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Hinrich Staecker

Publications and source records attributed to Hinrich Staecker.

18 recordsLinked to original sources
PubMed2006

Vector-mediated delivery of bcl-2 prevents degeneration of auditory hair cells and neurons after injury.

OBJECTIVE: To test the hypothesis that bcl-2 prevents oxidative stress-induced apoptosis of auditory sensory cells in explants of the organ of Corti and dissociated cell cultures of the spiral ganglion. METHODS: Organ of Corti explants and dissociated spiral ganglion cell cultures obtained from 3-day-old (P3) rats or adult spiral ganglion cell cultures from 28-day-old (P28) rats were transduced with vectors containing a human bcl-2 gene. Cultures were then exposed to neomycin, cisplatin or subjected to withdrawal of neurotrophin supplementation. Outcome measures included hair cell and neuron counts, mitochondrial membrane potential and a histological measure of apoptosis. RESULTS: Expression of bcl-2 in the organ of Corti explants and neuronal cell cultures provided a significant level of protection against cell death. Bcl-2 expression in the organ of Corti explants also protected mitochondria from loss of membrane potential and blocked an early step in the commitment of hair cells to apoptosis. CONCLUSION: Expression of bcl-2 in cochlear tissues protects sensory cells from a variety of insults that have been demonstrated to damage the inner ear.

Adenoviridae↗
PubMed2006

Pharmacodynamics of adenovector distribution within the inner ear tissues of the mouse.

Recent studies have demonstrated that delivery of genes to the inner ear can achieve a variety of effects ranging from support of auditory neuron survival to protection and restoration of hair cells, demonstrating the utility of vector based gene delivery. Translation of these findings to useful experimental systems or even clinical applications requires a detailed understanding of the pharmacokinetics of gene delivery in the inner ear. Ideal gene delivery systems will employ a well tolerated vector which efficiently transduces the appropriate target cells within a tissue, but spare non-target structures. Adenovectors based on serotype 5 (Ad 5) are commonly used vectors, are easy to construct and have a long track record of efficacious gene transfer in the inner ear. In this study we demonstrate that distribution of Ad5 vector occurs in a basal to apical gradient with rapid distribution of vector to the vestibule after delivery via a round window cochleostomy. Transduction of the vector and expression of the delivered transgene occurs by 10 min post vector delivery. At 24 h post delivery only 16% of vector that was initially detectable within the inner ear by quantitative PCR remained. Perilymph sampling was used to determine that vector concentrations in perilymph peaked at 30 min post delivery and then declined rapidly. Understanding these basic distribution patterns and parameters for delivery are important for the design of gene delivery vectors and vital for modeling dose responses to achieve safe efficacious delivery of a therapeutic agent.

Adenoviridae↗
PubMed2006

Nonorganic hearing loss.

Nonorganic hearing loss is a decrease in hearing that is unexplained by anatomic or physiologic abnormalities, or both. The term is synonymous with functional hearing loss and pseudohypacusis. The demographics and potential etiologies of nonorganic hearing loss are described. History and physical findings that indicate a functional hearing loss are also discussed. A review of the anatomy and physiology of the auditory system is provided as a background for the discussed objective tests of hearing thresholds. Finally, conditions that may mimic functional hearing loss are described in detail.

Hearing Loss, Functional↗
PubMed2005

Advances in inner ear gene therapy: exploring cochlear protection and regeneration.

PURPOSE OF REVIEW: To review the application of gene therapy in the inner ear. Gene delivery to the inner ear was first reported in 1996. Since then the field has progressed on multiple fronts. RECENT DEVELOPMENTS: More diverse and sophisticated vectors are improving the efficiency of delivery to the inner ear. Research is transitioning from the delivery of marker genes to the delivery of therapeutic genes in animal models of inner ear disease. Three distinct areas of research are developing: (1) delivery of genes for protection of spiral ganglion neurons with potential application in cochlear implantation, (2) delivery of genes for protection of hair cells and hearing preservation in degenerative diseases and cochlear insults and (3) the use of gene therapy to transform cells from one phenotype to another and replace lost cells, potentially restoring lost function. SUMMARY: Currently, no specific drugs are targeted at inner ear disease. The use of gene therapy in the inner ear is being applied in animal models of ototoxicity and ischemia reperfusion injury. Gene therapy can protect the inner ear from damage and even restore function through the regeneration of hair cells.

Animals↗
PubMed2004

Drug delivery to the inner ear using gene therapy.

The last 10 years have seen the development of numerous strategies for the delivery of genes to the inner ear. Besides being a useful research tool,gene therapy has significant promise as a potential clinical treatment. The human inner ear is easily accessible through either the round window or the stapes footplate. It is now possible to choose a variety of vectors to target a variety of different tissues. Modification of promoters yields different expression patterns as well as differences in degree of expression. Several animal studies have also demonstrated that expression of exogenous genes in the cochlea does not result in loss of hearing function. A variety of potential clinical applications are already evident from these early studies. Protective strategies such as prevention of neuronal degeneration and protection of auditory hair cells from oxidative stress are potential examples where gene therapy may be useful. As the understanding of gene therapy improves, investigators will be able to move toward targeted single-gene replacement to treat disorders such as connexin mutations and applying gene therapy to sensory cell replacement.

Administration, Topical↗
PubMed2004

Extended pericranial flap and bone graft reconstruction in anterior skull base surgery.

OBJECTIVES: The objectives of this study was to establish a rationale for repairing large anterior skull base defects with an extended pericranial flap and split calvarial bone graft; to define large anterior skull base defects as those spanning the anterior cranial measuring at least 3.0 x 4.0 cm; and to describe the surgical technique and compare it with alternative strategies. Study design Thirty-four patients underwent anterior craniofacial resection of anterior skull-based tumors of varying histology with reconstruction using an extended pericranial flap and split calvarial bone graft. RESULTS: The survival of the pericranial flap and bone graft was maintained in 33 of 34 patients. There was 1 episode of postoperative cerebrospinal fluid leak, 1 episode of osteomyelitis of the bone graft and an epidural abscess, and 1 episode of asymptomatic pneumocephalus. CONCLUSION: Split calvarial bone graft with an extended pericranial flap is an effective technique for reconstructing large anterior skull base defects.

Bone Transplantation↗
PubMed2003

The effect of diabetes on sensorineural hearing loss.

OBJECTIVE: To identify whether patients with diabetes have a higher incidence of sensorineural hearing loss than the general population and examine whether control of diabetes is related to severity of hearing loss. STUDY DESIGN: Retrospective database review; complete data mining of electronic medical record from 1989 to present. SETTING: Tertiary referral center. PATIENTS: Electronic medical records from 53461 nondiabetic age-matched patients and 12575 diabetic patients were reviewed. MAIN OUTCOME MEASURES: Presence or absence of diabetes and/or sensorineural hearing loss, serum creatinine, pure tone hearing (dB), speech discrimination (%), serum cholesterol, and triglycerides. RESULTS: Sensorineural hearing loss was more common in the diabetic patients than in age0matched nondiabetic patients from the same institutions. Poor control of diabetes, as measured by increasing serum creatinine, but not apparent in hemoglobin A1C laboratory data, correlated with worsening hearing in patients with diabetes who had sensorineural hearing loss. CONCLUSIONS: Sensorineural hearing loss was more common in patients with diabetes than in the control nondiabetic patients, and severity of hearing loss seemed to correlate with progression of disease as reflected in serum creatinine. This may have been due to microangiopathic disease in the inner ear.

Audiometry, Pure-Tone↗
PubMed2003

Arrest of apoptosis in auditory neurons: implications for sensorineural preservation in cochlear implantation.

HYPOTHESIS: The JNK/c-Jun cell death pathway is a major pathway responsible for the loss of oxidative stress-damaged auditory neurons. BACKGROUND: Implantation of patients with residual hearing accentuates the need to preserve functioning sensorineural elements. Although some auditory function may survive electrode insertion, the probability of initiating an ongoing loss of auditory neurons and hair cells is unknown. Cochlear implantation can potentially generate oxidative stress, which can initiate the cell death of both auditory neurons and hair cells. METHODS: Dissociated cell cultures of P4 rat auditory neurons identified the apoptotic pathway initiated by oxidative stress insults (e.g., loss of trophic factor support) and characterized this pathway by arresting translation of pathway-specific mRNA with antisense oligonucleotide treatment and with the use of pathway specific inhibitors. The presence or absence of apoptosis-specific protein and changes in the level of neuronal survival measured the efficacy of these interventional strategies. RESULTS: These in vitro studies identified the JNK/c-Jun cascade as a major initiator of apoptosis of auditory neurons in response to oxidative stress. Neurons pretreated with c-jun antisense oligonucleotide and exposed to high levels of oxidative stress were rescued from apoptosis, whereas neurons in treatment control cultures died. Treatment of oxidative-stressed cultures with either curcumin, a MAPKKK pathway inhibitor, or PD-098059, a MEK1 inhibitor, blocked loss of neurons via the JNK/c-Jun apoptotic pathway. CONCLUSION: Blocking the JNK/c-Jun cell death pathway is a feasible approach to treating oxidative stress-induced apoptosis within the cochlea and may have application as an otoprotective strategy during cochlear implantation.

Animals↗
PubMed2003

Clinical and histopathologic features of recurrent vestibular schwannoma (acoustic neuroma) after stereotactic radiosurgery.

OBJECTIVE: Stereotactic radiosurgery for vestibular schwannoma entails uncertain long-term risk of tumor recurrence and delayed cranial neuropathies. In addition, the underlying histopathologic changes to the tumor bed are not fully characterized. We seek to understand the clinical and histologic features of recurrent vestibular schwannoma after stereotactic radiation therapy. STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: Four patients who underwent microsurgical resection of vestibular schwannoma after primary stereotactic radiation therapy. INTERVENTION: Patients were treated primarily with gamma knife radiosurgery or fractionated stereotactic radiotherapy followed by salvage microsurgery. Retrosigmoid craniotomy was used in all cases. MAIN OUTCOME MEASURES: Histopathologic review. Preoperative and postoperative facial nerve function was assessed with the House-Brackmann scale. RESULTS: We observed highly inconsistent radiation changes in the cerebellopontine angle and internal auditory canal. Fibrosis outside and within the tumor bed varied markedly, complicating microsurgical dissection. Light microscopy confirmed the presence of viable tumor in all cases. Histopathologic features were typical of vestibular schwannoma, and there was no significant scarring that could be attributed to radiation effect. CONCLUSIONS: The variable fibrosis in the cerebellopontine angle and lack of radiation changes seen histopathologically in irradiated vestibular schwannoma suggest that a uniform treatment effect was not achieved in these cases. Although all four patients with preoperative cranial neuropathies were found intraoperatively to have fibrosis in the cerebellopontine angle, excellent preservation of facial nerve anatomy and function was possible with salvage microsurgical resection. Additional analyses are needed to clarify the histopathologic and molecular characteristics associated with vestibular schwannoma growth after stereotactic radiation.

Aged↗
PubMed2003

Making image guidance work: understanding control of accuracy.

Use of image-guided surgery is becoming increasingly common in both sinus surgery and neuro-otologic applications. The purpose of this study was to determine the effect of fiducial distribution and mean fiducial error on point accuracy. Using a plastic model, we determined that optimal navigation accuracy was achieved by surrounding the operative target with a widespread field of fiducials. True accuracy was always highest when we targeted a surface point. Accuracy was decreased at points removed from the center of the registration target zone created by the fiducials. Inaccurate registration resulted in increased mean fiducial error and lower accuracy at the target point. Understanding the registration process will enhance the utility of image-guided surgery in otolaryngology and skull base surgery.

Cranial Fossa, Middle↗
PubMed2002

Patient-based outcomes in patients with primary tinnitus undergoing tinnitus retraining therapy.

OBJECTIVE: To determine whether the Tinnitus Handicap Inventory (THI), a validated patient-based outcomes measure, may improve our ability to quantify impact and assess therapy for patients with tinnitus. DESIGN: Nonrandomized, prospective analysis of 32 patients undergoing tinnitus retraining therapy (TRT). Assessment tools included comprehensive audiology, a subjective self-assessment survey of tinnitus characteristics, and the THI. Tinnitus Handicap Inventory scores were assessed at baseline and 6 months following TRT. RESULTS: Baseline analysis revealed significant correlation between the subjective presence of hyperacusis and higher total, emotional, and catastrophic THI scores. Tinnitus Handicap Inventory scores correlated with subjective perception of overall tinnitus effect (P<.001). Mean pure-tone threshold average was 17.4 dB, and mean speech discrimination was 97.0%. There were no consistent correlations between baseline audiologic parameters and THI scores. Following 6 months of TRT, the total, emotional, functional, and catastrophic THI scores significantly improved (P<.001). Loudness discomfort levels also significantly improved (P< or =.02). CONCLUSIONS: There is significant improvement in self-perceived disability following TRT as measured by the THI. The results confirm the utility of the THI as a patient-based outcomes measure for quantifying treatment status in patients with primary tinnitus.

Adolescent↗
PubMed2002

Vertigo and abacavir.

Vertigo can cause significant morbidity and make a person unable to perform activities of daily life. A human immunodeficiency virus (HIV)-infected patient experienced vertigo while taking abacavir that resolved immediately on cessation of therapy. The mechanism by which abacavir appeared to be associated with vertigo in this patient is unknown.

Adult↗
PubMed2002

Steroid perfusion of the inner ear for sudden sensorineural hearing loss after failure of conventional therapy: a pilot study.

The aim of this study was to determine if high-dose delivery of methylprednisolone to the round window can improve hearing after the failure of conventional treatment for sudden sensorineural hearing loss (SSHL). In 6 patients with SSHL an Intraear microcatheter was placed in the round window niche and methylprednisolone (62.5 mg/ml) was infused at a rate of 10 microl/h for 8-10 days. Audiometric assessments (including measurement of speech discrimination) were made at presentation, either every day or every other day during treatment and 5 days after the completion of perfusion. Perfusion of methylprednisolone was beneficial for all 6 patients, with a 16.25-25 dB improvement in hearing threshold. A dramatic improvement in speech discrimination was also noted in all patients. In conclusion, methylprednisolone perfused at the level of the round window membrane resulted in significant recovery of hearing function after the failure of standard treatment of SSHL.

Administration, Topical↗
PubMedDate not supplied

Mechanisms of cell death in the injured auditory system: otoprotective strategies.

Oxidative stress insults such as neurotrophin withdrawal, sound trauma, hypoxia/ischemia, ototoxic antibiotics, and chemotherapeutic agents have been shown to induce apoptosis of both auditory hair cells and neurons. In this paper, we review some components of the apoptotic pathways leading to the death of hair cells and auditory induced by growth factor withdrawal or cisplatin intoxication: (1) reactive oxygen species and free radicals are formed as by-products of several metabolic pathways and these molecules can themselves cause cell damage by reacting with cellular proteins; (2) activation of caspases, and (3) activation of calpain. These mechanisms have several different points at which inhibitors could be targeted to protect cells from programmed cell death, including the prevention of oxidative stress-induced apoptosis and the activation of caspases and calpains.

Animals↗
PubMedDate not supplied

Hearing preservation after inner ear gene therapy: the effect of vector and surgical approach.

Over seventy studies have examined the potential of gene therapy in the inner ear. For the most part, they have focused on adenoviral vectors and delivery into the cochlea. Most studies have emphasized looking at the expression of marker genes driven by a CMV promoter and have used first-generation adenoviral constructs. E1/E3/E4 deleted adenoviral vectors carrying the green fluorescent protein (GFP) gene were injected into the round window, the basal turn of the cochlea (via a cochleostomy) or into the superior semicircular canal. Hearing was then tested 24 h after viral gene transfer. Large vector titers in small volumes of fluid were well tolerated with the round window approach resulting in complete hearing preservation with transfer of GFP to hair cells and spiral ganglion cells. Injection of comparable doses of vector into a basal turn cochleostomy resulted in high-frequency hearing loss. Addition of a pancaspase inhibitor protected hearing when larger volumes of fluid were administered to the inner ear.

Adenoviridae↗