A central role for the endothelial NADPH oxidase in atherosclerosis.

An increasing body of evidence has demonstrated that NADPH oxidase plays a critical role in several early steps leading toward the development of atherosclerosis. These effects appear to be carried out by both the ability of O2- to act as a small second messenger molecule, and potentially the oxidation of low density lipoprotein by O2-. We describe a model for the initiation and development of atherosclerosis that suggests targeted inhibition of NADPH oxidase as a powerful site for prevention and treatment of this disease.

Thrombin stimulated reactive oxygen species production in cultured human endothelial cells.

In order to study the major cellular source of reactive oxygen species (ROS) in perturbed human endothelial cells (EC), the effect of thrombin, a phospholipase A2 activator, on cultured EC ROS generation has been investigated. EC were incubated with 0.1-1 unit/ml thrombin and cellular superoxide anion (O(-)2) release and hydrogen peroxide (H2O2) production measured. Thrombin exposure caused an elevation in EC O(-)2 release and H2O2 production. The effects of protein kinase C, arachidonic acid metabolism, NADPH oxidase, and phospholipase A2 inhibitors on thrombin-induced EC H2O2 production were examined. EC were exposed to 0.5 unit/ml thrombin and cellular H2O2 production measured in the presence and absence of the protein kinase C inhibitor, H-7; arachidonic acid metabolism inhibitors, indomethacin, nordihydroguaiaretic acid, and SKF525A; NADPH oxidase inhibitor, apocynin; and phospholipase A2 inhibitor, 4-bromophenacyl bromide. All inhibitors, with the exception of H-7 and indomethacin, suppressed thrombin-induced EC H2O2 production. The pattern of effects of these metabolic antagonists on thrombin-induced EC ROS production is similar to that previously reported on ROS production in EC exposed to high low-density lipoprotein levels, and in stimulated leukocytes. These findings further implicate NADPH oxidase as a major ROS source in EC.

Identification of a functional leukocyte-type NADPH oxidase in human endothelial cells :a potential atherogenic source of reactive oxygen species.

Cultured human endothelial cells (EC) exposed to atherogenic low-density lipoprotein levels have increased reactive oxygen species (ROS) generation. The enzyme responsible for this ROS production elevation is unknown. We have examined for the presence of a functional leukocyte-type NADPH oxidase in EC to elucidate whether this enzyme could be the ROS source. The plasma membrane fraction of disrupted EC showed a reduced-minus-oxidized difference spectra with absorption peaks identical to those observed in the spectra of the leukocyte NADPH oxidase component, cytochrome b558. Western-blot analysis, using anti-gp91 -phox. anti -p22-phox. anti -p47-phox. and anti -p67-phox antibodies, demonstrated the protein expression of NADPH oxidase subunits in EC. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed the mRNA expression of gp91-phox, p22-phox, p47-phox, and p67-phox in EC. Sonicates from unstimulated EC produced no measurable superoxide; whereas, exogenously applied arachidonic acid activated superoxide generation in a manner that was dependent upon the presence of NADPH and both membrane and cytosolic fractions combined. Apocynin, a specific leukocyte NADPH oxidase inhibitor, was shown by Western-blot analysis of membrane and cytoplasmic fractions to inhibit the translocation of p47-phox to the membrane of stimulated EC. These findings support the presence of a functionally active leukocyte-type NADPH oxidase in EC. NADPH oxidase could be the major cellular ROS source in EC perturbation, which has been hypothesized to be a major contributing factor in the pathogenesis of atherosclerosis.

Low-density lipoprotein stimulated peroxide production and endocytosis in cultured human endothelial cells: mechanisms of action.

The effects of arachidonic acid metabolism and NADPH oxidase inhibitor on the hydrogen peroxide (H2O2) generation and endocytotic activity of cultured human endothelial cells (EC) exposed to atherogenic low-density lipoprotein (LDL) levels have been investigated. EC were incubated with 240 mg/dl LDL cholesterol and cellular H2O2 production and endocytotic activity measured in the presence and absence of the arachidonic acid metabolism inhibitors, indomethacin, nordihydroguaiaretic acid, and SKF525A, and NADPH oxidase inhibitor, apocynin. All inhibitors, with the exception of indomethacin, markedly reduced high LDL-induced increases in EC H2O2 generation and endocytotic activity. EC exposed to exogenously applied arachidonic acid had cellular functional changes similar to those induced by high LDL concentrations. EC incubated with 1-25 uM arachidonic acid had increased H2O2 production and heightened endocytotic activity. Likewise, EC pre-loaded with [3H]arachidonic acid when exposed to increasing LDL levels (90-330 mg/dl cholesterol) had a dose-dependent rise in cytosolic [3H]arachidonic acid. The phospholipase A2 inhibitors, 4-bromophenacyl bromide and 7,7-dimethyleicosadienoic acid, markedly inhibited H2O2 production in EC exposed to 240 mg/dl LDL cholesterol. These findings suggest that arachidonic acid contributes mechanistically to high LDL-perturbed EC H2O2 generation and heightened endocytosis. Such cellular functional changes add to our understanding of endothelial perturbation, which has been hypothesized to be a major contributing factor in the pathogenesis of atherosclerosis.

The clinical spectrum of post-streptococcal syndromes with arthritis in children.

Acute rheumatic fever (ARF) and post-streptococcal reactive arthritis (PSRA) are well known complications of streptococcal throat infections. We describe four children with arthritis following a streptococcal throat infection. In addition to arthritis, other clinical manifestations included erythema nodosum, livedo reticularis and cutaneous vasculitis. Because of the very diverse clinical manifestations that may appear after a streptococcal throat infection, we suggest a classification and treatment of post-streptococcal syndromes according to the severity of the disease.

Follow-up of treated coeliac patients: sugar absorption test and intestinal biopsies compared.

OBJECTIVE: To determine whether the sugar absorption test (SAT) during follow-up of patients with coeliac disease on a gluten-free diet (GFD) correlates with improvement of the villous architecture of the small intestine. METHODS: The SAT was performed in coeliacs at diagnosis and during follow-up with GFD. For the SAT, a solution of lactulose (L) and mannitol (M) was given to the fasting patient and the L-M ratio calculated in a 5-hour urine sample by gas chromatography: ratios > 0.089 are considered abnormal. The solution was made hyperosmolar by adding sucrose (1560 mmol/l). RESULTS: The L-M ratio was 2-3 times higher at diagnosis than either at 8 months to 2 years gluten free, or beyond 2 years gluten free, consecutively. The L-M ratio (mean, range) was significantly higher in cases of biopsies with (sub)total villous atrophy (VA) (0.388, 0.062-0.804, n = 28), partial VA (0.240, 0.062-0.841, n = 18) and villous irregularity (0.143, 0.017-0.322, n = 29) than in case of normalized histology after GFD (0.085, 0.021-0.230, n = 19). The rate of normalization of functional integrity was slower in adults than in children, demonstrated by a combination of histology and SAT. CONCLUSION: The SAT correlates well with the degree of VA. It is important for daily clinical practice that the simple and non-invasive SAT can be used as an indicator of intestinal damage, thus influencing need for and timing of intestinal biopsies.

Semiautomatic segmentation of brain exterior in magnetic resonance images driven by empirical procedures and anatomical knowledge.

This work demonstrates encouraging results for increasing the automation of a practical and precise magnetic resonance brain image segmentation method. The intensity threshold for segmenting the brain exterior is determined automatically by locating the choroid plexus. This is done by finding peaks in a series of histograms taken over regions specified using anatomical knowledge. Intensity inhomogeneities are accounted for by adjusting the global intensity to match the white matter peak intensity in local regions. Automated results are incorporated into the established manually guided segmentation method by providing a trained expert with the automated threshold. The results from 20 different brain scans (over 1000 images) obtained under different conditions are presented to validate the method which was able to determine the appropriate threshold in approximately 80% of the data.

Ovarian pregnancy: a morphologic description.

This case report presents a "true" ovarian pregnancy in a women using a Dalkon shield. The gestational sac was implanted in the ovary close to the corpus luteum and contained a normally developed embryo of Carnegie Stage 11. A morphologic description of the embryo is given. The importance of a morphologic description of the conceptus in cases of ovarian pregnancy is discussed.

PIP: This a case report of a true ovarian pregnancy and a morphologic description of the fetal development. Ovarian pregnancy, a specialized type of ectopic pregnancy, is a rare occurrence, with a 1/40,000 rate of occurrence. Only 1 of every 200 ectopic pregnancies is ovarian. Although there is an increased incidence of ovarian pregnancy in IUD users, the device itself is not believed to cause the condition. 1 researcher has calculated that tubal pregnancies are simply less well prevented by the IUD and ovarian pregnancies are not prevented at all.

Nutrition service availability: an interaction potential model.

Availability, defined as a measure of the supply of services relative to the needs in the community, is critical to older people, particularly the socially isolated and frail elderly who are less mobile than most of the population. This research proposes an interaction potential model to examine variation in availability of services by considering the capacity and location of service providers and demand for these services. The model does not constrain older people to meet their demand within their towns' borders. Several measures of availability are calculated for nutrition services in an area agency on aging region of Connecticut, using different beta values to represent varying levels of mobility for the total older population; considerable variation exists, depending on mobility assumptions. Availability measures can be used as independent variables in analyses of variation in actual use of services; a strong correlation exists between use and availability in Connecticut.

Title III services: variation in use within a state.

Using data from Connecticut's management information system for Title III funds, we found, first, that such services are reaching at least one person in every town and thus modestly fulfilling a gateway function; about 9% of Connecticut's elderly use Title III services, with 20% of the oldest old obtaining such services. Nutrition services are reaching the most elderly, both numerically and geographically; among the oldest old (85+), home care service use was most widespread. Indices of use were not statistically related to specific characteristics of the towns' populations (i.e., percentage of elderly, poor, or minority elderly), but small cities and rural towns had the highest use levels. Presence of nutrition sites within the town and service through two of the five area agencies on aging (AAAs) were also correlated with high service use, controlling for the rural-urban continuum. Those two AAAs received the highest per capita amount of Title III funds, based on the state's targeting formulas.

Distinctively elderly mobility: types and determinants.

"Distinctive types of mobility are identified for the [U.S.] elderly, many of whom also move for traditional reasons. Using a longitudinal data set from adult residents in Rhode Island, univariate, chi square, and logit analyses indicate associations between sociodemographic characteristics of the elderly and their mobility behavior. Mobility for assistance reasons is associated with older age, unmarried status, higher previous mobility, and renter status. Mobility in preparation for aging (e.g., to an elderly complex) is more likely for unmarried, previously mobile residents. Out-of-state mobility to amenity destinations is not limited to the elderly, but younger, married, more affluent elderly were more likely to make such moves."

[Neuro-arthropathy, a painless but very destructive disorder of frequently one joint]. / Neuroartropathie, een pijnloze maar zeer destructieve aandoening van vaak slechts één gewricht.

In a 38-year-old man who suffered from recurrent painless swelling of the right knee, neuroarthropathy was diagnosed, associated with tabes dorsalis. The patient was treated with a knee brace to stabilise the joint. Neuroarthropathy is a progressive degenerative joint disease caused by a central or a peripheral neurological disorder and causing denervation of the joint.

Costs and resources associated with the treatment of overactive bladder using retrospective medical care claims data.

The objectives of this study were to determine age- and gender-specific drug treatment prevalence rates for overactive bladder (OAB), and to compare resource use and costs among MCO members receiving drug treatment for OAB. Administrative claims data from seven affiliated health plans were analyzed for 8,661 members with a diagnosis or treatment indicative of OAB during 1998. Resource use and associated costs were analyzed over a four-month follow-up. In 1998, the prevalence of OAB among plan members was 1.1%. Of the patients with OAB, 71% did not receive pharmacotherapy. After multivariate analysis, treatment with tolterodine, oxybutynin, or other OAB treatment did not significantly affect the percent change in total per patient per month (PPPM) costs compared with the group not receiving a pharmacologic agent. Although the adjusted percent change in PPPM pharmacy costs was significantly higher within the tolterodine group, medical and total PPPM costs were not.

Preparing for Medicare single-provider contracting: becoming a center of excellence.

Hospitals and physicians participating in the CABG Surgery Demonstration Project will certainly have an advantage over the competition. Although HCFA has not issued specifics of the process to be applied for the expansion of the project, a review of the program goals and events leading the initial selection is instructive.

Integrating financial modeling and patient care reengineering.

Healthcare organizations face significant pressure to decrease costs and increase quality. In response, many organizations are attempting to reengineer patient care processes through standardization, using critical paths and processes such as total quality management. Many of the organizational initiatives to analyze patient care, explore alternative processes, and establish standardized patient care have been managed primarily by clinical personnel who have not adequately incorporated financial analyses. A thorough understanding and documentation of the costs of providing standardized patient care have become essential parts of hospital management, particularly with regard to managed care contracting and financial planning under healthcare reform. This article presents a practical methodology to integrate financial analysis with the development of standardized clinical practices.

Integration of a scanning ion conductance microscope into phase contrast optics and its application to the quantification of morphological parameters of selected cells.

We have previously described a pulse-mode scanning ion conductance microscope to investigate membrane surfaces and volume changes of individual cells in culture. We have now developed a miniaturized scanning headstage that enables us to select individual cells for recording under phase contrast optics, considerably improving the selection of individual cells for scanning as well as the positioning of the scanning frames with respect to the position of the cell somata. We show an application in which surfaces and volumes of somata and processes of cultured cells from the central nervous system were quantified separately.

A regional scale temporal analysis of the net migration patterns of elderly persons over time.

New England counties are grouped into categories using graphic displays of five decades of net migration rates for young and old elderly persons. Linear functions composed of social, economic, and geographic variables discriminate among the categories, yielding the following associations: positive rate counties are long-standing retirement and recreation areas; negative rate counties have large, old, declining cities; turnaround counties are nonmetropolitan counties with recently developed retirement/recreation facilities; miscellaneous counties include suburban counties with a temporary peak in net migration rates. The counties' patterns are relatively similar for young-old and old-old persons over the five decades.

Types of elderly residential mobility and their determinants.

Using data from the 1983 Annual Housing Survey, we identified four reasons for moving, which corresponded to changes in later life and which were much more frequently mentioned by movers aged 55 and older than by younger movers. These included moves made for reasons of amenity, kinship, retirement, or widowhood. The rates at which elderly persons engaged in these different types of mobility varied with age, household composition, and other characteristics. Amenity and retirement moves most often ended in destinations in the South and the West, whereas kinship and widowhood moves occurred in all regions, but were more common among those moving to nonmetropolitan than to metropolitan areas.