Mumtaz J. Khan

Biologic activity of mitochondrial metabolites on aging and age-related hearing loss.

HYPOTHESIS Compounds that upregulate mitochondrial function in an aging model will improve hearing and reduce some of the effects of aging. BACKGROUND Reactive oxygen metabolites (ROM) are known products of oxidative metabolism and are continuously generated in vivo. More than 100 human clinical conditions have been associated with ROM, including atherosclerosis, arthritis, autoimmune diseases, cancers, heart disease, cerebrovascular accidents, and aging. The ROM are extremely reactive and cause extensive DNA, cellular, and tissue damage. Specific deletions within the mitochondrial DNA (mtDNA) occur with increasing frequency in age and presbyacusis. These deletions are the result of chronic exposure to ROM. When enough mtDNA damage accrues, the cell becomes bioenergetically deficient. This mechanism is the basis of the mitochondrial clock theory of aging, also known as the membrane hypothesis of aging. Nutritional compounds have been identified that enhance mitochondrial function and reverse several age-related processes. It is the purpose of this article to describe the effects of two mitochondrial metabolites, alpha-lipoic acid and acetyl L-carnitine, on the preservation of age-related hearing loss. METHODS Twenty-one Fischer rats, aged 24 months, were divided into three groups: acetyl-l-carnitine, alpha-lipoic acid, and control. The subjects were orally supplemented with either a placebo or one of the two nutritional compounds for 6 weeks. Auditory brainstem response testing was used to obtain baseline and posttreatment hearing thresholds. Cochlear, brain, and skeletal muscle tissues were obtained to assess for mtDNA mutations. RESULTS The control group demonstrated an expected age-associated threshold deterioration of 3 to 7 dB in the 6-week study. The treated subjects experienced a delay in progression of hearing loss. Acetyl-l-carnitine improved auditory thresholds during the same time period (p<0.05). The mtDNA deletions associated with aging and presbyacusis were reduced in the treated groups in comparison with controls. CONCLUSIONS These results indicate that in the proposed decline in mitochondrial function with age, senescence may be delayed by treatment with mitochondrial metabolites. Acetyl-l-carnitine and alpha-lipoic acid reduce age-associated deterioration in auditory sensitivity and improve cochlear function. This effect appears to be related to the mitochondrial metabolite ability to protect and repair age-induced cochlear mtDNA damage, thereby upregulating mitochondrial function and improving energy-producing capabilities.

Gastroesophageal reflux and obstructive sleep apnea

Objective To determine the extent to which gastroesophageal reflux (GER)‐initiated laryngeal chemoreflexes contribute to obstructive sleep apnea (OSA).

Changes in Quality of Life Over 1 Year in Patients With Head and Neck Cancer

OBJECTIVES To characterize and compare quality of life (QOL) in patients with head and neck cancer shortly before initial treatment and 1 year later and to study the predictors of changes in QOL over 1 year. DESIGN Prospective cohort study. SETTING Three otolaryngology clinics. PATIENTS Three hundred sixteen patients having newly diagnosed squamous cell head and neck cancer. MAIN OUTCOME MEASURE Health-related QOL was assessed using the 36-item Short-Form Health Survey and a head and neck cancer-specific QOL scale. RESULTS Over 1 year, QOL decreased for physical functioning measures and eating but improved for mental health QOL. Depression and smoking were major predictors of poor QOL at baseline. Major predictors of change in QOL from baseline to 1 year were treatment factors, especially feeding tube placement (9 scales), chemotherapy (3 scales), and radiation therapy (3 scales). Baseline smoking and depressive symptoms also remained significant predictors of several QOL scales at 1 year. CONCLUSIONS Health-related physical QOL tended to decline over 1 year and mental health QOL improved. The major predictors of change in QOL were treatment factors, smoking, and depressive symptoms. Physicians should alert patients to the relative effects on QOL one may experience with different treatments.

Stereotactic body radiation therapy for primary, recurrent, and metastatic tumors in the head-and-neck region.

PURPOSE To determine the feasibility, safety, and efficacy of stereotactic body radiation therapy (SBRT), also known as radiosurgery, in patients with head-and-neck cancers. METHODS AND MATERIALS Patients with pathologically proven malignant lesions in the head-and-neck region were treated using single-dose SBRT (S-SBRT) or fractionated SBRT (F-SBRT). Radiation doses were either single-fraction 13-18 Gy for S-SBRT or 36-48 Gy in five to eight fractions for F-SBRT. Response evaluation was based on clinical examinations and computed tomography/magnetic resonance imaging scans. Pre- and post-SBRT tumor dimensions were measured in three axes, and tumor volumes were calculated. Response evaluation also was performed using World Health Organization criteria. RESULTS Fifty-five lesions were treated in 44 patients (25 men, 19 women). There were three groups of patients: those with primary (n = 10), recurrent (n = 21), and metastatic tumors (n = 13). The predominant histologic type was squamous cell carcinoma (n = 33). The majority of lesions were treated using F-SBRT (n = 37). Based on radiographic and clinical assessment, a 77% (complete + partial response) response rate was noted. Percentage of reduction in tumor volume was 52% +/- 38% based on follow-up scans in 24 patients. Tumor control rates at 1 year were 83.3% and 60.6% in the primary and recurrent groups, respectively. Median overall survival was 28.7, 6.7, and 5.6 months for the primary, recurrent, and metastatic groups, respectively. Radiation Therapy Oncology Group Grade 1-2 mucositis was noted in all patients treated for oropharyngeal or laryngeal lesions. CONCLUSIONS The SBRT in single or fractionated doses offers a viable treatment option for selected patients with primary, recurrent, and metastatic head-and-neck cancers with functional preservation.

Influence of lecithin on mitochondrial DNA and age-related hearing loss.

;OBJECTIVES: Lecithin is a polyunsaturated phosphatidylcholine (PPC), which are high energy functional and structural elements of all biologic membranes. PPC play a rate-limiting role in the activation of numerous membrane-located enzymes, including superoxide dismutase and glutathione, which are important antioxidants protecting cell membranes from damage by reactive oxygen species (ROS). ROS-induced damage to mitochondrial DNA may lead to reduced mitochondrial function in the cochlea and resultant hearing loss. STUDY DESIGN AND SETTING: The effects of lecithin on aging and age-associated hearing loss were studied in rats by measuring hearing sensitivities using auditory brainstem responses (ABR). In addition, mitochondrial function as a measure of aging was assessed by determining mitochondrial membrane potentials using flow cytometry and by amplifying mitochondrial DNA deletions associated with aging. Harlan-Fischer rats aged 18 to 20 months (n = 14) were divided into 2 groups. The experimental group was supplemented orally for 6 months with lecithin, a purified extract of soybean phospholipid (Nutritional Therapeutics, Allendale, NJ). RESULTS: The data obtained were compared with the control group. ABRs were recorded at 2-month intervals and showed significant preservation of hearing sensitivities in the treated subjects. Flow cytometry revealed significantly higher mitochondrial membrane potentials in the treated subjects, suggesting preserved mitochondrial function. Finally, the common aging mitochondrial DNA deletion (mtDNA4834) were amplified from brain and cochlear tissue including stria vascularis and auditory nerve. This specific deletion was found significantly less frequent in all tissues in the treated group compared with the controls. CONCLUSION: These experiments support our hypothesis and provide evidence that lecithin may preserve cochlear mitochondrial function and protect hearing loss associated with aging.

Association of Mitochondrial DNA Deletions and Cochlear Pathology: A Molecular Biologic Tool†‡

The purpose of these experiments was to develop a method of isolation, amplification, and identification of cochlear mitochondrial DNA (mtDNA) from minute quantities of tissue. Additionally, studies were designed to detect mtDNA deletions (mtDNA del) from the cochlea that previously have been amplified from other organ systems and tissues. MtDNA del have been associated with many pathologies, including neurological disorders, sensorineural hearing loss, ischemia, cardiomyopathies, and aging.

Health behaviors of head and neck cancer patients the first year after diagnosis

This prospective, cohort study is the first to describe 5 health behaviors of head and neck cancer patients the first year after diagnosis.

Comorbidities in head and neck cancer : Agreement between self-report and chart review

Objectives To determine the accuracy of self-reported comorbidities compared with medical record review and the clinical and sociodemographic characteristics associated with accuracy of self-reported comorbidities. Study Design We conducted a prospective study of 458 newly diagnosed head and neck cancer patients using self-administered questionnaire and medical chart review data. Overall and itemwise consistency between self-report and chart review was evaluated. Social, clinical, and demographic characteristics of consistent versus inconsistent responders were analyzed. Results Seventy-four percent of patients had at least one comorbidity. There was good overall consistency between self-report and chart review (k = 0.50). Compared with consistent responders, inconsistent responders were found to be older (P < 0.05), have lower sleep (P < 0.05) and physical activity scores (P < 0.05), be more depressed (P < 0.05), and have more severe comorbidities (P < 0.05). Conclusions and Significance Self-report may be considered as an alternative to chart review for comorbidity assessment in head and neck cancer patients. Younger patients, those with good general health, fewer depressive symptoms, and mild comorbidities, are more likely to give responses consistent with chart review.

Image-guided radiosurgery of head and neck cancers

OBJECTIVES: Radiosurgery precisely delivers a single high dose or a few fractionated doses of radiation to a localized tumor via the stereotactic approach. Some head and neck sites are suitable for radiosurgery since there is minimal or no organ motion. The clinical studies were carried out to determine the accuracy of stereotactic radiosurgery and to demonstrate the effectiveness of radiosurgery in head and neck cancers. MATERIALS AND METHODS: Thirteen patients were treated with either single-dose or fractionated radio-surgery to the tumor. All patients except one with cancer of the lip had received prior treatments including surgery, radiotherapy, and chemotherapy for the primary cancers. The dose ranged 12 to 18 Gy for single-dose radiosurgery and 30 Gy in 5 or 6 fractions twice a week for fractionated radiosurgery. Tumor localization was achieved via the stereotactic approach. RESULTS: Accuracy of radiosurgery was within 1.5 mm. Despite the recurrent disease from previous heavy treatments, 9 patients (70%) showed a significant response (complete or >50% tumor reduction) to radiosurgery, and 3 patients had stable disease. Complete tumor response was achieved in 6 patients. All patients had excellent pain relief with functional and cosmetic preservation. There was no acute and subacute radiation toxicity detected clinically during the minimal follow-up of 6 months. CONCLUSION: Image-guided radiosurgery is effective in achieving the local tumor control and pain relief. Radiosurgery provided excellent functional and cosmetic preservation with minimal complication. The results indicate the potential of radiosurgery in the treatment of recurrent and selected primary head and neck cancers. (Otolaryngol Head Neck Surg 2004;130:690-7.)

Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig

Abstract Glutamate excitotoxicity is implicated in both the genesis of neural injury and noise-induced hearing loss (NIHL). Acoustic overstimulation may result in excessive synaptic glutamate, resulting in excessive binding to post-synaptic receptors and the initiation of a destructive cascade of cellular events, thus leading to neuronal degeneration and NIHL. The purpose of this study was to determine whether this apparent excitotoxicity can be attenuated by kynurenic acid (KYNA), a broad-spectrum glutamate receptor antagonist, and protect against noise-induced temporary threshold shifts (TTS). Guinea pigs were randomly assigned to three separate groups. Baseline compound action potentials (CAP) thresholds and cochlear microphonics (CM) were recorded. Group I was treated with physiologic saline as a vehicle control applied to the round window membrane that was followed by 110 dB SPL wide-band noise for 90 min. Group II received 5 mM KYNA followed by noise exposure, and group III received 5 mM KYNA alone without noise exposure. Post-drug and noise levels of CAP thresholds and CM were then obtained. Noise exposure in the control group caused a significant temporary threshold shift (TTS) of 30–40 dB across the frequencies tested (from 3 kHz to18 kHz). Animals that received 5 mM KYNA prior to noise exposure (group II) showed statistically significant protection against noise-induced damage and demonstrated a minimal TTS ranging between 5 and 10 dB at the same frequencies. Animals in group III receiving KYNA without noise exposure showed no change in thresholds. Additionally, cochlear microphonics showed no considerable difference in threshold shifts when controls were compared to KYNA-treated animals. These results show that antagonizing glutamate receptors can attenuate noise-induced TTS, suggesting that glutamate excitotoxicity may play a role in acoustic trauma.