Correcting for missing and irregular data in home-range estimation.

Home-range estimation is an important application of animal tracking data that is frequently complicated by autocorrelation, sampling irregularity, and small effective sample sizes. We introduce a novel, optimal weighting method that accounts for temporal sampling bias in autocorrelated tracking data. This method corrects for irregular and missing data, such that oversampled times are downweighted and undersampled times are upweighted to minimize error in the home-range estimate. We also introduce computationally efficient algorithms that make this method feasible with large data sets. Generally speaking, there are three situations where weight optimization improves the accuracy of home-range estimates: with marine data, where the sampling schedule is highly irregular, with duty cycled data, where the sampling schedule changes during the observation period, and when a small number of home-range crossings are observed, making the beginning and end times more independent and informative than the intermediate times. Using both simulated data and empirical examples including reef manta ray, Mongolian gazelle, and African buffalo, optimal weighting is shown to reduce the error and increase the spatial resolution of home-range estimates. With a conveniently packaged and computationally efficient software implementation, this method broadens the array of data sets with which accurate space-use assessments can be made.

Estimating where and how animals travel: an optimal framework for path reconstruction from autocorrelated tracking data.

An animal's trajectory is a fundamental object of interest in movement ecology, as it directly informs a range of topics from resource selection to energy expenditure and behavioral states. Optimally inferring the mostly unobserved movement path and its dynamics from a limited sample of telemetry observations is a key unsolved problem, however. The field of geostatistics has focused significant attention on a mathematically analogous problem that has a statistically optimal solution coined after its inventor, Krige. Kriging revolutionized geostatistics and is now the gold standard for interpolating between a limited number of autocorrelated spatial point observations. Here we translate Kriging for use with animal movement data. Our Kriging formalism encompasses previous methods to estimate animal's trajectories--the Brownian bridge and continuous-time correlated random walk library--as special cases, informs users as to when these previous methods are appropriate, and provides a more general method when they are not. We demonstrate the capabilities of Kriging on a case study with Mongolian gazelles where, compared to the Brownian bridge, Kriging with a more optimal model was 10% more precise in interpolating locations and 500% more precise in estimating occurrence areas.

Rigorous home range estimation with movement data: a new autocorrelated kernel density estimator.

Quantifying animals' home ranges is a key problem in ecology and has important conservation and wildlife management applications. Kernel density estimation (KDE) is a workhorse technique for range delineation problems that is both statistically efficient and nonparametric. KDE assumes that the data are independent and identically distributed (IID). However, animal tracking data, which are routinely used as inputs to KDEs, are inherently autocorrelated and violate this key assumption. As we demonstrate, using realistically autocorrelated data in conventional KDEs results in grossly underestimated home ranges. We further show that the performance of conventional KDEs actually degrades as data quality improves, because autocorrelation strength increases as movement paths become more finely resolved. To remedy these flaws with the traditional KDE method, we derive an autocorrelated KDE (AKDE) from first principles to use autocorrelated data, making it perfectly suited for movement data sets. We illustrate the vastly improved performance of AKDE using analytical arguments, relocation data from Mongolian gazelles, and simulations based upon the gazelle's observed movement process. By yielding better minimum area estimates for threatened wildlife populations, we believe that future widespread use of AKDE will have significant impact on ecology and conservation biology.

Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma.

BACKGROUND: Management of inoperable parathyroid carcinoma presents a challenge because until recently, effective medical therapy was not available. Morbidity and mortality result primarily from severe hypercalcemia. We assessed the ability of the calcimimetic cinacalcet HCl to reduce serum calcium in patients with parathyroid carcinoma as well as its effect on PTH concentrations, bone turnover markers, safety, and health-related quality of life variables. METHODS: Twenty-nine patients with parathyroid carcinoma were enrolled in this open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated (30 mg twice daily to 90 mg four times daily) for 16 wk or until serum calcium was no more than 10.0 mg/dl. The study endpoint was the proportion of patients with at least a 1 mg/dl reduction in serum calcium at the end of the titration phase (responders). RESULTS: Mean (+/- se) serum calcium (14.1 +/- 0.4 mg/dl) and PTH (697 +/- 94 pg/ml) were markedly elevated at baseline. At the end of the titration period, serum calcium was reduced by at least 1 mg/dl in 62% of patients (mean decline to 12.4 +/- 0.5 mg/dl). In the 18 responders, serum calcium fell from 15.0 +/- 0.5 to 11.2 +/- 0.3 mg/dl (P < 0.001). The greatest reductions in serum calcium were observed in patients with highest baseline calcium levels. PTH levels decreased, but not significantly, to 635 +/- 73 pg/ml (-4.6%). Adverse events included nausea, vomiting, headache, and fracture. CONCLUSIONS: Cinacalcet effectively reduces hypercalcemia in approximately two thirds of patients with inoperable parathyroid carcinoma and may represent an important new treatment option for these patients.

Two regulators of Ste12p inhibit pheromone-responsive transcription by separate mechanisms.

The yeast Saccharomyces cerevisiae transcription factor Ste12p is responsible for activating genes in response to MAP kinase cascades controlling mating and filamentous growth. Ste12p is negatively regulated by two inhibitor proteins, Dig1p (also called Rst1p) and Dig2p (also called Rst2p). The expression of a C-terminal Ste12p fragment (residues 216 to 688) [Ste12p(216-688)] from a GAL promoter causes FUS1 induction in a strain expressing wild-type STE12, suggesting that this region can cause the activation of endogenous Ste12p. Residues 262 to 594 are sufficient to cause STE12-dependent FUS1 induction when overexpressed, and this region of Ste12p was found to bind Dig1p but not Dig2p in yeast extracts. In contrast, recombinant glutathione S-transferase-Dig2p binds to the Ste12p DNA-binding domain (DBD). Expression of DIG2, but not DIG1, from a GAL promoter inhibits transcriptional activation by an Ste12p DBD-VP16 fusion. Furthermore, disruption of dig1, but not dig2, causes elevated transcriptional activation by a LexA-Ste12p(216-688) fusion. Ste12p has multiple regions within the C terminus (flanking residue 474) that can promote multimerization in vitro, and we demonstrate that these interactions can contribute to the activation of endogenous Ste12p by overproduced C-terminal fragments. These results demonstrate that Dig1p and Dig2p do not function by redundant mechanisms but rather inhibit pheromone-responsive transcription through interactions with separate regions of Ste12p.

Cinacalcet HCI (Sensipar/Mimpara) is an effective chronic therapy for hemodialysis patients with secondary hyperparathyroidism.

AIMS: This 1-year double-blind, placebo-controlled, multicenter study evaluated the long-term safety and efficacy of cinacalcet for the treatment of secondary hyperparathyroidism in patients receiving hemodialysis. METHOD: Patients were randomly assigned in a 1:1 ratio to cinacalcet or control treatment groups. The initial dose of cinacalcet (or matching placebo) was 30 mg. Doses were titrated every 3 or 4 weeks based on the intact parathyroid hormone (iPTH) response and safety profile. Sequential doses included 30, 60, 90, 120 and 180 mg/d. Phosphate binders and vitamin D sterols were adjusted per protocol as needed to control levels of calcium and phosphorus. Efficacy and safety were compared between treatment groups among patients who completed the study (52 total weeks of treatment). Reasons for withdrawal are presented for patients who did not complete the study. RESULTS: A total of 210 patients completed 52 weeks of double-blinded treatment with cinacalcet (n = 99) or placebo (n = 111). Over the last 6 months of the study, a greater proportion of patients in the cinacalcet group than the control group achieved an iPTH level < or = 250 pg/ml (61.6 vs. 9.9%, p < 0.001) or a > or = 30% decrease in iPTH from baseline (81.8 vs. 21.6%, p < 0.001). Mean iPTH levels decreased by -47.8% in the cinacalcet group and increased by +12.9% in the control group. Mean percentage changes in other laboratory values in the cinacalcet and control groups included the following: serum calcium -6.5 vs. +0.9% (p < 0.001), serum phosphorus -3.6 vs. -1.1% (p = 0.465), and Ca x P -9.9 vs. -0.3% (p = 0.006). The most commonly reported adverse events related to study drug by the investigators included nausea (13% cinacalcet, 5% control), investigator-reported hypocalcemia (11% cinacalcet, 1% control), vomiting (9% cinacalcet, 2% control), dyspepsia (5% cinacalcet, 4% control), and diarrhea (5% cinacalcet, 2% control). CONCLUSIONS: Treatment with cinacalcet is a safe and effective therapy for long-term control of secondary hyperparathyroidism. 1-year therapy with cinacalcet was associated with sustained, clinically significant reductions in calcium, Ca x P and iPTH which allowed a greater percentage of patients to achieve NKF-KDOQI target goals for PTH and Ca x P.

A monoclonal antibody to human angiogenin suppresses tumor growth in athymic mice.

Human angiogenin, a potent inducer of neovascularization, is secreted by HT-29 colon adenocarcinoma cells. microgram doses of a monoclonal antibody that neutralizes the in vitro and in vivo activities of angiogenin prevent or delay the appearance of s.c. HT-29 tumors in athymic mice in a statistically significant, dose-dependent manner. The antibody is not cytotoxic to tumor cells in vitro, which indicates that inhibition of tumor growth most likely occurs by neutralization of the activity of angiogenin in vivo and further implies a critical role for angiogenin in the early development of HT-29 tumors. The results suggest a therapeutically useful approach to the treatment of angiogenin-dependent malignancy.

Prevention of human prostate tumor metastasis in athymic mice by antisense targeting of human angiogenin.

PURPOSE: Angiogenin is a potent positive mediator of neovascularization, a process required for both primary tumor growth and metastasis. In the present study, the effect of a fully phosphorothioated antisense oligodeoxynucleotide, designated JF2S, targeting the AUG translation initiation codon region of human angiogenin, on human prostate tumor development and metastasis in athymic mice was examined. EXPERIMENTAL DESIGN: JF2S was evaluated for its capacity to affect in vitro synthesis of angiogenin and subsequent tumorigenicity of transiently transfected prostate tumor cells in mice. In vivo treatment experiments were then conducted in which JF2S was used to prevent formation of tumors in an ectopic model and metastasis in an orthotopic model. RESULTS: Transient transfection of tumor cells with JF2S inhibited both angiogenin gene expression in vitro and tumorigenicity of these transfected cells in athymic mice. In therapy experiments, local treatment with JF2S completely protected mice from developing prostate tumors after s.c. injection of PC-3 human prostate tumor cells (P < 0.0001, survivor analysis). Most importantly, systemic prophylactic administration of JF2S prevented, in 47% of mice, formation of regional iliac lymph node micrometastases arising from primary tumors growing in the more natural orthotopic prostate setting (P = 0.0003, Fisher's exact test). Furthermore, total protection from regional metastasis occurred in those mice in which JF2S treatment successfully diminished human angiogenin expression in vivo. Tumor-associated angiogenesis was also impaired by JF2S treatment. When therapy was delayed until all of the mice harbored primary tumors in the prostate, the incidence of regional metastasis was still significantly decreased (P < 0.005, survivor analysis). CONCLUSIONS: These findings demonstrate that human prostate cancer establishment and spread in athymic mice is extremely susceptible to targeted disruption of tumor-derived human angiogenin gene expression. Therefore, angiogenin is a valid target against which to devise preventative strategies for prostate cancer metastasis.

Preserved cognitive skills in dementia of the Alzheimer type.

OBJECTIVE: To describe preserved cognitive skills in patients with dementia. DESIGN: Case series. SETTING: Community clinic. PATIENTS: Five patients who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's disease and were claimed to retain a cognitive skill. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Standard neuropsychological tests and individualized measures of patient's skilled behaviors. For patients who remained skilled at games, performance was compared with that of normal controls in direct competition. For the patient-trombonist, raters compared premorbid and postmorbid recordings of his play. RESULTS: One patient continued to play the trombone in a Dixieland band, although he could not name well-known numbers that he played. Another continued to solve adult jigsaw puzzles. A third patient retained skill at canasta, the fourth at dominoes. The fifth patient remained a skillful contract bridge player, although he could not name the suits or articulate simple bidding rules. Four patients had impaired performance on standard anterograde and remote memory and naming tests but performed normally on pursuit rotor and letter fluency tests. Mini-Mental State Examination scores for these patients ranged from 10 to 22. One patient refused neuropsychological testing but displayed his skill. CONCLUSIONS: Together with previous studies of preserved piano playing or painting skills, our findings indicate that a broad range of complex cognitive abilities may be preserved in patients with dementia of the Alzheimer type who cannot perform simpler actions.

Computed tomography ventricular size has no predictive value in diagnosing pseudotumor cerebri.

We compared linear indices of computed tomography ventricular size in patients with pseudotumor cerebri and in age-matched controls, and found no difference between these populations. Two physicians showed poor agreement and sensitivity when blindly judging whether patients and controls had "slit-like" ventricles. We conclude that ventricular size on routine CT has no predictive value when evaluating patients with suspected pseudotumor cerebri.

Expression of game-related and generic knowledge by dementia patients who retain skill at playing dominoes.

Patients with dementia who remain skilled at musical performance or playing bridge fail explicit memory tests for information related to their skills, suggesting that implicit memory mediates their preserved skills. To reexamine this issue, 23 dementia patients and 15 elderly controls of comparable domino-playing skill were compared on tests of naming, verbal fluency, and domino knowledge. On an explicit test of domino knowledge, the patients scored well below the elderly controls, performing no better than students who were unfamiliar with the game. But when game-like situations were created with real dominoes, both the skilled controls and the patients with dementia chose optimal moves and verbally explained their choices equally well. On naming and fluency tests, the skilled patients showed no advantage over patients of comparable dementia severity who had no retained skill. In dementia, some complex knowledge seems intact but is accessible only in particular contexts.

Prognosis of photoparoxysmal response in nonepileptic patients.

Photoparoxysmal response (PPR) is sometimes incidentally encountered in EEGs performed for evaluation of nonepileptic symptoms. We conducted the first long-term study of a cohort of nonepileptic patients to determine their risk of having seizures subsequent to incidental recording of PPR. After 6 to 12 years (mean, 9 years), none of the 33 patients had had epileptic seizures. To identify prognostic factors associated with PPR, we performed a case-control study comparing the cohort with 33 age-matched patients who had had epileptic seizures prior to PPR recording. There was no statistically significant difference between the two groups with respect to the clinical or EEG data. Morphology of the PPR discharge was not different between the two groups. Contrary to what is widely believed, persistence of PPR discharges beyond stimulation was not associated with a high risk of developing seizures. Prognosis of PPR is age-dependent and seems favorable in adults without previous epileptic seizures.

Placebo-controlled evaluation of Ritalin side effects.

OBJECTIVE: To address the frequency of side effects of Ritalin therapy in children with attention deficit hyperactivity disorder (ADHD) using the Barkeley Side Effects Questionnaire (BSEQ) in a clinical setting. DESIGN: Randomized double-blind placebo-controlled cross-over trial. SETTING: A large rural tertiary care clinic. PATIENTS: 234 consecutive children aged 5 through 15 years who met the Diagnostic and Statistical Manual of Mental Disorders (3rd ed, revised) criteria for ADHD were enrolled. Of these children, 206 had sufficient side effects data for analysis. INTERVENTIONS: 0.3 mg/kg per dose and 0.5 mg/kg per dose Ritalin compared to placebo in separate 2-week trials. Each treatment was given three times a day for 7 consecutive days. MEASUREMENTS AND MAIN RESULTS: Parents, blinded to the treatment assignment, assessed side effects via the BSEQ at baseline and at the end of each of the 4 treatment weeks. Univariate odds ratios (OR) were used to describe the magnitude of differences in observed side effects between Ritalin and placebo weeks of the trial for each of the items on the BSEQ. The frequency of the following side effects significantly increased with Ritalin therapy: insomnia (OR = 3.13, 95% confidence interval [CI] = (1.80,5.42)), appetite disturbance (OR = 19.00, 95% CI = (9.18,39.31)), stomachache (OR = 7.00, 95% CI = (3.29, 14.89)), headache (OR = 5.29, 95% CI = (2.51,11.15)), and dizziness (OR = 7.50, 95% CI = (1.93,29.13)). The frequency of the following side effects significantly decreased with Ritalin therapy: staring and daydreaming (OR = 0.47, 95% CI = (0.27,0.84)), irritability (OR = 0.33, 95% CI = (0.18,0.61)), anxiety (OR = 0.42, 95% CI = (0.23,0.76)), and nailbiting (OR = 0.19, 95% CI = (0.07, 0.53)). The incidence rates of the remaining BSEQ items did not differ significantly between the Ritalin and placebo weeks of the trial. CONCLUSION: The BSEQ proved to be clinically effective in tracking Ritalin side effects and should be incorporated into the routine evaluation and monitoring of ADHD patients for whom stimulants are prescribed.

Machine-related occupational injuries in farm residents.

Farm machinery is an important contributor to the high rates of occupational injury in agriculture. As part of a population-based case-control study, we studied risk factors for machine-related farm injuries. Case patients were farm residents residing in a geographically defined area of central Wisconsin who experienced a farm injury associated with a tractor, farm implement, or other machine which required medical or chiropractic care from May 1990 through April 1992. Controls were selected from an ad hoc census of farm residents in the same area. Telephone interviews regarding demographic characteristics, safety behaviors, and farming practices were completed for 97.8% of 90 case patients and for 82.8% of 221 control subjects. Personal characteristics significantly associated with an increased risk of machine-related injury included the number of hours worked per week and working primarily as a farmer. Dairy farms, farms with nonresident workers, and large farms were associated with an increased risk of injury while farms with registered cows and farms where cows were fed in the barn even in summer experienced fewer injuries. Based on a logistic regression model, the independent risk factors for machine-related farm injury included hours worked per week (2% increased risk/nonresident workers on farm (odds ratio) (OR) = 2.32; 95% confidence interval (CI): 1.07 to 5.06), cows fed in barn in summer (OR = 0.28; 95% CI: 0.12 to 0.64), and registered cows on farm (OR = 0.36; 95% CI: 0.17 to 0.79). Farm safety practices did not appreciably influence the risk of machine-related farm injury.

Pelvic and para-aortic lymphadenectomy for surgical staging of endometrial cancer: morbidity and mortality.

This analysis compared retrospectively the morbidity and mortality of patients with endometrial cancer who had total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO) alone or with pelvic and para-aortic lymphadenectomy performed by the same surgeon at one private institution. Between August 1987 and March 1991, 77 women with endometrial cancer were staged surgically by a standard protocol without preoperative radiotherapy. Thirty-five patients (45%) had TAH/BSO alone and 42 (55%) had TAH/BSO with pelvic and para-aortic lymphadenectomy. The median number of lymph nodes removed was 18. Patients having lymphadenectomy had an increased mean (+/- standard deviation) operative time (129 +/- 29 versus 87 +/- 26 minutes; P less than .0001), increased mean estimated blood loss (391 +/- 192 versus 272 +/- 219 mL; P = .013), and a longer postoperative hospital stay (P = .017) compared with patients having TAH/BSO alone. However, there was no difference in transfusion rate, febrile morbidity, postoperative complications, or mortality. We conclude that pelvic and para-aortic lymphadenectomy can be added to TAH/BSO in patients with endometrial cancer without a clinically significant increase in morbidity or mortality.

Representations of knowledge about dominoes in demented and normal elderly players.

1. Dementia patients who retain musical and game-playing skills exhibit impaired performance on explicit memory tests of knowledge about their retained skill. 2. Dementia patients who retain skill at playing dominoes can answer complex questions about the play of the game almost as well as normal elderly domino players when the questions are presented with real dominoes. 3. The aim of this study was to determine if skilled dementia patients could answer questions about domino play when the stimuli were two-dimensional drawings of dominoes. 4. Seventeen dementia patients and eight normal elderly domino players were tested on two forms of the Domino Quiz: first with real dominoes, then with two-dimensional drawings; other neuropsychological tests were given at the same time. 5. Fourteen of the 17 patients and all of the controls showed no decline in answering questions about domino play when two-dimensional drawings were used. These patients showed retained symbolic processing of information about dominoes despite declines in overall mental status, generation of words from specific semantic categories, and recognition memory for domino terminology. 6. Because the 14 patients with retained domino skill performed as accurately as controls on both administrations of a letter cancellation task, the ability to process familiar symbols may be important to their game-playing skill.

Prognostic factors of spinal cord stimulation for chronic back and leg pain.

Spinal cord stimulation (SCS) has been used for more than 20 years in the treatment of diverse pain conditions. Although recent studies have identified more clearly those conditions for which SCSoffers a favorable prognosis, the identification of a patient population in whom reasonably long-term success can be expected has been difficult. In an effort to improve patient selection and increase the overall success rate of treatment, we have examined various physical, demographic, and psychosocial variables as predictors of SCS outcome. The study population consisted of 40 patients with chronic low back and/or leg pain, 85% of whom were diagnosed with failed back surgery syndrome. Medical history and demographic data were collected as part of an initial assessment along with patient responses to the Minnesota Multiphasic Personality Inventory, the visual analogue pain rating scale (VAS), the McGill Pain Questionnaire, the Oswestry Disability Questionnaire, the Beck Depression Inventory, and the Sickness Impact Profile. Treatment outcomes were examined and found to improve significantly after 3 months of stimulation. Subsequent regression analysis revealed that patient age, the Minnesota Multiphasic Personality Inventory depression subscale D, and the evaluative subscale of the McGill Pain Questionnaire (MPQe) were important predictors of posttreatment pain status. Increased patient age and D subscale scores correlated negatively with pain status, as measured by the percentage of changes in pretreatment and posttreatment VAS scores, % delta VAS. In contrast, higher MPQe correlated with improved pain status. By the use of the following equation and the definition commonly associated with SCS success (at least 50% decrease in the VAS pain level), the success or failure of 3 months of SCS was correctly predicted in 88% of the study population. Our results suggest that patient age, Minnesota Multiphasic Personality Inventory depression, and MPQe may be clinically useful in the prediction of pain status after 3 months of SCS in patients with chronic low back and/or leg pain. % delta VAS = 112.57 - 1.98 (D)-1.68 (Age) + 35.54 (MPQe).

Influence of pupil size, anisocoria, and ambient light on pilocarpine miosis. Implications for supersensitivity testing.

BACKGROUND: This study determines how pupil size, anisocoria, and ambient light influence miotic responses to dilute pilocarpine. The aim is to establish whether mechanical properties of the iris affect miotic behavior using a cholinergic agonist and, if so, to define a more specific clinical definition of supersensitivity testing for suspected tonic pupil disorders. METHODS: The right pupil of 42 normal subjects was first dilated with phenylephrine to create an experimental anisocoria. Then, pilocarpine 0.1% was placed in both eyes. Net constriction of the larger right pupil was determined by subtracting the amount of pilocarpine-induced constriction of the control left pupil from the amount of pilocarpine-induced constriction of the experimental right pupil. Pupil diameters were measured in room light and darkness. RESULTS: In only a few subjects, the larger right pupil became smaller than the left pupil after pilocarpine administration. Net constriction of the right pupil was greater when determined in room light than in darkness. The amount of net constriction of the right pupil showed good correlation with the degree of baseline anisocoria when evaluated in room light, but not so in darkness. CONCLUSION: Pupil size, degree of anisocoria, and light conditions influence the amount of pilocarpine-induced change in anisocoria. If a patient's larger pupil becomes the smaller pupil in darkness after dilute pilocarpine is applied to both eyes, then it is likely that such a response occurred independent of mechanical properties of the iris, and likely represents a supersensitive response. Ophthalmology.