Consistency of dominance rank order: a comparison of David's Scores with I&SI and Bayesian methods in macaques.

In nonhuman primate social groups, dominance ranks are usually assigned to individuals based on outcomes of dyadic agonistic encounters. Multiple approaches have been used, but currently there is no consensus. One approach, David's Scores (DS), offers dual advantages of yielding cardinal scores that may in turn be used to compute hierarchical steepness. Here we correlate rank orders yielded by DS with those yielded by both the traditionally used I&SI approach and the recently proposed parametric Bayesian approach. We use six datasets for female macaques (three despotic and three tolerant groups), and 90 artificially generated datasets modeling macaque groups. We also use the artificial datasets to determine the impact of three characteristics (group size, interaction frequency, and directional asymmetry of aggression) on the magnitude of correlation coefficients, and assess the relative utility of two indices used to compute DS: Dij versus Pij. DS-based rank orders were strongly positively correlated with those yielded by the other two approaches for five out of the six macaque datasets, and for the majority of artificial datasets. Magnitudes of correlation coefficients were unrelated to group size or interaction frequency, but increased with directional asymmetry, suggesting methodological inconsistencies were more likely when dyads had more frequent reversals in directions of aggression. Finally, rank orders calculated using the Dij and Pij indices were similarly consistent with orders from other methods. We conclude that DS offers consistent estimates of rank orders, except perhaps in groups with very low levels of aggression asymmetry. In such "tolerant" groups, we suggest that the relatively greater methodological variability in rank orders may reflect behavioral characteristics of tolerant groups rather than computational inconsistencies between methods. We hypothesize that this quality may be quantified using posterior probability scores of Bayesian rank orders and may also index macaque social styles.

Using biological markets principles to examine patterns of grooming exchange in Macaca thibetana.

Biological markets principles offer testable hypotheses to explain variation in grooming exchange patterns among nonhuman primates. They predict that when within-group contest competition (WGC) is high and dominance hierarchies steep, grooming interchange with other "commodity" behaviors (such as agonistic support) should prevail. In contrast, when WGC is low and gradients shallow, market theory predicts that grooming reciprocity should prevail. We tested these predictions in a wild, provisioned Tibetan macaque (Macaca thibetana) group across six time periods during which the group had been subjected to varying degrees of range restriction. Data on female-female aggression, grooming, and support were collected using all-occurrences and focal animal sampling techniques, and analyzed using ANCOVA methods and correlation analyses. We found that hierarchical steepness varied significantly across periods, but did not correlate with two indirect indicators of WGC (group size and range restriction) in predicted directions. Contrary to expectations, we found a negative correlation between steepness and group size, perhaps because the responses of group members to external risks (i.e. prolonged and unavoidable exposure to humans) may have overshadowed the effects of WGC. As predicted, grooming reciprocity was significant in each period and negatively correlated with steepness, even after we controlled group size, kinship, rank differences, and proximity. In contrast, there was no evidence for grooming interchange with agonistic support or for a positive relationship between interchange and steepness. We hypothesize that stressful conditions and/or the presence of stable hierarchies during each period may have led to a greater market demand for grooming than support. We suggest that future studies testing these predictions consider more direct measures of WGC and commodities in addition to support, such as feeding tolerance and access to infants.

An evaluation of the P450 inhibition and induction potential of daptomycin in primary human hepatocytes.

Two in vitro studies assessed the potential of daptomycin (Cubicin), a newly marketed antibiotic, to affect the cytochrome P450 (CYP450) isoforms in primary cultured human hepatocytes. Both induction and inhibition of isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were evaluated. The highest concentrations of daptomycin used in both the induction and inhibition assays were approximately eight-fold higher than the peak total drug concentration (50-60 microg/mL), or the peak free drug concentration (estimated 5-6 microg/mL), in plasma at the clinical dose regimen of 4 mg/kg qd. Results in primary human hepatocytes indicate that daptomycin, at concentrations up to 400 microg total drug/mL, demonstrated no biologically significant induction of any of the CYP450 isoform activities in comparison with the negative control or known inducers. At daptomycin concentrations up to 40 microg free drug/mL, no biologically significant inhibition of the activities of these CYP450 isoforms was observed as compared with known inhibitors. The human hepatocyte results demonstrate that daptomycin has no effects on hepatic CYP450-mediated drug metabolism and, therefore, suggest that daptomycin is unlikely to show potential for pharmacokinetic interactions with concomitantly administered drugs that are metabolized by CYP450 isoforms.

Magnetic resonance imaging of the breast.

BACKGROUND: Magnetic resonance imaging (MRI) has the potential to become a useful adjunct in breast imaging. Contrast-enhanced breast MRI has demonstrated a high sensitivity in the detection of invasive breast cancer. In clinical studies, breast MRI has often altered the course of patient care. Although promising results have been generated, MRI of the breast is currently in a development stage. METHODS: The authors reviewed the literature on the potential indications, sensitivity, specificity, and limitations of MRI of the breast. RESULTS: Reported advantages of MRI of the breast over conventional imaging techniques include improved staging and treatment planning, enhanced evaluation of the augmented breast, better detection of recurrence, and improved screening of high-risk women. Contrast-enhanced breast MRI is a sensitive modality for detecting breast cancer, but its variable specificity is a major limitation. CONCLUSIONS: MRI of the breast is emerging as a valuable adjunct to mammography and sonography for specific clinical indications. Additional clinical studies that define indications, interpretation criteria, imaging parameters, and cost effectiveness are needed. A multi-institutional study designed to address these issues is in progress.

Randomized prospective evaluation of a novel technique for biopsy or lumpectomy of nonpalpable breast lesions: radioactive seed versus wire localization.

BACKGROUND: Standard wire localization (WL) and excision of nonpalpable breast lesions has several shortcomings. METHODS: Ninety-seven women with nonpalpable breast lesions were prospectively randomized to radioactive seed localization (RSL) or WL. For RSL, a titanium seed containing 125I was placed at the site of the lesion by using radiographical guidance. The surgeon used a handheld gamma detector to locate and excise the seed and lesion. RESULTS: Both techniques resulted in 100% retrieval of the lesions. Fewer RSL patients required resection of additional margins than WL patients (26% vs. 57%, respectively, P = .02). There were no significant differences in mean times for operative excision (5.4 vs. 6.1 minutes) or radiographical localization (13.9 vs. 13.2 minutes). There were also no significant differences in the subjective ease of the procedures as rated by surgeons, radiologists, and patients. All WLs were carried out on the same day as the excision, whereas RSL was performed up to 5 days before the operative procedure. CONCLUSIONS: RSL is as effective as WL for the excision of nonpalpable breast lesions and reduces the incidence of pathologically involved margins of excision. RSL also reduces scheduling conflicts and may allow elimination of intraoperative specimen mammography. RSL is an attractive alternative to WL.

Changes in yearling rhesus monkeys' relationships with their mothers after sibling birth.

The birth of a new sibling is believed to signify an abrupt and important transition in a young primate's relationship with its mother-one that is of potential importance from at least three theoretical perspectives: attachment theory, parent-offspring conflict theory, and dynamic assessment models. This study examines changes in relationships between free-ranging yearling rhesus monkeys (Macaca mulatta) and their mothers concomitant with the birth of the mother's next infant, and tests predictions derived from each theoretical perspective. We observed 31 yearling rhesus on Cayo Santiago, Puerto Rico, 3 months before and 3 months after their siblings' births, using focal animal sampling methods. Changes in measures related to mother-yearling interaction and yearling distress were examined using repeated-measures analysis of variance. After sibling birth, mothers and yearlings abruptly reduced amounts of time in contact and increased amounts of time at a distance and out of sight of one another. Mothers and yearlings played approximately equal roles in bringing about decreases in proximity, and yearlings took the primary roles in bringing about decreases in contact. Rates of maternal aggression toward yearlings increased immediately and markedly after birth, possibly providing yearlings with early cues regarding subsequent decreased levels of maternal care. There were no marked increases in overt signs of yearling distress (e.g., vocalizations or tantrums) following the births. We conclude that yearlings generally acquiesced to reduced levels of care, responding behaviorally with increased independence and maturity. In this sense, our study provides preliminary support for dynamic assessment models over attachment theory and parent-offspring conflict theory models.

Characteristics of the sentinel lymph node in breast cancer predict further involvement of higher-echelon nodes in the axilla: a study to evaluate the need for complete axillary lymph node dissection.

BACKGROUND: Sentinel lymph node (SLN) biopsy techniques provide accurate nodal staging for breast cancer. In the past, complete lymph node dissection (CLND) (levels 1 and 2) was performed for breast cancer staging, although the therapeutic benefit of this more extensive procedure has remained controversial. HYPOTHESIS: It has been demonstrated that if the axillary SLN has no evidence of micrometastases, the nonsentinel lymph nodes (NSLNs) are unlikely to have metastases. OBJECTIVE: To determine which variables predict the probability of NSLN involvement in patients with primary breast carcinoma and SLN metastases. METHODS: An analysis of 101 women with SLN metastases and subsequent CLND was performed. Variables included size of the primary tumor, tumor volume in the SLN, staining techniques used to initially identify the micrometastases (cytokeratin immunohistochemical vs hematoxylin-eosin), number of SLNs harvested, and number of NSLNs involved with the metastases. Tumor size was determined by the invasive component of the primary tumor. Patients with ductal carcinoma in situ who were upstaged with cytokeratin staining were considered to have stage T1a tumors. RESULTS: Sentinel lymph node micrometastases (<2 mm) detected initially by cytokeratin staining were associated with a 7.6% (2/26) incidence of positive CLND compared with a 25% (5/20) incidence when micrometastases were detected initially by routine hematoxylin-eosin staining. Sentinel lymph node micrometastases, regardless of identification technique, inferred a risk of 15.2% (7/46) for NSLN involvement. As the volume of tumor in the SLN increased (ie, <2 mm, >2 mm, grossly visible tumor), so did the risk of NSLN metastases (P<.001). CONCLUSIONS: Our study demonstrated that patients with micrometastases detected initially by cytokeratin staining had low-volume disease in the SLN with a small chance of having metastases in higher-echelon nodes in the regional basin other than the SLN. Characteristics of the SLN can provide information to determine the need for a complete axillary CLND. Complete lymph node dissection may not be necessary in patients with micrometastases detected initially by cytokeratin staining since the disease is confined to the SLN 92.4% of the time. However, the therapeutic value of CLND in breast cancer remains to be determined by further investigation.

An ecological perspective on in-stream temperature: natural heat dynamics and mechanisms of human-caused thermal degradation.

While external factors (drivers) determine the net heat energy and water delivered to a stream, the internal structure of a stream determines how heat and water will be distributed within and exchanged among a stream's components (channel, alluvial aquifer, and riparian zone/floodplain). Therefore, the interaction between external drivers of stream temperature and the internal structure of integrated stream systems ultimately determines channel water temperature. This paper presents a synoptic, ecologically based discussion of the external drivers of stream temperature, the internal structures and processes that insulate and buffer stream temperatures, and the mechanisms of human influence on stream temperature. It provides a holistic perspective on the diversity of natural dynamics and human activities that influence stream temperature, including discussions of the role of the hyporheic zone. Key management implications include: (1) Protecting or reestablishing in-stream flow is critical for restoring desirable thermal regimes in streams. (2) Modified riparian vegetation, groundwater dynamics, and channel morphology are all important pathways of human influence on channel-water temperature and each pathway should be addressed in management plans. (3) Stream temperature research and monitoring programs will be jeopardized by an inaccurate or incomplete conceptual understanding of complex temporal and spatial stream temperature response patterns to anthropogenic influences. (4) Analyses of land-use history and the historical vs contemporary structure of the stream channel, riparian zone, and alluvial aquifer are important prerequisites for applying mechanistic temperature models to develop management prescriptions to meet in-channel temperature goals.

The role of lymphoscintigraphy in the management of the patient with breast cancer.

INTRODUCTION: Regional nodal status is the most powerful predictor of recurrence and survival in women with breast cancer. Lymphatic mapping and sentinel lymph node (SLN) biopsy have been found to accurately predict the regional nodal status. Preoperative lymphoscintigraphy has been used in melanoma patients to identify the basins at risk for metastases when primary sites are located in watershed areas of the body. This study was performed to define the role of lymphoscintigraphy for axillary nodal staging in women with breast cancer. Specifically, can preoperative lymphoscintigraphy define a population of women with breast cancer who have multidirectional drainage or who do not drain to the axilla and need no axillary dissection? METHODS: 516 patients with invasive breast cancer were accrued in a national breast lymphatic mapping trial sponsored by the U.S. Department of Defense. Preoperative lymphoscintigraphy images were produced using filtered technetium-99 sulfur colloid. Lymphatic drainage to axillary and internal mammary sites was noted. RESULTS: Drainage to an axillary SLN was found in 335 (65%) patients, and internal mammary or extra-axillary drainage was noted in 52 (10%) patients. By using sensitive hand-held probes and vital blue dye intraoperatively, the overall success rate of finding an axillary SLN was 85%. Of the 335 patients who had an axillary SLN identified with imaging, all had successful SLN biopsy procedures. Although no SLNs could be imaged in 181 patients, 153 (85%) of these patients had an axillary SLN identified with intraoperative mapping. For 28 patients in which lymphoscintigraphy was negative and intraoperative mapping was unsuccessful, complete axillary node dissection was performed, and 13 (46%) of these patients were found to have metastatic disease in the basin. CONCLUSIONS: Preoperative lymphoscintigraphy can identify those women with primary breast cancers who have extra-axillary regional basin drainage such as internal mammary. The ability to image an axillary SLN was associated with a high success rate of being able to find the node intraoperatively with a combination mapping technique. In a high percentage of patients with negative lymphoscintigraphy, the SLN was identified with more sensitive hand-held probes. Therefore, patients who have a negative preoperative lymphoscintigraphy and intraoperatively are found to have no "hot" spot in the axilla with the hand-held probe still need an axillary node dissection, because 46% of these patients contain metastatic disease in the axilla.

The effects of postinjection massage on the sensitivity of lymphatic mapping in breast cancer.

BACKGROUND: The technique of lymphatic mapping and sentinel lymph node (SLN) biopsy is rapidly becoming the preferred method of staging the axilla of the breast cancer patient. This report describes the impact of postinjection massage on the sensitivity of this surgical technique. STUDY DESIGN: Lymphatic mapping at the H Lee Moffitt Cancer Center is performed using a combination of isosulfan blue dye and Tc99m labeled sulfur colloid. Data describing the rate of SLN identification and the node characteristics from 594 consecutive patients were calculated. Patients who received a 5-minute massage after injection of blue dye and radiocolloid were compared with a control group in which the patients did not receive a postinjection massage. RESULTS: When compared with controls, the proportion of patients who had their SLN identified using blue dye after massage increased from 73.0% to 88.3%, and the proportion of patients who had their SLN identified using radiocolloid after massage increased from 81.7% to 91.3%. The overall rate of SLN identification increased from 93.5% to 97.8%. The proportion of nodes that were stained blue among those removed increased from 73.4% to 79.7% after massage. CONCLUSIONS: As experience increases with this new procedure, the surgical technique of lymphatic mapping continues to evolve. The addition of a postinjection massage significantly improves the uptake of blue dye by SLNs and may also aid in the accumulation of radioactivity in the SLNs, further increasing the sensitivity of this procedure.

Cost consequences of sentinel lymph node biopsy in the treatment of breast cancer. A preliminary analysis.

OBJECTIVES: To assess whether sentinel lymph node biopsy (SLNB), an alternative to axillary lymph node dissection in treating female breast cancer, affords any cost savings. METHODS: We profile cumulative treatment costs of 811 breast cancer patients, 555 of whom received SLNB. Univariate and multivariate statistical tests are used to appraise whether these cost profiles differ between SLNB and other patients. RESULTS: The statistical results are mixed. However, none supports the conjecture that SLNB necessarily lowers the cost of treating the average breast patient. CONCLUSIONS: SLNB may be cost-effective, but longer term costs and outcomes must be estimated before firm conclusions can be reached.

Once-daily dosing in dogs optimizes daptomycin safety.

Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.

Immediate loading of implants in partially and fully edentulous jaws: a series of 27 case reports.

BACKGROUND: The concept of immediate loading of dental implants has been researched in animal and man. High predictability with titanium screw implants can be expected under certain circumstances. Delayed loading, which is empirically based, may offer roadblocks to success in the complex case. Micromotion under a denture, retention of compromised teeth, and the necessity for multiple implant surgeries complicate the situation. The present study was undertaken to demonstrate whether in partial and fully edentulous patients, titanium screw implants may be installed and loaded within 72 hours. METHODS: The study included 27 jaws (23 mandibles and 4 maxillas) in patients who refused to wear a denture or were told of the possibility of immediately loading their implants. Criteria similar to delayed loading was utilized. The patient had to have adequate volume and density for a minimum of 4 (10 mm) implants in the mandible and 6 in the maxilla, in addition to other requirements. After a thorough presurgical evaluation by the restorative dentist, a template and heat-cured/metal-reinforced provisional were fabricated. Following fixture installation, either the fixed provisional was placed or an impression was taken, and the provisional was seated within 72 hours. Once the temporary was placed, it remained until osseointegration was complete. RESULTS: Success rates similar to those in delayed loaded cases may be expected (95%). Fewer sandblasted/acid-etched titanium screws were lost than machined titanium screws. All patients went on to completion of their original prosthetic prescription. CONCLUSIONS: Patients who are partially or fully edentulous may predictably be restored with fixed implant prostheses immediately upon fixture placement if certain parameters are met.

Lymphatic mapping and sentinel lymph node biopsy in patients with breast cancer.

The standard of care for the evaluation of axillary nodal involvement remains complete lymph node dissection. Lymphatic mapping and sentinel lymph node (SLN) biopsy are changing this long-held paradigm; indeed, several leading institutions already reserve complete axillary dissection for patients with metastasis to the SLN. In addition to reviewing the literature, this chapter describes our lymphatic mapping experience at the H Lee Moffitt Cancer Center and Research Institute with 1147 breast cancer patients. Our results, in addition to a meta-analysis of data from 12 institutions comprising an additional 1842 patients undergoing complete axillary dissection, demonstrate that SLN biopsy is an accurate method of axillary staging. Although the results from small series may exaggerate the probability of false negative results, the risk of nodal disease based on tumor size and other risk factors should be evaluated when considering the results of SLN sampling.

Positron emission tomography in initial staging and diagnosis of persistent or recurrent disease.

Positron emission tomography (PET) constitutes a major advance in the diagnosis, staging, prognostic assessment, and follow-up of lung cancer. However, it is not a magic bullet that can solve all of the uncertainties that beguile the imaging of this disease. Small lesions, particularly those in the brain, may often be missed with PET, and three-dimensional localization of suspected sites may also be unreliable. We are still learning how best to apply this new technology in an environment that demands the efficient use of medical resources. PET will probably be used most enthusiastically in the prethoracotomy staging of patients who are considered operable or probably operable on the basis of computed tomography and in the assessment of treatment response and disease recurrence when clinical management will be determined by prompt recognition of these events.

Melanoma lymphoscintigraphy and lymphatic mapping.

Lymphoscintigraphy in melanoma has proven to be a reliable method to identify regional lymph nodes at risk for metastases. The first lymph node to drain a cutaneous lesion, the sentinel lymph node (SLN), is predictive of the metastatic status of the regional lymph node group. Lymphatic mapping allows for the identification of the SLN and for selective lymph node sampling. Selective lymph node sampling is less invasive and because only a small quantity of high-risk tissue is submitted for pathological examination, it allows for a more complete and comprehensive pathological examination, which identifies melanoma with up to 100 times the sensitivity of conventional examinations.

Implementation of new surgical technology: outcome measures for lymphatic mapping of breast carcinoma.

BACKGROUND: Recent advances in technology and the subsequent development of minimally invasive surgical techniques have heralded a new era in the surgical treatment of breast cancer. The dilemma of how to train surgeons in new technologies requires teaching, certification, and outcomes reporting in a non-threatening and non-economically damaging manner. This study examines 700 cases of lymphatic mapping and sentinel lymph node (SLN) biopsy for breast cancer and documents surgeon-specific and institution-specific learning curves. METHODS: Seven hundred cases of lymphatic mapping and SLN biopsy were examined. All procedures were performed using a combination of vital blue dye and radiolabeled sulfur colloid. Learning curves were generated for each surgeon as a plot of failure rate versus number of cases. RESULTS: Examination of the learning curves in this study demonstrates similar characteristics. Following a high initial failure rate, there is a rapid decrease after the first twenty cases. The learning curve, representing the mean of the five surgeons' experience, indicates that 23 cases and 53 cases are required to achieve success rates of 90% and 95%, respectively. CONCLUSIONS: The initial reports regarding lymphatic mapping combined with this experience of 700 cases confirm the presence of a significant learning curve. Although this procedure may have an inherent failure rate, it is important to identify those factors that are under the control of the surgeon and, therefore, subject to improvement. We believe that these data provide surgeons performing lymphatic mapping and SLN biopsy with a new paradigm for assessing their skill and adequacy of training.

Lymphatic mapping with sentinel lymph node biopsy in patients with breast cancers <1 centimeter (T1A-T1B).

Because of its high cost and attendant morbidity, the necessity of axillary dissection in patients with small invasive primary tumors has been questioned. Lymphatic mapping with sentinel lymph node (SLN) biopsy is an alternative to complete axillary dissection; however, researchers have excluded patients with T1A-T1B lesions. Seven hundred patients with newly diagnosed breast cancers underwent an Institutional Review Board-approved prospective trial of intraoperative lymphatic mapping using a combination of Lymphazurin and filtered technetium-labeled sulfur colloid. An SLN was defined as a blue node and/or hot node with a 10:1 ex vivo radioactivity ratio in the SLN versus non-SLNs. All SLNs were evaluated by both hematoxylin and eosin and cytokeratin immunohistochemical stains. Of the 700 patients, 665 (95.0%) were mapped successfully. One hundred ninety-six (28.0%) had T1A-T1B tumors. Forty patients (20.4%) with T1A-T1B tumors had metastases to the SLNs. We conclude that breast cancer SLN mapping is highly accurate and sensitive when combined dye techniques (radiocolloid and vital blue dye) are utilized. This technique is particularly useful in patients with small invasive primary tumors, which, despite their size, still demonstrate a significant rate of axillary metastasis. These patients should not be excluded from lymphatic mapping protocols.

Decreased resting metabolic rate in ballet dancers with menstrual irregularity.

We studied 21 ballet dancers aged 19.4 +/- 1.4 years, hypothesizing that undernutrition was a major factor in menstrual irregularity in this population. Menstrual history was determined by questionnaire. Eight dancers had always been regular (R). Thirteen subjects had a history of menstrual irregularity (HI). Of these, 2 were currently regularly menstruating, 3 had short cycles, 6 were oligomenorrheic, and 2 were amenorrheic. Subjects completed a weighed dietary record and an Eating Attitudes Test (EAT). The following physiological parameters were measured: body composition by anthropometry, resting metabolic rate (RMR) by open-circuit indirect calorimetry, and serum thyroid hormone concentrations by radioimmunoassay. R subjects had significantly higher RMR than HI subjects. Also, HI subjects had lower RMR than predicted by fat-free mass, compared to the R subjects. Neither reported energy intake nor serum thyroid hormone concentrations were different between R and HI subjects. EAT scores varied and were not different between groups. We concluded that in ballet dancers, low RMR is more strongly associated with menstrual irregularity than is current reported energy intake or serum thyroid hormone concentrations.