Retinopathy develops at similar glucose levels but higher HbA1c levels in people with black African ancestry compared to white European ancestry: evidence for the need to individualize HbA1c interpretation.

AIMS: To examine the association of HbA1c and glucose levels with incident diabetic retinopathy according to black African or white European ancestry. METHODS: In this retrospective cohort study of 202 500 US Veterans with diabetes (2000-2014), measures included HbA1c , outpatient random serum/plasma glucose, and incident retinopathy [conversion from negative to ≥2 positive evaluations (ICD-9 codes), without a subsequent negative]. RESULTS: At baseline, the study population had a mean age of 59.3 years, their mean BMI was 31.9 kg/m2 , HbA1c level was 57 mmol/mol (7.4%) and glucose level was 8.8 mmol/l, and 77% were of white European ancestry (white individuals) and 21% of black African ancestry (black individuals). HbA1c was 0.3% higher in black vs white individuals (P < 0.001), adjusting for baseline age, sex, BMI, estimated glomerular filtration rate (eGFR), haemoglobin, and average systolic blood pressure and glucose. Over 11 years, incident retinopathy occurred in 9% of black and 7% of white individuals, but black individuals had higher HbA1c , glucose, and systolic blood pressure (all P < 0.001); adjusted for these factors, incident retinopathy was reduced in black vs white individuals (P < 0.001). The population incidence of retinopathy (7%) was associated with higher mean baseline HbA1c in individuals with black vs white ancestry [63 mmol/mol (7.9%) vs 58 mmol/mol (7.5%); P < 0.001)], but with similar baseline glucose levels (9.0 vs 9.0 mmol/l; P = 0.660, all adjusted for baseline age, sex and BMI). CONCLUSIONS: Since retinopathy occurs at higher HbA1c levels in black people for a given level of average plasma glucose, strategies may be needed to individualize the interpretation of HbA1c measurements.

Impact of mismatches in HbA1c vs glucose values on the diagnostic classification of diabetes and prediabetes.

AIMS: To determine whether HbA1c mismatches (HbA1c levels that are higher or lower than expected for the average glucose levels in different individuals) could lead to errors if diagnostic classification is based only on HbA1c levels. METHODS: In a cross-sectional study, 3106 participants without known diabetes underwent a 75-g oral glucose tolerance test (fasting glucose and 2-h glucose) and a 50-g glucose challenge test (1-h glucose) on separate days. They were classified by oral glucose tolerance test results as having: normal glucose metabolism; prediabetes; or diabetes. Predicted HbA1c was determined from the linear regression modelling the relationship between observed HbA1c and average glucose (mean of fasting glucose and 2-h glucose from the oral glucose tolerance test, and 1-h glucose from the glucose challenge test) within oral glucose tolerance test groups. The haemoglobin glycation index was calculated as [observed - predicted HbA1c ], and divided into low, intermediate and high haemoglobin glycation index mismatch tertiles. RESULTS: Those participants with higher mismatches were more likely to be black, to be men, to be older, and to have higher BMI (all P<0.001). Using oral glucose tolerance test criteria, the distribution of normal glucose metabolism, prediabetes and diabetes was similar across mismatch tertiles; however, using HbA1c criteria, the participants with low mismatches were classified as 97% normal glucose metabolism, 3% prediabetes and 0% diabetes, i.e. mostly normal, while those with high mismatches were classified as 13% normal glucose metabolism, 77% prediabetes and 10% diabetes, i.e. mostly abnormal (P<0.001). CONCLUSIONS: Measuring only HbA1c could lead to under-diagnosis in people with low mismatches and over-diagnosis in those with high mismatches. Additional oral glucose tolerance tests and/or fasting glucose testing to complement HbA1c in diagnostic classification should be performed in most individuals.

Racial differences in performance of HbA1c for the classification of diabetes and prediabetes among US adults of non-Hispanic black and white race.

AIM: To characterize differences between black and white people in optimal HbA1c thresholds for diagnoses of diabetes and prediabetes. METHODS: Data were included from the National Health and Nutrition Examination Survey, 2005-2014. Black and white adults (age 18-70 years) who underwent an oral glucose tolerance test and had available fasting plasma glucose, 2-h plasma glucose and HbA1c measurements were eligible for inclusion. Diabetes or prediabetes status was defined by fasting plasma glucose and 2-h plasma glucose using American Diabetes Association criteria. Classification of diabetes, prediabetes and dysglycaemia by HbA1c was evaluated for a range of HbA1c thresholds, with optimal thresholds defined as those values that maximized the sum of sensitivity and specificity (Youden's index). RESULTS: In 5324 black (32.3%) and white (67.7%) individuals, Youden's index (optimal) thresholds for HbA1c were ≥42 mmol/mol (6.0%) and ≥39 mmol/mol (5.7%) for discriminating diabetes vs non-diabetes, ≥ 44 mmol/mol (6.2%) and ≥39 mmol/mol (5.7%) for discriminating diabetes vs prediabetes (excluding normoglycaemia), ≥39 mmol/mol (5.7%) and ≥37 mmol/mol (5.5%) for discriminating dysglycaemia vs normoglycaemia, and ≥39 mmol/mol (5.7%) and ≥37 mmol/mol (5.5%) for discriminating prediabetes vs normoglycaemia (excluding diabetes), in black and white people, respectively. CONCLUSIONS: Consistently higher optimal HbA1c thresholds in black people than in white people suggest a need to individualize HbA1c relative to glucose levels if HbA1c is used to diagnose diabetes and prediabetes.

SSB taxes and diet quality in US preschoolers: estimated changes in the 2010 Healthy Eating Index.

BACKGROUND: Taxing sugar-sweetened beverages (SSBs) has been proposed as a strategy to combat child obesity. Yet it is unclear how a tax on SSBs might influence the overall quality of diet in preschool children. Thus, we use simulated price increases and the 2010 Healthy Eating Index (HEI-2010) to explore the relationship between SSB taxes and diet quality in preschool children. METHODS: Price and purchase data from the 2009-2012 Nielsen Homescan Panel and a two-part marginal effects model were used to estimate relative changes in purchases with a 20% increase in the price of SSBs. Demand elasticities were applied to dietary intake data for children ages 2-5 years from the National Health and Nutrition Examination Survey (2009-2010 and 2011-2012) to estimate the impact of a 20% SSB tax on dietary intake and quality (HEI-2010). RESULTS: A 20% increase in the price of SSBs was associated with lower total caloric intake (-28 kcal d-1 , p < 0.01), caloric intake from juice drinks (-20 kcal d-1 , p < 0.01), added sugars (-4.1 servings d-1 , p = 0.03), refined grains (-0.63 servings d-1 , p < 0.01) and total meat (-0.56 servings d-1 , p < 0.01). Beneficial decreases in empty calories and refined grains were offset by unfavourable changes in fatty acid profile, total protein, vegetables and fruit, such that total HEI scores (0-100 range) were not meaningfully changed with a 20% increase in SSB price (difference: -0.85, p < 0.01). CONCLUSIONS: A 20% tax on SSBs could decrease caloric intake, and intakes of added sugars and SSBs, but may not improve diet quality as an isolated intervention among US preschool children.

Ten-year beverage intake trends among US preschool children: rapid declines between 2003 and 2010 but stagnancy in recent years.

BACKGROUND: It has been previously reported that total energy intake among US preschool children (ages 2-5 years) decreased between 2003-2004 and 2009-2010. However, little is known about how intakes of beverages among US preschoolers (ages 2-5 years) changed from 2003-2004 to 2011-2012. OBJECTIVES: This paper examines changes in intakes of key beverages during this period, as well as how eating location (at home or away from home) and source (store vs. others) may have contributed to these changes. METHODS: Cross-sectional day one dietary data among children ages 2-5 years from the National Health and Nutrition Examination Survey 2003-2004, 2005-2006, 2007-2008, 2009-2010 and 2011-2012 were used. Survey-weighted mean intakes by survey year, eating location and source were computed for total sugar-sweetened beverages (SSBs), milks, 100% juice, low/no-calorie beverages, 10 key beverages, total beverages and total foods. Means were compared using two-tailed z-tests with Bonferroni corrections (α < 0.05). RESULTS: Between 2003-2004 and 2011-2012, among 2-5 year olds, total caloric intake fell by 132 kcal d(-1) , with intakes of beverages falling by 55 kcal d(-1) . Decreases in intakes of total SSBs (-57 kcal d(-1) ), fruit-flavoured or juice drinks containing <100% juice (juice drinks) (-37 kcal d(-1) ), caloric soft drinks (-13 kcal d(-1) ) and >1% fat, low-sugar milk (-42 kcal d(-1) ) were among the major changes. By eating location, total beverage intake at home fell by 73 kcal d(-1) . By source, total beverage intake from stores fell by 106 kcal d(-1) . Changes in intakes occurred primarily between 2003-2004 and 2009-2010, as there were no significant differences in beverage intakes between 2009-2010 and 2011-2012. Intakes of total calories (+49 kcal d(-1) ) and calories from foods (+53 kcal d(-1) ) trended upward between 2009-2010 and 2011-2012, but changes were not significant. CONCLUSIONS: These findings suggest improvements in the diets of preschoolers between 2003-2004 and 2009-2010, of which stores were a major contributor.

In vivo markers of inflammatory response in recent-onset schizophrenia: a combined study using [(11)C]DPA-713 PET and analysis of CSF and plasma.

Several lines of evidence suggest aberrant immune response in schizophrenia, including elevated levels of cytokines. These cytokines are thought to be produced by activated microglia, the innate immune cells of the central nervous system. However, increase in translocator protein 18 kDa (TSPO), a marker of activated glia, has not been found in patients with chronic schizophrenia using second-generation radiotracers and positron emission tomography (PET)-based neuroimaging. In this study we focused on patients with recent onset of schizophrenia (within 5 years of diagnosis). Quantified levels of TSPO in the cortical and subcortical brain regions using the PET-based radiotracer [(11)C]DPA-713 were compared between the patients and healthy controls. Markers of inflammation, including interleukin 6 (IL-6), were assessed in the plasma and cerebrospinal fluid (CSF) in these participants. We observed no significant change in the binding of [(11)C]DPA-713 to TSPO in 12 patients with recent onset of schizophrenia compared with 14 controls. Nevertheless, the patients with recent onset of schizophrenia showed a significant increase in IL-6 in both plasma (P<0.001) and CSF (P=0.02). The CSF levels of IL-6 were significantly correlated with the levels of IL-6 in plasma within the total study population (P<0.001) and in patients with recent onset of schizophrenia alone (P=0.03). Our results suggest that increased levels of IL-6 may occur in the absence of changed TSPO PET signal in the brains of medicated patients with recent onset of schizophrenia. Future development of PET-based radiotracers targeting alternative markers of glial activation and immune response may be needed to capture the inflammatory signature present in the brains of patients with early-stage disease.

Dose intensification in curative head and neck cancer radiotherapy--linear quadratic analysis and preliminary assessment of clinical results.

PURPOSE: The feasibility of reducing overall treatment time by 2 weeks in the curative radiotherapeutic management of head and neck cancer patients is reported in a pilot trial of Hyperfractionated, Accelerated Radiotherapy with Dose Escalation (HARDE). This regimen prescribes 76 Gy in 5 weeks to definitive head and neck cancer patients, and 65 Gy in 5 weeks to high-risk postoperative patients. The linear quadratic model is used to compare predicted tumor cell kill with HARDE versus that expected with conventional fractionation (CF). MATERIALS AND METHODS: Between January 1991 and March 1992, 40 head and neck cancer patients were treated with HARDE at the University of Wisconsin Comprehensive Cancer Center. Case-matched controls treated with CF were identified from patients treated at the same institution between 1980-1990, based on tumor site, stage, and extent of prior surgery. Individual patient treatment data (total dose, fraction size, overall time) rather than idealized schedule data from each group were analyzed using the linear quadratic model. RESULTS: Seventy-nine case-matched controls were identified for comparison with HARDE patients. The predicted increase in log cell kill for HARDE patients over case-matched controls was 1.5 and 1.3 logs, respectively, in the definitive and postoperative settings. This difference in log cell kill projects an improvement in locoregional tumor control for HARDE patients of between 10-25%. HARDE patients experience very brisk acute mucosal reactions and moderately prolonged mucosal healing, however, 91% have completed therapy without a treatment break. CONCLUSION: A 2-week reduction in overall treatment time for curative head and neck cancer patients is feasible while maintaining doses > 70 Gy. Based on radiobiologic predictions, such treatment intensification may significantly improve rates of locoregional tumor control. However, intensified acute mucosal reactions accompany such accelerated therapy.

Histologic studies on the fate of soluble collagen injected into canine vocal folds.

Collagen is an essential component of the functionally important layered structure of the vocal cord. Soluble bovine collagen appears to be suitable for injection into vocal folds to correct glottic insufficiency. Clinical trials and preliminary laboratory studies with the canine larynx indicate that injectable collagen is safe, effective, easily injected, and well-tolerated. Bovine collagen softens scar tissue, attracts the ingrowth of host fibroblasts, and allows the eventual replacement of the implant by new host collagen. This study examines the fate of collagen injected into canine vocal folds. Two forms of soluble bovine collagen, differing only in the amount of chemically induced cross-linkage, were injected into vocal folds of dogs; the animals were then killed at 12-week intervals for 1 year. Gross and histologic examination showed that both substances tended to be resorbed when injected deeply in the vocalis muscle, but persisted when injected in the plane of the vocal ligament - a site normally composed of dense collagen. The invasion of the implant by active host fibroblasts and the secondary deposition of new host collagen were evident in histologic sections. Examination with polarized light confirmed the presence of birefringence characterizing host collagen. The invasion of fibroblasts and deposition of new collagen in the implant were seen with electron microscopy. Cellular invasion seemed to progress more rapidly in the cross-linked preparation. Injected collagen did not evoke a foreign body reaction in any specimen studied, and was well-tolerated during replacement by host tissue.

Advances and refinements in phonosurgery.

Scientific discovery, technological advances, and improved outcomes assessment have resulted in advances and refinements in phonosurgery. Three areas of substantial evolution are phonomicrosurgery, laryngeal framework surgery, and the use of implantable materials in vocal folds. Discovery of the importance of the superficial layers of the lamina propria has led to increased use of more limited medial microflap approaches and less frequent use of the classic lateral cordotomy flap approach. Alternative approaches to managing vocal fold scarring defects have addressed the separation of body and cover and provided suitable lamina propria replacement. Approaches to sulcus vocalis have been refined to address type II (linear vergeture) and type III (focal invasive pit) sulcus, where there is loss of lamina propria, while still recognizing the common nonpathological type I (physiological) sulcus. Technological advancements such as photodynamic therapy, tuned dye lasers, and laryngeal microdebridement have augmented the armamentarium for mechanical removal of laryngeal papillomata. Careful infusion-assisted microexcision and adjunctive medical management have been refined and made more effective. Laryngeal framework surgery has embraced the development of Silastic, hydroxylapatite, expanded polytetrafluoroethylene, and titanium shims. Anatomical studies have helped to improve operative precision and safety, and have led to inventive variations in arytenoid repositioning that improve closure of the posterior subunit. Vocal fold augmentation by injection has been facilitated by innovative use of the rigid telescope and intraoperative videostroboscopy. Anatomical studies have focused on the infrafold region and rheological studies have attempted to match viscoelastic properties of injectable substances to those of vocal fold tissues. Alloplastic materials such as Teflon have been largely supplanted by newer bioimplantables such as fat, collagen, and fascia.

Clinical experience with injectable collagen for vocal fold augmentation.

Injectable collagen appears to be safe and effective in treating glottic insufficiency. Fifty-four patients received vocal-fold injections of Zyderm Collagen Implant and their responses were followed for as long as 2 years. Videostroboscopy affords the best assessment of glottic function and correlates well with vocal quality. Maximum phonation time and transglottic airflow are the most sensitive measures of glottic efficiency; follow-up studies indicate that responses to treatment vary at 1 week, tend to stabilize by 3 months, and show only slight decrement over 1 year. One patient experienced a delayed hypersensitivity reaction, but it did not adversely affect his result. The use of cross-linked preparations of collagen should decrease the incidence of such responses. Treated patients were divided into diagnostic groups. Patients with bilaterally scarred vocal folds did not appear to respond optimally to collagen injection. Vocal rehabilitation was better if patients had at least one normal vocal fold. The best results occurred in patients with unilateral vocal fold paralysis and pre-existent bowing or atrophy did not affect these results. Collagen should be injected in the plane of the vocal ligament for best results; if the injection is too deep the implant is resorbed, and if too superficial, vocal-fold vibration is impaired.

Anterior commissure microwebs associated with vocal nodules: detection, prevalence, and significance.

Vocal fold nodules are a common cause of dysphonia generally attributed to vocal abuse. Anterior commissure microwebs have been reported as an incidental finding in surgical patients with nodules. In a series of 105 nodule patients evaluated at the University of Wisconsin Clinical Science Center voice laboratory (1987-1992), 11 microwebs were identified. Ten of these microweb patients were among the 20 nodule patients who did not respond to voice therapy and underwent microsurgery. In patients with nodules whose hoarseness is refractory to voice therapy, symptoms that occur early in life suggest the presence of occult vocal fold pathology. Microweb detection requires a high index of suspicion, observation during maximal vocal fold abduction, and clearance of secretions from the anterior commissure. Definitive identification is facilitated by gentle separation of the anterior vocal folds during direct microlaryngoscopy. The presence of these tiny shelves of tissue might be coincidental, or they might represent another expression of the tissue response to traumatic factors known to produce vocal nodules. We found little difference in vocal function parameters between two similar groups of nodule patients, one with and one without associated microwebs. Further work is needed to determine the significance of microwebs.

Persistence of injectable collagen in the human larynx: a histopathologic study.

This is a report of the histologic findings in a human larynx that had undergone collagen injection for glottic insufficiency 14 months prior to autopsy. The patient's management before augmentation with collagen included extended supraglottic laryngectomy, radiation therapy, and Polytef injection. Connective tissue changes secondary to other forms of treatment were apparent bilaterally and changes limited to the site of collagen injection were identified. There have been reports of persistence of injected collagen in the canine larynx at 1 year but this is the only study documenting persistence in a human subject. The implant appeared homogeneous and was easily distinguished from host collagen and the reactive fibrosis associated with particulate Polytef. These findings are similar to those observed in the canine model and suggest that there is persistence of injected collagen in the human larynx.

Sulcus vocalis in laryngeal cancer: a histopathologic study.

The incidental finding of sulcus vocalis in surgical specimens of patients with laryngeal cancer prompted this review. Sulcus deformities were histologically identified in 28 (48%) of 58 whole-mount coronal serial-sectioned laryngeal specimens procured from laryngeal cancer patients. The lesions were analyzed, described, and graded. A control group of 20 larynges, obtained from autopsies of patients without known laryngeal pathology, were similarly processed, and whole-mount histologic sections were studied. Four of these specimens (20%) also demonstrated sulcus deformities. In the control group, the shape and location of the sulci were similar, but the lesions were smaller than in the cancer group. The sulcus lesions revealed chronic inflammation of the subepithelial tissues with vascular ingrowth and fibrosis of the superficial lamina propria (Reinke's space); in the cancer group the sulcus was usually on the opposite vocal fold, where irritation from the tumor might be anticipated. Although the etiology of the sulci remains controversial, these findings suggest that irritation and inflammation might play a role in the pathogenesis of sulcus vocalis.

Autologous collagen vocal fold injection: a preliminary clinical study.

This preliminary study reports the first use of injectable autologous collagen for vocal fold augmentation. In previous studies, the authors showed cross-linked bovine collagen to be effective in more than 150 patients with glottic incompetence, particularly those with focal defects or scarred or atrophic vocal folds. However, concerns about possible adverse immunologic responses to the bovine material have limited its use. The authors studied eight patients with difficult vocal fold pathology, including sulcus vocalis, atrophy, and scarring secondary to trauma and cordectomy. Skin was harvested under local anesthesia, processed into a naturally cross-linked injectable form (Autologen), and injected using indirect laryngoscopy. Voice production was evaluated prior to the injection and at intervals after the injection, using subjective, perceptual, aerodynamic, acoustic, and videostroboscopic assessments. The results indicate that autologous collagen is comparable to injectable bovine collagen in the management of several difficult glottic insufficiency problems and that the likelihood of a hypersensitivity response is negligible. Unlike bovine collagen preparations, Autologen does not require breakdown of the natural collagen molecule, so it is anticipated that this material will be better tolerated and more stable over time.

Injectable collagen in laryngeal rehabilitation.

Glottic insufficiency has been successfully managed by Teflon augmentation of paretic vocal cords over the past two decades. Collagen fulfills the criteria for a suitable bioimplant and is an attractive alternative as it is a normal constituent of the extracellular protein matrix. This study explores the use of modified bovine collagen injected into the canine larynx. Clinical situations are simulated by creating lesions and injecting collagen at different sites. The technique permits precise placement and quantification. Histologic study of the collagen implant fails to show evidence of significant foreign body reaction. The injected collagen appears similar to viable connective tissue and is colonized by host fibroblasts and nourishing capillaries.

Correlation between vocal functions and glottal measurements in patients with unilateral vocal fold paralysis.

Observations and analysis of glottal characteristics are critical in choosing the best modality for surgery in patients with unilateral vocal fold paralysis (UVP). This study suggests that multiple glottal characteristics influence the vocal product in patients with UVP. In addition to the horizontal position of the paralyzed vocal fold (deviation from the midline), the glottal area, degree of bowing of the paralyzed and contralateral vocal folds, maximum separation between vocal folds, compensatory glottal maneuvers, and the vertical glottic closure plane significantly influenced the quality of the voice. Clinicians should be aware of these observations to facilitate treatment planning and assessment of the results of surgical procedures used to improve voice quality in cases of UVP.

Magnetic resonance imaging (MRI) assessment of vocal fold medialization surgery.

Historically, clinicians have used subjective assessment and perceptual judgments, supplemented with acoustic measures, aerodynamic studies, and videostroboscopy, to determine the effects of phonosurgery. When phonosurgical results are poor, magnetic resonance imaging (MRI) can be useful in determining how the surgical modifications contributed to the anatomical and functional status of the vocal folds. The authors present examples of MRI following vocal fold medialization by injection, thyroplasty, and arytenoid adduction. Findings reveal that the superior contrast resolution of MRI can precisely identify placement and persistence of injected implants and is particularly helpful in showing effects of the size and shape of alloplastic prostheses on vocal fold displacement. Such information is useful in troubleshooting suboptimal results and in planning revision thyroplasty by defining modification in the design of prostheses and the placement of cartilaginous windows in medialization thyroplasty. MRI can also aid in confirming indications for and limitations of certain procedures.

Significance of apparent intratympanic meningiomas.

Meningioma is the most common tumor of the central nervous system, but it has only been reported in 79 patients to involve the temporal bone. The 4 cases presented here show striking clinical similarity to a subgroup of 20 meningiomas reported to be entirely intratympanic; however, in each instance the extent, origin, and potential of the disease was not initially evident. Precise histopathologic diagnosis may be aided by electron microscopy. Current concepts of embryology lend credence to the possible role of arachnoid endothelial cells in the pathogenesis of intratympanic meningioma. An advanced intracranial meningioma may be overshadowed by the hearing loss, tinnitus, and otalgia calling attention to an intratympanic component. The clinician should remain suspicious of intracranial disease even after excision of an apparently well circumscribed intratemporal lesion. Progressive sensorineural hearing loss and persistent otalgia portend recurrent or intracranial disease. Follow-up for at least 10 years with judicious use of CT scans is suggested.

Physiologic assessment of botulinum toxin effects in the rat larynx.

OBJECTIVE: Botulinum toxin (BT) is a currently used treatment for spasmodic dysphonia (SD) and other related focal dystonias. The goal of this study is to provide a basis for using the rat larynx to objectively assess physiological and histological effects of BT. STUDY DESIGN: Dosages and volumes of BT injection were varied and three physiological parameters were measured. These measures included: optical density of PAS-stained laryngeal muscle after electrical stimulation, which is an indirect measure of denervation, spontaneous laryngeal muscle activity, and laryngeal movement. METHODS: A new microlaryngoscopic technique was developed, which made it possible to observe and manipulate the rat larynx endoscopically. Laryngeal movement and electromyographic (EMG) measures were made prior to injection and 3 days following BT injections of various dosages and volumes. Optical density measures were made 3 days after injection. RESULTS: Significant reductions in vocal fold motion and spontaneous laryngeal muscle activity as a function of increased BT dosage were observed. In addition, the optical density of PAS-stained laryngeal muscle after electrical stimulation was increased following BT injection. Significant volume effects in optical density were observed in the lateral thyroarytenoid and lateral cricoarytenoid muscles on the contralateral side. CONCLUSIONS: The rat laryngeal model is suitable for assessing BT effects. In addition, the three physiological variables provided useful and reliable measures of laryngeal function. It is the authors' intention to use the rat laryngeal model to further examine the physiological and histological effects of BT with the goal of developing new methods for the treatment of patients with SD and other focal dystonias.

Increased acute and chronic mitotic activity in rat laryngeal muscles after botulinum toxin injection.

OBJECTIVES: To characterize the acute and chronic cellular effects of botulinum toxin (BT) injection into rat laryngeal muscles. A complete characterization of these effects is important because patients with focal dystonias of the head and neck are commonly treated with BT injection. Further, potential muscular changes in the larynx must be carefully delineated owing to the critical phonatory and airway protective functions of these muscles. STUDY DESIGN: The acute and chronic cellular effects of BT injection were studied using 5'-bromo 2'-deoxyuridine (BrdU) following single and repeated BT injection into rat laryngeal muscles. BrdU is incorporated into mitotically active nuclei such that changes in cell proliferative behavior following BT injection can be monitored. RESULTS: Increased mitotic activity was detected in the tissue samples studied following BT injection. Differences in the times of the peak distribution of BrdU-labeled cells in each laryngeal muscle were observed. This may be related to the diffusion effects of BT. Prolonged muscle fiber changes, including splitting, were also observed as the result of repeated BT injection. CONCLUSIONS: The results of this study suggest that BT may induce a proliferative response in muscle tissue.