Identification of novel ligands for the gabapentin binding site on the alpha2delta subunit of a calcium channel and their evaluation as anticonvulsant agents.

As part of a program to investigate the structure-activity relationships of Gabapentin (Neurontin), a number of alkylated analogues were synthesized and evaluated in vitro for binding to the Gabapentin binding site located on the alpha2delta subunit of a calcium channel. A number of other bridged and heterocyclic analogues are also reported along with their in vitro data. Two compounds showing higher affinity than Gabapentin were selected for evaluation in an animal model of epilepsy. One of these compounds, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexyl)acetic acid hydrochloride (19), was shown to be effective in this model with a profile similar to that of Gabapentin itself.

Locating genes associated with root morphology and drought avoidance in rice via linkage to molecular markers.

This research was undertaken to identify and map quantitative trait loci (QTLs) associated with five parameters of rice root morphology and to determine if these QTLs are located in the same chromosomal regions as QTLs associated with drought avoidance/tolerance. Root thickness, root:shoot ratio, root dry weight per tiller, deep root dry weight per tiller, and maximum root length were measured in three replicated experiments (runs) of 203 recombinant inbred lines grown in a greenhouse. The lines were from a cross between indica cultivar Co39 andjaponica cultivar Moroberekan. The 203 RI lines were also grown in three replicated field experiments where they were drought-stressed at the seedling, early vegetative, and late-vegetative growth stage and assigned a visual rating based on leaf rolling as to their degree of drought avoidance/tolerance. The QTL analysis of greenhouse and field data was done using single-marker analysis (ANOVA) and interval analysis (Mapmaker QTL). Most QTLs that were identified were associated with root thickness, root/shoot ratio, and root dry weight per tiller, and only a few with deep root weight. None were reliably associated with maximum root depth due to genotype-by-experiment interaction. Root thickness and root dry weight per tiller were the characters found to be the least influenced by environmental differences between greenhouse runs. Correlations of root parameters measured in greenhouse experiments with field drought avoidance/tolerance were significant but not highly predictive. Twelve of the fourteen chromosomal regions containing putative QTLs associated with field drought avoidance/tolerance also contained QTLs associated with root morphology. Thus, selecting for Moroberekan alleles at marker loci associated with the putative root QTLs identified in this study may be an effective strategy for altering the root phenotype of rice towards that commonly associated with drought-resistant cultivars.

Amide bond replacements incorporated into CCK-B selective "dipeptoids".

This paper describes the chemical synthesis and CCK-B and CCK-A receptor binding affinities of a series of compounds in which the central amide bond of the CCK-B "dipeptoid" ligand tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,S*)]-[2-[[1-(hydroxymethyl)- 2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]carb amate (4) (CCK-B IC50 = 852 nM), and tricyclo[3.3.1.1(3,7)]dec-2-yl (R)-[1-(1H-indol-3-ylmethyl)-1-methyl- 2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate (23) (CCK-B IC50 = 32 nM) is replaced by 11 different amide replacements. These replacements are the methyleneamino (CH2NH), the reverse amide (NHCO), the ester (COO), the N-methylamide (CONMe), the thioamide (CSNH), the N-acetylmethyleneamino (CH2NAc), the cis double bond (CHCH), the ethylene (CH2CH2), the thiolester (COS), the hydroxyethylene (CHOHCH2), and a 4,5-dihydro-1,3-thiazole. Most of the replacements have weaker affinity and reduced selectivity for the CCK-B receptor than the parent amide. However, this affinity can be improved by appending a fumarate side chain to the phenethyl group, e.g. tricyclo[3.3.1.1(3,7)]dec-2-yl-3-(1H-indol-3-yl-methyl)-3-methyl-4 ,9- dioxo-7-phenyl-5,13-dioxa-2,8-diazatetradec-10-enoate (36) (CCK-B IC50 = 38.8 nM). Replacement of the amide of compound 4 with a 4,5-dihydro-1,3-thiazole gives tricyclo[3.3.1.1(3,7)]dec-2-yl [1-[4,5-dihydro-4-(phenylmethyl)-2- thiazolyl]-2-(1H-indol-3-yl)ethyl]carbamate (5), which is selective for the CCK-A receptor (CCK-A IC50 = 125 nM, CCK-B IC50 = 2580 nM, ratio = 21). The methyleneamino and hydroxyethylene replacements, which have been used elsewhere as transition-state inhibitors of enzymes, are poor mimics of the amide in these CCK-B receptor ligands. Some of the steric, lipophilic, and hydrogen bonding properties of amide replacements incorporated into the simple amide, N-methylacetamide, have been quantified with the aid of molecular modeling. These data will contribute to the rational selection of amide bond replacements in other substrates.

Influence of Osmotic Adjustment on Leaf Rolling and Tissue Death in Rice (Oryza sativa L.).

Osmotic adjustment, measured by the lowering of the osmotic potential at full turgor, and its influence on leaf rolling and leaf death was assessed in the lowland rice (Oryza sativa L.) cultivar IR36 in both the greenhouse and field. The degree of osmotic adjustment varied with the degree and duration of stress, but was usually 0.5 to 0.6 megapascal (maximally 0.8 to 0.9 megapascal) under severe stress conditions. In leaves in which osmotic adjustment was 0.5 to 0.6 megapascal, leaf rolling and leaf death occurred at lower leaf water potentials in adjusted than in nonadjusted leaves. We conclude that osmotic adjustment aids in the drought resistance of rice by delaying leaf rolling, thereby maintaining gas exchange, and by delaying leaf death.

Right atrial myxoma with atrial septal defect: a case report and review of the literature.

We report the case of a 63-year-old woman presenting with progressive dyspnea of insidious onset culminating in severe central cyanosis. Conventional studies including M-mode echocardiography did not point to the diagnosis. At cardiac catheterization a large right atrial myxoma producing partial dynamic tricuspid obstruction was discovered along with an atrial septal defect with a right to left shunt. After successful surgical excision of the tumor and repair of the atrial septal defect, the patient has been totally relieved of her presenting symptoms.

The role of intra-aortic balloon pump in the management of patients with main left coronary artery disease.

Seventy-five patients with greater than or equal to 70% stenosis of the left main coronary artery (LMCA) were treated surgically between January 1974 and February 1980. The group consisted of 57 men and 18 women with a mean age of 62.8 years. All patients were symptomatic with angina pectoris, and 64 (85%) had unstable angina. Twenty-nine patients (38.6%) had electrocardiographic evidence (ECG) of old myocardial infarction (MI) and only six (8%) had a normal resting ECG. Preoperative exercise testing was done in 22 of the 75 patients. The stress test was positive in all patients, 17 (77%) of whom had greater than 2 mm ST depression; 90.6% (68/75) had significant right coronary artery disease. The intra-aortic balloon pump (IABP) was inserted preoperatively in only four patients (5%) and was required in two additional patients postoperatively. The IABP was inserted preoperatively in four patients because of medically refractory angina and not on the basis of coronary anatomy alone. An average of three grafts per patient were inserted. There were three (4%) postoperative myocardial infarctions and two (2.6%) deaths. During the follow-up period, which comprised 105 patient-years, there was one myocardial infarction and one death. These data indicate that successful surgical treatment of left main coronary artery disease can be achieved with low mortality and that routine preoperative insertion of IABP is unnecessary.

Response of leaf water potential, stomatal resistance, and leaf rolling to water stress.

Numerous studies have associated increased stomatal resistance with response to water deficit in cereals. However, consideration of change in leaf form seems to have been neglected. The response of adaxial and abaxial stomatal resistance and leaf rolling in rice to decreasing leaf water potential was investigated. Two rice cultivars were subjected to control and water stress treatments in a deep (1-meter) aerobic soil. Concurrent measurements of leaf water potential, stomatal resistance, and degree of leaf rolling were made through a 29-day period after cessation of irrigation. Kinandang Patong, an upland adapted cultivar, maintained higher dawn and midday leaf water potential than IR28, a hybrid selected in irrigated conditions. This was not explained by differences in leaf diffusive resistance or leaf rolling, and is assumed to result from a difference in root system extent.Stomatal resistance increased more on the abaxial than the adaxial leaf surface in both cultivars. This was associated with a change in leaf form or rolling inward of the upper leaf surface. Both responses, increased stomatal resistance and leaf rolling, were initiated in a similar leaf water potential range (-8 to -12 bars). Leaves of IR28 became fully rolled at leaf water potential of about -22 bars; however, total leaf diffusive resistance was only about 4 to 5 seconds per centimeter (conductance 0.25 to 0.2 centimeter per second) at that stage. Leaf diffusive resistance and degree of leaf rolling were linearly related to leaf water potential. Thus, leaf rolling in rice may be used as an estimate of the other two less obvious effects of water deficit.

Aortic valvular insufficiency and postductal aortic coarctation in the adult. Combined surgical management through median sternotomy: a new surgical approach.

A new surgical technique for the relief of aortic coarctation and replacement of the aortic valve has been described. In our patient, aortic valve replacement was combined with a bypass graft from the ascending aorta to the retrocardiac descending thoracic aorta. The clinical findings and the technical details form the basis of this report.

Mesophyll Resistance and Carboxylase Activity: A Comparison under Water Stress Conditions.

The response of several leaf gas exchange parameters were monitored with decreasing leaf water potential in Phaseolus vulgaris L. leaflets. These included photosynthesis, transpiration, CO(2) compensation point, ribulose 1,5-diphosphate carboxylase activity, boundary layer plus stomatal, and mesophyll resistance to diffusion of CO(2). Mesophyll resistance was calculated under two assumptions: (a) the CO(2) concentration at the chloroplast was zero, and (b) it was equal to the CO(2) compensation point.Contrary to some reports on bean, the estimates of mesophyll resistance (both models) increased with decreasing leaf water potential. Concurrently, the CO(2) compensation point increased and ribulose 1,5-diphosphate carboxylase activity decreased as internal water stress increased.It is suggested that the mesophyll resistance term has been too liberally interpreted in the past and that future use be verified by an indicator of biochemical response to environmental stress such as the assay for ribulose 1,5-diphosphate carboxylase activity.

Pericarditis of acute myocardial infarction.

Forty patients with acute myocardial infarction and pericarditis (AMI-P) were encountered over a three-year period. The incidence of AMI-P was 7.2 percent (40 of 554 patients). Fifty consecutive patients with acute transmural infarction without pericarditis (AMI-C) were used as a control group. There were no significant differences between the AMI-P and AMI-C groups regarding age, sex, infarct location, hospital stay or mortality. Painful symptoms of pericarditis were experienced by 37 patients (92 percent), all of whom had developed symptoms by the fourth hospital day. The pericardial friction rub lasted three days or less in 34 patients (85 percent), but an occasional rub could be heard for up to eight days. Twenty patients with AMI-P (50 percent) developed pleural effusions and/or parenchymal pulmonary infliltrates. Twenty-eight AMI-P patients (70 percent) were thought to have had congestive heart failure (CHF) on the basis of their symptoms and physical findings. Radiographic examination could confirm only 13 cases of CHF among the 28 patients in whom the diagnosis was made clinically. Glucocorticoids were given parenterally to 31 of the 37 patients (84 percent) who had symptomatic pericarditis and was felt to be effective in ameliorating painful symptoms. Followup data was obtained on 28 of the 32 surviving patients. Five patients (15 percent) had seven episodes of the postmyocardial infarction syndrome (PMIS). Pericarditis is generally a shortlived complication of acute myocardial infarction. Pleural and parenchymal pulmonary abnormalities are common and probably account for the tendency to "overdiagnose" CHF in patients with AMI-P. PMIS appears to occur more frequently in patients who have had pericarditis at the time of the acute myocardial infarction.