A facile and new approach to synthesize 2-amino-4-(4-amoinophenyl)-1<Emphasis Type="Italic">H</Emphasis>-1,3-diazol-1-yl-alkylaminomethanethiones

An “intellectual connection” approach to design a facile and new synthesis of suitably substituted 2-aminoimidazole-based precursors of expected antiasthmatic agents through a benzidine type of rearrangement of 2-phenylazoimidazole and subsequent coupling of the product thus obtained with alkylisothiocyanates involving a degenerative operation, thereby improving the time frame of the overall synthetic sequence, is reported. The alkylisothiocyanates required in this synthetic sequence are prepared using a best combination of reported methods. The compounds reported here can be used to produce derivatives of other biological agents.     

Surrogate end points in heart failure

Because of the increasing number of pharmacologic strategies available for treatment of heart failure (HF), the time has come to reassess the adequacy of end points used to evaluate therapeutic efficacy. Interest in the use of surrogate end points in clinical studies is increasing. A surrogate end point is defined as a measurement that can substitute for a true end point for the purpose of comparing specific interventions or treatments in a clinical trial. A true end point is one that is of clinical importance to the patient (e.g., mortality or quality of life), whereas a surrogate end point is one biologically closer to the disease process (e.g., ejection fraction or left ventricular volume in HF). The prime motivation for the use of a surrogate end point concerns the possible reduction in sample size or trial duration. Such reductions have important cost implications and in some cases may influence trial feasibility. Another, perhaps more important, aspect of measuring surrogate end points is that they increase our understanding of the mechanism of action of drugs and thus may help physicians to take a more enlightened approach in managing their patients. In this article we have analyzed the possible potentials of the surrogate end points in clinical studies of patients with chronic HF. Other uses of possible surrogates are discussed, and the limitations in finding true surrogates are mentioned. At this time we conclude there is no well established surrogate in HF.     

Ultrastructural and immunohistochemical analysis of early myocardial changes following transmyocardial laser revascularization

BACKGROUND AND AIM OF THE STUDY: Transmyocardial laser revascularization (TMR) has demonstrated significant relief in patients presenting with refractory angina. However, the mechanism by which TMR improves clinical symptoms is unclear. This study analyzes the early immunohistochemical and ultrastructural features of the human myocardium following TMR. METHODS: Specimens of myocardium that contained laser channels were removed in toto at autopsy from three male patients, ages 41, 57, and 65 (mean age 55.8) who had died 1 to 11 days (mean 6.8) following laser revascularization. Consecutive parallel sections of specimens were stained with cell-type specific antibodies to CD3 (to identify T-lymphocytes), CD68 (macrophages), Factor VIII (endothelial cells), and myosin (myocytes). Additionally, adjacent areas of myocardium that contained laser channels were processed and analyzed by transmission electron microscopy. RESULTS: The internal lining surface of laser channels was composed of vacuolized and condensed myocardial debris. No obvious connections were noted between laser channels and the ventricular cavity. No endothelialization of channels was observed, whereas the adjacent noninjured myocardium demonstrated microvessels lined by well-preserved endothelial cells. The laser channels were surrounded by zones of necrotic cardiomyocytes. CONCLUSIONS: Our observations suggest that laser channels are not lined by endothelial cells during the early stages following TMR. Mechanisms other than direct myocardial perfusion from the ventricular cavity by patent endothelialized channels may explain the immediate relief from angina provided by TMR.     

Protein carbonyls and lipid peroxidation products as oxidation markers in preterm infant plasma: associations with chronic lung disease and retinopathy and effects of selenium supplementation

The purpose of this study was to determine whether protein carbonyls and the lipid peroxidation product malondialdehyde (MDA) are elevated in plasma from very low birth weight (<1500 g) infants, whether they are affected by selenium supplementation, and whether they are associated with poor respiratory outcome or retinopathy. The study group comprised 173 infants enrolled in a randomized controlled trial of selenium supplementation. Plasma samples, collected before randomization, at 7 and 28 d after birth, and at 36 wk postmenstrual age, were analyzed for protein carbonyls and total MDA. Respiratory outcome was assessed as oxygen requirement at 28 d of age or 36 wk postmenstrual age and as number of days on oxygen. Protein carbonyl concentrations in very low birth weight infants were significantly higher than for adults but lower than for cord blood from term infants. Median values decreased significantly by 28 d, and there was no relationship with birth weight. MDA concentrations in very low birth weight infants overlapped the ranges for healthy adults and cord blood from term infants. They correlated positively with birth weight at 28 d but not at other times. Supplementation almost doubled plasma selenium concentrations, but carbonyls and MDA did not differ between the supplemented and unsupplemented groups. There were no significant differences in oxidant marker levels in infants who did or did not develop chronic lung disease or retinopathy. Protein carbonyls and MDA measurements in plasma do not show evidence of systemic oxidative stress in <1500-g infants and are not affected by selenium supplementation. Oxidative injury at sites such as the lung may be important in prematurity, but markers from such sites must be measured to relate to outcome and antioxidant supplementation.     

Growth rate of corpus callosum in very premature infants

BACKGROUND AND PURPOSE: It is desirable to develop a bedside method for assessing cerebral development in the very premature infant to monitor the effectiveness of interventions aimed at improving cerebral development. Our aim was to describe the growth trajectory of the corpus callosum (CC) on cranial sonography in very premature infants. METHODS: We recruited 100 very-low-birth-weight infants admitted to a single regional level III neonatal intensive care unit from November 1998 to November 2000. Cranial sonography images of the CC were obtained for 64 (32 boys) infants (mean gestational age, 28 weeks; range, 23-33 weeks) in the first week of life and at term equivalency. The growth rate of the CC was compared in the 64 study infants to the expected growth rate of 0.20-0.27 mm/day from antenatal data and correlated with clinical outcome at 2 years of age by using Mental Development Index (MDI) and Psychomotor Development Index (PDI). RESULTS: The average growth rate of the CC was half of that expected from antenatal data. Mean growth rates were similar for all gestational ages (mean, 0.11 mm/day; range, 0.05-0.29; P = .4). The CC at term equivalency was longer for those in MDI class 2 (mean, 44.3 mm) compared with MDI class 3 (mean 40.2 mm; P = .003) as well as for PDI class 2 versus 3 (P = .017). CONCLUSION: Measurement of the length of the CC at cranial sonography is reproducible. Those with poorer neurodevelopmental outcomes have a shorter CC at term equivalency. The CC grows at a much lower rate postnatally than in utero among very premature infants.