The effects of continuous, intermittent and mode of exercise on mechanical bone remodelling

Bone health is known to deteriorate with age, which can increase the risk of osteoporotic fractures and subsequently all-cause mortality. Current life expectancies are higher than ever before and with our ageing population, osteoporosis and low bone density levels are an ever growing problem that command a lot of medical attention and resources. Women are at a greater risk than men due to increased rates of bone loss that occur in the early years following the menopause. Mechanical loading in the form of exercise is known to reduce the rates of postmenopausal bone loss although an optimal exercise programme is yet to be established. Furthermore, investigations conducted with animals have found intermittent mechanical loading to provide a greater stimulus for bone adaptation than continuous mechanical loading, this has not been investigated in human populations to date. The aim of this thesis was to establish a sufficient exercise mode for stimulating bone adaptation in postmenopausal women and investigate the effects of continuous and intermittent exercise on postmenopausal bone loss. This was attempted with a 12 month randomised controlled trial with postmenopausal women.The first study gave a systematic review of the current literature that investigated continuous or intermittent exercise. The review found that as the studies were not designed to specifically analyse continuous or intermittent exercise, there were numerous problems regarding the control of previous exercise programmes with regards to defined exercise and rest intervals. This was due to the design of the included studies, as many of them were not specifically designed to analyse the different effects of continuous and intermittent exercise on bone mineral density (BMD). In addition, BMD outcomes were not reported in a standardized manner, which complicated the comparisons drawn. From this investigation, it was evident that well-controlled exercise interventions (using a single exercise), are required for the comparison of the effect of continuous and intermittent exercise on BMD in human populations.The second study investigated the feasibility of developing a non-motorised treadmill exercise intervention that included both continuous and intermittent exercise groups. Non-motorised treadmill (NMT) locomotion allows for the instantaneous quantification of ground reaction forces (GRF) and is well suited to both continuous exercise and intermittent exercise with the potential for the use of a range of intermittent running based protocols. In order to establish the osteogenic potential of this mode of exercise, it was necessary to quantify the mechanical loading parameters. This study found that loading parameters showed large reductions during NMT locomotion when compared to overground or motorised treadmill locomotion (24 to 29 %), which could potentially compromise the level of bone adaptation if this mode of exercise was used for intervention purposes.The third study investigated the loading parameters of more traditional high impact exercises in a population of postmenopausal women. All exercises were performed under both continuous and intermittent conditions to assess for consistency during the two conditions. This project showed that countermovement jumps (CMJ) and box drops (BD) produced the highest loading parameters when compared to heel drops (HD) and stamping (STP) (d = 0.83 – 2.38), along with no statistical differences between continuous and intermittent conditions (continuous: 10.7 ± 4.8 g for CMJ, 9.6 ± 4.1 g for BD; intermittent 10.0 ± 5.0 g for CMJ, 9.5 ± 4.0 g for BD). CMJ, BD and HD exercises all appeared to generate a sufficient level of peak acceleration and acceleration gradient for osteogenic adaptation however. For consistency purposes and the fact that no equipment was required, CMJs were selected as the most appropriate home-based exercise for use in a 12 month intervention to reduce postmenopausal bone loss.The fourth study investigated the effects of continuous and intermittent exercise on BMD in early postmenopausal women over the course of a 12 month randomised control trial. Unfortunately the study was underpowered and in addition, the findings showed no statistically significant differences in the bone response between groups. Only the control group experienced a statistically significant loss in both lumbar spine (-2.7% [95%CI: -3.9 to -1.4]) and femoral neck (-3.0% [95%CI: -5.1 to -0.8]) BMD, which exceeded the 95% least significant change at the lumbar spine and femoral neck in 57% of control group participants. There appeared to be no beneficial effect of continuous or intermittent exercise on BMD, hip structural analysis (HSA) parameters or muscular force characteristics when compared to a control group however. In conclusion, this thesis has identified that future research should further investigate the effects of continuous and intermittent exercise on BMD with appropriately controlled randomised control trials, with greater participant numbers. Whilst CMJ and BD provide adequate loading parameters, this does not translate into BMD adaptations. Continuous and intermittent CMJ exercises had no effect on reducing postmenopausal BMD loss at the lumbar spine and the femoral neck, although further investigation is required in an adequately powered study

Critical values for Lawshe's content validity ratio: revisiting the original methods of calculation

YesThe content validity ratio originally proposed by Lawshe is widely used to quantify content validity and yet methods used to calculate the original critical values were never reported. Methods for original calculation of critical values are suggested along with tables of exact binomial probabilities

Neutrophil activation in systemic capillary leak syndrome (Clarkson disease)

Systemic capillary leak syndrome (SCLS; Clarkson disease) is a rare orphan disorder characterized by transient yet recurrent episodes of hypotension and peripheral oedema due to diffuse vascular leakage of fluids and proteins into soft tissues. Humoral mediators, cellular responses and genetic features accounting for the clinical phenotype of SCLS are virtually unknown. Here, we searched for factors altered in acute SCLS plasma relative to matched convalescent samples using multiplexed aptamer‐based proteomic screening. Relative amounts of 612 proteins were changed greater than twofold and 81 proteins were changed at least threefold. Among the most enriched proteins in acute SCLS plasma were neutrophil granule components including bactericidal permeability inducing protein, myeloperoxidase and matrix metalloproteinase 8. Neutrophils isolated from blood of subjects with SCLS or healthy controls responded similarly to routine pro‐inflammatory mediators. However, acute SCLS sera activated neutrophils relative to remission sera. Activated neutrophil supernatants increased permeability of endothelial cells from both controls and SCLS subjects equivalently. Our results suggest systemic neutrophil degranulation during SCLS acute flares, which may contribute to the clinical manifestations of acute vascular leak

Role of laeA in the regulation of alb1, gliP , Conidial Morphology and Virulence in Aspergillus fumigatus

The alb1 (pksP) gene has been reported as a virulence factor controlling the pigmentation and morphology of conidia in Aspergillus fumigatus. A recent report suggested that laeA regulates alb1 expression and conidial morphology but not pigmentation in the A. fumigatus strain AF293. laeA has also been reported to regulate the synthesis of secondary metabolites, such as gliotoxin. We compared the role of laeA in the regulation of conidial morphology and the expression of alb1 and gliP in strains B-5233 and AF293, which differ in colony morphology and nutritional requirements. Deletion of laeA did not affect conidial morphology or pigmentation in these strains, suggesting that laeA is not involved in alb1 regulation during conidial morphogenesis. Deletion of laeA, however, caused down-regulation of alb1 during mycelial growth in a liquid medium. Transcription of gliP, involved in the synthesis of gliotoxin, was drastically reduced in B-5233laeAΔ, and the gliotoxin level found in the culture filtrates was 20% of wild-type concentrations. While up-regulation of gliP in AF293 was comparable to that in B-5233, the relative mRNA level in AF293laeAΔ was about fourfold lower than that in B-5233laeAΔ. Strain B-5233lae4Δ caused slower onset of fatal infection in mice relative to that with B-5233. Histopathology of sections from lungs of infected mice corroborated the survival data. Culture filtrates from B-5233laeAΔ caused reduced death in thymoma cells and were less inhibitory to a respiratory burst of neutrophils than culture filtrates from B-5233. Our results suggest that while laeA is not involved in the regulation of alb1 function in conidial morphology, it regulates the synthesis of gliotoxin and the virulence of A. fumigatus

Hepatic abnormalities in patients with chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare congenital disorder characterized by repeated bacterial and fungal infections. Aside from a high incidence of liver abscess, little is known about hepatic involvement in CGD. The aim of this study was to describe the spectrum of liver abnormalities seen in CGD. The charts of 194 patients with CGD followed at the NIH were reviewed, with a focus on liver abnormalities. Liver enzyme elevations occurred on at least one occasion in 73% of patients during a mean of 8.9 years of follow-up. ALT elevations were generally transient. Although transient alkaline phosphatase (ALP) elevations were also common, persistent ALP elevations lasting up to 17.6 years were seen in 25% of patients. Liver abscess occurred in 35% of patients. Drug-induced hepatotoxicity was documented in 15% of patients but likely occurred more frequently. Hepatomegaly was found in 34% and splenomegaly in 56% of patients. Liver histology showed granulomata in 75% and lobular hepatitis in 90% of specimens. Venopathy of the portal vein was common (80%) and associated with splenomegaly. Venopathy of the central vein was also common (63%) and was associated with the number of abscess episodes. Nodular regenerative hyperplasia (NRH) was seen in 9 patients, including 6 of 12 autopsy specimens. CONCLUSION: Liver enzyme abnormalities occur frequently in patients with CGD. In addition to liver abscesses and granulomata, drug hepatotoxicity is likely underappreciated. Vascular lesions such as venopathy and--to a lesser extent--NRH are common. The cause and clinical consequences of venopathy await prospective evaluation

Short-Term Trends in Bastardy in Taiwan

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68002/2/10.1177_036319908000500303.pd