Improved risk stratification in unstable angina: identification of patients at low risk for in-hospital cardiac events by admission echocardiography

BACKGROUND: Current protocols for risk stratification of patients with acute chest pain syndromes rely on clinical parameters and are oriented toward identification of patients at high risk for adverse cardiac events; however, this paradigm for risk stratification does not adequately address the observation that adverse cardiac events are relatively uncommon in this population. In an era of cost containment, consideration also should be given to identification of patients at low risk for adverse cardiac events, who may be safely discharged without expensive inpatient hospitalization. HYPOTHESIS: The purpose of this study was to develop echocardiographic predictors that identify unstable angina patients at low risk for adverse cardiac events and that discriminate between low- and high-risk patients. METHODS: The predictive accuracy of retrospectively determined echocardiographic predictors were compared in a population-based sample of 66 consecutive unstable angina patients undergoing echocardiography within 24 h of admission. RESULTS: Echocardiographic predictors of adverse events included wall motion score index > or = 0.2, ejection fraction < or = 40%, and mitral regurgitation severity > 2. One or more echocardiographic predictors of adverse events were present in 32 patients (48%). A composite echocardiographic predictor of adverse events was specific, had a high positive predictive value for the identification of high-risk patients, and discriminated between unstable angina patients at high and low risk for adverse cardiac events. CONCLUSION: Echocardiographic predictors of adverse events are specific and discriminate between unstable angina patients at high and low risk for adverse cardiac events.     

Evidence for a phase transition in the early development of prehension

The genotoxicity of twenty one clinically used (or discontinued) antihistamines is reviewed. New results are also presented from an evaluation of selected antihistamines in the V79 in vitro micronucleus assay. For two antihistamines, no genotoxicity data is available. Of the remaining nineteen, nine have been reported as positive and one equivocal in at least one genotoxicity assay despite the fact that none possess structural alerts for genotoxicity. Ethidium displacement and bleomycin amplification studies in V79 cells indicate that nine of these ten antihistamines are capable of intercalative DNA binding. Further, nine of the ten positive compounds, but none of the tested compounds which also intercalate but are reported to be negative in gene-tox assays (e.g. triprolidine, chlorcyclizine, clemastine), possess a dimethylamino substituent suggesting the requirement for this cationic function in the genotoxicity. It is proposed that the apparent genotoxicity of antihistamines and possibly many other pharmaceuticals derives from a hitherto unappreciated propensity of these drugs for stabilized intercalative DNA binding. It is further proposed that the bleomycin amplification assay may provide a widely applicable means for assessing functional intercalative drug/DNA interaction in intact mammalian cells.     

Polymorphic expression of the UDP-glucuronosyltransferase UGT1A gene locus in human gastric epithelium

OBJECTIVES: Adenosine, a potent coronary vasodilator is used as a pharmacologic stress agent for the assessment of coronary artery disease. A paucity of data exists on its effects on filling dynamics. Accordingly, this study was undertaken to evaluate the effects of adenosine on left ventricular filling as assessed by Doppler echocardiography. METHODS AND RESULTS: We studied 69 patients (45 men, 24 women, aged 61+/-11 years) referred for evaluation of coronary artery disease. Two-dimensional echocardiography and pulsed-Doppler recordings at the mitral valve tips and annulus were performed at baseline and at maximal adenosine infusion of 140 microg/kg/min. During adenosine infusion, an increase in heart rate occurred (70+/-14 beats/min to 85+/-16 beats/min), with a mild decrease in blood pressure (130/75+/-26/13 mm Hg vs 119/66+/-25/13 mm Hg); both p < 0.02. Changes in filling dynamics included an increase in peak early inflow velocity, E/A ratio, and normalized peak filling rate. Of the patients investigated, 23 had one-vessel coronary artery disease, 29 had coronary disease in two vessels or more by angiography, and 17 had no significant disease. Patients without coronary artery disease (controls) had mild changes in E/A ratio (mean 7%). Patients with coronary artery disease had a more heterogeneous change in filling dynamics (range 43% to 369%, mean 26%), with a significant overlap with controls. However, changes in E/A ratio during adenosine infusion that exceeded the confidence limits of normal (-20% to +30%) were specific for coronary artery disease, with a positive predictive value of 84%. CONCLUSIONS: Normally, adenosine induces significant increases in early filling as assessed by Doppler. The changes in patients with coronary stenosis are more variable. When these changes fall outside the confidence limits of normal, they are predictive of coronary artery disease.     

Is NADH effective in the treatment of Parkinson''s disease?

SNAREs are compartmentally specific membrane proteins required for intracellular membrane fusion. Homologues of the Saccharomyces cerevisiae protein Sec1p interact with, and are likely to be involved in regulation of, the syntaxin family of SNAREs. In yeast there are 7 functionally distinct syntaxins but only four clearly identifiable homologues of Sec1p. One of these, Vps45p, is required for transport from Golgi to late endosomes, and has been implicated in the function of the late endosomal syntaxin Pep12p. However, there is evidence that not all the functions of Pep12p are equally dependent on Vps45p, and conversely that the phenotypes of vps45 mutants cannot be explained entirely by loss of Pep12p activity. We have recently characterised two yeast syntaxins which function in trans-Golgi or endosomal compartments, Tlg1p and Tlg2p. We show here that the principal binding site for Vps45p on intracellular membranes is provided by Tlg2p rather than Pep12p, and that Vps45p is required for stable expression of Tlg2p. Vps45p is also associated with Tlg1p as part of a triple complex containing both Tlg1p and Tlg2p. Since a deltavps45 deltatlg2 double mutant has a more severe vacuolar protein sorting defect than a deltatlg2 mutant, Vps45p cannot only interact with Tlg2p. It appears that the role of Vps45p in protein traffic is more complex than has previously been assumed.     

Plasma von Willebrand factor changes during various reproductive cycle stages in mixed-breed dogs with normal von Willebrand factor and in Doberman pinschers with type-I von Willebrand''s disease

The immediate effects of oxidized low density lipoprotein (OxLDL) on the metabolic activity of cultured macrophages (RAW 264.7) were studied using a microphysiometer. Administration of OxLDL acutely induced a concentration-dependent increase in metabolic activity, with an EC50 of 16 +/- 3 microg/ml OxLDL and a maximal effect of 35% +/- 4% (mean +/- SEM; n=5). A biphasic response was measured after administration of 75 or 100 microg/ml OxLDL consisting of an initial sharp increase, followed by the induction of a long-lasting hypoactivity of 80% of the control value. Incubation of cells with polyinosinic acid (polyI; 100 microg/ml) for 30 min prior to OxLDL administration could completely block the effect of 25 microg/ml OxLDL. In addition, polyI acted as a full antagonist on the decrease of the biphasic response of cells generated by 75 and 100 microg/ml OxLDL. Macrophages used in this study possessed a specific binding site for OxLDL, with a dissociation constant (KD) of 9 +/- 2 microg/ml and a maximal binding of 610 +/- 32 ng 125I-OxLDL/mg cell protein. Binding of 125I-OxLDL to macrophages could be completely competed for by unlabeled OxLDL, by polyI for 58%, and by AcLDL for 46%. In conclusion, OxLDL can acutely activate the metabolic state of macrophages by a receptor-mediated process in a concentration-dependent fashion, which could be antagonized by polyI. Metabolic responses to OxLDL may underlie the changes observed in macrophages in the early atherosclerotic plaque.     

Immunization with a single major histocompatibility complex class I-restricted cytotoxic T-lymphocyte recognition epitope of herpes simplex virus type 2 confers protective immunity

We have evaluated the potential of conferring protective immunity to herpes simplex virus type 2 (HSV-2) by selectively inducing an HSV-specific CD8(+) cytotoxic T-lymphocyte (CTL) response directed against a single major histocompatibility complex class I-restricted CTL recognition epitope. We generated a recombinant vaccinia virus (rVV-ES-gB498-505) which expresses the H-2Kb-restricted, HSV-1/2-cross-reactive CTL recognition epitope, HSV glycoprotein B residues 498 to 505 (SSIEFARL) (gB498-505), fused to the adenovirus type 5 E3/19K endoplasmic reticulum insertion sequence (ES). Mucosal immunization of C57BL/6 mice with this recombinant vaccinia virus induced both a primary CTL response in the draining lymph nodes and a splenic memory CTL response directed against HSV gB498-505. To determine the ability of the gB498-505-specific memory CTL response to provide protection from HSV infection, immunized mice were challenged with a lethal dose of HSV-2 strain 186 by the intranasal (i.n.) route. Development of the gB498-505-specific CTL response conferred resistance in 60 to 75% of mice challenged with a lethal dose of HSV-2 and significantly reduced the levels of infectious virus in the brains and trigeminal ganglia of challenged mice. Finally, i.n. immunization of C57BL/6 mice with either a recombinant influenza virus or a recombinant vaccinia virus expressing HSV gB498-505 without the ES was also demonstrated to induce an HSV-specific CTL response and provide protection from HSV infection. This finding confirms that the induction of an HSV-specific CTL response directed against a single epitope is sufficient for conferring protective immunity to HSV. Our findings support the role of CD8(+) T cells in the control of HSV infection of the central nervous system and suggest the potential importance of eliciting HSV-specific mucosal CD8(+) CTL in HSV vaccine design.     

Antiinflammatory effect of tepoxalin: blood and synovial tissue studied in patients with knee arthrosis

The role of carbohydrates in embryo implantation in the mouse was investigated using an embryo transfer model and a blastocyst-uterine epithelial cell co-culture system. The monoclonal antibody (mAb) AH6 directed to LeY oligosaccharide (Fuc alpha1-2 Gal beta 1-4 [Fuc alpha1-3] GlcNAc) and other three mAbs directed to carbohydrates whose structures are closely related to LeY were used to show the effect of carbohydrate specificity on implantation. In the embryo transfer model, donor blastocysts (4 days post-coitus) were pretreated with mAb AH6 (experimental) or other mAbs (control) and transferred into one uterine horn of a recipient. The implantation rate was checked after 5 days. Implantation was significantly inhibited by mAb AH6 pretreatment, and inhibition was not observed in control groups. In the co-culture system, the attachment and outgrowth rate of blastocysts on the surface of uterine epithelial cells was significantly inhibited when monolayer epithelial cells or blastocysts were pretreated with mAb AH6. The most obvious effect of mAb AH6 was obtained during 2-4 h co-incubation. No inhibition was observed in the control groups. It was, therefore, concluded that oligosaccharide LeY recognized by mAb AH6 plays an essential role at the initial stage of implantation. It may act as a mediator molecule for adhesion between the surface of blastocyst and epithelial cell, and its function is carbohydrate-specific.     

Laparoscopic inguinal herniorrhaphy: the new gold standard of hernia repair?

The surgical treatment of the common inguinal hernia has been one of the most analyzed and debated topics in medicine. Recently, with the success of laparoscopic cholecystectomy, interest in minimally invasive surgical techniques has led to it's application for inguinal hernia repair. Current laparoscopic herniorrhaphies are based on the principles of conventional open preperitoneal repairs and are classified into two types: 1) transabdominal preperitoneal repair (TAPP) and 2) totally extraperitoneal repair (TEP). Common advantages to both techniques include a decrease in postoperative pain, earlier return to normal activity, and improved cosmesis. Both laparoscopic techniques have the disadvantage of requiring general or regional anesthesia and increased procedural costs. Lastly, there is a concern that laparoscopic hernia repair has not been around long enough to know the risk of late recurrences. Laparoscopic herniorrhaphy, however, is a viable alternative to standard open inguinal hernia repair.     

The human capsaicin model of allodynia and hyperalgesia: sources of variability and methods for reduction

The paper deals with the hydrodynamics of artificial heart valves (AHVs) used in clinical practice. It reviews and analyzes the studies of AHV hydrodynamics, as well as the hydrodynamic beds which stimulate physiological flow through the valve. Photochronic imaging (PCI) is proposed for examination of AHV hydrodynamic characteristics under model physiological flow. The hydrodynamics of different AHVs was tested on the beds simulating blood flow through AHVs by employing PCI. PCI involved preparation of model photochronic solution that simulates blood, colour labels by using laser radiation. In the model photochronic solution, 10(-6)-10(-9)-sec laser radiation gave rise to linear colour labels whose movement was recorded by a speed camera in the flow behind the valve. The profiles of speed behind the valves, the dimensions of congestive areas, the positions of flow detachment and regurgitation flow were calculated by a speed shooting in different periods of valvular performance. PCI defined congestive areas behind the valves, the areas of closed circulations, the sizes of reversing flow areas and examined the time course of flow behind the valves as a whole. The paper is of interest for AHV designers and cardiac surgeons who apply various AHVs.