[Healthcare behavior of migraine and headache patients when treatment is accompanied by the digital migraine app]. / Gesundheitsverhalten von Migräne- und Kopfschmerzpatienten bei digitaler Therapiebegleitung mit der Migräne-App.

BACKGROUND: Tension-type headache and migraine are the second and third most prevalent disorders of mankind worldwide, after dental caries. The widespread implementation of smartphones enables the use of specific software applications (apps) for digital treatment accompaniment. In this study, the use of the migraine app (Migräne-App) for iOS and Android was examined in the practical treatment of migraine and headache patients in an extensive population sample. METHODS: An online survey was developed for the analysis of experiences as part of the treatment accompaniment and app usage. It contains questions concerning sociodemographic variables, the course of headache disorders and the previous treatment as well as the usage of the migraine app. The survey establishes compliance to the recommended treatment, the treatment plan, and treatment rules devised by the treating physician. The data collected were compared to traditional pen and paper documentation, prior to using the migraine app. RESULTS: A total of 1464 users participated in the standardized survey. The average age was 47.19 ± 11.37 years (87.4% female, 12.5% male). On average, users suffered from headaches for 27.28 ± 13.6 years. The majority (76.5%) were cared for by a general practitioner. Of the users 70.9% reported that they presented the aggregated data from the app to their physician on consultation, 76.4% reported that the migraine app helped them to adhere to the treatment plan designed together with their physician and the rules about headache therapy. It showed both a highly significant reduction of headache days per months prior to usage (13.30 ± 7.45 days) in comparison to at the time of conducting the survey (10.03 ± 7.30 days) as well as a highly significant reduction of intake of acute medication (before 7.61 ± 5.58 vs. ongoing 6.78 ± 4.72 days). CONCLUSION: The data show that the digital treatment control for therapy decisions made by the physician is highly relevant and established. Therapy compliance is improved and possible complications such as headache due to medication overuse are reduced. At the same time, a significant improvement of headache parameters and a marked overall improvement of treatment quality, amongst other things due to more easily available information and self-help tools can be observed.

Response to a standard behavioral weight loss intervention by age of onset of obesity.

BACKGROUND: The purpose of this study was to examine weight loss, physical activity, fitness and diet changes in response to a standard behavioral weight loss intervention in adults with self-reported juvenile onset (n = 61) or adult onset (n = 116) obesity. METHODS: Participants (n = 177; 43.0 ± 8.6 years; body mass index [BMI] = 33.0 ± 3.4 kg m-2) engaged in an 18-month standard behavioral weight loss intervention. Participants were randomized into three different intervention groups as part of the larger parent trial. BMI, physical activity, fitness and diet were assessed at baseline, 6, 12 and 18 months. Separate adjusted mixed models were constructed using SAS version 9.4 (SAS Institute, Cary, NC). RESULTS: There was significant weight loss, increased physical activity, improved fitness and reduced caloric intake over time (p < 0.001). There were no significant differences in these outcome variables by obesity onset group. However, there was a significant group by time interaction for fitness (p = 0.001), with the adult onset making significantly greater gains in fitness from baseline to 6 months (p < 0.001); however, this difference was no longer present at 12 or 18 months. CONCLUSIONS: With the exception of fitness at 6 months, weight loss, physical activity and diet did not differ between juvenile onset and adult onset participants, suggesting that those with juvenile onset obesity are equally responsive to a standard behavioral weight loss intervention in adulthood.

A review of recent advances in the spherical harmonics expansion method for semiconductor device simulation.

The Boltzmann transport equation is commonly considered to be the best semi-classical description of carrier transport in semiconductors, providing precise information about the distribution of carriers with respect to time (one dimension), location (three dimensions), and momentum (three dimensions). However, numerical solutions for the seven-dimensional carrier distribution functions are very demanding. The most common solution approach is the stochastic Monte Carlo method, because the gigabytes of memory requirements of deterministic direct solution approaches has not been available until recently. As a remedy, the higher accuracy provided by solutions of the Boltzmann transport equation is often exchanged for lower computational expense by using simpler models based on macroscopic quantities such as carrier density and mean carrier velocity. Recent developments for the deterministic spherical harmonics expansion method have reduced the computational cost for solving the Boltzmann transport equation, enabling the computation of carrier distribution functions even for spatially three-dimensional device simulations within minutes to hours. We summarize recent progress for the spherical harmonics expansion method and show that small currents, reasonable execution times, and rare events such as low-frequency noise, which are all hard or even impossible to simulate with the established Monte Carlo method, can be handled in a straight-forward manner. The applicability of the method for important practical applications is demonstrated for noise simulation, small-signal analysis, hot-carrier degradation, and avalanche breakdown.

[Is the thyroidectomy a surgical standard procedure for therapy of Graves' disease?]. / Stellt die Thyreoidektomie ein Standardverfahren zur Behandlung des Morbus Basedow dar?

Surgery is an important therapeutic option in the treatment of Graves' disease. Nevertheless it is still controversial discussed wether the extent of resection correlates with the rate of surgical complications and the therapeutic success. Therefore we performed a retrospective analysis on 75 surgically treated patients. 58 of these 75 patients were examined after a median interval of 34.2 months. The examination focussed on the appearance of temporary and permanent palsy of the recurrent laryngeal nerve, hypoparathyroidism, recurrences, and on the postoperative course of thyroid-stimulating-hormone-receptor antibody (TSH-ab) titers. Total thyroidectomy has been performed in 51 and bilateral resection with a remnant thyroid volume less than 2 ml each side in 24 patients. We could not confirm a significant difference concerning the postoperative complication rates between both groups. In the bilateral resection group we saw 3 cases of recurrent goitre and a more unfavourable course of TSH-ab titers than in the thyroidectomy group. For these reasons we propose the total thyroidectomy as surgical standard procedure for therapy of Graves' disease.

Improving balance by improving motor skills.

The effectiveness of a computer-assisted balance training was compared with a home based exercise program in healthy elderly subjects. Twenty-four physically active community dwelling elderly (median age 71 years) participated in the study. Balance was assessed by a summary performance score, measuring postural stability while standing, reaching, stepping and walking. Subjects of the computer-assisted balance training group could considerably improve their performance on the training device (p = 0.0078) as well as in the summary balance score (p = 0.0176). No improvement of balance was documented in the home-based exercise group. A superiority of the computer-assisted balance training exercise protocol over the home-based exercise group could not be documented (p = 0.3934). The study indicates that a computer-assisted balance training, focussing on one motor skill, can improve balance. It is suggested that a home-based exercise program is ineffective to improve balance in elderly persons, if there is no direct supervision.

Efficacy of the iodine-free computed tomography liver contrast agent, Dy-EOB-DTPA, in comparison with a conventional iodinated agent in normal and in tumor-bearing rabbits.

RATIONALE AND OBJECTIVES: To investigate the efficacy of the new liver-specific x-ray contrast agent, Dy-EOB-DTPA, in rabbits with VX2 liver tumors by spiral computed tomography (CT) in comparison to iopromide. MATERIALS AND METHODS: The time course of liver enhancement was determined in five groups of two normal anesthetized rabbits, which received intravenous injections of Dy-EOB-DTPA before anesthesia at a dose of 0.5 mmol/kg. Fifteen, 30, 45, 60, and 90 minutes after administration spiral CT images were obtained and the attenuation in the livers were determined. A second group of ten rabbits with implanted VX2 tumors received in a random crossover design either Dy-EOB-DTPA at a dose of 0.5 mmol/kg or, 1 day later, iopromide at a dose of 600 mg iodine/kg. CT images were obtained 60 minutes after Dy-EOB-DTPA administration and both in the arterial and portal-venous phases after iopromide injection. Three radiologists evaluated the images. The rabbits were killed, and their livers were investigated histologically for liver tumors. RESULTS: In normal animals, 0.5 mmol/kg Dy-EOB-DTPA resulted in a liver enhancement of 30 HU during the whole observation period of 90 minutes. In tumor-bearing animals, histology revealed 14 implanted tumors of 3-20 mm diameter. Sixty-five percent of the tumors were below 10 mm. Dy-EOB-DTPA was able to detect 13 tumors (93%), iopromide 11 (79%) both in the arterial and in the portal-venous phase. The difference was statistically not significant. In plain CT, seven tumors (50%) were found (P < 0.01 vs iopromide and Dy-EOB-DTPA). One scar and two sites of necrosis were detected by each of the methods. CONCLUSION: Dy-EOB-DTPA injection at a dose of 0.5 mmol/kg resulted in a long-lasting detectability of 93% of all implanted tumors versus 79% found with iopromide.

Characterization of continuously extruded iopromide-carrying liposomes for computed tomography blood-pool imaging.

RATIONALE AND OBJECTIVES: Contrast-carrying liposomes are potentially useful as computed tomography (CT) blood-pool agents. In the present study, preliminary safety, pharmacokinetics, and the CT imaging behavior of continuously extruded iopromide-carrying liposomes were studied. METHODS: Iopromide liposomes were prepared by continuous high-pressure extrusion. Cell membrane-damaging characteristics were assessed in vitro in dog erythrocytes. Acute and subchronic toxicity and pharmacokinetics parameters were determined in rats. Computed tomography imaging efficiency was studied in rabbits. RESULTS: The iopromide-carrying liposomes caused only minor morphological changes in dog erythrocytes. The median lethal dose in rats was approximately 4.5 g of total iodine per kilogram of body weight. In a subchronic tolerance study in rats that were administered six doses of 1 g iodine per kilogram twice a week, no adverse effects were observed. The pharmacokinetics in rats was dose dependent, and elimination of iopromide was almost complete within 7 days after intravenous administration. In rabbits, at a dose of 300 mg total iodine per kilogram, the iopromide-carrying liposomes displayed prolonged blood circulation, with mean CT density differences > 60 Hounsfield units (aorta) for up to 10 minutes. CONCLUSIONS: The iopromide liposomes were well tolerated, almost completely excreted, and have potential as a CT blood-pool imaging agent.

Modeling SSI financial eligibility and simulating the effect of policy options.

This article simulates eligibility for Supplemental Security Income (SSI) among the elderly, analyzes factors affecting participation, and looks at the potential effects of various options to modify financial eligibility standards for the federal SSI program. We find that in the estimated noninstitutional elderly population of 30.2 million in the United States in 1991, approximately 2 million individuals aged 65 or older were eligible for SSI (a 6.6 percent rate of eligibility). Our overall estimate of the rate of participation among eligible elderly is approximately 63 percent, suggesting that more than a third of those who are eligible do not participate in the program. The results of our analysis of factors affecting participation among the eligible elderly show that expected SSI benefits and a number of demographic and socioeconomic variables are associated with the probability of participation. We also simulate the effects of various policy options on the poverty rate, poverty gap, annual program cost, the number of participants, and the average estimated benefits among participants. The simulations consider the potential effects of five policy alternatives: Increase the general income exclusion (GIE) from $20 to $80. Increase the earned income exclusion (EIE) from $65 to $260. Increase the federal benefit rate (FBR) by $50 for individuals and $75 for couples and eliminate the GIE. Increase the asset threshold to $3,000 for individuals and $4,500 for couples. Increase the asset threshold to $6,000 for individuals and $9,000 for couples. Using 1991 microdata from the Survey of Income and Program Participation (SIPP) matched to Social Security Administration administrative records and making adjustments reflecting aggregate program statistics, we present the results of our simulations for December 1999. The results show substantial variation in the simulated effects of the five policy alternatives along the various outcome dimensions considered. The simulated effects on the poverty gap of the elderly population range from a 7.9 percent reduction ("Increase the GIE from $20 to $80") to a 0.1 percent reduction ("Increase the EIE from $65 to $260"). All simulated interventions are expected to increase the rate of SSI participation among the elderly from a high of 20.3 percent ("Increase the GIE from $20 to $80") to a low of 0.5 percent ("Increase the EIE from $65 to $260"). We also find that the interventions that have greater estimated effects in terms of increased participation and reduced poverty tend to cost more. At the high end, we estimate that increasing the GIE from $20 to $80 could raise annual federal SSI cash benefit outlays by about 46 percent, compared with only 0.9 percent for increasing the EIE from $65 to $260. Similar to the EIE intervention, raising the resource thresholds by 50 percent would reduce the overall poverty gap of the elderly by only 0.2 percent, would increase SSI participation only modestly (by 1.3 percent), but would entail slightly higher program costs (by 1.4 percent). Increasing the asset threshold by 200 percent would have higher estimated effects on all three outcomes, but it would still be associated with relatively low increases in both costs and benefits. Finally, the simulated effects on the three key outcomes of increasing the FBR by $50 for individuals and $75 for couples, combined with eliminating the GIE, are relatively large but are clearly less substantial than increasing the GIE from $20 to $80. This work relies on data from the SIPP matched to administrative data on federal SSI benefits that provide a more accurate picture of SSI participation than has been feasible for previous studies. We simulate eligibility for federal SSI benefits by applying the program rules to detailed information on the characteristics of individuals and couples based on the rich array of demographic and socioeconomic data in the SIPP, particularly the comprehensive information SIPP provides on assets and monthly income. A probit model is estimated to analyze factors affecting participation among the eligible elderly. Finally, we conduct the policy simulations using altered program rules represented by the policy alternatives and predicted participation probabilities to estimate outcomes under simulated program rules. We compare those simulated outcomes to observed outcomes under current program rules. The results of our simulations are conditional on the characteristics of participants and eligibles in 1991, but they also reflect aggregate adjustments capturing substantial changes in overall participation and program benefit levels between 1991 and 1999.

The effect of welfare reform on SSA's disability programs: design of policy evaluation and early evidence.

During the past several years, the U.S. social safety net has gone through substantial changes involving an emphasis on personal responsibility and incentives, the shift of certain responsibilities to the states, and new limits on entitlements for benefits. Two pieces of recent legislation affected the Social Security Administration's (SSA's) disability programs. Section 105 of Public Law 104-121, enacted on March 29, 1996, mandated the removal of persons from the Supplemental Security Income (SSI) and Social Security Disability Insurance (DI) rolls for whom drug addiction and alcoholism (DA&A) were material to the determination of disability. It eliminated allowances on the basis of DA&A immediately and required the termination of benefits to all persons receiving benefits at the time of enactment. The other major piece of legislation was the Personal Responsibility and Work Opportunity Reconciliation Act (PRWORA) of 1996, which was later amended by the Balanced Budget Act (BBA) of 1997. PRWORA converted the Aid to Families with Dependent Children (AFDC) program from an open-ended entitlement program into a block grant, Temporary Assistance for Needy Families (TANF), incorporating time limits on the receipt of benefits as well as strict work requirements. PRWORA also tightened child eligibility for SSI, narrowed eligibility for noncitizens, and reduced funding for food stamps. The BBA restored SSI eligibility for noncitizens receiving SSI prior to August 1996 and for legal noncitizens residing in the United States prior to August 1996 who become disabled in the future. SSA designed three studies to assess the effects of this legislation. Two of the studies focused on direct effects on SSA's disabled beneficiary population, targeting drug addicts and alcoholics and SSI children. The third study focused on the indirect effects of PRWORA, particularly the replacement of AFDC with TANF, on SSA's programs. The three studies were tied together by a concern of the overall effects--direct or indirect--of the legislative changes on SSA's beneficiary populations and a host of interrelated evaluation issues. The key methodological challenge of these evaluations is the nonexperimental nature of the evidence. The legislative pieces mandating the changes designed to affect SSA's target populations were implemented nationally, without prior demonstration projects. Nonexperimental strategies, such as comparison group designs, must therefore be used to measure the effects of interest. Other challenges relate to the time frames. Since implementing the changes requires a certain amount of time, and outcomes are realized over a period of time after that, the information that can be made available to interested policymakers in the short run is inherently limited to descriptive data on the populations affected and to impressionistic evidence from case studies and process study analyses. The timing problem is particularly acute with respect to measuring the indirect effects of replacing AFDC with TANF, because the most important likely effects will occur over a period of several years, and this time frame may substantially vary across states as a result of the decentralized nature of TANF programs. Finally, the analyses that can be conducted are constrained by the lack of relevant data from existing surveys. Administrative record data alleviate the need for survey information for some purposes, but the lack of survey data still seriously constrains the analyses that can be done in the short term. Because of these methodological challenges, SSA designed an evaluation strategy that uses several methods and data sources, including quantitative analyses of data from surveys and administrative records (particularly data from the Survey of Income and Program Participation, or SIPP, matched to data from administrative records) and qualitative analyses through case studies. (ABSTRACT TRUNCATED)

The net effects of the Project NetWork return-to-work case management experiment on participant earnings, benefit receipt, and other outcomes.

The Social Security Administration (SSA) initiated Project NetWork in 1991 to test case management as a means of promoting employment among persons with disabilities. The demonstration, which targeted Social Security Disability Insurance (DI) beneficiaries and Supplemental Security Income (SSI) applicants and recipients, offered intensive outreach, work-incentive waivers, and case management/referral services. Participation in Project NetWork was voluntary. Volunteers were randomly assigned to the "treatment" group or the "control" group. Those assigned to the treatment group met individually with a case or referral manager who arranged for rehabilitation and employment services, helped clients develop an individual employment plan, and provided direct employment counseling services. Volunteers assigned to the control group could not receive services from Project NetWork but remained eligible for any employment assistance already available in their communities. For both treatment and control groups, the demonstration waived specific DI and SSI program rules considered to be work disincentives. The experimental impact study thus measures the incremental effects of case and referral management services. The eight demonstration sites were successful in implementing the experimental design roughly as planned. Project NetWork staff were able to recruit large numbers of participants and to provide rehabilitation and employment services on a substantial scale. Most of the sites easily reached their enrollment targets and were able to attract volunteers with demographic characteristics similar to those of the entire SSI and DI caseload and a broad range of moderate and severe disabilities. However, by many measures, volunteers were generally more "work-ready" than project eligible in the demonstration areas who did not volunteer to receive NetWork services. Project NetWork case management increased average annual earnings by $220 per year over the first 2 years following random assignment. This statistically significant impact, an approximate 11-percent increase in earnings, is based on administrative data on earnings. For about 70 percent of sample members, a third year of followup data was available. For this limited sample, the estimated effect of Project NetWork on annual earnings declined to roughly zero in the third followup year. The findings suggest that the increase in earnings may have been short-lived and may have disappeared by the time Project NetWork services ended. Project NetWork did not reduce reliance on SSI or DI benefits by statistically significant amounts over the 30-42 month followup period. The services provided by Project NetWork thus did not reduce overall SSI and DI caseloads or benefits by substantial amounts, especially given that only about 5 percent of the eligible caseload volunteered to participate in Project NetWork. Project NetWork produced modest net benefits to persons with disabilities and net costs to taxpayers. Persons with disabilities gained mainly because the increases in their earnings easily outweighed the small (if any) reduction in average SSI and DI benefits. For SSA and the federal government as a whole, the costs of Project NetWork were not sufficiently offset by increases in tax receipts resulting from increased earnings or reductions in average SSI and DI benefits. The modest net benefits of Project NetWork to persons with disabilities are encouraging. How such benefits of an experimental intervention should be weighed against costs of taxpayers depends on value judgments of policymakers. Because different case management projects involve different kinds of services, these results cannot be directly generalized to other case management interventions. They are nevertheless instructive for planning new initiatives. Combining case and referral management services with various other interventions, such as longer term financial support for work or altered provider incentives, could produc

Eligibility for the Medicare buy-in programs, based on a survey of income and program participation simulation.

Medicare buy-in programs are designed to reduce out-of-pocket expenses of beneficiaries with modest income and assets. This article provides estimates of the size of the Medicare beneficiary population eligible for the Qualified Medicare Beneficiary (QMB) program, the Specified Low-Income Medicare Beneficiary (SLMB) program, and the Qualified Individual-1 (QI-1) program. The buy-in programs use the same resource limits (twice those used in the Supplemental Security Income (SSI) program) but different thresholds for determining income eligibility. The QMB program uses 100 percent of the poverty line as the cutoff, QI-1 covers persons above 120 percent but at or below 135 percent of the poverty line, and the SLMB program is in between. Making informed judgments about the rate of participation in the buy-in programs and the need for outreach requires an accurate estimate of the size of the eligible population. If that population is underestimated, policymakers might come to unduly optimistic conclusions about current buy-in participation. In contrast, an overestimate may make current participation seem too low. If policymakers react to an upwardly biased estimate of the eligible population by increasing outreach, they are bound to be disappointed by the results of that effort. Estimates of the eligible population from past studies of the QMB and SLMB programs range from 5.1 million to 9.1 million. In the absence of new information, it is difficult to judge the accuracy of those estimates because the methodologies had substantial shortcomings that might bias the results. The most common shortcomings include the lack of high-quality, monthly income data and the lack of information on assets from the same data file that was used to estimate participation and income eligibility for Medicare. The current study uses the most recently available (as of August 2000) Survey of Income and Program Participation (SIPP) file that is matched to the Social Security Administration's (SSA's) administrative records. The data file covers 1995 information. Estimates were also obtained using 1991 data to assess the sensitivity of eligibility estimates to the year chosen. The SIPP has several major advantages over other data sources because it contains relevant, high-quality information on both income and assets for establishing financial eligibility for the buy-in programs. First, the SIPP collects detailed and conceptually appropriate information on monthly, rather than annual, income and therefore has more complete information about income than do other surveys. As a result, SIPP-based estimates of poverty are substantially lower than estimates based on the Current Population Survey. Second, the SIPP also collects information on assets at the individual level. Thus, the survey provides enough detail to measure the major income and asset exclusions directly. Finally, the SIPP data are matched to SSA administrative records: Medicare eligibility can therefore be accurately measured, and self-reported data on Social Security and SSI benefits can be replaced with more accurate monthly information. Our 1995 simulation estimates that approximately 4.8 million persons in the U.S. noninstitutionalized population were eligible for the QMB program and an additional 1.6 million for the SLMB program. The total--roughly 6.5 million--is within the range of estimates from past studies but is closer to the lower end, suggesting that the eligible population is smaller than was previously believed. When the estimated QI-1 eligible population of 0.9 million is added, the total for the three buy-in programs is 7.4 million. Because the QI-1 program did not exist in 1995, only the estimated 6.5 million QMBs and SLMBs would actually have been eligible to receive benefits. The 7.4 million figure represents the 1995 Medicare beneficiaries who would be eligible for buy-in under program rules for 2000. Adjusting that number to account for increases in the Medicare population between 1995 and 1999 yields an estimated eligible population of 7.8 million in 1999. Compared with other elderly Medicare recipients, eligible elderly QMBs and SLMBs have poorer health, more functional limitations, and higher rates of health care use. Thus, not only are their income resources relatively limited, but their need for potentially expensive medical care is also greater. Similar differences were not found in health, functional limitations, and health care use among disabled participants in the QMB and SLMB programs. Our estimates imply that about 2.5 million noninstitutionalized individuals were eligible for but not enrolled in the QMB and SLMB programs in 1999. That finding suggests that fewer eligibles may be available for targeting by outreach efforts than was previously believed. Outreach may be more difficult than it would be with a larger eligible population. (ABSTRACT TRUNCATED)

The aspartic proteinase from the rodent parasite Plasmodium berghei as a potential model for plasmepsins from the human malaria parasite, Plasmodium falciparum.

The gene encoding an aspartic proteinase precursor (proplasmepsin) from the rodent malaria parasite Plasmodium berghei has been cloned. Recombinant P. berghei plasmepsin hydrolysed a synthetic peptide substrate and this cleavage was prevented by the general aspartic proteinase inhibitor, isovaleryl pepstatin and by Ro40-4388, a lead compound for the inhibition of plasmepsins from the human malaria parasite Plasmodium falciparum. Southern blotting detected only one proplasmepsin gene in P. berghei. Two plasmepsins have previously been reported in P. falciparum. Here, we describe two further proplasmepsin genes from this species. The suitability of P. berghei as a model for the in vivo evaluation of plasmepsin inhibitors is discussed.

The development of the Project NetWork administrative records database for policy evaluation.

This article describes the development of SSA's administrative records database for the Project NetWork return-to-work experiment targeting persons with disabilities. The article is part of a series of papers on the evaluation of the Project NetWork demonstration. In addition to 8,248 Project NetWork participants randomly assigned to receive case management services and a control group, the simulation identified 138,613 eligible nonparticipants in the demonstration areas. The output data files contain detailed monthly information on Supplemental Security Income (SSI) and Disability Insurance (DI) benefits, annual earnings, and a set of demographic and diagnostic variables. The data allow for the measurement of net outcomes and the analysis of factors affecting participation. The results suggest that it is feasible to simulate complex eligibility rules using administrative records, and create a clean and edited data file for a comprehensive and credible evaluation. The study shows that it is feasible to use administrative records data for selecting control or comparison groups in future demonstration evaluations.

Naturally-occurring and recombinant forms of the aspartic proteinases plasmepsins I and II from the human malaria parasite Plasmodium falciparum.

Comparable kinetic parameters were derived for the hydrolysis of peptide substrates and the interaction of synthetic inhibitors with recombinant and naturally-occurring forms of plasmepsin II. In contrast, recombinant plasmepsin I was extended by 12 residues at its N-terminus relative to its naturally-occurring counterpart and a 3-10-fold diminution in the k(cat) values was measured for substrate hydrolysis by the recombinant protein. However, comparable Ki values were derived for the interaction of two distinct inhibitors with both forms of plasmepsin I, thereby validating the use of recombinant material for drug screening. The value of plasmepsin I inhibitors was determined by assessing their selectivity using human aspartic proteinases.

Expression and characterisation of plasmepsin I from Plasmodium falciparum.

Two aspartic proteinases, plasmepsins I and II, are present in the digestive vacuole of the human malarial parasite Plasmodium falciparum and are believed to be essential for parasite degradation of haemoglobin. Here we report the expression and kinetic characterisation of functional recombinant plasmepsin I. In order to generate active plasmepsin I from its precursor, an autocatalytic cleavage site was introduced into the propart of the zymogen by mutation of Lys110P to Val (P indicates a propart residue). Appropriate refolding of the mutated zymogen then permitted pH-dependent autocatalytic processing of the zymogen to the active mature proteinase. A purification scheme was devised that removed aggregated and misfolded protein to yield pure, fully processable, proplasmepsin I. Kinetic constants for two synthetic peptide substrates and four inhibitors were determined for both recombinant plasmepsin I and recombinant plasmepsin II. Plasmepsin I had 5-10-fold lower k(cat)/Km values than plasmepsin II for the peptide substrates, while the aspartic proteinase inhibitors, selected for their ability to inhibit P. falciparum growth, were found to have up to 80-fold lower inhibition constants for plasmepsin I compared to plasmepsin II. The most active plasmepsin I inhibitors were antagonistic to the antimalarial action of chloroquine on cultured parasites. Northern blot analysis of RNA, isolated from specific stages of the erythrocytic cycle of P. falciparum, showed that the proplasmepsin I gene is expressed in the ring stages whereas the proplasmepsin II gene is not transcribed until the later trophozoite stage of parasite growth. The differences in kinetic properties and temporal expression of the two plasmepsins suggest they are not functionally redundant but play distinct roles in the parasite.

Auditory brainstem response: recent developments in recording and analysis.

During the past 25 years since the 'discovery' of the ABR, clinicians world-wide have exploited the clinical utility of this evoked response with many different populations. The 1970s and 1980s saw the development of ABR protocols for increasing the reliability and validity of the response in various clinical situations. Now, in the last decade of the century, advanced technology and the development of increasingly sophisticated software allows more flexibility in these measurements. Thus, ABR testing continues to evolve at a rapid pace. The main focus for ABR in the 1990s has been on developing techniques to improve the quality of the response, decrease the time in which it takes to record the response, and minimize human error through objective response analysis. Some of the major recent developments were reviewed in this chapter. The intent of this review is to provide the researcher and the clinician with an understanding of the underlying principles of the techniques which will be, and are already, available to them on their ABR equipment. Many of these techniques are promising for use with newborns, children, and difficult-to-test populations where time is a limiting factor in the amount of information that can be obtained. We encourage any and all clinicians to experiment with these techniques to determine how each technique might contribute to their particular clinic protocols. As with any new technique, there will be a learning curve associated with understanding the underlying principles, mastering the technical requirements, and realizing the most valuable clinical applications of these methods. Once the procedures become familiar to clinicians and applied in varied clinical settings, it is likely that the neurodiagnostic and audiologic value of ABR will be profoundly enhanced.

[Villous bile duct adenoma with mucinous bile ]. / Villöses Gallengangsadenom mit gallertartiger Galle.

HISTORY AND ADMISSION FINDINGS: A 75-year-old woman was admitted because of colicky upper abdominal pain. Physical examination was unremarkable. INVESTIGATIONS: Alkaline phosphatase and gamma-glutamyl transpeptidase activities as well erythrocyte sedimentation rate were increased. Sonography revealed mild enlargement of the hepatocholedochal duct to 1.1 cm. Retrograde endoscopy showed a band-like immobile structure in the cystic duct. TREATMENT AND COURSE: At operation the hepatocholedochal duct was found to contain a greenish mucinous mass: no cause was discovered. Three years later a tumor, 1 x 0.5 cm, was found in the common hepatic duct at sonography, with clinical signs of recurrent chronic cholitis and early liver damage. Because of hepatic dysfunction and hypersplenism no surgical intervention was undertaken. When cholestasis progressed further, a partial full-thickness resection of the hepatic duct with removal of the tumor and the mucinous bile had to be performed two years later. Histological examination revealed a villous adenoma with slight epithelial dysplasia and mucus formation. CONCLUSIONS: Villous bile duct adenoma is a very rare cause of cholestasis. Mucous production can lead to mucinous bile, with resulting chronic cholecystitis and secondary biliary cirrhosis. The adenoma should be completely excised because of the danger of malignant transformation and risk of local recurrence.