Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor.

Despite the usefulness of glucocorticoids, they may cause hazardous side effects that limit their use. Searching for compounds that are as equally efficient as glucocorticoids, but with less side effects, the current study compared plant steroids, namely, glycyrrhetinic acid, guggulsterone, boswellic acid, withaferin A, and diosgenin with the classical glucocorticoid, fluticasone. This was approached both in silico using molecular docking against glucocorticoid receptor (GR) and in vivo in two different animal models. All tested compounds interacted with GR, but only boswellic acid and withaferin A showed docking results comparable to fluticasone, as well as similar in vivo anti-inflammatory effects, by significantly decreasing serum levels of interleukin-6 and tumor necrosis factor-α in cotton pellet-induced granuloma in rats. In addition, both compounds significantly decreased the percent of change in ear weight in croton oil-induced ear edema in mice and the granuloma weight in cotton pellet-induced granuloma in rats, to levels comparable to that of fluticasone. Both boswellic acid and withaferin A had no effect on adrenal index, but only withaferin A significantly increased the thymus index. In conclusion, boswellic acid may have comparable anti-inflammatory effects to fluticasone with fewer side effects.

Anti-Inflammatory Effects of Cold Thermal Therapy on Allergic Skin Inflammation Induced by Trimellitic Anhydride in BALB/c Mice.

Cold and hot thermal therapies are widely used as a traditional therapy in many cultures and are often prescribed in the treatment of various musculoskeletal and neurological conditions which present themselves to primary care physicians. However, there are no reports that investigated either the effects of cold and hot thermal therapies on the skin inflammation of trimellitic anhydride- (TMA-) induced dermatitis-like contact hypersensitivity (CHS) mouse model, or the mechanism of thermal therapy on allergic skin inflammation. Therefore, in this study, to reveal the anti-inflammatory effect of thermal therapy and its mechanism on TMA-induced CHS, we analyzed ear-swelling response (ear edema), vascular permeability, serum IgE levels, histological examination, and histamine and Th2 cytokine levels. Cold thermal therapy reduced the ear-swelling response, the vascular permeability, the serum IgE levels, and the infiltration of eosinophils and mast cells as well as the mast cell degranulation. To determine the mechanism by which cold thermal therapy inhibits allergic skin inflammation, detailed studies were carried out revealing that cold thermal therapy suppressed IL-4 and IL-5 secretion and mast cell activation. These results indicated that cold thermal therapy cures skin inflammation of TMA-induced CHS by decreasing Th2 cytokine release, especially IL-4 and IL-5, and mast cell activation. These data suggest that new insight into the mechanism of robust therapeutic effects of cold thermal therapy against allergic dermatitis, and cold thermal therapy may prove to be a useful therapeutic modality on allergic inflammatory diseases as traditional use as well as Th2- or mast cell-mediated allergic responses.

Further characterization of atypical features in auriculocondylar syndrome caused by recessive PLCB4 mutations.

Auriculocondylar syndrome (ACS) is a branchial arch syndrome typically inherited in an autosomal dominant fashion. Patients with ACS display the following core symptoms with varying severity: a specific malformation of the external ear, known as a "question mark ear," micrognathia and mandibular condyle hypoplasia. Recently, phospholipase C, ß 4 (PLCB4) mutations were identified as the major cause of autosomal dominant ACS, with mutations of the PLCB4 catalytic domain predicted to have a dominant negative effect. In addition, one ACS patient born to related parents harbored a homozygous partial deletion of PLCB4, and presented with ACS plus central apnea and macropenis; these features had not been previously reported in association with ACS. His parents, each with a heterozygous partial PLCB4 deletion, were phenotypically normal, suggesting autosomal recessive inheritance of ACS, with complete loss of function of PLCB4 predicted in the patient. We herein describe two brothers with ACS caused by compound heterozygous splice site mutations in PLCB4. The patients were born to the same unrelated and healthy parents, with each parent harboring one of the mutations, indicating autosomal recessive ACS. Both patients reported here had mixed apneas, gastrointestinal transit defects and macropenis, in addition to typical craniofacial features of ACS. This is the first example of ACS caused by compound heterozygous splice site mutations in PLCB4, the second autosomal recessive case of ACS confirmed by molecular analysis, and strengthens the link between complete loss of function of PLCB4 and extra-craniofacial features.

Antibodies to myelin protein zero (P0) protein as markers of auto-immune inner ear diseases.

BACKGROUND/AIMS: The inner ear can be the target of autoimmune disorders. Recognition of autoimmune inner ear disease is important, as it is one of the very few forms of sensorineural hearing loss (HL) that can be successfully treated by medical therapy. The aim of this study was to evaluate whether the detection of antibodies to myelin protein P0 (MPZ) could be a diagnostic test for inner ear disease of autoimmune cause. METHODS: This multicentric prospective study included 129 patients: patients with progressive sensorineural HL or with Menière's disease, together with their control group corresponding to patients with similar symptoms, but of presumably known origin. Detection of antibodies to myelin P0 protein was performed by using western blots. NORMAL: The prevalence of antibodies to myelin P0 protein in patients with rapidly progressive HL was not statistically different from that of the control group corresponding to genetic HL patients (30 versus 28%). In patients with Menière's disease, the prevalence was lower than that of the control group corresponding to patients with benign paroxysmal positional vertigo (5.4 versus 18.7%). No patient with auto-immune disease had antibodies to myelin P0 protein. CONCLUSIONS: The sole presence of antibodies to myelin P0 may not be used as a marker of inner ear disease of autoimmune origin.

Otosyphilis mimics immune disorders of the inner ear.

Syphilis is a well established cause of hearing loss. Sensorineural hearing loss may develop in the congenital or acquired form. The clinical course of the early acquired and late congenital forms are similar: sudden or rapidly progressive bilateral sensorineural hearing loss with mild vestibular symptoms. Cochleovestibular involvement in early acquired syphilis has been related to a basilar meningitis with lymphocytic infiltration of the labyrinth and VIIIth nerve. However, neurosyphilis and inner ear syphilis are not the same disease. Prompt diagnosis and treatment with corticosteroids and penicillin are mandatory to reduce the immune response and fibrosis of the labyrinth and the endolymphatic sac. Unfortunately, early acquired syphilis is frequently overlooked in the differential diagnosis of other forms of sensorineural hearing loss, particularly autoimmune inner ear disease. Given the increasing number of luetic infection cases, especially in immunocompromised patients, this condition should be considered in any sexually active patients affected by sudden hearing loss. Cases of inner ear syphilis are presented. Immunopathology of luetic inner ear infection is discussed and compared with immune disorders of the inner ear.

Audit of local performance compared with standards recommended by the national guidelines for aetiologic investigation of permanent childhood hearing impairment.

BACKGROUND: National guidelines for aetiologic investigation of childhood deafness were developed as the Newborn Hearing Screening Program (NHSP) was being implemented in the United Kingdom. This guidance document was expected to be incorporated into the operational procedure of the NHSP. METHOD: This criterion-based audit compared local care set against developed guidelines that can be used to assess the appropriateness of specific investigations, services and outcomes. Data on children diagnosed to have sensorineural deafness from March 2002-2004 were extracted from an established computerized database for analysis. RESULTS: Forty-seven children were included; 17 have bilateral severe to profound hearing loss, 25 have bilateral mild to moderate loss and 5 with unilateral loss. A high proportion of Pakistani children were from consanguineous marriages with a family history of deafness. Total 29.8% of children were diagnosed through newborn screening and 70.2% detected through hearing surveillance programmes. For children with bilateral severe to profound deafness, 53.0% accepted, 5.9% declined and 41.2% were not offered imaging of their inner ears. A total of 47.1% accepted and 52.9% declined electrocardiograph (ECG) evaluation. Total 70.6% accepted and 29.4% declined connexin mutations testing. Parental requests were required for those with lesser degree of hearing loss. Total 24% accepted, 28% declined and 48% were not offered connexin testing. None were offered ECG and imaging. Testing for congenital infections was inappropriate for children over 1 year old. Ten subjects accepted and five declined this investigation. In the total group, 63.8% accepted, 17.0% declined and 19.1% were not offered referral to the ophthalmic service. Total 46.8% accepted, 44.7% declined and 8.5% were not offered referral to genetics service. Investigations resulted in two connexin-positive children with moderate loss. CONCLUSION: Our study identified key areas where guidelines were not followed. These were related to lack of funding and parental choice. This sample has a higher connexin 'hit' rate for lesser degree deafness.

Middle-ear disease in children exposed prenatally to polychlorinated biphenyls and polychlorinated dibenzofurans.

During 1978 and 1979, an episode of poisoning from ingestion of rice oil contaminated with polychlorinated biphenyls and polychlorinated dibenzofurans occurred in central Taiwan. We followed-up children who had been born between June 1978 and March 1985, as well as matched unexposed children. The mothers of exposed children had consumed contaminated oils before the children were born. In 1993, otolaryngologists examined the middle ear of each child with a pneumatic otoscope, and they measured the middle-ear pressure by tympanometry with a Rion RS20 impedance audiometer. The exposed children had a significantly higher prevalence of middle-ear diseases than their matched controls. The exposed children who had ear diseases had higher serum levels of 2,3,4,7,8-pentachloro- and 1,2,3,4,7,8-hexachloro-dibenzofurans than the children who did not have similar diseases. Therefore, in this study, children exposed to polychlorinated biphenyls and polychlorinated dibenzofurans had a higher incidence of middle-ear diseases than their controls.

Assessment of serum antibodies in patients with rapidly progressive sensorineural hearing loss and Menière's disease.

The immunoreactivity of sera from patients with rapidly progressive sensorineural hearing loss (SNHL) or Menière's disease with bovine inner ear material was determined using the Western blot technique. Patients with other otologic conditions, autoimmune disorders, or arthritic disorders and age-matched randomly chosen patients with no hearing complaints served as controls. Twenty-two percent of the patients with bilateral rapidly progressive SNHL and 30% of the patients with Menière's disease had antibodies that reacted with a 68 kd antigen in the inner ear material. In the control groups, the incidence of reactivity was 5.0% (P < .001). When the results of this study were compiled with data collected previously, it was found that of 279 patients with bilateral rapidly progressive SNHL, 90 (32%) were positive with the 68 kd protein. Thus, the anti-68 kd antibody may provide a good marker for an immune etiology of these patients' hearing loss.

Bleeding diathesis associated with variant von Willebrand factor in a Simmental calf.

A 10-month-old Simmental heifer was examined because of a 10-day history of epistaxis and aural hematomas. Examination of the calf also revealed hemarthrosis. Initial laboratory data indicated that platelet count, platelet size, prothrombin time, and partial thromboplastin time were not different from a clinically normal (control) cow. Mucosal bleeding time was prolonged, and platelet adhesion to glass beads was less than expected. The clinical signs, prolonged bleeding time, and platelet adhesion defect were corrected by infusion of bovine plasma. Subsequent laboratory testing revealed that the affected calf had a truncated multimeric structure of von Willebrand factor (vWF), low vWF activity, and impaired platelet aggregation in response to adenosine diphosphate, but concentration of vWF was not different from that in clinically normal control animals. These data were consistent with a diagnosis of variant von Willebrand disease. The relationship of this disease to the thrombopathy of Simmental cattle is unclear.

Distribution of ABO blood groups in secretory otitis media and cholesteatoma.

The ABO blood groups of 610 patients with documented secretory otitis media (SOM) and of 361 patients with cholesteatoma were compared with those of a control group. In cholesteatoma a normal distribution appeared while in SOM a preponderance of group A or shortage of group O was statistically significant and the incidence ratio was 1.49. In both disease entities a preponderance of males was found. The blood group abnormalities of SOM may indicate hereditary trends and they oppose the theories of SOM being the 'missing link' in the development of cholesteatoma.

Angiolymphoid hyperplasia with eosinophilia of the external ear canal.

Angioblastic lymphoid hyperplasia with eosinophilia, or Kimura's disease, is a clinically and histopathologically recognized entity that is characterized by cutaneous nodules, proliferating blood vessels with atypical histiocyte-like endothelial cells, and numerous eosinophils. It has been treated with steroids and by surgical excision, irradiation, cryotherapy, and electrodesiccation. Persistent residual disease and local recurrence are frequent. We review the literature and report two cases that involve the ear. We present the histopathologic and clinical results of laser removal of a conchal and external canal lesion.