Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.     

Pain drawings in the assessment of nerve root compression: a comparative study with lumbar spine magnetic resonance imaging

STUDY DESIGN: Prospective comparative study of pain drawings with findings on lumbar spine magnetic resonance imaging. OBJECTIVES: To assess the ability of the pain drawing to predict the presence of nerve root compression. SUMMARY OF BACKGROUND DATA: Most research work has concentrated on the ability of the pain drawing to act as a screening method for psychological distress with less work directed at the influence the anatomic abnormality has on the pain drawing. METHODS: One hundred thirty-four consecutive outpatients attending for lumbar magnetic resonance imaging in the investigation of back and leg pain completed pain drawings and psychological testing immediately before the examination. The pain drawing was analyzed by previously reported criteria, and the magnetic resonance imaging was assessed independently for the presence of nerve compression by three radiologists. Multivariate stepwise discriminant analysis was used to identify patients with nerve compression on the basis of their pain drawing. RESULTS: Nerve compression was predicted by numbness in the anterolateral aspect of the foot. There was considerable overlap in the appearances of the pain drawings between patients with and without nerve compression, and the pain drawing correctly classified only 58% of patients with nerve compression. CONCLUSIONS: The pain drawing is not a good predictor of nerve compression on magnetic resonance imaging in a group of patients investigated for back and leg pain. It should be interpreted with caution and in light of the full clinical picture.     

Clinical outcome of patients infected with hepatitis C virus infection on survival after primary liver transplantation under tacrolimus

In 1994, as a result of both programme evaluations which identified students' fears and apprehensions about their practical ability, and a review of the literature on skill acquisition, experiential skills teaching was resumed within the faculty. Having invested considerable finance into the reconstruction of a skills centre to teach skills, it is now imperative that its use be formally evaluated. Part of the evaluative process includes a review of the empirical literature on the acquisition of psychomotor skills in nursing. This paper summarizes this review.     

Orthotopic heart transplantation in a transgenic pig-to-primate model

BACKGROUND: Previous studies demonstrated that hearts from transgenic pigs expressing human decay-accelerating factor (hDAF) were not hyperacutely rejected when transplanted heterotopically into the abdomen of cynomolgus monkeys. This study examines orthotopic transplantation of hDAF transgenic pig hearts into baboon recipients. METHODS: Orthotopic xenogeneic heart transplantation was performed using piglets, transgenic for hDAF, as donors. Ten baboons were used as recipients and were immunosuppressed with a combination of cyclophosphamide, cyclosporine, and steroids. RESULTS: Five grafts failed within 18 hr without any histological signs of hyperacute rejection. Pulmonary artery thrombosis induced by a size mismatch was observed in two of these animals. The other three recipients died because of failure to produce even a low cardiac output and/or dysrhythmia. The remaining five animals survived between four and nine days. One animal died of bronchopneumonia on day 4. Three xenografts stopped beating on day 5 due to acute vascular rejection. The longest survivor was killed on day 9 with a beating, histologically normal xenograft, because of pancytopenia. CONCLUSIONS: The results reported here demonstrate that hDAF transgenic pig hearts are not hyperacutely rejected when transplanted into baboon recipients. Orthotopically transplanted transgenic pig hearts are capable of maintaining cardiac output in baboons. An optimum immunosuppressive regimen is the subject of ongoing research.     

Endocrine factors associated with recurrent spontaneous abortion

The role of endocrine factors as a cause of recurrent spontaneous abortion is controversial. Diabetes mellitus and thyroid disease do not represent a significant risk factor for recurrent pregnancy loss. Luteal-phase defect has been questioned because there are no accurate methods for diagnosis and no convincing evidence of correction with treatment exists. The corpus luteum is an unusual endocrine gland, highly diverse in function and important for successful reproduction in all mammalian species. Much controversy exists about the luteal function in humans and how defects in luteal function affects reproduction. Disagreement has been due to lack of accurate diagnosis and controlled studies to determine whether correction of the luteal-phase defect is worthwhile when treating female reproductive problems. The donor egg recipient model from assisted reproductive technology programs has shown that corpus luteum function can be replaced by estrogen and progesterone administration. The mechanism by which these steroids stimulate a uterus to be receptive to implantation of the embryo is not known. Several proteins produced by the endometrium are candidate markers for uterine receptivity. Further work needs to be done to correlate these markers with subsequent pregnancy outcome. A noninvasive marker for uterine receptivity is ultrasonographic evaluation of the endometrium. Although the sensitivity of this test is high (100%), its specificity is low (only 20% to 60%).     

Long-term evaluation of the ventricular defibrillation energy requirement

INTRODUCTION: Defibrillation energy requirements in patients with nonthoracotomy defibrillators may increase within several months after implantation. However, the stability of the defibrillation energy requirement beyond 1 year has not been reported. The purpose of this study was to characterize the defibrillation energy requirement during 2 years of clinical follow-up. METHODS AND RESULTS: Thirty-one consecutive patients with a biphasic nonthoracotomy defibrillation system underwent defibrillation energy requirement testing using a step-down technique (20, 15, 12, 10, 8, 6, 5, 4, 3, 2, and 1 J) during defibrillator implantation, and then 24 hours, 2 months, 1 year, and 2 years after implantation. The mean defibrillation energy requirement during these evaluations was 10.9+/-5.5 J, 12.3+/-7.3 J, 11.7+/-5.6 J, 10.2+/-4.0 J, and 11.7+/-7.4 J, respectively (P = 0.4). The defibrillation energy requirement was noted to have increased by 10 J or more after 2 years of follow-up in five patients. In one of these patients, the defibrillation energy requirement was no longer associated with an adequate safety margin, necessitating revision of the defibrillation system. There were no identifiable clinical characteristics that distinguished patients who did and did not develop a 10-J or more increase in the defibrillation energy requirement. CONCLUSION: The mean defibrillation energy requirement does not change significantly after 2 years of biphasic nonthoracotomy defibrillator system implantation. However, approximately 15% of patients develop a 10-J or greater elevation in the defibrillation energy requirement, and 3% may require a defibrillation system revision. Therefore, a yearly evaluation of the defibrillation energy requirement may be appropriate.     

Electrodeposited polytyramine as an immobilisation matrix for enzyme biosensors

The application of an electrodeposited polytyramine film as an immobilisation matrix for the construction of enzyme biosensors is described. Glucose oxidase (used as a model enzyme) is covalently attached to free amine groups on the polytyramine film using the coupling reagents 1-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide. The resultant recognition interface consisted of multilayers of GOx immobilised onto the polymer surface. This method of constructing enzyme biosensors is shown to produce a highly reproducible and stable device. The biosensor showed no loss in electrode response after four months of dry storage and exhibited only minor loss in response after 20 days of repeated use. The resultant biosensor had a linear range of 0.1-28 mM glucose and a detection limit of 0.01 mM.     

AK-5 tumor-induced expression of interleukin-12: role of IL-12 in NK-mediated AK-5 regression

Spontaneous regression of AK-5, a histiocytic tumor, is mediated by CD3-, CD8+ NK cells through ADCC. The onset of AK-5 regression is associated with the induction of humoral immune response and the augmentation of effector function. The mechanism of tumor cell death involves both necrosis and apoptosis. Interleukin-12, a 75-kDa heterodimeric cytokine, has multiple effects on T and NK cells. We have investigated the role of IL-12 in the NK cell-mediated AK-5 tumor regression process. Subcutaneous transplantation of AK-5 tumor induced the expression of IL-12 (p35 and p40) message by Day 6-8 in the splenocytes of syngenic rats. Similarly, analysis of serum samples from tumor-bearing animals showed the presence of circulating IL-12 around the same time. Interaction of immune cells with antibody-tagged AK-5 cells in vitro also triggered the expression of IL-12 message and protein by 3 hr. The circulating IL-12 in the sera of tumor-rejecting animals, as well as rIL-12, stimulated NK cell proliferation, expression of CD16 and CD25, and the activation of NK cells function. These observations suggest that the ability of the AK-5 tumor to induce the endogenous production of IL-12 may be responsible for keeping the NK cells constantly in an activated state, thus demonstrating an efficient mechanism for the complete regression of the tumor.