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PubMedDate not supplied

Processes for managing pathogens.

Wastewater contains human, animal, and plant pathogens capable of causing viral, bacterial, or parasitic infections. There are several routes whereby sewage pathogens may affect human health, including direct contact, contamination of food crops, zoonoses, and vectors. The range and numbers of pathogens in municipal wastewater vary with the level of endemic disease in the community, discharges from commercial activities, and seasonal factors. Regulations to control pathogen risk in the United States and Europe arising from land application of biosolids are based on the concept of multiple barriers to the prevention of transmission. The barriers are (i) treatment to reduce pathogen content and vector attraction, (ii) restrictions on crops grown on land to which biosolids have been applied, and (iii) minimum intervals following application and grazing or harvesting. Wastewater treatment reduces number of pathogens in the wastewater by concentrating them with the solids in the sludge. Although some treatment processes are designed specifically to inactivate pathogens, many are not, and the actual mechanisms of microbial inactivation are not fully understood for all processes. Vector attraction is reduced by stabilization (reduction of readily biodegradable material) and/or incorporation immediately following application. Concerns about health risks have renewed interest in the effects of treatment (on pathogens) and advanced treatment methods, and work performed in the United States suggests that Class A pathogen reduction can be achieved less expensively than previously thought. Effective pathogen risk management requires control to the complete chain of sludge treatment, biosolids handling and application, and post-application activities. This may be achieved by adherence to quality management systems based on hazard analysis critical control point (HACCP) principles.

Agriculture↗

PubMed2000

The Hunterian Neurosurgical Laboratory: the first 100 years of neurosurgical research.

Modern neurosurgery has long had a strong laboratory foundation, and much of this tradition can be traced to the Hunterian Neurosurgical Laboratory of the Johns Hopkins Hospital. Founded with the basic goals of investigating the causes and symptoms of disease and establishing the crucial role that surgeons may play in the treatment of disease, the Hunterian laboratory has adhered to these tenets, despite the dramatic changes in neurosurgery that have occurred in the last 100 years. Named for the famous English surgeon John Hunter (1728-1793), the Hunterian laboratory was conceived by William Welch and William Halsted as a special laboratory for experimental work in surgery and pathology. In 1904, Harvey Cushing was appointed by Halsted to direct the laboratory. With the three primary goals of student education, veterinary surgery that stressed surgical techniques, and meticulous surgical and laboratory record-keeping, the laboratory was quite productive, introducing the use of physiological saline solutions, describing the anatomic features and function of the pituitary gland, and establishing the field of endocrinology. In addition, the original development of hanging drop tissue culture, fundamental investigations into cerebrospinal fluid, and countless contributions to otolaryngology by Samuel Crowe all occurred during this "crucible" period. In 1912, Cushing was succeeded by Walter Dandy, whose work on experimental hydrocephalus and cerebrospinal fluid circulation led to the development of pneumoencephalography. The early days of neurosurgery evolved with close ties to general surgery, and so did the Hunterian laboratory. After Dandy began devoting his time to clinical work, general surgeons (first Jay McLean and then, in 1922, Ferdinand Lee) became the directors of the laboratory. Between 1928 and 1942, more than 150 original articles were issued from the Hunterian laboratory; these articles described significant advances in surgery, including pioneering research on calcium metabolism by William MacCallum and Carl Voegtlin and seminal preclinical work by Alfred Blalock and Vivian Thomas that led to the famous "blue baby" operation in 1944. With the introduction of the operating microscope in the 1950s, much of the focus in neurosurgical science shifted from the laboratory to the operating room. The old Hunterian building was demolished in 1956. The Hunterian laboratory for surgical and pathological research was rebuilt on its original site in 1987, and the Hunterian Neurosurgical Laboratory was reestablished in 1991, with a focus on novel treatments for brain tumors. The strong tradition of performing basic research with clinical relevance has continued.

Baltimore↗

PubMed2001

Decline in structural examination compliance in the hospital medical record with advancing level of training.

A retrospective review of 115 randomly pulled hospital charts of patients admitted to the care of osteopathic physicians at an American Osteopathic Association-accredited primary care hospital revealed a significant decline in the frequency of structural examinations in history and physical examinations during a merger and relocation, as well as with increasing level of training of the examiner (chi 2 test, P < .001). Attending physicians completed fewer structural examinations (45% of their history and physical examinations) compared to house staff (70%) and students (92%). A follow-up anonymous survey of 100 osteopathic physicians and students (response rate, 58%) revealed that the low overall frequency of structural examination completion (60%) was due primarily to attending physicians who considered this examination less relevant or impractical for their hospitalized patients. These results indicate that education on relevance of structural examination and manipulative treatment for acutely ill patients needs to be directed not only to house staff and students but also to attending physicians to preserve and improve the use of osteopathic principles at osteopathic hospitals.

Attitude of Health Personnel↗

PubMed1997

Functional guidance components and their cellular distribution in retinotectal co-cultures.

Recent advances in the study of the developmental processes that direct afferent axons toward their final destinations are beginning to elucidate the cellular and molecular bases for the early development of retinotectal topography. The present review focuses on two guidance components (repulsive and adhesive) and their cellular localization as revealed by a newly established retinotectal co-culture system. These co-cultures enable general outgrowth patterns to be examined when retinal ganglion cell (RGC) axons attempt to traverse cells dissociated from their target nuclei. Additionally, the recording of RGC growth cone responses to single living target cells allows a cellular localization of guidance components that is not possible by other methods. This co-culture system, therefore, complements the repertoire of cell-culture techniques used to investigate the sequence of cellular events that underlie the establishment of retinotopic development. With this new approach, time-lapse micrographs were collected when RGC growth cones from temporal or nasal regions of embryonic chick retinae encountered individual cells dissociated from optic tecta. Temporal RGC growth cones collapsed and retracted with a high probability from neuronal cells dissociated from posterior tecta, indicating that repellent components were enriched on posterior target neurons. The response to non-neuronal cells revealed a separate effect on axonal outgrowth that was less dependent upon the particular region of retina or tectum from which the cells originated: most RGC axons adhered to the edge of non-neuronal cells, without retracting. Together, the localization of repellent and adhesive components suggests a sequence of events that occurs during the early stages of tectal innervation and that results in the rudiments of retinotopic projection, and furthermore, it raises a number of experimentally approachable questions concerning the functional expression of several guidance components.

Animals↗

PubMed1989

Respiratory infections and acute lung injury in systemic illness.

We have discussed the relationship between systemic illness, infection, and lung disease. As we have seen, patients with a wide variety of disease states, including advanced age, diabetes mellitus, alcoholism, collagen vascular disease, cancer, heart failure, and organ transplantation are potentially at increased risk for pneumonia because of disease-related impairments in host defenses. In addition, two virtually ubiquitous conditions in hospitalized patients, malnutrition and therapeutic interventions (especially with common medications), frequently add to the risk of airway invasion by bacterial pathogens. Systemic illness not only makes lung infection more common, but may adversely affect outcome and resolution, as well as determine the clinical presentation of pneumonia. In one particular population, the intubated and mechanically ventilated patient, the risk of infection is particularly high, and nosocomial pneumonia is a major cause of mortality. To the extent that the host response itself leads to the symptoms and signs of infection, systemically ill individuals may have subtle clinical features when serious bacterial invasion is present. Many components of the host defense system can become abnormal with serious illness, but a common mechanism that ties many systemic diseases to pneumonia is an alteration in airway epithelial cell receptivity for bacteria, namely, bacterial adherence, a process that mediates airway colonization, the first pathogenetic step on the road to pneumonia. The impetus for understanding how serious illness promotes lung infection is that once these mechanisms are identified, potential preventative strategies to minimize infection risk in the individual with systemic disease may be developed. The relationship among systemic illness, the lung, and infection also exists in a different direction: infection of a systemic nature (the septic syndrome) can lead to disease in the lung (ARDS). We have described the features of the septic syndrome and identified how it may lead to lung injury, usually by indirect means, through activation of inflammatory mediators that are carried to the lung via the vasculature. Although it is frequently impossible to predict which specific patient with systemic sepsis will develop acute lung injury, the current state of knowledge does permit us to identify high-risk individuals. Surprisingly, clinical assessment rather than biochemical testing is the best predictor of the development of acute lung injury. Patients with severe injury, profound shock and multiple systemic insults are most prone to acute lung injury in the presence of systemic sepsis.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗

PubMed2003

The alcohol interlock: an underutilized resource for predicting and controlling drunk drivers.

This report summarizes evidence presented during the Third Annual Ignition Interlock Symposium at Vero Beach, Florida, 29 October 2002. The ignition interlock prevents a car from starting when blood alcohol concentration (BAC) is elevated. We review some of our prior work as well as introduce previously unpublished results to demonstrate the manner in which the data recorded by the alcohol ignition interlock device can serve as an advance predictor of future driving under the influence (DUI) of alcohol risks. Data used in this current report represent approximately 2,200 ignition interlock users from Alberta, Canada, and about 8,000 interlock users from Quebec, Canada; the Alberta data set contained 5.5 million breath tests and the Quebec data 18.8 million breath tests. All tests are time and date stamped and this information was used to characterize patterns of BAC and vehicle use, and the relationship between BAC elevations and DUI offenses that accumulated after the interlock was removed from the vehicles. Findings from Cox regression show that BAC elevations >.02-.04% are more potent predictors of repeat DUI (p<.0001) than even prior DUI (p<.006), usually found to be the strongest indicator of driver risk. Prior DUI obviously has no use for scaling the risk of first-time offenders. Drivers who are both multiple offenders and who have more than a few elevated interlock BAC tests are much more likely to repeat DUI. The timing and pattern of elevated BAC tests provided during the time drivers were required to use an alcohol ignition interlock device are remarkably similar on both a daily basis and an hourly basis when the interlock programs from the two provinces are compared directly. Both provinces had higher rates of elevated tests on Saturday and Sunday, and the fewest elevated tests on Tuesdays. The absolute rate of elevated tests is similar despite the two provinces adhering to different interlock lockout points (.02% Quebec;.04% Alberta). Charts tracking the Monday-Friday timing of elevated BAC tests by hour are nearly identical for both provinces. The most elevated BAC tests occurred between 7 and 9 A.M. Monday to Friday, even though most vehicle start attempts occurred much later in the day. This higher rate of elevated morning BAC likely represents drinking from the prior evening with alcohol not yet cleared from circulation; those with elevated BAC in the early morning were more likely to have a repeat offense even after accounting for prior DUI and the higher overall rate of elevated BAC tests. This is viewed as evidence of a drinking problem that will lead to impaired driving after the controlling function of the interlock is removed. Policy changes are discussed that might take better advantage of interlock information to improve the public response to drunk driving.

Accidents, Traffic↗

PubMed1976

[Influence of the administration of levamisole on the reactivity of T-lymphocytes in advanced cancer patients].

The effects of levamisole were studied by evaluating T-cell responsiveness to a low dose of PHA on 31 advanced cancer volunteers. Treatment consisted in a 3-time a week oral administration of 150 mg of levamisole, actual time of observation is comprized between 10 and 31 months: 14 out of 31 treated metastatic cases of various solid tumours are still alive. In a group of 25 untreated patients, mean survival times were 65 days for men and 48 days for women. An increase of the responsiveness to a low dose of PHA was associated with survival, while death occurred when T-cells were unable to respond to the stimulatory activity of levamisole. These preliminary data confirm the paramount importance of cellular immunity in controlling neoplasias. They suggest a possibility to augment the life-span of cancer patients if an impaired cellular immunity machinery could be restored by the direct and indirect (hormonal) actions of levamisole, evidencing these mechanisms were still potentially functionning. They suggest also a monitoring of anti-tumoral immunity by evaluating the magnitude of T-cell response following levamisole administration.

Administration, Oral↗

PubMed1988

Risk factors and prevention of atherosclerosis: specific prevention directed to the high-risk patients.

The high-risk population strategy of coronary heart disease prevention are not alternatives but complement each other, both being parts of a comprehensive community programme. High-risk persons must be detected through screening and require more individual and intensive protection than persons at lesser risk for whom the population approach provides adequate preventive care. The relative effectiveness of the two strategies may be compared, using data from prospective epidemiological studies. The high-risk strategy alone compares well with a limited population strategy alone but the balance is shifted in favour of the population at large. In practice, it does not matter to compare the two strategies in isolation but to assess their effectiveness in combination; it can be shown that the combined effect is likely to make a major dent in the burden of disease in the population. It used to be thought and hoped that the discovery of new and more powerful risk factors would discriminate more sharply between future cases and non-cases of coronary heart disease and thus concentrate the majority of new events in a minority of the population. An attempt was made to show that new advances will add to the preventive potential inherent in risk factors but are not likely to identify future victims of the disease with such precision that the high-risk strategy would eventually supplant the population strategy. Instead, new screening strategies must be developed to detect and protect to the greatest possible extent all the risk carriers who are scattered, in terms of single and multiple risk factors, all-over the population. A major responsibility for the effectiveness of the high-risk strategy is carried by the practicing physician, to select the best treatment for individuals and their families and to encourage adherence to a new life style, as well as compliance with drug therapy, if indicated.

Arteriosclerosis↗

PubMed2003

The alcohol interlock: an underutilized resource for predicting and controlling drunk drivers.

This report summarizes evidence presented during the Third Annual Ignition Interlock Symposium at Vero Beach, Florida, 29 October 2002. The ignition interlock prevents a car from starting when blood alcohol concentration (BAC) is elevated. We review some of our prior work as well as introduce previously unpublished results to demonstrate the manner in which the data recorded by the alcohol ignition interlock device can serve as an advance predictor of future driving under the influence (DUI) of alcohol risks. Data used in this current report represent approximately 2,200 ignition interlock users from Alberta, Canada, and about 8,000 interlock users from Quebec, Canada; the Alberta data set contained 5.5 million breath tests and the Quebec data 18.8 million breath tests. All tests are time and date stamped and this information was used to characterize patterns of BAC and vehicle use, and the relationship between BAC elevations and DUI offenses that accumulated after the interlock was removed from the vehicles. Findings from Cox regression (Marques et al., 2003) show that BAC elevations > .02-.04% are more potent predictors of repeat DUI (p < .0001) than even prior DUI (p < .006), usually found to be the strongest indicator of driver risk. Prior DUI obviously has no use for scaling the risk of first-time offenders. Drivers who are both multiple offenders and who have more than a few elevated interlock BAC tests are much more likely to repeat DUI. The timing and pattern of elevated BAC tests provided during the time drivers were required to use an alcohol ignition interlock device are remarkably similar on both a daily basis and an hourly basis when the interlock programs from the two provinces are compared directly. Both provinces had higher rates of elevated tests on Saturday and Sunday, and the fewest elevated tests on Tuesdays. The absolute rate of elevated tests is similar despite the two provinces adhering to different interlock lockout points (.02% Quebec; .04% Alberta). Charts tracking the Monday-Friday timing of elevated BAC tests by hour are nearly identical for both provinces. The most elevated BAC tests occurred between 7 and 9 A.M. Monday to Friday, even though most vehicle start attempts occurred much later in the day. This higher rate of elevated morning BAC likely represents drinking from the prior evening with alcohol not yet cleared from circulation; those with elevated BAC in the early morning were more likely to have a repeat offense even after accounting for prior DUI and the higher overall rate of elevated BAC tests. This is viewed as evidence of a drinking problem that will lead to impaired driving after the controlling function of the interlock is removed. Policy changes are discussed that might take better advantage of interlock information to improve the public response to drunk driving.

Accidents, Traffic↗

PubMed2003

Techniques of selective cannulation and sphincterotomy.

Selective access into the desired duct followed by incision of the sphincter, i. e. sphincterotomy, forms the cornerstone of any endoscopic intervention within the pancreaticobiliary system. The apprehensive beginner's performance and hesitance is aggravated by ignorance of ampullary anatomy and he considers selective cannulation to be the greatest hurdle. An understanding of ampullary morphology and its variations is vital in achieving selective cannulation. Technological advances have assisted in the form of development of better accessories, progressing from "immovable" catheters to movable cannulae and to single-, double-, and even triple-lumen sphincterotomes. Orientation along the long axis of the bile duct ensures access and avoids inadvertent and hazardous manipulation of the pancreatitic duct. Using guide wires, especially the 'angulated-tip' glide wire improves cannulation successs rates considerably. Precut accessotomy complements wire-guided selective cannulation, and can be used analogously to a controlled surgical incision to facilitate cannulation of the desired system after deroofing the papilla layer by layer. Published data have validated its role, demonstrating high efficacy and minimal complications when it is properly performed. Biliary sphincterotomy, using the right mode of blended current in the 11-12 o'clock direction and with the tip of the sphincterotome wire, provides a clean and bloodless splitting open of the sphincter of Oddi. Pancreatic precut, over-the-stent papillotomy and sphincterotomy over a guide wire have all been proven to be safe and effective measures, in large groups of patients. In special situations, such as where there are impacted stones or ampullary lesions, needle-knife infundibulotomy achieves reliable access. Techniques such as saline infiltration into the papilla and subtle body movements to re-position the scope enable biliary cannulation in difficult situations. Alterations in anatomy, for instance post Billroth II gastrectomy, no longer discourage the endoscopist from attempting intervention. Application of knowledge of reverse anatomy, specially designed instruments, and adherence to the proper technique improves success in these patients. Our experience of 9000 sphincterotomies over the past 12 years with minimal morbidity stands proof to the principles and techniques highlighted in this monograph. We recommend these to all aspiring endoscopists, with the assurance of improved technical success when they are implemented.

Biliary Tract Diseases↗

PubMed1997

[Recent advances in adjuvant chemotherapy in colonic cancers].

Carcinoma of the large bowel is one of the most common malignant disease. In France, 15,000 died each year from the metastatic or locoregional progression of this cancer. In the past, effective surgical adjuvant therapy has been an elusive goal with no evidence of benefit from chemotherapy or immunotherapy. However, a meta-analysis published in 1988 showed that one-year adjuvant chemotherapy using 5-fluorouracil (5-FU) containing regimens may slightly improve survival. Accelerated progress has been made since 1990: in colon cancer with regional nodal metastasis (stage C tumor), therapy with combined 5-FU and levamisole has resulted in a 33% reduction in the death rate. Controlled clinical trials demonstrated improved tumor response rates when the combination of 5-FU and leucovorin was compared with single-agent 5-FU in patients with metastatic colorectal cancer. Recent results indicate that this combination is effective in preventing tumor relapse and improving survival in patients with high risk colon cancer (especially stage C tumor). The comparison of 5-FU and leucovorin to 5-FU and levamisole is ongoing; the preliminary results of these controlled trials showed that 6 months of adjuvant therapy with 5-FU and leucovorin is as effective as the standard 12 months 5-FU and levamisole regimen and less toxic. No clear adjuvant benefit has been established in patients with Dukes' stage B2 colon cancer. The lack of statistical power of the trials and the 80% overall survival rate of these patients may explain these negative results. Almost all the specialists of these tumors considered that it is possible to select patients who are at sufficiently high risk of recurrence so that treatment can be justified. These patients are those who presented initially with tumor perforation or obstruction, adherence to or invasion of adjacent organs, young patients. Clinical trials suggest a survival benefit from the direct portal administration of the 5-FU in the immediate post-operative period, although the magnitude of the effect is less than that seen in the systemic therapy trials.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Lower body lift with superficial fascial system suspension.

Multiple body contour deformities of the trunk and thighs are commonly treated in separate stages to limit postoperative complications and disability. Recent advances in the surgical design of the medial thigh lift and the lateral thigh/buttock lift along with an understanding of the functional anatomy of the superficial fascial system have significantly improved results and decreased complications of trunk/thigh lifts. The enhanced safety of current trunk/thigh lifts has allowed new combinations to treat multiple body contour deformities in a single stage. Laxity of the entire lower trunk and thigh regions can be treated in one stage in selected patients. The lower body lift combines the transverse flank/thigh/buttock lift and the fascial anchoring medial thigh lift in one operation. In addition to the expected tightening of the flank, buttocks, and total thighs, this procedure results in a surprising degree of epigastric and hypogastric tightening of mild to moderate abdominal laxity without direct surgical undermining or umbilical transposition. Ten patients having the lower body lift alone or in combination with liposuction and other body contouring procedures were followed for 6 to 24 months. The primary indication for surgery is moderate to severe soft-tissue laxity of the lower trunk and thighs with minimal or mild residual fat deposits. Skin contour irregularities due to skin laxity (cellulite of laxity) or to postliposuction adhesions are frequently present and may be severe. Patients with significant fat deposits may be treated initially with liposuction 3 to 4 months earlier to become candidates for this procedure. Key technical elements of this procedure include (1) both supine and lateral decubitus positioning with the hip flexed and abducted to allow overcorrection, (2) appropriate direct surgical undermining through superficial fascial system zones of adherence in the superior thigh while avoiding the lymphatics of the femoral triangle, (3) more distal undermining of the thighs with an atraumatic undermining cannula, (4) resection of redundant lower trunk and thigh tissues with incisional closure within high-cut bikini lines, and (5) complete superficial fascial system and dermal suspension throughout the repair. The lower body lift requires 5 to 6 hours of operating time, 2 units of autologous blood, 2 nights of nursing care, and 3 weeks off work. Although no major complications occurred, minor complications were significantly higher than with the component procedures alone and occurred in 50 percent of patients. Technical changes and improved patient selection have significantly improved the rate of complications in subsequent patients. Results have been consistent, and patient satisfaction has remained high.

Adipose Tissue↗

PubMedDate not supplied

Novel biologically based therapies for myeloma.

Recent advances in our understanding of the molecular regulation of myeloma cells suggest novel strategies for treating multiple myeloma. Some myeloma cells express a 69 kD variant of Ku86, a heterodimer subunit that is essential for double-stranded DNA break repair. Presence of the variant impairs DNA repair; therefore normal Ku86 in myeloma cells confers resistance to therapy and may represent a therapeutic target. The upregulation of NF-kappaB-dependent interleukin-6 (IL-6) transcription and secretion that occurs following adhesion of myeloma cells to bone marrow stromal cells (BMSCs) may serve as a potential therapeutic target, as IL-6 is a growth and survival factor for myeloma cells. Accordingly, proteasome inhibitors inhibit activation of NF-kappaB and induce apoptosis of myeloma cells; they also inhibit the NF-kappaB-dependent up-regulation of IL-6 in BMSCs and related paracrine growth of adherent tumor cells. Therapeutic strategies may also target the mitogen-activated protein kinase (MAPK) pathway that is thought to mediate the IL-6-induced proliferation of myeloma cells. Vascular endothelial growth factor (VEGF) is also upregulated by adhesion of myeloma cells to BMSCs and may serve as a growth and/or survival factor for myeloma cells; preliminary studies suggest that VEGF receptor inhibitors may block proliferation of tumor cells. Thalidomide was recently used successfully to treat myeloma in patients whose disease was refractory to conventional treatment. An enhanced understanding of the mechanisms of action of thalidomide may result in the development of analogues with enhanced potency and fewer side effects. The potential mechanisms of action of thalidomide are reviewed, including antiangiogenic effects; direct effects of thalidomide on the growth and survival of myeloma cells and BMSCs; modulation of adhesive interactions; and regulation of secretion and bioactivity of cytokines. Immune-based strategies for treating multiple myeloma are also reviewed. Therapeutic obstacles include excessive toxicity after allografting, contaminating tumor cells in autografts, and the persistence of minimal residual disease (MRD) after high-dose therapy followed by allogenic or autologous stem cell transplantation. Allografting can be performed safely in myeloma, donor lymphocyte infusions (DLI) may effectively treat relapsed myeloma post allografting; and use of CD4+ T cell-enriched DLI may reduce the risk of graft-versus-host disease. Treatment with autografting is frequently compromised by MRD in the autograft and in the patient post myeloablative therapy. Adenoviral purging prior to autotransplantation and in vivo and ex vivo stimulation of autoimmune cells are discussed as potential approaches to address these problems.

Angiogenesis Inhibitors↗

PubMed1996

Coordination of protrusion and translocation of the keratocyte involves rolling of the cell body.

We have investigated the relationship between lamellipodium protrusion and forward translocation of the cell body in the rapidly moving keratocyte. It is first shown that the trailing, ellipsoidal cell body rotates during translocation. This was indicated by the rotation of the nucleus and the movement of cytoplasmic organelles, as well as of exogenously added beads used as markers. Activated or Con A-coated fluorescent beads that were overrun by cells were commonly endocytosed and rotated with the internal organelles. Alternatively, beads applied to the rear of the cell body via a micropipette adhered to the dorsal cell surface and also moved forward, indicating that both exterior and underlying cortical elements participated in rotation. Manipulation of keratocytes with microneedles demonstrated that pushing or restraining the cell body in the direction of locomotion, and squeezing it against the substrate, which temporarily increased the intracellular pressure, did not effect the rate of lamellipodium protrusion. Rotation and translocation of the cell body continued momentarily after arrest of lamellipodium protrusion by cytochalasin B, indicating that these processes were not directly dependent on actin polymerization. The cell body was commonly flanked by phase-dense "axles," extending from the cell body into the lamellipodium. Phalloidin staining showed these to be comprised of actin bundles that splayed forward into the flanks of the lamellipodium. Disruption of the bundles on one side of the nucleus by traumatic microinjection resulted in rapid retraction of the cell body in the opposite direction, indicating that the cell body was under lateral contractile stress. Myosin II, which colocalizes with the actin bundles, presumably provides the basis of tension generation across and traction of the cell body. We propose that the basis of coupling between lamellipodium protrusion and translocation of the cell body is a flow of actin filaments from the front, where they are nucleated and engage in protrusion, to the rear, where they collaborate with myosin in contraction. Myosin-dependent force is presumably transmitted from the ends of the cell body into the flanks of the lamellipodium via the actin bundles. This force induces the spindle-shaped cell body to roll between the axles that are created continuously from filaments supplied by the advancing lamellipodium.

Animals↗

PubMed2002

New targets for antithrombotic drugs.

The normal hemostatic process is initiated by disruption in the vascular continuity and exposure of the subendothelial components. Platelets adhere to subendothelium-bound von Willebrand factor via glycoprotein (GP) Ib complex. This initial interaction per se and the release of platelet agonists transduce signals that lead to the rise in intracellular Ca(2+). The rise in Ca(2+) induces shape change, prostaglandin synthesis, release of granular contents and conformational changes in platelet Gp IIb-IIIa. Gp IIb-IIIa in activated platelets becomes competent to bind fibrinogen and other adhesive proteins and mediates platelet cohesion (primary hemostatic plug). Furthermore, the activated platelet surface provides an efficient catalytic surface for the coagulation reactions, ultimately resulting in the formation of fibrin (secondary hemostasis). Normally the hemostatic process plays a delicate balance between keeping the blood in the fluid state to maintain flow and rapidly forming an occluding plug following vessel injury. Thrombosis occurs because of alteration in this delicate balance. Consequences of thrombosis are a major cause of morbidity and mortality in industrialized countries. Arterial thrombosis occurs in the setting of previous vessel wall injury mostly because of atherosclerosis, while venous thrombosis occurs in areas of stasis. The recent advances in our understanding of the hemostatic process have led to a better elucidation of the mechanism of action of many antithrombotic drugs and identification of new targets for drug development. The molecular target of the well known antiplatelet drug ticlopidine has been identified. Large numbers of IIb-IIIa inhibitors have been developed based on the crystal structure of a potent antagonist echistatin. The mechanism of action of heparin has been defined at the molecular level. As a result a synthetic pentasaccharide, based on antithrombin-binding domain of heparin, has been developed and tested successfully in clinical trials. New generation direct thrombin inhibitors are being developed based on the crystal structure of thrombin. Factor Xa has a critical position at the convergence of intrinsic and extrinsic pathway ways. The clinical tolerability and the efficacy of low molecular weight heparins led to the concept that inhibition of further thrombin generation, by blocking factor Xa alone, can be an effective way of preventing thrombus growth without inactivating thrombin. A large number of specific factor Xa inhibitors are under development. Some of these drugs have already undergone preliminary clinical trials and appear to be promising. Future clinical trials will determine whether these new drugs will provide better risk-benefit ratio in treatment of thrombotic disorders.

Anticoagulants↗

PubMed2004

A phase I and pharmacokinetic study of Col-3 (Metastat), an oral tetracycline derivative with potent matrix metalloproteinase and antitumor properties.

PURPOSE: The purpose of this research was to assess the feasibility of administering Col-3, an oral chemically modified tetracycline derivative with potent inhibitory effects on matrix metalloproteinase activity and production, and recommend a dose on an uninterrupted once-daily schedule. The study also sought to characterize the pharmacokinetic behavior of Col-3 and seek evidence of anticancer activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of Col-3 with dose level assignment according to an accelerated titration scheme. Because photosensitivity skin reactions were being reported in concurrent trials of Col-3, patients were instructed to apply sunscreen rigorously throughout the trial. The maximum tolerated dose was defined as the highest dose at which <2 of the first 6 new patients experienced dose-limiting toxicity. The pharmacokinetic behavior of Col-3 was characterized, and pharmacodynamic relationships were sought. RESULTS: Thirty-three patients were treated with 73 courses of Col-3 at four dose levels ranging from 36 to 98 mg/m2/day. Unacceptably high incidences of photosensitivity skin reactions and malaise were noted in the first 28-day courses of patients treated with Col-3 at doses exceeding 50 mg/m2/day. At 50 mg/m2/day, severe toxicity occurred in 2 of 12 new patients in first courses, and no additional dose-limiting toxicities were observed in subsequent courses. Other mild to modest adverse effects included nausea, vomiting, liver function tests abnormalities, diarrhea, mucositis, leukopenia, and thrombocytopenia. The pharmacokinetics of Col-3 were dose proportional, and mean trough concentrations at steady state were similar to biologically relevant concentrations in preclinical studies. Major responses did not occur, but durable disease stability was noted in 3 patients, one each with carcinosarcoma of the uterus, pancreas, and ovary, all of whom had experienced disease progression before Col-3 treatment. CONCLUSIONS: The recommended dose for Phase II studies of Col-3 administered once daily on an uninterrupted schedule is 50 mg/m2/day accompanied by efforts that promote adherence to the use of sunscreen and other photoprotective measures. Pharmacokinetic results indicate that plasma concentrations above biologically relevant concentrations are readily maintained at this dose, and additional disease-directed studies, particularly in patients with soft tissue sarcoma, should be considered.

Administration, Oral↗

PubMed2000

Changing concepts of atherogenesis.

This review discusses three stages in the life history of an atheroma: initiation, progression and complication. Recruitment of mononuclear leucocytes to the intima characterizes initiation of the atherosclerotic lesion. Specific adhesion molecules expressed on the surface of vascular endothelial cells mediate leucocyte adhesion: the selectins and members of the immunoglobulin superfamily such as vascular cell adhesion molecule-1 (VCAM-1). Once adherent, the leucocytes enter the artery wall directed by chemoattractant chemokines such as macrophage chemoattractant protein-1 (MCP-1). Modified lipoproteins contain oxidized phospholipids which can elicit expression of adhesion molecule and cytokines implicated in early atherogenesis. Progression of atheroma involves accumulation of smooth muscle cells which elaborate extracellular matrix macromolecules. These processes appear to result from an eventual net positive balance of growth stimulatory versus growth inhibitory stimuli, including proteins (cytokines and growth factors) and small molecules (e.g. prostanoids and nitric oxide). The clinically important complications of atheroma usually involve thrombosis. Arterial stenoses by themselves seldom cause acute unstable angina or acute myocardial infarction. Indeed, sizeable atheroma may remain silent for decades or produce only stable symptoms such as angina pectoris precipitated by increased demand. Recent research has furnished new insight into the molecular mechanisms that cause transition from the chronic to the acute phase of atherosclerosis. Thrombus formation usually occurs because of a physical disruption of atherosclerotic plaque. The majority of coronary thromboses result from a rupture of the plaque's protective fibrous cap, which permits contact between blood and the highly thrombogenic material located in the lesion's lipid core, e.g. tissue factor. Interstitial collagen accounts for most of the tensile strength of the plaque's fibrous cap. The amount of collagen in the lesion's fibrous cap depends upon its rate of biosynthesis stimulated by factors released from platelets (e.g. transforming growth factor beta or platelet-derived growth factor), but inhibited by gamma interferon, a product of activated T cells found in plaques. Degradation by specialized enzymes (matrix metalloproteinases) also influences the level of collagen in the plaque's fibrous cap. Such studies illustrate how the application of cellular and molecular approaches has fostered a deeper understanding of the pathogenesis of atherosclerosis. This increased knowledge of the basic mechanisms enables us to understand how current therapies for atherosclerosis may act. Moreover, the insights derived from recent scientific advances should aid the discovery of new therapeutic targets that would stimulate development of novel treatments. Such new treatments could further reduce the considerable burden of morbidity and mortality due to this modern scourge, and reduce reliance on costly technologies that address the symptoms rather than the cause of atherosclerosis.

Arteriosclerosis↗

PubMed2000

Minorities, women, and clinical cancer research: the charge, promise, and challenge.

Significant progress has been made since the war against cancer was launched. Discoveries in molecular medicine, genetics, and epidemiology have led to the recognition that certain cancers are potentially preventable and that elements of lifestyle, along with genetic, hormonal, and metabolic factors can be altered to reduce cancer risk. Advances in medical technology have led to the development of new imaging methods and computer technologies that can aid in efforts to detect, diagnosis, and treat cancer. Since the offensive against cancer was initiated, cancer treatments have become more powerful, more precise, less drastic, and safer. As a result, cancer incidence and mortality have begun to decline. Yet, while the nation boasts of the progress being achieved relative to cancer incidence and mortality, and federal research agencies retort that research applies to all populations, it is apparent that the declines do not translate to all populations in the United States. Clinical research is essential to cancer prevention and control. Within the oncology community, clinical cancer research trials are viewed as an efficient and economical way for patients to secure state-of-the-science medical care. Recognizing the need to improve access to state-of-the-science cancer treatment and control programs, minority and female participation in clinical cancer research trials has been encouraged. This recommendation is based on the belief that increased participation in well-designed clinical cancer research trials adhering to strict protocols and quality controls will, not only help validate the application of research findings to minority and female populations, but also result in better patient outcomes. Born out of a commitment to social equity, justice, beneficence, and the desire to ensure that data relevant to cancer prevention and control are both valid and generalizable to populations across the United States, several programs of research aimed toward increasing the representation of women and minorities in clinical cancer research have been pursued by the National Cancer Institute. This issue of the Annals of Epidemiology Minorities, Women, and Clinical Cancer Research presents issues and challenges that face the research community and descriptions of effective models, strategies, and practices that may be used to increase the participation of minorities and women in clinical cancer research trials and facilitate the conduct of research directed toward reducing the cancer burden within the United States.

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