Estrogen depletion and drug treatment alter the microstructure of type I collagen in bone.

The impact of estrogen depletion and drug treatment on type I collagen fibril nanomorphology and collagen fibril packing (microstructure) was evaluated by atomic force microscopy (AFM) using an ovariectomized (OVX) rabbit model of estrogen deficiency induced bone loss. Nine month-old New Zealand white female rabbits were treated as follows: sham-operated (Sham; n = 11), OVX + vehicle (OVX + Veh; n = 12), OVX + alendronate (ALN, 600 µg/kg/wk., s.c.; n = 12), and OVX + cathepsin-K inhibitor L-235 (CatKI, 10 mg/kg, daily, p.o.; n = 13) in prevention mode for 27 weeks. Samples from the cortical femur and trabecular lumbar vertebrae were polished, demineralized, and imaged using AFM. Auto-correlation of image patches was used to generate a vector field for each image that mathematically approximated the collagen fibril alignment. This vector field was used to compute an information-theoretic entropy that was employed as a quantitative fibril alignment parameter (FAP) to allow image-to-image and sample-to-sample comparison. For all samples, no change was observed in the average FAP values; however significant differences in the distribution of FAP values were observed. In particular, OVX + Veh lumbar vertebrae samples contained a tail of lower FAP values representing regions of greater fibril alignment. OVX + ALN treatment resulted in a FAP distribution with a tail indicating greater alignment for cortical femur and less alignment for trabecular lumbar vertebrae. OVX + CatKI treatment gave a distribution of FAP values with a tail indicating less alignment for cortical femur and no change for trabecular lumbar vertebrae. Fibril alignment was also evaluated by considering when a fibril was part of discrete bundles or sheets (classified as parallel) or not (classified as oblique). For this analysis, the percentage of parallel fibrils in cortical femur for the OVX group was 17% lower than the Sham group. OVX + ALN treatment partially prevented the proportion of parallel fibrils from decreasing and OVX + CatKI treatment completely prevented a change. In trabecular lumbar vertebrae, there was no difference in the percentage of parallel fibrils between Sham and any of the other treatment groups.

Ulcerative Dermatitis in C57BL/6NCrl Mice on a Low-Fat or High-Fat Diet With or Without a Mineralized Red-Algae Supplement.

Ulcerative dermatitis (UD) is a spontaneous idiopathic disease that often affects C57BL/6 mice or mice on a C57BL/6 background. UD is characterized by intense pruritus and lesion formation, most commonly on the head or dorsal thorax. Self-trauma likely contributes to wound severity and delayed wound healing. Histologically, changes are nonspecific, consisting of ulceration with neutrophilic and mastocytic infiltration and epithelial hyperplasia and hyperkeratosis. Diet appears to have a profound effect on the development and progression of UD lesions. We investigated the incidence and severity of UD in C57BL/6NCrl mice on a high-fat western-style diet (HFWD) compared with a standard rodent chow. In addition, we examined the protective effects of dietary supplementation with a multimineral-rich product derived from marine red algae on UD in these 2 diet groups. HFWD-fed mice had an increased incidence of UD. In addition, mice on a HFWD had significantly more severe clinical and histologic lesions. Dietary mineral supplementation in mice on a HFWD decreased the histologic severity of lesions and reduced the incidence of UD in female mice in both diets. In conclusion, a high-fat western-style diet may potentiate UD in C57BL/6NCrl mice. Insufficient mineral supply and mineral imbalance may contribute to disease development. Mineral supplementation may be beneficial in the treatment of UD.

Trends in Breast Cancer Screening: Impact of U.S. Preventive Services Task Force Recommendations.

INTRODUCTION: Although there is general agreement among various guidelines on benefits of routine screening mammography, the age of screening initiation and the optimal frequency of the test remain controversial. In 2009, the U.S. Preventive Services Task Force (USPSTF) recommended against routine breast cancer screening in women aged younger than 50 years. In this study, screening mammography guideline adherence among U.S. women is explored by examining patterns in rates of mammography age of initiation and utilization in years prior to and following the 2009 USPSTF guideline implementation. METHODS: U.S. population-based data from the 2007, 2008, 2010, and 2012 Behavioral Risk Factor Surveillance System surveys were used to measure the overall proportion and rate of change in the proportion of women who underwent screening mammography within the last year, by age and survey year. Data were accessed and analyzed in July 2014. RESULTS: Rates of mammography screening were lower in 2010 and 2012 compared with 2007 and 2008 (p<0.0001). The rate of screening initiation at age 40 years increased over time and was the highest in the years following USPSTF guideline changes (p=0.012). CONCLUSIONS: These data support no perceptible change in U.S. women's patterns of screening mammography age at initiation within 3 years of the USPSTF guideline revision. Whether this finding reflects a delayed effect of guideline revision in population trends or rather health provider practice and patient preference for more frequent screening is unclear and requires further investigation.

Analysis of temporal variation in human masticatory cycles during gum chewing.

OBJECTIVE: The study investigated modulation of fast and slow opening (FO, SO) and closing (FC, SC) chewing cycle phases using gum-chewing sequences in humans. DESIGN: Twenty-two healthy adult subjects participated by chewing gum for at least 20s on the right side and at least 20s on the left side while jaw movements were tracked with a 3D motion analysis system. Jaw movement data were digitized, and chewing cycle phases were identified and analysed for all chewing cycles in a complete sequence. RESULTS: All four chewing cycle phase durations were more variant than total cycle durations, a result found in other non-human primates. Significant negative correlations existed between the opening phases, SO and FO, and between the closing phases, SC and FC; however, there was less consistency in terms of which phases were negatively correlated both between subjects, and between chewing sides within subjects, compared with results reported in other species. CONCLUSIONS: The coordination of intra-cycle phases appears to be flexible and to follow complex rules during gum-chewing in humans. Alternatively, the observed intra-cycle phase relationships could simply reflect: (1) variation in jaw kinematics due to variation in how gum was handled by the tongue on a chew-by-chew basis in our experimental design or (2) by variation due to data sampling noise and/or how phases were defined and identified.

Type I collagen D-spacing in fibril bundles of dermis, tendon, and bone: bridging between nano- and micro-level tissue hierarchy.

Fibrillar collagens in connective tissues are organized into complex and diverse hierarchical networks. In dermis, bone, and tendon, one common phenomenon at the micrometer scale is the organization of fibrils into bundles. Previously, we have reported that collagen fibrils in these tissues exhibit a 10 nm width distribution of D-spacing values. This study expands the observation to a higher hierarchical level by examining fibril D-spacing distribution in relation to the bundle organization. We used atomic force microscopy imaging and two-dimensional fast Fourier transform analysis to investigate dermis, tendon, and bone tissues. We found that, in each tissue type, collagen fibril D-spacings within a single bundle were nearly identical and frequently differ by less than 1 nm. The full 10 nm range in D-spacing values arises from different values found in different bundles. The similarity in D-spacing was observed to persist for up to 40 µm in bundle length and width. A nested mixed model analysis of variance examining 107 bundles and 1710 fibrils from dermis, tendon, and bone indicated that fibril D-spacing differences arise primarily at the bundle level (∼76%), independent of species or tissue types.

Progression of ulcerative dermatitis lesions in C57BL/6Crl mice and the development of a scoring system for dermatitis lesions.

Ulcerative dermatitis (UD) is a common, spontaneous condition in mice with a C57BL/6 background. Although initial lesions may be mild, UD is a progressive disease that often results in ulcerations or debilitating fibrotic contractures. In addition, lesions typically are unresponsive to treatment. Euthanasia is often warranted in severe cases, thereby affecting study outcomes through the loss of research subjects. Because the clinical assessment of UD can be subjective, a quantitative scoring method and documentation of the likely time-frame of progression may be helpful in predicting when animals that develop dermatitis should be removed from a study. Such a system may also be helpful in quantitatively assessing success of various treatment strategies and be valuable to clinical laboratory animal veterinarians. In this 1.5-y, prospective cohort study, we followed 200 mice to monitor the development and course of UD. Mice were examined every 2 wk. A clinical sign (alopecia, pruritus, or peripheral lymphadenopathy) was not identified that predicted development of UD lesions in the subsequent 2-wk period. Once UD developed, pruritus, the character of the lesion (single or multiple crust, coalescing crust, erosion, or ulceration), and the size of the lesion were the only parameters that changed (increased) over the course of the disease. Pruritus was a factor in the rapid progression of UD lesions. We used these findings to develop a quantitative scoring system for the severity of UD. This enhanced understanding of the progression of UD and the quantitative scoring system will enhance the monitoring of UD.

Hard and soft tissue changes after crestal and subcrestal immediate implant placement.

BACKGROUND: The purpose of this study is to assess the influence of the placement level of implants with a laser-microtextured collar design on the outcomes of crestal bone and soft tissue levels. In addition, we assessed the vertical and horizontal defect fill and identified factors that influenced clinical outcomes of immediate implant placement. METHODS: Twenty-four patients, each with a hopeless tooth (anterior or premolar region), were recruited to receive dental implants. Patients were randomly assigned to have the implant placed at the palatal crest or 1 mm subcrestally. Clinical parameters including the keratinized gingival (KG) width, KG thickness, horizontal defect depth (HDD), facial and interproximal marginal bone levels (MBLs), facial threads exposed, tissue-implant horizontal distance, gingival index (GI), and plaque index (PI) were assessed at baseline and 4 months after surgery. In addition, soft tissue profile measurements including the papilla index, papilla height (PH), and gingival level (GL) were assessed after crown placement at 6 and 12 months post-surgery. RESULTS: The overall 4-month implant success rate was 95.8% (one implant failed). A total of 20 of 24 patients completed the study. At baseline, there were no significant differences between crestal and subcrestal groups in all clinical parameters except for the facial MBL (P = 0.035). At 4 months, the subcrestal group had significantly more tissue thickness gain (keratinized tissue) than the crestal group compared to baseline. Other clinical parameters (papilla index, PH, GL, PI, and GI) showed no significant differences between groups at any time. A facial plate thickness ≤1.5 mm and HDD ≥2 mm were strongly correlated with the facial marginal bone loss. A facial plate thickness ≤2 mm and HDD ≥3 were strongly correlated with horizontal dimensional changes. CONCLUSIONS: The use of immediate implants was a predictable surgical approach (96% survival rate), and the level of placement did not influence horizontal and vertical bone and soft tissue changes. This study suggests that a thick facial plate, small gaps, and premolar sites were more favorable for successful implant clinical outcomes in immediate implant placement.

Effect of registration on cyclical kinematic data.

Given growing interest in functional data analysis (FDA) as a useful method for analyzing human movement data, it is critical to understand the effects of standard FDA procedures, including registration, on biomechanical analyses. Registration is used to reduce phase variability between curves while preserving the individual curve's shape and amplitude. The application of three methods available to assess registration could benefit those in the biomechanics community using FDA techniques: comparison of mean curves, comparison of average RMS values, and assessment of time-warping functions. Therefore, the present study has two purposes. First, the necessity of registration applied to cyclical data after time normalization is assessed. Second, we illustrate the three methods for evaluating registration effects. Masticatory jaw movements of 22 healthy adults (2 males, 21 females) were tracked while subjects chewed a gum-based pellet for 20s. Motion data were captured at 60 Hz with two gen-locked video cameras. Individual chewing cycles were time normalized and then transformed into functional observations. Registration did not affect mean curves and warping functions were linear. Although registration decreased the RMS, indicating a decrease in inter-subject variability, the difference was not statistically significant. Together these results indicate that registration may not always be necessary for cyclical chewing data. An important contribution of this paper is the illustration of three methods for evaluating registration that are easy to apply and useful for judging whether the extra data manipulation is necessary.

Quantitative ultrasound backscatter for pulsed cavitational ultrasound therapy- histotripsy.

Histotripsy is a well-controlled ultrasonic tissue ablation technology that mechanically and progressively fractionates tissue structures using cavitation. The fractionated tissue volume can be monitored with ultrasound imaging because a significant ultrasound backscatter reduction occurs.This paper correlates the ultrasound backscatter reduction with the degree of tissue fractionation characterized by the percentage of remaining normal-appearing cell nuclei on histology.Different degrees of tissue fractionation were generated in vitro in freshly excised porcine kidneys by varying the number of therapeutic ultrasound pulses from 100 to 2000 pulses per treatment location. All ultrasound pulses were 15 cycles at 1 MHz delivered at 100 Hz pulse repetition frequency and 19 MPa peak negative pressure. The results showed that the normalized backscatter intensity decreased exponentially with increasing number of pulses. Correspondingly, the percentage of normal appearing nuclei in the treated area decreased exponentially as well. A linear correlation existed between the normalized backscatter intensity and the percentage of normal appearing cell nuclei in the treated region. This suggests that the normalized backscatter intensity may be a potential quantitative real-time feedback parameter for histotripsy-induced tissue fractionation. This quantitative feedback may allow the prediction of local clinical outcomes, i.e., when a tissue volume has been sufficiently treated.

Preoperative and intraoperative predictors of cardiac adverse events after general, vascular, and urological surgery.

BACKGROUND: The authors sought to determine the incidence and risk factors for perioperative cardiac adverse events (CAEs) after noncardiac surgery using detailed preoperative and intraoperative hemodynamic data. METHODS: The authors conducted a prospective observational study at a single university hospital from 2002 to 2006. All American College of Surgeons-National Surgical Quality Improvement Program patients undergoing general, vascular, and urological surgery were included. The CAE outcome definition included cardiac arrest, non-ST elevation myocardial infarction, Q-wave myocardial infarction, and new clinically significant cardiac dysrhythmia within the first 30 postoperative days. RESULTS: Four years of data demonstrated that of 7,740 noncardiac operations, 83 patients (1.1%) experienced a CAE within 30 days. Nine independent predictors were identified (P < or = 0.05): age > or = 68, body mass index > or = 30, emergent surgery, previous coronary intervention or cardiac surgery, active congestive heart failure, cerebrovascular disease, hypertension, operative duration > or = 3.8 h, and the administration of 1 or more units of packed red blood cells intraoperatively. The c-statistic of this model was 0.81 +/- 0.02. Univariate analysis demonstrated that high-risk patients experiencing a CAE were more likely to experience an episode of mean arterial pressure < 50 mmHg (6% vs. 24%, P = 0.02), experience an episode of 40% decrease in mean arterial pressure (26% vs. 53%, P = 0.01), and an episode of heart rate > 100 (22% vs. 34%, P = 0.05). CONCLUSIONS: In comparison with current risk stratification indices, the inclusion of intraoperative elements improves the ability to predict a perioperative CAE after noncardiac surgery.

Indirect estimation of the area density of Atg8 on the phagophore.

Atg8 is a ubiquitin-like protein that controls the expansion of the phagophore during autophagosome formation. It is recruited to the phagophore during the expansion stage and released upon the completion of the autophagosome. One possible model explaining the function of Atg8 is that it acts as an adaptor of a coat complex. Here, we tested the coat-adaptor model by estimating the area density of Atg8 molecules on the phagophore. We developed a computational process to simulate the random sectioning of vesicles heterogeneous in size. This method can be applied to estimate the original sizes of intracellular vesicles from sizes of their random sections obtained through transmission electron microscopy. Using this method, we found that the estimated area density of Atg8 is comparable with that of proteins that form the COPII coat.

Acoustic droplet vaporization threshold: effects of pulse duration and contrast agent.

The use of superheated liquid perfluorocarbon droplets encased in albumin shells has been proposed as a minimally invasive alternative to current treatment of cancer by means of occlusion therapy. In response to an applied acoustic field, these droplets, which are small enough to pass through capillaries, vaporize into large gas bubbles that subsequently lodge in the vasculature. This technique, known as acoustic droplet vaporization (ADV) has been shown to successfully reduce blood flow in vivo, but for in situ conditions where attenuation is present, lower acoustic frequency and ADV threshold may be desirable. Thus, two methods to lower the ADV threshold at a lower 1.44 MHz were explored. The first part of this study investigated the role of pulse duration on ADV. The second part investigated the role of inertial cavitation (IC) external to a droplet by lowering the IC threshold in the host liquid with the presence of Definity contrast agent (CA). The threshold was found to be 5.5-5.9 MPa for short microsecond pulses and decreased for millisecond pulses (3.8-4.6 MPa). When CAs were present and long millisecond pulses were used, the ADV threshold decreased to values as low as 0.41 MPa.

Disease burden in the managed care population at an academic medical center: the effect of adding local partners.

PURPOSE: Academic medical centers (AMCs) have traditionally cared for the most severely ill patients. AMCs' effort to meet the challenges of managed care contracts may be nullified by adverse selection unless payment mechanisms adequately consider the health risk of the AMC's managed care population. The authors compared the disease burden between the University of Michigan Health System (UMHS) and its community competitors and assessed the effect of adding local primary care partners through strategic outsourcing on these differences in disease burden. METHOD: This is a population-based study from one managed care plan in Michigan. The study population was commercial members (n = 127, 892) enrolled in the plan for the entire 12 months of 2001. The authors derived several morbidity measures from age and sex, Adjusted Clinical Groups, and Aggregated Diagnosis Groups using administrative data. RESULTS: Compared to community groups, the UMHS consistently had a higher disease burden, while the nonacademic groups as a whole had more young members with acute conditions. After the UMHS partnered with two local primary care practice groups in their area, this AMC-local partner group had an equal or lower disease burden than the remainder of the community groups that experienced a slightly higher proportion of members with multiple medical conditions. CONCLUSIONS: The higher disease burden borne by AMCs is a complex phenomenon. Without local partners, the UMHS did experience higher disease burden, although the degree depends on the measurement of morbidity. Partnering with carefully selected local primary care groups may ameliorate the AMC's disproportionate disease burden.

Controlled ultrasound tissue erosion: the role of dynamic interaction between insonation and microbubble activity.

Previous studies showed that ultrasound can mechanically remove tissue in a localized, controlled manner. Moreover, enhanced acoustic backscatter is highly correlated with the erosion process. "Initiation" and "extinction" of this highly backscattering environment were studied in this paper. The relationship between initiation and erosion, variability of initiation and extinction, and effects of pulse intensity and gas saturation on time to initiation (initiation delay time) were investigated. A 788-kHz single-element transducer was used. Multiple pulses at a 3-cycle pulse duration and a 20-kHz pulse repetition frequency were applied. I(SPPA) values between 1000 and 9000 W/cm2 and gas saturation ranges of 24%-28%, 39%-49%, and 77%-81% were tested. Results show the following: (1) without initiation, erosion was never observed; (2) initiation and extinction of the highly backscattering environment were stochastic in nature and dependent on acoustic parameters; (3) initiation delay times were shorter with higher intensity and higher gas saturation (e.g., the mean initiation delay time was 66.9 s at I(SPPA) of 4000 W/cm2 and 3.6 ms at I(SPPA) of 9000 W/cm2); and (4) once initiated by high-intensity pulses, the highly backscattering environment and erosion can be sustained using a significantly lower intensity than that required to initiate the process.