Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - A nationwide trial.

The clinical presentation of patients with slow-flow vascular malformations is very heterogeneous. High clinical burden and subsequent reduced health-related quality of life is something they have in common. There is an unmet medical need for these patients for whom regular treatments like surgery and embolization are either insufficient or technically impossible. Sirolimus has been reported to be effective and overall well-tolerated in most patients. However, the main limitation of sirolimus is the reported high toxicity, especially when target levels of 10-15 ng/mL are being used. We report the results of a phase IIB single-arm open-label clinical trial consisting of 68 (67 in the challenge phase and 68 in the rechallenge phase) evaluable patients (children n = 33 and adults n = 35) demonstrating that treatment with low sirolimus target levels (4-10 ng/mL) is effective in 79.1% of the patients. When sirolimus treatment was stopped, the majority of patients experienced a recurrence of symptoms, supporting prolonged or even lifelong treatment requirement. Adults experienced a higher baseline pain score compared with children, having an estimated marginal mean of 6.2 versus 4.1, p < 0.05; however, they showed a similar decrease to children. Furthermore, the pediatric population experienced less often a sirolimus-related grade I-IV adverse event (35.9% vs. 64.1%, p > 0.05) compared with adults. Additionally, response rates were higher in children compared with adults (93.8% vs. 65.7%, p < 0.05), and children responded faster (28 vs. 91 days, p < 0.05). These results suggest benefits of sirolimus in patients with slow-flow vascular malformations and support its initiation as young as possible.

Hedgehog signaling promotes endoneurial fibroblast migration and Vegf-A expression following facial nerve injury.

BACKGROUND: Peripheral nerve injuries are a common clinical problem which may result in permanent loss of motor or sensory function. A better understanding of the signaling pathways that lead to successful nerve regeneration may help in discovering new therapeutic targets. The Hedgehog (Hh) signaling pathway plays significant roles in nerve development and regeneration. In a mouse model of facial nerve injury, Hedgehog-responsive fibroblasts increase in number both at the site of injury and within the distal nerve. However, the role of these cells in facial nerve regeneration is not fully understood. We hypothesize that the Hh pathway plays an angiogenic and pro-migratory role following facial nerve injury. METHODS: Hedgehog pathway modulators were applied to murine endoneurial fibroblasts isolated from the murine facial nerve. The impact of pathway modulation on endoneurial fibroblast migration and cell proliferation was assessed. Gene expression changes of known Hedgehog target genes and the key angiogenic factor Vegf-A were determined by qPCR. In vivo, mice were treated with pathway agonist (SAG21k) and injured facial nerve specimens were analyzed via immunofluorescence and in situ hybridization. RESULTS: Hedgehog pathway activation in facial nerve fibroblasts via SAG21k treatment increases Gli1 and Ptch1 expression, the rate of cellular migration, and Vegf-A expression in vitro. In vivo, expression of Gli1 and Vegf-A expression appears to increase after injury, particularly at the site of nerve injury and the distal nerve, as detected by immunofluorescence and in situ hybridization. Additionally, Gli1 transcripts co-localize with Vegf-A following transection injury to the facial nerve. DISCUSSION: These findings describe an angiogenic and pro-migratory role for the Hedgehog pathway mediated through effects on nerve fibroblasts. Given the critical role of Vegf-A in nerve regeneration, modulation of this pathway may represent a potential therapeutic target to improve facial nerve regeneration following injury.

"Cloud" assemblies: quantum dots form electrostatically bound dynamic nebulae around large gold nanoparticles.

Dynamic self-assembled structures of nanoparticles can be produced using predominantly electrostatic interactions. Such assemblies were made from large, positively charged Au metal nanoparticles surrounded by an electrostatically bound cloud of smaller, negatively charged CdSe/ZnS or CdTe quantum dots. At low concentrations they are topologically similar to double electric layers of ions and corona-like assemblies linked by polymer chains. They can also be compared to the topological arrangement of some planetary systems in space. The great advantages of the cloud assemblies are (1) their highly dynamic nature compared to more rigid covalently bound assemblies, (2) simplicity of preparation, and (3) exceptional versatility in components and resulting optical properties. Photoluminescence intensity enhancement originating from quantum resonance between excitons and plasmons was observed for CdSe/ZnS quantum dots, although CdTe dots displayed emission quenching. To evaluate more attentively their dynamic behavior, emission data were collected for the cloud-assemblies with different ratios of the components and ionic strengths of the media. The emission of the system passes through a maximum for 80 QDs ∶ 1 Au NP as determined by the structure of the assemblies and light absorption conditions. Ionic strength dependence of luminescence intensity contradicts the predictions based on the Gouy-Chapman theory and osmotic pressure at high ionic strengths due to formation of larger chaotic colloidally stable assemblies. "Cloud" assemblies made from different nanoscale components can be used both for elucidation of most fundamental aspects of nanoparticle interactions, as well as for practical purposes in sensing and biology.

Light-controlled self-assembly of semiconductor nanoparticles into twisted ribbons.

The collective properties of nanoparticles manifest in their ability to self-organize into complex microscale structures. Slow oxidation of tellurium ions in cadmium telluride (CdTe) nanoparticles results in the assembly of 1- to 4-micrometer-long flat ribbons made of several layers of individual cadmium sulfide (CdS)/CdTe nanocrystals. Twisting of the ribbons with an equal distribution of left and right helices was induced by illumination with visible light. The pitch lengths (250 to 1500 nanometers) varied with illumination dose, and the twisting was associated with the relief of mechanical shear stress in assembled ribbons caused by photooxidation of CdS. Unusual shapes of multiparticle assemblies, such as ellipsoidal clouds, dog-bone agglomerates, and ribbon bunches, were observed as intermediate stages. Computer simulations revealed that the balance between attraction and electrostatic repulsion determines the resulting geometry and dimensionality of the nanoparticle assemblies.

In vitro toxicity testing of nanoparticles in 3D cell culture.

Common 2D cell cultures do not adequately represent the functions of 3D tissues that have extensive cell-cell and cell-matrix interactions, as well as markedly different diffusion/transport conditions. Hence, testing cytotoxicity in 2D cultures may not accurately reflect the actual toxicity of nanoparticles (NPs) and other nanostructures in the body. To obtain more adequate and detailed information about NP-tissue interactions, we here introduce a 3D-spheroid-culture-based NP toxicology testing system. Hydrogel inverted colloidal crystal (ICC) scaffolds are used to create a physiologically relevant and standardized 3D liver tissue spheroid model for in vitro assay application. Toxicity of CdTe and Au NPs are tested in both 2D and 3D spheroid cultures. The results reveal that NP toxic effects are significantly reduced in the spheroid culture when compared to the 2D culture data. Tissue-like morphology and phenotypic change are identified to be the major factors in diminishing toxicity. Acting as an intermediate stage bridging in vitro 2D and in vivo, our in vitro 3D cell-culture model would extend current cellular level cytotoxicity to the tissue level, thereby improving the predictive power of in vitro NP toxicology.

Cobalt chloride attenuates hypobaric hypoxia induced vascular leakage in rat brain: molecular mechanisms of action of cobalt chloride.

This study reports the efficacy of cobalt preconditioning in preventing hypobaric hypoxia induced vascular leakage (an indicator of cerebral edema) using male Sprague-Dawley rats as model system. Exposure of animals to hypobaric hypoxia led to a significant increase in vascular leakage, reactive oxygen species (ROS), nitric oxide (NO), and vascular endothelial growth factor (VEGF) levels. There was a marked increase in Nuclear Factor kappaB (NFkappaB) DNA binding activity and levels of pro-inflammatory cytokines such as Monocyte chemoattractant protein (MCP-1), Interferon-gamma (IFN-gamma), Interleukin-1 (IL-1), and Tumor Necrosis Factor-alpha (TNF-alpha) and cell adhesion molecules such as Vascular Cell Adhesion Molecule-1 (VCAM-1), and P-selectin. Chemical preconditioning by cobalt for 7 days (12.5 mg Co/kg b.w., oral) significantly attenuated cerebral vascular leakage and the expression of inflammatory mediators induced by hypoxia. Administration of NFkappaB inhibitor, curcumin (50 mg/kg b.w.; i.p.) appreciably inhibited hypoxia induced vascular leakage indicating the involvement of NFkappaB in causing vascular leakage. Interestingly, cobalt when administered at 12.5 mg Co/kg b.w. (i.p.), 1 h before hypoxia could not prevent the vascular leakage indicating that cobalt per se did not have an effect on NFkappaB. The lower levels of NFkappaB observed in the brains of cobalt administered animals might be due to higher levels of antioxidant and anti-inflammatory proteins (hemeoxygenase-1 and metallothionein). To conclude cobalt preconditioning inhibited hypobaric hypoxia induced cerebral vascular leakage by lowering NFkappaB DNA binding activity and its regulated pro-inflammatory mediators. This is contemplated to be mediated by cobalt induced reduction in ROS/NO and increase in HO-1 and MT.

Cranial arteritis: a medical emergency with orofacial manifestations.

BACKGROUND: Cranial arteritis, or CA, a vascular disease affecting primarily elderly people, may result in permanent blindness if untreated. Since it frequently mimics temporomandibular joint, myofascial or odontogenic pain, dentists must be familiar with this condition. CASE DESCRIPTION: The authors present reports of two patients who had signs and symptoms of CA, some of which were suggestive of other head and neck pain disorders. In both cases, the diagnosis of CA was confirmed by temporal artery biopsy, and treatment with systemic steroids resulted in rapid resolution of symptoms. CLINICAL IMPLICATIONS: Prompt diagnosis and treatment of CA not only results in resolution of symptoms, but also may prevent blindness, the most serious sequela of the condition.

[Head- and neck pain of non-dental origin]. / Nem fogeredetú fej- és nyakfájdalom.

Although temporomandibular joint and masticatory myofascial pain (TMD) are a common cause of chronic head and neck pain, there are a number of other conditions which may cause chronic head and neck pain with similar symptoms. Differentiation between the various causes of chronic head and neck pain must be based primarily on historical information because there are few objective physical, laboratory or imagery findings that establish a definitive diagnosis of a specific chronic head and neck pain disorder.

[Smoking and diseases of the oral cavity]. / A dohányzás es a szájüregi betegségek.

The paper gives a review on the etiology of oral cancer, discusses some of the mechanisms by which tobacco may bring about changes in oral tissues, and describe ways in which the dentist can help with the problem of tobacco use. Risk of developing oral cancer increases with the amount and length of cigarette-smoking and alcohol consumption. Hungry is ranked with the highest cigarette-consumption as third among 111 countries world-wide. Investigations of the authors on the pathogenesis of leukoplakia by tobacco, demonstrated increased tissue levels of inflammatory mediators, and stimulated keratinocyte proliferation. Finally, the dentist has an important role to play in society as an advocate for reducing tobacco use.

Irritant contact stomatitis: a review of the condition.

Several different types of interactions are possible between a chemical, a mixture of chemicals, and associated extrinsic factors (i.e., mechanical irritation) in the oral mucosa. These interactions can be broadly classified as irritative or allergenic in nature. In each case, the pathology usually includes mucosal inflammation. The information compiled and reviewed in this article suggests that, given the broad definition of surface lesions/mucosal abnormalities, there may be a continuum of irritation that can be termed "irritant contact stomatitis." This may be due to the fact that the mouth is lined with highly vascular mucosa that turns over rapidly compared to the skin, and may or may not be covered by keratin. Some regions in the mouth are uniquely sensitive to irritants because they can penetrate through the tissue easily. Key factors involved in the potential development of irritation are: inherent irritation potential of the agent, amount of exposure (concentration, duration, and frequency), ability to penetrate the tissue, and inherent reactivity of the subject as well as other extrinsic factors. Irritation leading to oral mucosal alterations is a common occurrence caused by a wide variety of exposures and insults to the oral cavity. Various irritants such as foods, chemicals, friction, thermal/mechanical injury, metals, spices, and oral care products have been documented to cause irritant reactions in susceptible individuals, particularly if used under exaggerated exposure conditions. It is important to note that most irritation in the oral cavity tends to reverse quickly when the causative agent is removed. Oral irritation is a commonly occurring phenomenon. Thus, it is important that the clinician be aware of the clinical manifestations and etiology of the condition.

Wegener's granulomatosis presenting as oral lesions: a case report.

Wegener's granulomatosis will classically present as a triad of respiratory, kidney, and vascular involvement. The disease may run a course of rapidly progressive or mild and indolent and escape diagnosis for some time. The clinician must be aware of the possibility of Wegener's granulomatosis presenting initially with intraoral lesions. Prompt biopsies and blood studies along with the proper referrals will give the patient their best chance at a remission with the least systemic damage. We present a case of Wegener's granulomatosis that presented with oral lesions before other signs and symptoms.

Abuse history and chronic pain in women: I. Prevalences of sexual abuse and physical abuse.

OBJECTIVE: To compare the prevalences of childhood and adult physical and sexual abuse in women with chronic pelvic pain to those in women with chronic nonpelvic pain (headache) and pain-free women. METHODS: Using a structured interview, we assessed the prevalence rates of both sexual abuse and physical abuse in 64 women with chronic pelvic pain, 42 women with chronic headache, and 46 pain-free women. Abuse histories were stratified by age at occurrence and severity. Demographic characteristics of the three groups were also assessed. RESULTS: Women with chronic pelvic pain were found to have a higher lifetime prevalence of sexual abuse, involving penetration or other contact with the unclothed genitals or anus (ie, major sexual abuse), than either comparison group. Further, more women in the chronic pelvic pain group had experienced major sexual abuse in both childhood and adulthood than women in the headache group, but there was no difference with the pain-free group. With respect to physical abuse, women in the chronic pelvic pain group had a higher lifetime prevalence than pain-free women, but not compared to those with chronic headache. In addition, more women with chronic pelvic pain reported physical abuse in both childhood and adulthood and both major sexual abuse and physical abuse at some time in their lives than did either comparison group. CONCLUSIONS: These results support a specific association between major sexual abuse and chronic pelvic pain and a more general association between physical abuse and chronic pain. Moreover, the global nature of the abuse histories of the women in the chronic pelvic pain group suggests that more rigorous studies of the relation between abuse history and chronic pelvic pain are needed.

Abuse history and chronic pain in women: II. A multivariate analysis of abuse and psychological morbidity.

OBJECTIVE: To assess the potential role of childhood and adulthood physical and sexual abuse and complaints of chronic pain in accounting for psychiatric symptomatology in adult women. METHODS: We assessed sexual abuse, physical abuse, depression, anxiety, and somatization in 64 women with chronic pelvic pain, 42 women with chronic headache, and 46 women without chronic pain complaints. Using multiple regression analyses, we tested a model comprising sociodemographic, chronic pain, childhood sexual abuse and physical abuse, and adulthood sexual abuse and physical abuse variables in the prediction of depression, anxiety and somatization. RESULTS: This model significantly predicted all three outcomes. However, childhood sexual abuse was not significant in the prediction of any of the outcome variables, whereas childhood physical abuse was significant in the prediction of all three. Further, the adulthood abuse variable set contributed significantly to the prediction of somatization, and the individual variable of adulthood sexual abuse was predictive of anxiety. CONCLUSIONS: The relation observed between childhood sexual abuse and the outcomes of depression, anxiety, and somatization in women may be a function of its association with other forms of abuse, particularly childhood physical abuse. Further investigation is clearly needed of the nature of the relations between the various categories of abuse and psychological morbidity.

Clinical, historic, and therapeutic features of cicatricial pemphigoid. A literature review and open therapeutic trial with corticosteroids.

Cicatricial pemphigoid is at present an incurable, autoimmune disease that involves mucosa and skin. We have documented the clinical, microscopic, and therapeutic features of 23 patients with cicatricial pemphigoid and added these to reports of past literature. The mean age at the time of diagnosis was 63 years, and women were involved twice as often as men. Eighty-three percent of patients had oral mucosal involvement, 70% had conjunctival involvement, and 22% had skin involved. Direct immunologic evaluation revealed IgG at the basement membrane in 57% of cases and C3 in 66%. We have been able to manage the disease adequately in most patients with topical or systemic corticosteroids. The most commonly encountered side effect was oral candidiasis.

Recurrent enlargement of the left maxillary alveolus.

Presented is a case report of osteosarcoma of the maxilla in a patient with Paget's disease. This case is unusual because of recurrent benign soft tissue enlargements at the site of eventual malignant disease.

Clinical, historic, and therapeutic features of aphthous stomatitis. Literature review and open clinical trial employing steroids.

The clinical and historic features of 50 patients with diagnosed aphthous stomatitis and treated with topical triamcinolone acetonide, 0.1% or 0.2% aqueous suspension; alone or in combination with initial burst therapy of 40 to 60 mg of prednisone, are reviewed. The mean age of our patients was 36.6 years (range 6 to 80 years). The duration of the chief complaint, usually oral pain, or more specifically, recurrent oral ulcers, was 11.1 years (range 4 weeks to 40 years). All patients showed a wide range of ulcer sizes when examined initially or at follow-up. Forty were followed up for an average of 22.9 months. Thirty-four reported prompt healing of ulcers identified at the time of initial evaluation, and no or markedly fewer ulcers subsequently if maintenance therapy of prophylactic topical triamcinolone, 0.1% or 0.2% aqueous rinse, was used. Five patients reported partial relief. No systemic side effects were noted even after long-term topical therapy. Local candidosis was a complication encountered in five patients.