Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept.

Objective: Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)-AS-1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.

Methods: (R)-AS-1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents.

Positive allosteric modulation of glutamate transporter reduces cocaine-induced locomotion and expression of cocaine conditioned place preference in rats.

The glutamatergic system, located throughout the brain including the prefrontal cortex and nucleus accumbens, plays a critical role in reward and reinforcement processing, and mediates the psychotropic effects of addictive drugs such as cocaine. Glutamate transporters, including EAAT2/GLT-1, are responsible for removing glutamate from the synaptic cleft. Reduced expression of GLT-1 following chronic cocaine use and abstinence has been reported.

Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators.

Excitatory amino acid transporters (EAATs) are essential CNS proteins that regulate glutamate levels. Excess glutamate release and alteration in EAAT expression are associated with several CNS disorders. Previously, we identified positive allosteric modulators (PAM) of EAAT2, the main CNS transporter, and have demonstrated their neuroprotective properties .

Discovery of ()--Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity .

[] showed broad-spectrum antiseizure activity across mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations.

Dopamine activates NF-κB and primes the NLRP3 inflammasome in primary human macrophages.

Induction of innate immune genes in the brain is thought to be a major factor in the development of addiction to substances of abuse. As the major component of the innate immune system in the brain, aberrant activation of myeloid cells such as macrophages and microglia due to substance use may mediate neuroinflammation and contribute to the development of addiction. All addictive drugs modulate the dopaminergic system and our previous studies have identified dopamine as a pro-inflammatory modulator of macrophage function.

Physician documentation of family alcohol problems.

This study was conducted to determine whether family medicine residents' documentation of patient and family alcohol problems corresponded with patients' assessments. A random sample of 180 patient charts from a university-based family practice was audited and 78% (n = 140) of these patients participated in telephone interviews. Of those who participated in the telephone interview, 40% (n = 56) reported a positive family history of drinking problems, 28% (n = 39) indicated that they were currently concerned about the alcohol use of someone in their family, and 24% (n = 34) reported that at least one family member currently had an alcohol problem.

A clinical trial to reduce the rate of low birth weight in an inner-city black population.

Background: The goal of our study was to measure the effectiveness of a home-based intervention for prevention of low birth weight with 154 high-risk, low-income black women attending a prenatal clinic in Cleveland.

Methods: Based on previous research, risk was defined by clinic registration between the 17th and 28th weeks of gestation, low family functioning score, and experience of at least one stressful life event prior to registration. Optional factors included being a smoker, a low maternal weight-height ratio, being age 27 or older, and a previous premature birth.

Feeding patterns of urban black infants.

Feeding patterns of 116 urban black infants were studied from 3 weeks to 6 months of age. Dietary data were collected using a diet history and a food frequency checklist completed by trained interviewers at each well child clinic visit at 3 weeks and at 2, 4, and 6 months of age. At 3 weeks, 20% of the infants were solely breast fed, 58% were formula fed, and 22% were partially breast fed.

Family function, respiratory illness, and otitis media in urban black infants.

Associations between maternal perceptions of family functioning and rates of infant presentation for respiratory illness and otitis media were analyzed using data collected prospectively in a sample of 114 urban black mother-infant pairs. Family functioning was evaluated using the Family APGAR, truncated versions of Olson's FACES II cohesion and adaptability subscales, and a shortened version of Hudson's Index of Family Relationships. Lower maternal scores of family function were significantly associated with higher rates of physician visits for infant respiratory illness and otitis media during the first 15 months of life.

Predicting low birthweight and complicated labor in urban black women: a biopsychosocial perspective.

This study explored demographic, biomedical and psychosocial factors as predictors of two adverse pregnancy outcomes: intrapartum complications and low birthweight, in 140 urban black pregnant women. The intrapartum complication rate was 18%. A four factor equation (low family functioning, advanced maternal age, working during pregnancy, and short stature) predicted intrapartum complications (80% sensitivity, 67% specificity and 35% positive predictive value).

Defining family in family medicine: perceived family vs household structure in an urban black population.

This paper explores two hypotheses: first, that household structure, the people who live in one's household, and perceived family, the people one considers members of one's family, are different entities among urban black pregnant women; and second, that the perceived family is a stronger predictor of social, psychological, and health outcomes than is household structure. The study data are from the first interview of a prospective study of a consecutive sample of 140 black pregnant women patients of a Cleveland, Ohio, university hospital family practice center. The study hypotheses are supported: household structure and perceived family differ in their size and the inclusion or exclusion of members of the family of origin and the father of the baby.

Clinical hypothesis testing in family practice: a biopsychosocial perspective.

Recent studies of the clinical problem-solving process have demonstrated the importance of hypothesis generation and testing in shaping the nature of information gathering, differential diagnosis, and therapeutic decision making. Family physicians and other primary care physicians are often faced with complex and undifferentiated illness problems that require them to go beyond the traditional biomedical model and entertain an expanded range of psychosocial hypotheses. In this paper the authors draw upon clinically relevant behavioral and social science research and propose several biopsychosocial hypotheses that have proven useful in the management of family practice patients.

Education of residents in the pediatric office.

Practicing pediatricians can contribute a much-needed dimension to the education of those primary care physicians who will care for children by teaching medical students and residents in their offices. This article is intended to help the prospective pediatrician-teacher plan, conduct, and evaluate productive educational experiences in his office. Approaches to planning primary care educational experiences are discussed.

Development of an instrument to identify attitudes of family practice and other physicians: a pilot study.

Research has shown that characteristic attitudes can be attributed to certain medical specialties and can affect specialty selection. The purpose of this study was to develop an attitude scale that would discriminate between family practice and other physician groups on current health care issues. From a sample of 490 randomly selected physicians, 40 percent (N = 193) responded to the study instrument, a 44-item, five-point Likert scale in which physicians were asked their level of agreement on various statements.

Postgraduate training in ambulatory pediatrics. Program evaluation.

Ambulatory pediatric, adolescent medicine, and child development fellowship programs listed in the Ambulatory Pediatric Association (APA) newsletter were surveyed to gather information about the programs for prospective fellows, to develop a descriptive summary, and to determine the extent to which programs adhere to APA guidelines. Number and types of positions offered, criteria for admission to programs, program educational objectives and activities, and career choice of graduates were examined for the 73 programs offering 132 fellowship positions in 1976 to 1977. In general, APA guidelines were followed.

Continuity of care in a university-based practice.

Effects of changes in a pediatric practice--expansion of the number of pediatricians and incorporation into a university hospital setting--on continuity of care and utilization were examined by means of a longitudinal study of a sample of 63 families. Continuity of care was measured by the following index: the number of visits with own physician divided by the total number of pediatric visits per year. Although continuity of well-child visits remained unchanged at the university setting, the continuity of sick visits declined markedly.

Pediatric clinical faculty structure and teaching hospital function.

An organization of clinical faculty has been formed at Rainbow Babies and Childrens Hospital, Cleveland, Ohio, to help coordinate the mutual goals but sometimes conflicting needs of practicing pediatricians and a teaching hospital. The organization has been active in developing and conducting educational experiences for students, house officers, and practitioners. It has contributed to efforts to improve ambulatory and inpatient care.

Comprehensive pediatric care: the patient viewpoint.

Two meanings of the term comprehensive care are delineated. The first refers to a wide scope of health services, the second to a humanistic approach to the patient. Findings from a sample of patients from one pediatric practice suggest that the two meanings constitute two independent variables with respect to patient expeciations.