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.

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.

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.

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.

Effect of postmenopausal hormone therapy on body weight and waist and hip girths. Postmenopausal Estrogen-Progestin Interventions Study Investigators.

Reports from cross-sectional comparisons, nonrandomized prospective studies, and relatively small clinical trials indicate that postmenopausal hormone therapy may slightly decrease the amount of weight typically gained by women during the decade following menopause. Despite this, widespread belief remains that hormone therapy may cause weight gain. We use data from the Postmenopausal Estrogen/Progestin Interventions trial to characterize the impact of postmenopausal hormone therapy on weight and fat distribution and to examine the consistency of this impact among subgroups of women defined by lifestyle, clinical, and demographic factors. The Postmenopausal Estrogen/Progestin Interventions trial was a 3-yr, placebo-controlled, randomized clinical trial of 875 women assessing the effects on cardiovascular risk factors of four hormone regimens: oral conjugated equine estrogen (CEE) therapy (0.625 mg daily alone), CEE in combination with medroxyprogesterone acetate (2.5 mg daily), CEE in combination with medroxyprogesterone acetate (10 mg daily on days 1-12), and CEE in combination with micronized progesterone (200 mg daily on days 1-12). Women randomly assigned to CEE with or without a progestational agent averaged 1.0 kg less weight gain at the end of 3 yr (P = 0.006) than those assigned to placebo. Assignment to CEE was also associated with averages of 1.2 cm less increase in waist girth (P = 0.01) and 0.3 cm less increase in hip (P = 0.07) girth. In regression models that included weight change as a covariate, none of these differences reached statistical significance. There were no significant differences in weight or girth changes among any of the four active hormone regimens. After accounting for the effects of assignment to active hormone therapy and baseline weight, older age (P 0.008) and higher physical activity level at baseline (P = 0.002) were also independently predictive of less weight gain. The impact of hormone therapy on weight gain was similar among subgroups, except for those defined by baseline smoking status (P = 0.04) and physical activity level at home (P = 0.02). Factors that were independently associated with smaller increases in girths were: for waist, greater overall activity (P = 0.005) and Hispanic ethnicity (P = 0.02); and for hip, work activity (P = 0.003) and greater alcohol consumption (P = 0.03). None of these factors significantly affected the observed overall relationships between estrogen and changes in girth.

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.

Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.

In an effort to discover a potent ultrashort-acting mu opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoi c acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

Modification of receptor selectivity and functional activity in cholecystokinin peptoid ligands.

Hybrid analogs of the cholecystokinin A (CCK-A) receptor selective tetrapeptide agonist Boc-Trp-Lys(Tac)-Asp-MePhe-NH2 (1,A-71623) and the CCK-B receptor selective antagonists PD-135118 (2) and CI-988 (3) were prepared. Incorporation of the Lys(Tac) side chain into 2 produced a moderately potent antagonist of CCK-8 in the isolated guinea pig gallbladder (GPGB). Incorporation of the Lys(Tac) side chain into 3 produced the novel agonist analog 7 (EC50 = 28 nM in the GPGB) with excellent affinity for both human CCK-A (IC50 = 12 nM) and CCK-B (IC50 = 17 nM) receptors. Analog 7 was a full agonist (EC50 = 3.5 nM) for calcium mobilization on CHO-K1 cells expressing hCCK-A receptors but a partial agonist on CHO-K1 cells expressing hCCK-B receptors, eliciting a weak agonist response (EC50 = 2800 nM) and antagonizing CCK-8-induced calcium mobilization (KB = 20 nM). Despite this unusual in vitro profile, analog 7 was a potent anorectic agent in rats (ED50 = 30 nmol/kg) following intraperitoneal administration.

Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity (II): Optimization of the C3 amino substituent.

Analogs of the previously reported 1,5-benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonist 1 were prepared which explore substitution and/or replacement of the C-3 phenyl urea moiety. Agonist efficacy on the isolated guinea pig gallbladder (GPGB) was retained with a variety of substituted ureas and amide analogs. Three compounds were identified which were orally active in the mouse gallbladder emptying assay (MGBE). The 2-indolamide (52) and N-(carboxymethyl)-2-indolamide (54) derivatives had improved affinity for the human CCK-A receptor but reduced agonist efficacy on the GPGB. Neither indolamide was orally active in a rat feeding assay. In contrast, the (3-carboxyphenyl)urea derivative (29, GW7854) had moderately increased affinity for the human CCK-B receptor but was a potent full agonist on the GPGB and was orally active in both the MGBE and rat feeding assays. GW7854 was a full agonist (EC50 = 60 nM) for calcium mobilization on CHO K1 cells expressing hCCK-A receptors and a potent antagonist of CCK-8 (pA2 = 9.1) on CHO K1 cells expressing hCCK-B receptors. GW7854 is a potent mixed CCK-A agonist/CCK-B antagonist which is orally active in two in vivo models of CCK-A-mediated agonist activity.

3-[2-(N-phenylacetamide)]-1,5-benzodiazepines: orally active, binding selective CCK-A agonists.

A series of modifications were made to the C-3 substituent of the 1,5-benzodiazepine CCK-A agonist 1. Replacement of the inner urea NH and addition of a methyl group to generate a C-3 quaternary carbon resulted in acetamide 6, which showed CCK-A receptor binding selectivity and sub-micromolar agonist activity in vitro. Benzodiazepine 6 was active in an in vivo mouse gallbladder emptying assay and represents a novel orally active, binding selective CCK-A agonist.

Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity. 1. Optimization of the agonist "trigger".

Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.

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.

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.

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.

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.

Etiology of iliotibial band friction syndrome in distance runners.

The objectives of our study were: 1) to examine differences between a noninjured cohort of runners (N = 70) and runners afflicted with iliotibial band friction syndrome (ITBFS) (N = 56) according to selected anthropometric, biomechanical, muscular strength, and training measures; 2) to explore multivariate relationships among these measures in both the well and injured groups; and 3) to develop specific hypotheses concerning risk factors for injury that will later be tested in a prospective observational study. High speed videography (200 fps), a force platform (500 Hz), and a Cybex II+ isokinetic dynamometer were used to assess rearfoot motion, ground reaction forces, and knee muscular strength and endurance, respectively. A linear discriminant function analysis of the training data revealed weekly mileage, training pace, number of months using current training protocol, % time spent swimming, and % time spent running on a track to be significant (P < 0.10). Height was a significant anthropometric discriminator, while seven isokinetic strength and endurance measures were found to discriminate significantly between the groups. Calcaneal to vertical touchdown angle, and maximum supination velocity were significant rearfoot movement discriminators. Maximum braking force was the only significant kinetic discriminator. A combined discriminant analysis using those variables found to be significant in the previous analyses revealed weekly mileage, and maximum normalized braking force to be the best discriminators (model P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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 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.

Exit-site care--is it time for a change?

Peritoneal catheter exit-site infections (ESI's) continue to impact significantly on morbidity and catheter longevity. The controversy concerning protocols for daily exit-site care continues for frequency, methodology, cleansing agent, and dressing. Routine daily exit-site care prior to January 1991 consisted of daily showers using liquid soap, povidone scrub, rinsing the shower, and drying with a 4 x 4-in. gauze pad. Catheters have always been immobilized, either with tape or an immobilizing device. Hydrogen peroxide was used only when needed to soften crust formation prior to showering. A light dressing, usually 2 x 2 in., was optional. A recent survey revealed that povidone iodine was the antiseptic of choice for catheter care in 75% of the respondents. However, povidone iodine irritates and dries the skin predisposing it to infection. ESI's are prospectively monitored as part of our quality improvement (QI) program. An incidence of 0.76 episodes/patient-year was noted between January 1989 and May 1991. Given the relative high frequency of ESI's, the protocol was modified and introduced during the January-May 1991 time frame. Routine care now consists of daily showers using only CC-500, a gentle antibacterial cleaner (Care-Tech Laboratories, Inc.), rinsing in the shower, and drying with a 4 x 4-in. gauze. Use of hydrogen peroxide and dressings has remained the same. Additionally, a protocol addressing the prophylaxis for traumatized exist sites was initiated. The incidence of ESI's has dropped significantly to 0.12 episodes/patient-year. Although our population size is small (n = 18), this study does point out the utility of prospectively monitoring trends for appropriate indicators within a QI program.(ABSTRACT TRUNCATED AT 250 WORDS)