The objective assessment of the effects on cognition functioning among military personnel exposed to hypobaric-hypoxia: A pilot fMRI study.

OBJECTIVE: To identify regions of the brain affected during cognitive working memory during tasks to assess attention, planning and decision making among military aviation personnel who have chronic intermittent exposure to high altitude environment. METHOD: A case-control study was conducted in the Universiti Putra Malaysia among eight military personnel, four of whom had chronic intermittent exposure to high altitude training. They were divided into two groups, chronic intermittent exposure group (CE) (n=4) and a control group (n=4). They underwent a task-based functional magnetic resonance imaging (fMRI) that utilised spatial working memory task to objectively evaluate the neural activation in response to the Tower of London paradigm. Each correct answer was given a score of one and the maximum achievable score was 100%. RESULTS: A consecutive dichotomised group of CE (4/8) and control (4/8) of age-matched military aviation personnel with a mean age of 37.23±5.52 years; showed significant activation in the right middle frontal gyrus (MFG). This in turn was positively correlated with response accuracy. A significant difference in the response accuracy was noted among both the groups at p<0.05. CONCLUSION: At the minimum results of power analysis of this preliminary fMRI study, our group of aviation personnel who had chronic intermittent exposure to hypobaric hypoxic environment, did not have any significant decrease in cognitive function namely attention, decision-making and problem solving compared to controls during a working memory task.

Modeling inter-sex and inter-individual variability in response to chronopharmacological administration of synthetic glucocorticoids.

Endogenous glucocorticoids have diverse physiological effects and are important regulators of metabolism, immunity, cardiovascular function, musculoskeletal health and central nervous system activity. Synthetic glucocorticoids have received widespread attention for their potent anti-inflammatory activity and have become an important class of drugs used to augment endogenous glucocorticoid activity for the treatment of a host of chronic inflammatory conditions. Chronic use of synthetic glucocorticoids is associated with a number of adverse effects as a result of the persistent dysregulation of glucocorticoid sensitive pathways. A failure to consider the pronounced circadian rhythmicity of endogenous glucocorticoids can result in either supraphysiological glucocorticoid exposure or severe suppression of endogenous glucocorticoid secretion, and is thought be a causal factor in the incidence of adverse effects during chronic glucocorticoid therapy. Furthermore, given that synthetic glucocorticoids have potent feedback effects on the hypothalamic-pituitary-adrenal (HPA) axis, physiological factors which can give rise to individual variability in HPA axis activity such as sex, age, and disease state might also have substantial implications for therapy. We use a semi-mechanistic mathematical model of the rodent HPA axis to study how putative sex differences and individual variability in HPA axis regulation can influence the effects of long-term synthetic exposure on endogenous glucocorticoid circadian rhythms. Model simulations suggest that for the same drug exposure, simulated females exhibit less endogenous suppression than males considering differences in adrenal sensitivity and negative feedback to the hypothalamus and pituitary. Simulations reveal that homeostatic regulatory variability and chronic stress-induced regulatory adaptations in the HPA axis network can result in substantial differences in the effects of synthetic exposure on the circadian rhythm of endogenous glucocorticoids. In general, our results provide insight into how the dosage and exposure profile of synthetic glucocorticoids could be manipulated in a personalized manner to preserve the circadian dynamics of endogenous glucocorticoids during chronic therapy, thus potentially minimizing the incidence of adverse effects associated with long-term use of glucocorticoids.

Modeling the influence of chronopharmacological administration of synthetic glucocorticoids on the hypothalamic-pituitary-adrenal axis.

Natural glucocorticoids, a class of cholesterol-derived hormones, modulate an array of metabolic, anti-inflammatory, immunosuppressive and cognitive signaling. The synthesis of natural glucocorticoids, largely cortisol in humans, is regulated by the hypothalamic-pituitary-adrenal (HPA) axis and exhibits pronounced circadian variation. Considering the central regulatory function of endogenous glucocorticoids, maintenance of the circadian activity of the HPA axis is essential to host survival and chronic disruption of such activity leads to systemic complications. There is a great deal of interest in synthetic glucocorticoids due to the immunosuppressive and anti-inflammatory properties and the development of novel dosing regimens that can minimize the disruption of endogenous activity, while still maintaining the pharmacological benefits of long-term synthetic glucocorticoid therapy. Synthetic glucocorticoids are associated with an increased risk of developing the pathological disorders related to chronic suppression of cortisol rhythmicity as a result of the potent negative feedback by synthetic glucocorticoids on the HPA axis precursors. In this study, a mathematical model was developed to explore the influence of chronopharmacological dosing of exogenous glucocorticoids on the endogenous cortisol rhythm considering intra-venous and oral dosing. Chronic daily dosing resulted in modification of the circadian rhythmicity of endogenous cortisol with the amplitude and acrophase of the altered rhythm dependent on the administration time. Simulations revealed that the circadian features of the endogenous cortisol rhythm can be preserved by proper timing of administration. The response following a single dose was not indicative of the response following long-term, repeated chronopharmacological dosing of synthetic glucocorticoids. Furthermore, simulations revealed the inductive influence of long-term treatment was only associated with low to moderate doses, while high doses generally led to suppression of endogenous activity regardless of the chronopharmacological dose. Finally, chronic daily dosing was found to alter the responsiveness of the HPA axis, such that a decrease in the amplitude of the cortisol rhythm resulted in a partial loss in the time-of-day dependent response to CRH stimulation, while an increase in the amplitude was associated with a more pronounced time-of-day dependence of the response.

Modeling the Influence of Seasonal Differences in the HPA Axis on Synchronization of the Circadian Clock and Cell Cycle.

Synchronization of biological functions to environmental signals enables organisms to anticipate and appropriately respond to daily external fluctuations and is critical to the maintenance of homeostasis. Misalignment of circadian rhythms with environmental cues is associated with adverse health outcomes. Cortisol, the downstream effector of hypothalamic-pituitary-adrenal (HPA) activity, facilitates synchronization of peripheral biological processes to the environment. Cortisol levels exhibit substantial seasonal rhythmicity, with peak levels occurring during the short-photoperiod winter months and reduced levels occurring in the long-photoperiod summer season. Seasonal changes in cortisol secretion could therefore alter its entraining capabilities, resulting in a season-dependent modification in the alignment of biological activities with the environment. We develop a mathematical model to investigate the influence of photoperiod-induced seasonal differences in the circadian rhythmicity of the HPA axis on the synchronization of the peripheral circadian clock and cell cycle in a heterogeneous cell population. Model simulations predict that the high-amplitude cortisol rhythms in winter result in the greatest entrainment of peripheral oscillators. Furthermore, simulations predict a circadian gating of the cell cycle with respect to the expression of peripheral clock genes. Seasonal differences in cortisol rhythmicity are also predicted to influence mitotic synchrony, with a high-amplitude winter rhythm resulting in the greatest synchrony and a shift in timing of the cell cycle phases, relative to summer. Our results highlight the primary interactions among the HPA axis, the peripheral circadian clock, and the cell cycle and thereby provide an improved understanding of the implications of circadian misalignment on the synchronization of peripheral regulatory processes.

Modeling the Sex Differences and Interindividual Variability in the Activity of the Hypothalamic-Pituitary-Adrenal Axis.

Significant sex differences exist in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. These differences are thought to contribute to the disparity in the prevalence of various autoimmune and infectious diseases between males and females. We used a mathematical model of the HPA axis to evaluate the hypothesis that differential sensitivity and negative feedback of the HPA axis network are causal factors for the observed sex differences in its activity. In doing so, we implicitly accounted for the differential influence of gonadal hormones on the HPA axis. Furthermore, we determined whether the putative mechanisms responsible for differences in basal HPA axis activity might also contribute to the observed differences in its stimulus-driven response. Model simulations predicted that the female HPA axis has greater adrenal sensitivity and weaker negative feedback. We identified two distinct sex-specific parameter spaces that generate corticosterone profiles in qualitative agreement with experimental results. We propose that these parameter subspaces indicate the interindividual variability in the regulatory mechanisms of the HPA axis. Furthermore, the model predicts that the maintenance of homeostatic rhythms in response to chronic stress requires specific regulatory adaptations resulting in a phenotype of allostatically driven chronic stress-sensitization. We propose that these adaptations indicate a physiological cost of adaptation to chronic stress. Model simulations suggest that individuals with high adrenal sensitivity are more vulnerable to chronic stress sensitization and might be more susceptible to the development of neuropsychiatric disorders. These results contribute to the study of sex differences in physiological feedback systems within a quantitative framework.

On the analysis of complex biological supply chains: From Process Systems Engineering to Quantitative Systems Pharmacology.

The use of models in biology has become particularly relevant as it enables investigators to develop a mechanistic framework for understanding the operating principles of living systems as well as in quantitatively predicting their response to both pathological perturbations and pharmacological interventions. This application has resulted in a synergistic convergence of systems biology and pharmacokinetic-pharmacodynamic modeling techniques that has led to the emergence of quantitative systems pharmacology (QSP). In this review, we discuss how the foundational principles of chemical process systems engineering inform the progressive development of more physiologically-based systems biology models.

An overview of recent patents on musculoskeletal interface tissue engineering.

Interface tissue engineering involves the development of engineered grafts that promote integration between multiple tissue types. Musculoskeletal tissue interfaces are critical to the safe and efficient transmission of mechanical forces between multiple musculoskeletal tissues, e.g., between ligament and bone tissue. However, these interfaces often do not physiologically regenerate upon injury, resulting in impaired tissue function. Therefore, interface tissue engineering approaches are considered to be particularly relevant for the structural restoration of musculoskeletal tissues interfaces. In this article, we provide an overview of the various strategies used for engineering musculoskeletal tissue interfaces with a specific focus on the recent important patents that have been issued for inventions that were specifically designed for engineering musculoskeletal interfaces as well as those that show promise to be adapted for this purpose.

The Potential of Circadian Realignment in Rheumatoid Arthritis.

In this short review, we discuss evidence supporting the modulation of peripheral circadian systems as a therapeutic strategy for rheumatoid arthritis (RA). We first review the role of proinflammatory cytokines and oxidative stress, two of the primary mediators of chronic inflammation in RA, and their regulation by circadian clock machinery. We further highlight the role of environmental and metabolic signals in regulating the central and peripheral circadian clocks, with an emphasis on seasonal variations in photoperiod and rhythmic metabolic input, respectively. Finally, we hypothesize that the entrainment and realignment of peripheral clock rhythms have the ability to modulate these mediators, improving clinical outcomes in RA patients. Our discussion emphasizes the use of light therapy and time-restricted feeding for entraining peripheral clocks either via the entrainment of the central circadian clock in suprachiasmatic nuclei (SCN) or directly by uncoupling the peripheral circadian clocks from SCN. In doing so, we highlight the use of nonpharmacologic interventions as a potential strategy for improving clinical outcomes in chronic inflammatory conditions such as RA.

Mechanical stability of a locked step-plate versus single compression screw fixation for medial displacement calcaneal osteotomy.

BACKGROUND: Reconstruction of a flatfoot commonly involves a calcaneal Medial Displacement Osteotomy (MDO) to correct hindfoot valgus in combination with soft tissue procedures. We compared fixation of an MDO using either a single, large cannulated screw versus a locking step-plate in load to failure in a cadaveric model. METHODS: Eight matched pairs of cadaveric limbs were loaded using a mechanical testing rig. Two pairs served as non-operated controls. The remaining paired limbs underwent a 10-mm MDO stabilized either with a single 7-mm screw or a step-plate with four locking screws. One pair was used as a pilot study and the remaining five pairs were loaded up to 4500 N to failure. RESULTS: In the five pairs loaded to failure, the median (with 95% CI) maximum force were 1779 N (1099-2312) and 826 N (288-1607) for the plate and screw, respectively (p = 0.043). With single screw fixation, the tuberosity fragment consistently failed by rotation and angulation into varus. With plate fixation, failure occurred as the screws cut through the internal surfaces of the tuberosity and body with no failure at the screw-plate interface. CONCLUSION: In this cadaveric model, a locked step-plate supported a significantly higher maximum force than a single large cannulated screw. CLINICAL RELEVANCE: The magnitude of the load supported by the locking step-plate suggests that allowing early weightbearing post-operation may be safe in clinical practice before union of the osteotomy.

Basal medial opening wedge first metatarsal osteotomy stabilized with a low profile wedge plate.

Twenty patients underwent 25 basal medial opening wedge osteotomies of the first metatarsal stabilized using a low-profile wedge plate in combination with a distal soft tissue release, distal metatarsal osteotomy and Akin osteotomy as required for correction of a hallux valgus deformity. The mean clinical and radiographic follow-up was 12.2 months. Pre- and post operative radiographs available in 15 cases showed that the median hallux valgus angle (HVA), intermetatarsal angle (IMA) and distal metatarsal articular angle (DMAA) were corrected from 45.5 to 13.1, 17.7 to 9.2 and 243 to 10.0 degrees respectively (p < 0.001). Final radiographic assessment for the whole series showed a median final HVA and IMA of 14.1 and 9.1 respectively. Radiographic union was noted in all but one case which was asymptomatic. One wound infection was treated with oral antibiotics, one hallux varus deformity required soft tissue reconstruction and there was one recurrence. The outcome was reported as good or satisfactory by the patients for 20 of 25 feet. Three patients reported stiffness in the first MTP joint, which improved with joint injection and manipulation. Two plates were removed for prominence. The basal medial opening wedge osteotomy stabilized with a low profile wedge plate was an effective addition for correcting a moderate to severe hallux valgus deformity as part of a double or triple first ray osteotomy.

Cobb procedure and Rose calcaneal osteotomy for the treatment of tibialis posterior tendon dysfunction.

Forty-three patients with stage 2 posterior tibialis tendon dysfunction underwent surgical reconstruction in the form of a Cobb procedure and Rose calcaneal osteotomy between 1997 and 2003, and were evaluated pre- and postoperatively. The average age was 57 years, and the mean followup time was 51 months (range 10-83). The average AOFAS score preoperatively was 58 and improved to 85 postoperatively (p < 0.0001). Sixty-six per cent of patients achieved a single heel raise. Eighty-four per cent expressed a subjective satisfaction rate, whilst 16% reported no improvement. Seventy-eight per cent of the patients were able to use normal shoes and 65% no longer required the use of any orthotics. The minor complication rate was 16% with no major complications. All osteotomies united uneventfully. Two patients have subsequently developed subtalar osteoarthritis, and six calcaneal screws had to be removed for prominence and tenderness. Our results compare very favourably with other less anatomical reconstructions, any donor site morbidity has been avoided and there have been very low complication rates.

Revision anterior cruciate ligament reconstruction using autografts with a polyester fixation device.

Twenty-nine patients who had undergone anterior cruciate ligament (ACL) revision were evaluated retrospectively between 1992 and 2000. A similar surgical technique was used in all cases. Twenty-six patients underwent revision following failed primary and revision surgery with the ABC scaffold ligament. There were 2 failed primary semitendinosus/gracilis (STG) autografts and one failed bone patella tendon bone (BPTB) autograft. Autologous hamstring tendons (STG) were used in 26 knees, quadriceps tendon in 2 and BPTB autograft in 1 knee. The Mark I Soffix soft tissue fixation device was used in 16 patients and 13 patients underwent reconstruction with the Mark II BH (Button Hole ) Soffix. Follow up evaluation included clinical examination, KT 2000 arthrometric side to side difference (SSD) assessment, Lysholm, Tegner and IKDC scoring. The average follow up time was 50+/-22 months. The overall SSD was 1.66+/-1.5 mm, a mean Lysholm score of 87.2+/-12.5 was obtained and 22 patients had an IKDC score of nearly normal (B). In the Mark II (BH Soffix) group knees were significantly tighter than in the Mark I Soffix group (P<0.05) with a mean SSD of 1.23+/-1.3 and 2.0+/-1.6 mm, respectively. However there were no significant differences in the other measured parameters between the two fixation devices. Multiply re-operated knees tended to have lower IKDC and Lysholm scores (not statistically significant). We concluded that the technique reported in this study can restore stability to the knee following failed primary or revision ACL reconstruction and the results in the non-multiply operated knees are comparable to primary reconstruction.

Evaluation of tibial bone tunnel enlargement using MRI scan cross-sectional area measurement after autologous hamstring tendon ACL replacement.

The aim of this study was to evaluate tibial bone tunnel enlargement following four-strand hamstring tendon anterior cruciate ligament (ACL) reconstruction, using a new method of magnetic resonance imaging (MRI) assessment. Correlation with clinical outcome was also examined. In a prospective study following ACL reconstruction, 24 patients underwent MRI and clinical assessment, at a mean follow-up of 6.5 months. A four-strand semitendinosus and gracilis (STG) tendon graft with the polyester Soffix (Surgicraft Ltd) fixation device was placed via an instrument guided tibial tunnel and an over-the-top femoral route. Cross-sectional area (CSA) perpendicular to the long axis of the tibial tunnel was calculated digitally at three levels, using MRI. Clinical assessment included physical examination, Lysholm subjective self-evaluation score and KT 2000 arthrometric measurement. A mean CSA tibial tunnel enlargement of 33% was found. The mean side-to-side KT-2000 arthrometric difference was 1.66 mm and the mean Lysholm score was 92. We concluded that this previously unused MRI evaluation using digital direct CSA measurements provides a highly accurate method of tunnel assessment. We found no correlation between tibial tunnel enlargement, knee stability, joint function and patient satisfaction scores in the short term.