Robert S. Butler

Consequences of repeated blood-brain barrier disruption in football players

The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. We tested the hypothesis that blood-brain barrier disruption (BBBD) and the accompanying surge of the astrocytic protein S100B in blood may cause an immune response associated with production of auto-antibodies. We also wished to determine whether these events result in disrupted white matter on diffusion tensor imaging (DT) scans. Players from three college football teams were enrolled (total of 67 volunteers). None of the players experienced a concussion. Blood samples were collected before and after games (n = 57); the number of head hits in all players was monitored by movie review and post-game interviews. S100B serum levels and auto-antibodies against S100B were measured and correlated by direct and reverse immunoassays (n = 15 players; 5 games). A subset of players underwent DTI scans pre- and post-season and after a 6-month interval (n = 10). Cognitive and functional assessments were also performed. After a game, transient BBB damage measured by serum S100B was detected only in players experiencing the greatest number of sub-concussive head hits. Elevated levels of auto-antibodies against S100B were elevated only after repeated sub-concussive events characterized by BBBD. Serum levels of S100B auto-antibodies also predicted persistence of MRI-DTI abnormalities which in turn correlated with cognitive changes. Even in the absence of concussion, football players may experience repeated BBBD and serum surges of the potential auto-antigen S100B. The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes.

Risk factors for hypopharyngeal/upper esophageal stricture formation after concurrent chemoradiation

Concurrent chemoradiation therapy has been demonstrated to be effective as an organ‐sparing treatment for select advanced head and neck squamous cell carcinoma (HNSCC). However, this treatment modality is not without side effects. One side effect is the formation of upper esophageal strictures. As concurrent chemoradiation treatment is used more frequently, it is important to identify risk factors associated with stricture formation.

Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors.

Due to the shortage of organs, living donor acceptance criteria are becoming less stringent. An accurate determination of the glomerular filtration rate (GFR) is critical in the evaluation of living kidney donors and a value exceeding 80 ml/min per 1.73 m(2) is usually considered suitable. To improve strategies for kidney donor screening, an understanding of factors that affect GFR is needed. Here we studied the relationships between donor GFR measured by (125)I-iothalamate clearances (mGFR) and age, gender, race, and decade of care in living kidney donors evaluated at the Cleveland Clinic from 1972 to 2005. We report the normal reference ranges for 1057 prospective donors (56% female, 11% African American). Females had slightly higher mGFR than males after adjustment for body surface area, but there were no differences due to race. The lower limit of normal for donors (5th percentile) was less than 80 ml/min per 1.73 m(2) for females over age 45 and for males over age 40. We found a significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors. The age of the donors and body mass index increased over time, but their mGFR, adjusted for body surface area, significantly declined by 1.49+/-0.61 ml/min per 1.73 m(2) per decade of testing. Our study shows that age and gender are important factors determining normal GFR in living kidney donors.

National Trends in Parathyroid Surgery from 1998 to 2008: A Decade of Change

BACKGROUND The introduction of limited explorations (LE) for parathyroidectomy broadened the management possibilities for hyperparathyroidism. We sought to document this evolution of change in parathyroid surgery. STUDY DESIGN Members of the American Association of Endocrine Surgeons and the American College of Surgeons were sent a 49-question survey, and 256 surgeons, accounting for 46% of parathyroid operations nationwide, responded. Associations derived from questionnaire data were tested for significance using chi-square and Kruskal-Wallis methods. RESULTS Currently, 10% of surgeons practice bilateral neck exploration, 68% practice LE, and 22% have a mixed practice. Five years ago, these percentages were, respectively, 26%, 43%, and 31%; and 10 years ago they were 74%, 11%, and 15%. Shift to LE was greatest among endocrine surgeons, high-volume surgeons, and surgeons trained by mentors who practiced LE. A focal, single-gland examination under general anesthesia and 23-hour observation are preferred by most surgeons. Half of all general surgeons, in contrast to fewer than 10% of endocrine surgeons, never monitor parathyroid hormone intraoperatively, even with LE. Dramatic differences were apparent among subsets of surgeons in operative volumes, indications for bilateral neck exploration, followup care, expertise with ultrasound and sestamibi, and perceptions of cure and complication rates. Evidence-based literature and guidance from surgical societies had the greatest influence on the decision to practice LE. CONCLUSIONS This survey formally documents the evolution of practice patterns in parathyroid surgery over the last decade. Although LE has achieved wide acceptance, surgical management of hyperparathyroidism has become increasingly disparate. This trend may highlight a need to define best-practice guidelines.

Chronic electrical stimulation of the contralesional lateral cerebellar nucleus enhances recovery of motor function after cerebral ischemia in rats

Novel neurorehabilitative strategies are needed to improve motor outcomes following stroke. Based on the disynaptic excitatory projections of the dentatothalamocortical pathway to the motor cortex as well as to anterior and posterior cortical areas, we hypothesize that chronic electrical stimulation of the contralesional dentate (lateral cerebellar) nucleus output can enhance motor recovery after ischemia via augmentation of perilesional cortical excitability. Seventy-five Wistar rats were pre-trained in the Montoya staircase task and subsequently underwent left cerebral ischemia with the 3-vessel occlusion model. All survivors underwent stereotactic right lateral cerebellar nucleus (LCN) implantation of bipolar electrodes. Rats were then randomized to 4 groups: LCN stimulation at 10 pps, 20 pps, 50 pps or sham stimulation, which was delivered for a period of 6 weeks. Performance on the Montoya staircase task was re-assessed over the last 4 weeks of the stimulation period. On the right (contralesional) side, motor performance of the groups undergoing sham, 10 pps, 20 pps and 50 pps stimulation was, respectively, 2.5+/-2.7; 2.1+/-2.5; 6.0+/-3.9 (p<0.01) and 4.5+/-3.5 pellets. There was no difference on the left (ipsilesional) side motor performance among the sham or stimulation groups, varying from 15.9+/-6.7 to 17.2+/-2.1 pellets. We conclude that contralesional chronic electrical stimulation of the lateral cerebellar nucleus at 20 pps but not at 10 or 50 pps improves motor recovery in rats following ischemic strokes. This effect is likely to be mediated by increased perilesional cortical excitability via chronic activation of the dentatothalamocortical pathway.

Biological and biomechanical responses to traditional epithelium-off and transepithelial riboflavin-UVA CXL techniques in rabbits.

PURPOSE To compare the biological effects of riboflavin-ultraviolet A (UVA) corneal cross-linking (CXL) performed with a traditional epithelium-off method to several transepithelial methods in a rabbit model. Preliminary experiments on biomechanical rigidity were also performed. METHODS Four treatment groups were included: (1) standard epithelium-off, (2) tetracaine transepithelial, (3) benzal-konium chloride-ethylenediaminetetraacetic acid (BKC-EDTA) transepithelial, and (4) femtosecond laser-assisted transepithelial riboflavin-UVA CXL. Six eyes from each treatment group and the untreated control group were analyzed at 24 hours and 2 months after treatment in wound healing studies. The TUNEL assay was performed to detect the extent of stromal cell death. Optical density was measured with a Scheimpflug analyzer. The corneal stiffening effect was quantitated in three eyes from each group using optical coherence elastography performed 2 months after treatments. RESULTS Twenty-four hours after CXL, stromal cell death extended full corneal thickness with both standard epithelium-off CXL and femtosecond laser-assisted CXL, but only approximately one-third stromal depth after BKC-EDTA transepithelial CXL. Negligible stromal cell death was detected with tetracaine transepithelial CXL. Cell death results were statistically different between the BKC-EDTA transepithelial CXL and standard epithelium-off CXL groups (P < .0001). Significant corneal opacity differences were noted. Standard epithelium-off CXL had the greatest density and tetracaine transepithelial CXL had the least density compared to the control group after treatment. As measured with optical coherence elastography, a trend toward greater mean stiffening was observed with BKC-EDTA transepithelial CXL than with epithelium-off CXL, femtosecond laser-assisted CXL, or tetracaine transepithelial CXL, but the result did not reach statistical significance. All of the CXL treatment groups exhibited significantly smaller variance of stiffness compared to the control group. CONCLUSION In the rabbit model, BKC-EDTA transepithelial CXL produced less stromal cell death and less risk of endothelial cell damage than standard epithelium-off CXL or femtosecond laser-assisted CXL. Additional study is needed to determine whether biomechanical stiffness is significantly different between the epithelium-off CXL and transepithelial CXL groups.

Cytokine Expression After Vaginal Distention of Different Durations in Virgin Sprague-Dawley Rats

PURPOSE We investigated the effect of the duration of vaginal distention on the differential expression of stem cell homing, tissue repair cytokines and cytokine receptors to identify the factors most important for recovery from injury. MATERIALS AND METHODS A total of 20, 10-week-old virgin Sprague-Dawley rats were divided into 4 groups, including 1, 4 and 6-hour vaginal distention, and anesthetized sham operation. The vagina, bladder, urethra and rectum were harvested immediately after vaginal distention. Real-time polymerase chain reaction was used to determine the relative expression of cytokines and receptors of interest. Mixed models analysis was used to determine associations between expression levels and vaginal distention duration. RESULTS Positive associations between vaginal distention duration and the urethral expression level were found for 1 of the receptors of monocyte chemotactic protein-3, CCR1 (p = 0.0001) as well as for monocyte chemotactic protein-3 (p = 0.025), CCR5 (p = 0.032) and hypoxia inducible factor-1alpha (p = 0.023). A positive relationship between vaginal distention duration and monocyte chemotactic protein-3 expression was also observed in rectal tissue (p = 0.035). Urethral expression of CCR2, another receptor for monocyte chemotactic protein-3, approached significance (p = 0.066). An inverse relationship between vaginal distention duration and interleukin-8 expression was found in the bladder (p = 0.0008). No association was noted between vaginal distention duration and the expression of stromal derived factor-1, CXCR4, CCR3 and vascular endothelial growth factor in any pelvic organs. CONCLUSIONS These data support a relationship between vaginal distention duration and the subsequent expression of monocyte chemotactic protein-3 and 1 of its associated receptors, CCR1, in the urethra immediately following vaginal distention. The increase in hypoxia-inducible factor1alpha expression in the urethra with prolonged vaginal distention suggests a limited role of tissue ischemia in the immediate response of pelvic organs to vaginal distention.

Relationship Between Proximal Femoral and Acetabular Alignment in Normal Hip Joints Using 3-Dimensional Computed Tomography

Background: The bony architecture of the hip depends upon functional adaptation to mechanical usage via the dynamic interaction between the acetabulum and femoral head. Acetabular retroversion is thought to be a contributing factor of pincer-type femoroacetabular impingement. Studies of pathological hip joints suggest proximal femoral anatomy compensates for acetabular retroversion. Hypothesis/Purpose: The purpose of this study was to determine if a predictable relationship exists between proximal femoral and acetabular angles, age, and gender in normal hip joints. We hypothesized that, through functional adaptation to mechanical loading, a complementary developmental relationship exists between the acetabulum and proximal femur. Study Design: Descriptive laboratory study. Methods: The femoral neck version, femoral neck shaft angle, acetabular version, acetabular inclination, and center edge angle were measured in 230 normal hip joints in 115 adults using 3-dimensional reconstruction software. Correlations between the angles, age, and gender were examined using the methods of stepwise regression and backward elimination. Results: Regarding side-to-side comparison and variability, there was no statistically significant difference between the left and right sides in the average value of each angle measurement. The correlations specifically between angles, age, and gender were similar on the left and right sides for all pairs except femoral version and acetabular inclination. Regarding significant findings of the study, a positive correlation (P < .05) was found between femoral version and acetabular version (0.38° to 1°). A positive correlation was found between femoral neck shaft angle and acetabular version (0.21° to 1°). A negative correlation was found between femoral neck shaft angle and age (–0.17° to 1°). A positive correlation was found between acetabular version and female gender (2.6° to 1°). A positive correlation was found between center edge angle and female gender (2.8° to 1°). A negative correlation was found between femoral version and acetabular inclination (–0.49° to 1°), although this latter relationship was only observed unilaterally (ie, left hip). Conclusion: This study demonstrates that a correlation exists between multiple proximal femoral and acetabular angles in normal hip joints. These findings support the hypothesis that a complementary developmental relationship occurs between the femoral head and acetabulum. Clinical Relevance: The results of this study suggest that, in some patients, what is thought to be pathological acetabular retroversion may actually be normal anatomy with a compensated femoral version. Investigating the relationship between these angles in patients with the signs and symptoms of pincer-type femoroacetabular impingement may alter a surgeon’s approach to this patient population.

Dual simulated childbirth injury delays anatomic recovery

A dual childbirth injury model, including vaginal distension (VD) and pudendal nerve crush (PNC), may best represent the injuries seen clinically. The objective of this study was to investigate urethral function, anatomy, and neurotrophin expression after several simulated childbirth injuries. Groups of 140 rats underwent PNC, VD, PNC+VD, or neither (C). Four days after injury, all injury groups had significantly decreased leak-point pressure (LPP) compared with C rats. Ten days after injury, LPP in PNC and PNC+VD rats remained significantly lower than C rats. Three weeks after injury, LPP in all injury groups had recovered to C values. Histological evidence of injury was still evident in the external urethral sphincter (EUS) after VD and PNC+VD 10 days after injury. Three weeks after injury, the EUS of PNC+VD rats remained disrupted. One day after VD, brain-derived neurotrophic factor (BDNF) expression in the EUS was reduced, while neurotrophin-4 (NT-4) and nerve growth factor (NGF) expression was unchanged. BDNF, NT-4, and NGF expression was dramatically upregulated in the EUS after PNC. After PNC+VD, NGF expression was upregulated, and BDNF and NT-4 expression was upregulated somewhat but not to the same extent as after PNC. Ten days after injury, PNC+VD had the least number of normal nerve fascicles near the EUS, followed by PNC and VD. Twenty-one days after injury, all injury groups had fewer normal nerve fascicles, but without significant differences compared with C rats. PNC+VD therefore provides a more severe injury than PNC or VD alone.

Effects of Meditation on Pain and Quality of Life in Multiple Sclerosis and Peripheral Neuropathy: A Pilot Study

The objective of this study was to determine whether meditation affects pain and quality of life in people with multiple sclerosis (MS) and peripheral neuropathy (PN). A total of 22 patients (10 with MS, 12 with PN) participated in a weekly meditation class over a 2-month period. A total of 18 controls (7 with MS, 11 with PN) received standard care. Primary outcome assessments were based on the 36-item Short Form Health Status Survey (SF-36) and a visual analogue scale (VAS) for pain at baseline and at 2 months. Secondary outcome measures included the Neuropathy Impairment Score (NIS) for PN patients and the Patient-Determined Disease Steps (PDDS) questionnaire and 5-item Modified Fatigue Impact Scale (MFIS-5) for MS patients. After 2 months, study participants who practiced meditation reported an improvement in pain on the VAS (P = .035 combined group), summed physical health scores on the SF-36 (P = .011 MS, P = .014 PN), summed mental health scores (P = .02 combined group), vitality (P = .005 combined group), and physical role (P = .003 combined group). A significant improvement was also observed for bodily pain (P = .031) in MS patients. In contrast, no significant differences before and after the intervention were observed for controls. Regarding the secondary measure of fatigue, improved scores for the cognitive and psychosocial components of the MFIS were noted in MS patients in the intervention group (P = .037, P = .032). No statistically significant changes were observed in the NIS for PN patients or in PDDS scores for MS patients. Meditation may be helpful in reducing pain and improving quality of life in patients with MS and PN. The lack of changes seen in mobility (MS) and sensorimotor deficits (PN) suggests that meditation may not affect the overall clinical course.