localization. Higher cytoplasmic immunoreactivity of LRIG1 correlated with older patient age and higher LRIG1 nuclear immunoreactivity with lower WHO Grade. LRIG1 displayed a stronger immunoreactivity in the cytoplasm and nuclei in spinal ependymomas than in the posterior fossa or supratentorial ependymomas, while perinuclear LRIG3 was more highly expressed in supratentorial than in infratentorial ependymomas. The indications that expression and subcellular localization of LRIG proteins could be pathogenetically associated with specific clinicopathological features of ependymoma tumors might be of importance in the carcinogeneses and tumor progression of human ependymomas.

Is the incidence of meningiomas underestimated? A regional survey.

We assessed the undercount of meningiomas in a population-based cancer registry. A comprehensive material was formed by compiling hospital sources with the Finnish Cancer Registry database. The completeness of each source ranged 62-69%. The corrected age-standardised meningioma incidence was 2.9/100,000 for men and 13.0/100,000 for women, a third higher than the cancer registry figures.

Stem cell protein BMI-1 is an independent marker for poor prognosis in oligodendroglial tumours.

AIMS: The polycomb factor BMI-1 has recently been implicated in tumorigenesis of the central nervous system in several experimental animal models. However, the significance of BMI-1 in human glioma has not been investigated. Here we describe expression of the polycomb protein BMI-1 and its downstream targets p16(Ink4a) and MDM2 in both high- and low-grade human glioma. METHODS: Tumour samples were collected from 305 adult patients treated for primary grades 2-4 gliomas between 1980 and 2006 in Finland and Germany. BMI-1, p16 and MDM2 expression was evaluated using immunohistochemistry in representative paraffin-embedded tumour tissue. The significance of observed immunoreactivity, age at onset, gender, histopathological findings and proliferative index was analysed in univariate and multivariate survival models. RESULTS: BMI-1 was expressed in all histologic types of diffuse gliomas. We found a significant correlation (P = 0.007) between the frequency of BMI-1 immunoreactive tumour cells and poor survival in World Health Organization grades II-III oligodendrogliomas and oligoastrocytomas (n = 62). The median survival of patients grouped by low, intermediate or high frequency of BMI-1 immunoreactive tumour cells was 191 months, 151 months and 68 months, respectively. This association was also significant in the Cox multivariate regression model. Nuclear p16 immunopositivity predicted better survival in astrocytomas and an inverse correlation between p16 expression and the Ki-67 mitotic index was also observed. CONCLUSIONS: BMI-1 is found in all histological types of gliomas and the relative protein expression of BMI-1 is a novel independent prognostic marker in oligodendroglial tumours.

Peroxiredoxins and antioxidant enzymes in pilocytic astrocytomas.

OBJECTIVE: Peroxiredoxins are antioxidant enzymes (AOEs), which are redox-regulated thiol proteins with potential effects on the growth, invasion and drug resistance of neoplastic cells. In this study, their biology and clinical significance were examined in pilocytic astrocytomas (PAs). MATERIAL AND METHODS: The expression of peroxiredoxins (Prx I-VI) was investigated in 105 PAs by the means of immunohistochemistry and compared with the expression of selected other antioxidant enzymes, cell proliferation, angiogenesis, apoptosis, p53, histopathology and patient survival. RESULTS: Peroxiredoxins were strongly expressed in general suggesting that oxidative damage and consequent defense takes place during the progression of pilocytic astrocytomas. In agreement with this hypothesis, several other AOEs correlated with the degenerative features and angiogenesis possibly associated with reactive oxygen species-derived cellular damage. Moreover, the expression of the AOEs was associated with each other indicating a concurrent activation of the enzymes. With the exception of manganese superoxide dismutase (MnSOD), a strong expression of AOEs was generally associated with higher cell proliferation. Prx VI seemed to have a positive association with a longer recurrence-free interval while other AOEs had no association with patient survival. Many AOEs, such as MnSOD, induce chemo- and radioresistance and are highly elevated in aggressive malignancies. PAs lack this confounding factor, and these tumors are treated only by surgery. CONCLUSIONS: Taken together, the results of this study on pilocytic astrocytomas suggest that the levels of Prxs and other AOEs and their related thiol proteins are generally strongly expressed in these tumors. At least Prx VI can contribute to tumor behavior which can make it a potential prognostic factor.

Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: relationship to cell proliferation.

The expression of peripheral-type benzodiazepine receptor (PBR) and diazepam binding inhibitor (DBI) were studied in human astrocytic tumors using immunocytochemistry and in situ hybridization. Both PBR and DBI were prominently expressed in neoplastic cells, whereas in normal brain their amount was low or undetectable. Immunocytochemical double staining demonstrated that PBR and DBI were present in the same cells, suggesting that DBI may act in an autocrine manner in these cells. Analysis of 86 cases showed that PBR expression was statistically significantly associated with tumor malignancy grade (P = 0.004) and the proliferative index as determined by immunocytochemistry with the MIB-1 antibody (P = 0.004). Patients having tumors with high levels of PBR-immunoreactive cells had a shorter life expectancy than patients whose tumors showed lower PBR contents (P = 0.024). In conclusion, these results show that PBR expression is higher in neoplastic cells than in normal brain tissue. They also suggest that PBR immunocytochemistry might be useful in evaluating malignancy in brain tumors.

Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques.

New genomic large-scale screening techniques have made the task of establishing an accurate molecular fingerprint of cancer cells feasible. Here, we have used a two-phase strategy for identification of molecular alterations in gliomas. First, cDNA microarrays (Clontech Laboratories, Inc., Research Genetics) were used to pinpoint differentially expressed genes between normal brain and diffuse astrocytomas (grades II-IV), and between a primary tumor and a later tumor reoccurrence in the same patient. More than 200 gene expression alterations were detected from glioblastomas, whereas relatively few changes were seen in grade II and grade III tumors. The most distinct progression-related expression change was the up-regulation of the insulin-like growth factor binding protein 2 (IGFBP2) gene. Second, a high-density tissue microarray of 418 brain tumors was constructed and used for clinical validation of gene expression changes. Strong expression of IGFBP2 was associated with progression and poor patient survival in diffuse astrocytomas (P < 0.0001). Third, comparisons of the data between (a) multiple spots retrieved from one predefined tumor region (IGFBP2 and vimentin immunohistochemistry, 20 tumors) or between (b) standard slides and arrayed tissues (p53 immunohistochemistry, 42 tumors) revealed very little variation. In conclusion, the combined use of DNA microarrays and tissue microarrays offers a powerful strategy for rapid identification and thorough characterization of differentially expressed genes in gliomas.

IGFBP2 potentiates nuclear EGFR-STAT3 signaling.

Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the tumor-promoting mechanisms of IGFBP2 are poorly understood. The contributions of intracellular IGFBP2 to tumor development and progression are also unclear. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of epidermal growth factor receptor (EGFR), which subsequently activates signal transducer and activator of transcription factor 3 (STAT3) signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via activation of the nuclear EGFR signaling pathway. Nuclear IGFBP2 directly influences the invasive and migratory capacities of human glioblastoma cells, providing a direct link between intracellular (and particularly nuclear) IGFBP2 and cancer hallmarks. These activities are also consistent with the strong association between IGFBP2 and STAT3-activated genes derived from The Cancer Genome Atlas database for human glioma. A high level of all three proteins (IGFBP2, EGFR and STAT3) was strongly correlated with poorer survival in an independent patient data set. These results identify a novel tumor-promoting function for IGFBP2 of activating EGFR/STAT3 signaling and facilitating EGFR accumulation in the nucleus, thereby deregulating EGFR signaling by two distinct mechanisms. As targeting EGFR in glioma has been relatively unsuccessful, this study suggests that IGFBP2 may be a novel therapeutic target.

p53 expression and cell proliferation as prognostic factors in laryngeal squamous cell carcinoma.

PURPOSE: To investigate the prognostic significance of p53 expression and proliferation markers in primary laryngeal squamous cell carcinoma. PATIENTS AND METHODS: Primary tumors for analyses were obtained from 103 patients, with complete follow-up data. All patients were treated between the years 1975 and 1990. The expression of p53 was analyzed with monoclonal D07 antibody and proliferative activity with Ki-67 (MIB-1) and PCNA (monoclonal 19A2) antibodies. Volume corrected mitotic (M/V) index and histological grade were determined in hematoxylin and cosin-stained slides. RESULTS: Sixty-eight percent of the tumors overexpressed p53. During a median follow-up of 62 months, 41 (40%) of patients relapsed. In univariate analysis site of the primary tumor, stage, p53 expression, histologic grade, and M/V index were significant predictors of disease-free survival. In multivariate analysis, only M/V index was a statistically significant predictor of disease-free survival. Overall survival was significantly better for those overexpressing p53 (10-year cumulative survival rate 68% v 44%, P = .004). In multivariate analysis, M/ V index (P = .02), p53 (P = .02), and stage (P = .007) were statistically significant predictors of overall survival. When this analysis includes stratification according to the type of treatment received, M/V index (P = .007), stage (P = .0002), and p53 (P = .006) were even more significant predictors of overall survival. No association between p53 status and proliferative activity was found. CONCLUSION: Overexpression of p53 is associated with favorable disease-free and overall survival in laryngeal squamous cell carcinoma. It may also have an independent prognostic value in laryngeal cancer. M/V index, p53 overexpression, and stage predict with significant accuracy the 10-year overall survival.

Ultrarapid Ki-67 immunostaining in frozen section interpretation of gliomas.

BACKGROUND: Astrocytic tumours, the most common gliomas, are often classified intraoperatively using standard morphological staining. The final diagnosis and grading of gliomas on paraffin wax sections is often assisted by Ki-67 immunohistochemistry, but standard immunostaining protocols take too long to be used intraoperatively. AIMS: To investigate a new rapid Ki-67 immunohistochemical test for its use in an intraoperative setting. METHODS: The new Ki-67 immunostaining (Ultrarapid-Ki67) method on frozen sections can be carried out in 10 minutes. Thirty four pilocytic and diffuse astrocytomas were immunostained by rapid Ki-67 and results were compared with corresponding MIB-1 staining, histological grading, and prognosis. RESULTS: The staining protocol was practical to perform and the results were morphologically and quantitatively indistinguishable from those after immunostaining with MIB-1, an antibody recognising Ki-67 in paraffin wax embedded tissue. A comparison of Ultrarapid-Ki67 and MIB-1 immunostaining of paraffin wax sections showed almost identical quantitative correlation in astrocytic gliomas (r = 0.916; p<0.001). The Ultrarapid-Ki67 indices (percentage of positive cells) of low grade (I/II) astrocytomas ranged from 0% to 6.1%, whereas those of representative high grade (III/IV) tumours were significantly higher (range, 5.6-45%; p<0.001). The best prognostic cutoff point for Ultrarapid-Ki67 was 7.5%, which divided diffuse grade II-IV astrocytomas into significantly differing subsets (p = 0.0008). CONCLUSION: Ultrarapid-Ki67 immunostaining is a useful adjunct to morphological diagnosis and grading of astrocytic tumours, and as a fast test (approximately 10 minutes for staining plus three to four minutes for scoring), it could be used in routine intraoperative diagnosis of gliomas and other neoplastic diseases.

No GIST-type c-kit gain of function mutations in neuroblastic tumours.

AIMS: Neuroblastic tumours (NTs) have been shown to respond to imatinib treatment in vivo and in vitro, possibly via inactivating the c-kit receptor. The purpose of this study was to identify gastrointestinal stromal tumour (GIST)-type c-kit gene associated mutations in exons 9, 11, 13, and 17 in NTs to recognise a subset of tumours that would probably respond to imatinib treatment. METHODS: Expression of the c-kit protein was detected immunohistochemically in a total of 37 archival paraffin wax embedded NTs using polyclonal rabbit antihuman c-kit antibody. After immunohistochemistry, c-kit gene associated chromosomal mutations in all cases of NT were detected with denaturing high performance liquid chromatography (HPLC). RESULTS: Denaturing HLPC analysis did not reveal GIST-type mutations in four immunohistochemically detected c-kit positive or in 33 c-kit negative NTs. CONCLUSIONS: c-kit receptor expression and GIST-type c-kit gene mutations are rare events in NTs. Oncogenic activation of c-kit in NTs presumably differs from that of GISTs, which may influence their responsiveness to imatinib treatment. Whether c-kit has an essential role in the pathogenesis of NTs remains to be investigated.

The p38-MK2-HuR pathway potentiates EGFRvIII-IL-1ß-driven IL-6 secretion in glioblastoma cells.

The microenvironment of glioblastoma (GBM) contains high levels of inflammatory cytokine interleukin 6 (IL-6), which contributes to promote tumour progression and invasion. The common epidermal growth factor receptor variant III (EGFRvIII) mutation in GBM is associated with significantly higher levels of IL-6. Furthermore, elevated IL-1ß levels in GBM tumours are also believed to activate GBM cells and enhance IL-6 production. However, the crosstalk between these intrinsic and extrinsic factors within the oncogene-microenvironment of GBM causing overproduction of IL-6 is poorly understood. Here, we show that EGFRvIII potentiates IL-1ß-induced IL-6 secretion from GBM cells. Importantly, exacerbation of IL-6 production is most effectively attenuated in EGFRvIII-expressing GBM cells with inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) and MAPK-activated protein kinase 2 (MK2). Enhanced IL-6 production and increased sensitivity toward pharmacological p38 MAPK and MK2 inhibitors in EGFRvIII-expressing GBM cells is associated with increased MK2-dependent nuclear-cytoplasmic shuttling and accumulation of human antigen R (HuR), an IL-6 mRNA-stabilising protein, in the cytosol. IL-1ß-stimulated activation of the p38 MAPK-MK2-HuR pathway significantly enhances IL-6 mRNA stability in GBM cells carrying EGFRvIII. Further supporting a role for the p38 MAPK-MK2-HuR pathway in the development of inflammatory environment in GBM, activated MK2 is found in more than 50% of investigated GBM tissues and correlates with lower grade and secondary GBMs. Taken together, p38 MAPK-MK2-HuR signalling may enhance the potential of intrinsic (EGFRvIII) and extrinsic (IL-1ß) factors to develop an inflammatory GBM environment. Hence, further improvement of brain-permeable and anti-inflammatory inhibitors targeting p38 MAPK, MK2 and HuR may combat progression of lower grade gliomas into aggressive GBMs.

Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia.

OBJECTIVE: To relate the expression of HIV regulatory proteins and HIV-specific mRNA in the brain cells of infected individuals with clinical neurological disease. DESIGN: Formalin-fixed postmortem brain tissue from 14 HIV-infected adult patients, with previous repeated neurological and neuroradiological examinations, was studied by immunohistochemical and molecular biological methods. Samples from non-infected brains served as controls. METHODS: Immunohistochemistry with monoclonal antibodies (MAb) was combined with in situ RNA hybridization. Target cells were identified with MAb to glial fibrillary acidic protein (GFAP; astrocytes), CD68 (activated macrophages) and Ricinus communis agglutinin (RCA-1; microglia, endothelial cells). For HIV, a panel of MAb against HIV Nef, Tat, Rev and Env proteins or probes specific for all classes of mRNA (nef), for singly or non-spliced mRNA (env) and for non-spliced mRNA (gag/pol) were used. RESULTS: Nef protein was detected in subcortical or subpial astrocytes in seven out of 14 samples, and in multinucleated giant cells in two cases. Gag/pol or env mRNA-expressing astrocytes were detected in four cases. In four out of five cases studied, HIV Rev, but not Tat, was also expressed in astrocytes. Six out of the seven patients with Nef-positive astrocytes had suffered from moderate to severe dementia. The patient with most rapidly progressing severe dementia showed extensive HIV mRNA expression together with Nef and Rev expression in astrocytes. CONCLUSION: In adult human brain, astrocytes are infected by HIV and preferentially express HIV Nef and Rev proteins but are also sometimes productively infected. Astrocyte infection is associated with moderate to severe dementia which agrees with recent knowledge on the housekeeping activities of astrocytes and their eventual role in learning and memory.

Good maintenance of exercise-induced bone gain with decreased training of female tennis and squash players: a prospective 5-year follow-up study of young and old starters and controls.

This prospective 5-year follow-up study of 64 adult female racquet sports players and 27 controls assessed the changes in the playing-to-nonplaying arm bone mineral content (BMC) differences to answer three questions: (1) Are training-induced bone gains lost with decreased training? (2) Is the bone response to decreased training different if the playing career has been started before or at puberty rather than after it? (3) Are the possible bone changes related to the changes in training? The players were divided into two groups according to the starting age of their tennis or squash playing. The mean starting age was 10.5 years (SD, 2.2) among the players who had started training before or at menarche (young starters; n = 36) while 26.4 years (SD, 8.0) among those players who had begun training a minimum of 1 year after menarche (old starters; n = 28). At baseline of the 5-year follow-up, the mean age of the young starters was 21.6 years (SD, 7.6) and that of old starters was 39.4 years (SD, 10.5). During the follow-up, the young starters had reduced the average training frequency from 4.7 times a week (2.7) to 1.4 times a week (1.3) and the old starters from 4.0 times a week (1.4) to 2.0 times a week (1.4), respectively. The 5-year follow-up revealed that despite reduced training the exercise-induced bone gain was well maintained in both groups of players regardless of their clearly different starting age of activity and different amount of exercise-induced bone gain. The gain was still 1.3-2.2 times greater in favor of the young starters (at the follow-up, the dominant-to-nondominant arm BMC difference was 22% [8.4] in the humeral shaft of the young starters versus 10% [3.8] in the old starters, and 3.5% [2.4] in controls). In the players, changes in training were only weakly related to changes in the side-to-side BMC difference (r(s) = 0.05-0.34, all NS), and this was true even among the players who had stopped training completely a minimum 1 year before the follow-up. In conclusion, if controlled interventions will confirm our findings that an exercise-induced bone gain can be well maintained with decreased activity and that the maintenance of the bone gain is independent of the starting age of activity, exercise can be recommended for preventing osteoporosis and related fractures.

Dimensions and estimated mechanical characteristics of the humerus after long-term tennis loading.

This study evaluated the effects of long-term unilateral physical activity (tennis) on the playing arm humerus. Total lengths of both humeri, site-specific widths, and the bone mineral contents (BMC) at the proximal, middle, and distal parts of the bones were measured using dual-energy X-ray absorptiometry (DXA). Bone mineral apparent density (BMAD), cortical wall thickness (CWT), cross-sectional moment of inertia (CSMI), and section modulus (Z) were approximated from the DXA data for describing the bone's mechanical characteristics more concretely. The study population consisted of 67 healthy, competitive tennis players (17 young men with a mean age [+/- SD] of 25 +/- 5 years, 30 young women with a mean age of 19 +/- 3 years, and 20 older women with a mean age of 43 +/- 5 years) and 57 sedentary controls (16 young men with mean age of 25 +/- 5 years, 25 years, 25 young women with a mean age of 21 +/- 3 years, and 16 older women with mean age of 39 +/- 6 years). All the players had competitive playing histories greater than 4 years. The young male and female players had started their playing careers in childhood (men at the age of 10 +/- 3 years, women 9 +/- 2 years), while the older female players started the training at adulthood (29 +/- 6 years). The playing-to-nonplaying or dominant-to-nondominant arm differences in humeral length ranged from +0.2 to +1.4%, the difference being significant in young male players (+1.4%), young female controls (+1.1%), and older female players (+0.7%). When comparing players' relative side-to-side length differences with those of the controls, no significant differences were found. Significant side-to-side differences in humeral width were observed in all groups except male controls. Compared with the controls, the relative side-to-side width differences were significantly larger at the proximal humerus of the young male players (controls +1.2%, players +3.7%) and the distal humerus of young female players (controls -0.2%, players +1.6%). Compared with the controls, the players' relative side-to-side differences in BMC (range, +7.6 to +25.2%), BMD (+5.8 to +22.5%), BMAD (+5.5 to +20.4%), CWT (+6.9 to +45.2%), CSMI (+7.8 to +26.4%), and Z (+3.0 to +21.7%) were significantly larger in all measured humeral sites except BMAD in the distal humeri of the older female players. These relative side-to-side differences were clearly and significantly larger in the young players (+11.7 to +45.2%) than in the older players (+3.0 to +12.4%). In conclusion, long-term intensive tennis playing, especially if started in childhood or adolescence, clearly increases the humeral BMC, BMD, and CWT but seems to have only a minor effect on the width of this particular bone. In this respect, there seems to be no sex difference. However, along with the increases in mineral mass and density, the changes in bone width are important in increasing the bending stiffness and strength of the humerus. In older players, the relative side-to-side differences are at the same level or only slightly larger than those in their age-matched controls. This suggests that even intense physical loading of a mature bone is only marginally better in increasing the bone mass, bone density, and CWT of the target bone than the normal daily use of the dominant extremity.

Development of mass, density, and estimated mechanical characteristics of bones in Caucasian females.

Three hundred and thirty healthy Finnish girls and premenopausal women, aged 7-47 years, were examined to evaluate the natural development of bone mineral mass and density from early childhood to menopause. Bone mineral content (BMC,g) and areal density (BMD, g/cm2) were measured from the spine (L2-L4), femoral neck, trochanter region of the femur, and distal radius using dual-energy X-ray absorptiometry (DXA). In addition, the bone mineral apparent density (BMAD, g/cm3) was assessed from the above described skeletal sites, and the mechanical competence of the femoral neck was estimated. Special attention was paid to the timing of the peak values of these bone parameters as well as to the evidence of premenopausal bone loss. The BMC, BMD, and BMAD of the spine, femoral neck, and trochanter region of the femur achieved peak values around the age of 20, and the bone loss seemed to start soon thereafter. In contrast, the bone mass of the distal radius slightly increased between the ages of 20 and 47. In the femoral neck, the estimated bending strength achieved its peak value around the age of 20 and showed a slight decrease during the following decades. The highest body weight and neck-length adjusted strength values of the femoral neck were, however, found in early childhood, with the values decreasing linearly thereafter. In conclusion, this study supports previous findings of rapid bone mineral accumulation in late adolescence, and occurrence of the peak bone mass and density around the age of 20. Premenopausal bone loss seems to occur in the proximal femur and lumbar spine. Our observations of femur strength development imply that from childhood to menopause the mechanical strength of the femoral neck is well adjusted to the biomechanical loading requirements of the body.

Effect of long-term unilateral activity on bone mineral density of female junior tennis players.

High peak bone mass in early adulthood is an important protective factor against osteoporotic fractures in later life, but little is known about the effects of exercise on growing bone. The purpose of this cross-sectional study was to determine at which state of maturity (Tanner stage), the areal bone mineral density (BMD) differences between the playing and nonplaying arms of junior tennis players become obvious, and to clarify in each developmental stage which training and background variables, if any, could explain the interindividual differences in bones' response to mechanical loading. Ninety-one 7- to 17-year-old female tennis players and 58 healthy female controls were measured. In each Tanner stage, differences in BMD in playing and nonplaying (dominant and nondominant) arms (proximal humerus, humeral shaft, and distal radius) and BMD of the lumbar spine and nondominant distal radius were compared between the controls and players. Within each Tanner stage of players, the associations between training and background variables and BMD differences were analyzed with Spearman rank correlation coefficients. In players, BMD differences between the playing and nonplaying arms were significant (P < 0.05- < 0.001) in all Tanner stages, with the mean difference ranging from 1.6 to 15.7%. In controls, these dominant-to-nondominant arm differences were clearly smaller (ranging from -0.2 to 4.6%), but significant at some measured sites. In comparison with the relative side-to-side arm differences between the players and controls (i.e., examination of the training effect), the mean difference was not obvious and significant until the adolescent growth spurt (i.e., the girls in Tanner stage III with a mean age of 12.6 years). In the lumbar spine, significant BMD differences between players and controls were not found until Tanner stage IV (mean age 13.5 years; 8.7%, P < 0.05) and V (mean age 15.5 years; 12.4%, P < 0.05). In a nonloaded site of the skeleton (nondominant distal radius), no significant BMD differences were found between the players and controls in any Tanner stage. In the correlation analysis, the Tanner I and II players (mean ages 9.4 and 10.8 years) showed no significant associations between any of the predictive variables and the side-to-side BMD differences, while in Tanner stages III, IV, and V, such associations could be found; the total amount of training hours during the playing career and the number of training sessions per week showed a significant and systematic correlation (rs ranging from 0.43 to 0.80) with the side-to-side BMD differences in several measured bone sites. In conclusion, this study suggests that in a majority of female junior tennis players, the benefit of unilateral activity on bone density does not become clearly evident until the adolescent growth spurt or Tanner stage III. The total amount of training during the player's career and the current training frequency (sessions per week) seem to best explain the training effect on bone tissue, leaving, however, room for speculation on the still unknown factors that modulate the loading response of a growing bone.