Search

Effective management of neurogenic orthostatic hypotension and supine hypertension (SH-OH) due autonomic failure requires a frequent and timely adjustment of medication throughout the day to maintain the blood pressure (BP) within the normal range, i.e., an accurate depiction of BP is a key prerequisite of effective management. One of the emerging technologies that provide one's circadian and long-term physiological status with increased usability is unobtrusive zero-effort monitoring. In this paper, a zero-effort device, a floor tile, was used to develop an unobtrusive BP monitoring technique. Namely, RJ-interval, the time between the J-peak of a ballistocardiogram and the R-peak of an electrocardiogram, was used to develop a classifier that can detect changes in systolic BP (SBP) induced by the Valsalva maneuver on healthy adults (i.e., a simulated SH-OH). A t-test was used to show statistical differences between the mean RJ-intervals of decreased SBP, baseline, and increased SBP. Following the t-test, a classifier that detected a change in SBP was developed based on a naïve Bayes classifier (NBC). The t-test showed a clear statistical difference between the mean RJ-intervals of the increased SBP, baseline, and decreased SBP. The NBC-based classifier was able to detect increased SBP with 89.3% true positive rate (TPR), 100% true negative rate (TNR), and 94% accuracy and detect decreased SBP with 92.3% TPR, 100% TNR, and 95% accuracy. The analysis showed strong potential in using the developed classifier to assist monitoring of people with SH-OH; the algorithm may be used clinically to detect a long-term trend of symptoms of SH-OH.

Background: The simultaneous increase in geographically dispersed families and general decrease in engagement in local communities is resulting in fewer opportunities for youth and older adults interact in meaningful ways. Technology is becoming increasingly pervasive and flexible and providing new opportunities to foster intergenerational connection that can be implemented and evaluated across a multitude of populations and contexts. What research has been done in this area is spread across disciplines and what aspects of technologies could make them more effective is not well understood., Method: The scoping review will be completed in five stages: (1) identifying the research question, (2) identifying relevant studies, (3) selecting studies, (4) charting the data, and (5) collating, summarizing, and reporting the results. Comprehensive descriptive data from each study will be presented along with an analysis of similarities and differences in research from different disciplines., Discussion: This scoping review focuses on a search of the literature to gain an understanding of what technologies have been used specifically for fostering intergenerational connectivity and to establish what future directions for research could be. To the authors' knowledge, it is the first scoping review of its kind.

Introduction: Pain can affect people regardless of age, gender or ethnicity. Chronic central neuropathic pain (CCNP) is a debilitating condition that affects populations such as stroke survivors, amputees, spinal cord injury patients and patients with multiple sclerosis, with prevalence rates between 30% and 80%. This condition can be caused by a lesion or disease affecting the somatosensory system. CCNP is notoriously drug resistant, and few effective CCNP treatment or management strategies exist. The emergence of non-invasive brain stimulation and neuromodulation techniques provide novel avenues for managing chronic central neuropathic pain. This scoping review aims to systematically identify the methods and effectiveness of non-invasive brain stimulation techniques for treating and managing chronic central neuropathic pain., Methods and Analysis: The following databases will be searched systematically: PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Institute of Electric and Electronic Engineers (IEEE), Association of Computing Machinary (ACM) and Scopus. Additional literature will be identified by searching the reference lists of identified studies. Studies will include reviews and original research in both published and grey literatures. Two reviewers will independently screen identified studies for final inclusion. A quantitative analysis on the intervention type, application and efficacy will be synthesised along with a qualitative analysis to describe the effectiveness of each intervention., Ethics and Dissemination: No primary data will be collected and hence formal ethics review is not required. The results of the scoping review will be presented at relevant national and international conferences, published in a peer-reviewed journal and provided to the stakeholders with plain language to be posted on their websites. This scoping review will provide a foundation to guide the development of future primary research on non-invasive brain stimulation and CCNP., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Although BCI technology has vastly improved in the last few years, very little research has been done into how different types of cues may affect the resulting signal. We have conducted preliminary work to examine the effects of using auditory versus visual cues on MRCP signal detection. While our sample size was small (n=5), the data for auditory and visual cues were not statistically different for young, healthy participants, suggesting that they are comparable for the parameters analyzed. Our results indicated that audio and visual cues likely produce similar MRCP signals, which is useful information for designing non-invasive BCIs. Future work includes expanding the sample size and conducting work with special needs populations, such as children with Autism Spectrum Disorder (ASD), who are known to have strong preferences for different interfaces.

Background: Technological advances are leading to the ability to autonomously monitor patient's health status in their own homes, to enable aging-in-place., Objectives: To understand the perceptions of seniors with heart failure (HF) regarding smart-home systems to monitor their physiological parameters., Methods: In this qualitative study, HF outpatients were invited to a smart-home lab, where they completed a sequence of activities, during which the capacity of 5 autonomous sensing modalities was compared to gold standard measures. Afterwards, a semi-structured interview was undertaken. These were transcribed and analyzed using an interpretive-descriptive approach., Results: Five themes emerged from the 26 interviews: (1) perceptions of technology, (2) perceived benefits of autonomous health monitoring, (3) disadvantages of autonomous monitoring, (4) lack of perceived need for continuous health monitoring, and (5) preferences for autonomous monitoring., Conclusions: Patient perception towards autonomous monitoring devices was positive, lending credence to zero-effort technology as a viable and promising approach., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Developing useful and usable assistive technologies often presents complex (or "wicked") challenges that require input from multiple disciplines and sectors. Transdisciplinary collaboration can enable holistic understanding of challenges that may lead to innovative, impactful and transformative solutions. This paper presents generalised principles that are intended to foster transdisciplinary assistive technology development. The paper introduces the area of assistive technology design before discussing general aspects of transdisciplinary collaboration followed by an overview of relevant concepts, including approaches, methodologies and frameworks for conducting and evaluating transdisciplinary working and assistive technology design. The principles for transdisciplinary development of assistive technologies are presented and applied post hoc to the COACH project, an ambient-assisted living technology for guiding completion of activities of daily living by older adults with dementia as an illustrative example. Future work includes the refinement and validation of these principles through their application to real-world transdisciplinary assistive technology projects. Implications for rehabilitation Transdisciplinarity encourages a focus on real world 'wicked' problems. A transdisciplinary approach involves transcending disciplinary boundaries and collaborating with interprofessional and community partners (including the technology's intended users) on a shared problem. Transdisciplinarity fosters new ways of thinking about and doing research, development, and implementation, expanding the scope, applicability, and commercial viability of assistive technologies.

The changes in cognitive abilities that accompany dementia can make it difficult to use everyday products that are required to complete activities of daily living. Products that are inherently more usable for people with dementia could facilitate independent activity completion, thus reducing the need for caregiver assistance. The objectives of this research were to: (1) gain an understanding of how water tap design impacted tap usability and (2) create an automated computerized tool that could assess tap usability. 27 older adults, who ranged from cognitively intact to advanced dementia, completed 1309 trials on five tap designs. Data were manually analyzed to investigate tap usability as well as used to develop an automated usability analysis tool. Researchers collaborated to modify existing techniques and to create novel ones to accomplish both goals. This paper presents lessons learned through the course of this research, which could be applicable in the development of other usability studies, automated vision-based assessments and the development of assistive technologies for cognitively impaired older adults. Collaborative interdisciplinary teamwork, which included older adult with dementia participants, was key to enabling innovative advances that achieved the projects' research goals. Implications for Rehabilitation Products that are implicitly familiar and usable by older adults could foster independent activity completion, potentially reducing reliance on a caregiver. The computer-based automated tool can significantly reduce the time and effort required to perform product usability analysis, making this type of analysis more feasible. Interdisciplinary collaboration can result in a more holistic understanding of assistive technology research challenges and enable innovative solutions.

Purpose: Assistive technologies (ATs) have tremendous potential to support occupations (i.e. meaningful daily activities) impacted by changes in cognition caused by dementia. However, little is known about what or how ATs are in use in community settings. This research created and piloted guided interviews intended to capture what ATs are in use, factors that affect use and gaps in support from multiple stakeholders., Method: Family caregivers (n = 3) and occupational therapists (n = 10) were chosen as pilot respondents because of their relationship to care provision, understanding of how occupations are impacted by changes in cognition and role in AT procurement. Data were analyzed using descriptive statistics., Results: The interviews' structures enabled data to be grouped into distinct categories and organized easily. The data illustrated the types of analysis that could be done given a larger sample size. It appeared that interviews captured ATs that were in use, as well as areas of non-use and perceived difficulties. Respondents identified several unmet needs and provided suggestions for desired outcomes., Conclusions: While the interview guides must be refined and validated, they are able to capture rich and comprehensive data that could be used by multiple stakeholders, such as clinicians, engineers and caregiver education groups, to target AT development, procurement, education and policy.

Background: Changes in cognition caused by dementia can significantly alter how a person perceives familiarity, impacting the recognition and usability of everyday products. A person who is unable to use products cannot autonomously complete associated activities, resulting in increased dependence on a caregiver and potential move to assisted living facilities. The research presented in this paper hypothesised that products that are more familiar will result in better usability for older adults with dementia. Better product usability could, in turn, potentially support independence and autonomy., Methods: This research investigated the impact of familiarity on the use of five faucet designs during 1309 handwashing trials by 27 older adults, who ranged from cognitively intact to the advanced (severe) stages of dementia. Human factors methods were used to collect empirical and self-reported data to gauge faucets' usability. Participants' data were grouped according to cognition (i.e., no/mild, moderate, or severe dementia). Logistic regression, ranking by odds, and Wald tests of odds ratios were used to compare performance of the three groups on the different faucets. Qualitative data were used in the interpretation of quantitative results., Results: Results indicated that more familiar faucets correlated with lower levels of assistance from a caregiver, fewer operational errors, and greater levels of operator satisfaction. Aspects such as the ability to control water temperature and flow as well as pleasing aesthetics appeared to positively impact participants' acceptance of a faucet. The dual lever design achieved the best overall usability., Conclusions: While work must be done to expand these findings to other products and tasks, this research provides evidence that familiarity plays a substantial role in product usability for older adults that appears to become more influential as dementia progresses. The methods used in this research could be adapted to analyse usability for other products by older adults with dementia.

Engagement in creative occupations has been shown to promote well-being for older adults with dementia. Providing access to such occupations is often difficult, as successful participation requires face-time with a person who is knowledgeable in facilitating engagement as well as access to any required resources, such as an arts studio. In response, a computer-based device, the Engaging Platform for Art Development (ePAD), was created to with the aim of enabling more independent access to art creation, ePAD is a an artificially intelligent touch-screen device that estimates a client's level of engagement and provides prompts to encourage engagement if the client becomes disengaged. ePAD is customizable such that an art therapist can choose themes and tools that they feel reflect their client's needs and preferences. This article presents a mixed-methods study that evaluated ePAD's usability by six older adult (with mild-to-moderate dementia) and art therapist dyads. Usability measures suggest that all participants found ePAD engaging but did not find prompts effective. Future development of ePAD includes improving the prompts, implementing the recommendations made by participants in this research, and long-term testing in more naturalistic art therapy contexts.

A person's ability to be independent is dependent on his or her overall health, mobility, and ability to complete activities of daily living. Intelligent assistive technologies (IATs) are devices that incorporate context into their decision-making process, which enables them to provide customised and dynamic assistance in an appropriate manner. IATs have tremendous potential to support people with cognitive impairments as they can be used to support many facets of well-being; from augmenting memory and decision making tasks to providing autonomous and early detection of possible changes in health. This paper presents IATs that are currently in development in the research community to support tasks that can be impacted by compromised cognition. While they are not yet ready for the general public, these devices showcase the capabilities of technologies one can expect to see in the consumer marketplace in the near future.

PURPOSE. Timely and adequate rehabilitation after a stroke is crucial to maximising recovery. A way of increasing treatment access could be through robots, which would aid therapists in providing post-stroke rehabilitation. This research sought to discover the needs and preferences of therapists with respect to a robot that focuses on upper limb rehabilitation. Understanding requirements for devices could help to increase integration into clinical practice. METHODS. An international online survey was distributed through professional organisations and e-mail list services to therapists. The survey contained 85 items covering topics such as therapist background and treatment approach, rehabilitation aims and robotic rehabilitation device attributes. RESULTS. Data were analysed for 233 respondents, most of whom were physiotherapists and occupational therapists from Australia, Canada and USA. Top attributes included: facilitating a variety of arm movements, being usable while seated, giving biofeedback to clients, having virtual activities specific to daily living, being useful in-home and having resistance adjustable to client needs. In addition, the device should cost under 6000 USD. CONCLUSIONS. Findings from this survey provide guidance for technology developers regarding therapists' specifications for a robotic device for upper limb rehabilitation. In addition, findings offer a better understanding of how acceptance of such devices may be facilitated.

Background: It has been shown that intense training can significantly improve post-stroke upper-limb functionality. However, opportunities for stroke survivors to practice rehabilitation exercises can be limited because of the finite availability of therapists and equipment. This paper presents a haptic-enabled exercise platform intended to assist therapists and moderate-level stroke survivors perform upper-limb reaching motion therapy. This work extends on existing knowledge by presenting: 1) an anthropometrically-inspired design that maximizes elbow and shoulder range of motions during exercise; 2) an unobtrusive upper body postural sensing system; and 3) a vibratory elbow stimulation device to encourage muscle movement., Methods: A multi-disciplinary team of professionals were involved in identifying the rehabilitation needs of stroke survivors incorporating these into a prototype device. The prototype system consisted of an exercise device, postural sensors, and a elbow stimulation to encourage the reaching movement. Eight experienced physical and occupational therapists participated in a pilot study exploring the usability of the prototype. Each therapist attended two sessions of one hour each to test and evaluate the proposed system. Feedback about the device was obtained through an administered questionnaire and combined with quantitative data., Results: Seven of the nine questions regarding the haptic exercise device scored higher than 3.0 (somewhat good) out of 4.0 (good). The postural sensors detected 93 of 96 (97%) therapist-simulated abnormal postures and correctly ignored 90 of 96 (94%) of normal postures. The elbow stimulation device had a score lower than 2.5 (neutral) for all aspects that were surveyed, however the therapists felt the rehabilitation system was sufficient for use without the elbow stimulation device., Conclusion: All eight therapists felt the exercise platform could be a good tool to use in upper-limb rehabilitation as the prototype was considered to be generally well designed and capable of delivering reaching task therapy. The next stage of this project is to proceed to clinical trials with stroke patients.

This pilot study investigated the willingness of two generational cohorts (current baby boomers and older adults) to accept home monitoring technology. Thirty individuals (15 baby boomers and 15 older adults) of both genders and living in the community participated in structured, mixed methods interviews. The participants' opinions and views on various technologies (e.g., personal emergency response systems, fall detection systems) and sensor types (e.g., switches, motion sensors, computer vision) were determined, including locations within the home where they would be willing to install and use such technologies. Overall, it was found that these technologies would be acceptable if they allowed the participants to remain in their own homes and to age in place. Furthermore, a between-group analysis indicated that there were not many statistically significant differences between the opinions of the two cohorts with respect to preferences about types and locations of these technologies.

Older adults with cognitive impairments are generally prohibited from using powered wheelchairs, because of the high risk of collisions with people and objects. This paper describes and presents the preliminary results of a system that uses an infrared sensor to provide anticollision and a prompting system for a powered wheelchair that helps guide the user safely past obstacles. Trials with the prototyped system detected collisions and stopped the chair in 95% of trials with an object and generated no false alarms.

The aim of this study was to investigate the transfer of celecoxib into human milk. In one group of 3 breastfeeding patients on celecoxib at steady state, milk levels were determined at set intervals over 24 hours. Plasma levels were determined in 2 of their infants, age 17 and 22 months. In a second group of 2 subjects, intravenous lines were placed and a single 200-mg dose of celecoxib was followed by multiple paired plasma and milk samples over 8 hours. The mean milk-to-plasma ratio for celecoxib was 0.23 (95% confidence interval [CI]: 0.15-0.31). The average concentration of celecoxib in milk during the 8-hour dosing interval was 66 microg/L (95% CI: 41-89). The absolute infant dose averaged 9.8 microg/kg/d (95% CI: 6.2-13.4); the mean relative infant dose was 0.30%. Therefore, the average clinical dose transferred to the infant daily would be approximately 0.3% of the weight-adjusted maternal dose. The authors suggest that the use of celecoxib in breastfeeding mothers at these doses is very unlikely to cause untoward effects in breastfed infants.

The Sudbury Neutrino Observatory has precisely determined the total active (nu(x)) 8B solar neutrino flux without assumptions about the energy dependence of the nu(e) survival probability. The measurements were made with dissolved NaCl in heavy water to enhance the sensitivity and signature for neutral-current interactions. The flux is found to be 5.21 +/- 0.27(stat)+/-0.38(syst) x 10(6) cm(-2) s(-1), in agreement with previous measurements and standard solar models. A global analysis of these and other solar and reactor neutrino results yields Deltam(2)=7.1(+1.2)(-0.6) x 10(-5) eV(2) and theta=32.5(+2.4)(-2.3) degrees. Maximal mixing is rejected at the equivalent of 5.4 standard deviations.

Solar neutrinos from (8)B decay have been detected at the Sudbury Neutrino Observatory via the charged current (CC) reaction on deuterium and the elastic scattering (ES) of electrons. The flux of nu(e)'s is measured by the CC reaction rate to be straight phi(CC)(nu(e)) = 1.75 +/- 0.07(stat)(+0.12)(-0.11)(syst) +/- 0.05(theor) x 10(6) cm(-2) s(-1). Comparison of straight phi(CC)(nu(e)) to the Super-Kamiokande Collaboration's precision value of the flux inferred from the ES reaction yields a 3.3 sigma difference, assuming the systematic uncertainties are normally distributed, providing evidence of an active non- nu(e) component in the solar flux. The total flux of active 8B neutrinos is determined to be 5.44+/-0.99 x 10(6) cm(-2) s(-1).

An optical heterodyne array imaging system is described for double-exposure interferometric measurement of objects that change because of stress or vibration. The signal measurement and processing approach is summarized, and the method is demonstrated in the laboratory. An advantage of this technique over other electronic interferometric imaging methods is that complex exposures are created with digital phase and amplitude values at each image pixel. In addition, measurement of object deformation does not require time synchronization between the camera exposure time, or laser pulse time, and object vibration frequency.

The Air Force Phillips Laboratory is in the process of demonstrating an advanced space surveillance capability with a heterodyne laser radar (ladar) system. Notable features of this ladar system include its narrow micropulses (<1.5 ns) contained in a pulse-burst wave form that allows high-resolution range data to be obtained and its high power (30 J/pulse burst) that permits reasonable signal returns from satellites. Recently, time-resolved image-domain signal-to-noise ratios have been derived for both the intensity projections calculated from the range-resolved reflective data and image information obtained with linear combinations of the projections. In this paper the signal-to-noise expression for intensity projections is validated by laboratory data.

Advanced heart failure (AHF) is a serious cause of mortality and morbidity in the United States. The treatment of AHF exacts a great financial and manpower toll on the healthcare infrastructure. The quality of life of patients with AHF also is reduced severely. When it is infused at home, Milrinone, which is an intravenous inodilator agent, reduces the number of hospitalizations. Milrinone decreases the overall treatment costs of AHF. Highly skilled home nursing care is required in the treatment of patients. The home care nurse plays a major role in the outcome of a patient with AHF.

VX-710 or (S)-N[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-piperidine-2-carboxylic acid 1,7-bis(3-pyridyl)-4-heptyl ester, a novel non-macrocyclic ligand of the FK506-binding protein FKBP12, was evaluated for its ability to reverse P-glycoprotein-mediated multidrug resistance in vitro. VX-710 at 0.5-5 microM restored sensitivity of a variety of multidrug resistant cells to the cytotoxic action of doxorubicin, vincristine, etoposide or paclitaxel, including drug-selected human myeloma and epithelial carcinoma cells, and human MDR1 cDNA-transfected mouse leukemia and fibroblast cells. Uptake experiments showed that VX-710 at 0.5-2.5 microM fully restored intracellular accumulation of [14C]doxorubicin in multidrug resistant cells, suggesting that VX-710 inhibits the drug efflux activity of P-glycoprotein. VX-710 effectively inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine or [125I]iodoaryl azidoprazosin with EC50 values of 0.75 and 0.55 microM. Moreover, P-glycoprotein was specifically labeled by a tritiated photoaffinity analog of VX-710 and unlabeled VX-710 inhibited analog binding with an EC50 of 0.75 microM. VX-710 also stimulated the vanadate-inhibitable P-glycoprotein ATPase activity 2- to 3-fold in a concentration-dependent manner with an apparent k(a) of 0.1 microM. These data indicate that a direct, high-affinity interaction of VX-710 with P-glycoprotein prevents efflux of cytotoxic drugs by the MDR1 gene product in multidrug resistant tumor cells.

The three-dimensional structures of the complexes of the aspartic proteinase from Rhizopus chinensis (Rhizopuspepsin, EC 3.4.23.6) with pepstatin and two pepstatin-like peptide inhibitors of renin have been determined by X-ray diffraction methods and refined by restrained least-squares procedures. The inhibitors adopt an extended conformation and lie in the deep groove located between the two domains of the enzyme. Inhibitor binding is accompanied by a conformational change at the "flap," a beta-hairpin loop region, that projects over the binding cleft and closes down over the inhibitor, excluding water molecules from the vicinity of the scissile bond. The hydroxyl group of the central statyl residue of the inhibitors replaces the water molecule found between the two active aspartates, Asp-35 and Asp-218, in the native structure. The refined structures provide additional data to define the specific subsites of the enzyme and also show a system of hydrogen bonding to the inhibitor backbone similar to that observed for a reduced inhibitor.

The hemoglobin and a hemoglobin binding protein have been characterized in the Arctic fish (Coregonus sardinella). The evolutionary significance of the hemoglobin and plasma protein differences between fish and mammals is still unresolved. Blood samples from the Alaskan Least Cisco were separated into plasma and hemoglobin fractions and the proteins in these fractions were analyzed both by alkaline agarose gel electrophoresis, by isolelectric focusing, and by capillary electrophoresis. Staining the plasma proteins gels with o-dianisidine revealed hemoglobin containing protein complexes. A hemoglobin-containing band was observed in hemolyzed plasma which did not migrate with free hemoglobin, and is believed to be hemoglobin-haptoglobin complex. Size exclusion chromatography further characterized the hemoglobin as disassociating freely into dimers, and hemoglobin-haptoglobin complex having a molecular weight greater then 200,000 daltons.

We have designed a low-cost, compact, head-only exposure system which is easy to use and allows exposure of up to 8 or 16 small rodents depending on the chamber used with the system. Animals are exposed without anesthesia or extreme restraint. Deflection tubes at the chamber inlet and outlet serve to provide turbulent flow within the chamber. Performance of the exposure system was evaluated by analyzing data which was collected during investigations of the kinetics of respirable nickel chloride (NiCl2) and cobalt chloride (CoCl2) aerosols in Sprague-Dawley rats. Acute 2 h exposure to NiCl2 at concentrations ranging from 129 to 1208 micrograms Ni/m3 (MMAD 0.7-0.9 micron, sigma g 1.2-1.5) had a mean run-to-run coefficient of variation (cv) in chamber concentration of 11.6%, and a mean within-run cv of 8.5%. A 26-day repeated exposure of 3 groups of rats to 18.4 micrograms Ni/m3 gave a mean run-to-run cv of 20.9%, mean within-run cv of 10.2%, and within-day cv of 14.5%. Acute exposure studies with CoCl2 at concentrations ranging from 298 to 1371 micrograms Co/m3 (MMAD 0.9, sigma g 1.4) produced a mean run-to-run cv of 8.4% and a mean within-run cv of 7.8%. The repeated exposure of 2 groups of rats for 5 days to CoCl2 at a concentration of 583 micrograms Co/m3 had a mean run-to-run cv of 10.1%, a within-run cv of 7.4% and a within-day cv of 6.8%. The distribution of aerosol within the chamber is shown to have been uniform, and chamber performance was linear over the range tested. This system provides an inexpensive and uniform means of conducting inhalation exposure studies with selected airborne contaminants that might represent a potential health hazard.

In order to establish whether CyP is the pharmacologically relevant CsA receptor, the CyP binding v immunosuppressive activity was measured for an extensive, structurally varied group of CsA analogues. Overall, CyP binding was found to parallel immunosuppressive activity. Other than MeAla6-CsA, the few exceptions to the correlation could be ascribed to cellular metabolism. These results strongly implicate CyP or a related protein in the mechanism of action of cyclosporine.

The interaction between mouse submaxillary gland renin and a statine-containing, iodinated substrate analog inhibitor was studied. The compound, 1 (Boc-His-Pro-Phe-(4-iodo)-Phe-Sta-Leu-Phe-NH2, Sta = (3S,4S)-4-amino-3-hydroxy-6-methyl-heptanoic acid), a statine-containing analog of the renin substrate octapeptide, was a competitive inhibitor of cleavage of synthetic tetradecapeptide renin substrate by mouse submaxillary gland renin, with a Ki of 6.2 x 10(-10) M (pH 7.2, 37 degrees C). Titration of the partial quenching of the tryptophan fluorescence of the enzyme by 1 revealed tight binding with a dissociation constant less than 3 nM and a binding stoichiometry of one mole 1 per mole enzyme. The time course of tight binding of 1 to mouse renin appeared to be fast, with kON greater than or equal to 1.3 x 10(6) s-1 M-1. The UV difference spectrum generated upon binding of 1 to mouse renin had two prominent features: a strong, broad band that had a minimum at 242 nm with delta epsilon (242) = -19,500 cm-1 M-1, and a triplet of enhanced bands centered at 286 nm with delta epsilon (286) about +1100 cm-1 M-1. The strong, broad, negative band was similar to the difference between the UV absorbance of 1 in methanol and in 0.1 M citrate phosphate pH 7.2. A structure-activity correlation for analogs of 1 showed some moieties of 1 that are important for potent inhibition of mouse renin. The inhibition data for these compounds versus human kidney renin suggested that the solution of the crystal structure of 1 bound to mouse renin will provide useful information for the design of inhibitors of human kidney renin.

Inspection of the active sites of the many enzymes whose structures are known at high resolution leads to the unsurprising conclusion that an enzyme may provide an environment that exquisitely stabilizes the transition state for an elementary catalytic step that is expected to be difficult. In an effort both to mimic such an environment and to have the opportunity of investigating the thermodynamic and kinetic consequences of juxtaposing polar and non-polar loci in the same molecule, we have synthesized several specifically functionalized alpha-cyclodextrins. One of these is designed to stabilize the trigonal bipyramidal transition state for an in-line displacement at the phosphorus of a phosphate monoester. This cyclodextrin contains three symmetrically disposed ammonium groups on the 'top' (at C-6) of the hydrophobic cavity formed by the hexa-glucose torus and the remaining 15 hydroxy groups are methylated. The thermodynamic consequences of adjacent hydrophobic and hydrogen-bonding and/or electrostatic binding sites are investigated using several charged and uncharged ligands. The feasibility of building host species explicitly to stabilize reaction transition states is discussed.

The proteolytic enzyme renin (EC3.4.99.19) cleaves the protein substrate angiotensinogen to yield angiotensin I, the decapeptide substrate transformed by converting enzyme into the pressor substance angiotensin II. Although the contribution of this pathway to the maintenance of normal blood pressure is unclear, it seems to be a major factor in various hypertensive states. Important progress in the control of hypertension has been achieved by development of the potent inhibitors SQ-14,225 (captopril) and MK-421 (enalapril maleate), which block the generation of angiotensin II by the inhibition of angiotensin converting enzyme. An attractive alternative to the inhibition of converting enzyme would be the blockade of the preceding step in the cascade, the renin reaction. We report here new highly potent (IC50 = 10(-9)-10(-8) M) competitive inhibitors of renin in which statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of the pig renin substrate (Fig. 1).

Nineteen tetrapeptides containing statine (Sta) and 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) were prepared. Solubility measurements of these compounds were carried out in H2O and in pH 7.4 phosphate buffer solution, and their partition coefficients were determined in a 1:1 1-octanol/sodium phosphate-citric acid buffer system. The tetrapeptides were tested in vitro for their ability to inhibit porcine, canine, and human plasma renins. Four compounds, 6, 12, 14, and 20, were potent inhibitors against all renins tested (IC50 = 10(-9) M). Compound 12 was administered orally to dogs and substantially inhibited plasma renin activity for up to 5 h. The addition of polar groups to the C-terminus of Sta- and ACHPA-containing tetrapeptides renders them soluble in aqueous milieu and provides a valuable tool with which to examine the role of the renin-angiotensin system in physiological and pathological circumstances.

The enzymes that catalyze the oxidative metabolism of arachidonic acid have provided fertile ground for the development of useful therapeutic agents for nearly a quarter century. Inhibitors of the enzyme cyclooxygenase prevent the formation of the prostaglandins and thromboxanes and are clinically useful antiinflammatories and peripheral analgesics. More recently it has been discovered that the enzyme 5-lipoxygenase is the first step in the formation of a series of biologically important metabolites of arachidonic acid, the leukotrienes. Evidence suggests that an inhibitor of 5-lipoxygenase may be a useful therapeutic agent in the treatment of asthma, immediate hypersensitivity, and inflammation. Various antioxidants have been examined as inhibitors of 5-lipoxygenase in vitro. We were intrigued by recent reports that the 2,3-dihydro-5-benzofuranol ring system maximizes the stereoelectronic effects necessary for efficient hydrogen atom abstraction by peroxyl radicals. In this study we describe the synthesis of over 50 new 2,3-dihydro-5-benzofuranols and their biological evaluation as inhibitors of leukotriene biosynthesis in isolated human polymorphonuclear leukocytes. We show that the 2,3-dihydro-5-benzofuranol ring system, although not a potent inhibitor of leukotriene biosynthesis in itself, can provide a useful template for the design of antioxidant-based inhibitors of leukotriene biosynthesis. Furthermore, within a structural class the potency of a given analogue can be predicted on the basis of its overall calculated lipophilicity (log P). The data are interpreted in terms of a model in which the observed inhibition by this class of inhibitors is dependent on the intrinsic ability of the antioxidant to reduce the enzyme and on the fraction of the inhibitor that is partitioned into the membrane.

Analogues of the renin octapeptide substrate were synthesized in which replacement of the scissile dipeptide with (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta) transformed the substrate sequence into potent, transition-state analogue, competitive inhibitors of renin. Synthesis and incorporation of the cyclohexylalanyl analogue of Sta, (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), gave the most potent inhibitors of renin yet reported, including N-isovaleryl-L-histidyl-L-prolyl-L-phenylalanyl-L-histidyl-ACHPA-L -leucyl-L- phenylalanyl amide [Iva-His-Pro-Phe-His-ACHPA-Leu-Phe-NH2,3], with renin inhibitions of Ki = 1.6 X 10(-10) M (human kidney renin), IC50 = 1.7 X 10(-10)M (human plasma renin), IC50 = 1.9 X 10(-9)M (dog plasma renin), and IC50 = 2.1 X 10(-8) M (rat plasma renin). This inhibitor 3, containing ACHPA, was 55-76 times more potent vs. human renin than the comparable Sta-containing inhibitor 1 and 17 times more potent vs. dog renin than 1. Inhibitor 3 lowered blood pressure in sodium-deficient dogs, with in vivo potency 19 times that shown by 1, in close agreement with the relative in vitro potencies. Structure-activity results are presented that show the minimal N-terminus for these inhibitors. An ACHPA-containing pentapeptide, N-[(ethyloxy)carbonyl]-L-phenylalanyl-L- histidyl-ACHPA-L-leucyl-L-phenylalanyl amide [Etoc-Phe-His-ACHPA-Leu-Phe-NH2,8], retained subnanomolar inhibitory potency. Molecular modelling studies are described that suggested the design of ACHPA.

The saturable nature of the clearance of soluble nickel compounds from the lung was studied by repeated exposures of rats to respirable submicron-size nickel aerosols. Using Michaelis-Menten type kinetics for removal of nickel lung burdens and a constant rate of deposition, the lung nickel burdens were simulated by computer. The computer simulation was used to design a repeated exposure regimen to test further the hypothesis of saturable clearance. Male Sprague-Dawley rats were exposed for 2 h/day to nickel chloride aerosols at either 90 or 400 micrograms Ni/m3 for up to 14 days. During the 22 h between exposures and up to 3 days post-exposure rats were kept in clean air. The particle size of the aerosol ranged from 0.7 to 0.9 micron mass median aerodynamic diameter with a geometric standard deviation of 1.2-1.4. A steady-state nickel lung burden was observed at 90 micrograms/m3, as predicted from computer modeling, while lung burdens continued to increase with repeated exposure to 400 micrograms Ni/m3. The best fit for the experimental data was obtained with a maximum clearance velocity (Vmax) of 34.6 ng Ni/g X h and a Michaelis-Menten constant for transport (Kt) of 1380 ng Ni/g. The percentage of submicron nickel chloride aerosols retained in the lung was 6.9%. These data support the hypothesis of a saturable clearance mechanism for soluble nickel and provide physiological constants useful for estimating human health risks from nickel inhalation.

Precision percutaneous needle aspiration biopsy under guidance of computed tomography is facilitated by injection of a small amount of contrast material during the biopsy procedure. CT scan immediately after biopsy clearly documents the biopsy site. There was no adverse effect of the contrast agents on the quality of staining or preservation of cellular architecture. To the contrary, the aspirates obtained after contrast injection were generally better preserved and better stained than the control specimens. This may be due to a decrease in drying, with the more fluid aspirates obtained after contrast injection.

The accuracy of interobserver variability of roentgenographic analysis for cardiac size in patients dying with chronic bronchitis and pulmonary emphysema were correlated with pathologic data derived from special studies. Three trained observers were able to accurately and consistently diagnose chronic bronchitis and pulmonary emphysema and to detect cardiomegaly on the chest x-ray film. The best criteria for chronic bronchitis and pulmonary emphysema were those of overinflation; however, none of the roentgenographic criteria usually suggested for the specific diagnosis of right ventricular or left ventricular hypertrophy were found to be reliable. The inaccuracy and interobserver variability in the detection of enlargement of specific chambers make it evident that the usual criteria are not valid and that roentgenographic appraisal of cardiac size in these patients in limited to findings of normalcy or cardiomegaly.

Comparative surface feature analyses of the VP1 sequences of hepatitis A virus (HAV) and poliovirus type 1 allowed an alignment of the two sequences and an identification of probable HAV neutralization antigenic sites. A synthetic peptide containing the HAV-specific amino acid sequence of one of these sites induced anti-HAV-neutralizing antibodies. It is concluded that a structural homology exists between the two viruses, despite minimal primary sequence conservation.

A series of statine-containing tetrapeptides, systematically modified at the carboxy terminus with various hydrophobic aromatic groups, is described. These compounds were tested in vitro for their ability to inhibit porcine, human plasma, and purified human kidney renins. These analogues help to define optimal binding aspects in a region of the enzyme that appears to be specific for spatial arrangement of aromatic groups. Replacement of the metabolically labile Phe amide with nonpeptidal groups proved possible while achieving inhibitory potency in the nanomolar range vs. porcine kidney renin. For the compounds 6i, 6m, and 6o, a large discrepancy in potency between the human plasma and the purified human kidney renin assays was observed. This disparity does not appear to be a consequence of a previously proposed plasma binding component.