Exploring thoracic kyphosis and incident fracture from vertebral morphology with high-intensity exercise in middle-aged and older men with osteopenia and osteoporosis: a secondary analysis of the LIFTMOR-M trial.

Our aim was to explore change in kyphosis and vertebral fracture incidence following 8 months of high-intensity resistance and impact training (HiRIT) or machine-based isometric axial compression (IAC) training in men with osteopenia and osteoporosis. HiRIT and IAC improved posture. HiRIT participants did not experience progression or incident vertebral fracture. IAC participants did experience progression and incident vertebral fracture. INTRODUCTION: The Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation for Men (LIFTMOR-M) trial examined efficacy and safety of an eight-month, supervised, high-intensity progressive resistance and impact training (HiRIT) program compared with machine-based isometric axial compression (IAC) training in middle-aged and older men with low areal bone mineral density (aBMD). The primary purpose of the current work was to explore change in thoracic kyphosis and incident fracture from vertebral morphology following eight-months of HiRIT or IAC training. The secondary purpose was to explore change in clinical kyphosis measures for HiRIT, IAC and a non-randomized, matched control group. METHODS: Men (≥ 45 yrs), with low aBMD, were recruited and randomized to HiRIT or IAC, or designated control. Clinical measures of thoracic kyphosis with inclinometry were determined. Cobb angle of kyphosis and vertebral fracture assessment using the Genant semi-quantitative method were determined from lateral thoracolumbar DXA (Medix DR, Medilink, France). Per-protocol (n = 40) and intention-to-treat (n = 93) analyses were conducted. RESULTS: Forty participants (HiRIT n = 20, IAC n = 20; 66.1 ± 7.8 yrs.; lumbar spine T-score - 0.1 ± 0.8; femoral neck T-score - 1.5 ± 0.5) underwent clinical kyphosis measures and thoracolumbar DXA at baseline and follow-up. No between-group differences were detected in kyphosis change, however, within-group improvements in neutral (HiRIT - 2.3 ± 0.8°; IAC - 2.5 ± 0.8°) and 'standing tall' (HiRIT - 2.4 ± 0.8°; IAC - 2.0 ± 0.8°) postures were observed (p < 0.05). HiRIT improved Cobb angle (- 3.5 ± 1.5°, p = 0.027) from baseline. Over the 8 months, no incident vertebral fractures nor progression of prevalent vertebral fractures occurred for HiRIT participants. Five incident fractures of thoracic vertebrae occurred for IAC and one wedge fracture progressed. Ninety-three participants underwent clinical kyphosis measures at both time-points (HiRIT n = 34, IAC n = 33, control n = 26). HiRIT exhibited a reduction in 'standing tall' kyphosis compared to control (- 2.3 ± 0.6° versus 1.4 ± 0.7°, p < 0.05), but no other between-group differences were detected. CONCLUSIONS: Although there was no difference in change between intervention groups, thoracic kyphosis appeared to improve in both HiRIT and IAC with exercise exposure. HiRIT improved 'standing tall' posture in comparison to usual activities. HiRIT was not associated with vertebral fracture progression or incident vertebral fracture, but for some IAC participants there was evidence of progression of vertebral fracture severity and incident vertebral fractures, in our small sample. Larger trials are required to confirm the observations of the current work, which was exploratory in nature.

High-intensity exercise did not cause vertebral fractures and improves thoracic kyphosis in postmenopausal women with low to very low bone mass: the LIFTMOR trial.

Our aim was to assess risk of vertebral fracture during high-intensity resistance and impact training (HiRIT) for postmenopausal women with low bone mass. HiRIT did not induce vertebral fracture, as evidenced by a reduction in kyphosis following 8 months of training and a lack of change in vertebral morphology. INTRODUCTION: The LIFTMOR trial demonstrated a novel, HiRIT program notably improved bone mass in postmenopausal women with osteopenia and osteoporosis. While no clinical signs or symptoms of vertebral crush fracture were evident during the trial, anecdotal feedback suggests that concerns about safety of HiRIT in the osteoporosis demographic remain. The aim of the current work was to assess vertebral body morphology, Cobb angle, and clinical measures of thoracic kyphosis in participants in the LIFTMOR trial for evidence of vertebral fracture following 8 months of supervised HiRIT. METHODS: Participants were randomized to either 8 months of 30-min, twice-weekly, supervised HiRIT or unsupervised, low-intensity, home-based exercise (CON). Lateral thoracolumbar DXA scans (Medix DR, Medilink, France) were performed at baseline and follow-up. Cobb angle was determined, and vertebral fracture identification was performed using the semiquantitative Genant method. Clinical kyphosis measurements were performed in relaxed standing (neutral posture) and standing tall using an inclinometer and a flexicurve. RESULTS: The HiRIT group exhibited a reduction in inclinometer-determined standing tall thoracic kyphosis compared to CON (- 6.7 ± 8.2° vs - 1.6 ± 8.1°, p = 0.031). Both the HiRIT and CON groups exhibited within-group improvement in kyphosis in relaxed standing as measured by both inclinometer and flexicurve (p < 0.05). There were no changes in vertebral fracture classification in the HiRIT group post-intervention. A single, new, wedge deformity was observed for CON. CONCLUSIONS: Supervised HiRIT was not associated with an increased risk of vertebral fracture in postmenopausal women with low bone mass. Indeed, a clinically relevant improvement in thoracic kyphosis was observed following 8 months of supervised HiRIT, further supporting its efficacy as an osteoporosis intervention for postmenopausal women with low to very low bone mass.

MMSE and MoCA in Parkinson's disease and dementia with Lewy bodies: a multicenter 1-year follow-up study.

The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are the most commonly used scales to test cognitive impairment in Lewy body disease (LBD), but there is no consensus on which is best suited to assess cognition in clinical practice and most sensitive to cognitive decline. Retrospective cohort study of 265 LBD patients [Parkinson's disease (PD) without dementia (PDnD, N = 197), PD with dementia (PDD, N = 40), and dementia with Lewy bodies (DLB, N = 28)] from an international consortium who completed both the MMSE and MoCA at baseline and 1-year follow-up (N = 153). Percentage of relative standard deviation (RSD%) at baseline was the measure of inter-individual variance, and estimation of change (Cohen's d) over time was calculated. RSD% for the MoCA (21 %) was greater than for the MMSE (13 %) (p = 0.03) in the whole group. This difference was significant only in PDnD (11 vs. 5 %, p < 0.01), but not in PDD (30 vs. 19 %, p = 0.37) or DLB (15 vs. 14 %, p = 0.78). In contrast, the 1-year estimation of change did not differ between the two tests in any of the groups (Cohen's effect <0.20 in each group). MMSE and MoCA are equal in measuring the rate of cognitive changes over time in LBD. However, in PDnD, the MoCA is a better measure of cognitive status as it lacks both ceiling and floor effects.

Improving the reliability of single-subject fMRI by weighting intra-run variability.

At present, functional magnetic resonance imaging (fMRI) is one of the most useful methods of studying cognitive processes in the human brain in vivo, both for basic science and clinical goals. Although neuroscience studies often rely on group analysis, clinical applications must investigate single subjects (patients) only. Particularly for the latter, issues regarding the reliability of fMRI readings remain to be resolved. To determine the ability of intra-run variability (IRV) weighting to consistently detect active voxels, we first acquired fMRI data from a sample of healthy subjects, each of whom performed 4 runs (4 blocks each) of self-paced finger-tapping. Each subject's data was analyzed using single-run general linear model (GLM), and each block was then analyzed separately to calculate the IRV weighting. Results show that integrating IRV information into standard single-subject GLM activation maps significantly improved the reliability (p=0.007) of the single-subject fMRI data. This suggests that taking IRV into account can help identify the most constant and relevant neuronal activity at the single-subject level.

Brain anatomical substrates of mirror movements in Kallmann syndrome.

Among male patients affected by Kallmann syndrome, a genetically determined disease due to defective neural migration leading to hypogonadropic hypogonadism and hypo/anosmia, about 40% present the peculiar phenomenon of mirror movements, i.e. involuntary movements mirroring contralateral voluntary hand movements. Several pathogenic hypotheses have been proposed, but the ultimate neurological mechanisms are still elusive. The aim of the present study was to investigate brain anatomical substrates of mirror movements in Kallmann syndrome by means of a panel of quantitative MRI analyses. Forty-nine male Kallmann syndrome patients underwent brain MRI. The study protocol included 3D-T1-weighted gradient echo, fluid attenuated inversion recovery and diffusion tensor imaging. Voxel-based morphometry, sulcation, curvature and cortical thickness analyses and tract based spatial statistics were performed using SPM8, Freesurfer and FSL. All patients underwent a complete physical and neurological examination including the evaluation of mirror movements (according to the Woods and Teuber criteria). Kallmann syndrome patients presenting with mirror movements (16/49, 32%) displayed the following brain changes: 1) increased gray matter density in the depth of the left precentral sulcus behind the middle frontal gyrus; 2) decreased cortical thickness in the precentral gyrus bilaterally, in the depth of right precentral sulcus and in the posterior portion of the right superior frontal gyrus; and 3) decreased fractional anisotropy in the left hemisphere involving the temporal lobe and peritrigonal white matter. No differences were shown by cortical curvature and sulcation analyses. The composite array of brain changes observed in Kallmann syndrome patients with mirror movements likely represents the anatomical-structural underpinnings leading to the peculiar derangement of the complex circuitry committed to unilateral hand voluntary movements.

Heavy resistance training is safe and improves bone, function, and stature in postmenopausal women with low to very low bone mass: novel early findings from the LIFTMOR trial.

UNLABELLED: The aim of the LIFTMOR (Lifting Intervention For Training Muscle and Osteoporosis Rehabilitation) trial is to determine the safety and efficacy of brief, bone-targeted, high-intensity progressive resistance training (HiPRT) with impact loading for postmenopausal women with low bone mass. Preliminary findings indicate the LIFTMOR program is safe and effective. INTRODUCTION: Despite a lack of notable efficacy, exercise guidelines for osteoporosis typically recommend moderate-intensity exercises, owing to a perceived risk of fracture from high-intensity loading. Indeed, safety concerns alone have prevented the well-recognised preferential response of bone tissue to high-intensity loads from being applied to those who stand to benefit the most. To progress from this therapeutic stalemate, a challenge to conventional wisdom was required. Our goal was to examine the safety and efficacy of HiPRT and impact loading for risk factors of osteoporotic fracture in postmenopausal women with low to very low bone mass. METHODS: Participants have been randomised to either 8 months of twice-weekly 30-min supervised HiPRT and impact loading or a low-intensity home-based exercise program of the same duration and dose. Testing at baseline and follow-up has included anthropometry; bone, muscle, and fat mass; and functional performance. RESULTS: Twenty-eight women (66.1 ± 4.8 years, mean lumbar spine T-score -2.15 ± 0.72) have completed the study. HiPRT and impact loading (n = 12) improved height (0.4 ± 0.2 cm vs -0.3 ± 0.1 cm, p = 0.003), femoral neck bone mineral density (0.3 ± 0.5 % vs -2.5 ± 0.8 %, p = 0.016), lumbar spine bone mineral density (1.6 ± 0.9 % vs -1.7 ± 0.6 %, p = 0.005), and functional performance (p < 0.05), compared to controls (n = 16). Compliance has been >87 %. There have been no injuries. CONCLUSIONS: Brief supervised HiPRT with impact loading is a safe and effective exercise therapy for postmenopausal women with low to very low bone mass.

Gene expression profiling in rat cerebellum following in utero and lactational exposure to mixtures of methylmercury, polychlorinated biphenyls and organochlorine pesticides.

Although human populations are continuously exposed to complex mixtures of contaminants, the effects of such exposure on the developing brain transcriptome are poorly characterized. Rats were exposed perinatally to the northern contaminant mixture (NCM) which was designed to reflect the blood contaminant profile of Canadian arctic populations, to components of the NCM administered separately (methylmercury (MeHg), polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs)) or to the goitrogen propylthiouracyl. Post-natal day (PND) 14 cerebellum global gene expression resulting from such exposures was investigated using high-density cDNA microarrays. Fifty known genes were identified as differentially expressed between the control group and at least one other treatment group. The microarray data were validated by quantitative PCR (qPCR) on a subset of 10 genes. The differentially expressed genes are involved in a variety of processes, including nerve cell differentiation, migration, myelination and synaptic transmission. The comparison of cerebellum gene expression profiles resulting from exposure to the NCM and its individual components in male and female pups revealed that (i) gender is a crucial biological variable influencing genomic response to environmental contaminants and (ii) contaminant co-exposure significantly masks the effects of individual mixture components on cerebellum gene expression.

Accurate positioning of RNA polymerase II on a natural TATA-less promoter is independent of TATA-binding-protein-associated factors and initiator-binding proteins.

Two promoter elements, the TATA element and initiator (Inr), are capable of directing specific transcription initiation of protein-encoding genes by RNA polymerase II (RNAPII). Although binding to the TATA element by the TATA-binding protein (TBP) has been shown to be the initial recognition step in transcription complex formation in vitro, the mechanism through which the basal machinery assembles into a functional complex on TATA-less promoters is controversial. Evidence supporting numerous models of Inr-mediated transcription complex formation exists, including the nucleation of a complex by Inr-binding proteins, a component of the TFIID complex, or a specific upstream activator common to many TATA-less promoters, Sp1. Using various techniques, we have undertaken a systematic analysis of the natural TATA-less human DNA polymerase beta (beta-pol) gene promoter. Although the beta-pol promoter contains upstream Sp1 elements and a functional Inr that binds YY1, neither of these factors is essential for Inr-mediated transcription complex formation. A complex containing TBP, TFIIB, TFIIF, and RNAPII (DBPolF complex) is capable of forming on the promoter in an Inr-dependent manner. A single point mutation within the Inr that affects DBPolF complex formation diminishes beta-pol transcriptional activity.

Factors involved in specific transcription by mammalian RNA polymerase II: role of transcription factors IIA, IID, and IIB during formation of a transcription-competent complex.

Human transcription factor TFIID, the TATA-binding protein, was partially purified to a form capable of associating stably with the TATA motif of the adenovirus major late promoter. Binding of the human and yeast TFIID to the TATA motif was stimulated by TFIIA. TFIIA is an integral part of a complex capable of binding other transcription factors. A complex formed with human TFIID and TFIIA (DA complex) was specifically recognized by TFIIB. We found that TFIIB activity was contained in a single polypeptide of 32 kDa and that this polypeptide participated in transcription and was capable of binding to the DA complex to form the DAB complex. Formation of the DAB complex required TFIIA, TFIID, and sequences downstream of the transcriptional start site; however, the DA complex could be formed on an oligonucleotide containing only the adenovirus major late promoter TATA motif. Using anti-TFIIB antibodies and reagents that affect the stability of a transcription-competent complex, we found that yeast and human TFIID yielded DAB complexes with different stabilities.

Modulated gap junctional intercellular communication as a biomarker of PAH epigenetic toxicity: structure-function relationship.

Cancer is a multistage multimechanism process involving gene and/or chromosomal mutations (genotoxic events), altered gene expression at the transcriptional, translational, and post-translational levels (epigenetic events), and altered cell survival (proliferation and apoptosis or necrosis), resulting in an imbalance of the organism's homeostasis. Maintenance of the organism's homeostasis depends on the intricate coordination of genetic and metabolic events between cells via extracellular and intercellular communication mechanisms. The release of a quiescent cell, whether normal or premalignant, from the suppressing effects of communicating neighbors requires the downregulation of intercellular communication via gap junctions, thereby allowing factors that control intracellular events to exceed a critical mass necessary for the cell to either proliferate or undergo apoptosis. Therefore, determining the role an environmental pollutant must play in the multistage carcinogenic process includes mechanisms of epigenetic toxicity such as the effects of a compound on gap junctional intercellular communication (GJIC). A classic example of a class of compounds in which determination of carcinogenicity focused on genotoxic events and ignored epigenetic events is polycyclic aromatic hydrocarbons (PAHs). The study of structure-activity relationships of PAHs has focused exclusively on the genotoxic and tumor-initiating properties of the compound. We report on the structure-activity relationships of two- to four-ringed PAHs on GJIC in a rat liver epithelial cell line. PAHs containing a bay or baylike region were more potent inhibitors of GJIC than the linear PAHs that do not contain these regions. These are some of the first studies of determine the epigenetic toxicity of PAHs at the epigenetic level.

Bay or baylike regions of polycyclic aromatic hydrocarbons were potent inhibitors of Gap junctional intercellular communication.

Many polycyclic aromatic hydrocarbons (PAHs) are known carcinogens, and a considerable amount of research has been devoted to predicting the tumor-initiating potential of PAHs based on chemical structure. However, there has been little research into the effects of PAHs on the epigenetic events of tumor promotion and no structural correlation has been made thereof. Gap junctional intercellular communication (GJIC) activity was used in this study as an epigenetic biomarker to determine the structure-activity relationships of twelve different PAHs. The PAHs used were naphthalene, 1-methylnaphthalene, 2-methylnaphthalene, anthracene, 1-methylanthracene, 2-methylanthracene, 9-methylanthracene, 9, 10-dimethylanthracene, phenanthrene, fluorene, 1-methylfluorene, and fluoranthene. Results showed that PAHs containing bay or baylike regions inhibited GJIC more than did the linear PAHs. The nonnaphthalene PAHs were not cytotoxic as determined by a vital dye uptake assay, but the naphthalene compounds were cytotoxic at the higher doses, indicating that the down regulation of GJIC by these naphthalenes could be a consequence of general membrane damage. Inhibition of GJIC by all the inhibitory PAHs was reversed when the cells were refreshed with PAH-free growth medium. Inhibition of GJIC occurred within 0.5-5 min and correlated with the aqueous solubility of the PAHs. The present study revealed that there are structural determinants of epigenetic toxicity as determined by GJIC activity.

Primary cerebral lymphoma with glomerular renal involvement.

We report a case of primary cerebral lymphoma metastasizing to the kidney with exclusive involvement of the glomeruli. We discuss the possible explanations of this unusual phenomenon, and present some of the unusual clinical features of the case. Nephropathologists interpreting glomerular hypercellularity should always consider metastatic neoplasms as a possible, though rare, cause.

Nasogastric tube feeding in infants on peritoneal dialysis.

Enteral nutritional support is an important component of the care provided to infants receiving long-term peritoneal dialysis. In the majority of published experiences on this subject, the use of the nasogastric tube has facilitated the provision of required calorie and protein intake and resulted in an improved patient outcome. Advantages of the nasogastric route of nutritional support include the ease of administration, while recurrent emesis remains the most troublesome and frequent short-term complication associated with its use. Impaired oral-motor development may also result from nonoral feeding and should be addressed throughout the course of tube feeding.

MR imaging of parosteal osteosarcoma in two skeletally immature patients.

Parosteal osteogenic sarcoma is an unusual tumor in young children. It usually has a tendency to affect people with mature skeletons. The biological behavior of this tumor in children appears to be identical to that in adults, resulting in excellent prognosis after curative operative procedures, even if there is minimal extension to the bone marrow. Magnetic resonance imaging has a significant role in staging the tumor, as other imaging modalities are inferior in demonstrating early bone marrow involvement.

MR imaging of a parosteal lipoma.

A case of a parosteal lipoma of the thigh is presented. Very little is known of the enhancement features of this tumor. In this case, mild enhancement of tissue in the region of the pedicle between reactive cortical bone hyperostosis and the lipomatous mass corresponded to fibrous tissue that outlined the hyperostotic reactive bone.

Total knee arthroplasty in chronic hemophilic arthropathy.

Nine total knee arthroplasties were performed in seven patients with either Hemophilia A (factor VIII deficiency) or Hemophilia B (factor IX deficiency) and followed for an average of 52 months. A total condylar prosthesis was used in eight virgin knees and a stemmed variable axis prosthesis was used in one revision case. All knees demonstrated the severe joint destruction and cartilage erosion characteristic of chronic hemophilic arthropathy. The average age at operation was 32 years. All patients were evaluated using the knee disability assessment of The Hospital for Special Surgery. All knees were postoperatively rated as either excellent or good. Pain, function, and range of motion were markedly improved. Postoperative radiographic alignment averaged 4 degrees of valgus with half of the virgin knees demonstrating 1 mm or less of non-progressive tibial radiolucency without clinical loosening. The only complication was hemarthrosis from 37 to 59 months postoperatively. This was thought to be secondary to trauma to residual synovium. Total knee arthroplasty in the hemophiliac is a viable alternative to conventional methods of treatment for chronic arthropathy and expectations for pain relief and functional gain can be high.