Beta adrenergic receptor antagonist can modify Pseudomonas aeruginosa biofilm formation in vitro: Implications for chronic wounds.

Non-healing wounds are a major medical challenge, affecting over 6.5 million people in the US alone, with associated healthcare costs of about $16 billion annually. They can result in prolonged hospitalizations, work loss, disability, poor quality of life, and in diabetic patients with foot ulcers, amputation of the affected limb in 25% of patients. Though chronic ulcers may arise from different underlying diseases, the unifying feature is chronic infection, driving persistent inflammation that prolongs the healing process. One of the most frequently cultured or genetically identified pathogens in skin wounds is Pseudomonas aeruginosa. This species avidly forms biofilms in the wound that impede bacterial eradication by the host's immune mechanisms and limit efficacy of systemic antibiotics. Thus, non-antibiotic approaches to limit the growth and biofilm formation of this wound pathogen would be an advance in the treatment of chronic wounds. Prior work has demonstrated that the growth of other microbial species can be modulated by catecholamine agonists and antagonists of the adrenergic receptors (ARs). Here, we demonstrate that not only can the growth of this common wound pathogen be modulated by catecholamines, but also that the beta-AR antagonists can significantly decrease their growth, and importantly, limit their ability to form biofilms. These findings suggest that beta adrenergic antagonists may have a therapeutic role in the treatment of chronic skin wounds.

Combination product of dermal matrix, preconditioned human mesenchymal stem cells and timolol promotes wound healing in the porcine wound model.

A combination product of human mesenchymal stem/stromal cells (MSCs) embedded in an extracellular matrix scaffold and preconditioned with hypoxia and the beta-adrenergic receptor antagonist, timolol, combined with sustained timolol application post implantation, has shown promising results for improving wound healing in a diabetic mouse model. In the present study, we extend those findings to the more translatable large animal porcine wound model and show that the combined treatment promotes wound reepithelialization in these excisional wounds by 40.2% and increases the CD31 immunostaining marker of angiogenesis compared with the matrix control, while maintaining an accumulated timolol plasma concentration below the clinically safe level of 0.3 ng/mL after the 15-day course of topical application. Human GAPDH was not elevated in the day 15 wounds treated with MSC-containing device relative to wounds treated with matrix alone, indicating that the xenografted human MSCs in the treatment do not persist in these immune-competent animals after 15 days. The work demonstrates the efficacy and safety of the combined treatment for improving healing in the clinically relevant porcine wound model.

Repurposing Ophthalmologic Timolol for Dermatologic Use: Caveats and Historical Review of Adverse Events.

Ophthalmic timolol solution is increasingly being repurposed as a topical therapeutic for a variety of dermatologic diseases, including pyogenic granulomas, infantile hemangiomas, and chronic wounds. There are no published guidelines or protocols for use in these indications in adults, and the dermatologic community may not be familiar with adverse events that have been extensively documented relating to its ophthalmic use. We review the evidence available relating to adverse events to topical timolol use to evaluate its safety in dermatologic applications and to alert clinicians to screening and monitoring that is needed when repurposing this drug for dermatologic use. The majority of serious adverse events associated with ophthalmic timolol were reported in the first 7 years of use, between 1978 and 1985, of which most common were cardiovascular and respiratory events, but also included 32 deaths. The available evidence suggests that ophthalmic timolol safety profiling may have been incomplete prior to widespread use. Recent clinical trials for dermatologic indications have focused on documenting efficacy and have not had rigorous monitoring for potential adverse events. Topical timolol may be safe and effective for the treatment of various dermatologic conditions in patients whose medical histories have been carefully reviewed for evidence of pre-existing cardiac or pulmonary disease and are monitored for potential adverse events. Despite the wide use of timolol in ophthalmologic practice, safe dermatologic repurposing requires recognition of the potential for facilitated systemic absorption though the skin and appreciation of its history of adverse events.

Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice.

Diabetic foot ulcers are a major health care concern with limited effective therapies. Mesenchymal stem cell (MSC)-based therapies are promising treatment options due to their beneficial effects of immunomodulation, angiogenesis, and other paracrine effects. We investigated whether a bioengineered scaffold device containing hypoxia-preconditioned, allogeneic human MSCs combined with the beta-adrenergic antagonist timolol could improve impaired wound healing in diabetic mice. Different iterations were tested to optimize the primary wound outcome, which was percent of wound epithelialization. MSC preconditioned in 1 µM timolol at 1% oxygen (hypoxia) seeded at a density of 2.5 × 105 cells/cm2 on Integra Matrix Wound Scaffold (MSC/T/H/S) applied to wounds and combined with daily topical timolol applications at 2.9 mM resulted in optimal wound epithelialization 65.6% (24.9% ± 13.0% with MSC/T/H/S vs 41.2% ± 20.1%, in control). Systemic absorption of timolol was below the HPLC limit of quantification, suggesting that with the 7-day treatment, accumulative steady-state timolol concentration is minimal. In the early inflammation stage of healing, the MSC/T/H/S treatment increased CCL2 expression, lowered the pro-inflammatory cytokines IL-1B and IL6 levels, decreased neutrophils by 44.8%, and shifted the macrophage ratio of M2/M1 to 1.9 in the wound, demonstrating an anti-inflammatory benefit. Importantly, expression of the endothelial marker CD31 was increased by 2.5-fold with this treatment. Overall, the combination device successfully improved wound healing and reduced the wound inflammatory response in the diabetic mouse model, suggesting that it could be translated to a therapy for patients with diabetic chronic wounds.

A tractable, simplified ex vivo human skin model of wound infection.

The prevalence of infection in chronic wounds is well documented in the literature but not optimally studied due to the drawbacks of current methodologies. Here, we describe a tractable and simplified ex vivo human skin model of infection that addresses the critical drawbacks of high costs and limited translatability. Wounds were generated from excised abdominal skin from cosmetic procedures and cultured, inoculated with Staphylococcus aureus strain UAMS-1, or under aseptic conditions. After three days, the infected wounds exhibited biofilm formation and significantly impaired reepithelialization compared to the control. Additionally, promigratory and proreparative genes were significantly downregulated, while proinflammatory genes were significantly upregulated, demonstrating molecular characterizations of impaired healing as in chronic wounds. This model allows for a simplified and versatile tool for the study of wound infection and subsequent development of novel therapies.

Drug-Induced Pancreatitis: A Rare Manifestation of Doxycycline Administration.

CONTEXT: Drug-induced pancreatitis (DIP) is rare, but as there are no systematic data on it, the true incidence is not known. Although numerous and varied drugs have been associated with DIP, the clinical evidence on doxycycline-induced pancreatitis is sparse. CASE REPORT: We present the case of a 58-year-old female who presented with complaints of nausea and severe epigastric pain. Her medications included doxycycline which she had been on for only 2 days. Computed tomography of her abdomen showed mild enlargement of body of the pancreas with peripancreatic fatty infiltration, along with lipase level suggestive of acute pancreatitis. In the absence of classical risk factors for acute pancreatitis, a diagnosis of DIP secondary to doxycycline therapy was made. Immediate withdrawal of the drug was accompanied by relief of symptoms and resolution of pancreatitis. CONCLUSION: This report implicates doxycycline as an etiological factor for acute pancreatitis. Knowledge regarding doxycycline related pancreatitis is of paramount importance in order to diagnose cases early and institute effective treatment in patients who are undergoing therapy with this drug.

Cervical vertebral actinomycosis mimicking malignancy in a paediatric patient.

Actinomyces spp are found in the flora of the oral cavity and vagina and may cause infection with abscess formation and draining sinuses. Cervicofacial manifestations of actinomycosis involve head and neck soft tissue, however, spread to the cervical spine is rare. We report a case of an 8-year-old boy, presenting with neck pain for 1 month and denying a history of trauma or procedures. Radiography revealed an ulceration of the posterior oropharyngeal mucosa with a defect extending to the C1-C2 vertebra, mimicking a neoplastic process. The patient underwent laryngoscopy and multiple biopsies were taken from the ulcer and bone, showing severe osteomyelitis and intraosseous filamentous organisms, morphologically consistent with Actinomyces spp. The boy received long-term antibiotics with response to treatment. Actinomycosis has rarely been reported in the cervical vertebrae of paediatric patients. This should be considered as a differential diagnosis for such a presentation as prompt antibiotic treatment may be lifesaving.

A Systematic Review of Acquired Uterine Arteriovenous Malformations: Pathophysiology, Diagnosis, and Transcatheter Treatment.

Objective An acquired uterine arteriovenous malformation (AVM) is a rare cause of vaginal bleeding and, although hysterectomy is the definitive therapy, transcatheter embolization (TCE) provides an alternative treatment option. This systematic review presents the indications, technique, and outcomes for transcatheter treatment of the acquired uterine AVMs. Study Design Literature databases were searched from 2003 to 2013 for eligible clinical studies, including the patient characteristics, procedural indication, results, complications, as well as descriptions on laterality and embolic agents utilized. Results A total of 40 studies were included comprising of 54 patients (average age of 33.4 years). TCE had a primary success rate with symptomatic control of 61% (31 patients) and secondary success rate of 91% after repeated embolization. When combined with medical therapy, symptom resolution was noted in 48 (85%) patients without more invasive surgical procedures. Conclusion Low-level evidence supports the role of TCE, including in the event of persistent bleeding following initial embolization, for the treatment of acquired uterine AVMs. The variety of embolic agents and laterality of approach delineate the importance of refining procedural protocols in the treatment of the acquired uterine AVM. Condensation A review on the management of patients with acquired uterine AVMs.

Nonthrombotic Pulmonary Embolism: A Potential Complication of Polyacrylamide Hydrogel Cosmetic Injection.

Context. Polyacrylamide hydrogel (PAAG) has gained importance as a synthetic soft tissue filling agent. It has been commonly employed by physicians in Europe for facial contouring and soft tissue augmentation. Previously, PAAG is considered nontoxic and well tolerated with a few mild procedural complications. Case Presentation. A 26-year-old female was hospitalized for dry cough, worsening dyspnea, and chest discomfort after 3 hours of multiple PAAG injections in buttocks. The patient's condition deteriorated and rapidly advanced to acute respiratory failure. Therein, the diagnosis of nonthrombotic pulmonary embolism (NTPE) was established on standard set of investigations. She was intubated; corticosteroid and empiric antibiotic therapy was initiated resulting in improvement of her condition. Subsequently, extubation was done, and she was discharged from the hospital after an uneventful recovery. On 1-month follow-up, the patient had no previous symptoms. Conclusion. This report implicates clinicians to maintain a high index of suspicion for NTPE in patients presenting with respiratory symptoms following PAAG usage.

Pineal parenchymal tumour of intermediate differentiation: a rare differential diagnosis of pineal region tumours.

Pineal parenchymal tumours of intermediate differentiation are a rare type of pineal parenchymal tumours. As indicated by their name, these tumours fall between pineoblastoma (a malignant pineal parenchymal tumour) and pineocytoma (a benign pineal parenchymal tumour). In this article, we present a case of pineal parenchymal tumour of intermediate differentiation that was successfully treated by resection via the supracerebellar approach. We also discuss the differential consideration based on epidemiological, pathological and radiological findings.

Dopamine transporter inhibition is necessary for cocaine-induced increases in dendritic spine density in the nucleus accumbens.

Repeated exposure to cocaine produces changes in the nervous system that facilitate drug-seeking behaviors. These drug-seeking behaviors have been studied with animal models, such as cocaine-induced locomotor sensitization. Cocaine is hypothesized to induce locomotor sensitization by neural changes, including an increase in the density of spines on the dendrites of neurons in the nucleus accumbens (NAC). However, how cocaine increases dendritic spine density in the NAC has been difficult to discern because cocaine inhibits the function of multiple targets, including the transporters for dopamine, serotonin, and norepinephrine. Previously, our lab created a tool that is useful for determining how inhibiting the dopamine transporter (DAT) contributes to the effects of cocaine by generating mice that express a cocaine-insensitive DAT (DAT-CI mice). In this study, we used DAT-CI mice to determine the contribution of DAT inhibition in cocaine-induced increases in dendritic spine density in the NAC. We repeatedly injected DAT-CI mice with either cocaine or saline, and measured both dendritic spine density in the NAC and locomotor activity. Unlike wild-type mice, DAT-CI mice did not show an increase in dendritic spine density in the NAC or in locomotor activity in response to repeated injections of cocaine. These data show that cocaine-induced increases in dendritic spine density in the NAC require DAT inhibition. Thus, DAT-inhibition may play a role in mediating the long-lasting neural changes associated with drug addiction.