Novel non-peptide fibrinogen receptor antagonists. 1. Synthesis and glycoprotein IIb-IIIa antagonistic activities of 1,3,4-trisubstituted 2-oxopiperazine derivatives incorporating side-chain functions of the RGDF peptide

Based on the lead tetrapeptide RGDF, two possible non-peptide glycoprotein (GP) IIb-IIIa antagonists possessing an (S)-2-oxopiperazine-3-acetic acid moiety as a scaffold incorporating the indispensable Asp fragment were prepared, and (S)-4-[[trans-[4-(guanidinomethyl)-cyclohexyl]carbonyl]glycyl]-2- oxopiperazine-1,3-diacetic acid, 1a, was identified as a potential lead. A series of 3-substituted 2-oxopiperazine-1-acetic acids bearing the Arg-Gly equivalent at the 4-position were prepared and evaluated for their ability to prevent platelet aggregation and for their binding affinity for the GP IIb-IIIa receptor purified from human HEL cells. (S)-4-[(4-Amidinobenzoyl)glycyl]-3-[(methoxycarbonyl)methyl]- 2-oxopiperazine-1-acetic acid, 9 (TAK-029), inhibited in vitro human platelet aggregation with an IC50 value of 0.03 microM and GP IIb-IIIa-fibrinogen binding with an IC50 value of 0.49 nM. The [4-(2-aminoethyl)benzoyl]glycyl derivative 26 showed activity comparable to that of 9 (IC50 = 0.093 microM, guinea pig platelet aggregation assay). Compound 9 dose-dependently inhibited ex vivo platelet aggregation in guinea pigs (0.03 and 0.1 mg/kg, i.v.), and long-lasting inhibition of platelet aggregation was observed upon oral administration of 9 (3 mg/kg) to guinea pigs. On the other hand, the activity of 26 disappeared within 1 h after a dose of 1 mg/kg (i.v.). Compound 9 may therefore be useful in the clinical treatment of arterial thrombotic diseases.     

Optimal planning for introducing dispersed generating sources in power systems based on an economical viewpoint

This paper discusses optimal planning problems for dispersed generating sources so as to provide a guideline for their introduction to power systems. First, a recursive method is developed from the viewpoint of supplying electric power only where solutions for one unit are superposed. The computational loads are decreased by selecting alternatives of buses based on the so-called penalty factor. However, for effective utilization of dispersed generating sources, it is indispensable to consider their thermal merits in addition to electric power. After applying the Kuhn-Tucker theory to the optimal dispatching problem including boiler fuel costs, thermal values of the dispersed generating units are evaluated quantitatively. Finally, the above-mentioned technique for the optimal planning basically is also effective and is extended into this case. The validity of the proposed algorithms are demonstrated using a real-scale model system.     

Optical responses recorded after local stimulation in rat neostriatal slice preparations: effects of GABA and glutamate antagonists, and dopamine agonists

Congenital syphilis has been diagnosed very seldom in ancient populations. The case that we examined comes from San Jeronimo's Church (17th and 18th centuries AD; Mexico City). Coffin 43 contained an incomplete skeleton of an approximately 2-year-old infant. The pathological lesions of this skeleton include bilateral osteochondritis, diaphyseal osteomyelitis, and osteitis and/or periostitis on the long bones. The radiographic appearance depicts symmetrical osteomyelitic foci, particularly at the proximal extremity of both tibiae (Wimberger's sign). The skull exhibits hydrocephaly and periosteal changes on the vault, and the unerupted upper incisors evince dental hypoplasia and other pathological alterations reminiscent of Hutchinson's incisors. All these features strongly suggest a case of early congenital syphilis.     

Highly Humidified Fabrication Method for Dithiolene Oxovanadium Complexes Molecular Rings

We have successfully fabricated molecular rings of (n-Bu₄N)₂[(dcbdt)₂VO] (dcbdt = 4,5-dicyanobenzene-1,2-dithiolato) and (n-Bu₄N)[(dmit)₂Zn] (dmit = 2-thioxo-1,3-dithiole-4,5-dithiolate) on a silicon substrate using simple and easy deposition method under ambient or highly humidified conditions. For (n-Bu₄N)₂[(dcbdt)₂VO] changing the process from ambient to highly humidified condition diminishes the size of molecular rings by 10 times smaller. Furthermore each molecular ring has same crystallinity as the corresponding single crystal.     

Urodynamic and cardiovascular measurements in patients with micturition syncope

We describe the findings of urodynamic studies, together with blood pressure and heart rate monitoring, in five patients with micturition syncope. All patients had almost normal storage and evacuation function and no evidence of prostate hypertrophy. Conventional head-up tilt testing with an empty urinary bladder caused no change in arterial blood pressure, but a moderate increase in heart rate. Urinary bladder filling caused minimal increases of the arterial pressure and heart rate. The sitting posture with a distended bladder caused mild orthostatic hypotension. Urinary bladder evacuation caused a fall in arterial pressure with a decrease in heart rate. These responses were similar to those described in vasovagal syncope. The central mechanism for the initiation of urinary evacuation, or sensory input from the lower urinary tract, may trigger micturition syncope.     

Suppression of reperfusion arrhythmias by preconditioning is inhibited by an ATP-sensitive potassium channel blocker, 5-hydroxydecanoate, but not by protein kinase C blockers in the rat

Nine children sustained a second fracture of the distal humerus after union of an ipsilateral supracondylar fracture which had healed with cubitus varus. There were eight boys and one girl with a mean age of five years (1 to 8) at the time of the second fracture which occurred at a mean of 1.5 years after the first. In all patients, the second fracture was an epiphyseal injury of the distal humerus, either associated with a fracture of the lateral metaphysis below the site of the previous supracondylar fracture, or a fracture-separation of the entire distal humeral epiphysis. This suggests that the physis and epiphysis tend to be more subject to injury than the metaphysis of the distal humerus in children who have had a previous supracondylar fracture with varus malunion.     

Structural family versus psychodynamic child therapy for problematic Hispanic boys.

Structural family therapy, psychodynamic child therapy, and a recreational control condition were compared for 69 six-to-twelve-year-old Hispanic boys who presented with behavioral and emotional problems. The results suggest that the control condition was significantly less effective in retaining cases than the two treatment conditions, which were apparently equivalent in reducing behavioral and emotional problems as well as in improving psychodynamic ratings of child functioning. Structural family therapy was more effective than psychodynamic child therapy in protecting the integrity of the family at 1-year follow-up. Finally, the results did not support basic assumptions of structural family systems therapy regarding the mechanisms mediating symptom reduction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Expression of keratinocyte growth factor mRNA in ex vivo and in vitro specimens of human cornea and conjunctiva

Treatment of HIV and related malignancies with pharmacologic and biologic agents has not appreciably modified the course of disease. Immunologic impairment remains the critical factor in response. We report the long-term results of a single session of low-flow (0.3 L/min) extracorporeal perfusion hyperthermia on 29 men and 2 women with disseminated Kaposi's sarcoma and profound immunologic impairment. Any antiretroviral drug employed by the patient was stopped 72 hours prior to treatment and withheld during the period of follow-up. Core temperature was raised to 42 degrees C and held for 1 hour with extracorporeal perfusion and ex vivo blood heating to 49 degrees C as the means of temperature control. Of 31 patients, 2 died of complications secondary to treatment (cardiac arrhythmia; CNS bleed). There were two cases of intravascular coagulopathy. Pressure point skin damage may occur despite adequate cushioning. At 30 days posttreatment complete or partial regressions were seen in 20/29 of those treated, with regressions persisting in 14/29 of those treated by 120 days posttreatment. At 360 days, 4/29 maintain tumor regressions with 1 in complete remission (at 26 months). The patient in complete remission remains culture-negative and PCR-negative for HIV. CD4+ counts rose from around 250 to, and remain around, 800 in this man. Selected healed lesions were biopsied to demonstrate tumor absence. Patients were selected for treatment if pretreatment testing of the tumor showed regression in vitro with heat exposure. Analysis of the early and midterm failures showed little sustained rise of the CD4+ cells if presenting total CD4+ counts were below 50 and had been at such low levels for extended periods, although other surrogate markers of HIV activity declined (semiquantitative PCR) during this period and is felt to support the hypothesis of apoptosis proposed in this illness. Analysis of the tumors of the few men not responding demonstrated elevated levels of IL-6 as compared to responders (12 vs < 1 pg/ml). At 120 days 29/31 patients remained alive (expected, 20). At 360 days, 21/31 remained alive (expected, 11). In no patient was HIV activity stimulated with heat exposure. CMV retinitis did clear in some patients treated (both techniques), but treatment alone did not prevent later development of retinopathy. EBV parameters were markedly altered in the short term with heat exposure in some patients. Few patients showed herpes simplex activation. Varicella-zoster virus remitted in some patients. There is utility in the use of systemic hyperthermia to control HIV and related malignancy.(ABSTRACT TRUNCATED AT 400 WORDS)