3-alkyl GABA and 3-alkylglutamic acid analogues: two new classes of anticonvulsant agents.

Recently we showed that 3-alkyl-4-aminobutanoic acids are in vitro activators of brain L-glutamic acid decarboxylase (GAD) that show anticonvulsant activity. Since activation of GAD leads to increased concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in vitro, these compounds could represent a new class of anticonvulsant agents. Here it is shown that 3-alkylglutamic acid analogues also activate GAD and that all of the compounds in both series are active anticonvulsant agents against low intensity electroshock in mice. The most active compound, 3-isobutyl GABA, was tested further against maximal electroshock in mice and was shown to be very potent after both intravenous and oral administration without causing ataxia. It is not known if brain GABA levels are elevated in vivo by administration of these compounds or if the mechanism of anticonvulsant activity is related to their ability to activate GAD.     

Reduced incidence and severity of accelerated graft atherosclerosis in cardiac transplant recipients treated with prophylactic antilymphocyte globulin.

Allograft coronary artery disease (ACAD) is the major factor limiting long-term survival of cardiac transplant recipients (CTRs). Although cyclosporine based triple drug immunosuppression has not decreased the occurrence of ACAD, some preliminary data suggests that prophylactic antilymphocyte preparations may reduce the incidence of this problem. All CTRs at Henry Ford Hospital have uniformly received prophylactic Minnesota Antilymphocyte Globulin (ALG), thereby providing a unique opportunity to investigate this hypothesis. One hundred three CTRs were followed for a median duration of 34 months with annual angiograms begun one year after transplant. Patients who died without an angiogram were considered to have ACAD based on autopsy results or if their death was clinically suspicious. Ninety-two patients underwent at least one angiogram. Fourteen patients had abnormal angiograms. Nine patients were identified as having ACAD by non-angiographic criteria. Five had autopsy proven disease, 3 died suspiciously, and 1 underwent successful re-transplantation for ACAD. By Kaplan-Meier analysis, the risk of developing ACAD was 12% in 1 year, 16% in 2 years, 22% in 3 years, 26% in 4 years, and 29% in 5 years. Risk of ACAD increased with older recipient's age, higher triglyceride levels, and diabetes, but was not affected by active CMV infection, number of acute rejection episodes, and HLA mismatching. These results suggest that prophylactic ALG reduces the occurrence of ACAD.     

Implantation response following clinical heart-lung transplantation

Implantation response has been a critical problem following heart-lung and lung transplantation. While the precise etiology of this problem remains unclear, improvements in organ preservation would be expected to have a beneficial effect on implantation response. The time-related profile of the implantation response was studied in 20 patients who underwent heart-lung transplantation between March 1984-March 1987. In 10 operations the donors had intravenous prostaglandin E-1 pretreatment while 10 had no vasodilatation before explantation of the organs. Otherwise lung preservation and early (2 weeks) immunotherapy were similar in both groups. The implantation response was evaluated by chest films and postoperative lung functions and mechanics. Roentgenographic implantation response was evident from the first postoperative day, was less evident at the seventh postoperative day and then gradually increased during the second postoperative week. There was a tendency towards less implantation response in the PGE-1 group than in the control group, but no statistical difference was observed. Patients with severe operative bleeding problems were excluded from the study. Only peak inspiratory pressures were significantly higher in the control group than in the PGE-1 group (p less than 0.01). Other lung function studies (alveolar-capillary pO2 difference, extubation time) were not different in the groups. This study supported the hypothesis that prostaglandin E-1 may have salutary effects on graft preservation and implantation response in heart-lung transplantation. Since 1986, we have performed 16 heart-lung transplantations using graft preservation with PGE-1 and flush perfusion. Thirty-day mortality is 0% and 13 of 16 patients are surviving.     

A case-control study of Alzheimer's disease in China.

We conducted a case-control study to assess possible factors associated with Alzheimer's disease (AD) with 70 clinically diagnosed AD patients and 140 age- and sex-matched nondemented neighborhood controls in China. Factors significantly associated with AD cases were family history of dementia in first-degree relatives, family history of psychotic disorders in first-degree relatives, and left-handedness/ambidexterity. A history of arthritis showed a significantly negative association with AD. Neither a family history for Down's syndrome, history of head trauma, nor other conditions that might support immune or viral hypotheses in AD were significantly associated with AD cases. These data support the role of familial/genetic factors in AD.     

A multicenter clinical trial of gadolite oral suspension as a contrast agent for MRI

The purpose of this study was to assess the effectiveness and safety of Gadolite Oral Suspension as a gastrointestinal (GI) contrast agent for MRI in a phase II and two phase III multicenter clinical trials. Gadolite was administered to 306 patients with known or suspected abdominal and/or pelvic disease. MRI with T1- and T2-weighted sequences was performed before and after ingestion. Efficacy was evaluated by having two masked readers rate the certainty of their MR diagnosis (0 = uncertain, 1 = probable, 2 = definite) on randomly presented pre- and post-Gadolite Oral Suspension enhanced images. Principal investigators also evaluated the images and established the final diagnosis. Vital signs, clinical chemistries, and adverse events were documented. Blood and urine samples were analyzed for gadolinium content to determine whether Gadolite Oral Suspension was absorbed systemically. Certainty in MR diagnosis increased significantly (P < .001) for both blinded readers between pre- and post-Gadolite images (.49–1.18 for reader 1; .46–1.53 for reader 2). Sensitivity, specificity, and accuracy also increased for both masked readers. No gadolinium was detected in blood or urine samples. There were no serious adverse events and no apparent drug-related trends in mean vital signs or laboratory values. Gadolite is a highly effective, safe, and well tolerated contrast agent for clinical use with MRI.     

Screening and surveillance for colorectal cancer

Pathologic reviews and clinical studies demonstrate that groups with increased cancer risk can be identified. It is estimated that about 3.5 per cent of colorectal cancers in this country are the result of known heritable cancer syndromes, such as familial polyposis. Much effort is currently being devoted to evaluation of biologic markers, such as cell surface antigens and their antibodies, ornithine decarboxylase, errors in DNA repair, abnormalities in metabolism of polyadenosine diphosphate, and application of molecular genetic techniques to identify patients with genetic cancer susceptibility.     

The aperture problem--II. Spatial integration of velocity information along contours

There exists a class of two-dimensional figures (including cumulative gaussian waveforms) whose contours have a limited range of orientations. These figures can appear as highly nonrigid if they undergo pure translation in the image plane. In the case of the cumulative gaussian waveform, it is the region around the inflection point that appears as nonrigid. Motivated by Hildreth's (1984) proposal, we made 5 predictions which were confirmed by the data: (0), rigidity of a figure can be dramatically increased if one attaches line terminators to the figure; (1), moving terminators "on" the figure increase rigidity far more than such terminators "off" the figure; (2) decreasing the velocity of the terminator decreases rigidity; (3) decreasing the distance between the terminator and the inflection point increases rigidity; (4) the effect of a moving terminator can be blocked by interposing a stationary terminator between it and a nonrigidly moving portion of the curve.