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1.  Enalapril Mitigates Focal Alveolar Lesions, A Histological Marker of Late Pulmonary Injury by Radiation to the Lung 
Radiation research  2013;179(4):465-474.
The goal of our study was to identify a histological marker for testing countermeasures for mitigation of late radiation injury to the lung. Pulmonary fibrosis is currently the best described “late effect” in survivors of acute radiation pneumonitis. However, robust fibrosis does not develop in some rodent strains for years after a single dose of radiation to the whole thorax. We observed radiation-associated focal alveolar lesions that were rich in giant cells and macrophages containing cholesterol clefts in the lungs of irradiated WAG/ RijCmcr rats. These lesions were first observed after pneumonitis, around 21 weeks after receiving a radiation dose of 13 Gy to the thorax but not until 71 weeks in unirradiated rats. The number of cholesterol clefts increased with time after irradiation through 64 weeks of observation, and at 30 weeks after 13 Gy, cholesterol clefts were associated with several indices of deterioration in lung function. The number of cholesterol clefts in irradiated lung sections were reduced by the angiotensin converting enzyme (ACE) inhibitor enalapril (25–42 mg/m2/day) from 18.7 ± 4.2/lung section to 6.8 ± 2.4 (P = 0.029), 5.2 ± 1.9 (P = 0.0051) and 6.7 ± 1.9 (P = 0.029) when the drug was started at 1 week, 5 or 15 weeks after irradiation, respectively, and continued. Similar lesions have been previously observed in the lungs of one strain of irradiated mice and in patients following radiotherapy. We propose that alveolar lesions with cholesterol clefts may be used as a histological marker of the severity of radiation lung injury and to study its mitigation in WAG/
PMCID: PMC3697111  PMID: 23480564
2.  Exposure to Neighborhood Green Space and Mental Health: Evidence from the Survey of the Health of Wisconsin  
Green space is now widely viewed as a health-promoting characteristic of residential environments, and has been linked to mental health benefits such as recovery from mental fatigue and reduced stress, particularly through experimental work in environmental psychology. Few population level studies have examined the relationships between green space and mental health. Further, few studies have considered the role of green space in non-urban settings. This study contributes a population-level perspective from the United States to examine the relationship between environmental green space and mental health outcomes in a study area that includes a spectrum of urban to rural environments. Multivariate survey regression analyses examine the association between green space and mental health using the unique, population-based Survey of the Health of Wisconsin database. Analyses were adjusted for length of residence in the neighborhood to reduce the impact of neighborhood selection bias. Higher levels of neighborhood green space were associated with significantly lower levels of symptomology for depression, anxiety and stress, after controlling for a wide range of confounding factors. Results suggest that “greening” could be a potential population mental health improvement strategy in the United States.
PMCID: PMC3987044  PMID: 24662966
green space; nature; neighborhood environment; mental health; population-based surveys; United States
3.  A Single Urban Center Experience with Adult Pedestrians Struck by Motor Vehicles 
Pedestrian-vehicle crashes are a significant problem in public health. Understanding contributing factors within a specific community helps recognize and target key intervention points.
Trauma registry analysis included all of the patients treated at a Level I trauma center following pedestrian-motor vehicle collisions from January 1, 2000 to December 31, 2010. Variables examined included patient demographics, timing of collision, abbreviated injury scale score, injury severity score (ISS), hospital and intensive care unit (ICU) length of stay (LOS), and emergency department and hospital disposition.
A total of 945 pedestrians were reviewed within the study period. Average age was 46.4 ± 19.4 years. One hundred seventy-seven (18.7%) patients were elderly and of the elderly group, 69 (39%) were 80 years of age or greater. The median ISS score was 12, average hospital LOS was 10.8 days and average ICU length of stay was 6.0 ± 7.5 days. More elderly patients required admission to the ICU than the nonelderly (61.6% vs 40.2%; P < 0.001), and more elderly patients required admission to a skilled nursing facility than nonelderly (42.1% vs. 9%; P < 0.001). The mortality rate for elderly patients was more than double that of nonelderly patients (20.9% vs 9.1%; P < 0.001). Pedestrian-motor vehicle collisions occurred disproportionately between the hours of 6 PM and midnight (P < 0.0001).
Elderly patients struck by a motor vehicle have a mortality rate twice that of the non-elderly and a higher rate of discharge to a skilled nursing facility, despite having a similar injury severity score on admission. This highlights the need for aggressive prevention efforts targeted at the elderly population.
PMCID: PMC3845352  PMID: 23894809
4.  A Prospective Randomized Double-blinded Pilot Study to Examine the Effect of Botulinum Toxin Type A Injection Versus Lidocaine/Depomedrol Injection on Residual and Phantom Limb Pain 
The Clinical journal of pain  2012;28(2):10.1097/AJP.0b013e3182264fe9.
Botulinum toxin type A (Botox) injection has been used to manage pain. However, it remains to be proved whether Botox injection is effective to relieve residual limb pain (RLP) and phantom limb pain (PLP).
Randomized, double-blinded pilot study.
Medical College and an outpatient clinic in Department of Physical Medicine and Rehabilitation.
Amputees (n=14) with intractable RLP and/or PLP who failed in the conventional treatments.
Study amputees were randomized to receive 1 Botox injection versus the combination of Lidocaine and Depomedrol injection. Each patient was evaluated at baseline and every month after the injection for 6 months.
Main Outcome Measure
The changes of RLP and PLP as recorded by VAS, and the changes of the pressure pain tolerance as determined by a pressure algometer.
All patients completed the protocol treatment without acute side effects, and monthly assessments of RLP, PLP, and pain tolerance after the treatment. The time trend in the outcomes was modeled as an immediate change owing to the treatment followed by a linear tread afterward. Repeated measures were incorporated using mixed effects modeling. We found that both Botox and Lidocaine/Depomedrol injections resulted in immediate improvements of RLP (Botox: P=0.002; Lidocaine/Depomedrol: P=0.06) and pain tolerance (Botox: P=0.01; Lidocaine/Depomedrol: P=0.07). The treatment effect lasted for 6 months in both groups. The patients who received Botox injection had higher starting pain than those who received Lidocaine/Depomedrol injection (P=0.07). However, there were no statistical differences in RLP and pain tolerance between these 2 groups. In addition, no improvement of PLP was observed after Botox or Lidocaine/Depomedrol injection.
Both Botox and Lidocaine/Depomedrol injections resulted in immediate improvement of RLP (not PLP) and pain tolerance, which lasted for 6 months in amputees who failed in conventional treatments.
PMCID: PMC3845354  PMID: 21750460
residual limb pain; phantom limb pain; amputees; botox; lidocaine; depomedrol
5.  Racial/Ethnic Variations in Emergency Department Wait Times for Nontraumatic Dental Condition Visits in the United States 
Studies have documented an association between wait times in emergency departments (EDs) and quality of care for medical conditions, but little is known about trends and factors associated with wait times for nontraumatic dental condition (NTDC) visits in EDs. We examined trends in wait time and associated factors for NTDC visits in EDs in the United States.
We analyzed data from the National Hospital Ambulatory Medical Care survey for 1997 to 2007, with 2001-2002 excluded due to lack of wait time information. We used survey-weighted linear regression of log-transformed waiting time model for the wait time for NTDC visits.
The geometric mean wait time for NTDC and non-NTDC visits was 29±1 and 25±0.6 minutes, respectively (p<0.0001). The geometric mean wait time for NTDC visits increased by 6% annually and from 20 minutes in 1997 to 37 minutes in 2007. Compared to Whites, Hispanics and Blacks had significantly longer wait times for NTDC visits (adjusted fold-difference [R] =1.2, 95% confidence interval [CI] = 1.13-1.31) and [R] = 1.3, [CI] = 1.29-1.38). Age, payer type, reason for visit and triaged category were significant predictors of wait time (R=2.3 and 2.4 for NTDC visits in triage category of 1-2 hours and >2-24hours respectively).
Nationally, wait times in EDs for NTDC visits increased over time. Hispanics (aged ≤ 33years old) and Blacks waited longer to receive care for NTDCs in EDs than Whites.
Practice Implication
Prolonged wait times for NTDC visits in emergency departments could adversely impact quality of care and patient outcomes.
PMCID: PMC3817612  PMID: 23813265
Emergency service; Dental service utilization; dental care
6.  Short-Term Treatment with a SOD/Catalase Mimetic, EUK-207, Mitigates Pneumonitis and Fibrosis after Single-Dose Total-Body or Whole-Thoracic Irradiation 
Radiation research  2012;178(5):468-480.
In the event of a radiological accident or terrorist attack, whole- or partial-body exposure can injure the lungs. To simulate such an incident, we used a single fraction of total-body irradiation (TBI) or whole-thoracic irradiation to induce pneumonitis or pulmonary fibrosis, respectively, in a rat model. The superoxide dismutase and catalase mimetic EUK-207 was given by subcutaneous injection (20 mg/kg/day, 5 days per week, once daily) starting at 7 days after irradiation and stopping before pneumonitis developed. After TBI, morbidity and the increase in breathing rates associated with pneumonitis were significantly improved in rats treated with EUK-207 compared to rats receiving irradiation alone. At 42 days after TBI (the peak of pneumonitis) changes in vascular end points including pulmonary hemodynamics ex vivo and relative arterial density in lungs were also mitigated by EUK-207. At 7 months after whole-thoracic irradiation, EUK-207 reduced synthesis of collagen as assessed by the Sircol collagen assay and Masson’s trichrome staining. Our results demonstrate promise for EUK-207 as a mitigator of radiation pneumonitis and fibrosis. We also demonstrate for the first time mitigation of multiple vascular injuries in the irradiated lung in vivo by EUK-207.
PMCID: PMC3678766  PMID: 23020094
7.  Nontraumatic dental condition-related visits to emergency departments on weekdays, weekends and night hours: findings from the National Hospital Ambulatory Medical Care survey 
To determine whether the rates of nontraumatic dental condition (NTDC)-related emergency department (ED) visits are higher during the typical working hours of dental offices and lower during night hours, as well as the associated factors.
We analyzed data from the National Hospital Ambulatory Medical Care Survey for 1997 through 2007 using multivariate binary and polytomous logistic regression adjusted for survey design to determine the effect of predictors on specified outcome variables.
Overall, 4,726 observations representing 16.4 million NTDC-related ED visits were identified. Significant differences in rates of NTDC-related ED visits were observed with 40%–50% higher rates during nonworking hours and 20% higher rates on weekends than the overall average rate of 170 visits per hour. Compared with 19–33 year olds, subjects < 18 years old had significantly higher relative rates of NTDC-related ED visits during nonworking hours [relative rate ratio (RRR) = 1.6 to 1.8], whereas those aged 73 and older had lower relative rates during nonworking hours (RRR = 0.4; overall P = 0.0005). Compared with those having private insurance, Medicaid and self-pay patients had significantly lower relative rates of NTDC visits during nonworking and night hours (RRR = 0.6 to 0.7, overall P < 0.0003). Patients with a dental reason for visit were overrepresented during the night hours (RRR = 1.3; overall P = 0.04).
NTDC-related visits to ED occurred at a higher rate during nonworking hours and on weekends and were significantly associated with age, patient-stated reason for visit and payer type.
PMCID: PMC3770522  PMID: 24039453
dental health services; dental care; emergency service; toothache
8.  Dose-modifying factor for captopril for mitigation of radiation injury to normal lung 
Journal of radiation research  2012;53(4):633-640.
Our goal is to develop countermeasures for pulmonary injury following unpredictable events such as radiological terrorism or nuclear accidents. We have previously demonstrated that captopril, an angiotensin converting enzyme (ACE) inhibitor, is more effective than losartan, an angiotensin type-1 receptor blocker, in mitigating radiation-pneumopathy in a relevant rodent model. In the current study we determined the dose modifying factors (DMFs) of captopril for mitigation of parameters of radiation pneumonitis. We used a whole animal model, irradiating 9–10-week-old female rats derived from a Wistar strain (WAG/RijCmcr) with a single dose of irradiation to the thorax of 11, 12, 13, 14 or 15 Gy. Our study develops methodology to measure DMFs for morbidity (survival) as well as physiological endpoints such as lung function, taking into account attrition due to lethal radiation-induced pneumonitis. Captopril delivered in drinking water (140–180 mg/m2/day, comparable with that given clinically) and started one week after irradiation has a DMF of 1.07–1.17 for morbidity up to 80 days (survival) and 1.21–1.35 for tachypnea at 42 days (at the peak of pneumonitis) after a single dose of ionizing radiation (X-rays). These encouraging results advance our goals, since DMF measurements are essential for drug labeling and comparison with other mitigators.
PMCID: PMC3393339  PMID: 22843631
radiation-pneumopathy; DMF; DRF; ACE inhibitors; breathing rate
Medical Care  2012;50(6):508-512.
Prior research has documented factors associated with non-traumatic dental condition (NTDC) visits to emergency departments (EDs), but little is known about the care received by patients in EDs for NTDC visits.
We examined national trends in prescription of analgesics and antibiotics in EDs for NTDC visits in the United States.
Research Design
We analyzed data from the National Hospital Ambulatory Medical Care survey for 1997 to 2007. We used a multivariable logistic regression model to examine factors associated with receiving analgesics and antibiotics for NTDC visit in EDs.
Overall 74% received at least one analgesic, 56% at least one antibiotic and 13% received no medication at all during an NTDC visit to the ED. The prescription of medications at EDs for NTDC visits steadily increased over time for analgesics (OR=1.11/year, p=<.0001) and antibiotics (OR=1.06/year, p<0.0001). In the multivariable analysis, self-pay patients had significantly higher adjusted odds of receiving antibiotics, while those with non-dental reason for visit and children (0–4 years) had significantly lower adjusted odds of receiving a prescription for antibiotics in EDs for NTDC visits. Children 0–4 years, adults 53–72 years and older adults (73 years and older) had lower adjusted odds (p<0.001) of receiving analgesics.
Nationally, analgesic and antibiotic prescriptions for NTDC visits to EDs have increased substantially over time. Self-pay patients had significantly higher odds of being prescribed antibiotics. Adults over 53 years and especially those 73 years and older had significantly lower odds of receiving analgesics in EDs for NTDC visits.
PMCID: PMC3353147  PMID: 22584886
Nontraumatic dental conditions; Emergency Department; Medications
10.  HNA-3a–specific antibodies recognize choline transporter–like protein-2 peptides containing arginine, but not glutamine at Position 154 
Transfusion  2011;51(10):2168-2174.
Antibodies specific for the neutrophil antigen HNA-3a cause severe, sometimes fatal transfusion-related acute lung disease (TRALI) when transfused, but it has not been possible to screen blood donors for anti-HNA-3a because using neutrophils as targets was impractical and molecular properties of the antigen were unknown. Recently it was shown that HNA-3a is carried on choline transporter–like protein-2 (CTL2) and that the HNA-3a/b phenotype is closely correlated with an R154Q amino acid polymorphism in CTL2. However, it has not been shown by direct experiment that R154 is essential for the HNA-3a epitope.
Preliminary attempts to express recombinant full-length CTL2 (R154) recognized by anti-HNA-3a were unsuccessful. We therefore tested HNA-3a–specific antibodies from donors implicated in TRALI reactions for reactivity against chemically synthesized linear and cyclic CTL2 peptides containing R154 or Q154.
Nine of 20 HNA-3a antibodies recognized the R154, but not the Q154 version of a cyclic 36-residue CTL2 peptide (D131-K166). However, 11 others failed to distinguish between the two versions of this peptide.
The findings provide direct evidence that R154 in the context of CTL2 D131-K166 is necessary to create the HNA-3a epitope but, in the context of cyclic CTL2 peptide D131-K166, is sufficient to detect only about one-half of the HNA-3a–specific antibodies implicated in TRALI. It is likely that fragments of CTL2 longer than can be made on a large scale with an automated synthesizer will be needed to produce a target capable of detecting all examples of anti-HNA-3a in donated blood.
PMCID: PMC3592927  PMID: 21517890
11.  Association Between the Female Athlete Triad and Endothelial Dysfunction in Dancers 
To determine the prevalence of the 3 components of the female athlete triad [disordered eating, menstrual dysfunction, low bone mineral density (BMD)] and their relationships with brachial artery flow-mediated dilation in professional dancers.
Prospective study.
Academic institution in the Midwest.
Twenty-two professional ballet dancers volunteered for this study.
The prevalence of the female athlete triad and its relationship to endothelial dysfunction.
Main Outcome Measures
Subjects completed questionnaires to assess disordered eating and menstrual status/history. They also completed a 3-day food record and wore an accelerometer for 3 days to determine energy availability. Serum baseline thyrotropin, prolactin, and hormonal concentrations were obtained. Bone mineral density and body composition were measured with a GE Lunar Prodigy dual-energy X-ray absorptiometry. Endothelial function was determined as flow-mediated vasodilation measured by high-frequency ultrasound in the brachial artery. An increase in brachial diameter <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction.
Seventeen dancers (77%) had evidence of low/negative energy availability. Thirty-two percent had disordered eating (EDE-Q score). Thirty-six percent had menstrual dysfunction and 14% were currently using hormone contraception. Twenty-three percent had evidence of low bone density (Z-score < −1.0). Sixty-four percent had abnormal brachial artery flow-mediated dilation (<5%). Flow-mediated dilation values were significantly correlated with serum estrogen and whole-body and lumbar BMD. All the 3 components of the triad plus endothelial dysfunction were present in 14% of the subjects.
Endothelial dysfunction was correlated with reduced BMD, menstrual dysfunction, and low serum estrogen. These findings may have profound implications for cardiovascular and bone health in professional women dancers.
PMCID: PMC3570811  PMID: 21358502
ballet dancers; energy availability; amenorrhea; osteoporosis; cardiovascular disease
12.  Rural–urban differences in dental service use among children enrolled in a private dental insurance plan in Wisconsin: analysis of administrative data 
BMC Oral Health  2012;12:58.
Studies on rural–urban differences in dental care have primarily focused on differences in utilization rates and preventive dental services. Little is known about rural–urban differences in the use of wider range of dental procedures. This study examined patterns of preventive, restorative, endodontic, and extraction procedures provided to children enrolled in Delta Dental of Wisconsin (DDWI).
We analyzed DDWI enrollment and claims data for children aged 0-18 years from 2002 to 2008. We modified and used a rural and urban classification based on ZIP codes developed by the Wisconsin Area Health Education Center (AHEC). We categorized the ZIP codes into 6 AHEC categories (3 rural and 3 urban). Descriptive and multivariable analysis using generalized linear mixed models (GLMM) were used to examine the patterns of dental procedures provided to children. Tukey-Kramer adjustment was used to control for multiple comparisons.
Approximately, 50%, 67% and 68 % of enrollees in inner-city Milwaukee, Rural 1 (less than 2500 people), and suburban-Milwaukee had at least one annual dental visit, respectively. Children in inner city-Milwaukee had the lowest utilization rates for all procedures examined, except for endodontic procedures. Compared to children from inner-city Milwaukee, children in other locations had significantly more preventive procedures. Children in Rural 1-ZIP codes had more restorative, endodontic and extraction procedures, compared to children from all other regions.
We found significant geographic variation in dental procedures received by children enrolled in DDWI.
PMCID: PMC3548684  PMID: 23259637
Oral health; Urban; Rural; Dental care for children; Dental Insurance; Health services accessibility
13.  Optimizing the Concentration and Bolus of a Drug Delivered by Continuous Infusion 
Biometrics  2011;67(4):1638-1646.
We consider treatment regimes in which an agent is administered continuously at a specified concentration until either a response is achieved or a predetermined maximum infusion time is reached. Response is an event defined to characterize therapeutic efficacy. A portion of the maximum planned total amount administered is given as an initial bolus. For such regimes, the amount of the agent received by the patient depends on the time to response. An additional complication when response is evaluated periodically rather than continuously is that the response time is interval censored. We address the problem of designing a clinical trial in which such response time data and a binary indicator of toxicity are used together to jointly optimize the concentration and the size of the bolus. We propose a sequentially adaptive Bayesian design that chooses the optimal treatment for successive patients by maximizing the posterior mean utility of the joint efficacy-toxicity outcome. The methodology is illustrated by a trial in which tissue plasminogen activator is infused intra-arterially as rapid treatment for acute ischemic stroke.
PMCID: PMC3137757  PMID: 21401568
Adaptive design; Bayesian design; Clinical trial; Continuous infusion; Phase I/II clinical trial; Stroke
14.  Medical Malpractice Claims Related to Cataract Surgery Complicated by Retained Lens Fragments (An American Ophthalmological Society Thesis) 
To review malpractice claims associated with retained lens fragments during cataract surgery to identify ways to improve patient outcomes.
Retrospective, noncomparative, consecutive case series. Closed claims data related to cataract surgeries complicated by retained lens fragments (1989 through 2009) from an ophthalmic insurance carrier were reviewed. Factors associated with these claims and claims outcomes were analyzed.
During the 21-year period, 117 (12.5%) of 937 closed claims associated with cataract surgery were related to retained lens fragments with 108 unique cataract surgeries, 97% against cataract surgeon and 3% against retinal surgeon. Twelve (11%) of 108 claims were resolved by a trial, 30 (28%) were settled, and 66 (61%) were dismissed. The defendant prevailed in 83% of trials. Indemnity payments totaling more than $3,586,000 were made in 32 (30%) of the claims (median payment, $90,000). The difference between the preoperative visual acuity and the final visual acuity was predictive of an indemnity payment (odds ratio [OR], 2.28; P=.001) and going to a trial (OR, 2.93; P=.000). Development of corneal edema was associated with an indemnity payment (OR, 3.50; P=.037). Timing of referral and elevated intraocular pressure (IOP) were statistically significant in univariate analyses but not in multivariate analyses for a trial.
Whereas the majority of claims were dismissed, claims associated with greater visual acuity decline, corneal edema, or elevated IOP were more likely to result in a trial or payment. Ways to reduce significant vision loss, including improved management of corneal edema and IOP, and timely referral to a subspecialist should be considered.
PMCID: PMC3671368  PMID: 23818737
15.  Folic Acid Supplementation Improves Vascular Function in Professional Dancers With Endothelial Dysfunction 
To determine if folic acid supplementation improves vascular function (brachial artery flow-mediated dilation [FMD]) in professional dancers with known endothelial dysfunction.
Prospective cross-sectional study.
Academic institution in the Midwestern United States.
Twenty-two professional ballet dancers volunteered for this study.
Main Outcome Measures
Subjects completed a 3-day food record to determine caloric and micronutrient intake. Menstrual status was determined by interview and questionnaire. Endothelial function was determined as flow-induced vasodilation measured by high-frequency ultrasound of the brachial artery. A change in brachial diameter of <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction. Subjects with abnormal FMD took 10 mg of folic acid daily for 4 weeks, and FMD testing was then repeated. Serum whole blood was measured for folic acid levels before and after supplementation.
Sixty-four percent of dancers (n = 14) had abnormal brachial artery FMD (<5%) (mean ± standard deviation, 2.9% ± 1.5%). After 4 weeks of folic acid supplementation (10 mg/day), FMD improved in all the subjects (7.1% ± 2.3%; P < .0001).
This study reveals that vascular endothelial function improves in dancers after supplementation with folic acid (10 mg/day) for at least 4 weeks. This finding may have clinically important implications for future cardiovascular disease risk prevention.
PMCID: PMC3328806  PMID: 21715240
16.  Patient characteristics and trends in nontraumatic dental condition visits to emergency departments in the United States 
We examined trends and patient characteristics for non-traumatic dental condition (NTDC) visits to emergency departments (EDs), and compared them to other ED visit types, specifically non-dental ambulatory care sensitive conditions (non-dental ACSCs) and non-ambulatory care sensitive conditions (non-ACSCs) in the United States.
We analyzed data from the National Hospital Ambulatory Medical Care survey (NHAMCS) for 1997 to 2007. We performed descriptive statistics and used a multivariate multinomial logistic regression to examine the odds of one of the three visit types occurring at an ED. All analyses were adjusted for the survey design.
NTDC visits accounted for 1.4% of all ED visits with a 4% annual rate of increase (from 1.0% in 1997 to 1.7% in 2007). Self-pay patients (32%) and Medicaid enrollees (27%) were over-represented among NTDC visits compared to non-dental ACSC and non-ACSC visits (P < 0.0001). Females consistently accounted for over 50% of all types of ED visits examined. Compared to whites, Hispanics had significantly lower odds of an NDTC visit versus other visit types (P < 0.0001). Blacks had significantly lower odds of making NDTC visits when compared to non-dental ACSC visits only (P < 0.0001). Compared to private insurance enrollees, Medicaid and self-pay patients had 2–3 times the odds of making NTDC visits compared to other visit types.
Nationally, NTDC visits to emergency departments increased over time. Medicaid and self-pay patients had significantly higher odds of making NDTC visits.
PMCID: PMC3652363  PMID: 23674919
emergency service; dental disease; adults; dental utilization
17.  PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization 
Oncogene  2010;30(14):1706-1715.
Tyrosine phosphorylation is tightly regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), and plays a critical role in malignant transformation and progression. While PTKs have a well-established role in regulating breast cancer growth, contribution of PTPs remains mostly unknown. Here, we report that the tyrosine phosphatase PTPH1 stimulates breast cancer growth through regulating vitamin D receptor (VDR) expression. PTPH1 was shown to be over-expressed in 49% of primary breast cancer and levels of its protein expression positively correlate with the clinic metastasis, suggesting its oncogenic activity. Indeed, PTPH1 promotes breast cancer growth by a mechanism independent of its phosphatase activity but dependent of its stimulatory effect on the nuclear receptor VDR protein expression and depletion of induced VDR abolishes the PTPH1 oncogenic activity. Additional analyses showed that PTPH1 binds VDR and increases its cytoplasmic accumulation leading to their mutual stabilization and stable expression of a nuclear localization deficient VDR abolishes the growth-inhibitory activity of the receptor independent of 1, 25-dihydroxyvitamin D3 (vitamin D3). These results reveal a new paradigm in which a protein tyrosine phosphatase may stimulate breast cancer growth through increasing cytoplasmic translocation of a nuclear receptor leading to their mutual stabilization.
PMCID: PMC3072445  PMID: 21119599
PTPH1; VDR; VDR cytoplasmic translocation; mutual stabilization; breast cancer
18.  Repeated Exposure to Severely Limited Sleep Results in Distinctive and Persistent Physiological Imbalances in Rats 
PLoS ONE  2011;6(8):e22987.
Chronic sleep disruption in laboratory rats leads to increased energy expenditure, connective tissue abnormalities, and increased weights of major organs relative to body weight. Here we report on expanded findings and the extent to which abnormalities become long-lasting, potentially permanent changes to health status after apparent recuperation from chronic sleep disruption. Rats were exposed 6 times to long periods of disrupted sleep or control conditions during 10 weeks to produce adaptations and then were permitted nearly 4 months of undisturbed sleep. Measurements were made in tissues from these groups and in preserved tissue from the experimental and control groups of an antecedent study that lacked a lengthy recuperation period. Cycles of sleep restriction resulted in energy deficiency marked by a progressive course of hyperphagia and major (15%) weight loss. Analyses of tissue composition in chronically sleep-restricted rats indicated that protein and lipid amounts in internal organs were largely spared, while adipose tissue depots appeared depleted. This suggests high metabolic demands may have preserved the size of the vital organs relative to expectations of severe energy deficiency alone. Low plasma corticosterone and leptin concentrations appear to reflect low substrate availability and diminished adiposity. After nearly 4 months of recuperation, sleep-restricted rats were consuming 20% more food and 35% more water than did comparison control rats, despite normalized weight, normalized adipocytes, and elevated plasma leptin concentrations. Plasma cholesterol levels in recuperated sleep-restricted rats were diminished relative to those of controls. The chronically increased intake of nutriments and water, along with altered negative feedback regulation and substrate use, indicate that internal processes are modified long after a severe period of prolonged and insufficient sleep has ended.
PMCID: PMC3154920  PMID: 21853062
19.  Increased Children's Access to Fluoride Varnish Treatment by Involving Medical Care Providers: Effect of a Medicaid Policy Change 
Health Services Research  2009;44(4):1144-1156.
In 2004, the State of Wisconsin introduced a change to their Medicaid Policy allowing medical care providers to be reimbursed for fluoride varnish treatment provided to Medicaid enrolled children.
To determine the extent by which a state-level policy change impacted access to fluoride varnish treatment (FVT) for Medicaid enrolled children.
Data Source
The Electronic Data Systems of Medicaid Evaluation and Decision Support database for Wisconsin from 2002 to 2006.
Study Design
We analyzed Wisconsin Medicaid claims for FVT for children between the ages of 1 and 6 years, comparing rates in the prepolicy period (2002–2003) to the period (2004–2006) following the policy change.
Principal Findings
Medicaid claims for FVT in 2002–2003 totaled 3,631. Following the policy change, claims for FVT increased to 28,303, with 38.0 percent submitted by medical care providers. FVT rates increased for children of both sexes and all ages, rising from 1.4 per 1,000 person-years of enrollment in 2002–2003 to 6.6 per 1,000 person-years in 2004–2006. Overall, 48.6 percent of the increase in FVT was attributable to medical care providers. The largest increase was seen in children 1–2 years of age, among whom medical care providers were responsible for 83.5 percent of the increase.
A state-level Medicaid policy change was followed by both a significant involvement of medical care providers and an overall increase in FVT. Children between the ages of 1 and 2 years appear to benefit the most from the involvement of medical care providers.
PMCID: PMC2739021  PMID: 19453390
Medicaid-enrolled children; oral health disparities; fluoride varnish treatment; medical care providers; policy change
20.  Provision of Fluoride Varnish Treatment by Medical and Dental Care Providers: Variation by Race/Ethnicity and Levels of Urban Influence 
In 2004, Wisconsin Medicaid policy changed to allow medical care providers to be reimbursed for fluoride varnish treatment (FVT) to children’s teeth to improve access and utilization. To date, no study has been published on whether geographic and racial/ethnic variation in the provision of FVT in response to this policy change exists.
To examine the association of rates of FVT for children enrolled in Wisconsin Medicaid with race/ethnicity, Urban Influence Codes (UIC), and Dental Health Professional Shortage Area (DHPSA) designation based on county of residence.
A retrospective, pre-post design was used based on FVT claims for children in the Wisconsin Medicaid program from 2002 to 2006. Poisson Regression Models were used to evaluate the association of rates of FVT claims with race/ethnicity, UIC, and DHPSA designation.
The rate of FVT claims varied by resident county-type according to UIC and DHPSA designation, age, and race/ethnicity. Post policy, the largest increases were observed for Native Americans residing in none DHPSA counties, enrollees living in rural counties and for Hispanics living in partial and entire DHPSA counties. African-Americans residing in partial DHPSA and metropolitan counties displayed the lowest rates of FVT claims.
Overall access and utilization of fluoride varnish treatment increased, but substantial racial/ethnic and geographic variation in the provision of FVT for children enrolled in Wisconsin Medicaid was observed. Future policies should incorporate measures that will specifically address the racial and geographic variations identified in this study.
PMCID: PMC2967666  PMID: 20459463
Fluoride varnish treatment; Children; Ethnic groups; Health services accessibility
21.  Quantifying the role of PSA screening in the US prostate cancer mortality decline 
Cancer causes & control : CCC  2007;19(2):175-181.
To quantify the plausible contribution of prostate-specific antigen (PSA) screening to the nearly 30% decline in the US prostate cancer mortality rate observed during the 1990s.
Two mathematical modeling teams of the US National Cancer Institute’s Cancer Intervention and Surveillance Modeling Network independently projected disease mortality in the absence and presence of PSA screening. Both teams relied on Surveillance, Epidemiology, and End Results (SEER) registry data for disease incidence, used common estimates of PSA screening rates, and assumed that screening, by shifting disease from distant to local-regional clinical stage, confers a corresponding improvement in disease-specific survival.
The teams projected similar mortality increases in the absence of screening and decreases in the presence of screening after 1985. By 2000, the models projected that 45% (Fred Hutchinson Cancer Research Center) to 70% (University of Michigan) of the observed decline in prostate cancer mortality could be plausibly attributed to the stage shift induced by screening.
PSA screening may account for much, but not all, of the observed drop in prostate cancer mortality. Other factors, such as changing treatment practices, may also have played a role in improving prostate cancer outcomes.
PMCID: PMC3064270  PMID: 18027095
Prostate-specific antigen; Prostate cancer; Public health; Computer simulation
22.  Prognostic implication of late gadolinium enhancement on cardiac MRI in light chain (AL) amyloidosis on long term follow up 
Light chain amyloidosis (AL) is a rare plasma cell dyscrasia associated with poor survival especially in the setting of heart failure. Late gadolinium enhancement (LGE) on cardiac MRI was recently found to correlate with myocardial amyloid deposition but the prognostic role is not established. The aim is to determine the prognostic significance of LGE in AL by comparing long term survival of AL patients with and without LGE.
Twenty nine consecutive patients (14 females; 62 ± 11 years) with biopsy-proven AL undergoing cardiac MRI with gadolinium as part of AL workup were included. Survival was prospectively followed 29 months (median) following MRI and compared between those with and without LGE by Kaplan-Meier and log-rank analyses.
LGE was positive in 23 subjects (79%) and negative in 6 (21%). Left ventricular ejection fraction was 66 ± 17% in LGE-positive and 69 ± 12% in LGE-negative patients (p = 0.8). Overall 1-year mortality was 36%. On follow-up, 14/23 LGE-positive and none of LGE-negative patients died (log rank p = 0.0061). Presenting New York Heart Association heart failure class was also associated with poor survival (p = 0.0059). Survival between two LGE groups stratified by heart failure class still showed a significant difference by a stratified log-rank test (p = 0.04).
Late gadolinium enhancement is common and is associated with poor long-term survival in light chain amyloidosis, even after adjustment for heart failure class presentation. The prognostic significance of late gadolinium enhancement in this disease may be useful in patient risk-stratification.
PMCID: PMC2686669  PMID: 19416541
23.  Correction: Statistical modeling for selecting housekeeper genes 
Genome Biology  2008;9(8):405.
A correction to Statistical modeling for selecting housekeeper genes by Aniko Szabo, Charles M Perou, Mehmet Karaca, Laurent Perreard, John F Quackenbush, and Philip S Bernard. Genome Biology 2004, 5:R59
PMCID: PMC2575510
24.  Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay 
Breast Cancer Research  2006;8(2):R23.
Predicting the clinical course of breast cancer is often difficult because it is a diverse disease comprised of many biological subtypes. Gene expression profiling by microarray analysis has identified breast cancer signatures that are important for prognosis and treatment. In the current article, we use microarray analysis and a real-time quantitative reverse-transcription (qRT)-PCR assay to risk-stratify breast cancers based on biological 'intrinsic' subtypes and proliferation.
Gene sets were selected from microarray data to assess proliferation and to classify breast cancers into four different molecular subtypes, designated Luminal, Normal-like, HER2+/ER-, and Basal-like. One-hundred and twenty-three breast samples (117 invasive carcinomas, one fibroadenoma and five normal tissues) and three breast cancer cell lines were prospectively analyzed using a microarray (Agilent) and a qRT-PCR assay comprised of 53 genes. Biological subtypes were assigned from the microarray and qRT-PCR data by hierarchical clustering. A proliferation signature was used as a single meta-gene (log2 average of 14 genes) to predict outcome within the context of estrogen receptor status and biological 'intrinsic' subtype.
We found that the qRT-PCR assay could determine the intrinsic subtype (93% concordance with microarray-based assignments) and that the intrinsic subtypes were predictive of outcome. The proliferation meta-gene provided additional prognostic information for patients with the Luminal subtype (P = 0.0012), and for patients with estrogen receptor-positive tumors (P = 3.4 × 10-6). High proliferation in the Luminal subtype conferred a 19-fold relative risk of relapse (confidence interval = 95%) compared with Luminal tumors with low proliferation.
A real-time qRT-PCR assay can recapitulate microarray classifications of breast cancer and can risk-stratify patients using the intrinsic subtype and proliferation. The proliferation meta-gene offers an objective and quantitative measurement for grade and adds significant prognostic information to the biological subtypes.
PMCID: PMC1557722  PMID: 16626501
25.  A conscious mouse model of gastric ileus using clinically relevant endpoints 
BMC Gastroenterology  2005;5:18.
Gastric ileus is an unsolved clinical problem and current treatment is limited to supportive measures. Models of ileus using anesthetized animals, muscle strips or isolated smooth muscle cells do not adequately reproduce the clinical situation. Thus, previous studies using these techniques have not led to a clear understanding of the pathophysiology of ileus. The feasibility of using food intake and fecal output as simple, clinically relevant endpoints for monitoring ileus in a conscious mouse model was evaluated by assessing the severity and time course of various insults known to cause ileus.
Delayed food intake and fecal output associated with ileus was monitored after intraperitoneal injection of endotoxin, laparotomy with bowel manipulation, thermal injury or cerulein induced acute pancreatitis. The correlation of decreased food intake after endotoxin injection with gastric ileus was validated by measuring gastric emptying. The effect of endotoxin on general activity level and feeding behavior was also determined. Small bowel transit was measured using a phenol red marker.
Each insult resulted in a transient and comparable decrease in food intake and fecal output consistent with the clinical picture of ileus. The endpoints were highly sensitive to small changes in low doses of endotoxin, the extent of bowel manipulation, and cerulein dose. The delay in food intake directly correlated with delayed gastric emptying. Changes in general activity and feeding behavior were insufficient to explain decreased food intake. Intestinal transit remained unchanged at the times measured.
Food intake and fecal output are sensitive markers of gastric dysfunction in four experimental models of ileus. In the mouse, delayed gastric emptying appears to be the major cause of the anorexic effect associated with ileus. Gastric dysfunction is more important than small bowel dysfunction in this model. Recovery of stomach function appears to be simultaneous to colonic recovery.
PMCID: PMC1177942  PMID: 15938756

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