Mice lacking substance P have normal bone modeling but diminished bone formation, increased resorption, and accelerated osteopenia with aging.

Substance P (SP) is a sensory neuropeptide that is expressed by the neurons innervating bone. There is considerable evidence that SP can regulate bone cell function in vitro, but it is unclear whether SP modulates bone modeling or remodeling in vivo. To answer this question we characterized the bone phenotype of mice with deletion of the Tac1 gene expressing SP. The phenotypes of 2-month-old and 5-month-old SP deficient mice and their wildtype controls were characterized by using µCT imaging, static and dynamic bone histomorphometry, and urinary deoxypyridinoline cross-links (DPD) measurement. No differences in bone phenotypes were observed between the 2 strains at 2 months of age. By 5 months both the wildtype and SP deficient mice had developed cancellous osteopenia, but relative to the wild-type mice the SP deficient mice had significantly greater cancellous bone loss. The SP deficient mice also exhibited decreased bone formation, increased osteoclast number, and increased urinary DPD levels. Cortical defect early repair was delayed in 5-month-old mice lacking SP. Collectively, these findings indicate that SP signaling is not required for bone modeling, but SP signaling reduces age-related osteopenia and accelerates cortical defect reparation, data supporting the hypothesis that SP is an anabolic physiologic regulator of bone metabolism.

Air embolism during operative hysteroscopy: TEE-guided resuscitation.

During hysteroscopic surgery there are concerns about potential complications such as venous air and gas embolism. The incidence of subclinical air emboli events during operative hysteroscopy is significantly underestimated. The manifestations of this complication may range from an unnoticeable decrease in P(ET)CO(2) to the need for resuscitation. Three cases of air embolism with variable outcomes occurring during general anesthesia for operative hysteroscopy in otherwise healthy patients are presented.

The role of enhanced cutaneous IL-1beta signaling in a rat tibia fracture model of complex regional pain syndrome.

Tibia fracture in rats initiates a syndrome resembling the complex regional pain syndrome type I. Accumulating evidence indicates that IL-1beta is involved in the modulation of nociceptive information and it acts as an intermediate inflammatory mediator via up-regulation of NGF. We hypothesized that IL-1beta signaling might mediate the development of the CRPS-like changes after tibial fracture, either directly or by stimulating NGF expression. Rats underwent distal tibia fracture and casting for 4 weeks and were chronically treated with an IL-1 receptor antagonist (IL-1ra). Nociceptive testing and assessment of edema and hindpaw warmth were performed at baseline and after cast removal. Bone microarchitecture was evaluated by micro-computed tomography. Confocal immunofluorescence and in situ hybridization techniques were used to evaluate changes in the cutaneous expression of IL-1beta at 4 weeks post-fracture. The nociceptive and vascular effects of intraplantar IL-1beta injections were evaluated in intact rats at different time points after injection. We found that: (1) IL-1ra reduced fracture-induced nociceptive sensitization, but did not decrease hindpaw edema or warmth, (2) fracture chronically up-regulated IL-1beta mRNA and protein expression in hindpaw skin keratinocytes, (3) IL-1beta intraplantar injection induced mechanical allodynia in a dose-dependent manner and stimulated keratinocyte NGF expression in the hindpaw skin, and (4) intraplantar injection of NGF-induced nociceptive sensitization. Collectively, these results indicate that cutaneous IL-1beta signaling can contribute to chronic regional nociceptive sensitization after fracture, possibly by stimulating NGF over-expression in keratinocytes. Our data also highlight the importance of the keratinocyte as the primary source of post-traumatic IL-1beta over-expression.

Pentoxifylline attenuates nociceptive sensitization and cytokine expression in a tibia fracture rat model of complex regional pain syndrome.

BACKGROUND: Tibia fracture in rats evokes chronic hindpaw warmth, edema, allodynia, and regional osteopenia, a syndrome resembling complex regional pain syndrome (CRPS). Previous studies suggest that the pathogenesis of some of these changes involves an exaggerated regional inflammatory response to injury and we postulated that inflammatory cytokines contribute to the development of CRPS-like changes after fracture. METHODS: The distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were given drinking water with or without the cytokine inhibitor pentoxifylline (PTX) starting the day before fracture and continuing for 4 weeks, after which time the cast was removed and multiple assays were performed in the hindpaw. PCR and immunoassays were used to evaluate changes in cytokine expression. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured by microcomputed tomography (microCT). RESULTS: Tibia fracture chronically up-regulated TNFalpha, IL-1beta and IL-6 mRNA and protein levels in hindpaw skin and PTX treatment significantly reduced the mRNA expression and cytokine protein levels for all these cytokines. PTX inhibited the nociceptive sensitization and some vascular changes, but had insignificant effects on most of the bone-related parameters measured in these studies. Immunostaining of hindpaw skin was negative for immunocyte infiltration at 4 weeks post-fracture. CONCLUSIONS: These results suggest that pro-inflammatory cytokines contribute to the nociceptive and vascular sequelae of fracture and that PTX treatment can reverse these CRPS-like changes.

Effect of anti-NGF antibodies in a rat tibia fracture model of complex regional pain syndrome type I.

Tibia fracture in rats evokes chronic hindpaw warmth, edema, allodynia, and regional osteopenia resembling the clinical characteristics of patients with complex regional pain syndrome type I (CRPS I). Nerve growth factor (NGF) has been shown to support nociceptive and other types of changes found in neuropathic pain models. We hypothesized that anti-NGF antibodies might reduce one or more of the CRPS I-like features of the rat fracture model. For our studies one distal tibia of each experimental rat was fractured and casted for 4 weeks. The rats were injected with anti-NGF or vehicle at days 17 and 24 post-fracture. Nociceptive testing as well as assessment of edema and hindpaw warmth were followed during this period. Molecular and biochemical techniques were used to follow cytokine, NGF and neuropeptide levels in hindpaw skin and sciatic nerves. Lumbar spinal cord Fos immunostaining was performed. Bone microarchitecture was measured using microcomputed tomography (microCT). We found that tibia fracture upregulated NGF expression in hindpaw skin and tibia bone along with sciatic nerve neuropeptide content. We also found nociceptive sensitization, enhanced spinal cord Fos expression, osteopenia and enhanced cytokine content of hindpaw skin on the side of the fracture. Anti-NGF treatment reduced neuropeptide levels in sciatic nerve and reduced nociceptive sensitization. There was less spinal cord Fos expression and bone loss in the anti-NGF treated animals. Conversely, anti-NGF did not decrease hindpaw edema, warmth or cytokine production. Collectively, anti-NGF reduced some but not all signs characteristic of CRPS illustrating the complexity of CRPS pathogenesis and NGF signaling.

Bone microstructure and its associated genetic variability in 12 inbred mouse strains: microCT study and in silico genome scan.

UNLABELLED: MicroCT analysis of 12 inbred strains of mice identified 5 novel chromosomal regions influencing skeletal phenotype. Bone morphology varied in a compartment- and site-specific fashion across strains and genetic influences contributed to the morphometric similarities observed in femoral and vertebral bone within the trabecular bone compartment. INTRODUCTION: Skeletal development is known to be regulated by both heritable and environmental factors, but whether genetic influence on peak bone mass is site- or compartment-specific is unknown. This study examined the genetic variation of cortical and trabecular bone microarchitecture across 12 strains of mice. MATERIALS AND METHODS: MicroCT scanning was used to measure trabecular and cortical bone morphometry in the femur and vertebra of 12 strains of 4-month-old inbred male mice. A computational genome mapping technique was used to identify chromosomal intervals associated with skeletal traits. RESULTS: Skeletal microarchitecture varied in a compartment- and site-specific fashion across strains. Genome mapping identified 13 chromosomal intervals associated with skeletal traits and 5 of these intervals were novel. Trabecular microarchitecture in different bone sites correlated across strains and most of the chromosomal intervals associated with these trabecular traits were shared between skeletal sites. Conversely, no chromosomal intervals were shared between the trabecular and cortical bone compartments in the femur, even though there was a strong correlation for these different bone compartments across strains, suggesting site-specific regulation by environmental or intrinsic factors. CONCLUSION: In summary, these data confirm that there are distinct genetic determinants that define the skeletal phenotype at the time when peak bone mass is being acquired, and that genomic regulation of bone morphology is specific for skeletal compartment.

TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I.

Tibia fracture in rats initiates a cascade of nociceptive, vascular, and bone changes resembling complex regional pain syndrome type I (CRPS I). Previous studies suggest that the pathogenesis of these changes is attributable to an exaggerated regional inflammatory response to injury. We postulated that the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) might mediate the development of CRPS-like changes after fracture. RT-PCR and EIA assays were used to evaluate changes in TNF expression and content in skin, nerve, and bone after fracture. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured using microcomputed tomography. Lumbar spinal cord Fos immunostaining was performed for quantification of Fos positive neurons. After baseline testing, the distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were subcutaneously injected either with a soluble TNF receptor type 1 (sTNF-R1, 5mg/kg/d) or saline every 3 days over 28 days and then were retested at 4 weeks post-fracture. Tibia fracture chronically upregulated TNF expression and protein levels in the hindpaw skin and sciatic nerve. After fracture the rats developed hindpaw mechanical allodynia and unweighting, which were reversed by sTNF-R1 treatment. Consistent with the behavioral data, spinal Fos increased after fracture and this effect was inhibited by sTNF-R1 treatment. Collectively, these data suggest that facilitated TNF signaling in the hindlimb is an important mediator of chronic regional nociceptive sensitization after fracture, but does not contribute to the hindlimb warmth, edema, and bone loss observed in this CRPS I model.

Propofol infusion syndrome: a case of increasing morbidity with traumatic brain injury.

A previously healthy 16-year-old boy with a closed, severe traumatic brain injury was admitted to a surgical and trauma intensive care unit. He was given a continuous infusion of propofol for sedation and to control intracranial pressure. About 3 days after the propofol infusion was started, metabolic acidosis and rhabdomyolysis developed. Acute renal failure ensued as a result of the rhabdomyolysis. Tachycardia with wide QRS complexes developed without hyperkalemia. The patient died of refractory cardiac dysrhythmia and circulatory collapse approximately 36 hours after the first signs of propofol infusion syndrome appeared. Propofol infusion syndrome is a rare but frequently fatal complication in critically ill children who are given prolonged high-dose infusions of the drug. The syndrome is characterized by severe metabolic acidosis, rhabdomyolysis, acute renal failure, refractory myocardial failure, and hyperlipidemia. Despite several publications on the subject in the past decade, most cases still seem to remain undetectable.