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Background: Heterotopic ossification (HO), the abnormal formation of lamellar bone in soft nonosseous tissue, has been identified as a potential complication following a traumatic amputation or traumatic brain injury (TBI). HO occurs at a dramatically higher rate among military casualties than among civilian casualties. Most investigators agree that in order for HO to form three conditions must be present: (1) osteogenic precursor cells, (2) an inducing agent or event, and 3) an environment conducive to ostoegenesis. Therefore impacting on any of these three conditions should impact on the formation of HO. Anecdotal clinical reports seem to show a decreased incidence of HO among cigarette smokers. The negative effect of smoking on bone growth as well as poor healing overall is well established in the literature. It makes intuitive sense that tobacco smoking would negatively impact on an environment conducive for HO. A review of the literature found no published work that evaluated a possible link between HO and tobacco use. This study sought to determine if a relationship exists between tobacco use and the formation of HO., Methods: A retrospective data review was conducted of military medical records for service members (SMs) who have experienced a traumatic amputation. Cases were matched to controls on the basis of factors known to be associated with the development of HO including age, gender, comorbid TBI, and deployment status. Bivariate logistic regression models were used to test for associations between age, gender, TBI, and deployment status with tobacco use., Results: A total of 3,132 records of SMs with an amputation were included for analysis with 18% overall developing HO. Those that developed HO were more likely to be younger, have sustained a TBI and to use tobacco compared to those that did not develop HO. An odds ratio analysis found that SMs who experienced a deployment-related traumatic amputation were 7.34 times more likely, SMs with a TBI were 6.45 times more likely, and smokers were 1.27 times more likely to develop HO when compared to nondeployment-related amputations. Older age and female gender were found to be protective against developing HO. In the final model after matching on potential confounders, tobacco use was not related to HO among this sample., Discussion: The incidence of HO among SMs with a traumatic amputation or TBI was similar to that found in other research. Also found in this study and supported in the literature is age as a confounder for HO and the prevalence of tobacco use among SMs who have deployed. However, female gender as protective against the development of HO was an unexpected finding mainly because there are so few studies of SMs with traumatic amputations including women in the analysis. In the final analysis, given all the literature on the negative impact of smoking on bone healing, it seems counterintuitive that HO formation is unrelated to smoking status. The methodology used in this study has inherent limitations and a prospective study should be conducted to validate results., (Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.)

Identifying key molecules that launch regeneration has been a long-sought goal. Multiple regenerative animals show an initial wound-associated proliferative response that transits into sustained proliferation if a considerable portion of the body part has been removed. In the axolotl, appendage amputation initiates a round of wound-associated cell cycle induction followed by continued proliferation that is dependent on nerve-derived signals. A wound-associated molecule that triggers the initial proliferative response to launch regeneration has remained obscure. Here, using an expression cloning strategy followed by in vivo gain- and loss-of-function assays, we identified axolotl MARCKS-like protein (MLP) as an extracellularly released factor that induces the initial cell cycle response during axolotl appendage regeneration. The identification of a regeneration-initiating molecule opens the possibility of understanding how to elicit regeneration in other animals.

Background: As a result of the global war on terrorism, there has been a significant increase in young service members with traumatic amputations. Few published data are available on metabolic requirements for young, active individuals after traumatic limb loss, especially lower limb loss., Objective: The purpose of this study was to determine which predictive energy equation best predicted resting energy expenditure (REE) in this population., Methods: One hundred service members, 50 with at least one traumatic lower limb loss and 50 without limb loss, completed this study. Mean (standard deviation [SD]) age, height, and weight were 27.3 years (±5.3), 178.5 cm (±7.7), 86.5 kg (±15.8) for those with limb loss; and 29.4 years (±5.8), 179.1 cm (±6.7), 85.9 kg (±12.6) for those without. REE was measured using the Oxycon Mobile metabolic system (CareFusion). Measured REE was compared with the following REE equations: Mifflin-St Joer, Harris Benedict, Owen, 25 kcal/kg, and 30 kcal/kg., Results: All equations tended to underestimate or overestimate REE for both groups (P<0.001); however, the 25 kcal/kg had a more even distribution of disagreement for individuals with limb loss and without (P=0.100 and P=0.308, respectively), with 52% within ±10%., Conclusions: The 25 kcal/kg best predicts REE for young, active individuals with or without limb loss. Future studies may determine that more appropriate equations are most useful for different subgroups of this population., (Published by Elsevier Inc.)

Background: The regrowth of amputated appendage extremities and the distal tips of digits represent models of tissue regeneration in multiple vertebrate taxa. In humans, digit tip injuries, including traumatic amputation and crush injuries, are among the most common type of injury to the human hand. Despite clinical reports demonstrating natural regeneration of appendages in lower vertebrates and human digits, current treatment options are suboptimal, and are complicated by the anatomical complexities and functions of the different tissues within the digits., Results: In light of these challenges, we focus on recent advancements in understanding appendage regeneration from model organisms. We pay special attention to the cellular programs underlying appendage regeneration, where cumulative data from salamanders, fish, frogs, and mice indicate that regeneration occurs by the actions of lineage-restricted precursors. We focus on pathologic states and the interdependency that exists, in both humans and animal models, between the nail organ and the peripheral nerves for successful regeneration., Conclusions: The increased understanding of regeneration in animal models may open new opportunities for basic and translational research aimed at understanding the mechanisms that support limb regeneration, as well as amelioration of limb abnormalities and pathologies., (© 2015 Wiley Periodicals, Inc.)

Body composition and metabolism may change considerably after traumatic amputation because of muscle atrophy and an increase in adiposity. The purpose of this study was to quantify changes in weight, body composition, and metabolic rate during the first year following traumatic amputation in military servicemembers. Servicemembers without amputation were included for comparison. Participants were measured within the first 12 wk after amputation (baseline) and at 6, 9, and 12 mo after amputation. Muscle mass, fat mass, weight, and metabolic rate were measured at each time point. There was a significant increase in weight and body mass index in the unilateral group between baseline and all follow-up visits (p < 0.01). Over the 12 mo period, total fat mass and trunk fat mass increased in both unilateral and bilateral groups; however, these changes were not statistically significant over time. Muscle mass increased in both the unilateral and bilateral group despite percent of lean mass decreasing. No changes in resting metabolism or walking energy expenditure were observed in any group. The results of this study conclude that weight significantly increased because of an increase in both fat mass and muscle mass in the first year following unilateral and bilateral amputation.

In this work, the effect of walking speed on the energy expenditure in traumatic lower-limb amputees was studied. The oxygen consumption was measured in 10 transfemoral amputees, 9 transtibial amputees and 13 control subjects, while they stood and walked at different speeds from 0.3 m s(-1) to near their maximum sustainable speed. Standing energy expenditure rate was the same in lower-limb amputees and in control subjects (approximately 1.85 W kg(-1)). On the contrary, during walking, the net energy expenditure rate was 30-60% greater in transfemoral amputees and 0-15% greater in transtibial amputees than in control subjects. The maximal sustainable speed was about 1.2 m s(-1) in transfemoral amputees and 1.6 m s(-1) in transtibial amputees, whereas it was above 2 m s(-1) in control subjects. Among these three groups, the cost of transport versus speed presented a U-shaped curve; the minimum cost increased with the level of amputation, and the speed at which this minimum occurred decreased.

Regeneration of mammalian digit tips is well described; however, associated cellular or molecular events have not been studied in humans. We describe an in vitro human fetal model of response to digit tip amputation, and report expression of the transcription repressor Msx1 in the developing and regrowing human digit tip. Human fetal digits from specimens ranging from 53 to 117 days' estimated gestational age (EGA) were cultured in a defined serum-free medium with supplemented oxygen for time periods from 4 days to 4 weeks. Histology and immunohistochemistry were performed on paired control and tip-amputated digits. Regrowing tissue covered the cut end of the distal phalanx in digits up to 80 days' EGA. Msx1 expression was detected beneath the nail field in control digits to at least 70 days' EGA and at the regrowing tip of 57-day digits at 4 and 7 days post-amputation. Our results show that human fetal digits regrow tissue in vitro in response to tip amputation. This process appears spatially associated with Msx1 expression. Msx1 expression appears increased at the regrowing tip of 57-day digits by 4 days after amputation.

Limb denervation leads to reorganization of the representational zones of the somatosensory cortex. Using [11C](R)-PK11195, a sensitive in vivo marker of glial cell activation, and PET, we provide first evidence that limb denervation induces a trans-synaptic increase in [11C](R)-PK11195 binding in the human thalamus but not somatosensory cortex: these brain structures appeared morphologically normal on magnetic resonance imaging (MRI). The increased thalamic signal was detectable many years after nerve injury, indicating persistent reorganization of the thalamus. This glial activation, beyond the first-order projection area of the injured neurons, may reflect continually altered afferent activity. Our findings support the view that long-term rearrangement of cortical representational maps is significantly determined within the thalamus.

On the model of allotransplantation of m. lumbricalis, previously subjected to acute total ischemia at temperature 37-38 degrees it was shown that morphological integrity and characteristic immunohistochemical properties of the muscle remain only during two hours of the thermic ischemia. A week later surviving muscular fibres (MF) and newly forming muscular tubules (MT) were found in the transplants of the muscle. Processing with antibodies of the fast twitch type myosin filaments revealed both fast- and slow-twitch types of fibres among MF, while B- and C-typed MF were identified at defining the activity of succinat dehydrogenase (SDG). High SDG activity, corresponding to C-type fibres was observed in MT. Staining with antibodies revealed fast-twitch type myosin. After 3-hour ischemia of the muscles, few surviving MF were found, while after the 4-6-hours one only MT appeared to be present in the transplants. Thus, refering to our data, obtained in the previous works and to the results of the research it is ascertained that there is a regularity, allowing to predict critical terms of development of irreversal ischemic disturbances in the muscle of severed extremity, depending on the ischemia duration and temperature.

Noradrenergic and GABA-ergic systems were correlated and dominated in the processes of spinal cord segmentary apparatus superactivity compensation. An increase in c-GMP content in the spinal cord suggests an intensification of the activation mechanism. An increase in the c-AMP content may suggest an inhibition of the compensatory intensification of noradrenergic or GABA-ergic mechanisms.

Unlabelled: Following traumatic limb amputation it is common clinical practice to maintain the ischemic tissues in a hypothermic state until surgical reimplantation. Of all extremity tissues, muscle is the most sensitive to ischemia; it is therefore imperative that reperfusion be established before diffuse muscle necrosis. Although it has been shown both clinically and experimentally that hypothermia prolongs the viability of ischemic skeletal muscle, the presumed mechanism by which this occurs has not been confirmed at the cellular level. This study was undertaken to quantify the effect of conventional iced-saline hypothermia on anaerobic cell metabolism and high-energy phosphate depletion in traumatically devascularized muscle., Methods: Phosphorus nuclear magnetic resonance spectroscopy (31P NMR) was employed to noninvasively monitor cellular phosphocreatine (PCr), ATP, and intracellular pH over time in ischemic cat hindlimb muscle under room temperature (22 degrees C) and 1 degree C hypothermic conditions., Results: Muscular PCr depletion was significantly retarded by tissue hypothermia but the rate of ATP depletion was not. A progressive, severe cellular acidosis was observed in the room-temperature muscle. Iced tissue cooling produced a dramatic initial rise in cell pH which significantly reduced the absolute degree of subsequent acidotic changes., Significance: These findings question our understanding of hypothermic tissue preservation, which has generally been assumed to work on the basis of decreased tissue metabolism, thus conserving critical cellular ATP levels. The empirical benefit derived by cooling muscle in an iced medium may actually be related to the cellular alkalinization produced by tissue cooling, as this significantly mitigates the profound acidosis that would otherwise occur.

The difference in physiological responses to ambulation effort, of above-knee (AK) amputees, using a prosthesis with open or locked knee mechanism was investigated at the Orthopaedic Rehabilitation Department of the Loewenstein Hospital. Of seventeen patients who were examined, fourteen were vascular patients over the age of fifty, and three were young traumatic amputees. Subjects performed an unrestrained walking test, using their prosthesis with an open-knee, and then with a locked knee joint mechanism. Heart rate and walking speed were measured, while oxygen consumption was evaluated only in the young patients. Results show that the use of a locked-knee joint resulted in a lower increase in heart rate in both groups. Comfortable walking velocity, as chosen by the subject himself, was higher with a locked-knee joint in the aged group and with an open-knee joint in the younger amputees. Oxygen consumption as measured for the younger patients was higher with an open-knee joint. In conclusion, a locked knee is recommended for the older amputees as it enables a higher walking velocity and lower effort. The preference of an open-knee in the young amputees is due to their better physical condition which enables a higher walking speed although energy expenditure and heart rate are higher.