A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma.

This study aims to develop a reproducible rat model for post-traumatic bisphosphonate-related osteonecrosis of the jaw (BRONJ). In our previous studies using dental extraction as an inducing factor, only 30%-60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified the zoledronate regimen and introduced repeated surgical extraction to illicit quantifiable BRONJ in all animals. Eighty retired-breeder female Sprague-Dawley rats were divided between the treatment (i.v. zoledronate; 80 µg/kg/week for 13 weeks) and control (saline) groups. On week 13, the left mandibular first molar was surgically extracted, followed by the second molar a week later. Animals were euthanized at 1-week, 2-weeks, and 8-weeks following extraction. The occurrence and severity of BRONJ were scored in each animal based on gross and MicroCT analysis. Parameters of bone formation and osteoclast functions at the extraction site were compared between groups. All zoledronate-treated animals developed a severe case of BRONJ that fulfilled the clinical definition of the condition in humans. Osteoclast attachment continued to be defective eight weeks after stopping the treatment. There were no signs of kidney or liver toxicity. Our data confirmed that repeated surgical extraction (major trauma) by itself consistently precipitated massive bone necrosis in ZA-treated animals, eliminating the need to induce pre-existing infection or comorbidity. These results will be the basis for further studies examining the in-vivo pathogenesis and prevention of BRONJ.

Evidence that increased 5-HT release evokes region-specific effects on blood-oxygenation level-dependent functional magnetic resonance imaging responses in the rat brain.

This study aimed to determine the potential of in vivo functional magnetic resonance imaging (fMRI) methods as a non-invasive means of detecting effects of increased 5-HT release in brain. Changes in blood-oxygenation level-dependent (BOLD) contrast induced by administration of the 5-HT-releasing agent, fenfluramine, were measured in selected brain regions of halothane-anesthetized rats. Initial immunohistochemical measurements of the marker of neural activation, Fos, confirmed that in halothane-anesthetized rats fenfluramine (10 mg/kg i.v.) evoked cellular responses in cortical regions which were attenuated by pre-treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (300 mg/kg i.p. once daily for 2 days). Fenfluramine-induced Fos was demonstrated in numerous glutamatergic pyramidal neurons (Fos/excitatory amino acid carrier 1 (EAAC1) co-labeled), but also a small number of GABA interneurons (Fos/glutamic acid decarboxylase (GAD)(67) colabeled). Fenfluramine (10 mg/kg i.v.) evoked changes in BOLD signal intensity in a number of cortical and sub-cortical regions with the greatest effects being observed in the nucleus accumbens (-13.0%+/-2.7%), prefrontal cortex (-10.1%+/-3.2%) and motor cortex (+2.3%+/-1.0%). Pre-treatment with p-chlorophenylalanine, significantly attenuated the response to fenfluramine (10 mg/kg i.v.) in all regions with the exception of the motor cortex which showed a trend. These experiments demonstrate that increased 5-HT release evokes region-specific changes in the BOLD signal in rats, and that this effect is attenuated in almost all regions by 5-HT depletion. These findings support the use of fMRI imaging methods as a non-invasive tool to study 5-HT function in animal models, with the potential for extension to clinical studies.

In vivo evidence that 5-HT(2C) receptors inhibit 5-HT neuronal activity via a GABAergic mechanism.

BACKGROUND AND PURPOSE: Recent evidence suggests that 5-HT(2C) receptor activation may inhibit midbrain 5-HT neurones by activating neighbouring GABA neurones. This hypothesis was tested using the putative selective 5-HT(2C) receptor agonist, WAY 161503. EXPERIMENTAL APPROACH: The effect of WAY 161503 on 5-HT cell firing in the dorsal raphe nucleus (DRN) was investigated in anaesthetised rats using single unit extracellular recordings. The effect of WAY 161503 on DRN GABA neurones was investigated using double label immunohistochemical measurements of Fos, glutamate decarboxylase (GAD) and 5-HT(2C) receptors. Finally, drug occupancy at 5-HT(2A) receptors was investigated using rat positron emission tomography and ex vivo binding studies with the 5-HT(2A) receptor radioligand [(11)C]MDL 100907. KEY RESULTS: WAY 161503 caused a dose-related inhibition of 5-HT cell firing which was reversed by the 5-HT(2) receptor antagonist ritanserin and the 5-HT(2C) receptor antagonist SB 242084 but not by the 5-HT(1A) receptor antagonist WAY 100635. SB 242084 pretreatment also prevented the response to WAY 161503. The blocking effects of SB 242084 likely involved 5-HT(2C) receptors because the drug did not demonstrate 5-HT(2A) receptor occupancy in vivo or ex vivo. The inhibition of 5-HT cell firing induced by WAY 161503 was partially reversed by the GABA(A) receptor antagonist picrotoxin. Also, WAY 161503 increased Fos expression in GAD positive DRN neurones and DRN GAD positive neurones expressed 5-HT(2C) receptor immunoreactivity. CONCLUSIONS AND IMPLICATIONS: These findings indicate that WAY 161503 inhibits 5-HT cell firing in the DRN in vivo, and support a mechanism involving 5-HT(2C) receptor-mediated activation of DRN GABA neurones.

Spontaneous pneumomediastinum presenting as jaw pain during labor.

BACKGROUND: Pneumomediastinum, or presence of free air within the mediastinum, is a rare complication of labor. Common symptoms of this condition include chest pain, dyspnea, and subcutaneous emphysema. CASE: A woman complained of right jaw pain 90 minutes after the onset of her second stage of labor. On examination, she was found to have swelling and crepitus over her face, neck, and supraclavicular region. A chest radiograph demonstrated a pneumomediastinum, which resolved spontaneously. CONCLUSION: Pneumomediastinum is associated with Valsalva maneuvers such as those seen during the second stage of labor. We report jaw pain as an unusual presenting symptom of this rare condition. Familiarity with the presenting symptoms of a pneumomediastinum is imperative for appropriate treatment and monitoring for significant complications.

Burrowing into prion disease.

Mice received intra-hippocampal injections of scrapie-infected brain homogenate. Open field activity increased from around week 12 post-injection. Concomitantly the tendency to displace food from a tube inside the home cage decreased. The food was generally dug out with the feet, rather than carried by mouth, so its displacement was called burrowing. Food restriction was unnecessary for this burrowing to occur. Only later, around 18 weeks, did more general motor impairments develop. As burrowing in scrapie-infected mice decreased when open field activity increased, and preceded later motor impairments, it was not due to motor dysfunction. Burrowing is a simple, sensitive, objective, ethological measure, sensitive to preclinical prion disease. Other potential applications are in transgenic and knockout mice, models of ageing and Alzheimer's disease, and pharmacology, particularly neuroleptics.

Invitation to a shared community ministry.

Health care reform presents new challenges as community clergy, health care chaplains, and parish nurses seek to provide spiritual care. This contribution describes both the advantages and barriers to a shared community ministry. Collaboration among these professionals can provide an important continuum of spiritual care. Health care chaplains can serve as a vital link between patients and their other spiritual caregivers. They should welcome community clergy as part of the healing team and offer resources such as residency programs and seminars. Parish nurses can expand the health ministry of the church and help community clergy and chaplains provide spiritual support. The skills and gifts of each can weave a shared community ministry to provide a holistic approach to the spiritual needs of congregants.

Docetaxel extravasation causing significant delayed tissue injury.

PURPOSE: Docetaxel is a relatively new taxane that has not been associated with significant tissue injury after extravasation. We present a case of a patient who had grade 4 tissue toxicity after extravasation of docetaxel infused through a peripheral intravenous site. CASE REPORT: A 71-year-old female was being treated for recurrent ovarian cancer with docetaxel and carboplatin. Shortly after the docetaxel infusion began, she experienced docetaxel extravasation into the dorsum of her left hand. The infusion was halted, and then the administration was continued in a peripheral intravenous site in the other upper extremity. Erythema was noted by the patient on the dorsum of her left hand 6 days after infiltration. The following day, the patient noted severe pain, decreased function, and blistering along with increased erythema. The patient presented to the gynecology oncology clinic 11 days after the extravasation injury occurred. Conservative management was undertaken, and over the next 4 weeks the patient had resolution of the skin changes and full return of function. CONCLUSION: Docetaxel can cause significant delayed tissue injury if extravasation occurs.