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Effects of immunization on cardiopulmonary alterations of gram-negative endotoxemia.

We studied the effects of an infusion of Serratia marcescens endotoxin on hemodynamic function, white blood cells, platelets, and the plasma levels of thromboxane B2 (TXB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in awake monitored sheep. The animals were immunized using the core glycolipid (CGL) fraction of Escherichia coli J5 0111. An additional group of animals was studied after passive transfer of immune serum from the actively immunized CGL animals. Active immunization with CGL was effective in preventing the hematologic and hemodynamic changes as well as the elevations in TXB2 and 6-keto-PGF1 alpha seen during gram-negative endotoxemia. Passive immunization also reduced some of the deleterious effects of endotoxin infusion but was less effective than active immunization. This study demonstrates the potential of cross-specific immunization to protect against the cardiopulmonary alterations caused by gram-negative endotoxemia.

6-Ketoprostaglandin F1 alpha↗

The role of a second isolated retinal artery in branch retinal vein obstruction.

PURPOSE: To evaluate the prevalence of a second isolated retinal artery in eyes with and without branch retinal vein obstruction (BRVO). METHODS: A retrospective study of the color photographs and fluorescein angiograms of 100 patients with unilateral BRVO (64 superotemporal and 34 inferotemporal) and a control group of 33 patients (66 eyes) with different ailments was made. The prevalence of a second isolated retinal artery, which coursed closer to the macular region, in BRVO eyes, fellow eyes and eyes of the control group was evaluated. The types and sites of arteriovenous crossings were also recorded for comparison. RESULTS: The eyes with BRVO, which involved the superotemporal quadrant, had significantly larger numbers of arteriovenous crossings than did fellow eyes (p = 0.02) and control eyes (p = 0.001). In the superotemporal quadrant, a significantly higher percentage (35 of 66, 53%) of the control eyes had a second isolated retinal artery than did BRVO eyes (16 of 64 cases, 25%, p = 0.001). CONCLUSIONS: The second isolated retinal artery, which has not been previously mentioned in the literature, may lower the chance of arteriovenous crossings and play a protective role in BRVO.

Adult↗

Synthetic recombinant vaccines against viral agents.

Synthetic recombinant vaccines are expression vectors incorporating defined epitope(s) of microbial agents. They are prepared by inserting synthetic oligonucleotide(s) coding for previously identified relevant epitopes into the genome of a desired vector, using recombinant DNA technology. The results discussed indicate that immunization with such vaccines carrying viral epitopes may lead to protective immunity against viral agents. Oligonucleotides coding for three influenza epitopes stimulating B cells, T helper cells and cytotoxic lymphocytes were individually inserted into the flagellin gene of a Salmonella vaccine strain. Immunization of mice with the resultant recombinant bacteria or their isolated flagella induced a specific mucosal anti-influenza protective response. The most efficient vaccine consisted of all three recombinant flagella, administered intranasally. The protection elicited was cross-strain specific, long-lasting and efficient against a lethal viral challenge.

Administration, Oral↗

Increased superoxide production during fatigue in the perfused rat diaphragm.

This study test the hypothesis that a temporal relationship exists between the production of superoxide anion (O2-) and the contractile activity of perfused rat diaphragm. O2- levels were determined minute to minute by measuring the reduction of cytochrome c in the perfusate as the diaphragms were subjected to various levels of contractile activity. After equilibrating at low contractile rates (one 500 ms 80 Hz train/min), diaphragms were fatigued by increasing their contractile activity for 5 min (one 500 ms 80 Hz train/s) and then allowed to recover for 30 min (one 500 ms 80 Hz train/min). During equilibration, diaphragms did not produce O2- above the background level measured in the presence of superoxide dismutase (SOD). Within the first minute of fatigue-inducing stimulation, however, the rate of O2- production increased to 0.70 +/- 0.17 nmol/min and remained elevated until the recovery period when production returned towards baseline. SOD blocked this stimulation-related increase of O2-. Tension (+/-SOD) fell to 12% of the control value during the fatigue-inducing stimulation. During recovery the contractile response returned to 51% of control, indicating long-lasting effects on the contractile machinery. SOD did not limit fatigue or improve recovery, probably because it is a large protein that cannot cross cell membranes and protect the cells by scavenging O2- at its site of production.

Animals↗

Research with participants in problem experience: challenges and strategies.

In this article, the author draws on his years of fieldwork contact with participants who experience various problem events in life, including truancy, running away, delinquency, vagrancy, homelessness, gang membership, criminal conviction, drug abuse, domestic abuse, sexual deviance, sexually transmitted disease, mental disorder, and infection with HIV/AIDS. He examines challenges from and explores strategies for research with participants in problem experience, on the matter of recruitment, participation, empowerment, cross-checking, and researcher protection. He includes examples to illustrate how generalizations in each category are made from real-world observation.

Humans↗

Population pharmacokinetics of recombinant factor XIII in cynomolgus monkeys.

Hemostasis in humans and other animals is a complex process that controls blood loss after a vascular injury. Factor XIII (FXIII) stabilizes clots primarily by cross-linking fibrin, thus protecting a newly formed clot from fibrinolysis by plasmin. Congenital deficiencies in humans involving FXIII are associated with delayed bleeding and wound healing and severe spontaneous hemorrhaging. These symptoms can be alleviated by intravenous administration of enriched FXIII plasma fractions. Circulating plasma FXIII is found as a heterotetramer that dissociates in the presence of calcium and thrombin into an active dimer and 2 inactive monomers. The recombinant FXIII under investigation is the active dimer alone. A 3-compartment, nonlinear population pharmacokinetic model was implemented in NONMEM V and then used to analyze data from preclinical studies in cynomolgus monkeys. The model simultaneously describes endogenous production of dimer (0.622 microg kg(-1) hr(-1)) and monomer (12.1 microg kg(-1) hr(-1)), and the administration of recombinant dimer. The model incorporates the rate and extent of complexation of recombinant dimer with available endogenous monomer (6.59 mg(-1) kg hr(-1)) to form the heterotetramer. Half-lives for dimer, heterotetramer, and monomer (3.33 hours, 2.83 days, and 3.94 hours for A(2), A(2)B(2), and B, respectively) were estimated, along with their variability in the population studied.

Animals↗

Risk of Alzheimer's disease and duration of NSAID use.

In a longitudinal study of 1,686 participants in the Baltimore Longitudinal Study of Aging, we examined whether the risk of Alzheimer's disease (AD) was reduced among reported users of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). In addition, we examined use of acetaminophen, a pain-relief medication with little or no anti-inflammatory activity, to assess the specificity of the association between AD risk and self-reported medications. Information on use of medications was collected during each biennial examination between 1980 and 1995. The relative risk (RR) for AD decreased with increasing duration of NSAID use. Among those with 2 or more years of reported NSAID use, the RR was 0.40 (95% confidence interval [CI]: 0.19-0.84) compared with 0.65 (95% CI: 0.33-1.29) for those with less than 2 years of NSAID use. The overall RR for AD among aspirin users was 0.74 (95% CI: 0.46-1.18), and no trend of decreasing risk of AD was observed with increasing duration of aspirin use. No association was found between AD risk and use of acetaminophen (RR = 1.35; 95% CI: 0.79-2.30), and there was no trend of decreasing risk with increasing duration of use. These findings are consistent with evidence from cross-sectional studies indicating protection against AD risk among NSAID users and with evidence suggesting that one stage of the pathophysiology leading to AD is characterized by an inflammatory process.

Acetaminophen↗

Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function.

Blood coagulation factor XIII (FXIII) is a protransglutaminase that becomes activated by the concerted action of thrombin and Ca2+ in the final stage of the clotting cascade. In addition to plasma, FXIII also occurs in platelets, monocytes, and monocyte-derived macrophages. While the plasma factor is a heterotetramer consisting of paired A and B subunits (A2B2), its cellular counterpart lacks the B subunits and is a homodimer of potentially active A subunits (A2). The gene coding for the A and B subunits has been localized to chromosomes 6p24-25 and 1q31-32.1, respectively. The genomic as well as the primary protein structure of both subunits has been established, and most recently the three-dimensional structure of recombinant cellular FXIII has also been revealed. Monocytes/macrophages synthesize their own FXIII, and very likely FXIII in platelets is synthesized by the megakaryocytes. Cells of bone marrow origin seem to be the primary site for the synthesis of subunit A in plasma FXIII, but hepatocytes might also contribute. The B subunit of plasma FXIII is synthesized in the liver. Plasma FXIII circulates in association with its substrate precursor, fibrinogen. Fibrin(ogen) has an important regulatory role in the activation of plasma FXIII. The most important steps of the activation of plasma FXIII are the proteolytic removal of activation peptide by thrombin, the dissociation of subunits A and B, and the exposure of the originally buried active site on the free A subunits. The end result of this process is the formation of an active transglutaminase, which cross-links peptide chains through epsilon(gamma-glutamyl)lysyl isopeptide bonds. Cellular FXIII in platelets becomes activated through a nonproteolytic process. When intracytoplasmic Ca2+ is raised during platelet activation, the zymogen--in the absence of subunit B--assumes an active configuration. The protein substrates of activated FXIII include components of the clotting-fibrinolytic system, adhesive and contractile proteins. The main physiological function of plasma FXIII is to cross-link fibrin and protect it from the fibrinolytic plasmin. The latter effect is achieved mainly by covalently linking alpha 2 antiplasmin, the most potent physiological inhibitor of plasmin, to fibrin. Plasma FXIII seems to be involved in wound healing and tissue repair, and it is essential to maintaining pregnancy. Cellular FXIII, if exposed to the surface of the cells, might support or perhaps take over the hemostatic functions of plasma FXIII; however, its intracellular role has remained mostly unexplored.

Animals↗

Regulation of B-CLL apoptosis through membrane receptors and Bcl-2 family proteins.

The accumulation of monoclonal chronic lymphocytic leukemia B (B-CLL) cells may be due to excessive proliferation and longevity. Clinical progression may thus come from a constitutive but altered expression of a number of genes that results in extended B-CLL cells life span, increased proliferative capacity and diminished cell death. B-CLL cells express a number of surface markers that characterise the normal B-cells phenotype. However, B-CLL cells are CD5 positive and most of them also express CD6, surface receptors that are present in just a small subset of normal B-cells. When exploring CD6 function, we found out that cross-linking of CD6 protected B-CLL from anti-IgM-induced apoptosis. CD6 activation blocked anti-IgM- induced Bax(alpha) up-regulation and, by doing so, corrected an imbalance in the Bcl-2/Bax ratio that accompanies apoptosis. Here, we review all surface receptors and cytokines that have been described as participating in the induction or protection of B-CLL apoptosis together with data on chemosensitivity and gene modulation, data on the Fas receptor/Fas ligand system, and the implications of all the latter for B-CLL cell survival.

Animals↗

Endogenous monocyte chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic peritonitis: cross-talk between MCP-1 and leukotriene B4.

We investigated the involvement of monocyte chemoattractant protein (MCP)-1 in a murine model of septic peritonitis induced by cecal ligation and puncture (CLP). Initial studies demonstrated that CLP induced a dramatic increase in MCP-1 production in the peritoneum, followed by an increase in the recruitment of leukocytes. MCP-1 blockade with anti-MCP-1 antiserum significantly decreased the survival rate following CLP, which was accompanied by an enhanced recovery of viable bacteria from the peritoneum. This was likely due to the reduction in the recruitment and activation of both macrophages and neutrophils. To understand the mechanisms whereby MCP-1 may influence neutrophil infiltration, levels of chemokines known to attract neutrophils were monitored, which showed that peritoneal levels of macrophage-inflammatory protein (MIP)-2, KC, and MIP-1alpha were not altered with anti-MCP-1 Abs. However, anti-MCP-1 Abs reduced the peritoneal levels of leukotriene B4 (LTB4) by 59%. The i.p. injection of MCP-1 into normal mice resulted in elevated levels of LTB4 in the peritoneum. In vitro, MCP-1 stimulated the production of LTB4 from peritoneal macrophages, in a dose-dependent manner. A specific LTB4 receptor antagonist (CP-105, 696) inhibited CLP-induced recruitment of both neutrophils and macrophages, which was accompanied by a reduced level of MCP-1 in the peritoneum. Finally, administration of CP-105,696 was extremely detrimental to the survival of mice following CLP. These experiments demonstrate that endogenous MCP-1 serves as an indirect mediator to attract neutrophils via the production of LTB4, and suggest the cross-talk can occur between MCP-1 and the lipid mediator LTB4 during septic peritonitis.

Animals↗

Conus hip prosthesis.

50 years ago, prosthetic replacement of the hip joint ushered in a new epoch in orthopaedics. Total hip replacement made it possible to remove a severely diseased, painful hip and restore normal function and a normal quality of life to the afflicted patient. The early results of total hip replacement are almost all spectacular and hip replacement has become the most successful type of orthopaedic surgery. These good results using an approach that was technically relatively simple resulted in a temptation to implant prosthetic hip joints with ever increasing frequency in ever younger patients. This led to the emergence of new problems, which were not so clearly recognised at the outset: it emerged that the stability of prosthetic hip joints was of limited duration. This had the following consequence: If a total hip prosthesis is implanted in an elderly person whose remaining life-expectancy is shorter than the longevity of the prosthesis, hip replacement is a life-long solution. We can therefore say that, for a patient who has only 10 to 15 years left to live, their hip problem is solved by total hip replacement. For young people, who still have a long life expectancy in front of them, it is different. They will experience failure of the artificial joint and require further surgery. The commonest and most important type of failure in total hip prostheses is aseptic loosening, which is associated with resorption of bone at the site of the prosthesis. The cause of this phenomenon has only gradually been recognised in the course of the years. Initially, the unanimous opinion was that the methacrylate cement, used to fix the components of the prosthesis in the bone, was the definitive cause of aseptic loosening because fissures and fractures of the cement were almost always found during surgical revision of loosened joints. There was talk of "cement disease" and great efforts were made to improve the quality of the cement and the cementing technique. Moreover, even today, there is no established answer to the question whether, over the course of many years, cement ages and becomes friable, a process that may have major implications for young patients. For this reason, ways of reliably fixing the prosthesis in the bone without methacrylate cement were also explored at the same time. Valuable pioneering work in this field was carried out with uncemented dental implants made of titanium and with a roughened surface. With these implants, the phenomenon of osseointegration, i.e. the deposition of bone directly on the roughened metal surface without any intervening connective tissue, was observed. This phenomenon has also been utilised successfully in hip prostheses: if artificial hips made of titanium alloy with a coarse-blasted surface and with a high primary mechanical stability are placed in the bone, osseointegration also occurs. In parallel with this development, Willert, from Göttingen, identified the most important cause of loosening of the prosthesis: he established that, when an artificial joint articulates, very fine particles of polyethylene are eroded from the prosthetic cup when the surfaces of the joint glide over one another and that these are only partially removed by the lymphatic system. A large proportion of the particles accumulates in the artificial joint and in the gap between the prosthesis and the bone, giving rise to foreign body granulomata, which resorb bone thus leading to loosening. The number of eroded particles is considerable. In 1998, Patricia Campbell, from Los Angeles, showed that 470,000 particles per step were produced from an articulation between a metal head and a polyethylene cup. This huge number gives an indication how small these particles are, since the linear erosion of the polyethylene surface only amounts to about 0.1 to 0.2 mm a year. This relatively recent recognition of "particle disease" has led to the investigation of other materials, which produce fewer erosion particles, for artificial joint articulations. Three possible options are available today, but it is not yet possible to decide for certain which of them is superior to the others: the longest experience has been with metal/metal articulation with articulatory pairings of cobalt/chromium/molybdenum alloy. In recent years, ceramic/ceramic articulations of aluminium oxide-ceramic and pairings of ceramic with highly crosslinked polyethylene have also been used. With these modern articulations, particle erosion can be reduced about 200 fold. If the erosion particles are an important cause of loosening of the prosthesis, it is reasonable to expect that, with these new joint pairings, the durability of an artificial joint can be substantially prolonged. The cone prosthesis described here has been developed on the basis of the knowledge and experience of the last 20 years. The conical anchoring of the stem, involving the placing of a conical implant in the conically reamed medullary cavity, results in continuous contact between the stem of the prosthesis and the bone, with a high degree of primary stability. The sharp longitudinal ribs on the stem, which cut a little into the bone, provide a high degree of rotational stability. In the case of conical fixation, the mechanical transmission of force varies with the diameter of the stem: the weight bearing surface of a cone in relation to its length is greater where the stem has a larger diameter than at the tip of the stem where the diameter is smaller. Therefore, for geometrical reasons, the conical fixation of the stem results in a transmission of force that is predominantly proximal and avoids proximal stress protection. The round cross-section permits free adjustment of the angle of anteversion and avoids any forced rotation as a result of bony deformity, which is very important in the case of dysplastic hips.

Adolescent↗

A preliminary diagnostic and treatment protocol.

The objectives of the preliminary diagnostic and treatment protocol are 1. To reveal retention or resistance form deficiencies. 2. To reveal need for augmentive periodontal crown-lengthening surgical procedures. 3. To evaluate pontic form for the existing space. 4. To preplan occlusal plane deficiencies and methods of corrective treatment to establish Curve of Spee. 5. To preplan occlusal scheme, i.e., canine guidance, group function, mutually protected occlusion, and cross-bite conditions. 6. To aid in preplanning sequence of treatment and method of preservation of occlusal vertical dimension. 7. To serve as a visual aid for discussion of treatment recommendations with patient prior to actual treatment. 8. To act as a medicolegal record to document the clinician's pretreatment planning in complex treatment situations for possible use in peer review or litigation. 9. To aid in fabrication of an elastomer reduction guide for use during crown preparation. 10. To aid in fabrication of a vacuum-formed template for provisional restoration of crown and abutment teeth after preparation.

Clinical Protocols↗

[Reconstruction of the anterior cruciate ligament: comparison of patellar bone-tendon-bone and hamstring tendon graft methods. Part 2. Short-term evaluation of the hamstring tendon graft technique with use of the Rigidfix system].

PURPOSE OF THE STUDY: The high number of patients with femoropatellar complaints following ACL reconstruction with bone-tendon-bone (B-T-B) autograft led us to use and subsequently evaluate hamstring tendon grafts fixed with the Rigidfix system. In this study we present the evaluation of short-term results. MATERIAL: We evaluated 85 patients (51 male and 34 female) at an average follow-up of 14 months. The average age of the group was 29.7 years (range, 16 to 59 years). In 46 patients we treated the right knee and in 39 patients the left knee. Fifty-five patients in this group also had an associated injury to the soft knee tissues. For reconstruction, a semitendinosus tendon graft was used in 56 knees and a semitendinosus-gracilis tendon graft in 29 patients. METHODS: The operation was carried out with tourniquet application to the extremity in a flexed position. The tendon of the semitendinosus muscle was harvested through an oblique incision and, in some cases, when its width and length was not sufficient for graft construction, the gracilis muscle tendon was harvested too. The graft, at least 75 mm by 8 mm in size, was prepared on a graft board. After having drilled the both tunnels, the femoral Rigidfix reamer was inserted in a routine manner and protective sleeves for Rigidfix cross pins were introduced. With the extremity in semiflexion, the inserted graft was fixed to the cortical bone by absorbable cross pins on the femur and absorbable interference screws on the tibia. The postoperative treatment involved procedures as in the B-T-B technique. RESULTS: The group was evaluated by the Lysholm score system, with an average of 84.3 scores achieved. The men showed better outcomes than women, i. e., 85.7 and 81.4, respectively. The scores in the patients with a single tendon did not differ significantly from the patients with a combined tendon (semitendinosus, 83.2 vs. semitendinosus-gracilis, 84.2), nor did they greatly differ between the patients with injury to ACL alone and those with ACL and associated soft tissue injuries (ACL, 83.9 vs. ACL+ associated injury, 85.5). Most of the patients (94 %) were satisfied with the outcome of treatment. The complications involved thrombosis of the operated lower extremity in three patients and repeat surgery for hematoma in two patients. Knee instability was found in five patients. One graft failed to restructure and incorporate, in two knee tunnels were incorrectly centered and two grafts ruptured due to trauma. Three of these patients underwent repeat surgery. DISCUSSION: Our results, as evaluated by the Lysholm score system, were in agreement with those of other authors. We did not find any difference in knee stability between the patients treated by the hamstring tendon technique and those undergoing reconstruction with a patellar B-T-B autograft. However, the patients with hamstring tendon reconstruction reported a considerably lower number of femoropatellar problems. CONCLUSIONS: ACL reconstruction with a hamstring tendon autograft fixed with the Rigidfix system is a suitable alternative technique to ACL reconstruction carried out with a patellar B-T-B graft. It provides equal knee stability but has significantly lower donor site morbidity. It is suitable for patients who have contraindications for the B-T-B technique and in persons practicing little or no sports.

Adolescent↗

Update on infection control.

Infection control is a dynamic and ever-changing subject and all dental staff should be kept aware of the most up-to-date procedures required to prevent the transmission of infection and should understand why these procedures are necessary. Regular monitoring and updating of all procedures in the light of new scientific evidence is necessary and all new staff must be trained in infection control procedures prior to working in the surgery. A practitioner who is routinely following an appropriate infection control policy, including the use of techniques and products of proven efficacy (perhaps through accreditation), is better placed to refute allegations arising in the course of civil litigation, health and safety at work prosecution, complaints and disciplinary procedures, or investigations by the GDC.

Cross Infection↗

[Preventive effect of carnosine on cataract development].

Carnosine (beta-alanyl-L-histidine) was the first and the simplest example of active peptides (actually a dipeptide). The anti-ageing effect of carnosine had been demonstrated in many studies in vivo and in vitro. More recently,there were some studies verifying the effect of carnosine on preventing cataract development. The molecular mechanisms are largely undetermined. The effect of carnosine on delaying the cataract formation may be through anti-glycation of protein, antioxidative impairment, protection protein against cross-links and DNA damage. Further study of carnosine on its biological features and the mechanisms of delaying the progression of cataractogenesis may provide a new therapy for preventing cataract.

Animals↗

Transplacental antiretroviral therapy with 9-(2-phosphonylmethoxyethyl)adenine is embryotoxic in transgenic mice.

Transgenic Mov-14 mice, which carry the provirus of Moloney murine leukemia virus (Mo-MuLV) in the germ line and begin to produce infectious virus on embryonic day 14, were used to evaluate the ability of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) to cross the placenta and protect embryos from viremia. We have used the Mov-14 model previously to demonstrate the antiviral efficacy and lack of teratogenicity of transplacental therapy with 3'-azido-3'-deoxythymidine (zidovudine, ZDV). PMEA was administered to pregnant females by daily intraperitoneal injection or by osmotic pump. In contrast to ZDV, PMEA was either noneffective in preventing viremia in the offspring or embryotoxic, depending on the dose. The specific toxic effects seen were resorption of pregnancy, low birth weight, and neonatal death. Histopathological analysis of neonatal mice exposed to PMEA showed severe lymphoid depletion of the thymus. We conclude that PMEA therapy is contraindicated for use during pregnancy.

Adenine↗

Evaluation of a dental unit designed to prevent retraction of oral fluids.

Most older units that drive high-speed dental handpieces include a retraction device designed to prevent dripping of fluids from the water-spray line after the unit has been turned off. Oral fluids and debris may be drawn, along with water, into the water line. Bacteria and debris, unless deliberately flushed out of the water line, may be transmitted to the next patient. Most new units now have mechanisms to prevent retraction. A new dental control unit, designed to eliminate mechanical aspiration of oral fluids, was tested. A kit to test the level of retraction in the water-spray line was also examined. The new unit was found to be effective in protecting the unit water from contamination by oral microorganisms, thereby protecting patients from cross-contamination. However, the control of retraction did not prevent the colonization of the water line by aquatic bacteria. Both internal and external sources of microorganisms must be controlled.

Cross Infection↗