Understanding and treating vein graft atherosclerosis.

BACKGROUND: Vein grafts have been used as bypass conduits for coronary artery disease since the 1960s. This widely used treatment, however, is complicated by the development of changes in the vein graft, which resemble atherosclerosis and are often termed as such. They occur at about 10 years, which leads to the need for reoperation in some patients. The purpose of this review is to summarize the knowledge regarding the pathophysiology of vein graft "atherosclerosis," as well as promising new treatments for this disease. METHODS: The relevant literature relating to the epidemiology, histology, cell and molecular pathophysiology and treatment of vein graft atherosclerosis is reviewed. RESULTS: The development of vein graft atherosclerosis differs from arterial atherosclerosis. Studies have examined the role of trauma, lipids, vasoactive mediators, smooth muscle cell mitogens, smooth muscle cells apoptosis, adhesion molecules and proteases. Therapies have been developed to prevent vein graft atherosclerosis based on these studies and have been tested using animal models and in patients. DISCUSSION: Promising new therapies have been developed based on current knowledge and further applications of genomics will allow for the further identification of risk factors and mechanistic insights. The use of arterial grafts such as the internal mammary artery, which have higher patency rates at 10 years compared with vein grafts as well as approaches to revascularize infarcted myocardium may one day replace the use of vascular conduits.     

Understanding and treating incompleteness in obsessive-compulsive disorder

Incompleteness-the troubling and irremediable sense that one's actions or experiences are not "just right"--appears to underlie many of the symptoms of obsessive-compulsive disorder (OCD). Because incompleteness may reflect basic sensory-affective dysfunction, it presents a challenge to clinicians wishing to apply cognitive-behavioral treatments. In this article, I review ways of adapting well-demonstrated treatment principles to this condition. A case is presented and then used to discuss challenges in conducting cognitive-behavioral therapy with this population. Behavioral methods aimed at habituation (e.g., exposure and ritual prevention [ERP]) are probably more applicable than conventional cognitive techniques. However, even these may result in modest long-term gains; relapse is a probability if they are not actively practiced after treatment cessation.     

Understanding and treating hoarding: a biopsychosocial perspective

This article offers a practice-friendly review of conceptualizing and treating hoarding based on biological and psychological research. Although hoarding has commonly been conceptualized as a variant of obsessive-compulsive disorder, research suggests a more complex pattern of overlap with attention deficit-hyperactivity disorder, organic brain disease, depression, anxiety, personality disorders, and impulsivity. The phenomenon of hoarding is discussed in terms of familial and environmental vulnerabilities, maladaptive cognitive process, maladaptive cognitive content, and maladaptive behavioral patterns. The article concludes with a summary of treatment efficacy and 10 promising clinical practices.     

HIV protease inhibitors and dyslipidemia

Highly active antiretroviral therapy (HAART) significantly prolongs the lives of HIV-infected patients. Current regimens may consist of a protease inhibitor (PI) combined with at least two or more other antiretroviral drugs. PI administration has been shown to be associated with alterations in plasma lipids (i.e. prompt and sustained increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides) and insulin levels that place PI-treated patients at risk for coronary heart disease (CHD). Because PI-associated dyslipidemia is generally asymptomatic and occurs in patients who are often younger than those traditionally at risk for CHD, the need for primary prevention of acute coronary events in these patients is often unappreciated. Statins form a significant component of pharmacotherapy for PI-associated dyslipidemia. However, because PIs and all statins except pravastatin are metabolized by the cytochrome P450 (CYP) system, co-administration of these agents produces a significant risk of drug interactions and statin-induced hepatotoxicity and myopathy. This risk can be greatly reduced by administering a statin not metabolized by CYP. The need for lipid reduction therapy may be minimized with the use of new PIs that are comparable in efficacy to current PIs but do not negatively affect lipid levels.     

Avascular necrosis and protease inhibitors

Avascular necrosis (AVN) indicates ischemic death of the bone due to insufficient arterial blood supply. The incidence rate of AVN is higher in HIV-infected patients than in the general population. Although the exact etiology of AVN remains unclear, the literature has shown a relationship between AVN and exposure to highly active antiretroviral therapy (HAART). It should be noted, however, that AVN has been reported before the era of HAART, thus suggesting the involvement of other causative factors as well. Three case reports based on patients attending the infectious disease clinic are presented. No cases of AVN are reported in our clinic population prior to this report. Affected sites of AVN included the hip and shoulders. The incidence of AVN within our patient population was higher than the general population. Although the introduction of HAART has improved patient longevity, it has also led to longer exposure to antiretroviral (ARV) therapy. Thus, it is likely that treatment-related complications may become more apparent in the HIV-infected population. This may be the case with AVN. Therefore, clinicians need to be alert to the potential complication of AVN in HIV-infected patients treated with HAART.     

New protease inhibitor

The FDA has approved Agenerase (generic name amprenavir), a new protease inhibitor which costs about $6,500 per year. Eight 150mg gelatin capsules, twice a day, can be taken without food restrictions. Potential side effects include nausea, fatigue, and headache. About 20 percent of patients developed a rash, that was life-threatening in 1 percent. Early data indicate that the drug does not cause lipodystrophy. Drug interactions are possible with some antihistamines, sedatives, and anti-fungal agents. Website contact information is provided.     

Trypsin-like protease of mites: purification and characterization of trypsin-like protease from mite faecal extract Dermatophagoides farinae. Relationship between trypsin-like protease and Der f III

A serine protease from mite faecal extract, Dermatophagoides farinae, was purified using DEAE-Sephacel anion exchange chromatography and Superdex 75 pg gel chromatography. The molecular weight of this protease was 34 kD on SDS-PAGE under reducing conditions. The optimal pH and temperature of the protease were 8.0 and 47 degrees C, respectively. In addition, this protease cleaved arginyl or lysyl residue containing substrates selectively and was only inhibited by aprotinin, FUT-175, and soy bean trypsin inhibitor and not by chymostatin, E-64 and iodoacetic acid. These results show that our purified serine protease belongs to the trypsin-type. Purified trypsin-like protease was shown to be allergenic by enzyme-linked immunosorbent assay. Antigenicity of trypsin-like protease was completely different from those of Der f I and Der f II. Both, 20 N-terminal amino acid sequence and amino acid compositions of the purified protease were very similar to those of Der f III. Good similarities were found between trypsin-like protease and Der f III concerning physicochemical properties such as molecular weight on SDS-PAGE and ammonium sulphate solubility. Summarizing the above data, it can be concluded that a trypsin-like protease from mite faecal extract is actually the Der f III allergen and that it may be involved in the digestive process of the mite as it was found not in mite body but in mite faeces.     

Hymenoptera venom protease allergens

BACKGROUND: Recent studies have shown the presence of additional allergenic proteins in honeybee and paper wasp venoms. Both venoms contain serine protease enzymes. OBJECTIVE: We isolated and obtained complete sequences of honeybee and Mediterranean paper wasp venom proteases, both of which have significant IgE binding activity. The structures are compared with bumblebee venom protease. METHODS: Venom proteases were chromatographically isolated from venoms and partial amino acid sequences determined. RT-PCR and rapid amplification of cDNA ends methods were used to clone cDNA, and complete sequences were determined for honeybee and a paper wasp venom protease. RESULTS: The venom proteases are all serine proteases of the trypsin type. The honeybee protease contains a complement, embryonic sea urchin protein, bone morphogenetic protein interaction domain as well as a linker and propeptide sequence, and a unique methionine residue near the active site. It has IgE binding activity. The paper wasp protease is a single trypsin domain and is an important allergen. The framework residues are poorly conserved among honeybee, bumblebee, and paper wasp enzymes. CONCLUSIONS: The 3 venom serine proteases have significant IgE binding activities. The structures are poorly conserved even among the Apidae , suggesting little cross-reactivity among the protein portions. The paper wasp venom proteases are important allergens.     

Trials for protease failure

The AIDS Clinical Trials Group (ACTG) is preparing two trials for persons who are on a protease inhibitor regimen that has failed. ACTG 398 will use the experimental drug, amprenavir (141W94), in addition to three drugs from different anti-HIV medication classes, and possibly one other protease inhibitor. ACTG 400 is for people whose viral load is greater than 1,000 after 16 weeks of treatment with Viracept (Nelfinavir). Some exclusion criteria are listed. Contact information is provided.     

SPINK家族与人类疾病

丝氨酸蛋白酶抑制物Kazal型(SPINK)家族与慢性胰腺炎、Netherton综合征、食管癌等疾病关系密切。目前对SPINK1、SPINK5、SPINK7等亚族的研究比较清楚,其他一些亚族还有待深入研究。本文综述了SPINK家族的基因定位、蛋白质结构、生理功能以及与人类疾病的关系。     

Serine protease inhibitors and cytotoxic T lymphocytes

Summary: Serine proteases control a wide variety of physiological and pathological processes in multi-cellular organisms, including blood clotting, cancer, cell death, osmoregulation, tissue remodeling, and immunity to infection. Cytotoxic T lymphocytes (CTLs) are required for adaptive cell-mediated immunity to intracellular pathogens by killing infected cells and through the development of memory T cells. Serine proteases not only allow a CTL to kill but also impose homeostatic control on CTL number. Serine protease inhibitors (serpins) are the physiological regulators of serine proteases’ activity. In this review, I discuss the role of serpins in controlling the recognition of antigen, effector function, and homeostatic control of CTLs through the inhibition of physiological serine protease targets. An emerging view of serpins is that they are important promoters of cellular viability through their inhibition of executioner proteases. This view is discussed in the context of the T-lymphocyte survival during effector responses and the development and persistence of long-lived memory T cells. Given the important role serpins play in CTL immunity, I discuss the potential for developing new immunotherapeutic approaches based directly on serpins or knowledge gained from identifying their physiologically relevant protease targets.     

Oxidant and protease injury of the lung

Oxidants are generated in vivo by multiple mechanisms, including stimulation of leukocytes, hyperoxia, metabolism of arachidonic acid, and the activation of various oxidases. When the biochemical defences to the oxidants are inadequate, injury of tissues results. This injury was observed in rabbits and rhesus monkeys when pulmonary inflammation was induced with phorbol esters or formylated peptide given intrabronchially. We have recently investigated metabolic changes in various cells exposed to oxidants that are generated from stimulated leukocytes, including H2O2, O2, and HOCl. The target cells used were P388D1 murine macrophage-like tumour cells, human peripheral lymphocytes, GM 1380 human fibroblasts and rabbit alveolar macrophages. The oxidants used were H2O2 and PMA stimulated PMNs or neutroplasts. Lysis could only be prevented when catalase was added within the first 30-40 min of H2O2 exposure indicating that early metabolic changes determined the fate of the cell. Within seconds after the addition of H2O2 to P388D1 cells activation of the hexose monophosphate shunt (HMPS) was observed indicative of increased glutathione cycle activity. At the same time DNA strand breaks (determined by an alkaline unwinding technique) were detected. They resulted in the activation of the DNA repair enzyme poly-ADP-ribose polymerase (pADP-RP) within minutes after the addition of H2O2. At the same time ATP and NAD (the substrate of pADP-RP) concentrations dropped and nicotinamide accumulated extracellularly. 10-15 min after oxidant exposure free intracellular Ca++ concentrations determined by Quin 2 fluorescence started to increase due to release from intracellular stores.(ABSTRACT TRUNCATED AT 250 WORDS)