Reverse engineering field-derived vertical distribution profiles to infer larval swimming behaviors.

Biophysical models are well-used tools for predicting the dispersal of marine larvae. Larval behavior has been shown to influence dispersal, but how to incorporate behavior effectively within dispersal models remains a challenge. Mechanisms of behavior are often derived from laboratory-based studies and therefore, may not reflect behavior in situ. Here, using state-of-the-art models, we explore the movements that larvae must undertake to achieve the vertical distribution patterns observed in nature. Results suggest that behaviors are not consistent with those described under the tidally synchronized vertical migration (TVM) hypothesis. Instead, we show (i) a need for swimming speed and direction to vary over the tidal cycle and (ii) that, in some instances, larval swimming cannot explain observed vertical patterns. We argue that current methods of behavioral parameterization are limited in their capacity to replicate in situ observations of vertical distribution, which may cause dispersal error to propagate over time, due to advective differences over depth and demonstrate an alternative to laboratory-based behavioral parameterization that encompasses the range of environmental cues that may be acting on planktic organisms.

Ultrasound-guided percutaneous tenotomy for the treatment of iliopsoas impingement: a description of technique and case study.

Iliopsoas impingement is a commonly recognised source of groin pain following total hip replacement. When conservative measures fail, open or arthroscopic iliopsoas tendon release can reliably alleviate pain and improve function. This article describes an alternative ultrasound-guided percutaneous technique, achieving iliopsoas tenotomy utilising a modified 18G coaxial needle and thus minimising the morbidity and cost associated with an open or arthroscopic procedure. This method proved successful with resultant complete resolution of patient symptoms. To the knowledge of the authors, this is the first case of ultrasound-guided percutaneous iliopsoas tenotomy for iliopsoas impingement post total hip replacement.

Dental workforce development as part of the oral health agenda for Brunei Darussalam.

BACKGROUND: Brunei Darussalam is a Sultanate with a Malay Islamic monarchy. There are high levels of dental disease among its 406,200 population. The population's oral health needs require an integrated blend of primary and specialist care, together with oral health promotion. PROCESS AND OUTCOMES: This paper describes the planning and measures taken to address these needs. In accordance with an oral health agenda published and launched in 2008, focusing on access, health promotion and prevention, and the education and training of the dental workforce, the Brunei Darussalam Ministry of Health is seeking to improve oral health status and reduce the burden of oral disease. It also seeks to transform the country's oral health services into a preventatively orientated, high-quality, seamless service underpinned by the concept of 'teeth for life'. In the process of effecting this transition, the Brunei Darussalam Ministry of Health is developing a dental workforce fit for future purpose, with an emphasis on a modern approach to skill mix. An important element of this programme has been the development of a highly successful Brunei Darussalam Diploma in Dental Therapy and Dental Hygiene. CONCLUSION: It is concluded that the Brunei Darussalam oral health agenda and, in particular, the forward-looking programme of dental workforce development is a model for other countries facing similar oral health challenges.

Efficacy of cyclo-oxygenase-2 inhibition by etoricoxib and naproxen on the axial manifestations of ankylosing spondylitis in the presence of peripheral arthritis.

OBJECTIVE: The combined efficacy of selective and non-selective cyclo-oxygenase-2 (COX-2) inhibition on the axial manifestations of ankylosing spondylitis (AS) in the presence or absence of chronic peripheral arthritis was evaluated. METHODS: In a post hoc subgroup analysis of a 6 week, randomised, double blind, placebo controlled trial, 387 patients with active axial AS were randomised to receive etoricoxib 90 mg or 120 mg once a day, naproxen 500 mg twice daily, or placebo. Randomisation was stratified by the presence or absence of chronic peripheral arthritis. The primary outcome measure was the time weighted average change from baseline of spine pain intensity. Efficacy data from the three groups receiving active treatment (the NSAID/COX-2 inhibitor group) were combined to improve precision. An analysis of covariance model was used to evaluate the effect of peripheral disease on treatment response. RESULTS: 93 patients were allocated to receive placebo and 294 to active treatment (naproxen or etoricoxib). The combined NSAID/COX-2 inhibitor group had a significant treatment response compared with the placebo group for all efficacy measures, both in patients with and without peripheral arthritis. A significantly greater difference in mean patient assessment of spine pain was found between active and placebo treatments in patients without compared with those with peripheral arthritis (p = 0.005; -32.5 mm v -17.0 mm, respectively). Similar differences, although not statistically significant, were seen for other end points. CONCLUSION: NSAIDs and COX-2 inhibitors have a clinically relevant symptomatic effect on axial AS irrespective of the presence of peripheral arthritis. In this exploratory analysis spinal improvement appeared to be greater in patients without peripheral disease.

Intraarticular gene transfer of TNFR:Fc suppresses experimental arthritis with reduced systemic distribution of the gene product.

Tumor necrosis factor alpha (TNFalpha) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). Blockage of TNFalpha actions by systemic administration of TNF antagonists has recently been shown to ameliorate joint symptoms in RA patients. In the present study, a streptococcal cell wall (SCW)-induced rat arthritis model was used to evaluate the effect of different gene transfer routes of a TNF antagonist on the development and severity of arthritis. Successful delivery of a plasmid DNA encoding a rat TNF receptor-immunoglobulin Fc (TNFR:Fc) fusion gene prompted the subsequent administration of a recombinant adeno-associated virus (rAAV) vector encoding the antagonist, either locally (intraarticular) or systemically (intramuscular). The TNFR:Fc gene, delivered by either route, resulted in profound suppression of the arthritis as reflected in decreased inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and mRNA expression of joint proinflammatory cytokines. Increased bioactive serum TNFR levels were detected as a result of rAAV-ratTNFR:Fc administration, concomitant with a decrease in circulating TNFalpha. Administration of the rAAV-ratTNFR:Fc vector to one joint also suppressed arthritis in the contralateral joint. Importantly, intraarticular administration resulted in significantly lower systemic distribution of the gene product. Hence, the use of rAAV as the delivery vector for TNFR:Fc effectively suppressed SCW-induced arthritis and may provide an approach for local delivery of antiarthritic therapy.

1,4-Benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonists.

A series of 1,4-benzodiazepines, N-1-substituted with an N-isopropyl-N-phenylacetamide moiety, was synthesized and screened for CCK-A agonist activity. In vitro agonist activity on isolated guinea pig gallbladder along with in vivo induction of satiety following intraperitoneal administration in a rat feeding assay was demonstrated.

When to press on or turn back: dispersal strategies for reef fish larvae.

Events that occur during the pelagic larval stage are thought to be important determinants of reef fish population dynamics. Recent research contradicts the early paradigm of larvae being advected as passive propagules and indicates that many late stage larvae have well-developed sensory and locomotory capabilities. Whether and how larvae use these capabilities to influence their dispersal is unknown. We compare alternative hypotheses regarding larval behavior. Contrary to the trend in dispersal modeling, we focus on larval biology rather than physical oceanographic considerations. Specifically, we present two streams of models: one that describes a return-based strategy and one in which dispersal is a central component. The models depend on different sets of behavioral assumptions for a pomacentrid species and for acanthurids, two groups with contrasting early life histories. Whether dispersal or return-based strategies are favored depends on the efficiency and sustainability of larval swimming methods and the environmental conditions experienced during dispersal. We argue that dispersal models should consider a variety of behavioral hypotheses and that the sensitivity of results to the behavioral assumptions made should be quantified.

Mixed effects logistic regression models for longitudinal ordinal functional response data with multiple-cause drop-out from the longitudinal study of aging.

In the context of analyzing ordinal functional limitation responses from the Longitudinal Study of Aging, we investigate the association between current functional limitation and previous year's limitation and its modification by physical activity and multiple causes of drop-out. We accommodate the longitudinal nature of the multiple causes of informative drop-out (death and unknown loss-to-follow-up) with a mixed effects logistic model. Under the proposed model with a random intercept and slope, the ordinal functional outcome and multiple discrete time survival profiles share a common random effect structure. This shared parameter selection model assumes that the multiple causes of drop-out are conditionally independent of the functional limitation outcome given the underlying random effect representing an individual's trajectory of general health status across time. Although it is not possible to fully assess the adequacy of this assumption, we assess the robustness of the approach by varying the assumptions underlying the proposed model, such as the random effects distribution and the drop-out component. It appears that between-subject differences in initial functional limitation are strongly associated with future functional limitation and that this association is stronger for those who do not have physical activity regardless of the random effects and informative drop-out specifications. In contrast, the association between current functional limitation and previous trajectory of functional status within an individual is weaker and more sensitive to changes in the random effects and drop-out assumptions.

Aerosolization of P2Y(2)-receptor agonists enhances mucociliary clearance in sheep.

The purpose of this study was to determine whether aerosolized INS316 (UTP) stimulates lung mucociliary clearance (MCC) in sheep and, if so, to compare its effects with INS365, a novel P2Y(2)-receptor agonist. In the first series of studies, we used a previously described roentgenographic technique to measure tracheal mucus velocity (TMV), an index of MCC, before and for 4 h after aerosolization of INS316 (10(-1) M and 10(-2) M) and INS365 (10(-1) M and 10(-2) M), or normal saline in a randomized crossover fashion (n = 6). In a second series of studies, we compared the ability of these agents to enhance total lung clearance. For these tests, the clearance of inhaled technetium-labeled human serum albumin was measured serially over a 2-h period after aerosolization of 10(-1) M concentration of each agent (n = 7). Aerosolization of both P2Y(2)-receptor agonists induced significant dose-related increases in TMV (P < 0.05) compared with saline. The greatest increase in TMV was observed between 15 and 30 min after drug treatment. The highest dose (10(-1) M) of INS316 produced a greater overall stimulation of TMV than did INS365 (10(-1) M). Both compounds, compared with saline, induced a significant increase in MCC (P < 0.05) within 20 min of treatment. This enhancement in MCC began to plateau at 60 min. Although the response to INS316 started earlier, there was no significant difference between the clearance curves for the two compounds. We conclude that inhaled P2Y(2)-receptor agonists can increase lung MCC in sheep and that for P2Y(2)-receptor stimulation TMV accurately reflects changes in whole lung MCC.

Chemical composition of seeds and oil of Xylopia aethiopica grown in Nigeria.

The chemical composition and mineral constituents of Xylopia aethiopica, which is valued as a spice in Nigeria, were determined along with the physicochemical characteristics of the seed oil. The seeds had the following chemical compositions moisture (8.43 g/100 g), ash (5.89 g/100 g), crude lipid (9.58 g/100 g), crude protein (12.45 g/100 g) crude fiber (8.66 g/100 g) and carbohydrate (63.65 g/100 g). Calcium and potassium were the major minerals in the seed. The extracted lipid was examined for fatty acid composition. Linoleic (45.1 g/100 g) and oleic (26.5 g/100 g) acids were the predominant unsaturated fatty acids, while palmitic acid (18.0 g/100 g) was the major saturated acid. The iodine value of 97 g/100 g indicates that the seed oil is a non-drying type.

The relationship of biochemical markers of bone turnover to bone density changes in postmenopausal women: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial.

We assessed the associations of eight bone turnover markers (BTMs) with baseline and 1-year percentage changes in lumbar spine and hip bone mineral density (BMD) of 293 postmenopausal women undergoing treatment with hormone replacement therapy (HRT) or placebo using squared correlation coefficients (R2). In 239 women assigned to treatment with estrogen alone or with with estrogen plus progestins (active treatment), mean percentage changes for all markers decreased significantly and remained below baseline values through 3 years of study, whereas mean percentage changes for 54 women assigned to the placebo group showed no significant change from baseline in any marker. At baseline, age and body mass index (BMI) together accounted for 16% and 25% of the variance in spine and hip BMD, respectively. The telopeptide resorption marker, cross-linked N-telopeptide of type I collagen (NTX), alone accounted for 12% and 8% of variance, respectively. Another telopeptide, carboxy-terminal telopeptide of type I collagen (Crosslaps), accounted for 8% and 7% of variance, respectively. A bone-specific alkaline phosphatase (BALP-2) accounted for 8% of variance at the spine and 5% at the hip. No other marker accounted for more than 5% of total variance at either site; adding either baseline NTX, Crosslaps, or BAP-2 to regressions containing age and BMI increased R2 values at the spine and hip to about 22% and 28%, respectively. In the placebo group, baseline spine BMD accounted for 4% of the variance in 1-year spine BMD percentage change, whereas baseline values for age and BMI accounted for 1% and 0% of the variance, respectively; none of the three accounted for more than 0% of hip BMD percentage change; Crosslaps and NTX contributed 5% and 4% to the variance in 1-year spine BMD percentage change, but other markers accounted for < 2% of variance at the spine. At the hip, another BALP (BALP-1) accounted for 4% of variance, but no other baseline marker except NTX accounted for more than 1% of variance. In the active treatment group, baseline values for age, BMI, and spine BMD together accounted for 13% of the percentage change in spine BMD and for 4% of the BMD change at the hip. No individual or pair of baseline markers significantly enhanced these R2 values, but addition of 1-year percentage changes in some individual markers did significantly increase it. The largest R2 value was obtained by adding the percentage change in BALP-2, which increased the R2 in spine BMD percentage change to 20% and that at the hip to 8%. Adding baseline and change variables for all eight markers to the regression increased R2 to 28% at the spine and 12% at the hip. Restricting the set of analyses to individuals who suppressed marker activity beyond the precision error for the measurement did not improve R2s for the regressions. When baseline marker values were stratified into quartiles, only NTX and osteocalcin showed significant relationships between quartile and change in spine BMD, and these did not reach significance at the hip. When the 1-year change in markers was stratified into quartiles, significant relationships with percentage change in spine BMD were observed only for BALP phosphatases. We conclude that BTMs are not a surrogate for BMD to identify women with low bone mass and that they offer little useful information for predicting BMD changes for individual untreated or HRT-treated postmenopausal women.

Validation of the PASE in older adults with knee pain and physical disability.

PURPOSE: To examine the validity of the Physical Activity Scale for the Elderly (PASE) among individuals with disability. METHODS: A sample of 471 participants (mean age = 71.36) in an epidemiological study of chronic knee pain completed the PASE and self-report measures of knee pain, perceived physical function, satisfaction with physical function, and importance of physical function. A 6-min walk test and an isokinetic assessment of knee strength were also administered. RESULTS: PASE scores were significantly correlated in expected directions with performance on the 6-min walk, knee strength, frequency of knee pain during transfer, and perceived difficulty with physical functioning. Gender and age were identified as significant moderators of PASE scores and the scale's construct validity was supported by testing a conceptually driven hypothesis regarding patterns of physical activity. CONCLUSIONS: These results support the PASE's validity for the assessment of physical activity among older adults with pain and disability.

Functional status, assistance, and the risk of a community-based move.

This study examined the effects of declining functional status and the availability of assistance on community-based residential mobility. Wolinsky and colleagues (1993), using data from the 1984, 1986, and 1988 waves of the Longitudinal Study on Aging, reported other transitions that result from increased health demand, namely those of nursing home placement and death. Using their functional health scales and recently available statistical techniques, we performed a two-stage analysis within a health behavior conceptual framework. We conclude that older adults who report several cognitive limitations in the absence of assistance in the home are more likely to make residential changes. Additionally, we determined that the independent effects of cognitive and lower body deterioration trigger, in this case, community-based moves even when adjusting for the effect of baseline levels of functional health and other factors in the model. Our analysis extends the earlier findings of Wolinsky and colleagues to encompass residential change as an ecological outcome of health decline in old age.

The Kidney Outcomes Prediction and Evaluation (KOPE) study: a prospective cohort investigation of patients undergoing hemodialysis. Study design and baseline characteristics.

PURPOSE: The purpose of the Kidney Outcomes Prediction and Evaluation (KOPE) study, was to more fully characterize the end-stage renal disease (ESRD) population with respect to social, psychological, and clinical characteristics, and to prospectively study the biomedical, social, and psychological factors that influence a range of ESRD outcomes in a large observational study of black and white patients on hemodialysis. This paper focuses on the KOPE study design as well as characteristics of patients at baseline. METHODS: KOPE was a prospective cohort investigation of patients treated at four dialysis centers in Forsyth County, North Carolina. Participants were interviewed at the dialysis centers, semi-annually over a 3 1/2 year period. Prevalent cases who were being treated with hemodialysis at the initiation of the study were enrolled into KOPE. Incident cases were subsequently enrolled as they presented to the participating units for hemodialysis. A total of 304 prevalent and 162 incident cases were enrolled into the study. The baseline health and sociodemographic characteristics of KOPE participants reported in this paper were obtained from medical records and Southeast Kidney Council data. Laboratory values taken within a 30-day interval around the baseline interview are also reported. RESULTS: KOPE participants differ from national statistics on race, age, and gender. Differences between KOPE participants and patients living in the region, but who did not participate in the study, can be explained by our recruitment criteria. CONCLUSIONS: KOPE will enable the characterization of the ESRD population, identification of factors related to poor outcomes, and identification of opportunities for interventions to prevent death and morbidity.

The timing of change: patterns in transitions in functional status among elderly persons.

Data from the Longitudinal Study on Aging (LSOA) were analyzed to describe the heterogeneity of functional status transitions over 2-years (single-state model), and to explore whether changes in status in the previous two to four year period enhance the prediction of a subsequent transition (two-state model). Multivariate logistic regression with a robust estimate of variance was used to analyze a 7-category nominal response of: functional status (4 levels), institutionalization, death, and missing. Weighted percentages for functional status transitions and stability (unchanged status) showed that unchanged or improved functioning were at least as common as death or worsened functional status. Initial disability level, morbidities, and self-rated health were the strongest predictors of disability status after 2-years. The two-state model revealed that a previous transition (positive or negative) increases the risk for a subsequent transition, independent of initial disability level. The predictive and explanatory quality of the two-state model is substantially improved over single-state models, particularly from its ability to identify subgroups of individuals with marked functional status instability.

Can we measure prior postmenopausal estrogen/progestin use? The Postmenopausal Estrogen/Progestin Interventions Trial. The PEPI Investigators.

The objective of this study was to assess: 1) the accuracy of a single self-report question about postmenopausal estrogen use; and 2) the performance and repeated measures agreement of a standardized hormone use interview. Women (n = 863) in the Postmenopausal Estrogen/Progestin Interventions Trial (PEPI) completed a self-report baseline questionnaire (BQ) at enrollment and a History of Hormone Use interview (HHU) at the 3-month follow-up visit (HHU3mos). A subsample of 101 women completed a second HHU interview 3 years later (HHU3yrs). As determined by the HHU3mos, 479 (56%) of women had ever used postmenopausal estrogen and 261 (30%) had ever used postmenopausal progestin. The mean number of years since last estrogen or progestin use was 2.2 and 1.3 years, respectively. Overall, there was 95% agreement between self-reported estrogen use on the BQ and the HHU3mos (kappa = 0.91). Using the HHU3mos as the criterion standard, the BQ misclassified 2.3% of women as false positives and 6.3% as false negatives. The average duration of estrogen use in the false-negative classifications was 1.9 years (range: 1-9 years). On the HHU3mos, 39.7% of participants could not recall at least one of the specific details of estrogen use (preparation, dose, route, or starting or stopping year); similar patterns of recall were found for progestin use. Factors associated with discordant reporting of ever-use of ERT (BQ vs. HHU3mos) or incomplete reporting of estrogen/progestin use on the HHU3mos were: route of administration, recency of hormone use, duration of hormone use, and race. Age, years since menopause, education, income, and hysterectomy status were not related to discordant and/or incomplete reporting. Agreement between the HHU3mos and HHU3yrs for ever-use of estrogen was 85.2% (kappa = 0.71). In sum, a single self-report question was adequate to ascertain ever-use of postmenopausal estrogen. When a structured interview form was used, details of postmenopausal estrogen and progestin use were not well remembered. Some features of hormone use and participant characteristics were associated with completeness of recalled hormone use, which suggests the potential for differential misclassification.

Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR.

Selective inhibition of type 2 5alpha-reductase has been shown to be efficacious in the treatment of benign prostatic hyperplasia. Pharmacokinetic and pharmacodynamic results are reported of treatment with a potent inhibitor of both 5alpha-reductase isozymes, GG745, in rats, dogs and men. In the rat, GG745 has a similar effect on DHT-driven prostatic growth as finasteride, another dual 5alpha-reductase inhibitor in this species. However, GG745 appears to be more potent in the rat, a result that likely reflects the greater inherent potency and terminal half-life of GG745 (14 hr) compared with that of finasteride (1 hr). These pharmacokinetic differences are also maintained in the dog (65 and 4 hr for GG745 and finasteride, respectively). From these results, the literature, and in vitro studies, we estimated doses of GG745 likely to prove efficacious in reducing DHT levels in man. These estimated values were predictive of single-dose effects of GG745 in man. Results from single-dose evaluations in man indicate that GG745 has a terminal half-life of approximately 240 hr, and single doses of >10 mg decreased DHT levels significantly more than did single 5-mg doses of finasteride. These data support the hypothesis that a molecule (GG745) that effectively inhibits both 5alpha-reductases will lower serum DHT levels significantly more than a molecule that inhibits only a single 5alpha-reductase isozyme (e.g., finasteride, a selective inhibitor of the type 2 enzyme in man).

Optimization of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepines as potent, orally active CCK-A agonists.

We previously described a series of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepine CCK-A agonists exemplified by compound 1 (GW 5823), which is the first reported binding selective CCK-A full agonist demonstrating oral efficacy in a rat feeding model. In this report we describe analogs of compound 1 designed to explore changes to the C3 and N1 pharmacophores and their effect on agonist activity and receptor selectivity. Agonist efficacy in this series was affected by stereoelectronic factors within the C3 moiety. Binding affinity for the CCK-A vs CCK-B receptor showed little dependence on the structure of the C3 moiety but was affected by the nature of the second substituent at C3. Structure-activity relationships at the N1-anilidoacetamide "trigger" moiety within the C3 indazole series were also investigated. Both agonist efficacy and binding affinity within this series were modulated by variation of substituents on the N1-anilidoacetamide moiety. Evaluation of several analogs in an vivo mouse gallbladder emptying assay revealed compound 1 to be the most potent and efficacious of all the analogs tested. The pharmacokinetic and pharmacodynamic profile of 1 in rats is also discussed.

Benefits of linkage to the National Death Index in the Longitudinal Study of Aging.

To reduce the potential bias resulting from differential loss to follow-up in the Longitudinal Study of Aging (LSOA), information obtained from household contact methods was supplemented with information from the National Death Index (NDI). This article examines the degree of agreement in the vital status data from two sources (reinterview contacts and the NDI system) and evaluates the potential gains of using the NDI data as a supplement to define participants' vital status. Results reveal that NDI information, used to supplement reinterview information, can substantially reduce bias due to the differential loss of participants to follow-up. Reliance on reinterview information alone was less likely to capture those deaths occurring in study participants who at the initial contact lived alone, were below the poverty index, were interviewed without use of a proxy, did not supply a phone number, and did not own a home.