Fluoride: From Nutrient to Suspected Neurotoxin.

The recollections of a former public health officer and research scientist who maintained good relations with both pro- and anti-fluoridationists over the course of a 60-year career in which fluoride has gone from being a "nutrient" to a suspected neurotoxin.

Concurrent Neoadjuvant Chemotherapy and Radiation Therapy in Locally Advanced Breast Cancer.

PURPOSE: To evaluate whether concurrent neoadjuvant radiation added to standard chemotherapy could increase the pathologic complete response (pCR) to treatment for locally advanced breast cancer (LABC). METHODS AND MATERIALS: This prospective phase 2 trial recruited 32 LABC patients from 2009 to 2011. Patients received neoadjuvant every-3-weekly 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) for 3 cycles, followed by weekly docetaxel (35 mg/m2) for 9 cycles. Regional radiation (45 Gy/25 plus 5.4 Gy/5) was delivered concurrently with docetaxel, then modified radical mastectomy. Patients were matched post hoc by a blinded statistician to a concurrent cohort treated with neoadjuvant chemotherapy, modified radical mastectomy, and adjuvant regional radiation. RESULTS: Thirty of 32 patients completed treatment. Twenty-seven were successfully matched by propensity score to 81 control patients by age, stage, and molecular subtype. The concurrent chemoradiation produced a significant increase in pCR (14% vs 22%, P<.001) but no statistically significant difference in disease-free and overall survival at 3 years (respectively, 69% vs 81%, P=.186, hazard ratio 0.51; and 74% vs 89%, P=.162, hazard ratio 0.46). Toxicity included 25% of patients with grade 3 pneumonitis and 25% of patients with dermatitis, and 1 death. CONCLUSIONS: Concurrent neoadjuvant radiation added to radiosensitizing chemotherapy significantly improved pCR. A prospective randomized clinical trial is warranted to exploit the improved response seen with concurrent therapy but using another radio-sensitizing taxane, to better minimize treatment-related toxicity and determine its impact on overall survival.

Pharmacokinetics of fluoride in toddlers after application of 5% sodium fluoride dental varnish.

The prevalence of dental caries (tooth decay) among preschool children is increasing, driven partially by an earlier age of onset of carious lesions. The American Academy of Pediatrics recommends application of 5% sodium fluoride varnish at intervals increasing with caries risk status, as soon as teeth are present. However, the varnishes are marketed for treatment of tooth sensitivity and are regulated as medical devices rather than approved by the US Food and Drug Administration for prevention of dental caries (tooth decay). The objective of this research is to examine the safety of use in toddlers by characterizing the absorption and distribution profile of a currently marketed fluoride varnish. We measured urinary fluoride for 5 hours after application of fluoride varnish to teeth in 6 toddlers aged 12 to 15 months. Baseline levels were measured on a separate day. The urine was extracted from disposable diapers, measured by rapid diffusion, and extrapolated to plasma levels. The mean estimated plasma fluoride concentration was 13 µg/L (SD, 9 µg/L) during the baseline visit and 21 µg/L (SD, 8 µg/L) during the 5 hours after treatment. Mean estimated peak plasma fluoride after treatment was 57 µg/L (SD, 22 µg/L), and 20 µg/kg (SD, 4 µg/L) was retained on average. Retained fluoride was 253 times lower than the acute toxic dose of 5 mg/kg. Mean plasma fluoride after placement of varnish was within an SD of control levels. Occasional application of fluoride varnish following American Academy of Pediatrics guidance is safe for toddlers.

Proof-of-principle pilot study of oropharyngeal air-pulse application in individuals with dysphagia after hemispheric stroke.

OBJECTIVE: To test the hypothesis that oropharyngeal air-pulse application is associated with increased swallowing rates in individuals with dysphagia secondary to stroke. DESIGN: Case control. SETTING: Stroke rehabilitation hospital or home setting. PARTICIPANTS: Convenience sample of individuals (N=8) with new-onset dysphagia after stroke. INTERVENTIONS: Air-pulse trains were applied to the oropharynx of 8 subjects who presented with dysphagia after hemispheric stroke. Resting swallowing rates were determined for 5 experimental conditions: baseline without air-pulse mouthpiece, baseline with mouthpiece in situ, unilateral right oropharyngeal air-pulse, unilateral left oropharyngeal air-pulse, and bilateral oropharyngeal air-pulse application. Individual swallowing responses were analyzed using a 2-SD band method. MAIN OUTCOME MEASURE: Swallowing rate (swallows/min). RESULTS: Swallowing rates associated with bilateral air-pulse application were greater than baseline in 4 of the 8 subjects. The 4 subjects who demonstrated this response to air-pulse application had greater baseline swallowing rates than did subjects whose swallowing rates were not altered in association with air-pulse application. CONCLUSIONS: Oropharyngeal air-pulse trains can be applied in individuals with swallowing impairment. Air-pulse application is associated with increased resting swallowing rates in some individuals with dysphagia secondary to hemispheric stroke. Further research should extend this proof-of-principle study by examining the efficacy of oropharyngeal air-pulse application in terms of improved swallowing and related outcomes in dysphagic stroke through a large randomized trial.

Short term serum pharmacokinetics of diammine silver fluoride after oral application.

BACKGROUND: There is growing interest in the use of diammine silver fluoride (DSF) as a topical agent to treat dentin hypersensitivity and dental caries as gauged by increasing published research from many parts of the world. While DSF has been available in various formulations for many years, most of its pharmacokinetic aspects within the therapeutic concentration range have never been fully characterized. METHODS: This preliminary study determined the applied doses (3 teeth treated), maximum serum concentrations, and time to maximum serum concentration for fluoride and silver in 6 adults over 4 h. Fluoride was determined using the indirect diffusion method with a fluoride selective electrode, and silver was determined using inductively coupled plasma-mass spectrometry. The mean amount of DSF solution applied to the 3 teeth was 7.57 mg (6.04 µL). RESULTS: Over the 4 hour observation period, the mean maximum serum concentrations were 1.86 µmol/L for fluoride and 206 nmol/L for silver. These maximums were reached 3.0 h and 2.5 h for fluoride and silver, respectively. CONCLUSIONS: Fluoride exposure was below the U.S. Environmental Protection Agency (EPA) oral reference dose. Silver exposure exceeded the EPA oral reference dose for cumulative daily exposure over a lifetime, but for occasional use was well below concentrations associated with toxicity. This preliminary study suggests that serum concentrations of fluoride and silver after topical application of DSF should pose little toxicity risk when used in adults. CLINICAL TRIALS REGISTRATION: NCT01664871.

The use of minimization in clinical trials.

Since its introduction in 1974 the use of the term Minimization has been broadened to include other algorithms. All algorithms use patient characteristics to determine the assignment that produces the best overall balance between treatment groups. They differ in whether or not they use all of the data from each previously assigned subject to assign subsequent subjects so the methods are classified as complete or partial minimization. PubMed, Citation Index and Cochrane searches determined the frequency of articles using these types of minimization and a subset was selected for detailed review regarding the adequacy of the usage and reporting of minimization. In the past 10 years usage has increased three fold over the previous decade but is still less than 2% of clinical trials. None of the studies makes maximum use of minimization and they are not following good reporting practices. Concerns about the use of minimization have involved selection bias and statistical analysis. Several modifications to minimization are suggested to reduce the possibility of selection bias so that adding randomization will rarely be required. Separating primary and secondary analyses can avoid the statistical problems that minimization poses. The two types of analyses are distinguished by opposite limiting signs, providing reliable, simplified statistical results. This will improve data utilization and make clinical trials more reproducible. Minimization should be the method of choice in assigning subjects in all clinical trials.

Rank-Minimization for balanced assignment of subjects in clinical trials.

Minimization (M) is the most popular algorithm for balancing large numbers of subject variables in treatment groups of small clinical trials. However, its use has been limited because of its complexity, vulnerability to selection bias and lack of a generally accepted method for statistical analysis of the data. Rank-Minimization (RM) is a promising new algorithm. It is less complex since it does not require unique programming for each clinical trial to convert continuous to categorical variables. In this study RM is compared to M for balance of variables and vulnerability to selection bias in 1000 simulated trials using 200 subjects with 15 continuous variables. With RM there were no instances of significant imbalance to cause rejection of the null hypothesis, i.e. a Student's t> or =2, although it occurred in 0.4% of the 15000 tests for M. For moderate imbalance, i.e. 1< or = t < 2, the figures were 3% (RM) and 12% (M). The probability of guessing the next assignment was 0.636 (RM) and 0.683 (M). The smaller figure is superior to that of restricted randomization in blocks of five per treatment group. Improvement in balance, a decrease in vulnerability to selection bias and ease of application along with improvements in the statistical analysis should result in the general acceptance of RM for assigning subjects to treatment groups in clinical trials.

Freehand versus guided breast biopsy: comparison of accuracy, needle motion, and biopsy time in a tissue model.

OBJECTIVE: Freehand ultrasound-guided breast biopsy may present difficulties in needle visualization within the scanning plane of the ultrasound image. Scanning plane and needle misalignment, an unknown needle insertion site (relative to the ultrasound image), needle trajectory before insertion, and physician experience play roles in the difficulty of these biopsy procedures. The objective of our study was to compare the currently used freehand technique with the use of a needle guidance system that limits needle motion to within the ultrasound scanning plane for breast biopsy. MATERIALS AND METHODS: We developed a needle guidance system for breast biopsy that is composed of an electronically tracked passive mechanical arm and braking mechanism. The system was attached to an ultrasound transducer, and biopsy needles were inserted through the guidance arm. Both experienced and inexperienced radiologists performed ultrasound-guided biopsy on simulated breast lesions with and without the guidance system. Success rates were scored on the basis of the presence of lesions in the core biopsy samples. The biopsy procedures were analyzed using procedure time and total needle tip travel distance before firing. RESULTS: The biopsy success rates were greater using the guidance system (p < 0.05) than using the freehand technique. Experienced radiologists and inexperienced radiologists performed biopsy significantly faster using the needle guidance system (p < 0.001). Additionally, needle tip motion was significantly greater when using the freehand technique (p < 0.001) than using the guidance system. CONCLUSION: Biopsy using the developed needle guidance system is feasible and its use decreases procedure time and decreases needle motion; thus, it has the potential to reduce patient morbidity. Moreover, less operator experience is required for a successful breast biopsy using the needle guidance system than using the freehand technique.

Cerebral cortical processing of swallowing in older adults.

While brain-imaging studies in young adults have implicated multiple cortical regions in swallowing, investigations in older subjects are lacking. This study examined the neural representations of voluntary saliva swallowing and water swallowing in older adults. Nine healthy females were examined with event-related functional magnetic resonance imaging (fMRI) while laryngeal swallow-related movements were recorded. Swallowing in the older adults, like young adults, activated multiple cortical regions, most prominently the lateral pericentral, perisylvian, and anterior cingulate cortex. Activation of the postcentral gyrus was lateralized to the left hemisphere for saliva and water swallowing, consistent with our findings in young female subjects. Comparison of saliva and water swallowing revealed a fourfold increase in the brain volume activated by the water swallow compared to the saliva swallow, particularly within the right premotor and prefrontal cortex. This task-specific activation pattern may represent a compensatory response to the demands of the water swallow in the face of age-related diminution of oral sensorimotor function.

Metastatic breast cancer to the gastrointestinal tract: a case series and review of the literature.

Metastatic breast cancer involving the hepatobiliary tract or ascites secondary to peritoneal carcinomatosis has been well described. Luminal gastrointestinal tract involvement is less common and recognition of the range of possible presentations is important for early and accurate diagnosis and treatment. We report 6 patients with a variety of presentations of metastatic breast cancer of the luminal gastrointestinal tract. These include oropharyngeal and esophageal involvement presenting as dysphagia with one case of pseudoachalasia, a linitis plastica-like picture with gastric narrowing and thickened folds, small bowel obstruction and multiple strictures mimicking Crohn's disease, and a colonic neoplasm presenting with obstruction. Lobular carcinoma, representing only 10% of breast cancers is more likely to metastasize to the gastrointestinal tract. These patients presented with gastrointestinal manifestations after an average of 9.5 years and as long as 20 years from initial diagnosis of breast cancer. Given the increased survival of breast cancer patients with current therapeutic regimes, more unusual presentations of metastatic disease, including involvement of the gastrointestinal tract can be anticipated.

Bolus location at the initiation of the pharyngeal stage of swallowing in healthy older adults.

This study characterized the vertical position of the bolus head at the onset of the pharyngeal swallow in healthy older adults. Lateral-view videofluoroscopic (VF) images were obtained from ten healthy volunteers (age-71.6 +/- 7.5 years, mean+/- SD) as they swallowed 5-cc thin liquid barium aliquots. For each swallow, the bolus head and several anatomic landmarks were digitally recorded from the image in which pharyngeal swallow-related hyoid bone elevation began. Vertical distance between the bolus head and the intersection of the tongue base and mandibular ramus (TMI) was computed. Bolus head position at swallow onset ranged from 47.4-mm above to 34.9-mm below the TMI (2.2 +/- 14.4-mm, mean +/- SD). Although the bolus head was below the level of the TMI for the majority of swallows, neither penetration nor aspiration occurred. For individual subjects, mean bolus head position ranged from 25.8 +/- 5.0-mm above to 15.5 +/- 6.5-mm below the TMI. Whereas five of ten subjects initiated the pharyngeal swallow with the bolus head consistently above or consistently below the TMI, five subjects initiated swallowing with the bolus head either above or below the TMI across trials. Older adults commonly initiate thin-liquid swallows with the bolus head well below the TMI without associated penetration or aspiration. Thus, bolus position alone does not differentiate between normal and pathologic swallowing within the healthy elderly. Bolus position at pharyngeal swallow onset can vary substantially from trial to trial within an individual, suggesting that the triggering of swallowing depends on multiple influences.

The intromission function of the foreskin.

Masters and Johnson observed that the foreskin unrolled with intercourse. However, they overlooked a prior observation that intromission was thereby made easier. To evaluate this observation an artificial introitus was mounted on a scales. Repeated measurements showed a 10-fold reduction of force on entry with an initially unretracted foreskin as compared to entry with a retracted foreskin. For the foreskin to reduce the force required it must cover most of the glans when the penis is erect. This may occur only in humans. These observations mean that foreskin and prepuce can no longer be considered synonymous. Why the penises of humans and chimpanzees evolved so differently should be addressed in light of these findings.

Optimum inorganic ion concentrations for hematopoiesis cultures.

Current limitations in the ability to culture hematopoietic cells may be due to the use of ion concentrations that reflect those in the general circulation rather than those expected at hematopoietic sites. Expected changes in calcium, phosphate and hydroxyl ion are calculated indirectly using published data. Results indicate doubling of normal concentrations for the first week, followed by 2 weeks of smaller elevations as the osteon undergoes resorption and replacement. The period of 3 weeks fits the expected time of the three stages of differentiation and proliferation of erythrocytes to the maturation phase. Mimicking the high concentrations of these ions in vitro may require the development of dynamic flow cultures because of problems with precipitation of calcium phosphate crystals. After 3 weeks 10% less than normal concentrations is expected as the bone mineral is replaced over a period of months, allowing a static system for maturation.