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PubMed2002

The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.

It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance.

Alzheimer Disease↗
PubMed2004

Growth cone pathfinding: a competition between deterministic and stochastic events.

BACKGROUND: Growth cone migratory patterns show evidence of both deterministic and stochastic search modes. RESULTS: We quantitatively examine how these two different migration modes affect the growth cone's pathfinding response, by simulating growth cone contact with a repulsive cue and measuring the resultant turn angle. We develop a dimensionless number, we call the determinism ratio Psi, to define the ratio of deterministic to stochastic influences driving the growth cone's migration in response to an external guidance cue. We find that the growth cone can exhibit three distinct types of turning behaviors depending on the magnitude of Psi. CONCLUSIONS: We conclude, within the context of these in silico studies, that only when deterministic and stochastic migration factors are in balance (i.e. Psi ~ 1) can the growth cone respond constructively to guidance cues.

Algorithms↗
PubMed1998

Medical outshopping intent: profiling the health care consumer.

The health care industry has been exposed to a tremendous upheaval in the last decade. The traditional practices have given way to new behaviors and structures. This is especially true for community hospitals that have long provided the major portion of health care services in their markets. Their traditional local service area, once thought of as fairly much their sole domain, is being redefined. Consumers are becoming more aware of alternative health delivery options, thus choosing to go outside of their local trading area for these alternatives. This study investigates consumer characteristics and influences driving this behavior. Implications for hospital marketing practices are discussed.

Adult↗
PubMed1992

Outcomes measurement in hospitals: can the system change the organization?

The U.S. health care industry is in crisis--a crisis of accountability. Many believe that improved information, especially outcomes information, is at least part of the solution. If this assessment is accurate, outcomes measurement could offer a powerful opportunity to help mold our dysfunctional health care machinery into an effective infrastructure. This article explores whether implementing an outcomes measurement system in a hospital compels this kind of change. It examines the experiences of 31 hospitals that implemented a market-leading outcomes measurement system. Despite its potential, MedisGroups did not compel important improvements in hospitals' quality of care or their internal practices. Hospitals found it particularly difficult to maintain momentum throughout implementation and to structure the system as a supporting tool, rather than a driving influence, in their pursuit of operating improvements.

Evaluation Studies as Topic↗
PubMed1994

Virtual reality in surgery and medicine.

This report documents the state of development of enhanced and virtual reality-based systems in medicine. Virtual reality systems seek to simulate a surgical procedure in a computer-generated world in order to improve training. Enhanced reality systems seek to augment or enhance reality by providing improved imaging alternatives for specific patient data. Virtual reality represents a paradigm shift in the way we teach and evaluate the skills of medical personnel. Driving the development of virtual reality-based simulators is laparoscopic abdominal surgery, where there is a perceived need for better training techniques; within a year, systems will be fielded for second-year residency students. Further refinements over perhaps the next five years should allow surgeons to evaluate and practice new techniques in a simulator before using them on patients. Technical developments are rapidly improving the realism of these machines to an amazing degree, as well as bringing the price down to affordable levels. In the next five years, many new anatomical models, procedures, and skills are likely to become available on simulators. Enhanced reality systems are generally being developed to improve visualization of specific patient data. Three-dimensional (3-D) stereovision systems for endoscopic applications, head-mounted displays, and stereotactic image navigation systems are being fielded now, with neurosurgery and laparoscopic surgery being major driving influences. Over perhaps the next five years, enhanced and virtual reality systems are likely to merge. This will permit patient-specific images to be used on virtual reality simulators or computer-generated landscapes to be input into surgical visualization instruments. Percolating all around these activities are developments in robotics and telesurgery. An advanced information infrastructure eventually will permit remote physicians to share video, audio, medical records, and imaging data with local physicians in real time. Surgical robots are likely to be deployed for specific tasks in the operating room (OR) and to support telesurgery applications. Technical developments in robotics and motion control are key components of many virtual reality systems. Since almost all of the virtual reality and enhanced reality systems will be digitally based, they are also capable of being put "on-line" for tele-training, consulting, and even surgery. Advancements in virtual and enhanced reality systems will be driven in part by consumer applications of this technology. Many of the companies that will supply systems for medical applications are also working on commercial products. A big consumer hit can benefit the entire industry by increasing volumes and bringing down costs.(ABSTRACT TRUNCATED AT 400 WORDS)

Computer Simulation↗
PubMed2002

Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain.

Although injury-induced afferent discharge declines significantly over time, experimental neuropathic pain persists unchanged for long periods. These observations suggest that processes that initiate experimental neuropathic pain may differ from those that maintain such pain. Here, the role of descending facilitation arising from developing plasticity in the rostral ventromedial medulla (RVM) in the initiation and maintenance of experimental neuropathic pain was explored. Tactile and thermal hypersensitivity were induced in rats by spinal nerve ligation (SNL). RVM lidocaine blocked SNL-induced tactile and thermal hypersensitivity on post-SNL days 6-12 but not on post-SNL day 3. Lesion of RVM cells expressing mu-opioid receptors with dermorphin-saporin did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Similarly, lesions of the dorsolateral funiculus (DLF) did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Lesions of the DLF also blocked the SNL-induced increase in spinal dynorphin content, which has been suggested to promote neuropathic pain. These data distinguish mechanisms that initiate the neuropathic state as independent of descending supraspinal influences and additional mechanism(s) that require supraspinal facilitation to maintain such pain. In addition, the data indicate that these time-dependent descending influences can underlie some of the SNL-induced plasticity at the spinal level. Such time-dependent descending influences driving associated spinal changes, such as the upregulation of dynorphin, are key elements in the maintenance, but not initiation, of neuropathic states.

Animals↗
PubMed2002

[Progress in developing anti-Alzheimer drugs].

According to the amyloid hypothesis, accumulation of beta amyloid in the brain seems to be the primary influence driving Alzheimer's disease pathogenesis. From the studies of A beta production, aggregation, degradation and clearance, several strategies for preventing or delaying the disease onset and progression have been postulated. These are beta-secretase inhibitors, gamma-secretase inhibitors, A beta degrading enzymes, anti-cholesterol drugs, non-steroidal anti-inflammatory drugs, beta-sheet breakers, chelating agents, SAP competitors, beta-amyloid vaccination, agents for trapping peripheral A beta, and so on. Here I review recent progress in developing anti-Alzheimer drugs.

Alzheimer Disease↗
PubMed2004

Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy?

beta-Secretase, a beta-site amyloid precursor protein (APP) cleaving enzyme (BACE), participates in the secretion of beta-amyloid peptides (Abeta), the major components of the toxic amyloid plaques found in the brains of patients with Alzheimer's disease (AD). According to the amyloid hypothesis, accumulation of Abeta is the primary influence driving AD pathogenesis. Lowering of Abeta secretion can be achieved by decreasing BACE activity rather than by down-regulation of the APP substrate protein. Therefore, beta-secretase is a primary target for anti-amyloid therapeutic drug design. Several approaches have been undertaken to find an effective inhibitor of human beta-secretase activity, mostly in the field of peptidomimetic, non-cleavable substrate analogues. This review describes strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids (siNAs). These include antisense oligonucleotides, catalytic nucleic acids - ribozymes and deoxyribozymes - as well as small interfering RNAs (siRNAs). While antisense oligonucleotides were first used to identify an aspartyl protease with beta-secretase activity, all the strategies now demonstrate that siNAs are able to inhibit BACE gene expression in a sequence-specific manner, measured both at the level of its mRNA and at the level of protein. Moreover, knock-down of BACE reduces the intra- and extracellular population of Abeta40 and Abeta42 peptides. An anti-amyloid effect of siNAs is observed in a wide spectrum of cell lines as well as in primary cortical neurons. Thus targeting BACE with small inhibitory nucleic acids may be beneficial for the treatment of Alzheimer's disease and for future drug design.

Alzheimer Disease↗
PubMed1976

[Proceedings: D-Amphetamine in manic syndrome (author's transl)].

Six manic patients were acutely treated with 30 or 50 mg d-amphetamine, respectively. There was no intensification in any of these patients of gross manic behavior or single manic symptoms. Conversely, there was sedation and considerable reduction of manic symptomatology in all of them. This effect lasted for 1 to 3 h only. The clinical subgroup "elated-grandiose" was significantly, the subgroup "paranoid-destructive" was not significantly influenced. "Drive" and "mood" were similarly reduced. There was, however, no complete recovery from mania.

Adult↗
PubMed1996

Socio-economic factors in cardiovascular disease.

INCREASING RATES OF CARDIOVASCULAR DISEASE AMONG LOWER SOCIO-ECONOMIC GROUPS: Evidence from English studies indicates that not only is cardiovascular disease mortality more common among lower social classes, but there is an inverse social gradient. For example, one study showed that the higher the employment grade the lower the mortality, a finding that also held for most of the major causes of death. Between the early 1970s and early 1980s, coronary heart disease mortality rates declined by 15% in men in non-manual occupations and increased by 1% in manual occupations. Differences could not be attributed to medical care alone. This widening social gap in mortality rates has continued, and a similar pattern has been observed in other countries. EAST-WEST DIFFERENCES: Through the 1950s and 1960s, cardiovascular mortality and life expectancy were similar in central European countries on both sides of the iron curtain. From the late 1960s, however, there was marked divergence in mortality rates with improvement in the West and stagnation or deterioration in the countries of central and eastern Europe. After 1989 with the lifting of the iron curtain, Russia and some other eastern countries began to show a marked deterioration in life expectancy. In Russia life expectancy appears to have declined from 63 to 59 years in about 4 years. CURRENT RESEARCH ON MULTIPLE PATHWAYS: As we understand more of the biological mechanisms underlying the pathogenesis of cardiovascular disease, the more it becomes clear that these processes have multiple influences driving them. In our current research, we are using a model of potential pathways linking socio-economic status to diabetes mellitus and coronary heart disease in an attempt to confirm or refute the links in this model.

Behavior↗
PubMed1987

Drug findings in 'Driving Under the Influence of Drugs' cases: a problem of illicit drug use.

Drug findings in 137 drug positive cases of Driving Under the Influence of Drugs (DUID) occurring in St. Louis, Missouri, U.S.A. from June 1983 through May 1986 are presented. Thirty-two different drugs were detected. A single agent was detected in only 34% (47/137) of cases. The most frequently encountered drugs, expressed as percent of positive cases, were: phencyclidine, 47%; marijuana, 47%; benzodiazepines, 22%; barbiturates, 15%; opiates, 11%; and cocaine, 9%. Most multiple drug cases involved popular illicit drug mixtures, such as cocaine and morphine (speedballs) or phencyclidine on marijuana (whack). All the drivers in this survey had displayed inappropriate or impaired operation of a motor vehicle to the extent that a law enforcement officer had stopped and charged them for DUID. In at least 81% of the drug positive cases, persons impaired in the operation of a motor vehicle from a drug or drugs other than alcohol, were impaired not as the result of side effects of therapeutic drug use, but as the result of deliberate self intoxication with illicit or controlled substances.

Automobile Driving↗
PubMedDate not supplied

On the high road: driving under the influence of cannabis in Ontario.

While cannabis is the most frequently found illegal drug in drivers killed or injured in motor vehicle collisions, little is know about driving under the influence of cannabis (DUIC) in the general population. We report information on the incidence of DUIC in a representative sample of the Ontario adult population. Among all drivers, 1.9% reported DUIC in the previous 12 months. Several factors influenced the likelihood of reported DUIC, including gender, age, marital status and education level. Among cannabis users, DUIC appeared to be a relatively common behaviour; 22.8% reported DUIC, and the probability of the behaviour was significantly influenced by gender and education level. As well, DUIC and drinking-driving were strongly related in this sample. These data underscore the need to obtain more information on this behaviour, including a more complete understanding of any risks involved.

Accidents, Traffic↗
PubMed2005

Driving under the influence of drugs in Sweden with zero concentration limits in blood for controlled substances.

OBJECTIVE: This article describes the background and implementation in Sweden of zero-concentration limits for controlled drugs in the blood of drivers. Eliminating the need to prove that a person's ability to drive safely was impaired by drugs has greatly simplified the prosecution case, which now rests primarily on the forensic toxicology report. Driving under the influence of a prescription drug listed as a controlled substance is exempt from the zero-limit law provided the medication was being used in accordance with a physician's direction and the person was not considered unfit to drive. METHODS: The prevalence of driving under the influence of drugs (DUID) in Sweden was evaluated from police reports with the main focus on the toxicological findings. A large case series of DUID suspects was compared before and after introducing zero concentration limits in blood for controlled substances on July 1, 1999. The spectrum of drugs used by typical offenders and the concentrations of various licit and illicit substances in blood were evaluated and compared. RESULTS: Immediately after the zero-limit law came into force, the number of cases of DUID submitted by the police for toxicological analysis increased sharply and is currently ten-fold higher than before the new legislation. Statistics show that about 85% of all blood samples sent for toxicological analysis have one or more banned substances present. Amphetamine is by far the leading drug of abuse in Sweden and was identified in about 50-60% of all DUID suspects either alone or together with other controlled substances. The next most frequently encountered illicit drug was tetrahydrocannabinol (THC), with positive findings in about 20-25% of cases. Various prescription drugs, mainly sedative-hypnotics like diazepam and flunitrazepam, were also highly prevalent and these occurred mostly together with illicit substances. Opiates, such as 6-acetyl morphine and morphine, the metabolites of heroin, were high on the list of substances identified. Most DUID suspects in Sweden were men (85%) who were poly-drug users combining illicit substances, like amphetamine and/or cannabis, with a prescription medication such as various benzodiazepines. CONCLUSIONS: Sweden's zero-concentration limit has done nothing to reduce DUID or deter the typical offender because recidivism is high in this population of individuals (40-50%). Indeed, many traffic delinquents in Sweden are criminal elements in society with previous convictions for drunk and/or drugged driving as well as other offenses. The spectrum of drugs identified in blood samples from DUID suspects has not changed much since the zero-limit law was introduced.

Automobile Driving↗
PubMed2004

Addicted to driving under the influence--a GHB/GBL case report.

A 38-year-old male was arrested 7 times over an 8-month period for driving under the influence (DUI) of drugs. In each incident, gamma-hydroxybutyrate (GHB) was determined to be the causative agent. A blood specimen was drawn between 1.5 and 2.5 h after first police contact in each arrest. GHB was analyzed by gas chromatography-mass spectrometry, following extraction from blood using ethyl acetate and subsequent derivatization using BSTFA/TMCS. Blood GHB concentrations ranged from 44 to 184 mg/L (N = 7, mean 100 mg/L, median 73 mg/L). Overall signs of impairment included erratic driving (severe lane travel, collisions, and near-collisions), slurred speech, disorientation, slow to react, shaking, agitation, unable to focus, poor coordination and balance, poor performance in field sobriety tests, somnolence, and unconsciousness. On only one occasion were other drugs present in the subject's blood (thiopental and diazepam), which may have contributed to the observed driving impairment. During several police interviews, the subject stated he was addicted to GHB and gamma-butyrolactone (GBL), and admitted to previously taking "RenewTrient", "Dream On", "V35", "fitness supplements", and/or "GBL". During the same period as his DUI arrests, the subject had been admitted at least six times to different hospitals for GHB/GBL intoxications.

4-Butyrolactone↗
PubMed2005

Oral fluid testing for driving under the influence of drugs: history, recent progress and remaining challenges.

In recent years the demand for drug testing in oral fluid in cases of driving under the influence has been increasing. The main advantages of saliva/oral fluid are the possibility for non-medical personnel to collect it without embarrassment and a better correlation between presence of drugs in oral fluid and impairment. Several surveys have been performed since the 1980s using saliva, and researchers encountered problems related to insufficient sample volume and insufficient sensitivity of the analytical methods. Steady progress has been shown in sample collection, knowledge of toxicokinetics in oral fluid, reliability of on-site and laboratory-based immunoassays and confirmation methods. In a few countries, legislation was passed that allows the use of saliva as a matrix for screening or confirmation. Despite this progress, some more work needs to be done, principally in the areas of the sensitivity and reliability of on-site screening devices, particularly for cannabis and benzodiazepines, knowledge about passive contamination and more generalised proficiency testing before oral fluid testing for DUID will have the reliability needed to be used forensically.

Automobile Driving↗
PubMed1996

Expectancies for driving under the influence of alcohol among Hispanics and non-Hispanic Whites.

A random sample of 1418 (40.8% male) Hispanics and 501 (46.1% male) non-Hispanic Whites were surveyed about their behavioral expectations for driving under the influence of alcoholic beverages (DUI). Hispanics reported more often than Whites that the effects of DUI would be driving carelessly, being angry at other drivers, feeling nervous, losing the respect of friends, feeling guilty, feeling too tired to drive, and losing their self-respect. There were gender differences among Hispanics but not among Whites. Hispanic abstainers reported the likelihood of the various outcomes more frequently than drinkers although drinking status produced no statistically significant differences among non-Hispanic Whites.

Acculturation↗
PubMed1994

[Driving under the influence of alcohol, drugs and narcotics].

The National Institute of Forensic Toxicology has registered a large increase in the number of samples from drivers suspected of driving under the influence of drugs other than alcohol. Illegal and prescribed drugs are detected in an increasing number of cases. In many of these cases, the drugs are combined with alcohol. The most frequent drugs detected in 1992 in addition to alcohol were tetrahydrocannabinol (the psychoactive compound in cannabis) and benzodiazepines, mostly detected at blood concentrations above therapeutic levels. Simultaneous use of different benzodiazepines and use of benzodiazepines in combination with illegal drugs are common. The number of samples containing amphetamine showed a significant increase in 1992 compared with 1991 (an increase of 80%).

Alcohol Drinking↗